WO2024051717A1 - Compound as plk1 inhibitor, and preparation method therefor and use thereof - Google Patents

Compound as plk1 inhibitor, and preparation method therefor and use thereof Download PDF

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WO2024051717A1
WO2024051717A1 PCT/CN2023/117138 CN2023117138W WO2024051717A1 WO 2024051717 A1 WO2024051717 A1 WO 2024051717A1 CN 2023117138 W CN2023117138 W CN 2023117138W WO 2024051717 A1 WO2024051717 A1 WO 2024051717A1
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alkyl
independently selected
alkoxy
alkynyl
alkenyl
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PCT/CN2023/117138
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French (fr)
Chinese (zh)
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李冬冬
张晓敏
朱正诞
王冬冬
孙伟杰
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上海深势唯思科技有限责任公司
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • 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
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • 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
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom

Definitions

  • the present invention provides a class of compounds as PLK1 inhibitors and their preparation methods and uses.
  • the compounds and compositions containing them can be used to prevent and/or treat tumor-related diseases.
  • PLK1 belongs to the Polo-like kinases (PLKs) family (including PLK1/2/3/4). It is a highly conserved Ser/Thr protein kinase that plays an important role in the normal operation of the cell cycle, centrosome maturation, and cytoplasmic separation. makes an important impact. PLK1 regulates the G2/M transition by phosphorylating downstream cell cycle proteins such as WEE1/CDK1; PLK1 inhibition causes cell mitosis to be arrested in the G2 phase and induces apoptosis (Sci Signal. 2018 Aug 14; 11(543):eaar4195). In addition, PLK1 also regulates cell functions other than mitosis. For example, PLK1 repairs damaged DNA and promotes tumor cell proliferation (Mol Cell.
  • PLK1 is overexpressed in most malignant tumors, including colorectal cancer, breast cancer, lung cancer, prostate cancer, leukemia and pancreatic cancer, mediating poor patient prognosis (Genes 2019,10,208; World J Gastroenterol 2005; 11(36) ):5644-5650).
  • PLK1 is highly related to multiple tumor-related targets and pathways. RAS mutations cause mitotic stress in cells, making tumor cells more dependent on PLK1 for mitosis. Interfering with the mitosis process can promote synthetic lethality in tumor cells.
  • PLK1 knockout or inhibition of PLK1 The kinase activity of RAS mutant cells arrests mitosis in the G2/M phase (Cell 137, 835–848, May 29, 2009); PLK1 can directly phosphorylate p53 protein to mediate p53 instability, or indirectly promote the phosphorylation of TOPORS and GTSE1, Degrade p53, causing it to lose its tumor suppressor effect; PLK1 directly stabilizes or promotes the expression of the oncogenic protein Myc, promoting the occurrence and development of tumors; PLK1 can also inhibit the phosphorylation of PTEN and activate the PI3K signaling pathway.
  • small molecules targeting the enzymatic activity of PLK1 have broad therapeutic effects on PLK1-related tumors.
  • the present invention provides a new PLK1 inhibitor that can be used to prevent and/or treat PLK1-related diseases, such as tumors.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or deuterated product thereof:
  • E is independently selected from C, N, O;
  • T, M, Q are independently selected from N, CR3;
  • X, Y and Z are independently selected from N and CR5;
  • Ring A is selected from phenyl and contains 1-3 5-11-membered heteroaryl groups independently selected from N, O, and S;
  • Ring B is connected to the ring carbon atom or ring nitrogen atom of A ring;
  • R1 is independently C 1-4 alkyl
  • two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which is optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substitution
  • the alkyl, Alkenyl, alkynyl, and alkoxy groups are optionally selected from one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 1-4 alkoxy group substituted;
  • R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyny
  • R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4
  • R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
  • R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • R6 is selected from NR8R9, NR8C(O)R9, C(O)NR8R9, C 1-4 alkyl, piperazinyl, bridged piperazinyl, spiropiperazinyl, the alkyl, piperazinyl, bridged piperazinyl Base, spiropiperazinyl is optionally substituted by one or more R7;
  • R6 together with its connected ring C atom, ring Y atom, and the bond between the ring C atom and ring Y atom, forms a 5-7 membered heterocycloalkane containing 1-3 independently selected from N, O, and S group, the ring may be optionally replaced by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy group substituted, the alkyl, alkenyl, alkynyl, alkoxy group optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2. Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 ;
  • R8 and R9 When R8 and R9 are connected on the same atom, R8 and R9 together with the atoms to which they are connected can form a 3-7-membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S.
  • the alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • n 0, 1, 2 or 3.
  • w 0, 1, 2.
  • the present invention provides a compound represented by the following formula (IA) or a pharmaceutically acceptable salt or deuterated product thereof:
  • T, M, Q are independently selected from N, CR3;
  • X, Y and Z are independently selected from N and CR5;
  • R1 is independently C 1-4 alkyl
  • the two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substituted, the alkyl group , alkenyl, alkynyl, alkoxy is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C Substituted with 2-4 alkynyl and C 1-4 alkoxy groups;
  • R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyny
  • R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4
  • R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
  • R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
  • R8 and R9 When R8 and R9 are connected on the same atom, R8 and R9 together with the atoms to which they are connected can form a 3-7-membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S.
  • the alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • T is N, M and Q are independently selected from CR3;
  • X, Y, Z are independently selected from CR5;
  • R1 is independently C 1-4 alkyl
  • the two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from Substituted with F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl groups;
  • R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl groups are optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl groups;
  • R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 al
  • R4 is selected from C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br;
  • R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, and the alkyl group is optionally selected from one or more independently selected from F, Cl, Br, OH , CN, NH 2 groups substituted;
  • R8 and R9 are independently selected from H, OH, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy groups are optionally one or more independently selected from F, Cl, Substituted by Br, OH, CN, NH 2 and C 1-4 alkyl groups;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4.
  • the present invention provides a compound represented by the following formula (IC) or a pharmaceutically acceptable salt or deuterated product thereof:
  • X and Y are independently selected from N and CR5;
  • R2 is independently selected from H, C 1-4 alkyl, -S(O) 2 R8, -P(O)R8R9, the alkyl group is optionally substituted by one or more groups independently selected from OH, C 1-4 alkoxy;
  • R3 is selected from H, F, Cl, Br, CN, C 1-4 alkyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Substituted by Br, CN, OH groups;
  • R5 is independently selected from H, CN;
  • R7 is independently selected from H, C 1-4 alkyl, the alkyl is optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN;
  • R8 and R9 are independently selected from NH 2 and C 1-4 alkyl.
  • the present invention provides a compound represented by the following formula (ID) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R3 is selected from H, F, Cl, Br, CN, methyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Replaced by Br, CN, OH groups.
  • the present invention provides a compound represented by the following formula (IB) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R1 is independently selected from H, methyl
  • R3 is selected from H, F, Cl, Br, methyl.
  • the present invention provides a compound represented by the following formula (IE) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R1 is independently selected from H, methyl
  • R3 is selected from H, F, Cl, Br, methyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br.
  • the present invention provides a compound represented by the following formula (IF) or a pharmaceutically acceptable salt or deuterated product thereof:
  • R3 is selected from H, F, Cl, Br, methyl
  • R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br; preferably Methoxy, trifluoromethoxy;
  • R6 is selected from
  • the compound of the present invention is selected from the following compounds or their pharmaceutically acceptable salts and deuterated products:
  • C 1-4 alkyl specifically refers to the independently disclosed methyl (i.e., C 1 alkyl), ethyl (i.e., C 2 alkyl), propyl (i.e., C 3 alkyl), butyl (i.e. C 4 alkyl).
  • examples of "containing 1-3 5-7-membered heterocycloalkyl groups independently selected from N, O, S” include but are not limited to tetrahydrofuran, thiolane, pyrrolidine, pyrrolidone, pyrrole pholine, dioxolane, oxazolidine, oxazolidinone, oxazoline, isoxazolidine, thiazolidine, isothiazolidine, thiazoline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrazoline Hydropyran, dihydropyran, pyran, piperidine, piperidone, 1,4-dioxane, morpholine, morpholinone, piperazine, azepane, epoxide, sulfide Heterocycloheptane, 1,4-oxazalane, 1,4-thiazepane.
  • examples of "containing 1-3 3-7-membered heterocycloalkyl groups independently selected from N, O, and S” include, in addition to the above, but are not limited to ethylene oxide, ethylene sulfide Alkane, aziridine, oxetane, N-lactam ring, ⁇ -lactam ring, ⁇ -lactam ring, ⁇ -lactone.
  • examples of "containing 1-3 5-6-membered heteroaryl groups independently selected from N, O, S” include but are not limited to furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, Isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole, pyridine, pyridone, pyrimidine, pyridazine, pyrazine, triazole Azine.
  • examples of "containing 1-3 5-11-membered heteroaryl groups independently selected from N, O, S” include but are not limited to the above.
  • benzazetidines benzo- ⁇ -lactam rings, benzo- ⁇ -lactones, benzoxdiones, benzofurans, benzothiophenes, benzopyrroles, benzopyrazoles, and benzimidazoles , benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzotriazole, benzoxadiazole, benzothiadiazole, benzodioxane, benzomorpholine , benzopiperidine, benzopyran, benzopyridine, benzopyrimidine, benzotriazine, benzopiperidone, benzmorpholinone, benzazepine, benzazepine Ketone, pyridoazetidine, pyrido beta-lactam ring,
  • Compounds of the present invention may be asymmetric, eg, possess one or more stereocenters. All stereoisomers, such as enantiomers and diastereomers, are included within the scope of the invention unless otherwise specified.
  • compounds containing asymmetrically substituted carbon atoms can be isolated in either optically active or racemic form. Various methods for preparing optically active forms are known in the art, for example by resolution of racemic mixtures or by stereospecific synthesis.
  • the present invention also includes pharmaceutically acceptable salts of the compounds.
  • the compounds of the present invention can be prepared into pharmaceutically acceptable salts by reaction with non-toxic inorganic or organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, hydrogen sulfate, boric acid, hemi-sulfuric acid, etc.
  • organic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, Undecanoic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, adipic acid, lactic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, methanesulfonic acid, ethyl sulfonate Acid, benzenesulfonic acid,
  • the present invention also includes hydrates and solvates of the compounds.
  • the present invention also includes all forms of the compounds in which the atoms are in the various isotopes.
  • Isotopes include all atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium.
  • the present invention also includes prodrugs of said compounds.
  • Prodrug refers to a compound obtained by structural modification of the compound that is inactive or less active outside the patient's body, but undergoes enzymatic or non-enzymatic transformation in the patient's body to release the compound and exert medicinal effects.
  • the compounds of the present invention can be prepared by various methods disclosed in the literature.
  • the compounds of the present invention may be reacted in suitable solvents, and those skilled in the art of organic synthesis can readily select suitable solvents that do not substantially react with reactants, intermediates or products.
  • the reaction can be carried out in one solvent or in a mixture of more than one solvent.
  • the reaction may be carried out at a suitable temperature to prepare the compounds of the invention, for example between the solidification temperature of the solvent and the boiling point temperature of the solvent.
  • the method of preparing the compounds of the present invention involves the protection and deprotection of various chemical groups. Those skilled in the field of organic synthesis can easily determine whether protection and deprotection of chemical groups are needed and select appropriate protecting groups.
  • the reaction for preparing the compounds of the invention can be monitored using any method known in the art, such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, chromatography, and the like.
  • the compounds of the present invention can be prepared, for example, by the following methods:
  • the synthesis reaction of Ib can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base is optional From lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, etc.;
  • ligands can be selected from Davephos, Xantphos, etc.;
  • catalysts can be selected from Pd 2 (dba) 3 , Pd(OAc) 2 , etc.
  • the synthesis reaction of I-c can be carried out in a solvent in the presence of a base.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof;
  • the base can be selected from bistrimethyl Lithium silylamide, lithium diisopropylamide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, etc.
  • the synthesis reaction of I-d can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from acetonitrile, tetrahydrofuran, toluene, methanol, 1,4-dioxane, etc. or any mixture thereof;
  • the reaction reagent can be selected from trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, etc.;
  • reaction reagents can be selected from phosphorus oxychloride, sulfoxide chloride, etc.; solvents can be selected from toluene, xylene, 1,4-dioxane, dichloromethane, etc. or any mixture thereof.
  • the synthesis reaction of compound (I) can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.
  • the ligand can be selected from triphenylphosphine, dppp, dppf, etc.
  • the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
  • the synthesis reaction of II-b can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.
  • the ligand can be selected from triphenylphosphine, dppp, dppf, etc.
  • the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base is optional From potassium carbonate, sodium carbonate, cesium carbonate, lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, etc.
  • the ligand can be selected from BINAP, Davephos, Xantphos, etc.
  • the catalyst can be selected from Pd 2 ( dba) 3 , Pd(OAc) 2 , etc.
  • the synthesis reaction of III-c can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from ethanol, methanol, water, etc. or any mixture thereof;
  • the reaction reagent can be a combination of cyanamide and hydrochloric acid, or a combination of S-methylisothiourea and potassium carbonate.
  • the synthesis reaction of III-f can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, methanol, water, etc. or any mixture thereof; the reaction reagent can be selected from hydrochloric acid, sulfuric acid, etc.
  • the synthesis reaction of III-g can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from N,N-dimethylformamide, toluene, xylene, etc. or any mixture thereof; the reaction reagent can be selected from N,N-dimethylformamide dimethyl acetal, etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base in a solvent.
  • the solvent can be selected from isopropyl alcohol, methanol, ethanol, tert-butyl Alcohol, N,N-dimethylformamide, dimethyl sulfoxide, etc. or any mixture thereof;
  • the base can be selected from potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium acetate, acetic acid Sodium etc.
  • the synthesis reaction of IV-b can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.
  • the ligand can be selected from triphenylphosphine, dppp, dppf, etc.
  • the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
  • the synthesis reaction of IV-c can be carried out in the presence of reaction reagents in a solvent.
  • the solvent can be selected from dichloromethane, tetrahydrofuran, water, 1,4-dioxane, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof;
  • reaction Reagents can be selected from Oxone, m-CPBA, etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base in a solvent.
  • the solvent can be selected from N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, etc. or any mixture thereof;
  • the base can be selected from potassium tert-butoxide, tert. Sodium butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, etc.
  • the synthesis reaction of Va can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base is optional From potassium carbonate, sodium carbonate, cesium carbonate, lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, etc.
  • the ligand can be selected from BINAP, Davephos, Xantphos, etc.
  • the catalyst can be selected from Pd 2 ( dba) 3 , Pd(OAc) 2 , etc.
  • the synthesis reaction of compound I can be carried out in the presence of a base, a ligand and a catalyst in a solvent.
  • the solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • the base can be selected from bistrimethylsilane Lithium amide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, etc.
  • ligands can be selected from Davephos, Xantphos, etc.
  • catalysts can be selected from Pd 2 (dba) 3 , Pd (OAc) 2 etc.
  • the compounds of the invention are able to inhibit PLK1. Therefore, according to another aspect of the invention, the invention provides a method of inhibiting PLK1 using a compound of the invention.
  • the present invention provides a method for preventing and/or treating PLK1-related diseases, wherein a therapeutically and/or preventive effective amount of a compound of the present invention or a pharmaceutical combination containing a compound of the present invention is administered to an individual in need thereof.
  • PLK1-related diseases include any disease directly and/or indirectly related to the expression and/or activity of PLK1, for example, diseases related to PLK1 overexpression; diseases that are prevented and/or treated by regulating, for example, inhibiting PLK1 activity, etc.
  • PLK1-related diseases include solid tumors, hematological tumors, etc.
  • solid tumors include, but are not limited to, colorectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, glioma, liver cancer, esophageal cancer, bladder cancer, kidney cancer, lymphoma tumors, melanoma, osteosarcoma, etc.
  • examples of hematological tumors include but are not limited to leukemia, myelodysplastic syndrome, etc.
  • the invention provides the use of the compounds of the invention in the preparation of PLK1 inhibitors.
  • the present invention provides the use of the compounds of the present invention in the preparation of for the prevention and/or treatment of PLK1-related diseases.
  • the compounds of the present invention may be administered in the form of pharmaceutical compositions. Therefore, according to another aspect of the invention, the invention provides a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be prepared by various methods disclosed in the literature.
  • the compounds or pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated.
  • it can be administered orally, parenterally (e.g. intravenous, arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion), intracranially e.g. intrathecally or intracerebroventricularly, transdermally, ocular, nasal, vaginal, rectal, pulmonary (e.g. Administer by inhalation or insufflation into powder or aerosol).
  • the pharmaceutical compositions of the present invention are generally provided in the form of tablets, capsules or solutions. Tablets may contain a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the carrier includes, but is not limited to, diluents, disintegrants, binders, lubricants, colorants or preservatives. Capsules include hard capsules and soft capsules.
  • the pharmaceutical composition of the present invention may be administered by intravenous injection, intramuscular injection, or subcutaneous injection. They are usually supplied as sterile aqueous solutions or suspensions or lyophilized powders, with appropriate pH and isotonicity adjusted.
  • the effective amount of a compound of the present invention will be determined by the specific use of the treatment, the mode of administration, and the condition of the individual in need thereof, e.g., the patient. Those skilled in the art will be able to determine effective amounts of compounds of the invention. Typical dosage ranges are, for example, 1 ⁇ g/kg/day to 1000 mg/kg/day.
  • the compounds of the invention can be used in combination with one or more other drugs.
  • Other drugs include immune checkpoint drugs, targeted drugs, chemotherapy drugs, etc.
  • Lithium solution in tetrahydrofuran (LiHMDS, 187 mL, 187.2 mmol) and N-methylpiperazine (12.5 g, 124.8 mmol) were heated to reflux overnight. Cool to room temperature, concentrate and dissolve the crude product in dichloromethane (200 mL). Wash the organic phase with water (50 mL ⁇ 2). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the crude product. :water 10%-70%, +0.1% ammonia) was purified to obtain a light yellow solid product (13.0g).
  • compound 6-bromo-4-iodo-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (1.3g, 2.88mmol) and dimethylphosphine oxide (292.0mg ,3.74mmol), tris(dibenzylideneacetone)dipalladium (265.0mg, 0.29mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (335.0mg, 0.58mmol) , triethylamine (874.3mg, 8.64mmol) was dissolved in 1,4-dioxane (10ml), and stirred at room temperature for 3 hours.
  • reaction solution is diluted with water (30 mL) and extracted with ethyl acetate (80 mL ⁇ 2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • the crude product was purified by silica gel column chromatography (0-15% methanol/dichloromethane) to obtain a white solid (550.0 mg).
  • the system was evacuated and replaced with nitrogen three times, and heated to 100 °C for 5 hours. When the reaction is complete, cool the reaction to room temperature.
  • the reaction solution was diluted with water (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined and washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), and the organic phase was dried with anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain crude product. After preparation and isolation, white solid PR-01-049 (39.7 mg) is obtained.
  • reaction system was replaced with nitrogen three times.
  • the reaction solution was stirred at 80°C for 5 hours.
  • LCMS detection showed that the reaction was complete.
  • the reaction solution was poured into water (5 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • Dissolve thiophene-3-carboxylic acid (500.0 mg, 3.90 mmol) in tetrahydrofuran (20 mL), evacuate and replace with nitrogen three times, cool the system to -70°C, and slowly add n-butyllithium (6 mL, 1.6 M) dropwise to the system. Cyclohexane solution, 9.60mmol), while keeping the temperature below -55°C. After the dropwise addition is completed, continue to stir the reaction at -70°C for 1 hour, then slowly add acetone (0.38mL, 5.17mmol). After the dropwise addition is completed, The temperature of the system rose to 0°C, and the reaction was continued to stir at this temperature for 3 hours.
  • reaction solution was cooled, and ethyl acetate was added to the reaction solution. (10mL), washed with water and saturated brine, collected organic The phase was dried over anhydrous sodium sulfate, and the reaction solution was separated to obtain light yellow solid PR-01-070 (36.1 mg).
  • 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (100 mg, 0.34 mmol), 5-(4-methylpiperdine)
  • oxazin-1-yl)-2-(trifluoromethoxy)aniline 104 mg, 0.38 mmol
  • cesium carbonate 223 mg, 0.68 mmol
  • Naphthalene-2,2'-bisdiphenylphosphine BINAP, 43.6 mg, 0.07 mmol
  • palladium acetate 7.6 mg, 0.034 mmol
  • the reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. Pour into water (5 mL) and extract with ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The solid was prepared alkaline to give a white solid (12.5 mg).
  • reaction solution was quenched by adding saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). Combine organic phases Wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude product.
  • Racemate PR-01-083 was separated and purified by SFC (chromatographic column: ChiralPak IB, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: phase A: carbon dioxide, phase B: [MEOH+0.1% 7mol/L NH 3 ]; gradient :B%: 20%-20%, 10.8min; 120min), white solid PR-01-083A and PR-01-083B were obtained.
  • 6-(2-Chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (150.0 mg, 0.51 mmol), 5-(4-methylpiperazine- 1-yl)-2-(2,2,2-trifluoroethoxy)aniline (common int-6) (223.1mg, 0.77mmol), palladium acetate (15.7mg, 0.07mmol), 1,1'- Binaphthyl-2,2'-bisdiphenylphosphine (64.0mg, 0.10mmol) and cesium carbonate (502.6mg, 1.54mmol) were suspended in 1,4-dioxane (2mL), and heated to 100 under nitrogen protection.
  • 6-Bromo-4-iodoisoindol-1-one (4.2g, 12.43mmol), 4-dimethylaminopyridine (460.0mg, 3.77mmol) and triethylamine (5.0g, 49.41 mmol) was dissolved in dichloromethane (100 mL), di-tert-butyl dicarbonate (8.1 g, 37.11 mmol) was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 18 hours. The reaction system was diluted with dichloromethane (50 mL), washed with water (100 mL), the organic phase was separated, dried, filtered, and spun to dryness.
  • 6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (45.0 mg, 0.13 mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (37.0mg, 0.13mmol), cesium carbonate (120.0mg, 0.37mmol), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (20.0mg, 0.03mmol) and palladium acetate (4.5mg, 0.02mmol) were dissolved in dioxane (2mL), under nitrogen protection, 100°C The reaction was carried out for 18 hours, the reaction system was spun to dryness, and the crude product was prepared by alkaline treatment to obtain a white solid (15.5 mg).
  • reaction solution was cooled and filtered, and the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 3), and concentrated to obtain an almost black oily substance, which was purified by preparative HPLC to obtain a white solid (60 mg).
  • reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL).
  • the organic phase was dried, spun to dryness, and separated and purified through alkaline (H 2 O/MeCN (0.1% NH 3 ⁇ H 2 O)) preparation to obtain a white solid (14.1 mg).
  • reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried, spun to dryness, and white solid (13.5 mg) was obtained through preparation, separation and purification.
  • the reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried and spun to dryness, and the crude product was prepared by reverse-phase alkaline preparation to obtain a white solid (8.1 mg).
  • 1,2-dimethylpiperazine (22.8 mg, 0.20 mmol) and 1M lithium bistrimethylsilylamide (0.3 mL, 0.3 mmol) were added to the reaction solution.
  • the reaction solution was stirred at 70°C for 5 hours and the reaction was completed by LCMS.
  • the reaction solution was poured into water (5 mL), extracted with ethyl acetate (5 mL ⁇ 3), the organic phases were combined and concentrated to dryness. Alkaline preparative HPLC purified to obtain a light yellow solid (20.0 mg).
  • Racemate PR-01-123 was separated and purified by SFC (chromatographic column: ChiralPakC-IG, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: A Phase: carbon dioxide, phase B: [MEOH+0.1% MEA]; gradient: B: 45%-45%, 8min; 120min) to obtain white solids PR-01-123A and PR-01-123B.
  • SFC chromatographic column: ChiralPakC-IG, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: A Phase: carbon dioxide, phase B: [MEOH+0.1% MEA]; gradient: B: 45%-45%, 8min; 120min
  • the reaction solution was stirred at 100°C for 16 hours under nitrogen protection. LCMS showed that the reaction was complete.
  • reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (30 mL ⁇ 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude black solid product. The crude product was purified by preparative HPLC to obtain a white solid (48.6 mg).
  • N-(5-bromo-2-(difluoromethoxy)pyridin-3-yl)-1,1-diphenylmethaneimine (2.3g, 5.70mmol)
  • N-methylpiperazine (685.2 mg, 6.84 mmol) of 1,4-dioxane suspension (25.0 mL)
  • tris(dibenzylideneacetone) dipalladium 522.0 mg, 0.57 mmol
  • 2-dicyclohexylphosphine-2′, 6'-dimethoxy-biphenyl 468.0 mg, 1.14 mmol
  • cesium carbonate 5.6 g, 17.19 mmol
  • the reaction system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction is complete, add water (10.0 mL) to dilute the reaction solution, and extract with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by preparative HPLC to obtain a yellow solid (17.0 mg).
  • N-(5-bromo-2-(2,2-difluorocyclopropyl)phenyl)-1,1-diphenylmethaneimine 350.0 mg, 0.85 mmol
  • N-methylpiperazine 102.1 mg, 1.02 mmol
  • sodium tert-butoxide 244.8 mg, 2.55 mmol
  • tris(dibenzylideneacetone) dipalladium 77.7 mg, 0.09 mmol
  • 1,1'-binaphthyl-2,2'- Bisdiphenylphosphine (105.7 mg, 0.17 mmol) was dissolved in toluene (8 mL) and reacted at 110°C for 3 hours.
  • the reaction solution was cooled and spun to dryness.
  • 1,4-dioxane to 1-(4-bromo-2-iodophenyl)cyclopropane-1-carbonitrile 500.0 mg, 1.44 mmol
  • diphenylmethane imine 312.5 mg, 1.72 mmol
  • 1,1'-binaphthyl-2,2'-bisdiphenylphosphine 178.9 mg, 0.29 mmol
  • tris(dibenzylideneacetone)dipalladium 263.2 mg, 0.29 mmol
  • cesium carbonate 1.g, 4.31mmol
  • the reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • reaction solution was heated and refluxed under nitrogen protection for 6 hours until the raw materials were completely consumed. After the reaction solution was cooled, the solvent was removed in vacuo, diluted with water (5 mL), and extracted with ethyl acetate (15 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. A white solid (20.7 mg) was obtained by basic preparation.
  • reaction solution was cooled and filtered, and the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 3), and concentrated to obtain an almost black oily substance, which was purified by preparative HPLC to obtain a white solid (55 mg).
  • reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, dried, filtered and spin-dried. The crude product was prepared by reverse phase formic acid to obtain a white solid (7.2 mg).
  • Racemate PR-01-113 was separated and purified by SFC (chromatographic column: ChiralPak AD, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: IPA (0.1% 7mol/L NH3in MeOH); gradient : B%: 30%; 7 min, 120 min), white solid PR-01-113A (13.0 mg) and white solid PR-01-113B (17.5 mg) were obtained.
  • SFC chromatographic column: ChiralPak AD, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: IPA (0.1% 7mol/L NH3in MeOH); gradient : B%: 30%; 7 min, 120 min), white solid PR-01-113A (13.0 mg) and white solid PR-01-113B (17.5 mg) were obtained.
  • Example 51 Synthesis of compounds DP-01-203, DP-01-203A, and DP-01-203B
  • the reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried and spin-dried.
  • a white solid (34.3 mg) was obtained by using reversed-phase formic acid.
  • Racemate DP-01-203 was separated and purified by SFC (chromatographic column: ChiralPak C-IG, 250 ⁇ 30mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; B: MeOH+0.1% NH 3 -H 2 O; Gradient: B%: 40%; 8.4min; 180min) to obtain white solid DP-01-203A (6.4mg) and white solid DP-01-203B (7.7mg).
  • Racemate DP-01-161 was separated and purified by SFC (chromatographic column: ChiralCel OX, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: phase A: CO 2 ; phase B: IPA+0.1% NH 3 -H 2 O; Gradient: B%: 30%, 6.9min; 180min), white solid DP-01-161A (5.0mg) and white solid DP-01-161B (7.0mg) were obtained.
  • SFC chromatographic column: ChiralCel OX, 250 ⁇ 21.2mm ID, 5 ⁇ m; mobile phase: phase A: CO 2 ; phase B: IPA+0.1% NH 3 -H 2 O; Gradient: B%: 30%, 6.9min; 180min), white solid DP-01-161A (5.0mg) and white solid DP-01-161B (7.0mg) were obtained.
  • methylsulfonyl chloride (139.7mg, 1.22mmol) was added dropwise to triethylamine (164.5mg, 1.63mmol) and (4-(3-bromo-4-(trifluoromethoxy)phenyl) -1-methylpiperazin-2-yl)methanol (common int-14) (300.0 mg, 0.81 mmol) in anhydrous dichloromethane (5 mL) and stirred at room temperature for 1 hour.
  • dichloromethane 5 mL
  • Dioxane was added to 5'-pinacol borate ester spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-9) (300.0 mg, 1.05 mmol) at room temperature.
  • 5mL and water (1mL) were added with 2,4-dichloro-5-fluoro-6-methylpyrimidine (228.5mg, 1.26mmol), [1,1'-bis(diphenylphosphine)diocene Iron] palladium dichloride (79.8 mg, 0.11 mmol), potassium phosphate (669.9 mg, 3.16 mmol). Nitrogen was replaced three times, and the resulting mixture was stirred at 90°C for 4 hours.
  • Racemate DP-01-219 was separated and purified by SFC (chromatographic column: CHIRALPAK C-IG 5 ⁇ m 4.6*100mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: EtOH (0.05% DEA v/v); Gradient: B%: 40.0%, 8 min) to obtain white solid DP-01-219A and white solid DP-01-219B.
  • SFC chromatographic column: CHIRALPAK C-IG 5 ⁇ m 4.6*100mm ID, 5 ⁇ m; mobile phase: Phase A: CO 2 ; Phase B: EtOH (0.05% DEA v/v); Gradient: B%: 40.0%, 8 min

Abstract

Provided are a class of compounds as PLK1 inhibitors as represented by formula (I). The compound and the composition containing same can inhibit PLK1, and thus can be used for preventing and/or treating PLK1-related diseases, such as tumors.

Description

作为PLK1抑制剂的化合物及其制备方法和用途Compounds as PLK1 inhibitors and preparation methods and uses thereof
本申请要求2022年9月8日向中国国家知识产权局提交的专利申请号为202211098253.8，发明名称为“作为PLK1抑制剂的化合物及其制备方法和用途”的，以及2023年5月16日向中国国家知识产权局提交的专利申请号为202310546619.1，发明名称为“作为PLK1抑制剂的化合物及其制备方法和用途”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。This application requires the patent application number 202211098253.8 submitted to the State Intellectual Property Office of China on September 8, 2022, and the invention name is "Compounds as PLK1 inhibitors and their preparation methods and uses", and the patent application number submitted to the Chinese National Intellectual Property Office on May 16, 2023 The patent application number submitted by the Intellectual Property Office is 202310546619.1, and the invention title is "Compounds as PLK1 inhibitors and their preparation methods and uses". The entirety of said prior application is incorporated into this application by reference.
技术领域Technical field
本发明提供了一类作为PLK1抑制剂的化合物及其制备方法和用途。所述化合物及包含其的组合物可用于预防和/或治疗肿瘤相关疾病。The present invention provides a class of compounds as PLK1 inhibitors and their preparation methods and uses. The compounds and compositions containing them can be used to prevent and/or treat tumor-related diseases.
背景技术Background technique
PLK1属Polo样激酶(Polo-like kinases，PLKs)家族(包括PLK1/2/3/4)，是高度保守的Ser/Thr蛋白激酶，在细胞周期的正常运行、中心体成熟、细胞质分离等方面起重要作用。PLK1通过磷酸化下游细胞周期蛋白如WEE1/CDK1等，调控G2/M转变；PLK1抑制导致细胞有丝分裂阻滞在G2期，并诱导凋亡(Sci Signal.2018Aug 14；11(543):eaar4195)。另外，PLK1对有丝分裂之外的细胞功能也具有调节作用，如PLK1修复受损DNA，使肿瘤细胞增殖(Mol Cell.2021Mar 4；81(5):1084-1099.e6.)。在包括结直肠癌、乳腺癌、肺癌、前列腺癌、白血病及胰腺癌等在内的大多数恶性肿瘤中PLK1过表达，介导患者预后不良(Genes 2019,10,208；World J Gastroenterol 2005；11(36):5644-5650)。另外，PLK1与肿瘤相关的多个靶点及通路高度关联，RAS突变引起细胞有丝分裂压力，使肿瘤细胞更依赖于PLK1进行有丝分裂，干扰有丝分裂过程可促进肿瘤细胞发生合成致死，PLK1敲除或抑制PLK1的激酶活性，使RAS突变细胞的有丝分裂停滞在G2/M期(Cell 137,835–848,May 29,2009)；PLK1能够直接磷酸化p53蛋白介导p53不稳定，或间接促进TOPORS及GTSE1磷酸化，降解p53，使其失去抑癌作用；PLK1直接稳定或促进致癌蛋白Myc的表达，促进肿瘤的发生发展；PLK1也能够抑制PTEN的磷酸化，激活PI3K信号通路。PLK1 belongs to the Polo-like kinases (PLKs) family (including PLK1/2/3/4). It is a highly conserved Ser/Thr protein kinase that plays an important role in the normal operation of the cell cycle, centrosome maturation, and cytoplasmic separation. makes an important impact. PLK1 regulates the G2/M transition by phosphorylating downstream cell cycle proteins such as WEE1/CDK1; PLK1 inhibition causes cell mitosis to be arrested in the G2 phase and induces apoptosis (Sci Signal. 2018 Aug 14; 11(543):eaar4195). In addition, PLK1 also regulates cell functions other than mitosis. For example, PLK1 repairs damaged DNA and promotes tumor cell proliferation (Mol Cell. 2021Mar 4;81(5):1084-1099.e6.). PLK1 is overexpressed in most malignant tumors, including colorectal cancer, breast cancer, lung cancer, prostate cancer, leukemia and pancreatic cancer, mediating poor patient prognosis (Genes 2019,10,208; World J Gastroenterol 2005; 11(36) ):5644-5650). In addition, PLK1 is highly related to multiple tumor-related targets and pathways. RAS mutations cause mitotic stress in cells, making tumor cells more dependent on PLK1 for mitosis. Interfering with the mitosis process can promote synthetic lethality in tumor cells. PLK1 knockout or inhibition of PLK1 The kinase activity of RAS mutant cells arrests mitosis in the G2/M phase (Cell 137, 835–848, May 29, 2009); PLK1 can directly phosphorylate p53 protein to mediate p53 instability, or indirectly promote the phosphorylation of TOPORS and GTSE1, Degrade p53, causing it to lose its tumor suppressor effect; PLK1 directly stabilizes or promotes the expression of the oncogenic protein Myc, promoting the occurrence and development of tumors; PLK1 can also inhibit the phosphorylation of PTEN and activate the PI3K signaling pathway.
因此，小分子靶向PLK1的酶活性对PLK1相关的肿瘤具有广泛的治疗作用。Therefore, small molecules targeting the enzymatic activity of PLK1 have broad therapeutic effects on PLK1-related tumors.
发明内容Contents of the invention
本发明提供了一种新的PLK1抑制剂，其可用于预防和/或治疗PLK1相关的疾病，例如肿瘤。The present invention provides a new PLK1 inhibitor that can be used to prevent and/or treat PLK1-related diseases, such as tumors.
根据本发明的一个方面，本发明提供了式(I)所示化合物或其药学上可接受的盐、氘代物：
According to one aspect of the present invention, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt or deuterated product thereof:
其中，in,
E独立地选自C、N、O；E is independently selected from C, N, O;
T、M、Q独立地选自N、CR3；T, M, Q are independently selected from N, CR3;
X、Y、Z独立地选自N、CR5；X, Y and Z are independently selected from N and CR5;
A环选自苯基、含有1-3个独立地选自N、O、S的5-11元杂芳基；Ring A is selected from phenyl and contains 1-3 5-11-membered heteroaryl groups independently selected from N, O, and S;
B环与A环的环碳原子或环氮原子相连；Ring B is connected to the ring carbon atom or ring nitrogen atom of A ring;
R1独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R1 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy base, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
当R1独立地为C1-4烷基时，两个R1连同其所连接的C一起可形成3-7元环烷基，该环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R1 is independently C 1-4 alkyl, two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which is optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substitution, the alkyl, Alkenyl, alkynyl, and alkoxy groups are optionally selected from one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 1-4 alkoxy group substituted;
R2独立地选自H、F、Cl、Br、OH、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基所取代；R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, containing Substituted with 1-3 3-7-membered heterocycloalkyl groups independently selected from N, O, and S, and 1-3 5-11-membered heteroaryl groups independently selected from N, O, S;
R3独立地选自H、F、Cl、Br、OH、CN、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-NR8C(O)R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、-NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基所取代； R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered containing 1-3 independently selected from N, O, S Substituted by heteroaryl;
R4选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
R5独立地选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
R6选自NR8R9、NR8C(O)R9、C(O)NR8R9、C1-4烷基、哌嗪基、桥环哌嗪基、螺环哌嗪基，所述烷基、哌嗪基、桥环哌嗪基、螺环哌嗪基任选地被一个或多个R7取代；R6 is selected from NR8R9, NR8C(O)R9, C(O)NR8R9, C 1-4 alkyl, piperazinyl, bridged piperazinyl, spiropiperazinyl, the alkyl, piperazinyl, bridged piperazinyl Base, spiropiperazinyl is optionally substituted by one or more R7;
或R6与其连接的环C原子、环Y原子、及该环C原子和环Y原子之间的键一起形成含有1-3个独立地选自N、O、S的5-7元杂环烷基，该环可任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；Or R6, together with its connected ring C atom, ring Y atom, and the bond between the ring C atom and ring Y atom, forms a 5-7 membered heterocycloalkane containing 1-3 independently selected from N, O, and S group, the ring may be optionally replaced by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy group substituted, the alkyl, alkenyl, alkynyl, alkoxy group optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2. Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
R7独立地选自H、F、Cl、Br、OH、CN、NR8R9、＝O、C1-4烷基、C1-4烷氧基、C3-7环烷基，所述烷基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R7 is independently selected from H, F, Cl, Br, OH, CN, NR8R9, =O, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, Alkoxy and cycloalkyl are optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
R8和R9独立地选自H、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基，所述烷基、烯基、炔基、烷氧基任选地被一个或多个选自F、Cl、Br、OH、CN、NH2的基团所取代；R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 ;
当R8和R9连接在同一原子上时，R8和R9连同其所连接的原子一起可形成含有1-3个独立地选自N、O、S的3-7元杂环烷基，该杂环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R8 and R9 are connected on the same atom, R8 and R9 together with the atoms to which they are connected can form a 3-7-membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S. The heterocyclic ring The alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
m为0、1、2或3。m is 0, 1, 2 or 3.
w为0、1、2。w is 0, 1, 2.
根据本发明的一个实施方式，本发明提供了如下式(IA)所示化合物或其药学上可接受的盐、氘代物：
According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (IA) or a pharmaceutically acceptable salt or deuterated product thereof:
其中，in,
T、M、Q独立地选自N、CR3；T, M, Q are independently selected from N, CR3;
X、Y、Z独立地选自N、CR5；X, Y and Z are independently selected from N and CR5;
R1独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R1 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy base, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
当R1独立地为C1-4烷基时，两个R1连同其所连接的C一起可形成3-7元环烷基，该环烷基可任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R1 is independently C 1-4 alkyl, the two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substituted, the alkyl group , alkenyl, alkynyl, alkoxy is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C Substituted with 2-4 alkynyl and C 1-4 alkoxy groups;
R2独立地选自H、F、Cl、Br、OH、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基所取代；R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, containing Substituted with 1-3 3-7-membered heterocycloalkyl groups independently selected from N, O, and S, and 1-3 5-6-membered heteroaryl groups independently selected from N, O, S;
R3独立地选自H、F、Cl、Br、OH、CN、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-NR8C(O)R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、-NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基所取代； R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Substituted by heteroaryl;
R4选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
R5独立地选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
R7独立地选自H、F、Cl、Br、OH、CN、NR8R9、＝O、C1-4烷基、C3-7环烷基，所述烷基和环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R7 is independently selected from H, F, Cl, Br, OH, CN, NR8R9, =O, C 1-4 alkyl, C 3-7 cycloalkyl, the alkyl and cycloalkyl are optionally replaced by one Or substituted by multiple groups independently selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
R8和R9独立地选自H、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基，所述烷基、烯基、炔基、烷氧基任选地被一个或多个选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
当R8和R9连接在同一原子上时，R8和R9连同其所连接的原子一起可形成含有1-3个独立地选自N、O、S的3-7元杂环烷基，该杂环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R8 and R9 are connected on the same atom, R8 and R9 together with the atoms to which they are connected can form a 3-7-membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S. The heterocyclic ring The alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
m为0、1、2或3；m is 0, 1, 2 or 3;
n为0、1、2、3、4、5、6、7或8。n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
在一个优选的实施方案中：In a preferred embodiment:
T为N，M、Q独立地选自CR3；T is N, M and Q are independently selected from CR3;
X、Y、Z独立地选自CR5；X, Y, Z are independently selected from CR5;
R1独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基，所述烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2的基团所取代；R1 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, the alkyl group is optionally selected from one or more independently selected from F, Cl, Substituted by Br, OH, CN, NH 2 groups;
当R1独立地为C1-4烷基时，两个R1连同其所连接的C一起可形成3-7元环烷基，该环烷基可任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；When R1 is independently C 1-4 alkyl, the two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from Substituted with F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl groups;
R2独立地选自H、F、Cl、Br、OH、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基的基团所取代；R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl groups are optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl groups;
R3独立地选自H、F、Cl、Br、OH、CN、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-NR8C(O)R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基的基团所取代；R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3 -7 cycloalkyl group substituted;
R4选自C1-4烷氧基，所述烷氧基任选地被一个或多个独立地选自F、Cl、Br的基团所取代； R4 is selected from C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br;
R5独立地选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基，所述烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2的基团所取代；R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, and the alkyl group is optionally selected from one or more independently selected from F, Cl, Br, OH , CN, NH 2 groups substituted;
R7独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基、C3-7环烷基，所述烷基和环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R7 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, C 3-7 cycloalkyl, the alkyl and cycloalkyl are optionally replaced by Substituted with one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl;
R8和R9独立地选自H、OH、C1-4烷基、C1-4烷氧基，所述烷基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R8 and R9 are independently selected from H, OH, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy groups are optionally one or more independently selected from F, Cl, Substituted by Br, OH, CN, NH 2 and C 1-4 alkyl groups;
m为0、1、2或3；m is 0, 1, 2 or 3;
n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.
根据本发明的一个实施方式，本发明提供了如下式(IC)所示化合物或其药学上可接受的盐、氘代物：
According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (IC) or a pharmaceutically acceptable salt or deuterated product thereof:
其中，in,
X、Y独立地选自N、CR5；X and Y are independently selected from N and CR5;
R1独立地选自H、OH、＝O、C1-4烷基；R1 is independently selected from H, OH, =O, C 1-4 alkyl;
当R1均为甲基时，两个R1连同其所连接的C一起可形成环丙烷基；When R1 is both methyl, the two R1 together with the C to which they are connected can form a cyclopropyl group;
R2独立地选自H、C1-4烷基、-S(O)2R8、-P(O)R8R9，所述烷基任选地被一个或多个独立地选自OH、C1-4烷氧基的基团所取代；R2 is independently selected from H, C 1-4 alkyl, -S(O) 2 R8, -P(O)R8R9, the alkyl group is optionally substituted by one or more groups independently selected from OH, C 1-4 alkoxy;
R3选自H、F、Cl、Br、CN、C1-4烷基；R3 is selected from H, F, Cl, Br, CN, C 1-4 alkyl;
R4选自C1-4烷基、C1-4烷氧基、环丙烷基，所述烷基、烷氧基、环丙烷基任选地被一个或多个独立地选自F、Cl、Br、CN、OH的基团所取代；R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Substituted by Br, CN, OH groups;
R5独立地选自H、CN；R5 is independently selected from H, CN;
R7独立地选自H、C1-4烷基，所述烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN的基团所取代；R7 is independently selected from H, C 1-4 alkyl, the alkyl is optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN;
R8和R9独立地选自NH2、C1-4烷基。R8 and R9 are independently selected from NH 2 and C 1-4 alkyl.
根据本发明的一个实施方式，本发明提供了如下式(ID)所示化合物或其药学上可接受的盐、氘代物：
According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (ID) or a pharmaceutically acceptable salt or deuterated product thereof:
其中，in,
R1独立地选自H、＝O、甲基；R1 is independently selected from H, =O, methyl;
当R1均为甲基时，两个R1连同其所连接的C一起可形成环丙烷基；When R1 is both methyl, the two R1 together with the C to which they are connected can form a cyclopropyl group;
R3选自H、F、Cl、Br、CN、甲基；R3 is selected from H, F, Cl, Br, CN, methyl;
R4选自C1-4烷基、C1-4烷氧基、环丙烷基，所述烷基、烷氧基、环丙烷基任选地被一个或多个独立地选自F、Cl、Br、CN、OH的基团所取代。R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Replaced by Br, CN, OH groups.
根据本发明的一个实施方式，本发明提供了如下式(IB)所示化合物或其药学上可接受的盐、氘代物：
According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (IB) or a pharmaceutically acceptable salt or deuterated product thereof:
其中，in,
R1独立地选自H、甲基；R1 is independently selected from H, methyl;
R3选自H、F、Cl、Br、甲基。R3 is selected from H, F, Cl, Br, methyl.
根据本发明的一个实施方式，本发明提供了如下式(IE)所示化合物或其药学上可接受的盐、氘代物：
According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (IE) or a pharmaceutically acceptable salt or deuterated product thereof:
其中，in,
R1独立地选自H、甲基；R1 is independently selected from H, methyl;
当R1均为甲基时，两个R1连同其所连接的C一起可形成环丙烷基；When R1 is both methyl, the two R1 together with the C to which they are connected can form a cyclopropyl group;
R3选自H、F、Cl、Br、甲基；R3 is selected from H, F, Cl, Br, methyl;
R4选自C1-4烷基、C1-4烷氧基，所述烷基、烷氧基任选地被一个或多个独立地选自F、Cl、Br的基团所取代。R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br.
根据本发明的一个实施方式，本发明提供了如下式(IF)所示化合物或其药学上可接受的盐、氘代物：
According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (IF) or a pharmaceutically acceptable salt or deuterated product thereof:
其中，in,
R3选自H、F、Cl、Br、甲基；R3 is selected from H, F, Cl, Br, methyl;
R4选自C1-4烷基、C1-4烷氧基，所述烷基、烷氧基任选地被一个或多个独立地选自F、Cl、Br的基团所取代；优选甲氧基、三氟甲氧基；R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br; preferably Methoxy, trifluoromethoxy;
R6选自 R6 is selected from
在优选的实施方案中，本发明的化合物选自如下化合物或其药学上可接受的盐、氘代物：



In a preferred embodiment, the compound of the present invention is selected from the following compounds or their pharmaceutically acceptable salts and deuterated products:



在本发明中，尽管取代基以基团组或范围公开，但本发明的基团组或范围特别指其所涵盖的每个具体的基团。例如，术语“C1-4烷基”特别指独立公开的甲基(即C1烷基)、乙基(即C2烷基)、丙基(即C3烷基)、丁基(即C4烷基)。In the present invention, although substituents are disclosed as groups or ranges, the groups or ranges of the invention specifically refer to each specific group encompassed by them. For example, the term "C 1-4 alkyl" specifically refers to the independently disclosed methyl (i.e., C 1 alkyl), ethyl (i.e., C 2 alkyl), propyl (i.e., C 3 alkyl), butyl (i.e. C 4 alkyl).
在本发明中，“含有1-3个独立地选自N、O、S的5-7元杂环烷基”的实例包括但不限于四氢呋喃、硫杂环戊烷、吡咯烷、吡咯烷酮、吡咯啉、二氧戊环、恶唑烷、恶唑烷酮、恶唑啉、异恶唑烷、噻唑烷、异噻唑烷、噻唑啉、咪唑烷、咪唑啉、吡唑烷、吡唑啉、四氢吡喃、二氢吡喃、吡喃、哌啶、哌啶酮、1,4-二氧六环、吗啡啉、吗啉酮、哌嗪、氮杂环庚烷、环氧己烷、硫杂环庚烷、1,4-噁氮杂烷、1,4-硫氮杂烷。In the present invention, examples of "containing 1-3 5-7-membered heterocycloalkyl groups independently selected from N, O, S" include but are not limited to tetrahydrofuran, thiolane, pyrrolidine, pyrrolidone, pyrrole pholine, dioxolane, oxazolidine, oxazolidinone, oxazoline, isoxazolidine, thiazolidine, isothiazolidine, thiazoline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrazoline Hydropyran, dihydropyran, pyran, piperidine, piperidone, 1,4-dioxane, morpholine, morpholinone, piperazine, azepane, epoxide, sulfide Heterocycloheptane, 1,4-oxazalane, 1,4-thiazepane.
在本发明中，“含有1-3个独立地选自N、O、S的3-7元杂环烷基”的实例除了以上之外，还包括但不限于环氧乙烷、环硫乙烷、氮杂环丙烷、氧杂环丁烷、N杂环丁烷、α-内酰胺环、β-内酰胺环、β-内酯。In the present invention, examples of "containing 1-3 3-7-membered heterocycloalkyl groups independently selected from N, O, and S" include, in addition to the above, but are not limited to ethylene oxide, ethylene sulfide Alkane, aziridine, oxetane, N-lactam ring, α-lactam ring, β-lactam ring, β-lactone.
在本发明中，“含有1-3个独立地选自N、O、S的5-6元杂芳基”的实例包括但不限于呋喃、噻吩、吡咯、恶唑、异恶唑、噻唑、异噻唑、吡唑、咪唑、1,2,3-三氮唑、1,2,4-三氮唑、恶二唑、噻二唑、吡啶、吡啶酮、嘧啶、哒嗪、吡嗪、三嗪。In the present invention, examples of "containing 1-3 5-6-membered heteroaryl groups independently selected from N, O, S" include but are not limited to furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, Isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole, pyridine, pyridone, pyrimidine, pyridazine, pyrazine, triazole Azine.
在本发明中，“含有1-3个独立地选自N、O、S的5-11元杂芳基”的实例除了以上之外，还包括但不 限于苯并氮杂环丁烷、苯并β-内酰胺环、苯并β-内酯、苯并恶二茂、苯并呋喃、苯并噻吩、苯并吡咯、苯并吡唑、苯并咪唑、苯并噻唑、苯并异噻唑、苯并恶唑、苯并异恶唑、苯并三氮唑、苯并恶二唑、苯并噻二唑、苯并二氧六环、苯并吗啉、苯并哌啶、苯并吡喃、苯并吡啶、苯并嘧啶、苯并三嗪、苯并哌啶酮、苯并吗啉酮、苯并氮杂环己酮、苯并氮杂环庚酮、吡啶并氮杂环丁烷、吡啶并β-内酰胺环、吡啶并β-内酯、吡啶并恶二茂、吡啶并呋喃、吡啶并噻吩、吡啶并吡咯、吡啶并吡唑、吡啶并咪唑、吡啶并噻唑、吡啶并异噻唑、吡啶并恶唑、吡啶并异恶唑、吡啶并三氮唑、吡啶并恶二唑、吡啶并噻二唑、吡啶并二氧六环、吡啶并吗啉、吡啶并哌啶、吡啶并吡喃、吡啶并吡啶、吡啶并嘧啶、吡啶并三嗪、吡啶并哌啶酮、吡啶并吗啉酮、吡啶并氮杂环己酮。In the present invention, examples of "containing 1-3 5-11-membered heteroaryl groups independently selected from N, O, S" include but are not limited to the above. Limited to benzazetidines, benzo-β-lactam rings, benzo-β-lactones, benzoxdiones, benzofurans, benzothiophenes, benzopyrroles, benzopyrazoles, and benzimidazoles , benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzotriazole, benzoxadiazole, benzothiadiazole, benzodioxane, benzomorpholine , benzopiperidine, benzopyran, benzopyridine, benzopyrimidine, benzotriazine, benzopiperidone, benzmorpholinone, benzazepine, benzazepine Ketone, pyridoazetidine, pyrido beta-lactam ring, pyrido beta-lactone, pyridooxadione, pyridofuran, pyridothiophene, pyridopyrrole, pyridopyrazole, pyrido Imidazole, pyridinothiazole, pyridinoisothiazole, pyridinoxazoles, pyridinoisoxazole, pyridonitriazole, pyridoxadiazole, pyridinothiadiazole, pyridodioxane, pyridinotriazole Phinoline, pyridopiperidine, pyridopyran, pyridopyridine, pyridopyrimidine, pyridotriazine, pyridopiperidone, pyridomorpholinone, pyridoazepinenone.
本发明的化合物可以是不对称的，例如，具有一个或多个立构中心。所有的立体异构体，如对映体和非对映体，都包括在本发明的范围之内，除非另外指明。在本发明中，含有不对称取代的碳原子的化合物可以以任一种旋光性形式或外消旋形式被分离。本领域已知各种制备旋光性形式的方法，例如通过对外消旋混合物进行拆分或通过立体有择合成。Compounds of the present invention may be asymmetric, eg, possess one or more stereocenters. All stereoisomers, such as enantiomers and diastereomers, are included within the scope of the invention unless otherwise specified. In the present invention, compounds containing asymmetrically substituted carbon atoms can be isolated in either optically active or racemic form. Various methods for preparing optically active forms are known in the art, for example by resolution of racemic mixtures or by stereospecific synthesis.
本发明还包括所述化合物的药学上可接受的盐。本发明的化合物可通过与无毒的无机或有机酸反应制备药学上可接受的盐。无机酸例如盐酸、氢溴酸、氢碘酸、磷酸、硫酸、硝酸、硫酸氢、硼酸、半硫酸等；有机酸例如甲酸、乙酸、丙酸、丁酸、戊酸、己酸、庚酸、十一烷酸、棕榈酸、硬脂酸、油酸、草酸、丙二酸、己二酸、乳酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、抗坏血酸、甲磺酸、乙磺酸、苯磺酸、苯甲酸、樟脑酸、樟脑磺酸、柠檬酸、富马酸、葡糖酸，以及各种氨基酸等。The present invention also includes pharmaceutically acceptable salts of the compounds. The compounds of the present invention can be prepared into pharmaceutically acceptable salts by reaction with non-toxic inorganic or organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, hydrogen sulfate, boric acid, hemi-sulfuric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, Undecanoic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, adipic acid, lactic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, methanesulfonic acid, ethyl sulfonate Acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, and various amino acids, etc.
本发明还包括所述化合物的水合物和溶剂合物。The present invention also includes hydrates and solvates of the compounds.
本发明还包括所述化合物其原子为各种同位素的所有形式。同位素包括具有相同原子序数但不同质量数的所有原子。例如氢的同位素包括氘。The present invention also includes all forms of the compounds in which the atoms are in the various isotopes. Isotopes include all atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium.
本发明还包括所述化合物的前药。“前药”是指所述化合物经结构修饰后得到的在患者体外无活性或活性较小、但在患者体内经酶或非酶的转化释放出所述化合物而发挥药效的化合物。The present invention also includes prodrugs of said compounds. "Prodrug" refers to a compound obtained by structural modification of the compound that is inactive or less active outside the patient's body, but undergoes enzymatic or non-enzymatic transformation in the patient's body to release the compound and exert medicinal effects.
本领域技术人员可以理解，本发明的化合物可以通过文献中已披露的各种方法制备得到。可在合适的溶剂中反应以制备本发明的化合物，有机合成领域的技术人员可以容易地选择合适的溶剂，其基本上不与反应物、中间体或产物反应。可在一种溶剂中或一种以上的溶剂的混合物中进行反应。可在适宜的温度下反应以制备本发明的化合物，例如在溶剂的凝固温度至溶剂的沸点温度之间。制备本发明的化合物的方法涉及将各种化学基团保护和脱保护，有机合成领域的技术人员可以容易地确定是否需要对化学基团进行保护和脱保护以及选择合适的保护基团。可使用本领域已知的任何方法监测制备本发明化合物的反应，例如核磁共振波谱、红外光谱、质谱、色谱等。Those skilled in the art will understand that the compounds of the present invention can be prepared by various methods disclosed in the literature. The compounds of the present invention may be reacted in suitable solvents, and those skilled in the art of organic synthesis can readily select suitable solvents that do not substantially react with reactants, intermediates or products. The reaction can be carried out in one solvent or in a mixture of more than one solvent. The reaction may be carried out at a suitable temperature to prepare the compounds of the invention, for example between the solidification temperature of the solvent and the boiling point temperature of the solvent. The method of preparing the compounds of the present invention involves the protection and deprotection of various chemical groups. Those skilled in the field of organic synthesis can easily determine whether protection and deprotection of chemical groups are needed and select appropriate protecting groups. The reaction for preparing the compounds of the invention can be monitored using any method known in the art, such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, chromatography, and the like.
本发明的化合物例如可以通过如下方法制备得到：The compounds of the present invention can be prepared, for example, by the following methods:
方法I：
Method I:
各式中基团的定义如上所述。The definitions of the groups in each formula are as described above.
其中，I-b的合成反应可以在碱、配体和催化剂存在下于溶剂中进行。溶剂可选自四氢呋喃、1,4-二氧六环、叔丁醇、甲苯、二甲苯、DME、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自双三甲基硅基胺基锂、叔丁醇钾、叔丁醇钠、碳酸钾、碳酸钠、碳酸铯等；配体可选自Davephos、Xantphos等；催化剂可选自Pd2(dba)3、Pd(OAc)2等。Among them, the synthesis reaction of Ib can be carried out in the presence of a base, a ligand and a catalyst in a solvent. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base is optional From lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, etc.; ligands can be selected from Davephos, Xantphos, etc.; catalysts can be selected from Pd 2 (dba) 3 , Pd(OAc) 2 , etc.
其中I-c的合成反应可以在碱存在下于溶剂中进行。溶剂可选自四氢呋喃、1,4-二氧六环、甲苯、二甲苯、DME、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自双三甲基硅基胺基锂、二异丙基氨基锂、叔丁醇钾、叔丁醇钠、碳酸钾、碳酸钠、碳酸铯等。The synthesis reaction of I-c can be carried out in a solvent in the presence of a base. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base can be selected from bistrimethyl Lithium silylamide, lithium diisopropylamide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, etc.
其中I-d的合成反应可以在反应试剂存在下于溶剂中进行。溶剂可选自乙腈、四氢呋喃、甲苯、甲醇、1,4-二氧六环等或其任意混合物；反应试剂可选自三甲基碘硅烷、三甲基溴硅烷、三甲基氯硅烷等；The synthesis reaction of I-d can be carried out in the presence of reaction reagents in a solvent. The solvent can be selected from acetonitrile, tetrahydrofuran, toluene, methanol, 1,4-dioxane, etc. or any mixture thereof; the reaction reagent can be selected from trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, etc.;
其中I-e的合成反应可以在反应试剂存在下于溶剂中进行。反应试剂可选自三氯氧磷、二氯亚砜等；溶剂可选自甲苯、二甲苯、1,4-二氧六环、二氯甲烷等或其任意混合物。The synthesis reaction of I-e can be carried out in the presence of reaction reagents in a solvent. Reaction reagents can be selected from phosphorus oxychloride, sulfoxide chloride, etc.; solvents can be selected from toluene, xylene, 1,4-dioxane, dichloromethane, etc. or any mixture thereof.
其中化合物(I)的合成反应可以在碱、配体和催化剂存在下于溶剂中进行。溶剂可选自1,4-二氧六环、四氢呋喃、水、甲醇、甲苯、二甲苯、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自磷酸钾、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠等；配体可选自三苯基膦、dppp、dppf等；催化剂可选自醋酸钯、四三苯基膦钯、Pd2(dba)3、Pd(dppf)Cl2、Pd(PPh3)2Cl2等。The synthesis reaction of compound (I) can be carried out in the presence of a base, a ligand and a catalyst in a solvent. The solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.; the ligand can be selected from triphenylphosphine, dppp, dppf, etc.; the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
方法II：
Method II:
各式中基团的定义如上所述。The definitions of the groups in each formula are as described above.
其中II-b的合成反应可以在碱、配体和催化剂的存在下于溶剂中进行。溶剂可选自1,4-二氧六环、四氢呋喃、水、甲醇、甲苯、二甲苯、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自磷酸钾、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠等；配体可选自三苯基膦、dppp、dppf等；催化剂可选自醋酸钯、四三苯基膦钯、Pd2(dba)3、Pd(dppf)Cl2、Pd(PPh3)2Cl2等。The synthesis reaction of II-b can be carried out in the presence of a base, a ligand and a catalyst in a solvent. The solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.; the ligand can be selected from triphenylphosphine, dppp, dppf, etc.; the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
其中化合物I的合成反应可在碱、配体和催化剂的存在下于溶剂中进行。溶剂可选自四氢呋喃、1,4-二氧六环、叔丁醇、甲苯、二甲苯、DME、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自碳酸钾、碳酸钠、碳酸铯、双三甲基硅基胺基锂、叔丁醇钾、叔丁醇钠等；配体可选自BINAP、Davephos、Xantphos等；催化剂可选自Pd2(dba)3、Pd(OAc)2等。The synthesis reaction of compound I can be carried out in the presence of a base, a ligand and a catalyst in a solvent. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base is optional From potassium carbonate, sodium carbonate, cesium carbonate, lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, etc.; the ligand can be selected from BINAP, Davephos, Xantphos, etc.; the catalyst can be selected from Pd 2 ( dba) 3 , Pd(OAc) 2 , etc.
方法III：
Method III:
各式中基团的定义如上所述。The definitions of the groups in each formula are as described above.
其中III-c的合成反应可以在反应试剂存在下于溶剂中进行。溶剂可选自乙醇、甲醇、水等或其任意混合物；反应试剂可以为氰胺和盐酸的组合、或者S-甲基异硫脲和碳酸钾的组合。The synthesis reaction of III-c can be carried out in the presence of reaction reagents in a solvent. The solvent can be selected from ethanol, methanol, water, etc. or any mixture thereof; the reaction reagent can be a combination of cyanamide and hydrochloric acid, or a combination of S-methylisothiourea and potassium carbonate.
其中III-f的合成反应可以在反应试剂存在下于溶剂中进行。溶剂可选自四氢呋喃、1,4-二氧六环、甲醇、水等或其任意混合物；反应试剂可选自盐酸、硫酸等。The synthesis reaction of III-f can be carried out in the presence of reaction reagents in a solvent. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, methanol, water, etc. or any mixture thereof; the reaction reagent can be selected from hydrochloric acid, sulfuric acid, etc.
其中III-g的合成反应可以在反应试剂存在下于溶剂中进行。溶剂可选自N,N-二甲基甲酰胺、甲苯、二甲苯等或其任意混合物；反应试剂可选自N,N-二甲基甲酰胺二甲缩醛等。The synthesis reaction of III-g can be carried out in the presence of reaction reagents in a solvent. The solvent can be selected from N,N-dimethylformamide, toluene, xylene, etc. or any mixture thereof; the reaction reagent can be selected from N,N-dimethylformamide dimethyl acetal, etc.
其中化合物I的合成反应可以在碱存在下于溶剂中进行。溶剂可选自异丙醇、甲醇、乙醇、叔丁 醇、N,N-二甲基甲酰胺、二甲基亚砜等或其任意混合物；碱可选自碳酸钾、碳酸钠、叔丁醇钾、氢氧化钠、氢氧化钾、醋酸钾、醋酸钠等。The synthesis reaction of compound I can be carried out in the presence of a base in a solvent. The solvent can be selected from isopropyl alcohol, methanol, ethanol, tert-butyl Alcohol, N,N-dimethylformamide, dimethyl sulfoxide, etc. or any mixture thereof; the base can be selected from potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium acetate, acetic acid Sodium etc.
方法IV：
Method IV:
各式中基团的定义如上所述。The definitions of the groups in each formula are as described above.
其中IV-b的合成反应可在碱、配体和催化剂的存在下于溶剂中进行。溶剂可选自1,4-二氧六环、四氢呋喃、水、甲醇、甲苯、二甲苯、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自磷酸钾、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠等；配体可选自三苯基膦、dppp、dppf等；催化剂可选自醋酸钯、四三苯基膦钯、Pd2(dba)3、Pd(dppf)Cl2、Pd(PPh3)2Cl2等。The synthesis reaction of IV-b can be carried out in the presence of a base, a ligand and a catalyst in a solvent. The solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base can be selected from phosphoric acid Potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.; the ligand can be selected from triphenylphosphine, dppp, dppf, etc.; the catalyst can be selected from palladium acetate, tetrakis triphenylphosphine palladium, Pd 2 (dba) 3. Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , etc.
其中IV-c的合成反应可以在反应试剂存在下于溶剂中进行。溶剂可选自二氯甲烷、四氢呋喃、水、1,4-二氧六环、甲醇、甲苯、二甲苯、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；反应试剂可选自Oxone、m-CPBA等。The synthesis reaction of IV-c can be carried out in the presence of reaction reagents in a solvent. The solvent can be selected from dichloromethane, tetrahydrofuran, water, 1,4-dioxane, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; reaction Reagents can be selected from Oxone, m-CPBA, etc.
其中化合物I的合成反应可以在碱存在下于溶剂中进行。溶剂可选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、二甲苯等或其任意混合物；碱可选自叔丁醇钾、叔丁醇钠、碳酸钾、碳酸钠、碳酸铯、醋酸钾、醋酸钠等。The synthesis reaction of compound I can be carried out in the presence of a base in a solvent. The solvent can be selected from N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, etc. or any mixture thereof; the base can be selected from potassium tert-butoxide, tert. Sodium butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, etc.
方法V:
Method V:
各式中基团的定义如上所述。The definitions of the groups in each formula are as described above.
其中V-a的合成反应可在碱、配体和催化剂的存在下于溶剂中进行。溶剂可选自四氢呋喃、1,4-二氧六环、叔丁醇、甲苯、二甲苯、DME、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自碳酸钾、碳酸钠、碳酸铯、双三甲基硅基胺基锂、叔丁醇钾、叔丁醇钠等；配体可选自BINAP、Davephos、Xantphos等；催化剂可选自Pd2(dba)3、Pd(OAc)2等。The synthesis reaction of Va can be carried out in the presence of a base, a ligand and a catalyst in a solvent. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base is optional From potassium carbonate, sodium carbonate, cesium carbonate, lithium bistrimethylsilylamide, potassium tert-butoxide, sodium tert-butoxide, etc.; the ligand can be selected from BINAP, Davephos, Xantphos, etc.; the catalyst can be selected from Pd 2 ( dba) 3 , Pd(OAc) 2 , etc.
其中，化合物I的合成反应可以在碱、配体和催化剂存在下于溶剂中进行。溶剂可选自四氢呋喃、 1,4-二氧六环、叔丁醇、甲苯、二甲苯、DME、二甲基亚砜、N,N-二甲基甲酰胺等或其任意混合物；碱可选自双三甲基硅基胺基锂、叔丁醇钾、叔丁醇钠、碳酸钾、碳酸钠、碳酸铯、磷酸钾等；配体可选自Davephos、Xantphos等；催化剂可选自Pd2(dba)3、Pd(OAc)2等。Among them, the synthesis reaction of compound I can be carried out in the presence of a base, a ligand and a catalyst in a solvent. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base can be selected from bistrimethylsilane Lithium amide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, etc.; ligands can be selected from Davephos, Xantphos, etc.; catalysts can be selected from Pd 2 (dba) 3 , Pd (OAc) 2 etc.
本发明的化合物能够抑制PLK1。因此，根据本发明的另一个方面，本发明提供一种抑制PLK1的方法，使用本发明的化合物。The compounds of the invention are able to inhibit PLK1. Therefore, according to another aspect of the invention, the invention provides a method of inhibiting PLK1 using a compound of the invention.
根据本发明的另一个方面，本发明提供一种预防和/或治疗PLK1相关疾病的方法，其中给予有需要的个体治疗和/或预防有效量的本发明的化合物或含有本发明化合物的药物组合物。PLK1相关疾病包括任何与PLK1的表达和/或活性直接和/或间接相关的疾病，例如，与PLK1过度表达相关的疾病；通过调节例如抑制PLK1活性得到预防和/或治疗的疾病等。According to another aspect of the present invention, the present invention provides a method for preventing and/or treating PLK1-related diseases, wherein a therapeutically and/or preventive effective amount of a compound of the present invention or a pharmaceutical combination containing a compound of the present invention is administered to an individual in need thereof. things. PLK1-related diseases include any disease directly and/or indirectly related to the expression and/or activity of PLK1, for example, diseases related to PLK1 overexpression; diseases that are prevented and/or treated by regulating, for example, inhibiting PLK1 activity, etc.
PLK1相关疾病包括实体瘤、血液瘤等。实体瘤的实例包括但不限于结直肠癌、肺癌、乳腺癌、前列腺癌、胰腺癌、胃癌、头颈癌、卵巢癌、子宫癌、胶质瘤、肝癌、食管癌、膀胱癌、肾癌、淋巴瘤、黑色素瘤、骨肉瘤等；血液瘤的实例包括但不限于白血病、骨髓增生异常综合征等。PLK1-related diseases include solid tumors, hematological tumors, etc. Examples of solid tumors include, but are not limited to, colorectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, glioma, liver cancer, esophageal cancer, bladder cancer, kidney cancer, lymphoma tumors, melanoma, osteosarcoma, etc.; examples of hematological tumors include but are not limited to leukemia, myelodysplastic syndrome, etc.
根据本发明的另一个方面，本发明提供本发明的化合物在制备PLK1抑制剂中的用途。According to another aspect of the invention, the invention provides the use of the compounds of the invention in the preparation of PLK1 inhibitors.
根据本发明的另一个方面，本发明提供本发明的化合物在制备用于预防和/或治疗PLK1相关疾病的用途。According to another aspect of the present invention, the present invention provides the use of the compounds of the present invention in the preparation of for the prevention and/or treatment of PLK1-related diseases.
当使用本发明的化合物预防和/或治疗PLK1相关疾病时，可以药物组合物的形式给予本发明的化合物。因此，根据本发明的另一个方面，本发明提供一种药物组合物，含有本发明的化合物和药学上可接受的载体。When using the compounds of the present invention to prevent and/or treat PLK1-related diseases, the compounds of the present invention may be administered in the form of pharmaceutical compositions. Therefore, according to another aspect of the invention, the invention provides a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable carrier.
本领域技术人员可以理解，本发明的药物组合物可以通过文献中已披露的各种方法制备得到。可通过多种途径给予本发明的化合物或药物组合物，取决于需要局部或全身治疗以及需要治疗的区域。例如，可通过口服、肠胃外(例如静脉、动脉、皮下、腹膜内、肌内注射或输注)、颅内例如鞘内或脑室内、透皮、眼、鼻、阴道、直肠、肺(例如通过吸入或吹入粉末或气雾剂)给药。Those skilled in the art will understand that the pharmaceutical composition of the present invention can be prepared by various methods disclosed in the literature. The compounds or pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. For example, it can be administered orally, parenterally (e.g. intravenous, arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion), intracranially e.g. intrathecally or intracerebroventricularly, transdermally, ocular, nasal, vaginal, rectal, pulmonary (e.g. Administer by inhalation or insufflation into powder or aerosol).
对于口服途径给药，本发明的药物组合物通常以片剂、胶囊剂或溶液的形式提供。片剂可以包含本发明的化合物或其药学上可接受的盐以及药学上可接受的载体。所述载体包括但不限于稀释剂、崩解剂、粘合剂、润滑剂、着色剂或防腐剂。胶囊剂包括硬胶囊剂和软胶囊剂。对于胃肠道外途径给药，本发明的药物组合物可以通过静脉内注射、肌内注射或皮下注射给药。其通常以无菌水溶液或混悬液或冻干粉末提供，并调节合适的pH和等渗性。For oral route administration, the pharmaceutical compositions of the present invention are generally provided in the form of tablets, capsules or solutions. Tablets may contain a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, diluents, disintegrants, binders, lubricants, colorants or preservatives. Capsules include hard capsules and soft capsules. For parenteral administration, the pharmaceutical composition of the present invention may be administered by intravenous injection, intramuscular injection, or subcutaneous injection. They are usually supplied as sterile aqueous solutions or suspensions or lyophilized powders, with appropriate pH and isotonicity adjusted.
本发明化合物的有效量可根据治疗的具体用途、给予的方式、有需要的个体例如患者的状态来确定。本领域技术人员有能力确定本发明化合物的有效量。典型的剂量范围例如1μg/kg/天～1000mg/kg/天。The effective amount of a compound of the present invention will be determined by the specific use of the treatment, the mode of administration, and the condition of the individual in need thereof, e.g., the patient. Those skilled in the art will be able to determine effective amounts of compounds of the invention. Typical dosage ranges are, for example, 1 μg/kg/day to 1000 mg/kg/day.
当预防和/或治疗PLK1相关疾病时，本发明的化合物可与一种或多种其他药物联合使用。其他药物例如免疫检查点类药物、靶向药物及化疗药物等等。When preventing and/or treating PLK1-related diseases, the compounds of the invention can be used in combination with one or more other drugs. Other drugs include immune checkpoint drugs, targeted drugs, chemotherapy drugs, etc.
具体实施方式Detailed ways
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。此外，应理解，在阅读了本发明所记载的内容之后，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发明所限定的范围。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. In addition, it should be understood that after reading the content described in the present invention, those skilled in the art can make various modifications to the present invention. Changes or modifications, these equivalent forms also fall within the scope of the present invention.
制备例1.共用中间体common int-1和common int-2的合成
Preparation Example 1. Synthesis of common intermediates common int-1 and common int-2
5-(4-甲基哌嗪-1-基)-2-[(三氟甲基)氧基]苯胺(common int-1)的合成：Synthesis of 5-(4-methylpiperazin-1-yl)-2-[(trifluoromethyl)oxy]aniline (common int-1):
将化合物2-三氟甲氧基-5-溴苯胺(20.0g,78.1mmol)、三(二亚苄基丙酮)二钯(Pd2dba3,710mg,0.78mmol)及2-二环己膦基-2'-(N,N-二甲胺)-联苯(Davephos,630mg,1.6mmol)溶于四氢呋喃(50mL)，在氮气保护下，向反应体系中加入1M双三甲基硅基胺基锂的四氢呋喃溶液(LiHMDS,187mL,187.2mmol)，N-甲基哌嗪(12.5g,124.8mmol)，反应体系加热到回流反应过夜。冷却到室温，浓缩得到的粗产品溶解在二氯甲烷中(200mL)，有机相用水洗(50mL×2)，有机相用无水硫酸钠干燥，过滤，浓缩的粗品，经反相Flash(乙腈:水10％-70％,+0.1％氨水)纯化得到淡黄色固体产品(13.0g)。LC-MS:[M+H]+:276.0。The compound 2-trifluoromethoxy-5-bromoaniline (20.0g, 78.1mmol), tris(dibenzylideneacetone)dipalladium (Pd 2 dba 3 , 710mg, 0.78mmol) and 2-dicyclohexylphosphine 2'-(N,N-dimethylamine)-biphenyl (Davephos, 630 mg, 1.6 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen protection, 1 M bistrimethylsilylamine was added to the reaction system. Lithium solution in tetrahydrofuran (LiHMDS, 187 mL, 187.2 mmol) and N-methylpiperazine (12.5 g, 124.8 mmol) were heated to reflux overnight. Cool to room temperature, concentrate and dissolve the crude product in dichloromethane (200 mL). Wash the organic phase with water (50 mL × 2). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the crude product. :water 10%-70%, +0.1% ammonia) was purified to obtain a light yellow solid product (13.0g). LC-MS: [M+H] + :276.0.
4-甲氧基-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(2)的合成：Synthesis of 4-methoxy-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (2):
将化合物5-(4-甲基哌嗪-1-基)-2-[(三氟甲基)氧基]苯胺(common int-1,10g,36.33mmol),2-氯-4-甲氧基嘧啶(10.5g,72.65mmol)溶于无水四氢呋喃(50mL)中，0℃氮气保护条件下滴加双三甲基硅基胺基锂(72.65mL,1mol/L)，反应液升至25℃条件下反应2小时。反应液倒入冰的氯化铵溶液中(50mL)，然后用乙酸乙酯萃取(50mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经柱层析(甲醇:二氯乙烷＝1:200-1:20)纯化得到白色固体2(10.7g,77.0％)。LC-MS:[M+H]+:384.0。Compound 5-(4-methylpiperazin-1-yl)-2-[(trifluoromethyl)oxy]aniline (common int-1, 10g, 36.33mmol), 2-chloro-4-methoxy Pyrimidine (10.5g, 72.65mmol) was dissolved in anhydrous tetrahydrofuran (50mL), lithium bistrimethylsilylamide (72.65mL, 1mol/L) was added dropwise under nitrogen protection at 0°C, and the reaction solution rose to 25 The reaction was carried out at ℃ for 2 hours. The reaction solution was poured into ice-cold ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to column chromatography (methanol: Dichloroethane=1:200-1:20) was purified to obtain white solid 2 (10.7g, 77.0%). LC-MS: [M+H] + :384.0.
2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-醇(3)的合成：Synthesis of 2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-ol (3):
将化合物4-甲氧基-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(160mg,0.42mmol)，碘化钠(125mg,0.84mmol)溶于乙腈(6mL)，然后滴加三甲基氯硅烷(135.8mg,1.25mmol)，90℃条件下反应2小时。反应液加H2O(5mL)，乙酸乙酯萃取，混合物依次用水和饱和氯化钠水溶液洗，收集有机相，用无水硫酸钠干燥，过滤，浓缩滤液得到粗品，经柱层析(甲醇:二氯甲烷＝1:100)得到白色固体(80mg)。LC-MS:[M-H]+:368.0。Compound 4-methoxy-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (160 mg, 0.42 mmol), Sodium iodide (125 mg, 0.84 mmol) was dissolved in acetonitrile (6 mL), then trimethylsilyl chloride (135.8 mg, 1.25 mmol) was added dropwise, and the reaction was carried out at 90°C for 2 hours. H 2 O (5 mL) was added to the reaction solution and extracted with ethyl acetate. The mixture was washed with water and saturated sodium chloride aqueous solution in sequence. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was subjected to column chromatography (methanol : dichloromethane=1:100) to obtain a white solid (80 mg). LC-MS: [MH] + :368.0.
4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-2)的合成：Synthesis of 4-chloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidine-2-amine (common int-2):
将化合物2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-醇(80mg)加入到三氯氧磷(4mL)中，80℃条件下反应2小时。反应液浓缩，粗品悬浮在乙酸乙酯(10mL)中，冰浴下用饱和 碳酸氢钠调节pH至9左右，收集乙酸乙酯层，干燥，过滤并浓缩，粗产品经柱层析(甲醇:二氯甲烷＝1:100)得到白色固体(30mg)。LC-MS:[M+H]+:388.0。Compound 2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-ol (80 mg) was added to phosphorus oxychloride ( 4 mL), react at 80°C for 2 hours. The reaction solution was concentrated, and the crude product was suspended in ethyl acetate (10 mL), and saturated with Adjust the pH to about 9 with sodium bicarbonate, collect the ethyl acetate layer, dry, filter and concentrate. The crude product is subjected to column chromatography (methanol:dichloromethane=1:100) to obtain a white solid (30 mg). LC-MS: [M+H] + :388.0.
制备例2.共用中间体common int-3的合成
Preparation Example 2. Synthesis of common intermediate common int-3
N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)甲酰胺(common int-3)的合成：Synthesis of N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)carboxamide (common int-3):
将乙酸酐(6.8mL,72.65mmol)和甲酸(4.1mL,108.98mmol)的混合物在室温下搅拌30分钟，然后将反应温度降至0℃后，缓慢滴加5-(4-甲基哌嗪-1-基)-2-[(三氟甲基)氧基]苯胺(common int-1,2.0g,7.27mmol)的二氯甲烷(3mL)溶液，并在室温下搅拌混合物2小时。将溶液浓缩后用乙酸乙酯(20mL)稀释，分别用饱和碳酸氢钠溶液(20mL)和水(20mL)洗涤。有机层浓缩后得到无色油状物(2.1g)，该产物可直接用于相关反应中。LC-MS:[M+H]+:304.0；1H NMR(400MHz,CDCl3).δ10.00(s,1H),8.32(d,J＝4.0,1H),7.84(d,J＝4.0Hz,1H),7.20(dd,J＝8.0,4.0Hz,1H),6.74(dd,J＝8.0,4.0Hz,1H),3.10-3.18(m,4H),2.43-2.45(m,4H),2.22(s,3H)。The mixture of acetic anhydride (6.8 mL, 72.65 mmol) and formic acid (4.1 mL, 108.98 mmol) was stirred at room temperature for 30 minutes. Then, after the reaction temperature was lowered to 0°C, 5-(4-methylpiperazine) was slowly added dropwise. A solution of -1-yl)-2-[(trifluoromethyl)oxy]aniline (common int-1, 2.0 g, 7.27 mmol) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The solution was concentrated and diluted with ethyl acetate (20 mL), and washed with saturated sodium bicarbonate solution (20 mL) and water (20 mL). The organic layer was concentrated to obtain a colorless oil (2.1 g), which could be directly used in related reactions. LC-MS: [M+H] + :304.0; 1 H NMR (400MHz, CDCl3). δ10.00 (s, 1H), 8.32 (d, J = 4.0, 1H), 7.84 (d, J = 4.0Hz ,1H),7.20(dd,J＝8.0,4.0Hz,1H),6.74(dd,J＝8.0,4.0Hz,1H),3.10-3.18(m,4H),2.43-2.45(m,4H), 2.22(s,3H).
制备例3.共用中间体common int-5的合成
Preparation Example 3. Synthesis of common intermediate common int-5
5-氯-4-甲氧基-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(1)的合成：Synthesis of 5-chloro-4-methoxy-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (1) :
将化合物5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(830.0mg,3.02mmol)、2,5-二氯-4-甲氧基嘧啶(1.1g,6.15mmol)溶于无水四氢呋喃(10.0mL)中，0℃氮气保护条件下滴加双三甲基硅基胺基锂(6.0mL,1.0mol/L)，缓慢升温至室温。室温继续搅拌反应1个小时后加20mL饱和氯化铵溶液淬灭，然后用乙酸乙酯萃取(15mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩，经过柱(二氯甲烷:甲醇＝150:1-80:1)(二氯甲烷:甲醇＝10:1,Rf＝0.3)纯化得到白色固体(940mg)。LC-MS:[M+H]+:418.1,420.1。Compound 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (830.0mg, 3.02mmol), 2,5-dichloro-4-methoxypyrimidine (1.1 g, 6.15 mmol) was dissolved in anhydrous tetrahydrofuran (10.0 mL), lithium bistrimethylsilylamide (6.0 mL, 1.0 mol/L) was added dropwise under nitrogen protection at 0°C, and the temperature was slowly raised to room temperature. Continue stirring the reaction at room temperature for 1 hour, add 20 mL of saturated ammonium chloride solution to quench, and then extract with ethyl acetate (15 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a column (dichloromethane). :methanol=150:1-80:1) (dichloromethane:methanol=10:1, Rf=0.3) and purified to obtain a white solid (940 mg). LC-MS: [M+H] + :418.1, 420.1.
5-氯-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-醇(2)的合成：Synthesis of 5-chloro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-ol (2):
将化合物5-氯-4-甲氧基-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(720.0mg,1.72mmol)溶于乙腈(7.0mL)中，滴加三甲基碘硅烷(1.0g,5.00mmol)，80℃条件下搅拌6个小时，加饱和碳酸氢钠溶液至弱碱性，用乙酸乙酯萃取(15mL×3)，合并有机相后无水硫酸钠干燥，过滤，浓缩，经硅胶柱层析(二氯甲烷:甲醇＝25:1-10:1)(Rf＝0.1,二氯甲烷:甲醇＝10:1)纯化得到白色固体(400.0mg)。LC-MS:[M+H]+:404.0,406.0。Compound 5-chloro-4-methoxy-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (720.0 mg , 1.72mmol) was dissolved in acetonitrile (7.0mL), add trimethylsilyl iodide (1.0g, 5.00mmol) dropwise, stir at 80°C for 6 hours, add saturated sodium bicarbonate solution until it becomes weakly alkaline, and use acetic acid to Extract with ethyl ester (15 mL Methane: methanol = 10:1) was purified to obtain a white solid (400.0 mg). LC-MS: [M+H] + :404.0, 406.0.
4,5-二氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-5)的合成： Synthesis of 4,5-dichloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (common int-5) :
将化合物5-氯-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-醇(320.0mg,0.79mmol)溶于三氯氧磷(2.0mL)中，80℃条件下搅拌1个小时。加饱和碳酸氢钠溶液调节反应液至弱碱性，用二氯甲烷萃取(15mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩，经过柱(二氯甲烷:甲醇＝150:1-50:1)(Rf＝0.4,二氯甲烷:甲醇＝10:1)纯化得到白色固体(200mg)。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.55(s,1H),7.23–7.18(m,1H),7.14(d,J＝3.2Hz,1H),6.86–6.81(m,1H),3.18–3.10(m,4H),2.47–2.40(m,4H),2.22(s,3H)；LC-MS:[M+H]+:422.3,424.3。Compound 5-chloro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-ol (320.0 mg, 0.79 mmol ) was dissolved in phosphorus oxychloride (2.0 mL) and stirred at 80°C for 1 hour. Add saturated sodium bicarbonate solution to adjust the reaction solution to weak alkalinity, extract with dichloromethane (15mL×3), dry the combined organic phases over anhydrous sodium sulfate, filter, concentrate, and pass through a column (dichloromethane:methanol=150: 1-50:1) (Rf=0.4, dichloromethane:methanol=10:1) was purified to obtain a white solid (200 mg). 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.55 (s, 1H), 7.23–7.18 (m, 1H), 7.14 (d, J = 3.2Hz, 1H), 6.86–6.81 (m,1H),3.18–3.10(m,4H),2.47–2.40(m,4H),2.22(s,3H); LC-MS: [M+H] + :422.3,424.3.
制备例4.共用中间体common int-6的合成
Preparation Example 4. Synthesis of common intermediate common int-6
4-溴-2-硝基-1-(2,2,2-三氟乙氧基)苯(2)的合成：Synthesis of 4-bromo-2-nitro-1-(2,2,2-trifluoroethoxy)benzene (2):
将化合物4-溴-2-硝基苯酚(5.0g,22.94mmol)、碳酸铯(15.0g,46.04mmol)加到N,N-二甲基甲酰胺(30mL)中，0℃氮气保护条件下缓慢滴加2,2,2-三氟乙基三氟甲磺酸酯(6.4g,27.52mmol)。反应缓慢升温至室温后继续搅拌3个小时。加20mL水稀释后用乙酸乙酯萃取(20mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩，经硅胶柱层析(石油醚:乙酸乙酯＝20:1-10:1)(Rf＝0.4,石油醚:乙酸乙酯＝10:1)纯化得到红色固体(5.5g)。1H NMR(400MHz,CDCl3)δ7.96(d,J＝2.4Hz,1H),7.62(dd,J＝8.8,2.4Hz,1H),6.96(d,J＝9.2Hz,1H),4.40(m,2H)。Add compound 4-bromo-2-nitrophenol (5.0g, 22.94mmol) and cesium carbonate (15.0g, 46.04mmol) to N,N-dimethylformamide (30mL) under nitrogen protection at 0°C. 2,2,2-Trifluoroethyl triflate (6.4g, 27.52mmol) was slowly added dropwise. The reaction slowly warmed to room temperature and continued to stir for 3 hours. Add 20 mL of water to dilute and extract with ethyl acetate (20 mL ) (Rf=0.4, petroleum ether:ethyl acetate=10:1) was purified to obtain a red solid (5.5g). 1 H NMR (400MHz, CDCl 3 ) δ7.96 (d, J = 2.4Hz, 1H), 7.62 (dd, J = 8.8, 2.4Hz, 1H), 6.96 (d, J = 9.2Hz, 1H), 4.40 (m,2H).
1-甲基-4-(3-硝基-4-(2,2,2-三氟乙氧基)苯基)哌嗪(3)的合成：Synthesis of 1-methyl-4-(3-nitro-4-(2,2,2-trifluoroethoxy)phenyl)piperazine (3):
将化合物4-溴-2-硝基-1-(2,2,2-三氟乙氧基)苯(1.9g,6.33mmol)、N-甲基哌嗪(1.0g,9.98mmol)、三(二亚苄基丙酮)二钯(576.9mg,0.63mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(364.5mg,0.63mmol)、碳酸铯(4.1g,12.58mmol)加入到无水二氧六环(20mL)中，100℃氮气保护条件下反应16个小时。加水(10mL)稀释后用乙酸乙酯萃取(15mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩，经硅胶柱层析(二氯甲烷:甲醇＝50:1～20:1)(二氯甲烷:甲醇＝20:1,Rf＝0.2)纯化得到白色固体(1.1g)。LC/MS:[M+H]+:320.1。Compound 4-bromo-2-nitro-1-(2,2,2-trifluoroethoxy)benzene (1.9g, 6.33mmol), N-methylpiperazine (1.0g, 9.98mmol), trifluoroethoxy (Dibenzylideneacetone) dipalladium (576.9mg, 0.63mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (364.5mg, 0.63mmol), cesium carbonate (4.1g , 12.58 mmol) was added to anhydrous dioxane (20 mL), and the reaction was carried out under nitrogen protection at 100°C for 16 hours. Add water (10 mL) to dilute and extract with ethyl acetate (15 mL ) (dichloromethane:methanol=20:1, Rf=0.2) was purified to obtain a white solid (1.1g). LC/MS: [M+H] + :320.1.
5-(4-甲基哌嗪-1-基)-2-(2,2,2-三氟乙氧基)苯胺(common int-6)的合成：Synthesis of 5-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoroethoxy)aniline (common int-6):
将化合物1-甲基-4-(3-硝基-4-(2,2,2-三氟乙氧基)苯基)哌嗪(1.1g,3.45mmol)溶于10mL甲醇中，加50.0mg Pd/C。室温氢气氛围条件下搅拌16个小时，过滤，浓缩，经过柱(二氯甲烷:甲醇＝20:1-10:1)(二氯甲烷:甲醇＝10:1,Rf＝0.35)纯化得到白色固体(800.0mg)。1H NMR(400MHz,CDCl3)δ6.66(d,J＝8.8Hz,1H),6.30(d,J＝2.8Hz,1H),6.21(dd,J＝8.4,2.8Hz,1H),4.21(m,2H),3.72(s,2H),3.06–3.01(m,4H),2.52–2.46(m,4H),2.27(s,3H)；LCMS:[M+H]+:290.1。Dissolve compound 1-methyl-4-(3-nitro-4-(2,2,2-trifluoroethoxy)phenyl)piperazine (1.1g, 3.45mmol) in 10mL methanol, add 50.0 mg Pd/C. Stir under room temperature hydrogen atmosphere for 16 hours, filter, concentrate, and purify through column (dichloromethane: methanol = 20:1-10:1) (dichloromethane: methanol = 10:1, Rf = 0.35) to obtain a white solid (800.0mg). 1 H NMR (400MHz, CDCl 3 ) δ6.66 (d, J = 8.8 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 6.21 (dd, J = 8.4, 2.8 Hz, 1H), 4.21 (m,2H),3.72(s,2H),3.06–3.01(m,4H),2.52–2.46(m,4H),2.27(s,3H); LCMS: [M+H] + :290.1.
制备例5.共用中间体common int-7的合成
Preparation Example 5. Synthesis of common intermediate common int-7
3,3-二甲基-6-(硼酸频哪醇酯)异吲哚-1-酮(2)的合成：Synthesis of 3,3-dimethyl-6-(pinacol borate)isoindol-1-one (2):
向6-溴-3,3-二甲基异吲哚-1-酮(250.0mg,1.04mmol)、联硼酸频那醇酯(396.1mg,1.56mmol)的二氧六环(8mL)悬浮液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(81.1mg,0.10mmol)和醋酸钾(204.1mg,2.08mmol)。反应体系在氮气保护下于80℃搅拌4小时后直接浓缩至干。粗产物用硅胶柱(乙酸乙酯:石油醚＝1:8,Rf＝0.2)纯化得到的棕色固体(280.0mg)。LC-MS:[M+H]+:288.1。To a suspension of 6-bromo-3,3-dimethylisoindol-1-one (250.0 mg, 1.04 mmol), pinacol diborate (396.1 mg, 1.56 mmol) in dioxane (8 mL) Add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (81.1 mg, 0.10 mmol) and potassium acetate (204.1 mg, 2.08 mmol). The reaction system was stirred at 80°C for 4 hours under nitrogen protection and then directly concentrated to dryness. The crude product was purified using a silica gel column (ethyl acetate: petroleum ether = 1:8, Rf = 0.2) to obtain a brown solid (280.0 mg). LC-MS: [M+H] + :288.1.
6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-7)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (common int-7):
在氮气保护下，向3,3-二甲基-6-(硼酸频哪醇酯)异吲哚-1-酮(100.0mg,0.35mmol)和2,4-二氯-5-氟嘧啶(58.4mg,0.35mmol)在二氧六环和水(3:1,8mL)中的搅拌悬浮液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(28.4mg,0.035mmol)以及碳酸钾(96.6mg,0.70mmol)。在氮气保护下70℃搅拌2小时后直接浓缩至干。粗品用硅胶柱纯化(乙酸乙酯:石油醚＝1:5,Rf＝0.3)得到产物为黄色固体(100.0mg)。LC-MS:[M+H]+:292.0,294.0。Under nitrogen protection, 3,3-dimethyl-6-(boronic acid pinacol ester) isoindol-1-one (100.0 mg, 0.35 mmol) and 2,4-dichloro-5-fluoropyrimidine ( 58.4 mg, 0.35 mmol) was added to a stirred suspension in dioxane and water (3:1, 8 mL) [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride Methane complex (28.4 mg, 0.035 mmol) and potassium carbonate (96.6 mg, 0.70 mmol). Stir at 70°C for 2 hours under nitrogen protection and then directly concentrate to dryness. The crude product was purified by silica gel column (ethyl acetate: petroleum ether = 1:5, Rf = 0.3) to obtain the product as a yellow solid (100.0 mg). LC-MS: [M+H] + :292.0, 294.0.
制备例6.共用中间体common int-8的合成
Preparation Example 6. Synthesis of common intermediate common int-8
N-(5-溴-2-(三氟甲氧基)苯基)甲酰胺(2)的合成：Synthesis of N-(5-bromo-2-(trifluoromethoxy)phenyl)carboxamide (2):
将乙酸酐(7.3mL,78.12mmol)和甲酸(4.4mL,117.18mmol)的混合物在室温下搅拌30分钟，然后降至0℃下缓慢加入5-溴-2-(三氟甲氧基)苯胺(2.0g,7.81mmol)的二氯甲烷(3mL)溶液，并在室温下搅拌混合物2小时。将溶液浓缩干再用乙酸乙酯(20mL)稀释并分别用碳酸氢钠饱和溶液(20mL)和水(20mL)洗涤。有机相无水硫酸钠干燥，浓缩得到粗品(2.1g)为无色油状物。LC-MS:[M+H]+:283.9，285.9。A mixture of acetic anhydride (7.3 mL, 78.12 mmol) and formic acid (4.4 mL, 117.18 mmol) was stirred at room temperature for 30 minutes, then lowered to 0°C and slowly added 5-bromo-2-(trifluoromethoxy)aniline. (2.0 g, 7.81 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 2 hours. The solution was concentrated to dryness and diluted with ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (20 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product (2.1g) as colorless oil. LC-MS: [M+H] + : 283.9, 285.9.
6-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-8)的合成：6-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one Synthesis of (common int-8):
将6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-7)(446.3mg,1.53mmol)、N-(5-溴-2-(三氟甲氧基)苯基)甲酰胺(435.0mg,1.53mmol)和碳酸铯(750.0mg,2.30mmol)溶解于乙腈(8mL)中，50℃反应18小时，反应液旋干，粗产品经硅胶柱层析(石油醚:乙酸乙酯＝5:1)得到白色固体(540.0mg)。LC-MS:[M+H]+:511.3,513.3。 6-(2-Chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (common int-7) (446.3 mg, 1.53 mmol), N-(5 -Bromo-2-(trifluoromethoxy)phenyl)formamide (435.0 mg, 1.53 mmol) and cesium carbonate (750.0 mg, 2.30 mmol) were dissolved in acetonitrile (8 mL) and reacted at 50°C for 18 hours. The reaction solution Spin to dryness, and the crude product is subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (540.0 mg). LC-MS: [M+H] + :511.3, 513.3.
制备例7.共用中间体common int-9、common int-10的合成
Preparation Example 7. Synthesis of common intermediates common int-9 and common int-10
螺[环丙烷-1,1'-异吲哚]-3'-酮(2)的合成：Synthesis of spiro[cyclopropane-1,1'-isoindole]-3'-one (2):
将2-氰基苯甲酸乙酯(2.4g,13.70mmol)溶于乙醚中，向反应中滴加钛酸四异丙酯(4.3g,15.13mmol)，然后滴加乙基溴化镁的四氢呋喃溶液(13.7mL,2mol/L)。反应液在室温下搅拌16小时。LCMS监测反应完全。向反应液中加入稀盐酸溶液(20mL,1mol/L)，然后用二氯甲烷萃取(40mL×3)。有机相用饱和食盐水(30mL)洗涤,分离出有机相干燥，过滤，浓缩然后通过柱层析(甲醇:二氯甲烷＝10％,Rf＝0.5)纯化得到产物为白色固体(800.0mg)。LCMS:[M+H]+:160.2。Dissolve ethyl 2-cyanobenzoate (2.4g, 13.70mmol) in diethyl ether, add tetraisopropyl titanate (4.3g, 15.13mmol) dropwise to the reaction, and then add ethylmagnesium bromide in tetrahydrofuran dropwise. Solution (13.7mL, 2mol/L). The reaction solution was stirred at room temperature for 16 hours. LCMS monitored the reaction to be complete. Dilute hydrochloric acid solution (20 mL, 1 mol/L) was added to the reaction solution, and then extracted with dichloromethane (40 mL × 3). The organic phase was washed with saturated brine (30 mL), and the separated organic phase was dried, filtered, concentrated and then purified by column chromatography (methanol:dichloromethane=10%, Rf=0.5) to obtain the product as a white solid (800.0 mg). LCMS: [M+H] + :160.2.
5'-溴螺[环丙烷-1,1'-异吲哚]-3'-酮(3)的合成：Synthesis of 5'-bromospiro[cyclopropane-1,1'-isoindole]-3'-one (3):
将无水三氯化铝(1.3g,9.75mmol)置于三口瓶中并用氮气保护，然后将螺[环丙烷-1,1'-异吲哚]-3'-酮(600.0mg,3.77mmol)溶于1,2-二氯乙烷后加入，然后滴加液溴(783.0mg,4.90mmol)。滴加完后将反应液升至80℃搅拌反应16小时，LCMS显示反应完全。饱和硫代硫酸钠(15mL)溶液淬灭反应，用乙酸乙酯萃取(3×20mL)，合并有机相并用饱和氯化钠洗涤一次(15mL)，无水硫酸钠干燥，浓缩得粗品。粗品经柱层析(乙酸乙酯:石油醚＝0-100％,乙酸乙酯:石油醚＝1:1,Rf＝0.5)得淡黄色固体(400.0mg)。LCMS:[M+H]+:238.1,240.1。Anhydrous aluminum trichloride (1.3g, 9.75mmol) was placed in a three-necked flask and protected with nitrogen, and then spiro[cyclopropane-1,1'-isoindole]-3'-one (600.0mg, 3.77mmol ) was dissolved in 1,2-dichloroethane and then added, and then liquid bromine (783.0 mg, 4.90 mmol) was added dropwise. After the dropwise addition, the reaction solution was raised to 80°C and stirred for 16 hours. LCMS showed that the reaction was complete. The reaction was quenched with saturated sodium thiosulfate (15 mL) solution, extracted with ethyl acetate (3 × 20 mL), the organic phases were combined and washed once with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 0-100%, ethyl acetate: petroleum ether = 1:1, Rf = 0.5) to obtain a light yellow solid (400.0 mg). LCMS: [M+H] + :238.1,240.1.
5'-硼酸频那醇酯螺[环丙烷-1,1'-异吲哚]-3'-酮(common int-9)的合成：Synthesis of 5'-pinacol borate ester spiro[cyclopropane-1,1'-isoindole]-3'-one (common int-9):
将5'-溴螺[环丙烷-1,1'-异吲哚]-3'-酮(400.0mg,1.68mmol)、醋酸钾(495.0mg,5.04mmol)，联硼酸频那醇酯(512.0mg,2.02mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(137.2mg,0.17mmol)溶于1,4-二氧六环(20mL)和水(3mL)中。反应液置于氮气保护下在100℃搅拌16小时，LCMS显示反应完全。反应液倒入水(20mL)中然后用乙酸乙酯萃取(15mL×3)，合并有机相并用饱和氯化钠洗涤一次(15mL)，无水硫酸钠干燥，浓缩得粗品产物为棕色固体(300.0mg)。粗品直接用于下一步反应。LCMS:[M+H]+:286.3。5'-bromospiro[cyclopropane-1,1'-isoindole]-3'-one (400.0mg, 1.68mmol), potassium acetate (495.0mg, 5.04mmol), pinacol diborate (512.0 mg, 2.02mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (137.2mg, 0.17mmol) dissolved in 1,4-dioxane (20mL) and water (3mL). The reaction solution was stirred at 100°C for 16 hours under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (15 mL mg). The crude product was directly used in the next reaction. LCMS: [M+H] + :286.3.
5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚]-3'-酮(common int-10)的合成：Synthesis of 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole]-3'-one (common int-10):
将化合物5'-硼酸频那醇酯螺[环丙烷-1,1'-异吲哚]-3'-酮(200.0mg,0.70mmol)、碳酸铯(455.0mg,1.40mmol)、1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(56.7mg,0.07mmol)、2,4-二氯-5-氟嘧啶(117.1mg,0.70mmol)悬浮于1,4-二氧六环和水(10mL,5:1)中，反应置于氮气保护下于100℃反应6小时。反 应液冷却至室温，倒入水(20mL)中，用乙酸乙酯(15mL×3)萃取。合并有机相并用饱和食盐水(10mL)洗涤，无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析(乙酸乙酯:石油醚＝2:1,Rf＝0.6)纯化得到黄色固体(150.0mg)。LC-MS:[M+H]+:290.2。The compound 5'-pinacol borate spiro[cyclopropane-1,1'-isoindole]-3'-one (200.0mg, 0.70mmol), cesium carbonate (455.0mg, 1.40mmol), 1,1 -Bis(diphenylphosphine)ferrocene palladium dichloromethane complex (56.7 mg, 0.07 mmol), 2,4-dichloro-5-fluoropyrimidine (117.1 mg, 0.70 mmol) were suspended in 1 , 4-dioxane and water (10 mL, 5:1), the reaction was placed under nitrogen protection at 100°C for 6 hours. opposite The solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1, Rf = 0.6) to obtain a yellow solid (150.0 mg ). LC-MS: [M+H] + :290.2.
制备例8.共用中间体common int-11的合成
Preparation Example 8. Synthesis of common intermediate common int-11
二乙烯基膦酸乙酯(2)的合成：Synthesis of ethyl divinylphosphonate (2):
将化合物二氯磷酸乙酯(10.0g,61.39mmol)溶于二氯甲烷(10mL)中，氮气保护下于-65℃下加入乙烯基溴化镁(1M的四氢呋喃溶液)(123.5mL,123.46mmol)，反应液在该温度下搅拌2h。向反应液中缓慢加入乙醇(20mL)后逐渐升至室温。反应液浓缩后经硅胶柱层析(甲醇:二氯甲烷＝0％-15％)纯化后得到浅黄色液体(3.2g)。LC-MS:[M+H]+:147.1。The compound ethyl dichlorophosphate (10.0g, 61.39mmol) was dissolved in dichloromethane (10mL), and vinyl magnesium bromide (1M tetrahydrofuran solution) (123.5mL, 123.46mmol) was added at -65°C under nitrogen protection. ), the reaction solution was stirred at this temperature for 2 h. Ethanol (20 mL) was slowly added to the reaction solution and then gradually warmed to room temperature. The reaction solution was concentrated and purified by silica gel column chromatography (methanol: dichloromethane = 0%-15%) to obtain a light yellow liquid (3.2g). LC-MS: [M+H] + :147.1.
4-乙氧基-1-甲基-1,4-氮杂膦-4-氧化物(3)的合成：Synthesis of 4-ethoxy-1-methyl-1,4-azaphosphine-4-oxide (3):
将二乙烯基膦酸乙酯(2.0g,13.70mmol)与甲胺的THF溶液(1M,20mL)混合后，微波70℃反应20小时。反应液冷却后浓缩得粗品，粗品经硅胶柱层析(甲醇:二氯甲烷＝0％-18％)纯化得到无色液体(1.0g)。LC-MS:[M+H]+:178.1。Ethyl divinylphosphonate (2.0g, 13.70mmol) and a THF solution of methylamine (1M, 20mL) were mixed and then reacted under microwave at 70°C for 20 hours. The reaction solution was cooled and concentrated to obtain a crude product, which was purified by silica gel column chromatography (methanol:dichloromethane=0%-18%) to obtain a colorless liquid (1.0g). LC-MS: [M+H] + :178.1.
1-甲基-1,4-氮杂膦-4-氧化物(common int-11)的合成：Synthesis of 1-methyl-1,4-azaphosphine-4-oxide (common int-11):
将化合物4-乙氧基-1-甲基-1,4-氮杂膦-4-氧化物(1.0g,5.65mmol)溶于四氢呋喃(10mL)中，0℃下缓慢加入氢化铝锂(214.4mg,5.65mmol),氮气保护下0℃反应2小时。向反应液中依次加入水(0.2mL)、15％氢氧化钠水溶液(0.2mL)、水(0.6mL)，室温搅拌半小时后，反应液用硅藻土过滤，乙酸乙酯洗涤滤饼。滤液用无水硫酸钠干燥，过滤浓缩。粗品经反相柱(乙腈:水＝5％-40％)纯化得白色固体(200.0mg)。LC-MS:[M+H]+:134.1。Compound 4-ethoxy-1-methyl-1,4-azaphosphine-4-oxide (1.0g, 5.65mmol) was dissolved in tetrahydrofuran (10mL), and lithium aluminum hydride (214.4 mg, 5.65mmol), reacted at 0°C for 2 hours under nitrogen protection. Water (0.2 mL), 15% sodium hydroxide aqueous solution (0.2 mL), and water (0.6 mL) were added to the reaction solution in sequence. After stirring at room temperature for half an hour, the reaction solution was filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase column (acetonitrile: water = 5%-40%) to obtain a white solid (200.0 mg). LC-MS: [M+H] + :134.1.
制备例9.共用中间体common int-12的合成
Preparation Example 9. Synthesis of common intermediate common int-12
5'-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-12)的合成：5'-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline Synthesis of ]-3'-ketone (common int-12):
将化合物N-(5-溴-2-(三氟甲氧基)苯基)甲酰胺(500mg,1.76mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(463.6mg,1.60mmol)和碳酸铯(1.0g,3.07mmol)溶于乙腈(8 mL)，置换氮气，升温至80℃，搅拌16小时，LCMS监测到原料已反应完，产物是主峰。将反应液旋干，加入水(20mL)溶解，用乙酸乙酯萃取(20mL×3)，合并有机相用饱和食盐水(30mL)洗一次，无水硫酸钠干燥，旋干得粗品，经硅胶柱(甲醇:二氯甲烷＝0-2％,二氯甲烷:甲醇＝10:1,Rf＝0.2)得淡黄色固体(260.0mg)。LC-MS:[M+H]+:509.1,511.1。Compound N-(5-bromo-2-(trifluoromethoxy)phenyl)carboxamide (500mg, 1.76mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[ring Propane-1,1'-isoindolin]-3'-one (common int-10) (463.6mg, 1.60mmol) and cesium carbonate (1.0g, 3.07mmol) were dissolved in acetonitrile (8 mL), replaced with nitrogen, raised the temperature to 80°C, and stirred for 16 hours. LCMS detected that the raw materials had reacted completely and the product was the main peak. Spin the reaction solution to dryness, add water (20 mL) to dissolve, extract with ethyl acetate (20 mL Column (methanol: dichloromethane = 0-2%, dichloromethane: methanol = 10:1, Rf = 0.2) gave a light yellow solid (260.0 mg). LC-MS: [M+H] + :509.1,511.1.
制备例10.共用中间体common int-13的合成
Preparation Example 10. Synthesis of common intermediate common int-13
2-氯-5-(二氟甲氧基)-4-碘吡啶(2)的合成：Synthesis of 2-chloro-5-(difluoromethoxy)-4-iodopyridine (2):
向6-氯-4-碘吡啶-3-醇(4.7g,18.40mmol)的N,N-二甲基甲酰胺(20mL)溶液中依次加入碳酸铯(7.79g,23.92mmol)和2-氯-2,2-二氟乙酸钠(5.61g,36.80mmol)。将混合物在于0℃下搅拌3小时。反应液用乙酸乙酯(200mL)稀释，用水和盐水洗涤，无水硫酸钠干燥，真空浓缩。粗品经硅胶柱层析(乙酸乙酯:石油醚＝1:10)纯化得到白色固体(4.4g)。LC-MS:[M+H]+:306.1,308.1。To a solution of 6-chloro-4-iodopyridin-3-ol (4.7g, 18.40mmol) in N,N-dimethylformamide (20mL) was added cesium carbonate (7.79g, 23.92mmol) and 2-chloro -Sodium 2,2-difluoroacetate (5.61g, 36.80mmol). The mixture was stirred at 0°C for 3 hours. The reaction solution was diluted with ethyl acetate (200 mL), washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain a white solid (4.4g). LC-MS: [M+H] + :306.1, 308.1.
N-(2-氯-5-(二氟甲氧基)吡啶-4-基)-1,1-二苯基甲烷亚胺(3)的合成：Synthesis of N-(2-chloro-5-(difluoromethoxy)pyridin-4-yl)-1,1-diphenylmethaneimine (3):
向2-氯-5-(二氟甲氧基)-4-碘吡啶(2.0g,6.51mmol)和二苯甲酮亚胺(1.4g,7.86mmol)的甲苯(30mL)溶液中依次加入1,1'-联萘-2,2'-双二苯膦(820.0mg,1.31mmol)、三(二亚苄基丙酮)二钯(600.0mg,0.66mmol)和碳酸铯(4.3g,13.19mmol)。混合物在60℃下搅拌1小时，直到原料完全消耗。将反应混合物冷却至室温后浓缩至干。粗品经硅胶柱层析(0-5％的甲醇/二氯甲烷)纯化得到黄色油状物(1.8g)。LC-MS:[M+H]+:359.2,361.2。To a solution of 2-chloro-5-(difluoromethoxy)-4-iodopyridine (2.0g, 6.51mmol) and benzophenone imine (1.4g, 7.86mmol) in toluene (30mL) was added 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (820.0mg, 1.31mmol), tris(dibenzylideneacetone)dipalladium (600.0mg, 0.66mmol) and cesium carbonate (4.3g, 13.19mmol) ). The mixture was stirred at 60°C for 1 hour until the starting material was completely consumed. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to obtain a yellow oil (1.8 g). LC-MS: [M+H] + :359.2, 361.2.
N-(5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-基)-1,1-二苯基甲烷亚胺(4)的合成：Synthesis of N-(5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1,1-diphenylmethaneimine (4):
向N-(2-氯-5-(二氟甲氧基)吡啶-4-基)-1,1-二苯基甲烷亚胺(400.0mg,1.12mmol)和1-甲基哌嗪(0.16mL,1.45mmol)的甲苯(20mL)溶液中依次加入1,1'-联萘-2,2'-双二苯膦(137.0mg,0.22mmol)、三(二亚苄基丙酮)二钯(102.1mg,0.11mmol)和叔丁醇钠(214.3mg,2.23mmol)，混合物在110℃下搅拌1小时。将反应物冷却至室温后真空浓缩，粗品经硅胶柱层析(0-5％的甲醇/二氯甲烷)纯化得到黄色油状物(430.0mg)。LC-MS:[M+H]+:423.2。To N-(2-chloro-5-(difluoromethoxy)pyridin-4-yl)-1,1-diphenylmethane imine (400.0 mg, 1.12 mmol) and 1-methylpiperazine (0.16 mL, 1.45 mmol) in toluene (20 mL) were added successively to a solution of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (137.0 mg, 0.22 mmol), tris(dibenzylideneacetone) dipalladium ( 102.1 mg, 0.11 mmol) and sodium tert-butoxide (214.3 mg, 2.23 mmol), and the mixture was stirred at 110°C for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to obtain a yellow oil (430.0 mg). LC-MS: [M+H] + :423.2.
5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-胺(common int-13)的合成： Synthesis of 5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-amine (common int-13):
在室温下，向N-(5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-基)-1,1-二苯基甲烷亚胺(400.0mg,0.95mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(1mL)，反应液在室温搅拌3小时后浓缩至干。所得残余物悬浮在盐酸(3mL,1N)中，用二氯甲烷(10mL×2)萃取。合并有机相再次用盐酸(1N,3mL)洗涤。合并水层并在减压下浓缩，得到棕色油状物(120.0mg)。LC-MS:[M+H]+:259.2。To N-(5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1,1-diphenylmethaneimine ( Trifluoroacetic acid (1 mL) was added to a solution of 400.0 mg, 0.95 mmol) in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 3 hours and then concentrated to dryness. The obtained residue was suspended in hydrochloric acid (3 mL, 1N), and extracted with dichloromethane (10 mL×2). The combined organic phases were washed again with hydrochloric acid (1N, 3 mL). The aqueous layers were combined and concentrated under reduced pressure to obtain a brown oil (120.0 mg). LC-MS: [M+H] + :259.2.
制备例11.共用中间体common int-14的合成
Preparation Example 11. Synthesis of common intermediate common int-14
4-(3-溴-4-(三氟甲氧基)苯基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(2)的合成：Synthesis of tert-butyl 4-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylate (2):
向2-溴-4-碘-1-(三氟甲氧基)苯(4.8g,13.08mmol)的二甲基亚砜(20mL)溶液中加入2-(羟甲基)哌嗪-1-羧酸叔丁酯(3.4g,15.72mmol)、碳酸铯(5.12g,15.71mmol、碘化亚铜(0.50g,2.63mmol)和L-脯氨酸(0.30g,2.61mmol)，在氮气保护下于60℃搅拌1小时。待反应完全，反应液加水(200mL)稀释，用乙酸乙酯(200mL×3)萃取。合并有机相用饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝8:1)纯化得到黄色油状液体(1.3g)。LC-MS:[M+H]+:455.1,457.1。To a solution of 2-bromo-4-iodo-1-(trifluoromethoxy)benzene (4.8 g, 13.08 mmol) in dimethyl sulfoxide (20 mL) was added 2-(hydroxymethyl)piperazine-1- Tert-butyl carboxylate (3.4g, 15.72mmol), cesium carbonate (5.12g, 15.71mmol), copper iodide (0.50g, 2.63mmol) and L-proline (0.30g, 2.61mmol), under nitrogen protection Stir for 1 hour at 60°C. When the reaction is complete, dilute the reaction solution with water (200mL) and extract with ethyl acetate (200mL×3). The combined organic phases are washed with saturated sodium chloride aqueous solution (100mL) and dried over anhydrous sodium sulfate. , filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain a yellow oily liquid (1.3g). LC-MS: [M+H] + : 455.1, 457.1.
(4-(3-溴-4-(三氟甲氧基)苯基)哌嗪-2-基)甲醇(3)的合成：Synthesis of (4-(3-bromo-4-(trifluoromethoxy)phenyl)piperazin-2-yl)methanol (3):
将4-(3-溴-4-(三氟甲氧基)苯基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(1.3g,2.86mmol)溶解在二氯甲烷(8mL)中，加入三氟乙酸(4mL)并在室温搅拌2小时。反应结束后将反应液旋干得到淡黄色油状物(960.0mg)。粗品产物直接用于下一步反应。LC-MS:[M+H]+:355.1,357.1。Dissolve 4-(3-bromo-4-(trifluoromethoxy)phenyl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.3g, 2.86mmol) in dichloromethane (8 mL), add trifluoroacetic acid (4 mL) and stir at room temperature for 2 hours. After the reaction was completed, the reaction liquid was spun dry to obtain a light yellow oil (960.0 mg). The crude product was directly used in the next reaction. LC-MS: [M+H] + :355.1, 357.1.
(4-(3-溴-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲醇(common int-14)的合成：Synthesis of (4-(3-bromo-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanol (common int-14):
将(4-(3-溴-4-(三氟甲氧基)苯基)哌嗪-2-基)甲醇(390.0mg,1.10mmol)溶于水(2mL)和乙腈(5mL)，然后缓慢加入37％甲醛水溶液(0.5mL)和乙酸(20.0mg,0.33mmol)，搅拌1小时后加入三乙酰氧基硼氢化钠(694.9mg,3.28mmol)。反应液于室温搅拌3小时后，用饱和碳酸氢钠水溶液(20mL)淬灭，用乙酸乙酯(30mL×2)萃取。合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(0-10％的甲醇/二氯甲烷)纯化得到黄色固体(280.0mg)。LC-MS:[M+H]+:369.1。Dissolve (4-(3-bromo-4-(trifluoromethoxy)phenyl)piperazin-2-yl)methanol (390.0mg, 1.10mmol) in water (2mL) and acetonitrile (5mL), then slowly 37% formaldehyde aqueous solution (0.5 mL) and acetic acid (20.0 mg, 0.33 mmol) were added, and after stirring for 1 hour, sodium triacetoxyborohydride (694.9 mg, 3.28 mmol) was added. The reaction solution was stirred at room temperature for 3 hours, then quenched with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (280.0 mg). LC-MS: [M+H] + :369.1.
制备例12.共用中间体common int-15的合成
Preparation Example 12. Synthesis of common intermediate common int-15
5-溴-3-碘-2-甲基苯甲酸甲酯(2)的合成：Synthesis of methyl 5-bromo-3-iodo-2-methylbenzoate (2):
将2-甲基-3-氨基-5-溴苯甲酸甲酯(5.0g,20.48mmol)溶解在6N盐酸(60mL)水溶液中-5℃下，将亚硝酸钠(1.6g,23.19mmol)溶解在水(20mL)中并滴加到反应体系中，待反应30分钟后将碘化钠(3.4g,22.68mmol)溶解在水(20mL)中并缓慢滴加到反应体系中，反应液升到室温并在90℃反应1个小时。冷却反应，用乙酸乙酯(15mL×3)萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，干燥，旋干，粗产品经柱层析(石油醚:乙酸乙酯＝10:1)纯化得到棕色固体(4.8g)。1H NMR(400MHz,DMSO)δ8.25(d,J＝2.0Hz,1H),7.86(d,J＝2.0Hz,1H),3.84(s,3H),2.49(s,3H)。Dissolve 2-methyl-3-amino-5-bromobenzoic acid methyl ester (5.0g, 20.48mmol) in 6N hydrochloric acid (60mL) aqueous solution at -5°C, and dissolve sodium nitrite (1.6g, 23.19mmol) in water (20 mL) and added dropwise to the reaction system. After reacting for 30 minutes, dissolve sodium iodide (3.4g, 22.68mmol) in water (20 mL) and slowly added dropwise to the reaction system. The reaction solution rose to room temperature and react at 90°C for 1 hour. Cool the reaction, extract with ethyl acetate (15 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (20 mL), dry, spin dry, and the crude product is subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) Purification gave a brown solid (4.8g). 1 H NMR (400MHz, DMSO) δ 8.25 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H), 2.49 (s, 3H).
5-溴-2-(溴甲基)-3-碘苯甲酸甲酯(3)的合成：Synthesis of 5-bromo-2-(bromomethyl)-3-iodobenzoic acid methyl ester (3):
将5-溴-3-碘-2-甲基苯甲酸甲酯(4.8g,13.38mmol)溶于四氯化碳(70mL)中，再依次加入N-溴代丁二酰亚胺(2.4g,13.48mmol)和过氧化二苯甲酰(320.0mg,1.32mmol)，升温至80℃反应18小时，冷却反应，溶剂旋干，粗产品经柱层析(乙酸乙酯:石油醚＝1:10)得到黄色固体(5.5g)。1H NMR(400MHz,DMSO)δ8.38(d,J＝2.1Hz,1H),8.00(d,J＝2.1Hz,1H),4.97(s,2H),3.88(s,3H)。Dissolve 5-bromo-3-iodo-2-methylbenzoic acid methyl ester (4.8g, 13.38mmol) in carbon tetrachloride (70mL), and then add N-bromosuccinimide (2.4g) , 13.48mmol) and dibenzoyl peroxide (320.0mg, 1.32mmol), raise the temperature to 80°C and react for 18 hours, cool the reaction, spin the solvent to dryness, and the crude product is subjected to column chromatography (ethyl acetate: petroleum ether = 1: 10) Obtained a yellow solid (5.5g). 1 H NMR (400MHz, DMSO) δ 8.38 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 4.97 (s, 2H), 3.88 (s, 3H).
6-溴-4-碘异吲哚-1-酮(4)的合成：Synthesis of 6-bromo-4-iodoisoindol-1-one (4):
将5-溴-2-(溴甲基)-3-碘苯甲酸甲酯(5.5g,12.68mmol)溶于7M氨气甲醇溶液(60mL)中，室温下搅拌反应2小时。反应液旋干后加入饱和碳酸氢钠水溶液(20mL)稀释，用二氯甲烷(20mL×3)萃取，有机相用无水硫酸钠干燥，过滤后旋干得到黄色固体(4.2g)。LC-MS:[M+H]+:338.1,340.1。5-Bromo-2-(bromomethyl)-3-iodobenzoic acid methyl ester (5.5g, 12.68mmol) was dissolved in 7M ammonia methanol solution (60mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was spin-dried, diluted with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a yellow solid (4.2 g). LC-MS: [M+H] + :338.1, 340.1.
6-溴-4-碘-1-氧代异吲哚-2-甲酸叔丁酯(5)的合成：Synthesis of tert-butyl 6-bromo-4-iodo-1-oxoisoindole-2-carboxylate (5):
将6-溴-4-碘异吲哚-1-酮(4.2g,12.43mmol)、4-二甲氨基吡啶(460.0mg,3.77mmol)及三乙胺(5.0g,49.41mmol)溶解在二氯甲烷(100mL)中，向反应体系缓慢滴加二碳酸二叔丁酯(8.1g,37.11mmol)，室温反应18小时。反应体系用二氯甲烷(50mL)稀释，用水(100mL)洗涤，分离有机相后干燥，过滤，旋干。粗产品经柱层析(石油醚:乙酸乙酯＝5:1)得到白色固体(2.7g).LC-MS:[M-tBu+H]+:382.1,384.1。Dissolve 6-bromo-4-iodoisoindol-1-one (4.2g, 12.43mmol), 4-dimethylaminopyridine (460.0mg, 3.77mmol) and triethylamine (5.0g, 49.41mmol) in di In methyl chloride (100 mL), di-tert-butyl dicarbonate (8.1 g, 37.11 mmol) was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 18 hours. The reaction system was diluted with dichloromethane (50 mL), washed with water (100 mL), the organic phase was separated, dried, filtered, and spun to dryness. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (2.7g). LC-MS: [M- t Bu+H] + : 382.1, 384.1.
6-溴-4-碘-3-甲基-1-氧代异吲哚-2-甲酸叔丁酯(common int-15)的合成：Synthesis of 6-bromo-4-iodo-3-methyl-1-oxoisoindole-2-carboxylic acid tert-butyl ester (common int-15):
将6-溴-4-碘-1-氧代异吲哚-2-甲酸叔丁酯(1.2g,2.74mmol)溶解于四氢呋喃(60mL)中，-70℃下滴加1M双三甲基硅基胺基锂(3.3mL,3.30mmol)，在-70℃下搅拌半个小时。碘甲烷(580.0mg,4.09mmol)滴加到反应体系中，反应升至室温后继续搅拌1小时，饱和氯化铵水溶液(20mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，干燥，旋干，得到白色固体(1.1g)。LC-MS:[M-tBu+H]+:396.0,398.0。Dissolve 6-bromo-4-iodo-1-oxoisoindole-2-carboxylic acid tert-butyl ester (1.2g, 2.74mmol) in tetrahydrofuran (60mL), and add 1M bistrimethylsilane dropwise at -70°C. Lithium amide (3.3 mL, 3.30 mmol) was stirred at -70°C for half an hour. Methyl iodide (580.0 mg, 4.09 mmol) was added dropwise to the reaction system. After the reaction rose to room temperature, stirring was continued for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The phase was washed with saturated aqueous sodium chloride solution (20 mL), dried, and spun to obtain a white solid (1.1 g). LC-MS: [M- tBu +H] + : 396.0, 398.0.
制备例13.共用中间体common int-16的合成
Preparation Example 13. Synthesis of common intermediate common int-16
1-(4-甲氧基-3-硝基苯基)-4-甲基哌嗪(2)的合成：Synthesis of 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine (2):
将化合物4-溴-1-甲氧基-2-硝基苯(500.0mg,2.16mmol)、1-甲基哌嗪(280.6mg,2.80mmol)、2-二环 己基膦-2′,6′-二甲氧基-联苯(88.5mg,0.22mmol)、碳酸铯(1404.2mg,4.31mmol)和三(二亚苄基丙酮)二钯(98.7mg,0.11mmol)溶于二氧六环(8mL)，氮气置换三次，升温至90℃搅拌6小时，LCMS检测原料反应完全。反应液加水(15mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝0-34％,石油醚/乙酸乙酯＝1:1,Rf＝0.2)纯化得黄色油状物(230.0mg)。LC-MS:[M+H]+:252.1。Compound 4-bromo-1-methoxy-2-nitrobenzene (500.0mg, 2.16mmol), 1-methylpiperazine (280.6mg, 2.80mmol), 2-bicyclo Hexylphosphine-2′,6′-dimethoxy-biphenyl (88.5mg, 0.22mmol), cesium carbonate (1404.2mg, 4.31mmol) and tris(dibenzylideneacetone)dipalladium (98.7mg, 0.11mmol) ) was dissolved in dioxane (8 mL), replaced with nitrogen three times, heated to 90°C and stirred for 6 hours. LCMS detected that the reaction of the raw materials was complete. The reaction solution was diluted with water (15 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-34%, petroleum ether/ethyl acetate = 1:1, Rf = 0.2) to obtain a yellow oil (230.0 mg). LC-MS: [M+H] + :252.1.
2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(common int-16)的合成：Synthesis of 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (common int-16):
将化合物1-(4-甲氧基-3-硝基苯基)-4-甲基哌嗪(180.0mg,0.72mmol)和Pd/C(80mg,10％w/w)悬浮于甲醇(5mL)中，氢气置换三次后室温搅拌反应4小时。LCMS监测反应完全后将反应液通过硅藻土过滤，滤饼用乙酸乙酯洗涤3次，滤液旋干后得黄色固体(150.0mg)。LC-MS:[M+H]+:222.2。Compound 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine (180.0 mg, 0.72 mmol) and Pd/C (80 mg, 10% w/w) were suspended in methanol (5 mL ), replace with hydrogen three times, stir and react at room temperature for 4 hours. After LCMS monitored that the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed three times with ethyl acetate, and the filtrate was spin-dried to obtain a yellow solid (150.0 mg). LC-MS: [M+H] + :222.2.
制备例14.共用中间体common int-17的合成
Preparation Example 14. Synthesis of common intermediate common int-17
将5-溴-7-碘-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(600.0mg,1.29mmol)、碳酸钾(533.7mg,3.86mmol)、乙烯三氟硼酸钾(189.7mg,1.42mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(47.1mg,0.065mmol)溶于二氧六环(6mL)和水(1mL)中，氮气保护下，95℃反应2小时，反应液旋干，粗产品经硅胶柱层析(石油醚:乙酸乙酯＝5:1)得到白色固体(470.0mg)。LC-MS:[M-t-Bu+H]+:310.1,312.1。5-Bromo-7-iodo-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (600.0mg, 1.29mmol), potassium carbonate (533.7mg, 3.86mmol), Potassium ethylene trifluoroborate (189.7mg, 1.42mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (47.1mg, 0.065mmol) were dissolved in dioxane (6mL) and water (1 mL), react at 95°C for 2 hours under nitrogen protection, spin the reaction liquid to dryness, and subject the crude product to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (470.0 mg). LC-MS: [Mt-Bu+H] + :310.1, 312.1.
制备例15.共用中间体common int-18的合成
Preparation Example 15. Synthesis of common intermediate common int-18
5-溴-7-碘-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(common int-18)的合成：Synthesis of 5-bromo-7-iodo-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (common int-18):
将6-溴-4-碘-3-甲基-1-氧代异吲哚-2-甲酸叔丁酯(1.1g,2.43mmol)溶解于四氢呋喃(60mL)中，-70℃搅拌下滴加1M双三甲基硅基胺基锂(2.9mL,2.90mmol)，在-70℃下搅拌半个小时。碘甲烷(1.0g,7.05mmol)滴加到反应体系后，反应升到室温并搅拌0.5小时，饱和氯化铵水溶液(50mL)淬灭反应，用乙酸乙酯(50mL×3)萃取，有机相用饱和氯化钠水溶液(100mL)洗涤，干燥，旋干，粗产品经柱层析(石油醚:乙酸乙酯＝10:1)得到白色固体(180.0mg)。LC-MS:[M-tBu+H]+:410.0,412.0。Dissolve 6-bromo-4-iodo-3-methyl-1-oxoisoindole-2-carboxylic acid tert-butyl ester (1.1g, 2.43mmol) in tetrahydrofuran (60mL), and add dropwise with stirring at -70°C. 1M lithium bistrimethylsilylamide (2.9 mL, 2.90 mmol), stir at -70°C for half an hour. After methyl iodide (1.0g, 7.05mmol) was added dropwise to the reaction system, the reaction was raised to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (50mL), and extracted with ethyl acetate (50mL×3). The organic phase Wash with saturated aqueous sodium chloride solution (100 mL), dry, and spin dry. The crude product is subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (180.0 mg). LC-MS: [M- tBu +H] + : 410.0, 412.0.
制备例16.共用中间体common int-19的合成
Preparation Example 16. Synthesis of common intermediate common int-19
6-溴-3,3-二甲基-4-(甲硫基)异吲哚啉-1-酮(common int-19)的合成： Synthesis of 6-bromo-3,3-dimethyl-4-(methylthio)isoindolin-1-one (common int-19):
将化合物5-溴-7-碘-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(1.0g,2.14mmol)、甲硫醇钠(451.4mg,6.44mmol)、碘化亚铜(40.9mg,0.21mmol)、(L)-脯氨酸钠盐(59.8mg,0.43mmol)置于二甲基亚砜(10.0mL)中。反应体系在氮气保护下于90℃搅拌2小时。待反应完全后加水(10.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经硅胶柱层析(二氯甲烷:甲醇＝20:1)纯化得到黄色固体(520.0mg)。LC-MS:[M+H]+:286.0,287.9。The compound 5-bromo-7-iodo-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (1.0g, 2.14mmol) and sodium methylmercaptide (451.4mg, 6.44mmol ), copper iodide (40.9 mg, 0.21 mmol), (L)-proline sodium salt (59.8 mg, 0.43 mmol) were placed in dimethyl sulfoxide (10.0 mL). The reaction system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction was complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a yellow solid (520.0 mg). LC-MS: [M+H] + :286.0, 287.9.
制备例17.共用中间体common int-20的合成
Preparation Example 17. Synthesis of common intermediate common int-20
(E)-5-溴-7-(2-乙氧基乙烯基)-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(1)的合成：Synthesis of (E)-tert-butyl 5-bromo-7-(2-ethoxyvinyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylate (1):
将5-溴-7-碘-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(250.0mg,0.54mmol)、(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(130.0mg,0.66mmol)、磷酸钾(250.0mg,1.18mmol)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(40.0mg,0.05mmol)溶解在二氧六环(5mL)和水(0.5mL)中，氮气保护下，100℃反应3小时。反应体系旋干，粗产品经硅胶柱层析(石油醚:乙酸乙酯＝10:1)得到白色固体(150.0mg)。1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.62(s,1H),6.88(d,J＝12.0Hz,1H),6.04(d,J＝12.4Hz,1H),3.97(q,J＝7.2Hz,2H),1.80(s,6H),1.61(s,9H),1.38(t,J＝7.2Hz,3H)。5-Bromo-7-iodo-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (250.0 mg, 0.54 mmol), (E)-2-(2-ethoxy (vinyl vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130.0 mg, 0.66 mmol), potassium phosphate (250.0 mg, 1.18 mmol) and [ 1,1'-Bis(diphenylphosphine)ferrocene]palladium dichloride (40.0mg, 0.05mmol) was dissolved in dioxane (5mL) and water (0.5mL), under nitrogen protection, 100℃ Reaction takes 3 hours. The reaction system was spun to dryness, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (150.0 mg). 1 H NMR (400MHz, CDCl 3 ) δ7.81 (s, 1H), 7.62 (s, 1H), 6.88 (d, J = 12.0Hz, 1H), 6.04 (d, J = 12.4Hz, 1H), 3.97 (q,J=7.2Hz,2H),1.80(s,6H),1.61(s,9H),1.38(t,J=7.2Hz,3H).
2-(6-溴-3,3-二甲基-1-氧代异吲哚-4-基)乙醛(2)的合成：Synthesis of 2-(6-bromo-3,3-dimethyl-1-oxoisoindol-4-yl)acetaldehyde (2):
将(E)-5-溴-7-(2-乙氧基乙烯基)-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(150.0mg,0.37mmol)溶解于四氢呋喃(3mL)中，室温下滴加浓盐酸(1mL)并搅拌3小时。向反应体系中滴加饱和碳酸氢钠水溶液，直到pH＝9。用乙酸乙酯萃取(5mL×3)，有机相用饱和食盐水(10mL)洗涤，干燥，旋干，得到白色粗产品(80.0mg)。LC-MS:[M+H]+:282.2,284.2。(E)-tert-butyl 5-bromo-7-(2-ethoxyvinyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylate (150.0 mg, 0.37 mmol) Dissolve in tetrahydrofuran (3 mL), add concentrated hydrochloric acid (1 mL) dropwise at room temperature and stir for 3 hours. Saturated aqueous sodium bicarbonate solution was added dropwise to the reaction system until pH=9. Extract with ethyl acetate (5 mL × 3), wash the organic phase with saturated brine (10 mL), dry, and spin dry to obtain a white crude product (80.0 mg). LC-MS: [M+H] + :282.2, 284.2.
6-溴-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(3)的合成：Synthesis of 6-bromo-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (3):
将化合物2-(6-溴-3,3-二甲基-1-氧代异吲哚-4-基)乙醛(80.0mg,0.28mmol)溶解在乙醇(4mL)中，室温加入硼氢化钠(85.0mg,2.25mmol)并反应1小时。冰水(8mL)淬灭反应，用乙酸乙酯(8mL×3)萃取，有机相用饱和氯化钠水溶液(8mL)洗涤，用无水硫酸钠干燥，过滤，浓缩得到白色粗品(80.0mg)。LC-MS:[M+H]+:284.1,286.1。Compound 2-(6-bromo-3,3-dimethyl-1-oxoisoindol-4-yl)acetaldehyde (80.0 mg, 0.28 mmol) was dissolved in ethanol (4 mL), and hydroboration was added at room temperature. Sodium (85.0 mg, 2.25 mmol) and reacted for 1 hour. Quench the reaction with ice water (8 mL), extract with ethyl acetate (8 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (8 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a white crude product (80.0 mg) . LC-MS: [M+H] + :284.1, 286.1.
4-(2-羟乙基)-3,3-二甲基-6-硼酸频那醇酯-异吲哚-1-酮(4)的合成：Synthesis of 4-(2-hydroxyethyl)-3,3-dimethyl-6-boronic acid pinacol ester-isoindol-1-one (4):
将化合物6-溴-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(80.0mg,0.28mmol)，联硼酸频那醇酯(85.0mg, 0.33mmol)、乙酸钾(70.0mg,0.71mmol)及[1,1'-双(二苯基膦)二茂铁]二氯化钯(20.0mg,0.03mmol)悬浮在无水二氧六环(4mL)中，氮气保护下于100℃反应18小时，向体系中加入水(10mL)，然后用乙酸乙酯萃取(10mL×3)，合并乙酸乙酯相用无水硫酸钠干燥，过滤，浓缩得到棕色粗品(80.0mg)。LC-MS:[M+H]+:332.0。Compound 6-bromo-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (80.0 mg, 0.28 mmol), pinacol diborate (85.0 mg, 0.33mmol), potassium acetate (70.0mg, 0.71mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20.0mg, 0.03mmol) were suspended in anhydrous dioxane (4mL), react at 100°C for 18 hours under nitrogen protection, add water (10mL) to the system, and then extract with ethyl acetate (10mL×3), combine the ethyl acetate phases, dry over anhydrous sodium sulfate, and filter. Concentration gave crude brown product (80.0 mg). LC-MS: [M+H] + :332.0.
6-(2-氯-5-氟嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(common int-20)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (common int-20):
将化合物4-(2-羟乙基)-3,3-二甲基-6-硼酸频那醇酯-异吲哚-1-酮(80.0mg,0.24mmol)、2,4-二氯-5-氟嘧啶(50.0mg,0.30mmol)、磷酸钾(125.0mg,0.59mmol)及[1,1'-双(二苯基膦)二茂铁]二氯化钯(17.0mg,0.02mmol)悬浮在无水二氧六环(4mL)和水(0.8mL)中，氮气保护下于100℃下反应2小时。反应体系旋干，粗产品经硅胶柱层析(二氯甲烷:甲醇＝10:1)得到棕色固体(60.0mg)。LC-MS:[M+H]+:336.3。Compound 4-(2-hydroxyethyl)-3,3-dimethyl-6-boronic acid pinacol ester-isoindol-1-one (80.0 mg, 0.24 mmol), 2,4-dichloro- 5-fluoropyrimidine (50.0mg, 0.30mmol), potassium phosphate (125.0mg, 0.59mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (17.0mg, 0.02mmol) Suspended in anhydrous dioxane (4 mL) and water (0.8 mL), react at 100°C for 2 hours under nitrogen protection. The reaction system was spun to dryness, and the crude product was subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to obtain a brown solid (60.0 mg). LC-MS: [M+H] + :336.3.
制备例18.共用中间体common int-21的合成
Preparation Example 18. Synthesis of common intermediate common int-21
4-溴-1-乙氧基-2-硝基苯(2)的合成：Synthesis of 4-bromo-1-ethoxy-2-nitrobenzene (2):
将4-溴-1-氟-2-硝基苯(1.0g,4.55mmol)溶解在N,N-二甲基甲酰胺(10mL)中，向溶液中加入乙醇钠(619.3mg,9.1mmol)。将混合物50℃下搅拌12小时，直到原料完全消耗。反应液冷却，加水(10mL)淬灭反应，用乙酸乙酯萃取(50mL×3)。合并有机相，再用饱和食盐水洗涤(15mL×3)，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(石油醚:乙酸乙酯＝3:1)得到白色固体(1.0g)。LC-MS:[M+H]+:246.2。Dissolve 4-bromo-1-fluoro-2-nitrobenzene (1.0g, 4.55mmol) in N,N-dimethylformamide (10mL), and add sodium ethoxide (619.3mg, 9.1mmol) to the solution . The mixture was stirred at 50°C for 12 hours until the starting materials were completely consumed. The reaction solution was cooled, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 3), and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Separate by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a white solid (1.0g). LC-MS: [M+H] + :246.2.
1-(4-乙氧基-3-硝基苯基)-4-甲基哌嗪(3)的合成：Synthesis of 1-(4-ethoxy-3-nitrophenyl)-4-methylpiperazine (3):
向4-溴-1-乙氧基-2-硝基苯(1.0g,4.06mmol)的二氧六环(10mL)溶液中依次加入1-甲基哌嗪(529.2mg,5.28mmol)、三(二亚苄基丙酮)二钯(186.1mg,0.20mmol)、2-双环己基膦-2',6'-二甲氧基联苯(166.9mg,0.41mmol)和碳酸铯(2648.3mg,8.13mmol)。将所得混合物在氮气保护下于100℃搅拌6小时。待反应液冷却后加水(10mL)稀释，用乙酸乙酯萃取(15mL×3)。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(石油醚:乙酸乙酯＝3:1)得到白色固体(400.0mg)。LC-MS:[M+H]+:266.2。To a solution of 4-bromo-1-ethoxy-2-nitrobenzene (1.0g, 4.06mmol) in dioxane (10mL), 1-methylpiperazine (529.2mg, 5.28mmol), trimethylpiperazine (529.2mg, 5.28mmol) were added in sequence. (dibenzylideneacetone) dipalladium (186.1 mg, 0.20 mmol), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (166.9 mg, 0.41 mmol) and cesium carbonate (2648.3 mg, 8.13 mmol). The resulting mixture was stirred at 100°C for 6 hours under nitrogen protection. After the reaction solution was cooled, water (10 mL) was added to dilute it, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (400.0 mg). LC-MS: [M+H] + :266.2.
2-乙氧基-5-(4-甲基哌嗪-1-基)苯胺(4)的合成：Synthesis of 2-ethoxy-5-(4-methylpiperazin-1-yl)aniline (4):
将1-(4-乙氧基-3-硝基苯基)-4-甲基哌嗪(200.0mg,0.75mmol)和钯碳(80.2mg,10％w/w)溶解在甲醇(3mL)中。插入氢气球并置换三次氢气。将混合物室温搅拌5小时，直到原料完全消耗。将反应液过滤浓缩得到黑色固体(120.0mg)。LC-MS:[M+H]+:236.2。Dissolve 1-(4-ethoxy-3-nitrophenyl)-4-methylpiperazine (200.0 mg, 0.75 mmol) and palladium on carbon (80.2 mg, 10% w/w) in methanol (3 mL) middle. Insert a hydrogen balloon and replace the hydrogen gas three times. The mixture was stirred at room temperature for 5 hours until the starting materials were completely consumed. The reaction solution was filtered and concentrated to obtain a black solid (120.0 mg). LC-MS: [M+H] + :236.2.
制备例19.共用中间体common int-22的合成
Preparation Example 19. Synthesis of common intermediate common int-22
6-溴-4-(二甲基磷酰基)-3-甲基-1-氧代异吲哚啉-2-甲酸叔丁酯(2)的合成：Synthesis of 6-bromo-4-(dimethylphosphoryl)-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (2):
氮气保护下，将化合物6-溴-4-碘-3-甲基-1-氧代异吲哚啉-2-甲酸叔丁酯(1.3g,2.88mmol)、二甲基氧化膦(292.0mg,3.74mmol)、三(二亚苄基丙酮)二钯(265.0mg,0.29mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(335.0mg,0.58mmol)、三乙胺(874.3mg,8.64mmol)溶于1,4-二氧六环(10ml)中，并于室温搅拌3小时。待反应完全，反应液加水(30mL)稀释，用乙酸乙酯(80mL×2)萃取。合并有机相用饱和食盐水洗涤(80mL)，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(0-15％的甲醇/二氯甲烷)纯化得白色固体(550.0mg)。LC-MS:[M+H]+:402.1,404.1。Under nitrogen protection, compound 6-bromo-4-iodo-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (1.3g, 2.88mmol) and dimethylphosphine oxide (292.0mg ,3.74mmol), tris(dibenzylideneacetone)dipalladium (265.0mg, 0.29mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (335.0mg, 0.58mmol) , triethylamine (874.3mg, 8.64mmol) was dissolved in 1,4-dioxane (10ml), and stirred at room temperature for 3 hours. When the reaction is complete, the reaction solution is diluted with water (30 mL) and extracted with ethyl acetate (80 mL × 2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (0-15% methanol/dichloromethane) to obtain a white solid (550.0 mg). LC-MS: [M+H] + :402.1, 404.1.
4-(二甲基磷酰基)-3-甲基-1-氧代-6-硼酸频那醇酯异吲哚啉-2-甲酸叔丁酯(3)的合成：Synthesis of 4-(dimethylphosphoryl)-3-methyl-1-oxo-6-boronic acid pinacol ester isoindoline-2-carboxylic acid tert-butyl ester (3):
氮气保护下，将化合物6-溴-4-(二甲基磷酰基)-3-甲基-1-氧代异吲哚啉-2-甲酸叔丁酯(530.0mg,1.32mmol)、联硼酸频那醇酯(503.0mg,1.98mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(94.0mg,0.13mmol)、醋酸钾(388.0mg,3.95mmol)置于1,4-二氧六环(6ml)，并于90℃反应10小时。反应液冷却浓缩得到黑色固体粗品(1.2g)，直接用于下一步反应。LC-MS:[M+H]+:450.2。Under nitrogen protection, compound 6-bromo-4-(dimethylphosphoryl)-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (530.0 mg, 1.32 mmol), diboronic acid Pinacol ester (503.0mg, 1.98mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (94.0mg, 0.13mmol), potassium acetate (388.0mg, 3.95mmol) Place 1,4-dioxane (6 ml) and react at 90°C for 10 hours. The reaction solution was cooled and concentrated to obtain crude black solid product (1.2g), which was directly used in the next reaction. LC-MS: [M+H] + :450.2.
6-(2-氯-5-氟嘧啶-4-基)-4-(二甲基磷酰基)-3-甲基-1-氧代异吲哚啉-2-甲酸叔丁酯(common int-22)的合成：6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-(dimethylphosphoryl)-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (common int -22) synthesis:
氮气保护下，将化合物4-(二甲基磷酰基)-3-甲基-1-氧代-6-硼酸频那醇酯异吲哚啉-2-甲酸叔丁酯(1.2g,粗品)、2,4-二氯-5-氟嘧啶(239.0mg,1.43mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(87.0mg,0.12mmol)、磷酸钾(763.0mg,3.59mmol)溶于1,4-二氧六环(10ml)，于90℃反应2小时。反应液加水(50mL)稀释，用乙酸乙酯(100mL×2)萃取。合并有机相用饱和氯化钠溶液洗涤(150mL)，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(0-15％的甲醇/二氯甲烷)纯化得白色固体(420.0mg)。LC-MS:[M+H]+:454.1。Under nitrogen protection, compound 4-(dimethylphosphoryl)-3-methyl-1-oxo-6-boronic acid pinacol ester isoindoline-2-carboxylic acid tert-butyl ester (1.2g, crude product) , 2,4-dichloro-5-fluoropyrimidine (239.0mg, 1.43mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (87.0mg, 0.12mmol), phosphoric acid Potassium (763.0 mg, 3.59 mmol) was dissolved in 1,4-dioxane (10 ml) and reacted at 90°C for 2 hours. The reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (0-15% methanol/dichloromethane) to obtain a white solid (420.0 mg). LC-MS: [M+H] + :454.1.
制备例20.共用中间体common int-23的合成
Preparation Example 20. Synthesis of common intermediate common int-23
2-氰基噻吩-3-羧酸甲酯(2)的合成：Synthesis of 2-cyanothiophene-3-carboxylic acid methyl ester (2):
将2-溴噻吩-3-羧酸甲酯(25.0g,113.09mmol)溶于N-甲基吡咯烷酮(150mL)中，加入氰化亚铜(20.2g,225.55mmol)，反应在氮气保护下于120℃搅拌18小时。LCMS监测反应完全。反应液冷却至室温后加水(1000mL)稀释，用乙酸乙酯(500mL×3)萃取。合并有机相用无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化得到淡黄色固体产物(12.0g)。LC-MS:[M+H]+:168.1。Dissolve 2-bromothiophene-3-carboxylic acid methyl ester (25.0g, 113.09mmol) in N-methylpyrrolidone (150mL), add copper cyanide (20.2g, 225.55mmol), and react under nitrogen protection. Stir at 120°C for 18 hours. LCMS monitored the reaction to be complete. The reaction solution was cooled to room temperature, diluted with water (1000 mL), and extracted with ethyl acetate (500 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain a light yellow solid product (12.0g). LC-MS: [M+H] + :168.1.
螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-4'(5'H)-酮(3)的合成：Synthesis of spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (3):
将2-氰基噻吩-3-羧酸甲酯(10.0g,59.82mmol)溶于乙醚(600mL)中，室温下加入钛酸四异丙酯(18.7g,65.79mmol)，然后滴加乙基溴化镁的四氢呋喃溶液(65.8mL,2mol/L,131.60mmol)。滴毕，反应液在室温下搅拌两小时。LCMS检测反应完全。向反应液中加入稀盐酸水溶液(100mL,1mol/L)，用乙酸乙酯萃取(400mL×3)。合并有机相用饱和食盐水(300mL)洗涤，分离出有机相用无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(二氯甲烷:乙酸乙酯＝1:1)纯化得到棕色固体(2.2g)。LCMS:[M+H]+:166.2。Dissolve 2-cyanothiophene-3-carboxylic acid methyl ester (10.0g, 59.82mmol) in diethyl ether (600mL), add tetraisopropyl titanate (18.7g, 65.79mmol) at room temperature, and then add ethyl ether dropwise Magnesium bromide solution in tetrahydrofuran (65.8mL, 2mol/L, 131.60mmol). After the dropping is completed, the reaction solution is stirred at room temperature for two hours. LCMS detection showed that the reaction was complete. Dilute hydrochloric acid aqueous solution (100 mL, 1 mol/L) was added to the reaction solution, and extracted with ethyl acetate (400 mL × 3). The combined organic phases were washed with saturated brine (300 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate=1:1) to obtain a brown solid (2.2g). LCMS: [M+H] + :166.2.
2'-溴螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-4'(5'H)-酮(4)的合成：Synthesis of 2'-bromospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (4):
将螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-4'(5'H)-酮(2.2g,13.32mmol)溶于乙酸/水＝1.2:1(20mL)中，并置于冰浴下冷却，然后缓慢滴加溴素(2.3g,14.39mmol)。滴加完后反应液搅拌0.5小时。LCMS显示反应完全。向反应液中倒入饱和硫代硫酸钠(30mL)水溶液淬灭反应，接着用乙酸乙酯萃取(100mL×3)。合并有机相并用饱和氯化钠洗涤(50mL)，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(二氯甲烷:乙酸乙酯＝1:1)纯化得棕黄色固体(1.5g)。LCMS:[M+H]+:244.2,246.2。Dissolve spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (2.2g, 13.32mmol) in acetic acid/water = 1.2:1 (20mL ), and place it in an ice bath to cool, then slowly add bromine (2.3g, 14.39mmol) dropwise. After the dropwise addition, the reaction solution was stirred for 0.5 hours. LCMS showed the reaction was complete. A saturated sodium thiosulfate aqueous solution (30 mL) was poured into the reaction solution to quench the reaction, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate=1:1) to obtain a brown solid (1.5g). LCMS: [M+H] + :244.2,246.2.
2'-溴-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(5)的合成：Synthesis of 2'-bromo-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid tert-butyl ester (5) :
将2'-溴螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-4'(5'H)-酮(1.5g,6.14mmol)溶于二氯甲烷(20mL)中，冰浴下冷却后，加入二碳酸二叔丁酯(2.7g,12.37mmol)和三乙胺(1.2g,11.86mmol)，最后加入4-二甲氨基吡啶(80.0mg,0.65mmol)。反应液于室温搅拌1小时。LCMS显示反应完全。反应液直接浓缩得粗品经硅胶柱层析(石油醚:乙酸乙酯＝5:1)纯化得淡黄色固体(930.0mg)。LCMS:[M+H-tBu]+:288.1,290.1。Dissolve 2'-bromospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (1.5g, 6.14mmol) in dichloromethane (20mL ), after cooling in an ice bath, add di-tert-butyl dicarbonate (2.7g, 12.37mmol) and triethylamine (1.2g, 11.86mmol), and finally add 4-dimethylaminopyridine (80.0mg, 0.65mmol) . The reaction solution was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction solution was directly concentrated to obtain a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a light yellow solid (930.0 mg). LCMS: [M+H-tBu] + :288.1,290.1.
4'-氧代-2'-硼酸频那醇酯螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(6)的合成：4'-Oxo-2'-boronic acid pinacol ester spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid tert-butyl ester ( 6) Synthesis:
将2'-溴-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(800.0mg,2.32mmol)、醋酸钾(684.0mg,6.97mmol)、联硼酸频那醇酯(708.0mg,2.79mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(170.0mg,0.23mmol)溶于无水1,4-二氧六环(8mL)中。反应液置于氮气保护下在80℃搅拌0.5小时，LCMS显示反应完全。反应液直接用于下一步反应。LCMS:[M+H-tBu]+:336.2。2'-Bromo-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid tert-butyl ester (800.0 mg, 2.32mmol), potassium acetate (684.0mg, 6.97mmol), pinacol diborate (708.0mg, 2.79mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride ( 170.0 mg, 0.23 mmol) was dissolved in anhydrous 1,4-dioxane (8 mL). The reaction solution was stirred at 80°C for 0.5 hours under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was directly used in the next reaction. LCMS: [M+H- tBu ] + :336.2.
2'-(2-氯-5-氟嘧啶-4-基)-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(common int-23)的合成：2'-(2-Chloro-5-fluoropyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4' Synthesis of H)-tert-butyl carboxylate (common int-23):
氮气保护下，将4'-氧代-2'-硼酸频那醇酯螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(300.0mg,0.77mmol)、磷酸钾(489.0mg,2.30mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(56.1mg,0.077mmol)和2,4-二氯-5-氟嘧啶(128.0mg,0.77mmol)置于1,4-二氧六环和水(8mL,5:1)中，反应液加热至80℃搅拌2小时。LCMS监测反应完全。反应液冷却至室温后加水(20mL)稀释，用乙酸乙酯(15mL×3)萃取。合并有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析(乙酸乙酯:石油醚＝2:1)纯化得到白色固体(150.0mg)。LCMS:[M+H-tBu]+:340.3。 Under nitrogen protection, 4'-oxo-2'-boronic acid pinacol ester spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid Tert-butyl acid ester (300.0mg, 0.77mmol), potassium phosphate (489.0mg, 2.30mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (56.1mg, 0.077mmol) and 2,4-dichloro-5-fluoropyrimidine (128.0 mg, 0.77 mmol) were placed in 1,4-dioxane and water (8 mL, 5:1), and the reaction solution was heated to 80°C and stirred for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1) to obtain a white solid (150.0 mg). LCMS: [M+H-tBu] + :340.3.
实施例1.化合物PR-01-049的合成
Example 1. Synthesis of compound PR-01-049
1-异吲哚酮-6-硼酸频哪醇酯(2)的合成：Synthesis of 1-isoindolinone-6-boronic acid pinacol ester (2):
将化合物6-溴-2,3-二氢-1H-异吲哚-1-酮(500mg,2.36mmol)，联硼酸频那醇酯(898mg,3.54mmol)，乙酸钾(693mg,7.07mmol)，1,1-双(二苯基膦)二茂铁二氯化钯(PdCl2dppf,176mg,0.24mmol)悬浮在无水二氧六环(15mL)中，N2保护下于100℃条件下反应3个小时，向体系中加入水(10mL)，然后用乙酸乙酯萃取(20mL×3)，合并乙酸乙酯相用无水硫酸钠干燥，过滤，浓缩得到粗品，经柱层析(甲醇:二氯甲烷＝1:100到1:50)纯化得到白色固体(280mg)。LC-MS:[M+H]+:260.0。Compound 6-bromo-2,3-dihydro-1H-isoindol-1-one (500mg, 2.36mmol), pinacol diborate (898mg, 3.54mmol), potassium acetate (693mg, 7.07mmol) , 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (PdCl 2 dppf, 176mg, 0.24mmol) was suspended in anhydrous dioxane (15mL), under N 2 protection at 100°C React for 3 hours, add water (10 mL) to the system, and then extract with ethyl acetate (20 mL Methanol: dichloromethane = 1:100 to 1:50) was purified to obtain a white solid (280 mg). LC-MS: [M+H] + :260.0.
6-(2-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)异吲哚-1-酮(PR-01-049)的合成：6-(2-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)isoindol-1-one (PR -01-049) synthesis:
将化合物1-异吲哚酮-6-硼酸频哪醇酯(180mg,0.70mmol)、4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-2,323mg,0.83mmol)、1,1'-双(二苯基膦)二茂铁二氯化钯(Pd(dppf)Cl2,51mg,0.07mmol)、磷酸钾(427mg,2.01mmol)溶于1,4-二氧六环(8mL)与水(0.8mL)的混合溶液中，对体系进行抽真空氮气置换三次，加热至100℃反应5小时，待反应完全，将反应冷却至室温。反应液加水(10mL)稀释，水相用乙酸乙酯(10mL×3)萃取，合并有机相并依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到粗品，经制备分离得白色固体PR-01-049(39.7mg)。1H NMR(400MHz,CD3OD)δ8.61(s,1H),8.54(d,J＝5.3Hz,1H),8.36(d,J＝8.0Hz,1H),8.30(d,J＝2.8Hz,1H),7.74(d,J＝8.0Hz,1H),7.47(d,J＝5.2Hz,1H),7.25(d,J＝8.4Hz,1H),6.76(dd,J＝9.0,2.8Hz,1H),4.55(s,2H),3.48-3.40(m,4H),3.19-3.10(m,4H),2.74(s,3H)；LC-MS:[M+H]+:485.2。Compound 1-isoindolin-6-boronic acid pinacol ester (180 mg, 0.70 mmol), 4-chloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoro Methoxy)phenyl)pyrimidin-2-amine (common int-2,323mg,0.83mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (Pd(dppf)Cl 2 , 51 mg, 0.07 mmol) and potassium phosphate (427 mg, 2.01 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (0.8 mL). The system was evacuated and replaced with nitrogen three times, and heated to 100 °C for 5 hours. When the reaction is complete, cool the reaction to room temperature. The reaction solution was diluted with water (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), and the organic phase was dried with anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain crude product. After preparation and isolation, white solid PR-01-049 (39.7 mg) is obtained. 1 H NMR (400MHz, CD 3 OD) δ8.61 (s, 1H), 8.54 (d, J = 5.3Hz, 1H), 8.36 (d, J = 8.0Hz, 1H), 8.30 (d, J = 2.8 Hz,1H),7.74(d,J＝8.0Hz,1H),7.47(d,J＝5.2Hz,1H),7.25(d,J＝8.4Hz,1H),6.76(dd,J＝9.0,2.8 Hz, 1H), 4.55 (s, 2H), 3.48-3.40 (m, 4H), 3.19-3.10 (m, 4H), 2.74 (s, 3H); LC-MS: [M+H] + : 485.2.
实施例2.化合物PR-01-075的合成
Example 2. Synthesis of compound PR-01-075
3,3-二甲基-6-(2-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)异吲哚-1-酮(PR-01-075)合成： 3,3-Dimethyl-6-(2-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)iso Synthesis of indole-1-one (PR-01-075):
按照化合物PR-01-049类似的步骤以3,3-二甲基-6-硼酸频哪醇酯异吲哚-1-酮为起始原料合成得到白色固体PR-01-075(2.3mg)。1H NMR(400MHz,CD3OD)δ8.53(d,J＝5.1Hz,1H),8.46(s,1H),8.40(d,J＝8.2Hz,1H),8.18(s,1H),7.72(d,J＝7.9Hz,1H),7.44(d,J＝5.3Hz,1H),7.21(d,J＝8.9Hz,1H),6.72(d,J＝8.9Hz,1H),3.27(m,4H),2.63(m,4H),2.34(s,3H),1.58(s,6H)；LCMS:[M+H]+:513.4。Following similar steps to compound PR-01-049, white solid PR-01-075 (2.3 mg) was synthesized using 3,3-dimethyl-6-boronic acid pinacol ester isoindolin-1-one as the starting material. . 1 H NMR (400MHz, CD 3 OD) δ8.53(d,J＝5.1Hz,1H),8.46(s,1H),8.40(d,J＝8.2Hz,1H),8.18(s,1H), 7.72(d,J＝7.9Hz,1H),7.44(d,J＝5.3Hz,1H),7.21(d,J＝8.9Hz,1H),6.72(d,J＝8.9Hz,1H),3.27( m, 4H), 2.63 (m, 4H), 2.34 (s, 3H), 1.58 (s, 6H); LCMS: [M+H] + : 513.4.
实施例3.化合物PR-01-066的合成
Example 3. Synthesis of compound PR-01-066
(5-氧代-6,7-二氢-5H-吡咯并[3,4-b]吡啶-3-基)硼酸(2)的合成：Synthesis of (5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronic acid (2):
将3-溴-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(50.0mg,0.24mmol)，联硼酸频那醇酯(78.7mg,0.31mmol)和醋酸钾(97.4mg,0.99mmol)溶于1,4-二氧六环(2mL)中，再将1,1'-二(二苯膦基)二茂铁二氯化钯(II)(PdCl2dppf,19.2mg,0.026mmol)加入反应液中，氮气置换三次。反应液在80℃搅拌3小时。LCMC检测反应完全。反应液浓缩得粗产品为黑色固体(150mg)，粗品没有做进一步的纯化而直接用于下一步。LCMS:[M+H]+:179.1。3-Bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (50.0 mg, 0.24 mmol), pinacol diborate (78.7 mg, 0.31 mmol) and Potassium acetate (97.4 mg, 0.99 mmol) was dissolved in 1,4-dioxane (2 mL), and then 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (PdCl 2 dppf, 19.2 mg, 0.026 mmol) was added to the reaction solution, and nitrogen was replaced three times. The reaction solution was stirred at 80°C for 3 hours. LCMC detection reaction was complete. The reaction solution was concentrated to obtain a crude product as a black solid (150 mg). The crude product was used directly in the next step without further purification. LCMS: [M+H] + :179.1.
3-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(PR-01-066)的合成：3-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-6,7-dihydro- Synthesis of 5H-pyrrolo[3,4-b]pyridin-5-one (PR-01-066):
将5-氧代-6,7-二氢-5H-吡咯并[3,4-b]吡啶-3-基)硼酸(150.0mg,0.84mmol)，4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-2,200mg,0.52mmol)溶于1,4-二氧六环(3mL)和水(0.5mL)中，再将碳酸钾(42.8mg,0.31mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(8.4mg,0.01mmol)加入反应液中。反应体系用氮气置换三次。反应液在80℃搅拌5小时。LCMS检测反应完全。将反应液倒入水中(5mL)，乙酸乙酯萃取(10mL×3)。有机相合并后干燥浓缩，硅胶柱纯化(二氯甲烷:甲醇＝100:1-6:1,Rf＝0.2)，再反相(碱性)制备得白色固体PR-01-066(22.9mg)。1H NMR(400MHz,DMSO)δ9.47(d,J＝2.0Hz,1H),9.06(s,1H),8.92(s,1H),8.70(d,J＝2.0Hz,1H),8.58(d,J＝4.0Hz,1H),7.64(d,J＝4.0Hz,1H),7.53(d,J＝4.0Hz,1H),7.23(dd,J＝9.1,1.3Hz,1H),6.78(dd,J＝12.0,4.0Hz,1H),4.52(s,2H),3.20-3.11(m,4H),2.48-2.42(m,4H),2.21(s,3H)；LCMS:[M+H]+:486.2。5-Oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronic acid (150.0 mg, 0.84 mmol), 4-chloro-N-(5-(4 -Methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (common int-2, 200 mg, 0.52 mmol) was dissolved in 1,4-dioxane (3 mL ) and water (0.5mL), then add potassium carbonate (42.8mg, 0.31mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.4mg, 0.01mmol) Add to the reaction solution. The reaction system was replaced with nitrogen three times. The reaction solution was stirred at 80°C for 5 hours. LCMS detection showed that the reaction was complete. The reaction solution was poured into water (5 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried and concentrated, purified on a silica gel column (dichloromethane: methanol = 100:1-6:1, Rf = 0.2), and then reversed phase (alkaline) to prepare a white solid PR-01-066 (22.9mg) . 1 H NMR (400MHz, DMSO) δ9.47 (d, J = 2.0 Hz, 1H), 9.06 (s, 1H), 8.92 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.58 ( d,J＝4.0Hz,1H),7.64(d,J＝4.0Hz,1H),7.53(d,J＝4.0Hz,1H),7.23(dd,J＝9.1,1.3Hz,1H),6.78( dd,J＝12.0,4.0Hz,1H),4.52(s,2H),3.20-3.11(m,4H),2.48-2.42(m,4H),2.21(s,3H); LCMS:[M+H ] + :486.2.
实施例4.化合物PR-01-055的合成
Example 4. Synthesis of compound PR-01-055
5-溴-2-甲基噻吩-3-羧酸甲酯(2)的合成：Synthesis of 5-bromo-2-methylthiophene-3-carboxylic acid methyl ester (2):
将化合物2-甲基噻吩-3-羧酸甲酯(2.00g,12.80mmol)、NBS(2.70g,15.17mmol)溶于DMF(20mL)中，室温下反应16小时。向反应液中加入水(15mL)，用正己烷萃取(20mL×3),收集有机相用无水硫酸钠干燥，过滤浓缩得到黄色油状化合物(2.3g)。1H NMR(400MHz,CDCl3)δ7.34(s,1H),3.86(s,3H),2.69(s,3H)。Compounds 2-methylthiophene-3-carboxylic acid methyl ester (2.00g, 12.80mmol) and NBS (2.70g, 15.17mmol) were dissolved in DMF (20mL) and reacted at room temperature for 16 hours. Water (15 mL) was added to the reaction solution, extracted with n-hexane (20 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily compound (2.3 g). 1 H NMR (400MHz, CDCl 3 ) δ 7.34 (s, 1H), 3.86 (s, 3H), 2.69 (s, 3H).
5-溴-2-(二溴甲基)噻吩-3-甲酸甲酯(3)的合成：Synthesis of 5-bromo-2-(dibromomethyl)thiophene-3-carboxylic acid methyl ester (3):
将化合物5-溴-2-甲基噻吩-3-羧酸甲酯(1.00g,4.25mmol)、NBS(1.90g,10.68mmol)、偶氮二异丁腈(AIBN,70.6mg,0.43mmol)溶于四氯化碳(10mL)中，并加热至80℃搅拌16小时。向反应液中加入水(10mL)，用二氯甲烷萃取(10mL×3)，合并有机相用无水硫酸钠干燥，过滤浓缩得到粗品后，经柱层析(石油醚:乙酸乙酯＝100:1)得到白色固体(1.2g)。1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.32(s,1H),3.89(s,3H)。Compound 5-bromo-2-methylthiophene-3-carboxylic acid methyl ester (1.00g, 4.25mmol), NBS (1.90g, 10.68mmol), azobisisobutyronitrile (AIBN, 70.6mg, 0.43mmol) Dissolve in carbon tetrachloride (10 mL), heat to 80°C and stir for 16 hours. Add water (10 mL) to the reaction solution, extract with dichloromethane (10 mL :1) Obtain white solid (1.2g). 1 H NMR (400MHz, CDCl 3 ) δ7.82 (s, 1H), 7.32 (s, 1H), 3.89 (s, 3H).
5-溴-2-甲酰基噻吩-3-羧酸甲酯(4)的合成：Synthesis of 5-bromo-2-formylthiophene-3-carboxylic acid methyl ester (4):
将化合物5-溴-2-(二溴甲基)噻吩-3-甲酸甲酯(1.20g,3.05mmol)、硝酸银(518.1mg,3.05mmol)溶于乙醇(48.8mL)和水(7.2mL)加热至65℃反应6小时。TLC监测原料消失，冷却至室温，滤除固体后收集滤液旋干，得到粗品。加入水(10mL)，乙酸乙酯萃取(10mL×3)，收集有机相用无水硫酸钠干燥，过滤，浓缩得到黄色固体(700mg)。1H NMR(400MHz,CDCl3)δ10.41(s,1H),7.46(d,J＝9.7Hz,1H),3.88(s,3H)。Compound 5-bromo-2-(dibromomethyl)thiophene-3-carboxylic acid methyl ester (1.20g, 3.05mmol) and silver nitrate (518.1mg, 3.05mmol) were dissolved in ethanol (48.8mL) and water (7.2mL ) and heated to 65°C for 6 hours. TLC monitors the disappearance of raw materials, cools to room temperature, filters out the solid, collects the filtrate and spins it dry to obtain crude product. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid (700 mg). 1 H NMR (400MHz, CDCl 3 ) δ 10.41 (s, 1H), 7.46 (d, J = 9.7Hz, 1H), 3.88 (s, 3H).
5-溴-2-(3,4-二甲氧基苄基)氨基)甲基噻吩-3-羧酸甲酯(5)的合成：Synthesis of methyl 5-bromo-2-(3,4-dimethoxybenzyl)amino)methylthiophene-3-carboxylate (5):
将化合物5-溴-2-甲酰基噻吩-3-羧酸甲酯(828mg,3.32mmol)、(3,4-二甲氧基苯基)甲胺(DMBNH2,837.7mg,5.01mmol)溶于二氯甲烷(16.6mL)和冰乙酸(2.07mL)，升温至35℃，搅拌30分钟，之后加入三乙酰氧基硼氢化钠(2.1g,9.91mmol)，继续搅拌18小时。向反应液加入二氯甲烷(5mL)稀释，用水(5mL)和盐水(5mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析(乙酸乙酯:石油醚＝10:1到5:2)纯化得到黄色固体5(624mg)。LC-MS:[M+H]+:400.0。 Dissolve the compound 5-bromo-2-formylthiophene-3-carboxylic acid methyl ester (828 mg, 3.32 mmol) and (3,4-dimethoxyphenyl) methylamine (DMBNH 2 , 837.7 mg, 5.01 mmol). Add dichloromethane (16.6 mL) and glacial acetic acid (2.07 mL), raise the temperature to 35°C, stir for 30 minutes, then add sodium triacetoxyborohydride (2.1 g, 9.91 mmol), and continue stirring for 18 hours. Dichloromethane (5 mL) was added to the reaction solution to dilute, washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purification by column chromatography (ethyl acetate:petroleum ether=10:1 to 5:2) gave yellow solid 5 (624 mg). LC-MS: [M+H] + :400.0.
5-溴-2-(3,4-二甲氧基苄基)氨基)甲基噻吩-3-羧酸(6)的合成：Synthesis of 5-bromo-2-(3,4-dimethoxybenzyl)amino)methylthiophene-3-carboxylic acid (6):
将化合物5-溴-2-(3,4-二甲氧基苄基)氨基)甲基噻吩-3-羧酸甲酯(624mg,1.56mmol)溶于甲醇中(1mL)、加入5M NaOH(3.1mL,15.59mmol)，室温搅拌温5小时。将反应液中的甲醇旋出，加入水(2mL)稀释，用6N盐酸调节溶液pH＝5-6，有固体析出，过滤，真空干燥得黄色固体(510mg)。LC-MS:[M+H]+:386.0。Compound 5-bromo-2-(3,4-dimethoxybenzyl)amino)methylthiophene-3-carboxylic acid methyl ester (624 mg, 1.56 mmol) was dissolved in methanol (1 mL), and 5 M NaOH ( 3.1 mL, 15.59 mmol), stirred at room temperature for 5 hours. Spin out the methanol in the reaction solution, add water (2 mL) to dilute, and adjust the pH of the solution to 5-6 with 6N hydrochloric acid. If a solid precipitates, filter and dry under vacuum to obtain a yellow solid (510 mg). LC-MS: [M+H] + :386.0.
2-溴-5-(3,4-二甲氧基苄基)-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(7)的合成：Synthesis of 2-bromo-5-(3,4-dimethoxybenzyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (7):
将化合物5-溴-2-(3,4-二甲氧基苄基)氨基)甲基噻吩-3-羧酸(510mg,1.32mmol)、1-羟基苯并三唑(268mg,1.98mmol)、TEA(400mg,3.95mmol)溶于DMF(10mL)中，升温至50℃搅拌10分钟，之后加入EDCI(380mg,1.98mmol)，保持50℃搅拌3小时。将反应液用乙酸乙酯稀释(20mL)用水(10mL×2)和饱和食盐水(5mL×2)洗涤，有机相用无水硫酸钠干燥，过滤浓缩，粗品经柱层析(石油醚:乙酸乙酯＝6:1到3:1)纯化得黄色油状物(250mg)。1H NMR(400MHz,CDCl3)δ7.24(s,1H),7.20(d,J＝8.0Hz,1H),6.49-6.41(m,2H),4.67(s,2H),4.28(s,2H),3.83(s,3H),3.79(s,3H)。Compound 5-bromo-2-(3,4-dimethoxybenzyl)amino)methylthiophene-3-carboxylic acid (510mg, 1.32mmol) and 1-hydroxybenzotriazole (268mg, 1.98mmol) , TEA (400mg, 3.95mmol) was dissolved in DMF (10mL), the temperature was raised to 50°C and stirred for 10 minutes, then EDCI (380mg, 1.98mmol) was added, and the mixture was maintained at 50°C and stirred for 3 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with water (10 mL × 2) and saturated brine (5 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to column chromatography (petroleum ether: acetic acid Ethyl ester = 6:1 to 3:1) was purified to obtain a yellow oil (250 mg). 1 H NMR (400MHz, CDCl 3 ) δ7.24 (s, 1H), 7.20 (d, J = 8.0Hz, 1H), 6.49-6.41 (m, 2H), 4.67 (s, 2H), 4.28 (s, 2H),3.83(s,3H),3.79(s,3H).
5-(3,4-二甲氧基苄基)-2-硼酸频哪醇酯-5,6-二氢-4H-噻吩[2,3-c]吡咯-4-酮(8)的合成：Synthesis of 5-(3,4-dimethoxybenzyl)-2-boronic acid pinacol ester-5,6-dihydro-4H-thiophene[2,3-c]pyrrole-4-one (8) :
将化合物2-溴-5-(3,4-二甲氧基苄基)-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(150mg,0.41mmol)、[1,1'-双(二苯基膦)二茂铁]二氯钯(II)(32mg,0.044mmol)、联硼酸频那醇酯(155mg,0.61mmol)、醋酸钾(44mg,0.44mmol)溶于1,4-二氧六环(2mL)中，氮气保护下加热至80℃反应3小时。生成化合物的反应液直接用于下一步反应。LC-MS:[M+H]+:416.0。Compound 2-bromo-5-(3,4-dimethoxybenzyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (150 mg, 0.41 mmol) , [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (32mg, 0.044mmol), pinacol diborate (155mg, 0.61mmol), potassium acetate (44mg, 0.44 mmol) was dissolved in 1,4-dioxane (2 mL), heated to 80°C under nitrogen protection, and reacted for 3 hours. The reaction solution to generate the compound is directly used in the next reaction. LC-MS: [M+H] + :416.0.
5-(3,4-二甲氧基苄基)-2-(2-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-5,6-二氢-4H-噻吩[2,3-c]吡咯-4-酮(9)的合成5-(3,4-Dimethoxybenzyl)-2-(2-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino) Synthesis of pyrimidin-4-yl)-5,6-dihydro-4H-thiophene[2,3-c]pyrrole-4-one (9)
向上述反应液中加入4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-2,85.3mg,0.22mmol)、[1,1'-双(二苯基膦)二茂铁]二氯钯(II)(26mg,0.036mmol)、碳酸钾(99.5mg,0.72mmol)、水(2ml)，氮气保护下加热至80℃反应3小时。加入乙酸乙酯(5mL)稀释，用水(5mL×2)洗，有机相用无水硫酸钠干燥，过滤，浓缩至干,经柱层析(甲醇:二氯甲烷＝0:100到1:10)纯化得黑色油状物(73mg)。LC-MS:[M+H]+:641.0。To the above reaction solution, 4-chloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (common int-2 , 85.3mg, 0.22mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (26mg, 0.036mmol), potassium carbonate (99.5mg, 0.72mmol), water ( 2ml), heated to 80°C for 3 hours under nitrogen protection. Add ethyl acetate (5mL) to dilute, wash with water (5mL×2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate to dryness, and perform column chromatography (methanol:dichloromethane=0:100 to 1:10 ) was purified to obtain black oil (73 mg). LC-MS: [M+H] + :641.0.
2-(2-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-5,6-二氢-4H-噻吩[2,3-c]吡咯-4-酮(PR-01-055)的合成：2-(2-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H -Synthesis of thiophene[2,3-c]pyrrole-4-one (PR-01-055):
将化合物5-[(3,4-二甲氧基苯基)甲基]-2-(2-{[5-(4-甲基哌嗪-1-基)-2-[(三氟甲基)氧基]苯基]氨基}嘧啶-4-基)-5,6-二氢-4H-噻吩[3,2-c]吡咯-4-酮(60mg,0.094mmol)和三乙基硅烷(144.2mg,1.24mmol)溶于三氟乙酸(0.8mL)中，升温至50℃搅拌2小时。用油泵将反应液浓缩至干，经制备分离得到白色固体PR-01-055(0.7mg)。1H NMR(400MHz,CDCl3)δ8.48(d,J＝5.1Hz,1H),8.30(d,J＝2.8Hz,1H),7.85(s,1H),7.43(s,1H),7.16(d,J＝8.4Hz,1H),7.11(d,J＝5.2Hz,1H),6.57(dd,J＝9.0,2.7Hz,1H),6.05(s,1H),4.59(s,2H),3.39-3.29(m,4H),2.67-2.56(m,4H),2.38(s,3H)；LC-MS(ESI):(M+H)+491.4。Compound 5-[(3,4-dimethoxyphenyl)methyl]-2-(2-{[5-(4-methylpiperazin-1-yl)-2-[(trifluoromethyl yl)oxy]phenyl]amino}pyrimidin-4-yl)-5,6-dihydro-4H-thiophene[3,2-c]pyrrole-4-one (60 mg, 0.094 mmol) and triethylsilane (144.2 mg, 1.24 mmol) was dissolved in trifluoroacetic acid (0.8 mL), heated to 50°C and stirred for 2 hours. The reaction solution was concentrated to dryness using an oil pump, and white solid PR-01-055 (0.7 mg) was obtained through preparation and separation. 1 H NMR (400MHz, CDCl 3 ) δ8.48(d,J＝5.1Hz,1H),8.30(d,J＝2.8Hz,1H),7.85(s,1H),7.43(s,1H),7.16 (d,J＝8.4Hz,1H),7.11(d,J＝5.2Hz,1H),6.57(dd,J＝9.0,2.7Hz,1H),6.05(s,1H),4.59(s,2H) ,3.39-3.29(m,4H),2.67-2.56(m,4H),2.38(s,3H); LC-MS(ESI):(M+H) + 491.4.
实施例5.化合物PR-01-054的合成
Example 5. Synthesis of compound PR-01-054
2-(2-羟基丙烷-2-基)噻吩-3-羧酸(2)的合成：Synthesis of 2-(2-hydroxypropan-2-yl)thiophene-3-carboxylic acid (2):
将噻吩-3-羧酸(500.0mg，3.90mmol)溶于四氢呋喃(20mL)，抽真空换氮气三次，将体系冷却至-70℃，缓慢向体系中滴加正丁基锂(6mL,1.6M环己烷溶液,9.60mmol)，同时温度保持在-55℃以下，滴加完成后-70℃温度下继续搅拌反应1小时，接着缓慢加入丙酮(0.38mL,5.17mmol)滴加完毕后，把体系温度升至0℃，在这个温度下继续搅拌反应3小时，反应完毕后，滴加4M盐酸(3mL)，升至室温继续搅拌过夜。反应完全后，通过硅藻土垫过滤反应混合物，并用甲苯洗涤固体。滤液减压浓缩得到黄色液体(434.0mg)。Dissolve thiophene-3-carboxylic acid (500.0 mg, 3.90 mmol) in tetrahydrofuran (20 mL), evacuate and replace with nitrogen three times, cool the system to -70°C, and slowly add n-butyllithium (6 mL, 1.6 M) dropwise to the system. Cyclohexane solution, 9.60mmol), while keeping the temperature below -55°C. After the dropwise addition is completed, continue to stir the reaction at -70°C for 1 hour, then slowly add acetone (0.38mL, 5.17mmol). After the dropwise addition is completed, The temperature of the system rose to 0°C, and the reaction was continued to stir at this temperature for 3 hours. After the reaction was completed, 4M hydrochloric acid (3 mL) was added dropwise, and the mixture was raised to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was filtered through a pad of Celite and the solid was washed with toluene. The filtrate was concentrated under reduced pressure to obtain a yellow liquid (434.0 mg).
5-乙酰基-6,6-二甲基-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(3)的合成：Synthesis of 5-acetyl-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (3):
将2-(2-羟基丙烷-2-基)噻吩-3-羧酸(200.0mg，1.07mmol)溶于乙腈(8mL)，抽真空换氮三次，在室温下往体系中添加三氟化硼乙醚(0.16mL，1.29mmol)，把混合物加热至60℃反应16小时。反应完毕后，旋去溶剂，经柱层析分离(石油醚:乙酸乙酯＝10:1，Rf＝0.6)得到白色固体(75.0mg)。LC-MS:[M+H]+:210.0。Dissolve 2-(2-hydroxypropan-2-yl)thiophene-3-carboxylic acid (200.0 mg, 1.07 mmol) in acetonitrile (8 mL), vacuum and replace nitrogen three times, and add boron trifluoride to the system at room temperature. diethyl ether (0.16 mL, 1.29 mmol), and the mixture was heated to 60°C for reaction for 16 hours. After the reaction was completed, the solvent was removed and separated by column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.6) to obtain a white solid (75.0 mg). LC-MS: [M+H] + :210.0.
6,6-二甲基-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(4)的合成：Synthesis of 6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (4):
将化合物5-乙酰基-6,6-二甲基-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(500.0mg,2.39mmol)，氢氧化钠(286.8mg，7.17mmol)溶于甲醇(15mL)与水(15mL)混合溶液中，室温搅拌2小时。待反应完全，加入1N盐酸溶液调节pH＝5，用乙酸乙酯萃取(15mL×3)三次,合并有机相，用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(二氯甲烷:甲醇＝10:1，Rf＝0.4)得到白色固体(320.0mg)。LC-MS:[M+H]+:168.1。The compound 5-acetyl-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (500.0mg, 2.39mmol), sodium hydroxide ( 286.8 mg, 7.17 mmol) was dissolved in a mixed solution of methanol (15 mL) and water (15 mL), and stirred at room temperature for 2 hours. When the reaction is complete, add 1N hydrochloric acid solution to adjust pH = 5, extract with ethyl acetate (15 mL × 3) three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate by column chromatography (dichloromethane:methanol=10:1, Rf=0.4) to obtain a white solid (320.0 mg). LC-MS: [M+H] + :168.1.
2-溴-6,6-二甲基-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(5)的合成：Synthesis of 2-bromo-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (5):
将化合物6,6-二甲基-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(170.0mg,1.02mmol)，溶于醋酸(2.8mL)与水(2.2mL)混合溶液中，将体系冷却至0℃，往体系中缓慢滴加液溴(179.0mg，1.12mmol)，滴加完毕后，保持0℃继续反应0.5小时。待反应完全，加入水(3mL)淬灭反应，用乙酸乙酯萃取三次，合并有机相，用饱和亚硫酸钠水溶液洗涤，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(二氯甲烷:甲醇＝10:1，Rf＝0.3)得到棕黄色固体(230.0mg)。LC-MS:[M+H]+:245.9。Compound 6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (170.0mg, 1.02mmol) was dissolved in acetic acid (2.8mL) and water (2.2 mL) mixed solution, cool the system to 0°C, and slowly drop liquid bromine (179.0 mg, 1.12 mmol) into the system. After the dropwise addition is completed, keep 0°C and continue the reaction for 0.5 hours. When the reaction is complete, add water (3 mL) to quench the reaction, extract three times with ethyl acetate, combine the organic phases, wash with saturated sodium sulfite aqueous solution, then wash with saturated brine, and finally dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product . Separate by column chromatography (dichloromethane:methanol=10:1, Rf=0.3) to obtain a brown solid (230.0 mg). LC-MS: [M+H] + :245.9.
6,6-二甲基-2-硼酸频哪醇酯-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(6)的合成：Synthesis of 6,6-dimethyl-2-boronic acid pinacol ester-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (6):
将化合物2-溴-6,6-二甲基-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(100.0mg,0.41mmol)，醋酸钾(119.5mg，1.22mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(29.7mg,0.04mmol)，联硼酸频那醇酯(134.0mg， 0.53mmol)溶于1,4-二氧六环(3mL)，对体系进行抽真空换氮气三次，加热至90℃反应2小时，待反应完全，将反应冷却至室温。反应液加水(10mL)稀释，水相用乙酸乙酯(10mL×3)，合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到粗品。经柱层析分离(二氯甲烷：甲醇＝10:1，Rf＝0.3)得到白色固体(26.0mg)。LC-MS:[M+H]+:294.1。Compound 2-bromo-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (100.0mg, 0.41mmol), potassium acetate (119.5mg , 1.22mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (29.7mg, 0.04mmol), pinacol diborate (134.0mg, 0.53 mmol) was dissolved in 1,4-dioxane (3 mL). The system was evacuated and replaced with nitrogen three times, heated to 90°C and reacted for 2 hours. When the reaction was complete, the reaction was cooled to room temperature. The reaction solution was diluted with water (10 mL), and the aqueous phase was washed with ethyl acetate (10 mL The filtrate was concentrated to obtain crude product. Separate by column chromatography (dichloromethane: methanol = 10:1, Rf = 0.3) to obtain a white solid (26.0 mg). LC-MS: [M+H] + :294.1.
6,6-二甲基-2-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-5,6-双氢-4H-噻吩[2,3-c]吡咯-4-酮(PR-01-054)的合成：6,6-Dimethyl-2-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl) Synthesis of -5,6-dihydro-4H-thiophene[2,3-c]pyrrol-4-one (PR-01-054):
将化合物6,6-二甲基-2-硼酸频哪醇酯-5,6-双氢-4H-噻吩并[2,3-c]吡咯-4-酮(26.0mg,0.09mmol),4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-2,41.5mg,0.11mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯(II)(6.5mg,0.01mmol)、磷酸钾(57.3mg,0.27mmol)溶于1,4-二氧六环(1mL)与水(0.1mL))的混合溶液中，对体系进行抽真空换氮气三次，加热至90℃反应2小时，待反应完全，将反应冷却至室温。反应液加水(10mL)稀释，水相用乙酸乙酯萃取(10mL×3)，合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到粗品，经制备分离得白色固体PR-01-054(6.8mg)。1H NMR(400MHz,DMSO)δ8.84(s,1H),8.62(s,1H),8.48(d,J＝5.2Hz,1H),8.05(s,1H),7.66(d,J＝2.8Hz,1H),7.47(d,J＝5.2Hz,1H),7.21(dd,J＝9.0,1.3Hz,1H),6.73(dd,J＝9.1,3.0Hz,1H),3.21(s,4H),2.47(d,J＝4.8Hz,4H),2.22(s,3H),1.52(s,6H)；LC-MS:[M+H]+:519.2。Compound 6,6-dimethyl-2-boronic acid pinacol ester-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (26.0 mg, 0.09 mmol), 4 -Chloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (common int-2, 41.5 mg, 0.11 mmol) , 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (6.5mg, 0.01mmol), potassium phosphate (57.3mg, 0.27mmol) dissolved in 1,4-dioxane (1 mL) and water (0.1 mL)), evacuate the system and replace it with nitrogen three times, heat to 90°C and react for 2 hours. When the reaction is complete, cool the reaction to room temperature. The reaction solution was diluted with water (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL , the filtrate was concentrated to obtain crude product, and white solid PR-01-054 (6.8 mg) was obtained through preparation and isolation. 1 H NMR (400MHz, DMSO) δ8.84 (s, 1H), 8.62 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.05 (s, 1H), 7.66 (d, J = 2.8 Hz,1H),7.47(d,J＝5.2Hz,1H),7.21(dd,J＝9.0,1.3Hz,1H),6.73(dd,J＝9.1,3.0Hz,1H),3.21(s,4H ), 2.47 (d, J=4.8Hz, 4H), 2.22 (s, 3H), 1.52 (s, 6H); LC-MS: [M+H] + : 519.2.
实施例6.化合物PR-01-070的合成
Example 6. Synthesis of compound PR-01-070
6-(2-氯-5-氟嘧啶-4-基)异吲哚-1-酮(2)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)isoindol-1-one (2):
将化合物6-硼酸频哪醇酯异吲哚-1-酮(500mg,1.93mmol)、2,4-二氯-5-氟嘧啶(451.1mg,2.702mmol)、双三苯基膦二氯化钯(135.4mg,0.193mmol)及磷酸钾(1.20g,5.65mmol)溶于1,4-二氧六环(3mL)中，氮气保护下加热至80℃反应16小时，反应液冷却，向反应液中加入二氯甲烷(20mL)稀释并过滤，有机相用水洗涤，合并有机相用无水硫酸钠干燥，浓缩后经柱层析(二氯甲烷/甲醇:10/1Rf＝0.6)纯化。产物溶于5mL二氯甲烷后加入20mL乙酸乙酯并在40℃水浴中蒸发溶剂直至有固体析出，冷却后过滤得到粉红色固体产物(180mg)。LC-MS:[M+H]+:264.0。Compound 6-boronic acid pinacol ester isoindolin-1-one (500 mg, 1.93 mmol), 2,4-dichloro-5-fluoropyrimidine (451.1 mg, 2.702 mmol), and bistriphenylphosphine dichloride Palladium (135.4 mg, 0.193 mmol) and potassium phosphate (1.20 g, 5.65 mmol) were dissolved in 1,4-dioxane (3 mL), heated to 80°C under nitrogen protection, and reacted for 16 hours. The reaction solution was cooled, and the reaction solution was cooled. Dichloromethane (20 mL) was added to the solution to dilute and filter, the organic phase was washed with water, the combined organic phases were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (dichloromethane/methanol: 10/1Rf=0.6). The product was dissolved in 5 mL of methylene chloride, 20 mL of ethyl acetate was added, and the solvent was evaporated in a 40°C water bath until solid precipitated. After cooling, the product was filtered to obtain a pink solid product (180 mg). LC-MS: [M+H] + :264.0.
6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)异吲哚-1-酮(PR-01-070)的合成：6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)isoindole- Synthesis of 1-ketone (PR-01-070):
将化合物6-(2-氯-5-氟嘧啶-4-基)异吲哚-1-酮(160mg,0.61mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1,250.6mg,0.91mmol)、醋酸钯(13.62mg,0.061mmol)、1,1'-联萘-2,2'-双二苯膦(75.6mg,0.12mmol)及碳酸铯(593.2mg,1.82mmol)溶于1,4-二氧六环(2mL)中，氮气保护下加热至100℃反应3小时，反应液冷却，向反应液中加入乙酸乙酯(10mL)稀释，用水和饱和食盐水洗，收集有机 相用无水硫酸钠干燥，反应液经制备分离得到淡黄色固体PR-01-070(36.1mg)。1H NMR(400MHz,DMSO)δ9.07(s,1H),8.73(s,1H),8.64(d,J＝3.5Hz,1H),8.28(s,1H),8.24(d,J＝8.1Hz,1H),7.76(d,J＝8.1Hz,1H),7.55(d,J＝2.9Hz,1H),7.21(d,J＝7.9Hz,1H),6.75(dd,J＝9.1,2.9Hz,1H),4.48(s,2H),3.18-3.14(m,4H),2.48-2.42(m,4H),2.21(s,3H)；LC-MS:[M+H]+:503.1。Compound 6-(2-chloro-5-fluoropyrimidin-4-yl)isoindol-1-one (160 mg, 0.61 mmol), 5-(4-methylpiperazin-1-yl)-2-( Trifluoromethoxy)aniline (common int-1,250.6mg, 0.91mmol), palladium acetate (13.62mg, 0.061mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (75.6mg, 0.12 mmol) and cesium carbonate (593.2 mg, 1.82 mmol) were dissolved in 1,4-dioxane (2 mL), heated to 100°C under nitrogen protection, and reacted for 3 hours. The reaction solution was cooled, and ethyl acetate was added to the reaction solution. (10mL), washed with water and saturated brine, collected organic The phase was dried over anhydrous sodium sulfate, and the reaction solution was separated to obtain light yellow solid PR-01-070 (36.1 mg). 1 H NMR (400MHz, DMSO) δ9.07 (s, 1H), 8.73 (s, 1H), 8.64 (d, J = 3.5Hz, 1H), 8.28 (s, 1H), 8.24 (d, J = 8.1 Hz,1H),7.76(d,J＝8.1Hz,1H),7.55(d,J＝2.9Hz,1H),7.21(d,J＝7.9Hz,1H),6.75(dd,J＝9.1,2.9 Hz, 1H), 4.48 (s, 2H), 3.18-3.14 (m, 4H), 2.48-2.42 (m, 4H), 2.21 (s, 3H); LC-MS: [M+H] + : 503.1.
实施例7.化合物PR-01-069的合成
Example 7. Synthesis of compound PR-01-069
6-(5-氯-2-(甲硫基)嘧啶-4-基)-异吲哚-1-酮(2)的合成：Synthesis of 6-(5-chloro-2-(methylthio)pyrimidin-4-yl)-isoindol-1-one (2):
将化合物4,5-二氯-2-(甲硫基)嘧啶(600mg,3.08mmol)，6-硼酸频哪醇酯-异吲哚-1-酮(956.4mg,3.70mmol)，碳酸钠(815.1mg,7.70mmol)，1,1'-双二苯基膦二茂铁二氯化钯(179.9mg,0.25mmol)溶于1,4-二氧六环(6mL)和水(1.5mL)中，在80℃氮气保护条件下反应2个小时，浓缩反应液后经柱层析(甲醇:二氯甲烷＝1:200-1:100,Rf＝0.4)纯化得到白色固体(650mg)。LC-MS:[M+H]+:292.0。Compound 4,5-dichloro-2-(methylthio)pyrimidine (600mg, 3.08mmol), 6-boronic acid pinacol ester-isoindol-1-one (956.4mg, 3.70mmol), sodium carbonate ( 815.1 mg, 7.70 mmol), 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (179.9 mg, 0.25 mmol) was dissolved in 1,4-dioxane (6 mL) and water (1.5 mL) in, react for 2 hours under nitrogen protection at 80°C. Concentrate the reaction solution and purify it by column chromatography (methanol: dichloromethane = 1:200-1:100, Rf = 0.4) to obtain a white solid (650 mg). LC-MS: [M+H] + :292.0.
6-(5-氯-2-(甲硫基)嘧啶-4-基)-1-氧代异二氢吲哚-2-羧酸叔丁酯(3)的合成：Synthesis of 6-(5-chloro-2-(methylthio)pyrimidin-4-yl)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (3):
将化合物6-(5-氯-2-(甲硫基)嘧啶-4-基)异吲哚-1-酮(650mg,2.23mmol)，4-二甲氨基吡啶(544.4mg,4.46mmol)，三乙胺(451.3mg,4.46mmol)溶于二氯甲烷(8mL)中，0℃条件下加入二碳酸二叔丁酯(972.5mg,4.46mmol)，25℃条件下反应2个小时。加10mL水，加入二氯甲烷(10mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经柱层析(石油醚：乙酸乙酯＝10:1-5:1,Rf＝0.3)纯化得到白色固体3(670mg)。LC-MS:[M-t-Bu+H]+:336.0。Compound 6-(5-chloro-2-(methylthio)pyrimidin-4-yl)isoindol-1-one (650 mg, 2.23 mmol), 4-dimethylaminopyridine (544.4 mg, 4.46 mmol), Triethylamine (451.3 mg, 4.46 mmol) was dissolved in dichloromethane (8 mL), di-tert-butyl dicarbonate (972.5 mg, 4.46 mmol) was added at 0°C, and the reaction was carried out at 25°C for 2 hours. Add 10 mL of water, add dichloromethane (10 mL , Rf = 0.3) and purified to obtain white solid 3 (670 mg). LC-MS: [Mt-Bu+H] + :336.0.
6-(5-氯-2-(甲基磺酰基)嘧啶-4-基)-1-氧代异二氢吲哚-2-羧酸叔丁酯(4)的合成：Synthesis of 6-(5-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (4):
将化合物6-(5-氯-2-(甲硫基)嘧啶-4-基)-1-氧代异二氢吲哚-2-羧酸叔丁酯(670mg,1.71mmol)溶于二氯甲烷(15mL)中，0℃条件慢慢加间氯过氧苯甲酸(1.18g,6.84mmol)，室温条件下反应2小时，反应液中加入饱和碳酸氢钠溶液(3mL)，加5mL水，加入二氯甲烷(5mL×3)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经柱层析(石油醚:乙酸乙酯＝5:1-3:1,Rf＝0.2)纯化得到白色固体(670mg)。LC-MS:[M-Boc+H]+:324.0。Compound 6-(5-chloro-2-(methylthio)pyrimidin-4-yl)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (670 mg, 1.71 mmol) was dissolved in dichloro In methane (15mL), slowly add m-chloroperoxybenzoic acid (1.18g, 6.84mmol) at 0°C, and react at room temperature for 2 hours. Add saturated sodium bicarbonate solution (3mL) to the reaction solution, and add 5mL of water. Dichloromethane (5mL×3) was added for extraction, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1-3:1, Rf = 0.2 ) was purified to obtain a white solid (670 mg). LC-MS: [M-Boc+H] + :324.0.
6-(5-氯-2-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基苯基)氨基)嘧啶-4-基)-1-氧代异吲哚-2-羧酸叔丁酯(5)的合成：6-(5-chloro-2-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxyphenyl)amino)pyrimidin-4-yl)-1-oxoiso Synthesis of indole-2-carboxylic acid tert-butyl ester (5):
向N-[5-(4-甲基哌嗪-1-基)-2-[(三氟甲基)氧基]苯基]甲酰胺(common int-3,107mg,0.35mmol)和6-(5- 氯-2-(甲基磺酰基)嘧啶-4-基)-1-氧代异二氢吲哚-2-羧酸叔丁酯(100mg,0.24mmol)的干燥DMF(4mL)悬浮液中加入碳酸铯(115mg,0.35mmol)。将混合物在70℃下搅拌2小时。将反应液用MeCN/H2O＝1:1的C18反相柱纯化，得到产物(70mg)为黄色固体。LC-MS:[M+H]+:619.2.To N-[5-(4-methylpiperazin-1-yl)-2-[(trifluoromethyl)oxy]phenyl]carboxamide (common int-3, 107 mg, 0.35 mmol) and 6-( 5- To a suspension of chloro-2-(methylsulfonyl)pyrimidin-4-yl)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (100 mg, 0.24 mmol) in dry DMF (4 mL) was added Cesium carbonate (115 mg, 0.35 mmol). The mixture was stirred at 70°C for 2 hours. The reaction solution was purified using a C18 reverse-phase column with MeCN/H 2 O = 1:1 to obtain the product (70 mg) as a yellow solid. LC-MS: [M+H] + :619.2.
6-(5-氯-2-(5-甲基哌嗪-1-基)-2-(三氟甲氧基苯基)氨基)嘧啶-4-基)-异吲哚-1-酮(PR-01-069)的合成：6-(5-chloro-2-(5-methylpiperazin-1-yl)-2-(trifluoromethoxyphenyl)amino)pyrimidin-4-yl)-isoindol-1-one ( PR-01-069) synthesis:
将6-(5-氯-2-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基苯基)氨基)嘧啶-4-基)-1-氧代异吲哚-2-羧酸叔丁酯(62mg,0.10mmol)溶在二氯甲烷(5mL)中，缓慢加入三氟乙酸(0.5mL,6.73mmol)，并在室温下搅拌6小时。该混合物经高效液相色谱纯化，得到产物PR-01-069(37mg)为白色固体。1H NMR(400MHz,DMSO)δ9.30(s,1H),8.72(s,1H),8.62(s,1H),8.06(s,1H),8.01(d,J＝4.0,1H),7.73(d,J＝8.0Hz,1H),7.49(d,J＝4.0Hz,1H),7.19(d,J＝12.0Hz,1H),6.75(dd,J＝8.0,4.0Hz,1H),4.48(s,2H),3.18-3.06(m,4H),2.46-2.36(m,4H),2.21(s,3H).LC-MS[M+H]+:519.1。6-(5-chloro-2-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxyphenyl)amino)pyrimidin-4-yl)-1-oxo Isoindole-2-carboxylic acid tert-butyl ester (62 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL, 6.73 mmol) was slowly added, and stirred at room temperature for 6 hours. The mixture was purified by high performance liquid chromatography to obtain the product PR-01-069 (37 mg) as a white solid. 1 H NMR (400MHz, DMSO) δ9.30 (s, 1H), 8.72 (s, 1H), 8.62 (s, 1H), 8.06 (s, 1H), 8.01 (d, J = 4.0, 1H), 7.73 (d,J＝8.0Hz,1H),7.49(d,J＝4.0Hz,1H),7.19(d,J＝12.0Hz,1H),6.75(dd,J＝8.0,4.0Hz,1H),4.48 (s,2H),3.18-3.06(m,4H),2.46-2.36(m,4H),2.21(s,3H).LC-MS[M+H] + :519.1.
实施例8.化合物PR-01-068的合成
Example 8. Synthesis of compound PR-01-068
6-(5-甲基-2-(甲硫基)嘧啶-4-基)异吲哚-1-酮(2)的合成：Synthesis of 6-(5-methyl-2-(methylthio)pyrimidin-4-yl)isoindol-1-one (2):
将4-氯-5-甲基-2-(甲硫基)嘧啶(200mg,1.15mmol)和6-硼酸频哪醇酯异吲哚-1-酮(297.8mg,1.15mmol)溶于1,4-二氧六环(5mL)和水(0.5mL)中，再将碳酸钾(317.9mg,2.30mmol)和(1,1'-双(二苯基膦基)二茂铁)二氯化钯(Pd(dppf)Cl2,87.8mg,0.12mmol)加入反应液中，氮气置换三次。反应液在80℃搅拌2小时。LCMS检测反应完全，冷却至室温，向反应液倒入水中(5mL)，二氯甲烷萃取(10mL×3)。合并有机相，用10mL盐水洗一次，分液，有机相用无水硫酸钠干燥，过滤，浓缩得到粗产物。粗品经柱层析(乙酸乙酯:石油醚＝0-75％)得棕色固体(190mg)。LC-MS:[M+H]+:272.1。Dissolve 4-chloro-5-methyl-2-(methylthio)pyrimidine (200mg, 1.15mmol) and 6-boronic acid pinacol ester isoindol-1-one (297.8mg, 1.15mmol) in 1, In 4-dioxane (5mL) and water (0.5mL), potassium carbonate (317.9mg, 2.30mmol) and (1,1'-bis(diphenylphosphino)ferrocene) were dichlorinated Palladium (Pd(dppf)Cl 2 , 87.8 mg, 0.12 mmol) was added to the reaction solution, and nitrogen was substituted three times. The reaction solution was stirred at 80°C for 2 hours. LCMS detected that the reaction was complete, cooled to room temperature, poured water (5 mL) into the reaction solution, and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed once with 10 mL of brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 0-75%) to obtain a brown solid (190 mg). LC-MS: [M+H] + :272.1.
6-(5-甲基-2-(甲硫基)嘧啶-4-基)-1-氧异吲哚-2-羧酸叔丁酯(3)的合成：Synthesis of tert-butyl 6-(5-methyl-2-(methylthio)pyrimidin-4-yl)-1-oxoisoindole-2-carboxylate (3):
将化合物6-(5-甲基-2-(甲硫基)嘧啶-4-基)异吲哚-1-酮(190.0mg,0.70mmol)、三乙胺(212.5mg,2.1mmol)、4-二甲氨基吡啶(DMAP,52.5mg,0.43mmol)溶于二氯甲烷(5.0mL)中，在0℃下加入二碳酸二叔丁酯((Boc)2O,93.4mg,0.43mmol)，室温下搅拌5小时。TLC板检测原料反应完(石油醚：乙酸乙酯＝1:1,Rf＝0.4)，向反应液中加入水(5mL)，收集有机相用无水硫酸钠干燥，过滤浓缩得到粗品后，经柱层析(乙酸乙酯:石油醚＝0-30％)得到黄色固体(200.0mg)。LC-MS:[M+H]+:372.1。 Compound 6-(5-methyl-2-(methylthio)pyrimidin-4-yl)isoindol-1-one (190.0 mg, 0.70 mmol), triethylamine (212.5 mg, 2.1 mmol), 4 -Dimethylaminopyridine (DMAP, 52.5 mg, 0.43 mmol) was dissolved in dichloromethane (5.0 mL), and di-tert-butyl dicarbonate ((Boc) 2 O, 93.4 mg, 0.43 mmol) was added at 0°C. Stir at room temperature for 5 hours. TLC plate detects that the raw material reaction is complete (petroleum ether: ethyl acetate = 1:1, Rf = 0.4), add water (5 mL) to the reaction solution, collect the organic phase, dry it over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, Column chromatography (ethyl acetate: petroleum ether = 0-30%) obtained a yellow solid (200.0 mg). LC-MS: [M+H] + :372.1.
6-(5-甲基-2-(甲基磺酰基)嘧啶-4-基)-1-氧异吲哚-2-羧酸叔丁酯(4)的合成：Synthesis of 6-(5-methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1-oxisoindole-2-carboxylic acid tert-butyl ester (4):
将化合物6-(5-甲基-2-(甲硫基)嘧啶-4-基)-1-氧异吲哚-2-羧酸叔丁酯(200.0mg,0.54mmol)溶于二氯甲烷(5mL)，在0℃下加入间氯过氧苯甲酸(m-CPBA,279.6mg,1.62mmol)，随后升至室温搅拌6小时，TLC板检测原料反应完(石油醚:乙酸乙酯＝3:1,Rf＝0.2)向反应液加入饱和碳酸氢钠溶液(5mL)，用二氯甲烷萃取(5mL×3),收集有机相用无水硫酸钠干燥，过滤浓缩得到粗品后，经柱层析经柱层析(乙酸乙酯:石油醚＝0-40％)得到白色固体(189mg)。LC-MS:[M-H]-:402.0。Compound 6-(5-methyl-2-(methylthio)pyrimidin-4-yl)-1-oxisoindole-2-carboxylic acid tert-butyl ester (200.0 mg, 0.54 mmol) was dissolved in dichloromethane (5mL), add m-chloroperoxybenzoic acid (m-CPBA, 279.6mg, 1.62mmol) at 0°C, then raise to room temperature and stir for 6 hours. TLC plate detects that the raw material reaction is complete (petroleum ether: ethyl acetate = 3 :1, Rf = 0.2) Add saturated sodium bicarbonate solution (5mL) to the reaction solution, extract with dichloromethane (5mL×3), collect the organic phase and dry it over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, then pass through column layer Column chromatography (ethyl acetate: petroleum ether = 0-40%) gave a white solid (189 mg). LC-MS: [MH] - :402.0.
6-(5-甲基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧异吲哚-2-羧酸叔丁酯(5)的合成：6-(5-methyl-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1- Synthesis of tert-butyl oxyisoindole-2-carboxylate (5):
将化合物6-(5-甲基-2-(甲基磺酰基)嘧啶-4-基)-1-氧异吲哚-2-羧酸叔丁酯(139.0mg,0.35mmol)、N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)甲酰胺(common int-3,124.3mg,0.41mmol)、碳酸铯(168.4mg,0.52mmol)溶于超干的N,N-二甲基甲酰胺(2mL)中，升温至80℃搅拌4小时。LCMS检测反应完全,反应结束后向反应液加入水(5mL)，乙酸乙酯萃取(10mL×3)，合并有机相用饱和食盐水洗一次，无水硫酸钠干燥，过滤，旋蒸，得到粗品，经反向柱层析(乙腈:水＝5-85％)得到黄色固体(88mg)。LC-MS[M+H]+:599.0。Compound 6-(5-methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1-oxisoindole-2-carboxylic acid tert-butyl ester (139.0 mg, 0.35 mmol), N-( 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)carboxamide (common int-3, 124.3 mg, 0.41 mmol), cesium carbonate (168.4 mg, 0.52 mmol) dissolved In ultra-dry N,N-dimethylformamide (2 mL), the temperature was raised to 80°C and stirred for 4 hours. LCMS detected that the reaction was complete. After the reaction, water (5 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. A yellow solid (88 mg) was obtained by reverse column chromatography (acetonitrile: water = 5-85%). LC-MS[M+H] + :599.0.
6-(5-甲基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)异吲哚-1-酮(PR-01-068)的合成：6-(5-methyl-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)isoindole Synthesis of -1-one (PR-01-068):
将化合物6-(5-甲基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧异吲哚-2-羧酸叔丁酯(83.0mg,0.14mmol)溶于二氯甲烷(2.5mL)中加入三氟乙酸(0.5mL,6.7mmol)室温下搅拌4小时。LCMS检测反应完全，用油泵旋干反应液，经制备得白色固体(41mg)。1H NMR(400MHz,CDCl3)δ8.44(d,J＝2.9Hz,1H),8.40(s,1H),8.16(s,1H),7.95(dd,J＝7.9,1.4Hz,1H),7.61(d,J＝7.9Hz,1H),7.41(s,1H),7.13(dd,J＝9.0,1.3Hz,1H),6.77(s,1H),6.50(dd,J＝9.0,2.9Hz,1H),4.55(s,2H),3.28-3.07(m,4H),2.60-2.49(m,4H),2.34(d,J＝2.4Hz,6H)；LC-MS:[M+H]+:499.7。Compound 6-(5-methyl-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)- 1-Oxoisoindole-2-carboxylic acid tert-butyl ester (83.0 mg, 0.14 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL, 6.7 mmol) was added and the mixture was stirred at room temperature for 4 hours. LCMS detected that the reaction was complete. Use an oil pump to spin the reaction solution dry, and prepare a white solid (41 mg). 1 H NMR (400MHz, CDCl3) δ8.44(d,J＝2.9Hz,1H),8.40(s,1H),8.16(s,1H),7.95(dd,J＝7.9,1.4Hz,1H), 7.61(d,J＝7.9Hz,1H),7.41(s,1H),7.13(dd,J＝9.0,1.3Hz,1H),6.77(s,1H),6.50(dd,J＝9.0,2.9Hz ,1H),4.55(s,2H),3.28-3.07(m,4H),2.60-2.49(m,4H),2.34(d,J＝2.4Hz,6H); LC-MS:[M+H] + :499.7.
实施例9.化合物PR-01-076的合成
Example 9. Synthesis of compound PR-01-076
5-(硼酸频哪醇酯)-2H-异吲哚-1,3-二酮(2)的合成：Synthesis of 5-(pinacol borate)-2H-isoindole-1,3-dione (2):
将5-溴-2H-异吲哚-1,3-二酮(400.0mg,1.77mmol)、联硼酸频那醇酯(675.5mg,2.66mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(145.9mg，0.18mmol)和醋酸钾(347.4mg,3.54mmol)在二氧六环(8mL)中的混合物于90℃下搅拌4小时。反应液用乙酸乙酯(10mL)稀释，用水(12mL)洗涤。将有机相浓缩并通过硅胶柱纯化，(石油醚/乙酸乙酯＝4:1,Rf＝0.2)得到黄色固体产物(300mg)。LC-MS:[M+H]+:274.1。5-Bromo-2H-isoindole-1,3-dione (400.0mg, 1.77mmol), pinacol diborate (675.5mg, 2.66mmol), [1,1'-bis(diphenyl A mixture of phosphine)ferrocene]palladium dichloride dichloromethane complex (145.9 mg, 0.18 mmol) and potassium acetate (347.4 mg, 3.54 mmol) in dioxane (8 mL) was stirred at 90°C for 4 Hour. The reaction solution was diluted with ethyl acetate (10 mL) and washed with water (12 mL). The organic phase was concentrated and purified through a silica gel column (petroleum ether/ethyl acetate=4:1, Rf=0.2) to obtain a yellow solid product (300 mg). LC-MS: [M+H] + :274.1.
2-氨基甲酰基-4-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)苯甲酸(3)的合成： 2-Carbamoyl-4-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)benzoic acid Synthesis of (3):
将5-硼酸频哪醇酯)-2H-异吲哚-1,3-二酮(100mg,0.37mmol)、4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(143.5mg,0.37mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(30.0mg,0.037mmol)和碳酸钾(101mg,0.73mmol)的混合物悬浮于二氧六环-水(3:1,4mL)中，反应液在氮气保护下于70℃搅拌4小时后直接浓缩。粗品经反相柱层析纯化得到黄色固体产物(80mg)。LC-MS:[M+H]+:517.1。5-Boronic acid pinacol ester)-2H-isoindole-1,3-dione (100mg, 0.37mmol), 4-chloro-N-(5-(4-methylpiperazin-1-yl) -2-(Trifluoromethoxy)phenyl)pyrimidin-2-amine (143.5mg, 0.37mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane A mixture of complex (30.0 mg, 0.037 mmol) and potassium carbonate (101 mg, 0.73 mmol) was suspended in dioxane-water (3:1, 4 mL). The reaction solution was stirred at 70°C for 4 hours under nitrogen protection. Then concentrate directly. The crude product was purified by reverse-phase column chromatography to obtain a yellow solid product (80 mg). LC-MS: [M+H] + :517.1.
5-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)异吲哚-1,3-二酮(PR-01-076)的合成：5-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)isoindole-1,3- Synthesis of diketone (PR-01-076):
向2-氨基甲酰基-4-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)苯甲酸(80mg,0.15mmol)，N,N'-羰基二咪唑(37.3mg,0.23mmol)的四氢呋喃(2mL)溶液中缓慢加入三乙胺(47.6mg,0.47mmol)，并在室温下搅拌16小时。反应液浓缩后经制备纯化得到淡黄色固体产物(29mg)。LC-MS:[M+H]+:499.1。To 2-carbamoyl-4-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)benzene To a solution of formic acid (80 mg, 0.15 mmol) and N,N'-carbonyldiimidazole (37.3 mg, 0.23 mmol) in tetrahydrofuran (2 mL), triethylamine (47.6 mg, 0.47 mmol) was slowly added and stirred at room temperature for 16 hours. . The reaction solution was concentrated and purified to obtain a light yellow solid product (29 mg). LC-MS: [M+H] + :499.1.
实施例10.化合物PR-01-067的合成
Example 10. Synthesis of compound PR-01-067
6-溴-3-甲基-吡啶-2-羧酸乙基酯(2)的合成：Synthesis of 6-bromo-3-methyl-pyridine-2-carboxylic acid ethyl ester (2):
将化合物6-溴-3-甲基吡啶甲酸(1.0g,4.63mmol)，碳酸钾(1.6g,11.57mmol)及碘乙烷(867.2mg,5.56mmol)溶于N,N-二甲基甲酰胺(10mL)中。反应液在50℃下搅拌过夜。LCMS和TLC检测反应完全。用饱和氯化铵溶液(40mL)淬灭反应，体系用乙酸乙酯萃取三次(30mL×3)，合并有机相，依次用水和饱和氯化钠溶液洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗产品，经柱层析(乙酸乙酯：石油醚＝1：4，Rf＝0.5)得到淡黄色油状产品(0.96g)。LC-MS:[M+H]+:244.0,246.0。Compound 6-bromo-3-methylpicolinic acid (1.0g, 4.63mmol), potassium carbonate (1.6g, 11.57mmol) and iodoethane (867.2mg, 5.56mmol) were dissolved in N,N-dimethylmethane amide (10 mL). The reaction solution was stirred at 50°C overnight. LCMS and TLC detected that the reaction was complete. The reaction was quenched with saturated ammonium chloride solution (40mL). The system was extracted three times with ethyl acetate (30mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution in sequence, and the organic phase was dried with anhydrous sodium sulfate and filtered. , concentrated to obtain a crude product, and column chromatography (ethyl acetate:petroleum ether=1:4, Rf=0.5) obtained a light yellow oily product (0.96g). LC-MS: [M+H] + :244.0, 246.0.
6-溴-3-(溴甲基)吡啶甲酸乙酯(3)的合成：Synthesis of ethyl 6-bromo-3-(bromomethyl)picolinate (3):
将化合物6-溴-3-甲基吡啶-2-甲酸乙酯(800.0mg,3.28mmol)溶解于四氯化碳(10mL)，加入N-溴代丁二酰亚胺(583.8mg,3.28mmol)，偶氮二异丁腈(AIBN,54.2mg,0.33mmol)，置于80℃油浴中搅拌过夜，LCMS和TLC检测反应完全。然后用饱和氯化铵溶液(40mL)淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，用无水硫酸钠干燥，过滤，浓缩滤液得到粗品，经柱层析(乙酸乙酯:石油醚＝1:4,Rf＝0.4)得到淡黄色油状产品(700.0mg)。LC-MS:[M+H]+:321.9,323.9。Compound 6-bromo-3-methylpyridine-2-carboxylic acid ethyl ester (800.0 mg, 3.28 mmol) was dissolved in carbon tetrachloride (10 mL), and N-bromosuccinimide (583.8 mg, 3.28 mmol) was added ), azobisisobutyronitrile (AIBN, 54.2 mg, 0.33 mmol) was placed in an 80°C oil bath and stirred overnight. LCMS and TLC detected that the reaction was complete. Then it was quenched with saturated ammonium chloride solution (40 mL), extracted three times with ethyl acetate (20 mL Ester: petroleum ether = 1:4, Rf = 0.4) to obtain a light yellow oily product (700.0 mg). LC-MS: [M+H] + :321.9, 323.9.
2-溴-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(4)的合成：Synthesis of 2-bromo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (4):
将化合物6-溴-3-(溴甲基)吡啶甲酸乙酯(700.0mg,2.17mmol)溶于7M氨甲醇(10mL)中，室温下反 应1小时，LCMS和TLC检测反应完全。将析出固体过滤，干燥得到白色固体产品(350.0mg)，LC-MS:[M+H]+:213.0,215.0。Compound 6-bromo-3-(bromomethyl)picolinate ethyl ester (700.0 mg, 2.17 mmol) was dissolved in 7M ammoniamethanol (10 mL) and reacted at room temperature. It should take 1 hour for the reaction to be complete by LCMS and TLC. The precipitated solid was filtered and dried to obtain a white solid product (350.0 mg), LC-MS: [M+H] + : 213.0, 215.0.
2-溴-7-氧代-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-羧酸叔丁酯(5)的合成：Synthesis of 2-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (5):
将化合物2-溴-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(300mg,1.41mmol)溶解于N,N-二甲基甲酰胺(6mL)，加入二碳酸二叔丁酯(460.0mg,2.11mmol)，三乙胺(285.4mg,2.82mmol)，4-二甲氨基吡啶(17.2mg,0.14mmol)，50℃搅拌1小时，LCMS和TLC检测反应完全。然后用饱和氯化铵溶液(40mL)淬灭，体系用乙酸乙酯萃取(30mL×3)，合并有机相，依次用水和饱和氯化钠溶液洗，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到粗品，经柱层析(甲醇:二氯甲烷＝1:20，Rf＝0.6)得到淡黄色固体产品(430.0mg)。LC-MS:[M+H-Boc]+:213.0,215.0。Compound 2-bromo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (300 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (6 mL). Add di-tert-butyl dicarbonate (460.0mg, 2.11mmol), triethylamine (285.4mg, 2.82mmol), 4-dimethylaminopyridine (17.2mg, 0.14mmol), stir at 50°C for 1 hour, and detect by LCMS and TLC. Complete response. Then it was quenched with saturated ammonium chloride solution (40mL), and the system was extracted with ethyl acetate (30mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution in sequence, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, and column chromatography (methanol:dichloromethane=1:20, Rf=0.6) was performed to obtain a light yellow solid product (430.0 mg). LC-MS: [M+H-Boc] + :213.0, 215.0.
7-氧代-2-(三甲基锡基)-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-羧酸叔丁酯(6)的合成：Synthesis of 7-oxo-2-(trimethyltinyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (6):
将化合物2-溴-7-氧代-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-羧酸叔丁酯(300.0mg,0.96mmol)溶于干燥甲苯(5mL)，加入六甲基二锡(629mg,1.92mmol)及四三苯基磷钯(115.6mg,0.10mmol)，氮气置换三次，在100℃下搅拌1.5h，LCMS和TLC检测反应完全。浓缩，爬大板得到黄色油状产品(160.0mg)。LC-MS:[M+H]+:399.0。Compound 2-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (300.0 mg, 0.96 mmol) was dissolved in dry toluene ( 5 mL), add hexamethyldisin (629 mg, 1.92 mmol) and tetrakis triphenylphosphorus palladium (115.6 mg, 0.10 mmol), replace with nitrogen three times, stir at 100°C for 1.5 h, LCMS and TLC detect that the reaction is complete. Concentrate and climb up the plate to obtain a yellow oily product (160.0mg). LC-MS: [M+H] + :399.0.
2-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-7-氧代-5,7-二氢-6H-吡咯[3,4-b]吡啶-6-羧酸叔丁酯(7)的合成：2-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-7-oxo-5, Synthesis of tert-butyl 7-dihydro-6H-pyrrole[3,4-b]pyridine-6-carboxylate (7):
将化合物7-氧代-2-(三甲基锡基)-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-羧酸叔丁酯(160mg,0.40mmol)溶解于甲苯(5mL)，加入4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(155.1mg,0.40mmol)，四三苯基膦钯(46.2mg,0.04mmol)，氮气置换三次，100℃搅拌16小时，然后在用饱和氯化铵溶液(10mL)淬灭，体系用乙酸乙酯萃取(10mL×3)，合并有机相，依次用水和饱和氯化钠溶液洗，有机相用无水硫酸钠干燥，过滤，浓缩，制备TLC纯化得到白色固体(50.0mg)。LC-MS:[M+H]+:586.2。Compound 7-oxo-2-(trimethyltinyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (160 mg, 0.40 mmol) Dissolve in toluene (5 mL), add 4-chloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (155.1 mg ,0.40mmol), tetrakistriphenylphosphine palladium (46.2mg, 0.04mmol), replaced with nitrogen three times, stirred at 100°C for 16 hours, then quenched with saturated ammonium chloride solution (10mL), and the system was extracted with ethyl acetate ( 10 mL×3), combine the organic phases, wash with water and saturated sodium chloride solution in sequence, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by preparative TLC to obtain a white solid (50.0 mg). LC-MS: [M+H] + :586.2.
2-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(PR-01-067)的合成：2-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro- Synthesis of 7H-pyrrolo[3,4-b]pyridin-7-one (PR-01-067):
将化合物2-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-7-氧代-5,7-二氢-6H-吡咯[3,4-b]吡啶-6-羧酸叔丁酯(50mg,0.085mmol)溶解于二氯甲烷(4mL)，加入三氟乙酸(1mL)，25℃搅拌1小时，然后在用饱和碳酸氢钠溶液(10mL)淬灭，体系用乙酸乙酯萃取三次(10mL×3)，合并有机相，依次用水和饱和氯化钠溶液洗，有机相用无水硫酸钠干燥，过滤，浓缩，制备得到白色固体(7.3mg)。LC-MS:[M+H]+:486.1。1H NMR(400MHz,DMSO)δ9.10(s,1H),9.03(s,1H),8.65(d,J＝5.2Hz,1H),8.46(d,J＝8.0Hz,1H),8.23(d,J＝8.0Hz,1H),7.78(d,J＝5.2Hz,1H),7.58(d,J＝2.8Hz,1H),7.23(dd,J＝9.2,1.6Hz,1H),6.78(dd,J＝8.8,2.8Hz,1H),4.49(s,2H),3.21–3.16(m,4H),2.48–2.43(m,4H),2.23(s,3H)；LC-MS:[M+H]+:486.1。Compound 2-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-7-oxo- 5,7-Dihydro-6H-pyrrole[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (50mg, 0.085mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (1mL) was added, 25 °C for 1 hour, and then quenched with saturated sodium bicarbonate solution (10 mL). The system was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water and saturated sodium chloride solution in sequence, and the organic phase was washed with Dry over sodium sulfate, filter, and concentrate to prepare a white solid (7.3 mg). LC-MS: [M+H] + :486.1. 1 H NMR (400MHz, DMSO) δ9.10 (s, 1H), 9.03 (s, 1H), 8.65 (d, J = 5.2Hz, 1H), 8.46 (d, J = 8.0Hz, 1H), 8.23 ( d,J＝8.0Hz,1H),7.78(d,J＝5.2Hz,1H),7.58(d,J＝2.8Hz,1H),7.23(dd,J＝9.2,1.6Hz,1H),6.78( dd,J＝8.8,2.8Hz,1H),4.49(s,2H),3.21–3.16(m,4H),2.48–2.43(m,4H),2.23(s,3H); LC-MS: [M +H] + :486.1.
实施例11.化合物PR-01-071的合成
Example 11. Synthesis of compound PR-01-071
2-(甲硫基)-4-(3-氧代异吲哚-5-基)嘧啶-5-甲腈(2)的合成：Synthesis of 2-(methylthio)-4-(3-oxoisoindol-5-yl)pyrimidine-5-carbonitrile (2):
将4-氯-2-(甲硫基)嘧啶-5-腈(1.00g,5.39mmol)，6-(硼酸频哪醇酯)异吲哚-1-酮(1.5g,5.79mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(437.7mg,0.54mmol)和碳酸钾(2.2g,15.91mmol)溶于1,4-二氧六环中(20mL)中，将反应液氮气置换三次。反应液在100℃搅拌过夜。LCMS检测反应完全。将反应液浓缩后通过柱层析(甲醇:二氯甲烷＝0-10％,甲醇:二氯甲烷＝1:10,Rf＝0.5)纯化得到产物棕色固体(1.35g)。LCMS:[M+H]+:283.2。4-Chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.00g, 5.39mmol), 6-(pinacol borate)isoindol-1-one (1.5g, 5.79mmol), [ 1,1'-Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (437.7mg, 0.54mmol) and potassium carbonate (2.2g, 15.91mmol) were dissolved in 1,4-dichloromethane In 20 mL of oxygen hexane, the reaction liquid was replaced with nitrogen three times. The reaction solution was stirred at 100°C overnight. LCMS detection showed that the reaction was complete. The reaction solution was concentrated and purified by column chromatography (methanol: dichloromethane = 0-10%, methanol: dichloromethane = 1:10, Rf = 0.5) to obtain the product as a brown solid (1.35 g). LCMS: [M+H] + :283.2.
6-(5-氰基-2-(甲硫基)嘧啶-4-基)-1-氧代二氢异吲哚-2-羧酸叔丁酯(3)的合成：Synthesis of 6-(5-cyano-2-(methylthio)pyrimidin-4-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester (3):
将2-(甲硫基)-4-(3-氧代异吲哚啉-5-基)嘧啶-5-甲腈(1.35g,4.78mmol)溶于二氯甲烷(20mL)中并置于冰浴下冷却，然后依次加入二碳酸二叔丁酯(1.57g,7.19mmol)，三乙胺(0.97g,9.59mmol)和4-二甲氨基吡啶(58.6mg,0.48mmol)。反应液逐渐升至室温后继续搅拌3小时，LCMS显示反应完全。将反应液倒入水(20mL)中,用二氯甲烷萃取(20mL×3)，合并有机相并用饱和氯化钠洗涤(15mL),无水硫酸钠干燥，浓缩得粗品。粗品经柱层析(乙酸乙酯:石油醚＝0-50％,乙酸乙酯:石油醚＝1:1,Rf＝0.5)得淡黄色固体(1.1g)。LCMS:[M-t-Bu+H]+:327.3。Dissolve 2-(methylthio)-4-(3-oxoisoindolin-5-yl)pyrimidine-5-carbonitrile (1.35g, 4.78mmol) in dichloromethane (20mL) and place Cool under ice bath, and then add di-tert-butyl dicarbonate (1.57g, 7.19mmol), triethylamine (0.97g, 9.59mmol) and 4-dimethylaminopyridine (58.6mg, 0.48mmol) in sequence. The reaction solution gradually rose to room temperature and continued to stir for 3 hours. LCMS showed that the reaction was complete. Pour the reaction solution into water (20 mL), extract with dichloromethane (20 mL × 3), combine the organic phases and wash with saturated sodium chloride (15 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 0-50%, ethyl acetate: petroleum ether = 1:1, Rf = 0.5) to obtain a light yellow solid (1.1g). LCMS: [Mt-Bu+H] + :327.3.
6-(5-氰基-2-(甲基磺酰基)嘧啶-4-基)-1-氧代二氢异吲哚-2-羧酸叔丁酯(4)的合成：Synthesis of 6-(5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester (4):
将6-(5-氰基-2-(甲硫基)嘧啶-4-基)-1-氧代二氢异吲哚-2-羧酸叔丁酯(450mg,1.18mmol)溶于THF(5mL)和水(5mL)中，过氧硫酸氢钾复合盐(2.17g,6.27mmol)加入到反应液中。反应液在室温下搅拌过夜，LCMS显示反应完全。反应液倒入水(20mL)中然后用乙酸乙酯(10mL×3)萃取，合并有机相并用饱和氯化钠洗涤(15mL),无水硫酸钠干燥，浓缩得粗品产物淡黄色固体(300mg)。LCMS:[M-t-Bu+H]+:359.3。6-(5-cyano-2-(methylthio)pyrimidin-4-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester (450 mg, 1.18 mmol) was dissolved in THF ( 5 mL) and water (5 mL), potassium hydrogen peroxysulfate complex salt (2.17 g, 6.27 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature overnight, and LCMS showed that the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product as a light yellow solid (300 mg). . LCMS: [Mt-Bu+H] + :359.3.
6-(5-氰基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧代二氢异吲哚-2-羧酸叔丁酯(5)的合成：6-(5-cyano-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1- Synthesis of tert-butyl oxodihydroisoindole-2-carboxylate (5):
将N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)甲酰胺(300mg,0.99mmol)，碳酸铯(644.6mg,1.98mmol)溶于N,N-二甲基甲酰胺(5mL)中，将反应液置于-10℃下，6-(5-氰基-2-(甲基磺酰基)嘧啶-4-基)-1-氧代二氢异吲哚-2-羧酸叔丁酯(491.9mg,1.19mmol)溶于N,N-二甲基甲酰胺(5mL)后加入到反应液中。反应液在-10℃下搅拌3小时，LCMS显示反应约10％产物生成但原料消失。反应液倒入水(30mL)中， 用乙酸乙酯萃取(15mL×3)，有机相用饱和食盐水洗涤后分离出有机相。将有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经柱层析(乙酸乙酯:石油醚＝0-50％,乙酸乙酯:石油醚＝1:1,Rf＝0.6)纯化得到黄色固体(30mg)。LCMS:[M+H]+:610.3。Dissolve N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)carboxamide (300mg, 0.99mmol) and cesium carbonate (644.6mg, 1.98mmol) In N,N-dimethylformamide (5 mL), the reaction solution was placed at -10°C, 6-(5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1- Oxoisoindole-2-carboxylic acid tert-butyl ester (491.9 mg, 1.19 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added to the reaction solution. The reaction solution was stirred at -10°C for 3 hours. LCMS showed that about 10% of the product was produced but the raw materials disappeared. Pour the reaction solution into water (30mL). Extract with ethyl acetate (15 mL×3), wash the organic phase with saturated brine, and separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 0-50%, ethyl acetate: petroleum ether = 1:1, Rf = 0.6) to obtain a yellow solid (30 mg). LCMS: [M+H] + :610.3.
2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-4-(3-氧代异吲哚啉-5-基)嘧啶-5-腈(PR-01-071)的合成：2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4-(3-oxoisoindolin-5-yl) Synthesis of pyrimidine-5-nitrile (PR-01-071):
将6-(5-氰基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧代二氢异吲哚-2-羧酸叔丁酯(30mg,0.05mmol)溶于二氯甲烷(2mL)中，三氟乙酸(0.2mL)滴加入到反应液中。反应液在室温下搅拌一小时。LCMS显示反应完全。反应液浓缩后经过制备纯化得到白色固体(2.2mg)。1H NMR(400MHz,DMSO)δ10.15(s,1H),8.93(s,1H),8.75(s,1H),8.19(s,1H),8.12(d,J＝7.6Hz,1H),7.78(d,J＝8.0Hz,1H),7.36-7.17(m,2H),6.88-6.85(m,1H),4.49(s,2H),3.17-3.15(m,4H),2.45-2.33(m,4H),2.21(s,3H)；LCMS:[M+H]+:510.4。6-(5-cyano-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1 - Oxoisoindole-2-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added dropwise to the reaction solution. The reaction was stirred at room temperature for one hour. LCMS showed the reaction was complete. The reaction solution was concentrated and purified to obtain a white solid (2.2 mg). 1 H NMR (400MHz, DMSO) δ10.15 (s, 1H), 8.93 (s, 1H), 8.75 (s, 1H), 8.19 (s, 1H), 8.12 (d, J = 7.6Hz, 1H), 7.78(d,J＝8.0Hz,1H),7.36-7.17(m,2H),6.88-6.85(m,1H),4.49(s,2H),3.17-3.15(m,4H),2.45-2.33( m, 4H), 2.21 (s, 3H); LCMS: [M+H] + : 510.4.
实施例12.化合物PR-01-095的合成
Example 12. Synthesis of compound PR-01-095
3,3-二甲基-6-(硼酸频哪醇酯)异吲哚-1-酮(2)的合成：Synthesis of 3,3-dimethyl-6-(pinacol borate)isoindol-1-one (2):
向6-溴-3,3-二甲基异吲哚-1-酮(250mg,1.04mmol)、联硼酸频那醇酯(396.1mg,1.56mmol)的二氧六环(8mL)悬浮液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(81.1mg,0.10mmol)和醋酸钾(204.1mg,2.08mmol)。反应体系在氮气保护下于80℃搅拌4小时后直接浓缩至干。粗产物用硅胶柱(乙酸乙酯:石油醚＝1:8,Rf＝0.2)纯化得到的棕色固体(280mg)。LC-MS:[M+H]+:288.1。To a suspension of 6-bromo-3,3-dimethylisoindol-1-one (250 mg, 1.04 mmol) and pinacol diborate (396.1 mg, 1.56 mmol) in dioxane (8 mL) [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (81.1 mg, 0.10 mmol) and potassium acetate (204.1 mg, 2.08 mmol) were added. The reaction system was stirred at 80°C for 4 hours under nitrogen protection and then directly concentrated to dryness. The crude product was purified using a silica gel column (ethyl acetate: petroleum ether = 1:8, Rf = 0.2) to obtain a brown solid (280 mg). LC-MS: [M+H] + :288.1.
6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(3)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (3):
在氮气保护下，向3,3-二甲基-6-(硼酸频哪醇酯)异吲哚-1-酮(100mg,0.35mmol)和2,4-二氯-5-氟嘧啶(58.4mg,0.35mmol)在二氧六环和水(3:1,8mL)中的搅拌悬浮液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(28.4mg,0.035mmol)以及碳酸钾(96.6mg,0.70mmol)。在氮气保护下70℃搅拌2小时后直接浓缩至干。粗品用硅胶柱纯化(乙酸乙酯:石油醚＝1:5,Rf＝0.3)得到产物为黄色固体(100mg)。LC-MS:[M+H]+:292.0,294.0。Under nitrogen protection, 3,3-dimethyl-6-(boronic acid pinacol ester) isoindol-1-one (100 mg, 0.35 mmol) and 2,4-dichloro-5-fluoropyrimidine (58.4 mg, 0.35 mmol) to a stirred suspension in dioxane and water (3:1, 8 mL) was added [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride in dichloromethane complex (28.4 mg, 0.035 mmol) and potassium carbonate (96.6 mg, 0.70 mmol). Stir at 70°C for 2 hours under nitrogen protection and then directly concentrate to dryness. The crude product was purified by silica gel column (ethyl acetate: petroleum ether = 1:5, Rf = 0.3) to obtain the product as a yellow solid (100 mg). LC-MS: [M+H] + :292.0, 294.0.
6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-095)的合成：6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-3,3 -Synthesis of dimethylisoindol-1-one (PR-01-095):
氮气保护下向6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(100mg,0.34mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(104mg,0.38mmol)和碳酸铯(223mg,0.68mmol)的二氧六环(6mL)悬浮液中加入1,1'-联萘-2,2'-双二苯膦(BINAP,43.6mg,0.07mmol)和醋酸钯(7.6mg,0.034mmol)。在氮气保护下于 100℃搅拌反应16小时后直接浓缩至干。粗品经制备液相色谱纯化得到白色固体(31mg)。1H NMR(400MHz,DMSO)δ9.07(s,1H),8.82(s,1H),8.64(d,J＝3.2Hz 1H),8.21-8.19(m,2H),7.81(d,J＝8.0Hz,1H),7.54(s,1H),7.20(d,J＝9.2Hz,1H),6.75(d,J＝9.2Hz,1H),3.16(s,4H),2.44(s,4H),2.21(s,3H),1.49(s,6H)；LC-MS:[M+H]+:531.6。Under nitrogen protection, 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (100 mg, 0.34 mmol), 5-(4-methylpiperdine) To a suspension of oxazin-1-yl)-2-(trifluoromethoxy)aniline (104 mg, 0.38 mmol) and cesium carbonate (223 mg, 0.68 mmol) in dioxane (6 mL) was added Naphthalene-2,2'-bisdiphenylphosphine (BINAP, 43.6 mg, 0.07 mmol) and palladium acetate (7.6 mg, 0.034 mmol). under nitrogen protection at The reaction was stirred at 100°C for 16 hours and then directly concentrated to dryness. The crude product was purified by preparative liquid chromatography to obtain a white solid (31 mg). 1 H NMR (400MHz, DMSO) δ9.07 (s, 1H), 8.82 (s, 1H), 8.64 (d, J＝3.2Hz 1H), 8.21-8.19 (m, 2H), 7.81 (d, J＝ 8.0Hz,1H),7.54(s,1H),7.20(d,J＝9.2Hz,1H),6.75(d,J＝9.2Hz,1H),3.16(s,4H),2.44(s,4H) ,2.21(s,3H),1.49(s,6H); LC-MS: [M+H] + :531.6.
实施例13.化合物PR-01-081的合成
Example 13. Synthesis of compound PR-01-081
6-(2,5-二氯嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(2)的合成：Synthesis of 6-(2,5-dichloropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (2):
将化合物2,4,5-三氯嘧啶(166.1mg,0.90mmol)、3,3-二甲基-6-(硼酸频哪醇酯)异吲哚-1-酮(200.0mg,0.70mmol)溶于1,4二氧六环(5mL)和水(1mL)中，并加入碳酸钾(192.5mg,1.39mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(56.7mg,0.07mmol)然后在N2下搅拌加热至90℃反应12小时，LCMS检测反应完全，反应液倒入水中(10mL)，乙酸乙酯萃取(15mL×3)，合并有机相，用水洗两次(40mL x 2)，40mL盐水洗一次，浓缩得到粗产物。粗品经柱层析(乙酸乙酯:石油醚＝0-30％,乙酸乙酯:石油醚＝1:5,Rf＝0.3)得白色固体(105mg)。LC-MS:[M+H]+:307.9。Compound 2,4,5-trichloropyrimidine (166.1mg, 0.90mmol) and 3,3-dimethyl-6-(boronic acid pinacol ester) isoindol-1-one (200.0mg, 0.70mmol) Dissolve in 1,4dioxane (5mL) and water (1mL), and add potassium carbonate (192.5mg, 1.39mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloride The palladium dichloromethane complex (56.7mg, 0.07mmol) was then stirred and heated to 90°C under N2 for 12 hours. LCMS detected that the reaction was complete. The reaction solution was poured into water (10mL) and extracted with ethyl acetate (15mL× 3), combine the organic phases, wash twice with water (40mL x 2), wash once with 40mL brine, and concentrate to obtain crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 0-30%, ethyl acetate: petroleum ether = 1:5, Rf = 0.3) to obtain a white solid (105 mg). LC-MS: [M+H] + :307.9.
6-(5-氯-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-081)的合成：6-(5-chloro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-3,3 -Synthesis of dimethylisoindol-1-one (PR-01-081):
将化合物6-(2,5-二氯嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(100mg,0.32mmol)和5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(88.1mg,0.32mmol)溶解在二氧六环(5mL)中，然后加入醋酸钯(7.2mg,0.032mmol)、碳酸铯(208.5mg,0.64mmol)和1,1'-联萘-2,2'-双二苯膦(43.6mg,0.07mmol)置换三次氮气，加热到100℃反应12小时。将反应混合物冷却至室温并真空浓缩以除去大部分溶剂。将其倒入水中(5mL)并用乙酸乙酯(30mL)萃取。有机层用硫酸镁干燥，过滤并浓缩。固体经碱性制备得到白色固体(12.5mg)。1H NMR(400MHz,DMSO)δ9.28(s,1H),8.80(s,1H),8.62(s,1H),7.97-8.01(m,2H),7.78(d,J＝7.6Hz,1H),7.53(d,J＝2.8Hz,1H),7.19(d,J＝8.8Hz,1H),6.72-6.75(m,1H),3.16–3.06(m,4H),2.44–2.32(m,4H),2.20(s,3H),1.49(s,6H)；LC-MS:[M+H]+:547.4。Compound 6-(2,5-dichloropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (100 mg, 0.32 mmol) and 5-(4-methylpiperazine-1 -2-(trifluoromethoxy)aniline (88.1 mg, 0.32 mmol) was dissolved in dioxane (5 mL), and then palladium acetate (7.2 mg, 0.032 mmol) and cesium carbonate (208.5 mg, 0.64 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.6 mg, 0.07 mmol) were substituted three times for nitrogen, and the reaction was heated to 100°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. Pour into water (5 mL) and extract with ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The solid was prepared alkaline to give a white solid (12.5 mg). 1 H NMR (400MHz, DMSO) δ9.28 (s, 1H), 8.80 (s, 1H), 8.62 (s, 1H), 7.97-8.01 (m, 2H), 7.78 (d, J＝7.6Hz, 1H ),7.53(d,J＝2.8Hz,1H),7.19(d,J＝8.8Hz,1H),6.72-6.75(m,1H),3.16–3.06(m,4H),2.44–2.32(m, 4H), 2.20 (s, 3H), 1.49 (s, 6H); LC-MS: [M+H] + : 547.4.
实施例14.化合物PR-01-037的合成
Example 14. Synthesis of compound PR-01-037
2-溴-5-(二溴甲基)噻唑-4-羧酸甲酯(2)的合成：Synthesis of 2-bromo-5-(dibromomethyl)thiazole-4-carboxylic acid methyl ester (2):
在氮气保护下，向四氯化碳溶液中(35.0mL)加入2-溴-5-甲基噻唑-4-羧酸甲酯(5.0g,21.18mmol)、N-溴代丁二酰亚胺(11.3g,63.48mmol)、过氧化二苯甲酰(513.5mg,2.12mmol)。将体系加热到80℃搅拌反应5小时，待反应完全后加入水(50.0mL)淬灭反应，用二氯甲烷萃取(50mL×3)，合并有机相，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(PE:EA＝100:1)得到淡黄色固体(3.3g)。Under nitrogen protection, add 2-bromo-5-methylthiazole-4-carboxylic acid methyl ester (5.0g, 21.18mmol) and N-bromosuccinimide to the carbon tetrachloride solution (35.0mL). (11.3g, 63.48mmol), dibenzoyl peroxide (513.5mg, 2.12mmol). Heat the system to 80°C and stir for 5 hours. After the reaction is complete, add water (50.0 mL) to quench the reaction. Extract with dichloromethane (50 mL × 3). Combine the organic phases, wash with saturated brine, and finally with Dry over sodium sulfate, filter, and concentrate to obtain crude product. Separate by column chromatography (PE:EA=100:1) to obtain a light yellow solid (3.3g).
2-溴-5-甲酰基噻唑-4-羧酸甲酯(3)的合成：Synthesis of 2-bromo-5-formylthiazole-4-carboxylic acid methyl ester (3):
在氮气保护下，向乙醇(300.0mL)和水(100.0mL)的混合溶液中加入2-溴-5-(二溴甲基)噻唑-4-羧酸甲酯(16.0g,40.60mmol)和硝酸银(13.8g,81.24mmol)。将体系加热到80℃搅拌反应3小时，待反应完全后冷却过滤。用二氯甲烷萃取三次(100mL×3)，合并有机相，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(PE:EA＝10:1)得到白色固体(5.6g)。LC-MS:[M+H]+:249.9,252.0。Under nitrogen protection, to a mixed solution of ethanol (300.0 mL) and water (100.0 mL), 2-bromo-5-(dibromomethyl)thiazole-4-carboxylic acid methyl ester (16.0 g, 40.60 mmol) and Silver nitrate (13.8g, 81.24mmol). Heat the system to 80°C and stir for 3 hours. After the reaction is complete, cool and filter. Extract three times with dichloromethane (100 mL × 3), combine the organic phases, wash with saturated brine, and finally dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Separate by column chromatography (PE:EA=10:1) to obtain a white solid (5.6g). LC-MS: [M+H] + :249.9, 252.0.
2-溴-5-(羟甲基)噻唑-4-羧酸甲酯(4)的合成：Synthesis of 2-bromo-5-(hydroxymethyl)thiazole-4-carboxylic acid methyl ester (4):
将化合物2-溴-5-甲酰基噻唑-4-羧酸甲酯(5.6g,22.31mmol)溶于甲醇(100.0mL)中，将体系冷却至0℃,缓慢加入硼氢化钠(1.3g,34.36mmol)，升至室温搅拌反应1小时，待反应完全，降温至0℃加入氯化铵饱和水溶液(50.0mL)淬灭反应，用乙酸乙酯萃取三次(50mL×3)，合并有机相，用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(PE:EA＝4:1)得到白色固体(3.7g)。LC-MS:[M+H]+:252.0,254.0。 Dissolve compound 2-bromo-5-formylthiazole-4-carboxylic acid methyl ester (5.6g, 22.31mmol) in methanol (100.0mL), cool the system to 0°C, and slowly add sodium borohydride (1.3g, 34.36 mmol), raise to room temperature and stir for 1 hour. When the reaction is complete, cool to 0°C and add saturated aqueous ammonium chloride solution (50.0 mL) to quench the reaction. Extract three times with ethyl acetate (50 mL × 3). Combine the organic phases. Wash with saturated brine, finally dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude product. Separate by column chromatography (PE:EA=4:1) to obtain a white solid (3.7g). LC-MS: [M+H] + :252.0, 254.0.
5-(羟甲基)-2-(5-甲基-2-(甲硫基)嘧啶-4-基)噻唑-4-羧酸甲酯(5)的合成：Synthesis of methyl 5-(hydroxymethyl)-2-(5-methyl-2-(methylthio)pyrimidin-4-yl)thiazole-4-carboxylate (5):
向2-溴-5-(羟甲基)噻唑-4-羧酸甲酯(1.3g,5.14mmol)、5-甲基-2-(甲硫基)-4-(三甲基锡基)嘧啶(1.4g,4.62mmol)的二氧六环(40mL)悬浮液中加入二(三苯基膦)二氯化钯(356.6mg,0.51mmol)和碘化亚铜(194.3mg,1.02mmol)。反应体系在氮气保护下于110℃搅拌反应2小时。待反应完全后加入氟化钾水溶液(50.0mL)淬灭反应，用二氯甲烷萃取三次(50mL×3)，合并有机相，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(PE:EA＝2:1)得到棕色油状液体(600.0mg)。LC-MS:[M+H]+:312.0。To 2-bromo-5-(hydroxymethyl)thiazole-4-carboxylic acid methyl ester (1.3g, 5.14mmol), 5-methyl-2-(methylthio)-4-(trimethyltinyl) To a suspension of pyrimidine (1.4g, 4.62mmol) in dioxane (40mL) were added bis(triphenylphosphine)palladium dichloride (356.6mg, 0.51mmol) and copper iodide (194.3mg, 1.02mmol) . The reaction system was stirred and reacted at 110°C for 2 hours under nitrogen protection. After the reaction is complete, add potassium fluoride aqueous solution (50.0 mL) to quench the reaction, extract with dichloromethane three times (50 mL × 3), combine the organic phases, wash with saturated brine, and finally dry with anhydrous sodium sulfate and filter. Concentrate to obtain crude product. Separate by column chromatography (PE:EA=2:1) to obtain brown oily liquid (600.0 mg). LC-MS: [M+H] + :312.0.
2-(5-甲基-2-(甲硫基)嘧啶-4-基)-5-(((甲磺酰基)氧基)甲基)噻唑-4-羧酸甲酯(6)的合成：Synthesis of 2-(5-methyl-2-(methylthio)pyrimidin-4-yl)-5-(((methanesulfonyl)oxy)methyl)thiazole-4-carboxylic acid methyl ester (6) :
将化合物5-(羟甲基)-2-(5-甲基-2-(甲硫基)嘧啶-4-基)噻唑-4-羧酸甲酯(1.0g,3.22mmol)、三乙胺(649.6mg,6.42mmol)溶于二氯甲烷溶液中(10.0mL)。将体系冷却到0℃，向体系中缓慢滴加甲基磺酰氯(551.8mg,4.82mmol)。滴加完毕后，在0℃继续搅拌反应2小时。待反应完全，加入氯化铵饱和水溶液(15.0mL)淬灭反应，用乙酸乙酯萃取三次(15mL×3)，合并有机相，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝10:1)得到棕色油状液体(560.0mg)。LC-MS:[M+H]+:389.9。Compound 5-(hydroxymethyl)-2-(5-methyl-2-(methylthio)pyrimidin-4-yl)thiazole-4-carboxylic acid methyl ester (1.0g, 3.22mmol), triethylamine (649.6 mg, 6.42 mmol) was dissolved in dichloromethane solution (10.0 mL). The system was cooled to 0°C, and methylsulfonyl chloride (551.8 mg, 4.82 mmol) was slowly added dropwise to the system. After the dropwise addition was completed, the stirring reaction was continued at 0°C for 2 hours. When the reaction is complete, add saturated aqueous ammonium chloride solution (15.0 mL) to quench the reaction, extract three times with ethyl acetate (15 mL × 3), combine the organic phases, wash with saturated brine, and finally dry with anhydrous sodium sulfate and filter. , concentrated to obtain crude product. Separate by column chromatography (DCM:MeOH=10:1) to obtain brown oily liquid (560.0 mg). LC-MS: [M+H] + :389.9.
5-(((2,4-二甲氧基苄基)氨基)甲基)-2-(5-甲基-2-(甲硫基)嘧啶-4-基)噻唑-4-甲酸甲酯(7)的合成：Methyl 5-(((2,4-dimethoxybenzyl)amino)methyl)-2-(5-methyl-2-(methylthio)pyrimidin-4-yl)thiazole-4-carboxylate Synthesis of (7):
将化合物2,4-二甲氧基苄胺(2.0g,11.96mmol)、三乙胺(1.2g,11.86mmol)溶于乙腈溶液中(50.0mL)。将体系冷却到0℃，向体系中缓慢滴加2-(5-甲基-2-(甲硫基)嘧啶-4-基)-5-(((甲磺酰基)氧基)甲基)噻唑-4-羧酸甲酯(930.0mg,2.39mmol)。滴加完毕后，在0℃继续搅拌反应2小时。待反应完全，真空减压旋去溶剂，经柱层析分离(DCM:MeOH＝10:1)得到黄色固体(540.0mg)。LC-MS:[M+H]+:461.1。Compounds 2,4-dimethoxybenzylamine (2.0g, 11.96mmol) and triethylamine (1.2g, 11.86mmol) were dissolved in acetonitrile solution (50.0mL). Cool the system to 0°C, and slowly add 2-(5-methyl-2-(methylthio)pyrimidin-4-yl)-5-(((methanesulfonyl)oxy)methyl) into the system dropwise Thiazole-4-carboxylic acid methyl ester (930.0 mg, 2.39 mmol). After the dropwise addition was completed, the stirring reaction was continued at 0°C for 2 hours. When the reaction was complete, the solvent was removed under vacuum and separated by column chromatography (DCM:MeOH=10:1) to obtain a yellow solid (540.0 mg). LC-MS: [M+H] + :461.1.
5-(((2,4-二甲氧基苄基)氨基)甲基)-2-(5-甲基-2-(甲硫基)嘧啶-4-基)噻唑-4-羧酸(8)的合成：5-(((2,4-Dimethoxybenzyl)amino)methyl)-2-(5-methyl-2-(methylthio)pyrimidin-4-yl)thiazole-4-carboxylic acid ( 8) Synthesis:
将化合物5-(((2,4-二甲氧基苄基)氨基)甲基)-2-(5-甲基-2-(甲硫基)嘧啶-4-基)噻唑-4-甲酸甲酯(575.0mg,1.25mmol)、一水合氢氧化锂(104.9mg,2.50mmol)溶于四氢呋喃(2.0mL)和水(4.0mL)的混合溶液中。在室温下搅拌反应2小时。待反应完全，加入2N盐酸调节溶液pH至3-4，真空减压旋去溶剂得到棕黄色油状产物，无需进一步纯化。LC-MS:[M+H]+:447.1。The compound 5-(((2,4-dimethoxybenzyl)amino)methyl)-2-(5-methyl-2-(methylthio)pyrimidin-4-yl)thiazole-4-carboxylic acid Methyl ester (575.0 mg, 1.25 mmol) and lithium hydroxide monohydrate (104.9 mg, 2.50 mmol) were dissolved in a mixed solution of tetrahydrofuran (2.0 mL) and water (4.0 mL). The reaction was stirred at room temperature for 2 hours. When the reaction is complete, add 2N hydrochloric acid to adjust the pH of the solution to 3-4, and spin off the solvent under vacuum to obtain a brown oily product without further purification. LC-MS: [M+H] + :447.1.
5-(2,4-二甲氧基苄基)-2-(5-甲基-2-(甲硫基)嘧啶-4-基)-5,6-二氢-4H-吡咯[3,4-d]噻唑-4-酮(9)的合成：5-(2,4-dimethoxybenzyl)-2-(5-methyl-2-(methylthio)pyrimidin-4-yl)-5,6-dihydro-4H-pyrrole[3, Synthesis of 4-d]thiazol-4-one (9):
将上述粗产物和N,N-二异丙基乙胺(484.7mg,3.75mmol)溶于N,N-二甲基甲酰胺(60.0mL)中，将体系冷却到0℃，向体系中缓慢加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(570.4mg,1.50mmol)。加完后，升温至室温，搅拌反应1小时。待反应完全后加入水淬灭反应，用乙酸乙酯萃取三次(50mL×3)，合并有机相，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝10:1)得到黄色油状液体(125.0mg)。LC-MS:[M+H]+:429.1。Dissolve the above crude product and N,N-diisopropylethylamine (484.7mg, 3.75mmol) in N,N-dimethylformamide (60.0mL), cool the system to 0°C, and slowly add it to the system. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (570.4 mg, 1.50 mmol) was added. After the addition is completed, the temperature is raised to room temperature and the reaction is stirred for 1 hour. After the reaction is complete, add water to quench the reaction, extract with ethyl acetate three times (50 mL × 3), combine the organic phases, wash with saturated brine, and finally dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate by column chromatography (DCM:MeOH=10:1) to obtain a yellow oily liquid (125.0 mg). LC-MS: [M+H] + :429.1.
5-(2,4-二甲氧基苄基)-2-(5-甲基-2-(甲磺酰基)嘧啶-4-基)-5,6-二氢-4H-吡咯[3,4-d]噻唑-4-酮(10)的合成：5-(2,4-dimethoxybenzyl)-2-(5-methyl-2-(methanesulfonyl)pyrimidin-4-yl)-5,6-dihydro-4H-pyrrole[3, Synthesis of 4-d]thiazol-4-one (10):
将5-(2,4-二甲氧基苄基)-2-(5-甲基-2-(甲硫基)嘧啶-4-基)-5,6-二氢-4H-吡咯[3,4-d]噻唑-4-酮(200.0mg,0.47mmol)溶于二氯甲烷(4.0mL)中，将体系冷却到0℃，向体系中缓慢加入间氯过氧苯甲酸(161.1mg,0.93mmol)。加完后，在0℃搅拌反应2小时。待反应完全后加入碳酸氢钠水溶液淬灭反应，将有机相用碳酸氢钠洗三次，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层 析分离(DCM:MeOH＝10:1)得到黄色固体(85.0mg)。LC-MS:[M+H]+:461.1。5-(2,4-Dimethoxybenzyl)-2-(5-methyl-2-(methylthio)pyrimidin-4-yl)-5,6-dihydro-4H-pyrrole [3 , 4-d]thiazol-4-one (200.0mg, 0.47mmol) was dissolved in dichloromethane (4.0mL), the system was cooled to 0°C, and m-chloroperoxybenzoic acid (161.1mg, 0.93mmol). After the addition was completed, the reaction was stirred at 0°C for 2 hours. After the reaction is complete, aqueous sodium bicarbonate solution is added to quench the reaction. The organic phase is washed three times with sodium bicarbonate and then with saturated brine. Finally, it is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Meridian layer After analytical separation (DCM:MeOH=10:1), a yellow solid (85.0 mg) was obtained. LC-MS: [M+H] + :461.1.
5-(2,4-二甲氧基苄基)-2-(5-甲基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-5,6-二氢-4H-吡咯并[3,4-d]噻唑-4-酮(11)的合成：5-(2,4-dimethoxybenzyl)-2-(5-methyl-2-((5-(4-methylpiperazin-1-yl))-2-(trifluoromethoxy Synthesis of )phenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-one (11):
将5-(2,4-二甲氧基苄基)-2-(5-甲基-2-(甲磺酰基)嘧啶-4-基)-5,6-二氢-4H-吡咯[3,4-d]噻唑-4-酮(30.0mg,0.07mmol)、N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)甲酰胺(common int-3)(23.7mg,0.08mmol)、碳酸钾(18.0mg,0.13mmol)溶于N,N-二甲基甲酰胺(1.0mL)中。反应体系在氮气保护下于90℃搅拌反应16小时。待反应完全后加入饱和氯化铵水溶液(5.0mL)淬灭反应，用二氯甲烷萃取三次(10mL×3)，合并有机相，再用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝10:1)得到黄色油状液体(4.0mg)。LC-MS:[M+H]+:656.2。5-(2,4-Dimethoxybenzyl)-2-(5-methyl-2-(methanesulfonyl)pyrimidin-4-yl)-5,6-dihydro-4H-pyrrole [3 ,4-d]thiazol-4-one (30.0mg, 0.07mmol), N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)carboxamide (common int-3) (23.7 mg, 0.08 mmol) and potassium carbonate (18.0 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.0 mL). The reaction system was stirred and reacted at 90°C for 16 hours under nitrogen protection. After the reaction is complete, add saturated aqueous ammonium chloride solution (5.0 mL) to quench the reaction, extract with dichloromethane three times (10 mL × 3), combine the organic phases, wash with saturated brine, and finally dry with anhydrous sodium sulfate and filter. , concentrated to obtain crude product. Separate by column chromatography (DCM:MeOH=10:1) to obtain a yellow oily liquid (4.0 mg). LC-MS: [M+H] + :656.2.
5-甲基-2-(甲硫基)-4-(三甲基锡基)嘧啶(13)的合成：Synthesis of 5-methyl-2-(methylthio)-4-(trimethyltinyl)pyrimidine (13):
向4-氯-5-甲基-2-(甲硫基)嘧啶(4.5g,25.77mmol)、六甲基二锡(16.9g,51.54mmol)的1,4-二氧六环(50mL)悬浮液中加入四(三苯基膦)钯(1.5g,1.29mmol)。反应体系在氮气保护下于80℃搅拌12小时。待反应完全后加入氟化钾水溶液(50.0mL)淬灭反应，二氯甲烷萃取(50mL×3)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(PE:EA＝2:1)得到无色油状液体(3.0g)。LC-MS:[M+H]+:305.1。To 4-chloro-5-methyl-2-(methylthio)pyrimidine (4.5g, 25.77mmol), hexamethyldisin (16.9g, 51.54mmol), 1,4-dioxane (50mL) Tetrakis(triphenylphosphine)palladium (1.5g, 1.29mmol) was added to the suspension. The reaction system was stirred at 80°C for 12 hours under nitrogen protection. After the reaction is complete, add potassium fluoride aqueous solution (50.0 mL) to quench the reaction, extract with dichloromethane (50 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate by column chromatography (PE:EA=2:1) to obtain a colorless oily liquid (3.0g). LC-MS: [M+H] + :305.1.
2-(5-甲基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-5,6-二氢-4H-吡咯并[3,4-d]噻唑-4-酮(PR-01-037)的合成：2-(5-methyl-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-5, Synthesis of 6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-one (PR-01-037):
将5-(2,4-二甲氧基苄基)-2-(5-甲基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-5,6-二氢-4H-吡咯并[3,4-d]噻唑-4-酮(13.0mg,0.02mmol)溶于三氟乙酸(0.5mL)、三乙基硅烷(0.1mL)、二氯甲烷(0.5mL)中。反应体系在氮气保护下于50℃搅拌反应12小时。待反应完全后直接浓缩至干。粗品经制备液相色谱纯化得到黄色固体(4.0mg)。1H NMR(400MHz,CD3OD)δ8.53(s,1H),8.09(s,1H),7.24(d,J＝9.2Hz 1H),6.74(d,J＝9.2Hz,1H),4.58(s,2H),3.42(s,4H),3.04(s,4H),2.65(s,6H)；LC-MS:[M+H]+:506.1。5-(2,4-Dimethoxybenzyl)-2-(5-methyl-2-((5-(4-methylpiperazin-1-yl))-2-(trifluoromethoxy Base)phenyl)amino)pyrimidin-4-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-one (13.0mg, 0.02mmol) was dissolved in trifluoroacetic acid ( 0.5 mL), triethylsilane (0.1 mL), and dichloromethane (0.5 mL). The reaction system was stirred and reacted at 50°C for 12 hours under nitrogen protection. After the reaction is complete, concentrate directly to dryness. The crude product was purified by preparative liquid chromatography to obtain a yellow solid (4.0 mg). 1 H NMR (400MHz, CD 3 OD) δ8.53 (s, 1H), 8.09 (s, 1H), 7.24 (d, J = 9.2Hz 1H), 6.74 (d, J = 9.2Hz, 1H), 4.58 (s,2H),3.42(s,4H),3.04(s,4H),2.65(s,6H); LC-MS: [M+H] + :506.1.
实施例15.化合物PR-01-091的合成
Example 15. Synthesis of compound PR-01-091
1-氧代-3,5-二氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(2)的合成：Synthesis of 1-oxo-3,5-dihydropyrro[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2):
将对甲基苯磺酰甲基异腈(586.0mg,3.00mmol)溶于四氢呋喃(10mL)中，常温搅拌下加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(457.0mg,3.00mmol)，搅拌15分钟后加入2-氧代-2,5-二氢-1H-吡咯-1-羧酸叔丁酯(500.0mg,2.73mmol)常温搅拌反应5小时。待反应完成后向体系中加入水(20mL)，然后用乙酸乙 酯萃取(30mL×3)，合并乙酸乙酯相用无水硫酸钠干燥，过滤，浓缩得到粗品，经柱层析(二氯甲烷:甲醇＝50:1-10:1,二氯甲烷:甲醇＝10:1,Rf＝0.3)纯化得到棕黄固体(260.0mg)。LCMS:[M+H]+:223.2。Dissolve p-toluenesulfonylmethylisonitrile (586.0 mg, 3.00 mmol) in tetrahydrofuran (10 mL), and add 1,8-diazabicyclo[5.4.0]undec-7- under stirring at room temperature. Alkene (457.0 mg, 3.00 mmol), stir for 15 minutes, add 2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (500.0 mg, 2.73 mmol) and stir at room temperature for 5 hours. After the reaction is completed, add water (20 mL) to the system, and then use ethyl acetate to Ester extraction (30mL =10:1, Rf=0.3) and purified to obtain a brown solid (260.0 mg). LCMS:[M+H] + :223.2.
5-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧代-3,5-二氢吡咯[3,4-c]吡咯-2(1H)-羧酸叔丁酯(3)的合成：5-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-oxo-3, Synthesis of 5-dihydropyrrole[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (3):
将化合物1-氧代-3,5-二氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(80.0mg,0.36mmol)溶于N,N-二甲基甲酰胺(5mL)中，氮气保护下加入4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-2)(140.0mg,0.36mmol)和碳酸铯(235.0mg,0.72mmol)。体系升至100℃反应1小时。反应体系加入水(10mL)，用乙酸乙酯萃取(30mL×3)，浓缩得粗品经制备TLC(二氯甲烷:醇＝20:1,Rf＝0.4)纯化得到黄色固体(40.0mg)。LCMS:[M+H]+:574.6。Compound 1-oxo-3,5-dihydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (80.0mg, 0.36mmol) was dissolved in N,N-dimethyl To formamide (5 mL), add 4-chloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine under nitrogen protection. (common int-2) (140.0 mg, 0.36 mmol) and cesium carbonate (235.0 mg, 0.72 mmol). The system was raised to 100°C and reacted for 1 hour. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (30 mL × 3), and concentrated to obtain a crude product that was purified by preparative TLC (dichloromethane:alcohol=20:1, Rf=0.4) to obtain a yellow solid (40.0 mg). LCMS: [M+H] + :574.6.
5-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,5-二氢吡咯[3,4-c]吡咯-1(2H)-酮(PR-01-091)的合成：5-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-3,5-dihydropyrrole Synthesis of [3,4-c]pyrrole-1(2H)-one (PR-01-091):
将化合物5-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧代-3,5-二氢吡咯[3,4-c]吡咯-2(1H)-羧酸叔丁酯(40.0mg,0.07mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.2mL)反应室温搅拌1小时，反应液浓缩至干，经制备纯化得到白色固体(23.5mg)。1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.48(d,J＝5.6Hz,1H),8.04(s,1H),7.93(s,1H),7.57(s,1H),7.35(d,J＝2.8Hz,1H),7.23(d,J＝6.0Hz,2H),6.80(dd,J＝9.2,2.8Hz,1H),4.23(s,2H),3.17(s,4H),2.46(s,4H),2.22(s,3H)；LCMS:[M+H]+:474.1。Compound 5-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-oxo- 3,5-Dihydropyrrole[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (40.0mg, 0.07mmol) was dissolved in dichloromethane (1mL), and trifluoroacetic acid (0.2mL ) reaction was stirred at room temperature for 1 hour, the reaction solution was concentrated to dryness, and a white solid (23.5 mg) was obtained through preparation and purification. 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.48 (d, J = 5.6Hz, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.57 (s, 1H ),7.35(d,J＝2.8Hz,1H),7.23(d,J＝6.0Hz,2H),6.80(dd,J＝9.2,2.8Hz,1H),4.23(s,2H),3.17(s ,4H),2.46(s,4H),2.22(s,3H); LCMS: [M+H] + :474.1.
实施例16.化合物PR-01-098的合成
Example 16. Synthesis of compound PR-01-098
5-(2-氯-5-氟嘧啶-4-基)-1-氧代-3,5-二氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(2)的合成：5-(2-Chloro-5-fluoropyrimidin-4-yl)-1-oxo-3,5-dihydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester ( 2) Synthesis:
将化合物1-氧代-3,5-二氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯1(220.0mg,0.99mmol)、2,4-二氯-5-氟嘧啶(165.0mg,0.99mmol)溶于乙腈(10mL)中，氮气保护下加入碳酸钾(410.0mg,2.97mmol)。体系升至80℃反应12小时。待反应完成后反应液浓缩至干，向反应体系加入水(10mL)，用乙酸乙酯萃取(20mL×3)，浓缩得粗品经制备TLC(二氯甲烷:甲醇＝20:1,Rf＝0.6)纯化得到浅黄色固体(104.0mg)。LCMS:[M-tBu+H]+:296.9。Compound 1-oxo-3,5-dihydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 1 (220.0 mg, 0.99mmol), 2,4-dichloro- 5-Fluoropyrimidine (165.0 mg, 0.99 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (410.0 mg, 2.97 mmol) was added under nitrogen protection. The system was raised to 80°C and reacted for 12 hours. After the reaction is completed, the reaction solution is concentrated to dryness, water (10 mL) is added to the reaction system, extracted with ethyl acetate (20 mL ) was purified to obtain a light yellow solid (104.0 mg). LCMS:[M- tBu +H] + :296.9.
5-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧代-3,5-二氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(3)的合成：5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-oxo Synthesis of tert-butyl-3,5-dihydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3):
将化合物5-(2-氯-5-氟嘧啶-4-基)-1-氧代-3,5-二氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(151.0mg,0.43mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(117.0mg,0.43mmol)、醋酸钯(9.0 mg,0.04mmol)和1,1'-联萘-2,2'-双二苯膦(56.0mg,0.09mmol)溶于1,4-二氧六环(2mL)中，体系在氮气保护下加入碳酸铯(277.0mg,0.85mmol)。反应升至100℃后搅拌6小时后LCMS检测反应完全。向反应液中加入水并用二氯甲烷(20mL×3)萃取，合并有机相后干燥浓缩得粗品经柱层析(二氯甲烷:甲醇＝20:1,Rf＝0.3)纯化得棕黄固体(85.0mg)。LCMS:[M+H]+:592.3。Compound 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-oxo-3,5-dihydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl Ester (151.0 mg, 0.43 mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (117.0 mg, 0.43 mmol), palladium acetate (9.0 mg, 0.04mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (56.0mg, 0.09mmol) were dissolved in 1,4-dioxane (2mL), and the system was protected by nitrogen. Cesium carbonate (277.0 mg, 0.85 mmol) was added. After the reaction was raised to 100°C and stirred for 6 hours, LCMS detected that the reaction was complete. Water was added to the reaction solution and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried and concentrated to obtain a crude product which was purified by column chromatography (dichloromethane: methanol = 20:1, Rf = 0.3) to obtain a brown solid ( 85.0mg). LCMS: [M+H] + :592.3.
5-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,5-二氢吡咯[3,4-c]吡咯-1(2H)-酮(PR-01-098)的合成：5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-3,5 -Synthesis of dihydropyrrole[3,4-c]pyrrole-1(2H)-one (PR-01-098):
将化合物5-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-氧代-3,5-二氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(85.0mg,0.14mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.2mL)。反应室温搅拌1小时，反应液浓缩至干，经制备纯化得白色固体(29.5mg)。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.66(d,J＝4.0Hz,1H),8.09(s,1H),7.72(s,1H),7.44(s,1H),7.34(d,J＝2.8Hz,1H),7.23(d,J＝8.0Hz,1H),6.79(dd,J＝9.2,2.8Hz,1H),4.24(s,2H),3.19–3.13(m,4H),2.47–2.42(m,4H),2.22(s,3H)；LCMS:[M+H]+:492.2。Compound 5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1 -Oxo-3,5-dihydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (85.0 mg, 0.14 mmol) was dissolved in dichloromethane (1 mL), and three Fluoroacetic acid (0.2 mL). The reaction was stirred at room temperature for 1 hour, the reaction solution was concentrated to dryness, and a white solid (29.5 mg) was obtained through preparation and purification. 1 H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 8.66 (d, J = 4.0Hz, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.44 (s, 1H ),7.34(d,J＝2.8Hz,1H),7.23(d,J＝8.0Hz,1H),6.79(dd,J＝9.2,2.8Hz,1H),4.24(s,2H),3.19–3.13 (m,4H),2.47–2.42(m,4H),2.22(s,3H); LCMS: [M+H] + :492.2.
实施例17.化合物DP-01-130的合成
Example 17. Synthesis of compound DP-01-130
1-(4-溴-1H-吡咯-2-基)-N-(2,4-二甲氧基苄基)甲胺(2)的合成：Synthesis of 1-(4-bromo-1H-pyrrol-2-yl)-N-(2,4-dimethoxybenzyl)methanamine (2):
将化合物4-溴-1H-吡咯-2-甲醛(2.0g,11.50mmol)和2,4-二甲氧基苄胺(1.92g,11.48mmol)溶于甲醇(20mL)中，在室温下搅拌3小时后降温至0℃，分批加入硼氢化钠(0.43g,11.37mmol)，恢复至室温搅拌1小时，LCMS监测到原料已反应完。加水(40mL)淬灭反应，将反应液中的甲醇旋除后用乙酸乙酯(30mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，旋蒸得粗品。粗品经硅胶柱层析(甲醇:二氯甲烷＝0-3％；二氯甲烷/甲醇＝10/1,Rf＝0.6)得黄色油状物(3.2g)。LC-MS:[M+H]+:325.0,327.0。Compounds 4-bromo-1H-pyrrole-2-carbaldehyde (2.0g, 11.50mmol) and 2,4-dimethoxybenzylamine (1.92g, 11.48mmol) were dissolved in methanol (20mL) and stirred at room temperature. After 3 hours, the temperature was lowered to 0°C, sodium borohydride (0.43g, 11.37mmol) was added in batches, returned to room temperature and stirred for 1 hour. LCMS detected that the raw materials had reacted completely. Add water (40 mL) to quench the reaction, spin off the methanol in the reaction solution, and extract with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain crude product. The crude product was subjected to silica gel column chromatography (methanol: dichloromethane = 0-3%; dichloromethane/methanol = 10/1, Rf = 0.6) to obtain a yellow oil (3.2g). LC-MS: [M+H] + :325.0, 327.0.
6-溴-2-(2,4-二甲氧基苄基)-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(3)的合成：Synthesis of 6-bromo-2-(2,4-dimethoxybenzyl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-one (3):
将化合物1-(4-溴-1H-吡咯-2-基)-N-(2,4-二甲氧基苄基)甲胺(500.0mg,1.54mmol)溶于THF(8mL)中，置换氮气三次，降温至0℃，分批加入N,N'-羰基二咪唑(374.0mg,2.31mmol)，恢复至室温搅拌1小时。降温至0℃，分批加入60％氢化钠(123.0mg,3.08mmol)，恢复至室温继续搅拌2小时，LCMS监测原料已反应完。反应液加入饱和氯化铵溶液(20mL)淬灭，用乙酸乙酯萃取(20mL×3)。合并有机相 用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝0-20％,石油醚/乙酸乙酯＝1:5,Rf＝0.4)纯化得亮黄色固体(450.0mg)。LC-MS:[M+H]+:351.1,353.1。Compound 1-(4-bromo-1H-pyrrol-2-yl)-N-(2,4-dimethoxybenzyl)methanamine (500.0mg, 1.54mmol) was dissolved in THF (8mL), and replaced Nitrogen was added three times, the temperature was lowered to 0°C, N,N'-carbonyldiimidazole (374.0 mg, 2.31 mmol) was added in batches, and the mixture was returned to room temperature and stirred for 1 hour. Cool the temperature to 0°C, add 60% sodium hydride (123.0 mg, 3.08 mmol) in batches, return to room temperature and continue stirring for 2 hours. LCMS monitors that the raw materials have reacted completely. The reaction solution was quenched by adding saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL × 3). Combine organic phases Wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%, petroleum ether/ethyl acetate = 1:5, Rf = 0.4) to obtain a bright yellow solid (450.0 mg). LC-MS: [M+H] + :351.1, 353.1.
2-(2,4-二甲氧基苄基)-6-硼酸频哪醇酯-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(4)的合成：2-(2,4-dimethoxybenzyl)-6-boronic acid pinacol ester-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (4) synthesis:
将化合物6-溴-2-(2,4-二甲氧基苄基)-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(400.0mg,1.14mmol)、联硼酸频哪醇酯(433.8mg,1.71mmol)、醋酸钾(223.6mg,2.28mmol)、[1,1'-双(二苯基膦)二茂铁]二氯钯(82.7mg,0.113mmol)溶于1,4-二氧六环(10mL)中，氮气保护下加热到80℃反应4小时，LCMS监测原料已反应。反应液直接用于下一步反应。LC-MS:[M+H]+:399.0。Compound 6-bromo-2-(2,4-dimethoxybenzyl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (400.0 mg, 1.14 mmol ), pinacol diborate (433.8mg, 1.71mmol), potassium acetate (223.6mg, 2.28mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (82.7mg, 0.113 mmol) was dissolved in 1,4-dioxane (10 mL), heated to 80°C under nitrogen protection, and reacted for 4 hours. LCMS monitored that the raw materials had reacted. The reaction solution was directly used in the next reaction. LC-MS: [M+H] + :399.0.
6-(2-氯-5-氟嘧啶-4-基)-2-(2,4-二甲氧基苄基)-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(5)的合成：6-(2-Chloro-5-fluoropyrimidin-4-yl)-2-(2,4-dimethoxybenzyl)-1,2-dihydro-3H-pyrrolo[1,2-c] Synthesis of imidazole-3-one (5):
将化合物2-(2,4-二甲氧基苄基)-6-硼酸频哪醇酯-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(400.0mg,1.00mmol)、2,4-二氯-5-氟嘧啶(167.7mg,1.00mmol)、碳酸钾(416.4mg,3.01mmol)和[1,1'-双(二苯基膦)二茂铁]二氯钯(72.9mg,0.10mmol)溶于1,4-二氧六环(10mL)和水(3mL)中，置换氮气三次，升温至80℃搅拌4小时。LCMS监测原料已反应完，加水(20mL)淬灭，分液，收集有机相，水相用二氯甲烷(10mL×3)萃取。合并有机相后用无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝0-25％；石油醚/乙酸乙酯＝4/1,Rf＝0.3)纯化得白色固体(72.0mg)。LC-MS:[M+H]+:403.1。Compound 2-(2,4-dimethoxybenzyl)-6-boronic acid pinacol ester-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (400.0 mg, 1.00mmol), 2,4-dichloro-5-fluoropyrimidine (167.7mg, 1.00mmol), potassium carbonate (416.4mg, 3.01mmol) and [1,1'-bis(diphenylphosphine)diocene Iron] dichloropalladium (72.9 mg, 0.10 mmol) was dissolved in 1,4-dioxane (10 mL) and water (3 mL), replaced with nitrogen three times, heated to 80°C and stirred for 4 hours. LCMS monitors that the raw materials have reacted completely, add water (20 mL) to quench, separate the liquids, collect the organic phase, and extract the aqueous phase with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25%; petroleum ether/ethyl acetate = 4/1, Rf = 0.3) to obtain a white solid (72.0 mg). LC-MS: [M+H] + :403.1.
2-(2,4-二甲氧基苄基)-6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(6)的合成：2-(2,4-dimethoxybenzyl)-6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl))-2-(trifluoromethoxy) Synthesis of phenyl)amino)pyrimidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (6):
将化合物6-(2-氯-5-氟嘧啶-4-基)-2-(2,4-二甲氧基苄基)-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(60.0mg,0.15mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(41.0mg,0.15mmol)、1,1'-联萘-2,2'-双二苯膦(18.6mg,0.03mmol)、醋酸钯(4.5mg,0.02mmol)和碳酸铯(145.6mg,0.45mmol)溶于二氧六环(5mL)中，置换氮气，升温至90℃搅拌6小时，LCMS监测到原料已反应完。反应液加水(5mL)稀释，乙酸乙酯萃取(5mL×3)。合并有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。经硅胶柱层析(甲醇:二氯甲烷＝0-3％；二氯甲烷/甲醇＝20:1,Rf＝0.4)纯化得黄色固体(90.0mg)。LC-MS:[M+H]+:642.3。Compound 6-(2-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-dimethoxybenzyl)-1,2-dihydro-3H-pyrrolo[1,2- c] Imidazol-3-one (60.0mg, 0.15mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (41.0mg, 0.15mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (18.6mg, 0.03mmol), palladium acetate (4.5mg, 0.02mmol) and cesium carbonate (145.6mg, 0.45mmol) were dissolved in In dioxane (5 mL), nitrogen was replaced, the temperature was raised to 90°C and stirred for 6 hours. LCMS detected that the raw materials had reacted completely. The reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Purify through silica gel column chromatography (methanol: dichloromethane = 0-3%; dichloromethane/methanol = 20:1, Rf = 0.4) to obtain a yellow solid (90.0 mg). LC-MS: [M+H] + :642.3.
6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1,2-二氢-3H-吡咯并[1,2-c]咪唑-3-酮(DP-01-130)的合成：6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1,2 -Synthesis of dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (DP-01-130):
将化合物2-(2,4-二甲氧基苄基)-6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1,2-二氢-3H-吡咯并[1，2-c]咪唑-3-酮(90.0mg,0.14mmol)溶于二氯甲烷(2.5mL)中，向上述溶液中加入三氟乙酸(5mL)和三乙基硅氢(2mL)，升温至50℃搅拌16小时，LCMS监测原料已反应完。反应液旋干后经制备纯化得白色固体(17.0mg)。1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.29(s,1H),7.93(s,1H),7.37(s,1H),7.15(d,J＝8.8Hz,1H),6.83(s,1H),6.53(d,J＝8.8Hz,1H),5.92(s,1H),4.51(s,2H),3.33(s,4H),2.67(s,4H),2.41(s,3H)；LC-MS:[M+H]+:492.3。Compound 2-(2,4-dimethoxybenzyl)-6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl))-2-(trifluoromethoxy Base)phenyl)amino)pyrimidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (90.0mg, 0.14mmol) was dissolved in dichloromethane ( 2.5 mL), add trifluoroacetic acid (5 mL) and triethylsilyl hydrogen (2 mL) to the above solution, raise the temperature to 50°C and stir for 16 hours. LCMS monitors that the raw materials have reacted completely. The reaction solution was spin-dried and purified to obtain a white solid (17.0 mg). 1 H NMR (400MHz, CDCl 3 ) δ8.32 (s, 1H), 8.29 (s, 1H), 7.93 (s, 1H), 7.37 (s, 1H), 7.15 (d, J = 8.8Hz, 1H) ,6.83(s,1H),6.53(d,J＝8.8Hz,1H),5.92(s,1H),4.51(s,2H),3.33(s,4H),2.67(s,4H),2.41( s,3H); LC-MS: [M+H] + :492.3.
实施例18.化合物PR-01-096的合成
Example 18. Synthesis of compound PR-01-096
5-乙酰基-2-溴-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(2)的合成：Synthesis of 5-acetyl-2-bromo-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (2):
将化合物5-乙酰基-6,6-二甲基-5,6-二氢-4H-噻吩[2,3-c]吡咯-4-酮(450.0mg,2.15mmol)溶于醋酸(12.0mL)与水(10.0mL)混合溶液中，将体系冷却至0℃，往体系中缓慢滴加液溴(377.9mg,2.36mmol)，滴加完毕后，保持0℃继续反应1小时。待反应完全，加水(15mL)稀释，用乙酸乙酯萃取(15mL×3)，合并有机相，依次用饱和亚硫酸钠水溶液(15mL)和饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝10:1)得到白色固体(583.2mg)。LC-MS:[M+H]+:288.0,290.0。Compound 5-acetyl-6,6-dimethyl-5,6-dihydro-4H-thiophene[2,3-c]pyrrol-4-one (450.0mg, 2.15mmol) was dissolved in acetic acid (12.0mL ) and water (10.0 mL), cool the system to 0°C, and slowly add liquid bromine (377.9 mg, 2.36 mmol) dropwise into the system. After the dropwise addition is completed, maintain 0°C and continue the reaction for 1 hour. When the reaction is complete, add water (15 mL) to dilute, extract with ethyl acetate (15 mL × 3), combine the organic phases, wash with saturated aqueous sodium sulfite solution (15 mL) and saturated brine (10 mL), dry over anhydrous sodium sulfate, and filter. Concentrate to obtain crude product. Separate by column chromatography (DCM:MeOH=10:1) to obtain a white solid (583.2 mg). LC-MS: [M+H] + :288.0, 290.0.
5-乙酰基-6,6-二甲基-2-硼酸频那醇酯-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(3)的合成：Synthesis of 5-acetyl-6,6-dimethyl-2-boronic acid pinacol ester-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (3):
将化合物5-乙酰基-2-溴-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(100.0mg,0.35mmol)、醋酸钾(102.4mg,1.04mmol)、1,1-双(二苯基膦)二茂铁二氯化钯(25.4mg,0.04mmol)、联硼酸频那醇酯(114.8mg,0.45mmol)溶于1,4-二氧六环(3mL)中。对体系进行抽真空置换氮气三次，加热至80℃反应1小时，待反应完全，将反应冷却至室温。体系为棕黑色混浊溶液，不需要进一步处理，直接用于下一步反应。LC-MS:[M+H]+:336.2。Compound 5-acetyl-2-bromo-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (100.0 mg, 0.35 mmol), Potassium acetate (102.4mg, 1.04mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (25.4mg, 0.04mmol), pinacol diborate (114.8mg, 0.45mmol) dissolved in 1,4-dioxane (3 mL). The system was evacuated and replaced with nitrogen three times, heated to 80°C and reacted for 1 hour. When the reaction was complete, the reaction was cooled to room temperature. The system was a brown-black turbid solution, which did not require further treatment and was used directly for the next reaction. LC-MS: [M+H] + :336.2.
5-乙酰基-2-(5-氯-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(4)的合成：5-acetyl-2-(5-chloro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl Synthesis of )-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (4):
将化合物5-乙酰基-6,6-二甲基-2-硼酸频那醇酯-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(81.5mg,0.24mmol)、4,5-二氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(common int-5)(123.0mg,0.29mmol)、1,1-双(二苯基膦)二茂铁二氯化钯(17.8mg,0.02mmol)、磷酸钾(154.7mg,0.73mmol)溶于1,4-二氧六环(2.5mL)溶液中，对体系进行抽真空置换氮气三次，加热至90℃反应2小时后将反应冷却至室温。反应液加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)，合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，经制备分离得淡黄色固体(72.1mg)。LC-MS:[M+H]+:595.1。The compound 5-acetyl-6,6-dimethyl-2-boronic acid pinacol ester-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (81.5 mg, 0.24mmol), 4,5-dichloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (common int- 5) (123.0mg, 0.29mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (17.8mg, 0.02mmol), potassium phosphate (154.7mg, 0.73mmol) were dissolved in 1,4 -In the dioxane (2.5 mL) solution, evacuate the system and replace the nitrogen three times, heat to 90°C and react for 2 hours, then cool the reaction to room temperature. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL A crude product was obtained, and a light yellow solid (72.1 mg) was obtained through preparation and isolation. LC-MS: [M+H] + :595.1.
2-(5-氯-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并 [2,3-c]吡咯-4-酮(PR-01-096)的合成：2-(5-chloro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-6,6 -Dimethyl-5,6-dihydro-4H-thieno Synthesis of [2,3-c]pyrrole-4-one (PR-01-096):
将化合物5-乙酰基-2-(5-氯-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(100.0mg,0.17mmol)、氢氧化钠(20.2mg,0.51mmol)溶于甲醇(4.0mL)与水(4.0mL)的混合溶液中，室温搅拌反应2小时。待反应完全，加水(10mL)稀释，水相用乙酸乙酯萃取(10mL×3)，合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到粗品，经制备分离得黄色固体(2.5mg)。1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),8.30(s,1H),7.90(d,J＝2.8Hz,1H),7.27(dd,J＝9.2,1.2Hz,1H),6.83(dd,J＝9.2,2.8Hz,1H),3.89(m,2H),3.61(m,2H),3.29(m,2H),3.17(m,2H),2.97(s,3H),1.63(s,6H)；LC-MS：[M+H]+:553.1。Compound 5-acetyl-2-(5-chloro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidine-4 -yl)-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (100.0mg, 0.17mmol), sodium hydroxide (20.2mg, 0.51 mmol) was dissolved in a mixed solution of methanol (4.0 mL) and water (4.0 mL), and the reaction was stirred at room temperature for 2 hours. When the reaction is complete, add water (10 mL) to dilute, extract the aqueous phase with ethyl acetate (10 mL , filtered, and the filtrate was concentrated to obtain crude product. After preparation and isolation, a yellow solid (2.5 mg) was obtained. 1 H NMR (400MHz, Methanol-d4) δ8.50 (s, 1H), 8.30 (s, 1H), 7.90 (d, J = 2.8Hz, 1H), 7.27 (dd, J = 9.2, 1.2Hz, 1H ),6.83(dd,J＝9.2,2.8Hz,1H),3.89(m,2H),3.61(m,2H),3.29(m,2H),3.17(m,2H),2.97(s,3H) ,1.63(s,6H); LC-MS: [M+H] + :553.1.
实施例19.化合物PR-01-097的合成
Example 19. Synthesis of compound PR-01-097
5-乙酰基-2-(2-氯-5-氟嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(2)的合成：5-acetyl-2-(2-chloro-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole- Synthesis of 4-keto(2):
将化合物5-乙酰基-6,6-二甲基-2-硼酸频哪醇酯-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(116.3mg,0.35mmol)、2,4-二氯-5-氟嘧啶(69.5mg,0.42mmol)、1,1-二(二苯膦基)二茂铁二氯化钯(25.4mg,0.04mmol)、磷酸钾(221.0mg,1.04mmol)溶于1,4-二氧六环(4.0mL)和水(0.4mL)中，对体系进行抽真空置换氮气三次。加热至90℃反应2小时，待反应完全，将反应液冷却至室温。反应液加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)，合并有机相并依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤。有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝10:1)得到白色固体(91.2mg)。LC-MS:[M+H]+:340.0。The compound 5-acetyl-6,6-dimethyl-2-boronic acid pinacol ester-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (116.3 mg, 0.35mmol), 2,4-dichloro-5-fluoropyrimidine (69.5mg, 0.42mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (25.4mg, 0.04mmol), phosphoric acid Potassium (221.0 mg, 1.04 mmol) was dissolved in 1,4-dioxane (4.0 mL) and water (0.4 mL), and the system was evacuated and replaced with nitrogen three times. Heat to 90°C and react for 2 hours. When the reaction is complete, cool the reaction solution to room temperature. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with water (10 mL) and saturated sodium chloride aqueous solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (DCM:MeOH=10:1) to obtain a white solid (91.2 mg). LC-MS: [M+H] + :340.0.
5-乙酰基-2-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(3)的合成：5-acetyl-2-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl Synthesis of )-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (3):
将化合物5-乙酰基-2-(2-氯-5-氟嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(92.0mg,0.27mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(82.0mg,0.30mmol)、醋酸钯(9.0mg,0.04mmol)、1,1'-联萘-2,2'-双二苯膦(33.7mg,0.05mmol)、碳酸铯(176.6mg,0.54mmol)溶于1,4-二氧六环(5.0mL)中，对体系进行抽真空置换氮气三次，加热至100℃反应16小时。待反应完全，将反应冷却至室温。反应液加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)，合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩滤液得到粗品。经硅胶柱层析分离(DCM:MeOH＝10:1)得到黄色固体(98.4mg)。LC-MS:[M+H]+:579.3。Compound 5-acetyl-2-(2-chloro-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c] Pyrrol-4-one (92.0mg, 0.27mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (82.0mg, 0.30mmol) ), palladium acetate (9.0mg, 0.04mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (33.7mg, 0.05mmol), cesium carbonate (176.6mg, 0.54mmol) were dissolved in 1, In 4-dioxane (5.0 mL), the system was evacuated and replaced with nitrogen three times, and heated to 100°C for 16 hours. When the reaction is complete, cool the reaction to room temperature. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL The crude product was obtained from the filtrate. Separate via silica gel column chromatography (DCM:MeOH=10:1) to obtain a yellow solid (98.4 mg). LC-MS: [M+H] + :579.3.
2-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(PR-01-097)的合成： 2-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-6,6 -Synthesis of dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (PR-01-097):
将化合物5-乙酰基-2-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(110.0mg,0.19mmol)、氢氧化钠(22.8mg,0.57mmol)溶于甲醇(4.0mL)与水(4.0mL)的混合溶液中，室温搅拌反应2小时。待反应完全，加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)，合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤。有机相用无水硫酸钠干燥，过滤，浓缩滤液得到粗品，经制备分离得黄色固体(34.4mg)。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.68(s,1H),8.63(d,J＝3.2Hz,1H),7.71(d,J＝1.6Hz,1H),7.55(d,J＝2.8Hz,1H),7.20(d,J＝8.0Hz,1H),6.74(dd,J＝8.8,2.8Hz,1H),3.23–3.15(m,4H),2.47–2.40(m,4H),2.21(s,3H),1.54(s,6H)；LC-MS:[M+H]+:537.2。Compound 5-acetyl-2-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidine-4 -yl)-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (110.0mg, 0.19mmol), sodium hydroxide (22.8mg, 0.57 mmol) was dissolved in a mixed solution of methanol (4.0 mL) and water (4.0 mL), and the reaction was stirred at room temperature for 2 hours. When the reaction is complete, add water (10 mL) to dilute, extract with ethyl acetate (10 mL × 3), combine the organic phases and wash with water (10 mL) and saturated sodium chloride aqueous solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product. After preparation and isolation, a yellow solid (34.4 mg) was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.68 (s, 1H), 8.63 (d, J = 3.2Hz, 1H), 7.71 (d, J = 1.6Hz, 1H), 7.55(d,J＝2.8Hz,1H),7.20(d,J＝8.0Hz,1H),6.74(dd,J＝8.8,2.8Hz,1H),3.23–3.15(m,4H),2.47–2.40 (m,4H),2.21(s,3H),1.54(s,6H); LC-MS: [M+H] + :537.2.
实施例20.化合物PR-01-107的合成
Example 20. Synthesis of compound PR-01-107
5-溴-1-甲基-1,2-二氢-3H-吲唑-3-酮(2)的合成：Synthesis of 5-bromo-1-methyl-1,2-dihydro-3H-indazol-3-one (2):
将5-溴-2-氟苯甲酸甲酯(1.0g,4.29mmol)、甲基肼(0.2g,4.34mmol)溶于N,N-二甲基乙酰胺(10mL)中，在封管中加热至150℃反应8小时后，反应液冷却，加入乙酸乙酯(50mL)稀释，经饱和食盐水洗涤三次后，合并有机相并经由无水硫酸钠干燥，有机相经真空浓缩，由柱层析(石油醚/乙酸乙酯＝1/10)得到无色液体(580.0mg)。LC-MS:[M+H]+:226.9,228.9。Dissolve methyl 5-bromo-2-fluorobenzoate (1.0g, 4.29mmol) and methylhydrazine (0.2g, 4.34mmol) in N,N-dimethylacetamide (10mL) in a sealed tube. After heating to 150°C and reacting for 8 hours, the reaction solution was cooled, diluted with ethyl acetate (50 mL), and washed three times with saturated brine. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and separated from the column layer. After separation (petroleum ether/ethyl acetate = 1/10), a colorless liquid (580.0 mg) was obtained. LC-MS: [M+H] + :226.9, 228.9.
1-甲基-5-硼酸频那醇酯-1,2-二氢-3H-吲唑-3-酮(3)的合成：Synthesis of 1-methyl-5-boronic acid pinacol ester-1,2-dihydro-3H-indazol-3-one (3):
将化合物5-溴-1-甲基-1,2-二氢-3H-吲唑-3-酮(250.0mg,1.10mmol)、联硼酸频那醇酯(419.3mg,1.65mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(89.9mg,0.11mmol)及乙酸钾(324.2mg,3.30mmol)溶于1,4-二氧六环(2mL)中，氮气保护下加热至80℃下反应3小时。向反应液中加入乙酸乙酯(10mL)稀释，过滤。滤液用水和饱和食盐水洗涤三次，合并有机相并用无水硫酸钠干燥，浓缩经柱层析(石油醚/乙酸乙酯＝1/8)纯化，得到白色固体产物(210.0mg)。LC-MS:[M+H]+:275.1。Compound 5-bromo-1-methyl-1,2-dihydro-3H-indazol-3-one (250.0 mg, 1.10 mmol), pinacol diborate (419.3 mg, 1.65 mmol), [1 ,1'-Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (89.9mg, 0.11mmol) and potassium acetate (324.2mg, 3.30mmol) were dissolved in 1,4-dioxy Six rings (2 mL), heated to 80°C under nitrogen protection and reacted for 3 hours. Ethyl acetate (10 mL) was added to the reaction solution to dilute and filtered. The filtrate was washed three times with water and saturated brine, the organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (petroleum ether/ethyl acetate = 1/8) to obtain a white solid product (210.0 mg). LC-MS: [M+H] + :275.1.
5-(2-氯-5-氟嘧啶-4-基)-1-甲基-1,2-二氢-3H-吲唑-3-酮(4)的合成：Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1,2-dihydro-3H-indazol-3-one (4):
将化合物1-甲基-5-硼酸频那醇酯-1,2-二氢-3H-吲唑-3-酮(200.0mg,0.73mmol)、2,4-二氯-5-氟嘧啶(182.7mg,1.09mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(59.6mg,0.07mmol)及磷酸钾(464.6mg,2.19mmol)溶于1,4-二氧六环(2mL)和水(2mL)中，氮气保护下加热至80℃下反应2小时。 向反应液中加入乙酸乙酯(10mL)稀释，萃取分液。合并有机相并用无水硫酸钠干燥，浓缩经柱层析(石油醚/乙酸乙酯＝1/3)纯化，得到白色固体产物(130.0mg)。LC-MS:[M+H]+:279.0。Compound 1-methyl-5-boronic acid pinacol ester-1,2-dihydro-3H-indazol-3-one (200.0 mg, 0.73 mmol), 2,4-dichloro-5-fluoropyrimidine ( 182.7mg, 1.09mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (59.6mg, 0.07mmol) and potassium phosphate (464.6mg, 2.19mmol) ) was dissolved in 1,4-dioxane (2mL) and water (2mL), heated to 80°C under nitrogen protection and reacted for 2 hours. Ethyl acetate (10 mL) was added to the reaction solution to dilute, and the mixture was extracted and separated. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (petroleum ether/ethyl acetate = 1/3) to obtain a white solid product (130.0 mg). LC-MS: [M+H] + :279.0.
5-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-甲基-1,2-二氢-3H-吲唑-3-酮(PR-01-107)的合成：5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-methyl Synthesis of base-1,2-dihydro-3H-indazol-3-one (PR-01-107):
将化合物5-(2-氯-5-氟嘧啶-4-基)-1-甲基-1,2-二氢-3H-吲唑-3-酮(100.0mg,0.36mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(59.5mg,0.22mmol)、碳酸铯(223.0mg,0.69mmol)、1,1'-联萘-2,2'-双二苯膦(44.7mg,0.07mmol)和醋酸钯(11.2mg,0.05mmol)溶于1,4-二氧六环(2mL)中，氮气保护下加热至100℃下反应4小时。反应液中加入乙酸乙酯(10mL)稀释，萃取分液。合并有机相并用无水硫酸钠干燥，浓缩经反相制备纯化，得到浅黄色固体产物(96.0mg)。1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.48(d,J＝2.8Hz,1H),7.64(d,J＝8.8Hz,1H),7.46–7.40(m,2H),7.11–6.99(m,2H),6.91(d,J＝2.8Hz,1H),6.66(dd,J＝6.4,2.8Hz,1H),3.99(s,3H),2.94–2.87(m,4H),2.39–2.31(m,4H),2.20(s,3H)；LC-MS:[M+H]+:518.3。Compound 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1,2-dihydro-3H-indazol-3-one (100.0 mg, 0.36 mmol), 5-( 4-Methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (59.5mg, 0.22mmol), cesium carbonate (223.0mg, 0.69mmol), 1,1'-Binaphthyl-2,2'-bisdiphenylphosphine (44.7mg, 0.07mmol) and palladium acetate (11.2mg, 0.05mmol) were dissolved in 1,4-dioxane (2mL), and heated to React at 100°C for 4 hours. Ethyl acetate (10 mL) was added to the reaction solution to dilute, and the mixture was extracted and separated. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by reverse phase preparation to obtain a light yellow solid product (96.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.48(d,J＝2.8Hz,1H),7.64(d,J＝8.8Hz,1H),7.46–7.40(m,2H ),7.11–6.99(m,2H),6.91(d,J＝2.8Hz,1H),6.66(dd,J＝6.4,2.8Hz,1H),3.99(s,3H),2.94–2.87(m, 4H), 2.39–2.31 (m, 4H), 2.20 (s, 3H); LC-MS: [M+H] + : 518.3.
实施例21.化合物PR-01-083、PR-01-083A、PR-01-083B的合成
Example 21. Synthesis of compounds PR-01-083, PR-01-083A, and PR-01-083B
6-溴-1-氧代异吲哚-2-甲酸叔丁酯(2)的合成：Synthesis of tert-butyl 6-bromo-1-oxoisoindole-2-carboxylate (2):
将化合物6-溴-1-异吲哚啉酮(1.0g,4.72mmol)溶于二氯甲烷(20mL)中，冰浴下加入二碳酸二叔丁酯(1.5g,6.87mmol)和4-二甲胺基吡啶(288.3mg,2.36mmol)并升至室温搅拌6小时。反应液倒入水中(20mL)，然后用二氯甲烷萃取(40mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经柱层析(石油醚:乙酸乙酯＝10:1,Rf＝0.5)纯化得到白色固体(1.2g)。LC-MS:[M+H]+:314.0。Compound 6-bromo-1-isoindolinone (1.0g, 4.72mmol) was dissolved in dichloromethane (20mL), and di-tert-butyl dicarbonate (1.5g, 6.87mmol) and 4-dicarbonate were added under ice bath. dimethylaminopyridine (288.3 mg, 2.36 mmol) and warmed to room temperature and stirred for 6 hours. The reaction solution was poured into water (20 mL), and then extracted with dichloromethane (40 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to column chromatography (petroleum ether: ethyl acetate = 10 :1, Rf=0.5) and purified to obtain a white solid (1.2g). LC-MS: [M+H] + :314.0.
5-溴-1-甲基-3-氧代异吲哚-2-甲酸叔丁酯(3)的合成：Synthesis of 5-bromo-1-methyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (3):
将化合物6-溴-1-氧代异吲哚-2-甲酸叔丁酯(500.0mg,1.60mmol)溶于无水四氢呋喃(5mL)中，氮气置换三次并将反应降温至-78℃，保护条件下逐滴加入1M双三甲基硅基胺基锂(1.9mL,1.92mmol)，保持恒温条件下反应1个小时后加入碘甲烷(454.9mg,3.20mmol)。反应液逐步升至室温搅拌2小时，待反应完成将反应液倒入氯化铵水溶液中(20mL)，然后用乙酸乙酯萃取(40mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经层析柱(石油醚:乙酸乙酯＝10:1,Rf＝0.6)纯化得到浅黄色油状(250.0mg)。LC-MS:[M-tBu+H]+:270.0,272.0。Compound 6-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester (500.0 mg, 1.60 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), replaced with nitrogen three times, and the reaction was cooled to -78°C and protected. 1M lithium bistrimethylsilylamide (1.9 mL, 1.92 mmol) was added dropwise under the same conditions, and methyl iodide (454.9 mg, 3.20 mmol) was added after the reaction was maintained at constant temperature for 1 hour. The reaction solution was gradually raised to room temperature and stirred for 2 hours. When the reaction was completed, the reaction solution was poured into an aqueous ammonium chloride solution (20mL), and then extracted with ethyl acetate (40mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. , concentrated to dryness, and purified by chromatography column (petroleum ether: ethyl acetate = 10:1, Rf = 0.6) to obtain light yellow oil (250.0 mg). LC-MS: [M- tBu +H] + : 270.0, 272.0.
1-甲基-3-氧代-5-硼酸频哪醇酯异吲哚-2-羧酸叔丁酯(4)的合成： Synthesis of 1-methyl-3-oxo-5-boronic acid pinacol ester isoindole-2-carboxylic acid tert-butyl ester (4):
将化合物5-溴-1-甲基-3-氧代异吲哚-2-甲酸叔丁酯(250.0mg,0.77mmol)溶于1,4-二氧六环(5mL)中，依次加入1,1'-双(二苯基膦)二茂铁]二氯化钯(56.1mg,0.08mmol)、联硼酸频那醇酯(253.0mg,1.00mmol)和乙酸钾(225.7mg,2.30mmol)并用氮气置换3次。将反应液升温至80℃条件下反应2个小时。待反应完成将反应液加水(15mL)和乙酸乙酯(20mL×3)洗萃，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经层析柱(石油醚:乙酸乙酯＝30:1,Rf＝0.5)纯化，浓缩得到黄色油状(242.0mg)。LC-MS:[M-Boc+H]-:272.0。Dissolve compound 5-bromo-1-methyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (250.0 mg, 0.77mmol) in 1,4-dioxane (5 mL), and add 1 ,1'-Bis(diphenylphosphine)ferrocene]palladium dichloride (56.1mg, 0.08mmol), pinacol diborate (253.0mg, 1.00mmol) and potassium acetate (225.7mg, 2.30mmol) And replaced with nitrogen three times. The reaction solution was heated to 80°C and reacted for 2 hours. After the reaction is completed, add water (15 mL) and ethyl acetate (20 mL 30:1, Rf=0.5), and concentrated to obtain yellow oil (242.0 mg). LC-MS: [M-Boc+H] - :272.0.
5-(2-氯-5-氟嘧啶-4-基)-1-甲基-3-氧代异吲哚-2-羧酸叔丁酯(5)的合成：Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (5):
将化合物1-甲基-3-氧代-5-硼酸频哪醇酯异吲哚-2-羧酸叔丁酯(240.0mg,0.64mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(47.1mg,0.06mmol)溶于1,4-二氧六环(6mL)和水(2mL)中，氮气保护条件下加入磷酸钾(409.4mg,1.93mmol)，反应液升至100℃反应1小时。待反应完成将反应液倒入水溶液中(30mL)，然后用乙酸乙酯萃取(30mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经层析柱(石油醚:乙酸乙酯＝5:1,Rf＝0.5)纯化得到黄色固体(94.0mg)。LC-MS:[M-tBu+H]+:322.0。The compound 1-methyl-3-oxo-5-boronic acid pinacol ester isoindole-2-carboxylic acid tert-butyl ester (240.0 mg, 0.64 mmol) and 1,1'-bis(diphenylphosphine) Ferrocene]palladium dichloride (47.1 mg, 0.06 mmol) was dissolved in 1,4-dioxane (6 mL) and water (2 mL), and potassium phosphate (409.4 mg, 1.93 mmol) was added under nitrogen protection. The reaction solution was raised to 100°C and reacted for 1 hour. When the reaction is completed, pour the reaction solution into an aqueous solution (30 mL), and then extract with ethyl acetate (30 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and passed through a chromatography column (petroleum ether: Ethyl acetate = 5:1, Rf = 0.5) was purified to obtain a yellow solid (94.0 mg). LC-MS: [M- tBu +H] + : 322.0.
5-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-甲基-3-氧代异吲哚-2-羧酸叔丁酯(6)的合成：5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-methyl Synthesis of tert-butyl-3-oxoisoindole-2-carboxylate (6):
将化合物5-(2-氯-5-氟嘧啶-4-基)-1-甲基-3-氧代异吲哚-2-羧酸叔丁酯(80.0mg,0.21mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(58.3mg,0.21mmol)、醋酸钯(6.7mg,0.03mmol)和1,1'-联萘-2,2'-双二苯膦(26.4mg,0.04mmol)溶于无水1,4-二氧六环(3mL)中，氮气保护下加入碳酸铯(138.0mg,0.42mmol)，反应液升至90℃反应5个小时。待反应完全后加水稀释(20mL)，用二氯甲烷萃取(30mL×3)。合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经制备TLC纯化(二氯甲烷:甲醇＝20:1,Rf＝0.4)得黄色固体(95.0mg)。LC-MS:[M+H]+:617.2。Compound 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (80.0 mg, 0.21 mmol), 5-( 4-Methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (58.3 mg, 0.21 mmol), palladium acetate (6.7 mg, 0.03 mmol) and 1,1'-Binaphthyl-2,2'-bisdiphenylphosphine (26.4mg, 0.04mmol) was dissolved in anhydrous 1,4-dioxane (3mL), and cesium carbonate (138.0mg, 0.42mmol) was added under nitrogen protection. , the reaction solution was raised to 90°C and reacted for 5 hours. After the reaction is complete, add water to dilute (20 mL), and extract with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by preparative TLC (dichloromethane:methanol=20:1, Rf=0.4) to obtain a yellow solid (95.0 mg). LC-MS: [M+H] + :617.2.
6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3-甲基异吲哚-1-酮(PR-01-083)的合成：6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-3-methyl Synthesis of isoindol-1-one (PR-01-083):
将化合物5-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1-甲基-3-氧代异吲哚-2-羧酸叔丁酯(20.0mg,0.03mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.2mL)后室温搅拌1小时，反应液浓缩至干，经制备分离得到白色固体(2.5mg)。1H NMR(400MHz,CDCl3)δ8.57(s,1H),8.44(s,1H),8.38(d,J＝7.6Hz,1H),8.31(s,1H),7.57(d,J＝8.0Hz,1H),7.46(s,1H),7.16(d,J＝9.2Hz,1H),6.55(d,J＝8.4Hz,1H),6.20(s,1H),4.79(d,J＝6.4Hz,1H),3.28(s,4H),2.60(s,4H),2.38(s,3H),1.56(s,3H)；LC-MS:[M+H]+:517.3。Compound 5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1 -Methyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (20.0mg, 0.03mmol) was dissolved in dichloromethane (1mL), trifluoroacetic acid (0.2mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, and a white solid (2.5 mg) was obtained by preparation and isolation. 1 H NMR (400MHz, CDCl 3 ) δ8.57(s,1H),8.44(s,1H),8.38(d,J＝7.6Hz,1H),8.31(s,1H),7.57(d,J＝ 8.0Hz,1H),7.46(s,1H),7.16(d,J＝9.2Hz,1H),6.55(d,J＝8.4Hz,1H),6.20(s,1H),4.79(d,J＝ 6.4Hz, 1H), 3.28 (s, 4H), 2.60 (s, 4H), 2.38 (s, 3H), 1.56 (s, 3H); LC-MS: [M+H] + : 517.3.
消旋体PR-01-083经过SFC分离纯化(色谱柱：ChiralPak IB,250×30mm I.D.,5μm；流动相：A相：二氧化碳，B相：[MEOH+0.1％7mol/L NH3]；梯度：B％：20％-20％,10.8min；120min)后得到白色固体PR-01-083A和PR-01-083B。Racemate PR-01-083 was separated and purified by SFC (chromatographic column: ChiralPak IB, 250×30mm ID, 5μm; mobile phase: phase A: carbon dioxide, phase B: [MEOH+0.1% 7mol/L NH 3 ]; gradient :B%: 20%-20%, 10.8min; 120min), white solid PR-01-083A and PR-01-083B were obtained.
PR-01-083A:PR-01-083A:
手性分析条件：色谱柱：CHIRALPAK IB 100*4.6mm 5μm；流动相：A相：二氧化碳；B相：MeOH(0.05％DEA v/v)；梯度：B％：20％-20％；保留时间：3.059min；ee％＝99.7％。Chiral analysis conditions: chromatographic column: CHIRALPAK IB 100*4.6mm 5μm; mobile phase: A phase: carbon dioxide; B phase: MeOH (0.05% DEA v/v); gradient: B%: 20%-20%; retention time :3.059min;ee%=99.7%.
1H NMR(400MHz,MeOD)δ8.48(s,2H),8.31(d,J＝8.0Hz,1H),8.20(s,1H),7.72(d,J＝8.0Hz,1H),7.24(d,J＝9.2Hz,1H),6.76(d,J＝8.8Hz,1H),4.81–4.76(m,1H),3.47(s,6H),3.31(s,2H),2.99(s, 3H),1.52(d,J＝6.4Hz,3H)；LC-MS:[M+H]+:517.2。 1 H NMR (400MHz, MeOD) δ8.48(s,2H),8.31(d,J＝8.0Hz,1H),8.20(s,1H),7.72(d,J＝8.0Hz,1H),7.24( d,J＝9.2Hz,1H),6.76(d,J＝8.8Hz,1H),4.81–4.76(m,1H),3.47(s,6H),3.31(s,2H),2.99(s, 3H), 1.52 (d, J=6.4Hz, 3H); LC-MS: [M+H] + : 517.2.
PR-01-083B:PR-01-083B:
手性分析条件：色谱柱：CHIRALPAK IB 100*4.6mm 5μm；流动相：A相：二氧化碳；B相：MeOH(0.05％DEA v/v)；梯度：B％：20％-20％；保留时间：3.692min；ee％＝99.1％。Chiral analysis conditions: chromatographic column: CHIRALPAK IB 100*4.6mm 5μm; mobile phase: A phase: carbon dioxide; B phase: MeOH (0.05% DEA v/v); gradient: B%: 20%-20%; retention time :3.692min;ee%=99.1%.
1H NMR(400MHz,MeOD)δ8.51(s,1H),8.46(s,1H),8.37(d,J＝8.0Hz,1H),8.13(s,1H),7.74(d,J＝8.4Hz,1H),7.19(d,J＝8.8Hz,1H),6.69(d,J＝9.2Hz,1H),4.81(q,J＝6.4Hz,1H),3.24(s,4H),2.61(s,4H),2.35(s,3H),1.52(d,J＝6.8Hz,3H)；LC-MS:[M+H]+:517.2。 1 H NMR (400MHz, MeOD) δ8.51 (s, 1H), 8.46 (s, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.13 (s, 1H), 7.74 (d, J = 8.4 Hz,1H),7.19(d,J＝8.8Hz,1H),6.69(d,J＝9.2Hz,1H),4.81(q,J＝6.4Hz,1H),3.24(s,4H),2.61( s, 4H), 2.35 (s, 3H), 1.52 (d, J = 6.8Hz, 3H); LC-MS: [M+H] + : 517.2.
实施例22.化合物PR-01-104的合成
Example 22. Synthesis of compound PR-01-104
6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(2,2,2-三氟乙氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-104)的合成：6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrimidine-4- Synthesis of 3,3-dimethylisoindol-1-one (PR-01-104):
将6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(150.0mg,0.51mmol)、5-(4-甲基哌嗪-1-基)-2-(2,2,2-三氟乙氧基)苯胺(common int-6)(223.1mg,0.77mmol)、醋酸钯(15.7mg,0.07mmol)、1,1'-联萘-2,2'-双二苯膦(64.0mg,0.10mmol)及碳酸铯(502.6mg,1.54mmol)悬浮于1,4-二氧六环(2mL)中，氮气保护下加热至100℃反应3小时后，反应液冷却，过滤。滤液浓缩后得到的棕色固体粗品经制备纯化得到黄色固体(59.8mg)。1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.65(d,J＝3.6Hz,1H),8.28(s,1H),8.24–8.16(m,2H),7.87–7.77(m,2H),7.08(d,J＝8.8Hz,1H),6.66–6.62(m,1H),8.24–8.16(m,2H),3.09–3.07(m,4H),2.49–2.43(m,4H),2.23(s,3H),1.50(s,6H)；LC-MS:[M+H]+:545.2。6-(2-Chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (150.0 mg, 0.51 mmol), 5-(4-methylpiperazine- 1-yl)-2-(2,2,2-trifluoroethoxy)aniline (common int-6) (223.1mg, 0.77mmol), palladium acetate (15.7mg, 0.07mmol), 1,1'- Binaphthyl-2,2'-bisdiphenylphosphine (64.0mg, 0.10mmol) and cesium carbonate (502.6mg, 1.54mmol) were suspended in 1,4-dioxane (2mL), and heated to 100 under nitrogen protection. After reacting for 3 hours at ℃, the reaction solution was cooled and filtered. The crude brown solid obtained after the filtrate was concentrated was preparatively and purified to obtain a yellow solid (59.8 mg). 1 H NMR (400MHz, DMSO-d6) δ8.83 (s, 1H), 8.65 (d, J = 3.6Hz, 1H), 8.28 (s, 1H), 8.24–8.16 (m, 2H), 7.87–7.77 (m,2H),7.08(d,J＝8.8Hz,1H),6.66–6.62(m,1H),8.24–8.16(m,2H),3.09–3.07(m,4H),2.49–2.43(m ,4H), 2.23(s,3H),1.50(s,6H); LC-MS: [M+H] + :545.2.
实施例23.化合物PR-01-121的合成
Example 23. Synthesis of compound PR-01-121
4-溴-1-(二氟甲氧基)-2-硝基苯(2)的合成：Synthesis of 4-bromo-1-(difluoromethoxy)-2-nitrobenzene (2):
将化合物4-溴-2-硝基苯酚(1.0g,4.59mmol)溶于无水四氢呋喃(20.0mL)中，氮气置换3次，冰浴条件下加入60％氢化钠(1.8g,45.87mmol)并搅拌0.5小时。缓慢滴加溴二氟甲基膦酸二乙酯(2.5g,9.36mmol)并将反应升至室温反应2个小时，反应液倒入冰水中(20.0mL)，然后用乙酸乙酯萃取(30.0mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩至干。粗品经硅胶柱层析(石油醚:乙酸乙酯＝20:1-5:1)纯化得到浅黄色油状物(897.0mg)。1H NMR(400MHz,DMSO)δ8.34(s,1H),8.00(d,J＝8.8Hz,1H),7.50(d,J＝8.8Hz,1H),7.37(t,J＝72.0Hz,1H)。Compound 4-bromo-2-nitrophenol (1.0g, 4.59mmol) was dissolved in anhydrous tetrahydrofuran (20.0mL), replaced with nitrogen three times, and 60% sodium hydride (1.8g, 45.87mmol) was added under ice bath conditions. and stir for 0.5 hours. Diethyl bromodifluoromethylphosphonate (2.5g, 9.36mmol) was slowly added dropwise and the reaction was raised to room temperature for 2 hours. The reaction solution was poured into ice water (20.0mL), and then extracted with ethyl acetate (30.0 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-5:1) to obtain a light yellow oil (897.0 mg). 1 H NMR (400MHz, DMSO) δ8.34 (s, 1H), 8.00 (d, J = 8.8Hz, 1H), 7.50 (d, J = 8.8Hz, 1H), 7.37 (t, J = 72.0Hz, 1H).
1-(4-(二氟甲氧基)-3-硝基苯基)-4-甲基哌嗪(3)的合成：Synthesis of 1-(4-(difluoromethoxy)-3-nitrophenyl)-4-methylpiperazine (3):
将化合物4-溴-1-(二氟甲氧基)-2-硝基苯(550.0mg,2.05mmol)溶于无水甲苯(6.0mL)中，依次加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(121.5mg,0.21mmol)和三(二亚苄基丙酮)二钯(94.0mg,0.10mmol)。氮气保护条件下加入碳酸铯(1.3g,4.0mmol)和N-甲基哌嗪(308.4mg,3.08mmol)，反应液升至90℃反应12个小时。待反应完全后将反应液倒入水中(20.0mL)，然后用乙酸乙酯萃取(30.0mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩至干。粗品经硅胶层析柱(二氯甲烷:甲醇＝10:1)纯化得到棕色油状物(490.0mg)。LC-MS:[M+1]+:288.1。Compound 4-bromo-1-(difluoromethoxy)-2-nitrobenzene (550.0 mg, 2.05 mmol) was dissolved in anhydrous toluene (6.0 mL), and 4,5-bisdiphenylphosphine was added successively -9,9-dimethylxanthene (121.5 mg, 0.21 mmol) and tris(dibenzylideneacetone)dipalladium (94.0 mg, 0.10 mmol). Cesium carbonate (1.3g, 4.0mmol) and N-methylpiperazine (308.4mg, 3.08mmol) were added under nitrogen protection, and the reaction solution was raised to 90°C for 12 hours. After the reaction is complete, pour the reaction solution into water (20.0 mL), and then extract with ethyl acetate (30.0 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography column (dichloromethane:methanol=10:1) to obtain brown oil (490.0 mg). LC-MS: [M+1] + :288.1.
2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)苯胺(4)的合成：Synthesis of 2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)aniline (4):
将化合物1-(4-(二氟甲氧基)-3-硝基苯基)-4-甲基哌嗪(100.0mg,0.35mmol)溶于乙酸乙酯(2.0mL)中，氮气保护下加入钯碳(20％)(30.0mg)并用氢气置换3次。将反应液升温至40℃条件下反应16个小时。待反应完成将反应液垫硅藻土过滤，滤饼用少量乙酸乙酯洗涤两次，浓缩得到黄色固体(65.0mg)。LC-MS:[M+1]+:258.2。Compound 1-(4-(difluoromethoxy)-3-nitrophenyl)-4-methylpiperazine (100.0 mg, 0.35 mmol) was dissolved in ethyl acetate (2.0 mL) under nitrogen protection. Palladium on carbon (20%) (30.0 mg) was added and replaced with hydrogen three times. The reaction solution was heated to 40°C and reacted for 16 hours. After the reaction is completed, the reaction solution is filtered through diatomaceous earth, and the filter cake is washed twice with a small amount of ethyl acetate and concentrated to obtain a yellow solid (65.0 mg). LC-MS: [M+1] + :258.2.
6-(2-((2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-121)的合成：6-(2-((2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3 -Synthesis of dimethylisoindol-1-one (PR-01-121):
将化合物2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)苯胺(50.0mg,0.20mmol)、6-(2-氯-5-氟嘧啶-4-基)-3,3- 二甲基异吲哚-1-酮(common int-7)(56.7mg,0.19mmol)、醋酸钯(5.8mg,0.026mmol)和1,1'-联萘-2,2'-双二苯膦(24.2mg,0.04mmol)溶于无水1,4-二氧六环(3mL)中，氮气保护条件下加入碳酸铯(126.6mg,0.39mmol)，反应液升至70℃条件下反应5小时。待反应完成将反应液倒入水溶液中(20mL)，然后用二氯甲烷萃取(20mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩至干，经制备分离纯化得到黄色固体(21.5mg)。1H NMR(400MHz,DMSO)δ8.82(s,1H),8.65(d,J＝3.6Hz,2H),8.23–8.19(m,2H),7.82(d,J＝8.0Hz,1H),7.67(s,1H),7.09(d,J＝8.8Hz,1H),6.96(t,J＝74.8Hz,1H),6.70(d,J＝9.2Hz,1H),3.12(s,4H),2.43(s,4H),2.21(s,3H),1.49(s,6H)；LC-MS:[M+1]+:513.3。Compound 2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)aniline (50.0mg, 0.20mmol), 6-(2-chloro-5-fluoropyrimidin-4-yl) )-3,3- Dimethylisoindol-1-one (common int-7) (56.7mg, 0.19mmol), palladium acetate (5.8mg, 0.026mmol) and 1,1'-binaphthyl-2,2'-biphenyl Phosphine (24.2 mg, 0.04 mmol) was dissolved in anhydrous 1,4-dioxane (3 mL), cesium carbonate (126.6 mg, 0.39 mmol) was added under nitrogen protection, and the reaction solution was raised to 70°C for reaction 5 Hour. When the reaction is completed, pour the reaction solution into an aqueous solution (20 mL), and then extract with dichloromethane (20 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. After preparation, separation and purification, a yellow solid ( 21.5mg). 1 H NMR (400MHz, DMSO) δ8.82 (s, 1H), 8.65 (d, J = 3.6Hz, 2H), 8.23–8.19 (m, 2H), 7.82 (d, J = 8.0Hz, 1H), 7.67(s,1H),7.09(d,J＝8.8Hz,1H),6.96(t,J＝74.8Hz,1H),6.70(d,J＝9.2Hz,1H),3.12(s,4H), 2.43 (s, 4H), 2.21 (s, 3H), 1.49 (s, 6H); LC-MS: [M+1] + : 513.3.
实施例24.化合物DP-01-140的合成
Example 24. Synthesis of compound DP-01-140
5-(2-((5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-基)氨基)-5-氟嘧啶-4-基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(2)的合成：5-(2-((5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-yl)amino)-5-fluoropyrimidin-4-yl)- Synthesis of 1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (2):
向5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-胺(common int-13)(200.0mg,0.77mmol)和5-(2-氯-5-氟嘧啶-4-基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(303.4mg,0.77mmol)的甲苯(10mL)溶液中依次加入1,1'-联萘-2,2'-双二苯膦(96.39mg,0.16mmol)、三(二亚苄基丙酮)二钯(141.8mg,0.16mmol)和碳酸铯(756.6mg,2.32mmol)，在氮气保护下，80℃搅拌反应2小时。反应液冷却至室温，加水(20mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相，分别用水(20mL)和盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩。粗品经硅胶柱层析(二氯甲烷:甲醇＝0-10％)纯化得到白色固体(315.0mg)。LC-MS:[M+H]+:614.2To 5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-amine (common int-13) (200.0 mg, 0.77 mmol) and 5-(2-chloro -5-fluoropyrimidin-4-yl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylic acid tert-butyl ester (303.4 mg, 0.77 mmol) in toluene (10 mL) Add 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (96.39mg, 0.16mmol), tris(dibenzylideneacetone)dipalladium (141.8mg, 0.16mmol) and cesium carbonate (756.6mg). 2.32mmol), stirred and reacted at 80°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=0-10%) to obtain a white solid (315.0 mg). LC-MS:[M+H] + :614.2
6-(2-((5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(DP-01-140)的合成：6-(2-((5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-yl)amino)-5-fluoropyrimidin-4-yl)- Synthesis of 3,3-dimethylisoindol-1-one (DP-01-140):
室温下，将5-(2-((5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-基)氨基)-5-氟嘧啶-4-基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(315.0mg,0.51mmol)溶于二氯甲烷(10mL)中，将三氟乙酸(2mL)加入反应液中并搅拌1小时。反应液浓缩所得粗品经制备纯化得白色固体(140.0mg)。1H NMR(400MHz,DMSO-d6)δ8.86(s,2H),8.80(s,1H),8.28–8.25(m,2H),7.95(s,2H),7.85(d,J＝8.0Hz,1H),7.03(t,J＝73.6Hz,1H),3.45(s,4H),2.39(s,4H),2.20(s,3H),1.51(s,6H)；LC-MS:[M+H]+:514.2。At room temperature, 5-(2-((5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-yl)amino)-5-fluoropyrimidine-4 -1,1-Dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (315.0 mg, 0.51 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL ) was added to the reaction solution and stirred for 1 hour. The crude product obtained by concentrating the reaction solution was preparatively and purified to obtain a white solid (140.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.86 (s, 2H), 8.80 (s, 1H), 8.28–8.25 (m, 2H), 7.95 (s, 2H), 7.85 (d, J＝8.0Hz ,1H),7.03(t,J=73.6Hz,1H),3.45(s,4H),2.39(s,4H),2.20(s,3H),1.51(s,6H); LC-MS:[M +H] + :514.2.
实施例25.化合物PR-01-105的合成
Example 25. Synthesis of compound PR-01-105
5-溴-3-碘-2-甲基苯甲酸甲酯(2)的合成：Synthesis of methyl 5-bromo-3-iodo-2-methylbenzoate (2):
将2-甲基-3-氨基-5-溴苯甲酸甲酯(5.0g,20.48mmol)溶解在6N盐酸(60mL,360.00mmol)水溶液中-5℃下，将亚硝酸钠(1.6g,23.19mmol)溶解在水(20mL)中并滴加到反应体系中，待反应30分钟后将碘化钠(3.4g,22.68mmol)溶解在水(20mL)中并缓慢滴加到反应体系中，反应液升到室温并在90℃反应1个小时。冷却反应，乙酸乙酯(15mL×3)萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，干燥，旋干，粗产品经柱层析(石油醚:乙酸乙酯＝10:1)纯化得到棕色固体(4.8g)。1H NMR(400MHz,DMSO)δ8.25(d,J＝2.0Hz,1H),7.86(d,J＝2.0Hz,1H),3.84(s,3H),2.49(s,3H)。Dissolve 2-methyl-3-amino-5-bromobenzoic acid methyl ester (5.0g, 20.48mmol) in 6N hydrochloric acid (60mL, 360.00mmol) aqueous solution at -5°C, and add sodium nitrite (1.6g, 23.19 mmol) in water (20 mL) and added dropwise to the reaction system. After 30 minutes of reaction, sodium iodide (3.4g, 22.68 mmol) was dissolved in water (20 mL) and slowly added dropwise to the reaction system. The reaction The liquid was raised to room temperature and reacted at 90°C for 1 hour. Cool the reaction, extract with ethyl acetate (15 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (20 mL), dry, and spin dry. The crude product is purified by column chromatography (petroleum ether: ethyl acetate = 10:1). A brown solid (4.8g) was obtained. 1 H NMR (400MHz, DMSO) δ 8.25 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H), 2.49 (s, 3H).
5-溴-2-(溴甲基)-3-碘苯甲酸甲酯(3)的合成：Synthesis of 5-bromo-2-(bromomethyl)-3-iodobenzoic acid methyl ester (3):
将5-溴-3-碘-2-甲基苯甲酸甲酯(4.8g,13.38mmol)溶于四氯化碳(70mL)中，再依次加入N-溴代丁二酰亚胺(2.4g,13.48mmol)和过氧化二苯甲酰(320.0mg,1.32mmol)，升温至80℃反应18小时，冷却反应，溶剂旋干，粗产品经柱层析(乙酸乙酯:石油醚＝1:10)得到黄色固体(5.5g)。1H NMR(400MHz,DMSO)δ8.38(d,J＝2.1Hz,1H),8.00(d,J＝2.1Hz,1H),4.97(s,2H),3.88(s,3H)。Dissolve 5-bromo-3-iodo-2-methylbenzoic acid methyl ester (4.8g, 13.38mmol) in carbon tetrachloride (70mL), and then add N-bromosuccinimide (2.4g) , 13.48mmol) and dibenzoyl peroxide (320.0mg, 1.32mmol), raise the temperature to 80°C and react for 18 hours, cool the reaction, spin the solvent to dryness, and the crude product is subjected to column chromatography (ethyl acetate: petroleum ether = 1: 10) Obtained a yellow solid (5.5g). 1 H NMR (400MHz, DMSO) δ 8.38 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 4.97 (s, 2H), 3.88 (s, 3H).
6-溴-4-碘异吲哚-1-酮(4)的合成：Synthesis of 6-bromo-4-iodoisoindol-1-one (4):
将5-溴-2-(溴甲基)-3-碘苯甲酸甲酯(5.5g,12.68mmol)溶于7M氨气甲醇溶液(60mL)中，室温下搅拌反应2小时。反应液旋干后加入饱和碳酸氢钠水溶液(20mL)稀释，用二氯甲烷(20mL×3)萃取，有机相用无水硫酸钠干燥，过滤后旋干得到黄色固体(4.2g)。LC-MS:[M+H]+:338.1,340.1。5-Bromo-2-(bromomethyl)-3-iodobenzoic acid methyl ester (5.5g, 12.68mmol) was dissolved in 7M ammonia methanol solution (60mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was spin-dried, diluted with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a yellow solid (4.2 g). LC-MS: [M+H] + :338.1, 340.1.
6-溴-4-碘-1-氧代异吲哚-2-甲酸叔丁酯(5)的合成：Synthesis of tert-butyl 6-bromo-4-iodo-1-oxoisoindole-2-carboxylate (5):
将6-溴-4-碘异吲哚-1-酮(4.2g,12.43mmol)、4-二甲氨基吡啶(460.0mg,3.77mmol)及三乙胺(5.0g, 49.41mmol)溶解在二氯甲烷(100mL)中，向反应体系缓慢滴加二碳酸二叔丁酯(8.1g,37.11mmol)，室温反应18小时。反应体系用二氯甲烷(50mL)稀释，用水(100mL)洗涤，分离有机相后干燥，过滤，旋干。粗产品经柱层析(石油醚:乙酸乙酯＝5:1)得到白色固体(2.7g).LC-MS:[M-tBu+H]+:382.1,384.1。6-Bromo-4-iodoisoindol-1-one (4.2g, 12.43mmol), 4-dimethylaminopyridine (460.0mg, 3.77mmol) and triethylamine (5.0g, 49.41 mmol) was dissolved in dichloromethane (100 mL), di-tert-butyl dicarbonate (8.1 g, 37.11 mmol) was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 18 hours. The reaction system was diluted with dichloromethane (50 mL), washed with water (100 mL), the organic phase was separated, dried, filtered, and spun to dryness. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (2.7g). LC-MS: [M- t Bu+H] + : 382.1, 384.1.
6-溴-4-碘-3-甲基-1-氧代异吲哚-2-甲酸叔丁酯(6)的合成：Synthesis of tert-butyl 6-bromo-4-iodo-3-methyl-1-oxoisoindole-2-carboxylate (6):
将6-溴-4-碘-1-氧代异吲哚-2-甲酸叔丁酯(1.2g,2.74mmol)溶解于四氢呋喃(60mL)中，-70℃下滴加1M双三甲基硅基胺基锂(3.3mL,3.30mmol)，在-70℃下搅拌半个小时。碘甲烷(580.0mg,4.09mmol)滴加到反应体系中，反应升至室温后继续搅拌0.5小时，饱和氯化铵水溶液(20mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，干燥，旋干，得到白色固体(1.1g)。LC-MS:[M-tBu+H]+:396.0,398.0。Dissolve 6-bromo-4-iodo-1-oxoisoindole-2-carboxylic acid tert-butyl ester (1.2g, 2.74mmol) in tetrahydrofuran (60mL), and add 1M bistrimethylsilane dropwise at -70°C. Lithium amide (3.3 mL, 3.30 mmol) was stirred at -70°C for half an hour. Methyl iodide (580.0 mg, 4.09 mmol) was added dropwise to the reaction system. After the reaction rose to room temperature, stirring was continued for 0.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The phase was washed with saturated aqueous sodium chloride solution (20 mL), dried, and spun to obtain a white solid (1.1 g). LC-MS: [M- tBu +H] + : 396.0, 398.0.
5-溴-7-碘-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(7)的合成：Synthesis of tert-butyl 5-bromo-7-iodo-1,1-dimethyl-3-oxoisoindole-2-carboxylate (7):
将6-溴-4-碘-3-甲基-1-氧代异吲哚-2-甲酸叔丁酯(1.1g,2.43mmol)溶解于四氢呋喃(60mL)中，-70℃搅拌下滴加1M双三甲基硅基胺基锂(2.9mL,2.90mmol)，在-70℃下搅拌半个小时。碘甲烷(1.0g,7.05mmol)滴加到反应体系中，反应升到室温并搅拌0.5小时，饱和氯化铵水溶液(50mL)淬灭反应，用乙酸乙酯(50mL×3)萃取，有机相用饱和氯化钠水溶液(100mL)洗涤，干燥，旋干，粗产品经柱层析(石油醚:乙酸乙酯＝10:1)得到白色固体(180.0mg)，LC-MS:[M-tBu+H]+:410.0,412.0。Dissolve 6-bromo-4-iodo-3-methyl-1-oxoisoindole-2-carboxylic acid tert-butyl ester (1.1g, 2.43mmol) in tetrahydrofuran (60mL), and add dropwise with stirring at -70°C. 1M lithium bistrimethylsilylamide (2.9 mL, 2.90 mmol), stir at -70°C for half an hour. Methyl iodide (1.0g, 7.05mmol) was added dropwise to the reaction system. The reaction was raised to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (50mL), and extracted with ethyl acetate (50mL×3). The organic phase Wash with saturated aqueous sodium chloride solution (100 mL), dry, and spin dry. The crude product is subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (180.0 mg), LC-MS: [M-tBu +H] + :410.0,412.0.
(E)-5-溴-7-(2-乙氧基乙烯基)-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(8)的合成：Synthesis of (E)-tert-butyl 5-bromo-7-(2-ethoxyvinyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylate (8):
将5-溴-7-碘-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(250.0mg,0.54mmol)、(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(130.0mg,0.66mmol)、磷酸钾(250.0mg,1.18mmol)以及1,1'-双(二苯基膦)二茂铁]二氯化钯(40.0mg,0.06mmol)溶解在二氧六环(5mL)和水(0.5mL)中，氮气保护下，100℃反应3小时。反应体系旋干，粗产品经硅胶柱层析(石油醚:乙酸乙酯＝10:1)得到白色固体(150.0mg)。1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.62(s,1H),6.88(d,J＝12.0Hz,1H),6.04(d,J＝12.4Hz,1H),3.97(q,J＝7.2Hz,2H),1.80(s,6H),1.61(s,9H),1.38(t,J＝7.2Hz,3H).5-Bromo-7-iodo-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (250.0 mg, 0.54 mmol), (E)-2-(2-ethoxy vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130.0 mg, 0.66 mmol), potassium phosphate (250.0 mg, 1.18 mmol) and 1 , 1'-bis(diphenylphosphine)ferrocene]palladium dichloride (40.0mg, 0.06mmol) was dissolved in dioxane (5mL) and water (0.5mL), reacted at 100°C under nitrogen protection 3 hours. The reaction system was spun to dryness, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (150.0 mg). 1 H NMR (400MHz, CDCl 3 ) δ7.81 (s, 1H), 7.62 (s, 1H), 6.88 (d, J = 12.0Hz, 1H), 6.04 (d, J = 12.4Hz, 1H), 3.97 (q,J＝7.2Hz,2H),1.80(s,6H),1.61(s,9H),1.38(t,J＝7.2Hz,3H).
2-(6-溴-3,3-二甲基-1-氧代异吲哚-4-基)乙醛(9)的合成：Synthesis of 2-(6-bromo-3,3-dimethyl-1-oxoisoindol-4-yl)acetaldehyde (9):
将(E)-5-溴-7-(2-乙氧基乙烯基)-1,1-二甲基-3-氧代异吲哚-2-甲酸叔丁酯(150.0mg,0.37mmol)溶解于四氢呋喃(3mL)中，室温下滴加浓盐酸(1mL,0.24mmol)并搅拌3小时。向反应体系中滴加饱和碳酸氢钠水溶液，直到pH＝9。用乙酸乙酯萃取(5mL×3)，有机相用饱和食盐水(10mL)洗涤，干燥，旋干，得到白色粗产品(80.0mg)。LC-MS:[M+H]+:282.2,284.2。(E)-tert-butyl 5-bromo-7-(2-ethoxyvinyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylate (150.0 mg, 0.37 mmol) Dissolve in tetrahydrofuran (3 mL), add concentrated hydrochloric acid (1 mL, 0.24 mmol) dropwise at room temperature and stir for 3 hours. Saturated aqueous sodium bicarbonate solution was added dropwise to the reaction system until pH=9. Extract with ethyl acetate (5 mL × 3), wash the organic phase with saturated brine (10 mL), dry, and spin dry to obtain a white crude product (80.0 mg). LC-MS: [M+H] + :282.2, 284.2.
6-溴-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(10)的合成：Synthesis of 6-bromo-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (10):
将化合物2-(6-溴-3,3-二甲基-1-氧代异吲哚-4-基)乙醛(80.0mg,0.28mmol)溶解在乙醇(4mL)中，室温加入硼氢化钠(85.0mg,2.25mmol)并反应1小时。冰水(8mL)淬灭反应，用乙酸乙酯(8mL×3)萃取，有机相用饱和氯化钠水溶液(8mL)洗涤，用无水硫酸钠干燥，过滤，浓缩得到白色粗品(80.0mg)。LC-MS:[M+H]+:284.1,286.1。Compound 2-(6-bromo-3,3-dimethyl-1-oxoisoindol-4-yl)acetaldehyde (80.0 mg, 0.28 mmol) was dissolved in ethanol (4 mL), and hydroboration was added at room temperature. Sodium (85.0 mg, 2.25 mmol) and reacted for 1 hour. Quench the reaction with ice water (8 mL), extract with ethyl acetate (8 mL × 3), wash the organic phase with saturated aqueous sodium chloride solution (8 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a white crude product (80.0 mg) . LC-MS: [M+H] + :284.1, 286.1.
4-(2-羟乙基)-3,3-二甲基-6-硼酸频那醇酯-异吲哚-1-酮(11)的合成：Synthesis of 4-(2-hydroxyethyl)-3,3-dimethyl-6-boronic acid pinacol ester-isoindol-1-one (11):
将化合物6-溴-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(80.0mg,0.28mmol)、联硼酸频那醇酯(85.0mg,0.34mmol)、乙酸钾(70.0mg,0.71mmol)及1,1'-双(二苯基膦)二茂铁]二氯化钯(20.0mg,0.03mmol)悬浮 在无水二氧六环(4mL)中，氮气保护下于100℃反应18小时，向体系中加入水(10mL)，然后用乙酸乙酯萃取(10mL×3)，合并乙酸乙酯相用无水硫酸钠干燥，过滤，浓缩得到棕色粗品(80.0mg)。LC-MS:[M+H]+:332.0。Compound 6-bromo-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (80.0mg, 0.28mmol) and pinacol diborate (85.0mg, 0.34mmol) ), potassium acetate (70.0mg, 0.71mmol) and 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20.0mg, 0.03mmol) suspended In anhydrous dioxane (4 mL), react at 100°C for 18 hours under nitrogen protection. Add water (10 mL) to the system, and then extract with ethyl acetate (10 mL × 3). Combine the ethyl acetate phases and use Dry over sodium sulfate, filter, and concentrate to obtain brown crude product (80.0 mg). LC-MS: [M+H] + :332.0.
6-(2-氯-5-氟嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(12)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (12):
将化合物4-(2-羟乙基)-3,3-二甲基-6-硼酸频那醇酯-异吲哚-1-酮(80.0mg,0.24mmol)、2,4-二氯-5-氟嘧啶(50.0mg,0.30mmol)、磷酸钾(125.0mg,0.59mmol)及1,1'-双(二苯基膦)二茂铁]二氯化钯(17.0mg,0.02mmol)悬浮在无水二氧六环(4mL)和水(0.8mL)中，氮气保护下于100℃下反应2小时。反应体系旋干，粗产品经硅胶柱层析(二氯甲烷:甲醇＝10:1)得到棕色固体(60.0mg)。LC-MS:[M+H]+:336.3。Compound 4-(2-hydroxyethyl)-3,3-dimethyl-6-boronic acid pinacol ester-isoindol-1-one (80.0 mg, 0.24 mmol), 2,4-dichloro- 5-fluoropyrimidine (50.0mg, 0.30mmol), potassium phosphate (125.0mg, 0.59mmol) and 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (17.0mg, 0.02mmol) suspended React in anhydrous dioxane (4 mL) and water (0.8 mL) at 100°C for 2 hours under nitrogen protection. The reaction system was spun to dryness, and the crude product was subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to obtain a brown solid (60.0 mg). LC-MS: [M+H] + :336.3.
6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(PR-01-105)的合成：6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-4-( Synthesis of 2-hydroxyethyl)-3,3-dimethylisoindol-1-one (PR-01-105):
将6-(2-氯-5-氟嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(45.0mg,0.13mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(37.0mg,0.13mmol)、碳酸铯(120.0mg,0.37mmol)、1,1'-联萘-2,2'-双二苯膦(20.0mg,0.03mmol)及醋酸钯(4.5mg,0.02mmol)溶解在二氧六环(2mL)中，氮气保护下，100℃反应18小时，反应体系旋干，粗产品经碱性制备得到白色固体(15.5mg)。1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.79(s,1H),8.62(d,J＝3.2Hz,1H),8.04(s,2H),7.46(s,1H),7.20(d,J＝8.8Hz,1H),6.77(d,J＝9.2Hz,1H),4.90(s,1H),3.68(s,2H),3.15(s,4H),2.99(t,J＝6.8Hz,2H),2.44(s,4H),2.21(s,3H),2.07(s,1H),1.56(s,6H)；LC-MS:[M+H]+:575.5。6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (45.0 mg, 0.13 mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (37.0mg, 0.13mmol), cesium carbonate (120.0mg, 0.37mmol), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (20.0mg, 0.03mmol) and palladium acetate (4.5mg, 0.02mmol) were dissolved in dioxane (2mL), under nitrogen protection, 100℃ The reaction was carried out for 18 hours, the reaction system was spun to dryness, and the crude product was prepared by alkaline treatment to obtain a white solid (15.5 mg). 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.79 (s, 1H), 8.62 (d, J = 3.2Hz, 1H), 8.04 (s, 2H), 7.46 (s, 1H) ),7.20(d,J＝8.8Hz,1H),6.77(d,J＝9.2Hz,1H),4.90(s,1H),3.68(s,2H),3.15(s,4H),2.99(t ,J＝6.8Hz,2H),2.44(s,4H),2.21(s,3H),2.07(s,1H),1.56(s,6H); LC-MS: [M+H] + :575.5.
实施例26.化合物PR-01-119的合成
Example 26. Synthesis of compound PR-01-119
5-溴-4-碘-2-(三氟甲氧基)苯胺(2)的合成：Synthesis of 5-bromo-4-iodo-2-(trifluoromethoxy)aniline (2):
将5-溴-2-(三氟甲氧基)苯胺(1.0g,3.91mmol)、N-碘代丁二酰亚胺(970.0mg,4.30mmol)溶于N,N-二甲基甲酰胺(20mL)中，在室温反应8小时后，加入乙酸乙酯(60mL)稀释。有机相用饱和食盐水洗涤三次，无水硫酸钠干燥，过滤浓缩。硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)得到棕色液体(810.0mg)。LC-MS:[M+H]+:381.9,383.9。Dissolve 5-bromo-2-(trifluoromethoxy)aniline (1.0g, 3.91mmol) and N-iodosuccinimide (970.0mg, 4.30mmol) in N,N-dimethylformamide (20 mL), after reacting at room temperature for 8 hours, ethyl acetate (60 mL) was added to dilute. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) gave a brown liquid (810.0 mg). LC-MS: [M+H] + :381.9, 383.9.
4-氨基-2-溴-5-(三氟甲氧基)苯甲腈(3)的合成： Synthesis of 4-amino-2-bromo-5-(trifluoromethoxy)benzonitrile (3):
将化合物5-溴-4-碘-2-(三氟甲氧基)苯胺(420.0mg,1.10mmol)、氰化锌(64.6mg,0.55mmol)、四(三苯基膦)钯(127.1mg,0.11mmol)溶于N,N-二甲基甲酰胺(4mL)中，氮气保护下加热至90℃反应16小时。向反应液中加入乙酸乙酯(20mL)稀释，过滤。滤液依次用水和饱和食盐水洗涤三次，合并有机相并用无水硫酸钠干燥，减压浓缩后经硅胶柱层析(石油醚/乙酸乙酯＝2/3)纯化得黄色固体产物(290.0mg)。LC-MS:[M-H]-:279.0,281.0。Compound 5-bromo-4-iodo-2-(trifluoromethoxy)aniline (420.0mg, 1.10mmol), zinc cyanide (64.6mg, 0.55mmol), tetrakis(triphenylphosphine)palladium (127.1mg , 0.11 mmol) was dissolved in N,N-dimethylformamide (4 mL), heated to 90°C under nitrogen protection, and reacted for 16 hours. Ethyl acetate (20 mL) was added to the reaction solution to dilute and filtered. The filtrate was washed three times with water and saturated brine, the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/3) to obtain a yellow solid product (290.0 mg) . LC-MS: [MH] - :279.0,281.0.
2-溴-4-((4-(1,1-二甲基-3-氧代异吲哚-5-基)-5-氟嘧啶-2-基)氨基)-5-(三氟甲氧基)苯甲腈(4)的合成：2-Bromo-4-((4-(1,1-dimethyl-3-oxoisoindol-5-yl)-5-fluoropyrimidin-2-yl)amino)-5-(trifluoromethyl Synthesis of oxy)benzonitrile (4):
将4-氨基-2-溴-5-(三氟甲氧基)苯甲腈(200.0mg,0.71mmol)、6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-7)(249.1mg,0.85mmol)和碳酸铯(695.6mg,2.14mmol)溶于N,N-二甲基甲酰胺(5mL)中，反应液80℃搅拌6小时。冷却至室温后加入乙酸乙酯(40mL)稀释，有机相用饱和氯化钠水溶液(30mL×3)洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析(PE/EA＝1/1)得白色固体(210.0mg)。LCMS:[M+H]+:536.2,538.2。4-Amino-2-bromo-5-(trifluoromethoxy)benzonitrile (200.0 mg, 0.71 mmol), 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3- Dimethylisoindol-1-one (common int-7) (249.1mg, 0.85mmol) and cesium carbonate (695.6mg, 2.14mmol) were dissolved in N,N-dimethylformamide (5mL) and reacted The solution was stirred at 80°C for 6 hours. After cooling to room temperature, add ethyl acetate (40 mL) to dilute. The organic phase was washed with saturated aqueous sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (PE/EA=1/1) to obtain White solid (210.0 mg). LCMS: [M+H] + :536.2,538.2.
4-((4-(1,1-二甲基-3-氧代异吲哚-5-基)-5-氟嘧啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)-5-5-(三氟甲氧基)苯甲腈(PR-01-119)的合成：4-((4-(1,1-Dimethyl-3-oxoisoindol-5-yl)-5-fluoropyrimidin-2-yl)amino)-2-(4-methylpiperazine- Synthesis of 1-yl)-5-5-(trifluoromethoxy)benzonitrile (PR-01-119):
将2-溴-4-((4-(1,1-二甲基-3-氧代异吲哚-5-基)-5-氟嘧啶-2-基)氨基)-5-(三氟甲氧基)苯甲腈(30.0mg,0.06mmol)、1-甲基哌嗪(11.2mg,0.11mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.01mmol)，2-二环己膦基-2'-(N,N-二甲胺)-联苯(3.9mg,0.01mmol)悬浮于四氢呋喃(1mL)中。氩气保护下室温缓慢加入1M双三甲基硅基胺基锂(0.2mL,0.20mmol)。反应液加热至70℃搅拌2小时后LCMS检测反应完全。反应液加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)。合并有机相并用无水硫酸钠干燥，浓缩。碱性制备纯化得白色固体(6.0mg)。1H NMR(400MHz,Methanol-d4)δ8.63(d,J＝3.2Hz,1H),8.59(s,1H),8.46(s,1H),8.39(d,J＝8.2Hz,1H),7.801(d,J＝8.0Hz,1H),7.618(s,1H),3.31(s,4H),2.67(s,4H),2.37(s,3H),1.60(s,6H)；LCMS:[M+H]+:556.1。2-Bromo-4-((4-(1,1-dimethyl-3-oxoisoindol-5-yl)-5-fluoropyrimidin-2-yl)amino)-5-(trifluoro Methoxy)benzonitrile (30.0mg, 0.06mmol), 1-methylpiperazine (11.2mg, 0.11mmol), tris(dibenzylideneacetone)dipalladium (9.2mg, 0.01mmol), 2-di Cyclohexophosphino-2'-(N,N-dimethylamine)-biphenyl (3.9 mg, 0.01 mmol) was suspended in tetrahydrofuran (1 mL). Slowly add 1M lithium bistrimethylsilylamide (0.2 mL, 0.20 mmol) at room temperature under argon protection. The reaction solution was heated to 70°C and stirred for 2 hours. Then LCMS detected that the reaction was complete. The reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Basic preparation and purification gave a white solid (6.0 mg). 1 H NMR (400MHz, Methanol-d 4 ) δ8.63 (d, J = 3.2 Hz, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H) ,7.801(d,J＝8.0Hz,1H),7.618(s,1H),3.31(s,4H),2.67(s,4H),2.37(s,3H),1.60(s,6H); LCMS: [M+H] + :556.1.
实施例27.化合物PR-01-116A的合成
Example 27. Synthesis of compound PR-01-116A
6-(5-氟-2-((5-(1-甲基-4-氧化-1,4-氮杂膦-4-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-116A)的合成：6-(5-fluoro-2-((5-(1-methyl-4-oxy-1,4-azaphosphine-4-yl)-2-(trifluoromethoxy)phenyl)amino) Synthesis of pyrimidin-4-yl)-3,3-dimethylisoindol-1-one (PR-01-116A):
将化合物1-甲基-1,4-氮杂膦-4-氧化物(40.0mg,0.30mmol)、6-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-8)(153.8mg,0.30mmol)、三(二亚苄基丙酮)二钯(27.5mg,0.03mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(17.4mg,0.03mmol)、磷酸钾(127.2mg,0.6mmol)溶于N,N-二甲基甲酰胺(2mL)中，氮气保护下于100℃反应4小时。反应液冷却过滤，滤液加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取后浓缩得到类黑色油状物，通过制备HPLC纯化得白色固体(60mg)。1H NMR(400MHz,MeOD)δ8.92(d,J＝12.8Hz,1H),8.56(s,1H),8.43–8.40(m,2H),7.78(d,J＝7.4Hz, 1H),7.59–7.57(m,2H),3.00–2.88(m,2H),2.88–2.79(m,2H),2.37(s,3H),2.33–2.30(m,2H),2.13(t,J＝16.4Hz,2H),1.59(s,6H)；LC-MS:[M+H]+:564.3。Compound 1-methyl-1,4-azaphosphine-4-oxide (40.0 mg, 0.30 mmol), 6-(2-((5-bromo-2-(trifluoromethoxy)phenyl) Amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (common int-8) (153.8 mg, 0.30 mmol), tris(dibenzylideneacetone)di Palladium (27.5mg, 0.03mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (17.4mg, 0.03mmol), potassium phosphate (127.2mg, 0.6mmol) were dissolved in N, In N-dimethylformamide (2 mL), react at 100°C for 4 hours under nitrogen protection. The reaction solution was cooled and filtered, and the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and concentrated to obtain an almost black oily substance, which was purified by preparative HPLC to obtain a white solid (60 mg). 1 H NMR(400MHz,MeOD)δ8.92(d,J＝12.8Hz,1H),8.56(s,1H),8.43–8.40(m,2H),7.78(d,J＝7.4Hz, 1H),7.59–7.57(m,2H),3.00–2.88(m,2H),2.88–2.79(m,2H),2.37(s,3H),2.33–2.30(m,2H),2.13(t, J=16.4Hz, 2H), 1.59 (s, 6H); LC-MS: [M+H] + : 564.3.
实施例28.化合物PR-01-109的合成
Example 28. Synthesis of compound PR-01-109
6-(5-氟-2-((5-(4-异丙基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-109)的合成：6-(5-fluoro-2-((5-(4-isopropylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-3, Synthesis of 3-dimethylisoindol-1-one (PR-01-109):
将化合物6-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-8)(50.0mg,0.10mmol)、1-异丙基哌嗪(19.2mg,0.15mmol)、三(二亚苄基丙酮)钯(9.0mg,0.01mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(7.7mg,0.02mmol)及1M双三甲基硅基胺基锂(0.49mL,0.49mmol)溶解于四氢呋喃(0.5mL)中，氮气保护下，70℃反应6小时。冷却反应体系，用饱和氯化铵水溶液(1mL)淬灭，乙酸乙酯(2mL)萃取。有机相干燥，旋干，经碱性(H2O/MeCN(0.1％NH3·H2O))制备分离纯化得到白色固体(14.1mg)。1H NMR(400MHz,MeOD)δ8.51(d,J＝3.3Hz,1H),8.43(s,1H),8.35(d,J＝7.9Hz,1H),8.20(d,J＝2.6Hz,1H),7.74(d,J＝8.0Hz,1H),7.19(d,J＝8.9Hz,1H),6.68(m,1H),3.26–3.20(m,4H),2.71–2.70(m,5H),1.59(s,6H),1.12(d,J＝6.5Hz,6H)；LCMS:[M+H]+:559.4。Compound 6-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindole-1 -Ketone (common int-8) (50.0mg, 0.10mmol), 1-isopropylpiperazine (19.2mg, 0.15mmol), tris(dibenzylideneacetone)palladium (9.0mg, 0.01mmol), 2- Dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (7.7mg, 0.02mmol) and 1M lithium bistrimethylsilylamide (0.49mL, 0.49mmol) were dissolved in tetrahydrofuran ( 0.5 mL), react under nitrogen protection at 70°C for 6 hours. The reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried, spun to dryness, and separated and purified through alkaline (H 2 O/MeCN (0.1% NH 3 ·H 2 O)) preparation to obtain a white solid (14.1 mg). 1 H NMR (400MHz, MeOD) δ8.51 (d, J = 3.3Hz, 1H), 8.43 (s, 1H), 8.35 (d, J = 7.9Hz, 1H), 8.20 (d, J = 2.6Hz, 1H),7.74(d,J＝8.0Hz,1H),7.19(d,J＝8.9Hz,1H),6.68(m,1H),3.26–3.20(m,4H),2.71–2.70(m,5H ), 1.59 (s, 6H), 1.12 (d, J = 6.5Hz, 6H); LCMS: [M+H] + : 559.4.
实施例29.化合物PR-01-110的合成
Example 29. Synthesis of compound PR-01-110
6-(2-((5-(4-环丙基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-110)的合成：6-(2-((5-(4-cyclopropylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3, Synthesis of 3-dimethylisoindol-1-one (PR-01-110):
将化合物6-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-8)(50mg,0.10mmol)、N-环丙基哌嗪(18.9mg,0.15mmol)、三(二亚苄基丙酮)钯(9.0mg,0.01mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(7.7mg,0.02mmol)及1M双三甲基硅基胺基锂(0.49mL,0.49mmol)溶解于四氢呋喃(0.5mL)中，氮气保护下，70℃反应6小时。冷却反应体系，用饱和氯化铵水溶液(1mL)淬灭，乙酸乙酯(2mL)萃取。有机相干燥，旋干，经制备分离纯化得到白色固体(13.5mg)。1H NMR(400MHz,DMSO)δ9.08(s,1H),8.81(s,1H),8.64(d,J＝3.2Hz,1H),8.19–8.18(m,2H),7.80(d,J＝8.0Hz,1H),7.56(d,J＝2.4Hz,1H),7.20(d,J＝8.8Hz,1H),6.73(dd,J＝9.2,2.8Hz,1H),3.10(d,J＝4.8Hz,4H),2.65(d,J＝4.8Hz,4H),1.65(s,1H),1.49(s,6H),0.43–0.42(m,2H),0.34(d,J＝2.8Hz,2H)；LC-MS:[M+1]+:557.2。 Compound 6-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindole-1 -Ketone (common int-8) (50mg, 0.10mmol), N-cyclopropylpiperazine (18.9mg, 0.15mmol), tris(dibenzylideneacetone)palladium (9.0mg, 0.01mmol), 2-di Cyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (7.7mg, 0.02mmol) and 1M lithium bistrimethylsilylamide (0.49mL, 0.49mmol) were dissolved in tetrahydrofuran (0.5 mL), react under nitrogen protection at 70°C for 6 hours. The reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried, spun to dryness, and white solid (13.5 mg) was obtained through preparation, separation and purification. 1 H NMR (400MHz, DMSO) δ9.08 (s, 1H), 8.81 (s, 1H), 8.64 (d, J = 3.2Hz, 1H), 8.19–8.18 (m, 2H), 7.80 (d, J ＝8.0Hz,1H),7.56(d,J＝2.4Hz,1H),7.20(d,J＝8.8Hz,1H),6.73(dd,J＝9.2,2.8Hz,1H),3.10(d,J ＝4.8Hz,4H),2.65(d,J＝4.8Hz,4H),1.65(s,1H),1.49(s,6H),0.43–0.42(m,2H),0.34(d,J＝2.8Hz ,2H); LC-MS: [M+1] + :557.2.
实施例30.化合物PR-01-111的合成
Example 30. Synthesis of compound PR-01-111
1-(2-((叔丁基二甲基硅)氧)乙基)哌嗪(2)的合成：Synthesis of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazine (2):
在0℃、氮气保护下，向N-羟乙基哌嗪(1.9mL,15.37mmol)和1H-咪唑(1.6g,23.50mmol)的四氢呋喃(15mL)溶液中，滴加叔丁基二甲基氯硅烷(3.5g,23.22mmol)，室温搅拌过夜，将反应混合物真空浓缩以除去大部分溶剂，得到粗产品。粗品经柱层析(二氯甲烷:甲醇＝0-70％)得到白色固体(900.0mg)。LC-MS:[M+H-t-Bu]+:189.3。At 0°C and under nitrogen protection, add tert-butyldimethyl dropwise to a solution of N-hydroxyethylpiperazine (1.9mL, 15.37mmol) and 1H-imidazole (1.6g, 23.50mmol) in tetrahydrofuran (15mL). Chlorosilane (3.5g, 23.22mmol) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove most of the solvent to obtain crude product. The crude product was subjected to column chromatography (dichloromethane:methanol=0-70%) to obtain a white solid (900.0 mg). LC-MS: [M+Ht-Bu] + :189.3.
5-(4-(2-((叔丁基二甲基硅烷基)氧基)乙基)哌嗪-1-基)-2-(三氟甲氧基)苯胺(3)的合成：Synthesis of 5-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazin-1-yl)-2-(trifluoromethoxy)aniline (3):
在25℃、氮气保护下，向5-溴-2-(三氟甲氧基)苯胺(200.0mg,0.78mmol)、三(二亚苄基丙酮)二钯(36.6mg,0.04mmol)和2-二环己膦基-2'-(N,N-二甲胺)-联苯(31.5mg,0.08mmol)的四氢呋喃(2mL)溶液中，加入1M双三甲基硅基胺基锂(2.3mL,2.34mmol)和1-(2-((叔丁基二甲基硅)氧)乙基)哌嗪(381.9mg,1.56mmol)，将所得混合物在80℃下搅拌6小时，将反应混合物冷却至室温并真空浓缩以除去大部分溶剂。将残余物倒入水(5mL)中并用乙酸乙酯(10mL×3)萃取。有机层用无水硫酸钠干燥，固体经柱层析(二氯甲烷:甲醇＝10:1,Rf＝0.5)得到白色固体(50mg)。LC-MS:[M+H-t-Bu]+:364.5。Under nitrogen protection at 25°C, add 5-bromo-2-(trifluoromethoxy)aniline (200.0mg, 0.78mmol), tris(dibenzylideneacetone)dipalladium (36.6mg, 0.04mmol) and 2 -To a solution of dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (31.5 mg, 0.08 mmol) in tetrahydrofuran (2 mL), add 1 M lithium bistrimethylsilylamide (2.3 mL, 2.34mmol) and 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazine (381.9mg, 1.56mmol), the resulting mixture was stirred at 80°C for 6 hours, and the reaction mixture was Cool to room temperature and concentrate in vacuo to remove most of the solvent. The residue was poured into water (5 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was dried over anhydrous sodium sulfate, and the solid was subjected to column chromatography (dichloromethane:methanol=10:1, Rf=0.5) to obtain a white solid (50 mg). LC-MS: [M+Ht-Bu] + :364.5.
6-(2-((5-(4-(2-(叔丁基二甲基甲硅烷基)氧基)乙基)哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(4)的合成：6-(2-((5-(4-(2-(tert-butyldimethylsilyl)oxy)ethyl)piperazin-1-yl)-2-(trifluoromethoxy)benzene Synthesis of (base)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (4):
向5-(4-(2-((叔丁基二甲基硅烷基)氧基)乙基)哌嗪-1-基)-2-(三氟甲氧基)苯胺(30.0mg,0.07mmol)和6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-7)(20.9mg,0.07mmol)的二氧六环(5mL)溶液中，加入碳酸铯(45.6mg,0.14mmol)，然后在N2下搅拌下加入醋酸钯(2.2mg,0.01mmol)以及1,1'-联萘-2,2'-双二苯膦(6.2mg,0.01mmol)。将混合物回流16小时，将反应混合物冷却至室温并真空浓缩以除去大部分溶剂。将残余物倒入水(3mL)中并用乙酸乙酯(5mL×3)萃取。有机层用无水硫酸钠干燥、过 滤并浓缩。固体经柱层析(二氯甲烷:甲醇＝10:1,Rf＝0.3)得到白色固体(20.0mg)。LC-MS:[M+H-t-Bu]+:619.3。To 5-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazin-1-yl)-2-(trifluoromethoxy)aniline (30.0 mg, 0.07mmol ) and 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (common int-7) (20.9 mg, 0.07 mmol) dioxane To the ring (5 mL) solution, add cesium carbonate (45.6 mg, 0.14 mmol), then add palladium acetate (2.2 mg, 0.01 mmol) and 1,1'-binaphthyl-2,2'-bis with stirring under N2 . Diphenylphosphine (6.2 mg, 0.01 mmol). The mixture was refluxed for 16 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. The residue was poured into water (3 mL) and extracted with ethyl acetate (5 mL×3). The organic layer was dried with anhydrous sodium sulfate and filtered Filter and concentrate. The solid was subjected to column chromatography (dichloromethane:methanol=10:1, Rf=0.3) to obtain a white solid (20.0 mg). LC-MS: [M+Ht-Bu] + :619.3.
6-(5-氟-2-((5-(4-(2-羟乙基)哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-111)的合成：6-(5-fluoro-2-((5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl Synthesis of )-3,3-dimethylisoindol-1-one (PR-01-111):
在室温下将6-(2-((5-(4-(2-(叔丁基二甲基甲硅烷基)氧基)乙基)哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(50.0mg,0.07mmol)加入到四氢呋喃(1mL)中，在N2下加入1M四丁基氟化铵(1mL,1mmol)。将所得混合物在25℃下搅拌5小时，将反应液真空浓缩以除去大部分溶剂，固体经碱性制备得到白色固体(11.2mg)。1H NMR(400MHz,Methanol-d4)δ8.52(d,J＝3.6Hz,1H),8.44(d,J＝1.2Hz,1H),8.40–8.35(m,1H),8.17(d,J＝2.8Hz,1H),7.74(dd,J＝8.0,0.4Hz,1H),7.19(dd,J＝9.2,1.6Hz,1H),6.69(dd,J＝9.2,2.8Hz,1H),3.72(t,J＝6.0Hz,2H),3.28–3.21(m,4H),2.69(t,J＝5.2Hz,4H),2.59(t,J＝5.6Hz,2H),1.59(s,6H).；LC-MS:[M+H]+:561.1。6-(2-((5-(4-(2-(tert-butyldimethylsilyl)oxy)ethyl)piperazin-1-yl)-2-(trifluoromethyl Oxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindol-1-one (50.0 mg, 0.07 mmol) was added to tetrahydrofuran (1 mL), and the mixture was dissolved in N Add 1M tetrabutylammonium fluoride (1 mL, 1 mmol) at 2° C. The resulting mixture was stirred at 25°C for 5 hours, and the reaction solution was concentrated in vacuo to remove most of the solvent. The solid was alkalinely prepared to obtain a white solid (11.2 mg). 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (d, J = 3.6 Hz, 1H), 8.44 (d, J = 1.2 Hz, 1H), 8.40–8.35 (m, 1H), 8.17 (d, J＝2.8Hz,1H),7.74(dd,J＝8.0,0.4Hz,1H),7.19(dd,J＝9.2,1.6Hz,1H),6.69(dd,J＝9.2,2.8Hz,1H), 3.72(t,J＝6.0Hz,2H),3.28–3.21(m,4H),2.69(t,J＝5.2Hz,4H),2.59(t,J＝5.6Hz,2H),1.59(s,6H ).; LC-MS: [M+H] + :561.1.
实施例31.化合物PR-01-112的合成
Example 31. Synthesis of compound PR-01-112
6-(5-氟-2-((5-(4-(2-氟乙基)哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-112)的合成：6-(5-fluoro-2-((5-(4-(2-fluoroethyl)piperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl Synthesis of )-3,3-dimethylisoindol-1-one (PR-01-112):
将化合物6-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-8)(50.0mg,0.10mmol)、1-(2-氟乙基)-哌嗪(20.0mg,0.15mmol)、三(二亚苄基丙酮)钯(9.0mg,0.01mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(7.7mg,0.02mmol)及1M双三甲基硅基胺基锂(0.5mL,0.50mmol)溶解于四氢呋喃(0.5mL)中，氮气保护下，70℃反应6小时。冷却反应体系，用饱和氯化铵水溶液(1mL)淬灭，乙酸乙酯(2mL)萃取。有机相干燥，旋干，粗产品经硅胶板制备(石油醚:乙酸乙酯:二氯甲烷:甲醇＝10:10:10:1)得到白色固体(5.0mg)。1H NMR(400MHz,MeOD)δ8.52(s,1H),8.44(s,1H),8.37(d,J＝7.6Hz,1H),8.19(s,1H),7.75(d,J＝8.0Hz,1H),7.19(d,J＝8.8Hz,1H),6.69(d,J＝9.2Hz,1H),4.67(s,1H),4.55(s,1H),3.25(s,4H),2.80(s,1H),2.71(s,5H),1.59(s,6H)；LC-MS:[M+H]+:563.4。Compound 6-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindole-1 -Ketone (common int-8) (50.0mg, 0.10mmol), 1-(2-fluoroethyl)-piperazine (20.0mg, 0.15mmol), tris(dibenzylideneacetone)palladium (9.0mg, 0.01 mmol), 2-dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (7.7mg, 0.02mmol) and 1M lithium bistrimethylsilylamide (0.5mL, 0.50mmol) ) was dissolved in tetrahydrofuran (0.5 mL), and reacted at 70°C for 6 hours under nitrogen protection. The reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried and spin-dried, and the crude product was prepared on a silica gel plate (petroleum ether: ethyl acetate: dichloromethane: methanol = 10:10:10:1) to obtain a white solid (5.0 mg). 1 H NMR (400MHz, MeOD) δ8.52 (s, 1H), 8.44 (s, 1H), 8.37 (d, J = 7.6Hz, 1H), 8.19 (s, 1H), 7.75 (d, J = 8.0 Hz,1H),7.19(d,J＝8.8Hz,1H),6.69(d,J＝9.2Hz,1H),4.67(s,1H),4.55(s,1H),3.25(s,4H), 2.80 (s, 1H), 2.71 (s, 5H), 1.59 (s, 6H); LC-MS: [M+H] + : 563.4.
实施例32.化合物PR-01-114的合成
Example 32. Synthesis of compound PR-01-114
6-(5-氟-2-((5-(3-甲基-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-114)的合成：6-(5-fluoro-2-((5-(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-(trifluoromethoxy)benzene Synthesis of (yl)amino)pyrimidin-4-yl)-3,3-dimethylisoindol-1-one (PR-01-114):
将化合物6-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-8)(50.0mg,0.10mmol)、3-甲基-3,7-二氮杂双环[3.1.1]庚烷(16.8mg,0.15mmol)、三(二亚苄基丙酮)钯(9.0mg,0.01mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(7.7mg,0.02mmol)及1M双三甲基硅基胺基锂(0.49mL,0.49mmol)溶解于四氢呋喃(0.5mL)中，氮气保护下，70℃反应6小时。冷却反应体系，用饱和氯化铵水溶液(1mL)淬灭，乙酸乙酯(2mL)萃取。有机相干燥，旋干，粗产品经反相碱性制备得到白色固体(8.1mg)。1H NMR(400MHz,MeOD)δ8.53(s,1H),8.40(d,J＝8.4Hz,2H),8.32(d,J＝8.0Hz,1H),7.76(s,2H),7.24(d,J＝8.0Hz,1H),6.29(d,J＝8.4Hz,1H),4.39(d,J＝5.2Hz,2H),3.46(d,J＝13.2Hz,2H),3.27(s,1H),2.79–2.77(m,1H),2.47(s,3H),2.04(d,J＝8.8Hz,1H),1.59(s,6H)；LC-MS:[M+H]+:543.5。Compound 6-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindole-1 -Ketone (common int-8) (50.0mg, 0.10mmol), 3-methyl-3,7-diazabicyclo[3.1.1]heptane (16.8mg, 0.15mmol), tris(dibenzylidene) Acetone) palladium (9.0mg, 0.01mmol), 2-dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (7.7mg, 0.02mmol) and 1M bistrimethylsilylamine Lithium (0.49 mL, 0.49 mmol) was dissolved in tetrahydrofuran (0.5 mL), and the reaction was carried out at 70°C for 6 hours under nitrogen protection. The reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried and spun to dryness, and the crude product was prepared by reverse-phase alkaline preparation to obtain a white solid (8.1 mg). 1 H NMR (400MHz, MeOD) δ8.53 (s, 1H), 8.40 (d, J = 8.4Hz, 2H), 8.32 (d, J = 8.0Hz, 1H), 7.76 (s, 2H), 7.24 ( d,J＝8.0Hz,1H),6.29(d,J＝8.4Hz,1H),4.39(d,J＝5.2Hz,2H),3.46(d,J＝13.2Hz,2H),3.27(s, 1H),2.79–2.77(m,1H),2.47(s,3H),2.04(d,J＝8.8Hz,1H),1.59(s,6H); LC-MS:[M+H] + :543.5 .
实施例33.化合物PR-01-123、PR-01-123A、PR-01-123B的合成
Example 33. Synthesis of compounds PR-01-123, PR-01-123A, and PR-01-123B
6-(2-((5-(3,4-二甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(PR-01-123)的合成：6-(2-((5-(3,4-dimethylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)- Synthesis of 3,3-dimethylisoindol-1-one (PR-01-123):
将6-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)-3,3-二甲基异吲哚-1-酮(common int-8)(50.0mg,0.10mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(3.9mg,0.01mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.01mmol)加入到四氢呋喃(1.5mL)中，氮气置换三次。再将1,2-二甲基哌嗪(22.8mg,0.20mmol)和1M双三甲基硅基胺基锂(0.3mL,0.3mmol)加入到反应液中。反应液于70℃搅拌5小时后LCMS检测反应完全。反应液倒入水(5mL)中，用乙酸乙酯萃取(5mL×3)，合并有机相后浓缩至干。碱性制备HPLC纯化得浅黄的固体(20.0mg)。1H NMR(400MHz,Methanol-d4)δ8.51(d,J＝3.2Hz,1H),8.44(s,1H),8.37(d,J＝8.0Hz,1H),8.12–8.10(m,1H),7.75(d,J＝8.0Hz,1H),7.19(d,J＝8.8Hz,1H),6.70–6.67(m,1H),3.58(d,J＝12.0Hz,1H),3.50(d,J＝12.0Hz,1H),2.93–2.86(m,2H),2.55–2.41(m,2H),2.33(s,4H),1.58(s,6H),1.05(d,J＝6.4Hz,3H)；LC-MS:[M+H]+:545.2。6-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)-3,3-dimethylisoindole-1- Ketone (common int-8) (50.0mg, 0.10mmol), 2-dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (3.9mg, 0.01mmol), tris(dimethylamine) Benzyl acetone) dipalladium (9.2 mg, 0.01 mmol) was added to tetrahydrofuran (1.5 mL), and nitrogen was substituted three times. Then 1,2-dimethylpiperazine (22.8 mg, 0.20 mmol) and 1M lithium bistrimethylsilylamide (0.3 mL, 0.3 mmol) were added to the reaction solution. The reaction solution was stirred at 70°C for 5 hours and the reaction was completed by LCMS. The reaction solution was poured into water (5 mL), extracted with ethyl acetate (5 mL × 3), the organic phases were combined and concentrated to dryness. Alkaline preparative HPLC purified to obtain a light yellow solid (20.0 mg). 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (d, J = 3.2 Hz, 1H), 8.44 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.12–8.10 (m, 1H),7.75(d,J＝8.0Hz,1H),7.19(d,J＝8.8Hz,1H),6.70–6.67(m,1H),3.58(d,J＝12.0Hz,1H),3.50( d,J＝12.0Hz,1H),2.93–2.86(m,2H),2.55–2.41(m,2H),2.33(s,4H),1.58(s,6H),1.05(d,J＝6.4Hz ,3H); LC-MS: [M+H] + :545.2.
消旋体PR-01-123经过SFC分离纯化(色谱柱：ChiralPakC-IG,250×21.2mm I.D.,5μm；流动相：A 相：二氧化碳，B相：[MEOH+0.1％MEA]；梯度：B：45％-45％,8min；120min)后得到白色固体PR-01-123A和PR-01-123B。Racemate PR-01-123 was separated and purified by SFC (chromatographic column: ChiralPakC-IG, 250×21.2mm ID, 5μm; mobile phase: A Phase: carbon dioxide, phase B: [MEOH+0.1% MEA]; gradient: B: 45%-45%, 8min; 120min) to obtain white solids PR-01-123A and PR-01-123B.
PR-01-123A：PR-01-123A:
手性分析条件：色谱柱：CHIRALPAK IB 100*4.6mm 5μm；流动相：A相：二氧化碳；B相：MeOH(0.05％DEA v/v)；梯度：B：40％-40％；保留时间：2.987min；ee％＝100％。Chiral analysis conditions: chromatographic column: CHIRALPAK IB 100*4.6mm 5μm; mobile phase: A phase: carbon dioxide; B phase: MeOH (0.05% DEA v/v); gradient: B: 40%-40%; retention time: 2.987min;ee%=100%.
1H NMR(400MHz,Methanol-d4)δ8.51(d,J＝3.2Hz,1H),8.44(s,1H),8.37(d,J＝8.0Hz,1H),8.11(d,J＝3.2Hz,1H),7.76(d,J＝8.0Hz,1H),7.19(d,J＝9.2Hz,1H),6.68(d,J＝8.8Hz,1H),3.59(d,J＝11.6Hz,1H),3.50(d,J＝12.0Hz,1H),2.91–2.85(m,2H),2.57–2.43(m,2H),2.33–2.32(m,4H),1.58(s,6H),1.04(d,J＝6.4Hz,3H)；LC-MS:[M+H]+:545.4。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (d, J = 3.2 Hz, 1H), 8.44 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 3.2Hz,1H),7.76(d,J＝8.0Hz,1H),7.19(d,J＝9.2Hz,1H),6.68(d,J＝8.8Hz,1H),3.59(d,J＝11.6Hz ,1H),3.50(d,J＝12.0Hz,1H),2.91–2.85(m,2H),2.57–2.43(m,2H),2.33–2.32(m,4H),1.58(s,6H), 1.04 (d, J=6.4Hz, 3H); LC-MS: [M+H] + :545.4.
PR-01-123B：PR-01-123B:
手性分析条件：色谱柱：CHIRALPAK IB 100*4.6mm 5μm；流动相：A相：二氧化碳；B相：MeOH(0.05％DEA v/v)；梯度：B：40％-40％；保留时间：4.407min；ee％＝100％。Chiral analysis conditions: chromatographic column: CHIRALPAK IB 100*4.6mm 5μm; mobile phase: A phase: carbon dioxide; B phase: MeOH (0.05% DEA v/v); gradient: B: 40%-40%; retention time: 4.407min;ee%=100%.
1H NMR(400MHz,Methanol-d4)δ8.51(d,J＝2.8Hz,1H),8.44(s,1H),8.37(d,J＝8.0Hz,1H),8.11(s,1H),7.76(d,J＝8.4Hz,1H),7.19(d,J＝9.2Hz,1H),6.68(d,J＝9.2Hz,1H),3.59(d,J＝12.0Hz,1H),3.49(d,J＝12.4Hz,1H),2.91–2.85(m,2H),2.53–2.40(m,2H),2.325(s,4H),1.59(s,6H),1.04(d,J＝6.4Hz,3H)；LC-MS:[M+H]+:545.4。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (d, J = 2.8 Hz, 1H), 8.44 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H) ,7.76(d,J＝8.4Hz,1H),7.19(d,J＝9.2Hz,1H),6.68(d,J＝9.2Hz,1H),3.59(d,J＝12.0Hz,1H),3.49 (d,J＝12.4Hz,1H),2.91–2.85(m,2H),2.53–2.40(m,2H),2.325(s,4H),1.59(s,6H),1.04(d,J＝6.4 Hz, 3H); LC-MS: [M+H] + :545.4.
实施例34.化合物PR-01-080的合成
Example 34. Synthesis of compound PR-01-080
5'-(5-氯-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-1,2-二氢嘧啶-4-基)螺[环丙烷-1,1'-异吲哚]-3'-酮(PR-01-080)的合成：5'-(5-chloro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-1,2-dihydropyrimidine- Synthesis of 4-yl)spiro[cyclopropane-1,1'-isoindole]-3'-one (PR-01-080):
将5'-硼酸频那醇酯螺[环丙烷-1,1'-异吲哚]-3'-酮(common int-9)(100.0mg,0.35mmol)、碳酸钾(144.9mg,1.05mmol)、4,5-二氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)-1,2-二氢嘧啶-2-胺(common int-5)(176.8mg,0.42mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(29.1mg,0.04mmol)溶于1,4-二氧六环(20mL)和水(3mL)中。反应液置于氮气保护下在100℃搅拌16小时，LCMS显示反应完全。反应液倒入水(15mL)中，然后用乙酸乙酯萃取(3×15mL)，有机相用饱和食盐水洗涤，然后分离出有机相。将有机相用无水硫酸钠干燥，过滤，浓缩，柱层析(乙酸乙酯:石油醚＝0-100％,Rf＝0.6)纯化得到粗品。粗品经过制备纯化得白色固体(30.0mg)。1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.43(s,1H),8.32(d,J＝2.8Hz,1H),8.10(dd,J＝8.0,1.6Hz,1H),7.49(s,1H),7.21–7.11(m,2H),6.94(s,1H),6.54(dd,J＝9.2,2.8Hz,1H),3.24–3.18(m,4H),2.57–2.50(m,4H),2.34(s,3H),1.64(s,4H)；LCMS:[M+H]+:545.5。5'-Pinacol borate spiro[cyclopropane-1,1'-isoindole]-3'-one (common int-9) (100.0mg, 0.35mmol), potassium carbonate (144.9mg, 1.05mmol) ), 4,5-dichloro-N-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)-1,2-dihydropyrimidine-2- Amine (common int-5) (176.8mg, 0.42mmol), [1,1'-bis(diphenylphosphine)ferrocene] dichloride palladium dichloromethane complex (29.1mg, 0.04mmol) dissolved in 1,4-dioxane (20 mL) and water (3 mL). The reaction solution was stirred at 100°C for 16 hours under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was poured into water (15 mL), and then extracted with ethyl acetate (3×15 mL). The organic phase was washed with saturated brine, and then the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether=0-100%, Rf=0.6) to obtain the crude product. The crude product was preparatively purified to obtain a white solid (30.0 mg). 1 H NMR (400MHz, CDCl 3 ) δ8.51 (s, 1H), 8.43 (s, 1H), 8.32 (d, J = 2.8Hz, 1H), 8.10 (dd, J = 8.0, 1.6Hz, 1H) ,7.49(s,1H),7.21–7.11(m,2H),6.94(s,1H),6.54(dd,J＝9.2,2.8Hz,1H),3.24–3.18(m,4H),2.57–2.50 (m,4H),2.34(s,3H),1.64(s,4H); LCMS: [M+H] + :545.5.
实施例35.化合物PR-01-106的合成：
Example 35. Synthesis of compound PR-01-106:
5'-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚]-3'-酮(PR-01-106)的合成：5'-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)spiro[ring Synthesis of propane-1,1'-isoindole]-3'-one (PR-01-106):
将化合物5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚]-3'-酮(common int-10)(150.0mg,0.52mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(155.0mg,0.56mmol)、碳酸铯(506.0mg,1.55mmol)、三(二亚苄基丙酮)二钯(47.4mg,0.05mmol)、1,1'-联萘-2,2'-双二苯膦(64.5mg,0.10mmol)悬浮于甲苯(10mL)中，反应液置于氮气保护下于120℃反应6小时。反应液冷却至室温，倒入水(20mL)中，用乙酸乙酯(15mL×3)萃取，合并有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析(二氯甲烷:甲醇＝10:1,Rf＝0.6)得到粗品。粗品经制备纯化得到白色固体(43.5mg)。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.87(s,1H),8.63(d,J＝3.6Hz,1H),8.29(s,1H),8.19(d,J＝8.4Hz,1H),7.51(d,J＝2.8Hz,1H),7.47(d,J＝8.4Hz,1H),7.22–7.19(m,1H),6.75(dd,J＝9.2,2.8Hz,1H),3.16(t,J＝4.4Hz,4H),2.45–2.43(m,4H),2.21(s,3H),1.53(s,4H)；LC-MS:[M+H]+:529.2。Compound 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole]-3'-one (common int-10) (150.0 mg, 0.52 mmol ), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (155.0mg, 0.56mmol), cesium carbonate (506.0mg, 1.55mmol) , tris(dibenzylideneacetone)dipalladium (47.4mg, 0.05mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (64.5mg, 0.10mmol) were suspended in toluene (10mL) , the reaction solution was placed under nitrogen protection and reacted at 120°C for 6 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), extracted with ethyl acetate (15 mL × 3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column. Chromatography (dichloromethane:methanol=10:1, Rf=0.6) obtained the crude product. The crude product was preparatively purified to obtain a white solid (43.5 mg). 1 H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 8.87 (s, 1H), 8.63 (d, J = 3.6Hz, 1H), 8.29 (s, 1H), 8.19 (d, J ＝8.4Hz,1H),7.51(d,J＝2.8Hz,1H),7.47(d,J＝8.4Hz,1H),7.22–7.19(m,1H),6.75(dd,J＝9.2,2.8Hz ,1H),3.16(t,J＝4.4Hz,4H),2.45–2.43(m,4H),2.21(s,3H),1.53(s,4H); LC-MS:[M+H] + : 529.2.
实施例36.化合物PR-01-117的合成
Example 36. Synthesis of compound PR-01-117
2-氯-4-碘-5-(三氟甲氧基)吡啶(2)的合成：Synthesis of 2-chloro-4-iodo-5-(trifluoromethoxy)pyridine (2):
将化合物2-氯-5-(三氟甲氧基)吡啶(1.0g,5.06mmol)溶于无水四氢呋喃(10mL)，冷却至-78℃后缓慢滴加二异丙基胺基锂(3.1mL,6.08mmol,2mol/L)，保持温度继续搅拌1小时后滴加碘(1.41g,5.56mmol)的四氢呋喃溶液(5mL)。反应液逐渐升至室温后继续搅拌2个小时。LCMS监测反应完全。将反应液倒入氯化铵水溶液中(20mL)，并用乙酸乙酯萃取(20mL×3)，合并有机相用无水硫酸钠干燥，过滤， 浓缩至干。经硅胶柱层析(石油醚:乙酸乙酯＝5:1,Rf＝0.4)纯化得到黄色固体(980.0mg)。1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.88(s,1H)。Compound 2-chloro-5-(trifluoromethoxy)pyridine (1.0g, 5.06mmol) was dissolved in anhydrous tetrahydrofuran (10mL), cooled to -78°C, and then slowly added lithium diisopropylamide (3.1 mL, 6.08mmol, 2mol/L), maintain the temperature and continue stirring for 1 hour, then dropwise add iodine (1.41g, 5.56mmol) in tetrahydrofuran solution (5mL). The reaction solution gradually rose to room temperature and continued to stir for 2 hours. LCMS monitored the reaction to be complete. Pour the reaction solution into an aqueous ammonium chloride solution (20 mL), and extract with ethyl acetate (20 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate and filtered. Concentrate to dryness. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, Rf = 0.4), a yellow solid (980.0 mg) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ 8.25 (s, 1H), 7.88 (s, 1H).
N-(2-氯-5-(三氟甲氧基)吡啶-4-基)-1,1-二苯基甲烷亚胺(3)的合成：Synthesis of N-(2-chloro-5-(trifluoromethoxy)pyridin-4-yl)-1,1-diphenylmethaneimine (3):
将化合物2-氯-4-碘-5-(三氟甲氧基)吡啶(840.0mg,2.60mmol)、二苯甲酮亚胺(470.0mg,2.60mmol)、三(二亚苄基丙酮)二钯(238.0mg,0.26mmol)、1,1'-联萘-2,2'-双二苯膦(323.0mg,0.52mmol)、碳酸铯(2.5g,7.67mmol)溶于无水甲苯(10mL)中。氮气保护下于60℃反应5个小时。LCMS监测原料反应完全。将反应液直接浓缩后经硅胶柱层析(乙酸乙酯:石油醚＝5:1,Rf＝0.5)纯化得到黄色油状(750.0mg)。LC-MS:[M+1]+:377.2,379.2.The compound 2-chloro-4-iodo-5-(trifluoromethoxy)pyridine (840.0mg, 2.60mmol), benzophenone imine (470.0mg, 2.60mmol), tris(dibenzylideneacetone) Dipalladium (238.0mg, 0.26mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (323.0mg, 0.52mmol), cesium carbonate (2.5g, 7.67mmol) were dissolved in anhydrous toluene ( 10mL). React at 60°C for 5 hours under nitrogen protection. LCMS monitored the complete reaction of raw materials. The reaction solution was directly concentrated and then purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5:1, Rf = 0.5) to obtain a yellow oil (750.0 mg). LC-MS: [M+1] + :377.2,379.2.
N-(2-(4-甲基哌嗪-1-基)-5-(三氟甲氧基)吡啶-4-基)-1,1-二苯基甲烷亚胺(4)的合成：Synthesis of N-(2-(4-methylpiperazin-1-yl)-5-(trifluoromethoxy)pyridin-4-yl)-1,1-diphenylmethaneimine (4):
将化合物N-(2-氯-5-(三氟甲氧基)吡啶-4-基)-1,1-二苯基甲烷亚胺(800.0mg,2.12mmol)、1-甲基哌嗪(213.0mg,2.13mmol)、三(二亚苄基丙酮)二钯(195.0mg,0.21mmol)、2-二环己基膦-2',6'-二甲氧基联苯(172.0mg,0.42mmol)、叔丁醇钠(612.0mg,6.37mmol)溶于无水甲苯(10mL)中，氮气置换三次，反应液加热至110℃搅拌16小时。LCMS监测反应完全。将反应液直接浓缩后经硅胶柱层析(二氯甲烷:甲醇＝10:1,Rf＝0.5)纯化得到黄色固体(680.0mg)。LC-MS:[M+1]+:441.5。Compound N-(2-chloro-5-(trifluoromethoxy)pyridin-4-yl)-1,1-diphenylmethaneimine (800.0 mg, 2.12 mmol), 1-methylpiperazine ( 213.0mg, 2.13mmol), tris(dibenzylideneacetone)dipalladium (195.0mg, 0.21mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (172.0mg, 0.42mmol) ), sodium tert-butoxide (612.0 mg, 6.37 mmol) were dissolved in anhydrous toluene (10 mL), replaced with nitrogen three times, and the reaction solution was heated to 110°C and stirred for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was directly concentrated and then purified by silica gel column chromatography (dichloromethane:methanol=10:1, Rf=0.5) to obtain a yellow solid (680.0 mg). LC-MS: [M+1] + :441.5.
2-(4-甲基哌嗪-1-基)-5-(三氟甲氧基)吡啶-4-胺(5)的合成：Synthesis of 2-(4-methylpiperazin-1-yl)-5-(trifluoromethoxy)pyridin-4-amine (5):
将化合物N-(2-(4-甲基哌嗪-1-基)-5-(三氟甲氧基)吡啶-4-基)-1,1-二苯基甲烷亚胺(680.0mg,1.54mmol)溶于二氯甲烷(10mL)中，氮气保护下滴加三氟乙酸(2mL)。将反应液于室温搅拌4小时，LCMS监测反应完全。反应液直接浓缩然后经过柱层析(二氯甲烷:甲醇＝15:1)纯化得到黄色油状(400.0mg,)。LC-MS:[M+1]+:277.4。Compound N-(2-(4-methylpiperazin-1-yl)-5-(trifluoromethoxy)pyridin-4-yl)-1,1-diphenylmethaneimine (680.0 mg, 1.54 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise under nitrogen protection. The reaction solution was stirred at room temperature for 4 hours, and LCMS monitored that the reaction was complete. The reaction solution was directly concentrated and then purified by column chromatography (dichloromethane:methanol=15:1) to obtain a yellow oil (400.0 mg,). LC-MS: [M+1] + :277.4.
5'-(5-氟-2-((2-(4-甲基哌嗪-1-基)-5-(三氟甲氧基)吡啶-4-基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(PR-01-117)的合成：5'-(5-fluoro-2-((2-(4-methylpiperazin-1-yl)-5-(trifluoromethoxy)pyridin-4-yl)amino)pyrimidin-4-yl) Synthesis of spiro[cyclopropane-1,1'-isoindoline]-3'-one (PR-01-117):
将化合物2-(4-甲基哌嗪-1-基)-5-(三氟甲氧基)吡啶-4-胺(120.0mg,0.43mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚]-3'-酮(common int-10)(126.0mg,0.43mmol)、三(二亚苄基丙酮)二钯(40.0mg,0.04mmol)、1,1'-联萘-2,2'-双二苯膦(54.0mg,0.087mmol)、碳酸铯(425.0mg,1.30mmol)溶于无水甲苯(5mL)中，反应液氮气置换三次后升温至100℃搅拌6小时。反应液直接浓缩后经过柱层析(二氯甲烷:甲醇＝5:1)得到粗品产物。粗品经制备HPLC纯化得类白色固体(22.0mg)。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.91(s,1H),8.79(s,1H),8.34(s,1H)，8.25(d,J＝8.0Hz,1H),8.06(s,1H),7.85(s,1H),7.51(d,J＝8.0Hz,1H),3.48(s,4H),2.39(s,4H),2.21(s,3H),1.55(s,4H)；LC-MS:[M+1]+:530.4。Compound 2-(4-methylpiperazin-1-yl)-5-(trifluoromethoxy)pyridin-4-amine (120.0 mg, 0.43 mmol), 5'-(2-chloro-5-fluoro Pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole]-3'-one (common int-10) (126.0mg, 0.43mmol), tris(dibenzylideneacetone)dipalladium ( 40.0mg, 0.04mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (54.0mg, 0.087mmol), cesium carbonate (425.0mg, 1.30mmol) were dissolved in anhydrous toluene (5mL) , the reaction liquid was replaced with nitrogen three times, then the temperature was raised to 100°C and stirred for 6 hours. The reaction solution was directly concentrated and then subjected to column chromatography (dichloromethane:methanol=5:1) to obtain the crude product. The crude product was purified by preparative HPLC to obtain an off-white solid (22.0 mg). 1 H NMR (400MHz, DMSO-d6) δ9.51 (s, 1H), 8.91 (s, 1H), 8.79 (s, 1H), 8.34 (s, 1H), 8.25 (d, J = 8.0Hz, 1H ),8.06(s,1H),7.85(s,1H),7.51(d,J＝8.0Hz,1H),3.48(s,4H),2.39(s,4H),2.21(s,3H),1.55 (s,4H); LC-MS: [M+1] + :530.4.
实施例37.化合物DP-01-135的合成
Example 37. Synthesis of compound DP-01-135
4-溴-1-(二氟甲氧基)-2-硝基苯(2)的合成：Synthesis of 4-bromo-1-(difluoromethoxy)-2-nitrobenzene (2):
将化合物4-溴-2-硝基苯酚(1.0g,4.59mmol)、二氟氯乙酸(0.72g,5.52mmol)、碳酸铯(4.5g,13.81mmol)悬浮于DMF(25.0mL)中，80℃下搅拌3h。反应液加水(80ml)稀释，用乙酸乙酯(80mL×3)萃取。合并有机相后用饱和氯化钠(100mL)水溶液洗涤，无水硫酸钠干燥，过滤浓缩得粗品。经硅胶柱层析(石油醚:乙酸乙酯＝0％～5％)纯化后得到白色固体(0.6g)。LC-MS:[M+H]+:268.1,270.1。Compound 4-bromo-2-nitrophenol (1.0g, 4.59mmol), difluorochloroacetic acid (0.72g, 5.52mmol), and cesium carbonate (4.5g, 13.81mmol) were suspended in DMF (25.0mL), 80 Stir at ℃ for 3h. The reaction solution was diluted with water (80 ml), and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL) aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 0% to 5%), a white solid (0.6g) was obtained. LC-MS: [M+H] + :268.1, 270.1.
1-(4-(二氟甲氧基)-3-硝基苯基)-4-甲基哌嗪(3)的合成：Synthesis of 1-(4-(difluoromethoxy)-3-nitrophenyl)-4-methylpiperazine (3):
将化合物4-溴-1-(二氟甲氧基)-2-硝基苯(0.6g,2.24mmol)、1-甲基哌嗪(268.8mg,2.69mmol)、三[二亚苄基丙酮]二钯(201.3mg,0.22mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(127.2mg,0.22mmol)、碳酸铯(1.5g,4.60mmol)悬浮于甲苯(10mL)中，于90℃反应12h。反应液过滤旋干后经硅胶柱层析(石油醚:乙酸乙酯＝0％～35％)纯化得到白色固体(340.0mg)。LC-MS:[M+H]+:288.1。Compound 4-bromo-1-(difluoromethoxy)-2-nitrobenzene (0.6g, 2.24mmol), 1-methylpiperazine (268.8mg, 2.69mmol), tris[dibenzylideneacetone ] Dipalladium (201.3mg, 0.22mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (127.2mg, 0.22mmol), and cesium carbonate (1.5g, 4.60mmol) were suspended in in toluene (10 mL), and reacted at 90°C for 12 h. The reaction solution was filtered and spin-dried, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0% to 35%) to obtain a white solid (340.0 mg). LC-MS: [M+H] + :288.1.
2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)苯胺(4)的合成：Synthesis of 2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)aniline (4):
将化合物1-(4-(二氟甲氧基)-3-硝基苯基)-4-甲基哌嗪(290.0mg,1.01mmol)、Pd/C(100mg,10％w/w)悬浮于乙酸乙酯(5mL)中，氢气氛围(1大气压)下于40℃反应2h。反应液过滤，滤饼用乙酸乙酯(50mL×3)洗涤。滤液浓缩得浅黄色固体粗品(250.0mg)。LC-MS:[M+H]+:258.1。Compound 1-(4-(difluoromethoxy)-3-nitrophenyl)-4-methylpiperazine (290.0 mg, 1.01 mmol), Pd/C (100 mg, 10% w/w) was suspended React in ethyl acetate (5 mL) at 40°C for 2 h under hydrogen atmosphere (1 atmosphere). The reaction solution was filtered, and the filter cake was washed with ethyl acetate (50 mL × 3). The filtrate was concentrated to obtain a pale yellow solid crude product (250.0 mg). LC-MS: [M+H] + :258.1.
5'-(2-((2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-135)的合成：5'-(2-((2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[ring Synthesis of propane-1,1'-isoindoline]-3'-one (DP-01-135):
将化合物2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)苯胺(100.0mg,0.39mmol)，、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(112.5mg,0.39mmol)、醋酸钯(9.6mg,0.04mmol)、1,1'-联萘-2,2'-双二苯膦(24.8mg,0.04mmol)、碳酸铯(253.5mg,0.78mmol)溶于1,4-二氧六环(1mL)，氮气保护下加热至90℃反应5h。反应液冷却后加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取。合并有机相后用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤浓缩得黑色固体粗品。粗品经制备HPLC纯化得到白色固体(48.6mg)。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.65–8.63(m,2H),8.29(s,1H),8.20(dd,J＝7.2,1.6Hz,1H),7.65(d,J＝2.8Hz,1H),7.47(d,J＝8.0Hz,1H),7.14–6.77(m,2H),6.69(dd,J＝9.2,2.8Hz,1H),3.13(t,J＝4.8Hz,4H),2.46(t,J＝4.8Hz,4H),2.23(s,3H),1.54(s,4H)；LC-MS:[M+H]+:511.2。Compound 2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)aniline (100.0mg, 0.39mmol), 5'-(2-chloro-5-fluoropyrimidine-4 -base)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (112.5mg, 0.39mmol), palladium acetate (9.6mg, 0.04mmol), 1,1 '-Binaphthyl-2,2'-bisdiphenylphosphine (24.8mg, 0.04mmol) and cesium carbonate (253.5mg, 0.78mmol) were dissolved in 1,4-dioxane (1mL), and heated to React at 90°C for 5 hours. After cooling, the reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude black solid product. The crude product was purified by preparative HPLC to obtain a white solid (48.6 mg). 1 H NMR (400MHz, DMSO-d6) δ8.88 (s, 1H), 8.65–8.63 (m, 2H), 8.29 (s, 1H), 8.20 (dd, J＝7.2, 1.6Hz, 1H), 7.65 (d,J＝2.8Hz,1H),7.47(d,J＝8.0Hz,1H),7.14–6.77(m,2H),6.69(dd,J＝9.2,2.8Hz,1H),3.13(t, J=4.8Hz, 4H), 2.46 (t, J=4.8Hz, 4H), 2.23 (s, 3H), 1.54 (s, 4H); LC-MS: [M+H] + : 511.2.
实施例38.化合物DP-01-138的合成
Example 38. Synthesis of compound DP-01-138
(5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-基)-5-氟-4-(螺[环丙烷-1,1'-异吲哚啉]-5'-基)嘧啶-2-胺(DP-01-138)的合成：(5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-yl)-5-fluoro-4-(spiro[cyclopropane-1,1'-iso Synthesis of indoline]-5'-yl)pyrimidin-2-amine (DP-01-138):
向5-(二氟甲氧基)-2-(4-甲基哌嗪-1-基)吡啶-4-胺(common int-13)(120.0mg,0.46mmol)和5’-(2-氯-5- 氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3’-酮(common int-10)(127.9mg,0.44mmol)的甲苯(10mL)溶液中依次加入1,1'-联萘-2,2'-双二苯膦(57.9mg,0.09mmol)、三(二亚苄基丙酮)二钯(85.1mg,0.09mmol)、碳酸铯(302.8mg,0.93mmol)。将混合物在85℃下搅拌16小时。反应液加水稀释(20mL)，用乙酸乙酯(50mL)萃取。合并有机相用无水硫酸钠干燥，过滤浓缩得粗品。粗品经制备HPLC分离纯化得到黄色固体(13.0mg)。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.88(s,1H),8.80(d,J＝3.2Hz,1H),8.35(s,1H),8.26(d,J＝8.0Hz,1H),7.95(s,1H),7.93(s,1H),7.52(d,J＝8.0Hz,1H),7.03(t,J＝73.8Hz,1H),3.49–3.41(m,4H),2.43–2.35(m,4H),2.21(s,3H),1.56(s,4H)；LC-MS:[M+H]+:512.2。To 5-(difluoromethoxy)-2-(4-methylpiperazin-1-yl)pyridin-4-amine (common int-13) (120.0 mg, 0.46 mmol) and 5'-(2- Chlorine-5- To a solution of fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (127.9 mg, 0.44 mmol) in toluene (10 mL), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (57.9mg, 0.09mmol), tris(dibenzylideneacetone)dipalladium (85.1mg, 0.09mmol), cesium carbonate (302.8mg, 0.93mmol) ). The mixture was stirred at 85°C for 16 hours. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was separated and purified by preparative HPLC to obtain a yellow solid (13.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.88(s,1H),8.80(d,J＝3.2Hz,1H),8.35(s,1H),8.26(d,J ＝8.0Hz,1H),7.95(s,1H),7.93(s,1H),7.52(d,J＝8.0Hz,1H),7.03(t,J＝73.8Hz,1H),3.49–3.41(m ,4H),2.43–2.35(m,4H),2.21(s,3H),1.56(s,4H); LC-MS: [M+H] + :512.2.
实施例39.化合物DP-01-139的合成
Example 39. Synthesis of compound DP-01-139
5-溴-2-(二氟甲氧基)-3-碘吡啶(2)的合成：Synthesis of 5-bromo-2-(difluoromethoxy)-3-iodopyridine (2):
氮气保护下，向N,N-二甲基甲酰胺中(300.0mL)加入5-溴-3-碘吡啶-2-醇(30.4g,101.37mmol)、碳酸铯(43.0g,131.97mmol)、二氟氯乙酸钠(31.3g,205.3mmol)。将体系加热到80℃搅拌反应24小时，待反应完全后加入水(100.0mL)淬灭反应，用乙酸乙酯萃取(100mL×3)，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(PE:EA＝10:1)得到淡黄色固体(13.4g)。LC-MS:[M+H]+:349.9,351.9。Under nitrogen protection, add 5-bromo-3-iodopyridin-2-ol (30.4g, 101.37mmol), cesium carbonate (43.0g, 131.97mmol), to N,N-dimethylformamide (300.0mL). Sodium difluorochloroacetate (31.3g, 205.3mmol). Heat the system to 80°C and stir for 24 hours. After the reaction is complete, add water (100.0 mL) to quench the reaction. Extract with ethyl acetate (100 mL × 3). Combine the organic phases and wash with saturated brine and anhydrous sodium sulfate. Dry, filter and concentrate to obtain crude product. Separate by column chromatography (PE:EA=10:1) to obtain a light yellow solid (13.4g). LC-MS: [M+H] + :349.9, 351.9.
N-(5-溴-2-(二氟甲氧基)吡啶-3-基)-1,1-二苯基甲烷亚胺(3)的合成：Synthesis of N-(5-bromo-2-(difluoromethoxy)pyridin-3-yl)-1,1-diphenylmethaneimine (3):
向5-溴-2-(二氟甲氧基)-3-碘吡啶(13.4g,38.19mmol)、二苯甲酮亚胺(9.0g,49.66mmol)的N,N-二甲基甲酰胺(130.0mL)悬浮液中加入溴化亚铜(1.1g,7.66mmol)、(±)-1,1’-联(2-萘酚)(2.2g,7.66mmol)和磷酸钾(16.3g,76.8mmol)。反应体系在氮气保护下于70℃搅拌8小时。待反应完全后加水(50.0mL)淬灭反应，反应液用乙酸乙酯萃取(100mL×3)，合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经硅胶柱层析纯化(PE:EA＝2:1)得到棕色油状液体(2.3g)。LC-MS:[M+H]+:403.1,405.1。To 5-bromo-2-(difluoromethoxy)-3-iodopyridine (13.4g, 38.19mmol), benzophenone imine (9.0g, 49.66mmol), N,N-dimethylformamide (130.0mL) suspension was added with copper bromide (1.1g, 7.66mmol), (±)-1,1'-bis(2-naphthol) (2.2g, 7.66mmol) and potassium phosphate (16.3g, 76.8mmol). The reaction system was stirred at 70°C for 8 hours under nitrogen protection. After the reaction is complete, add water (50.0 mL) to quench the reaction. The reaction solution is extracted with ethyl acetate (100 mL × 3). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purified by silica gel column chromatography (PE:EA=2:1) to obtain brown oily liquid (2.3g). LC-MS: [M+H] + :403.1, 405.1.
N-(2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)吡啶-3-基)-1,1-二苯基甲烷亚胺(4)的合成：Synthesis of N-(2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1,1-diphenylmethaneimine (4):
向N-(5-溴-2-(二氟甲氧基)吡啶-3-基)-1,1-二苯基甲烷亚胺(2.3g,5.70mmol)、N-甲基哌嗪(685.2mg,6.84mmol)的1,4-二氧六环悬浮液中(25.0mL)加入三(二亚苄基丙酮)二钯(522.0mg,0.57mmol)、2-二环己基膦-2′,6′-二甲氧基-联苯(468.0mg,1.14mmol)和碳酸铯(5.6g,17.19mmol)。反应在氮气保护下于 90℃搅拌12小时。待反应完全后加水(50.0mL)淬灭，用乙酸乙酯萃取(50mL×3)。合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经硅胶柱层析(PE:EA＝2:1)纯化得到棕色油状液体(310.0mg)。LC-MS:[M+H]+:423.3。To N-(5-bromo-2-(difluoromethoxy)pyridin-3-yl)-1,1-diphenylmethaneimine (2.3g, 5.70mmol), N-methylpiperazine (685.2 mg, 6.84 mmol) of 1,4-dioxane suspension (25.0 mL) were added tris(dibenzylideneacetone) dipalladium (522.0 mg, 0.57 mmol) and 2-dicyclohexylphosphine-2′, 6'-dimethoxy-biphenyl (468.0 mg, 1.14 mmol) and cesium carbonate (5.6 g, 17.19 mmol). The reaction was carried out under nitrogen protection at Stir at 90°C for 12 hours. After the reaction was complete, add water (50.0 mL) to quench, and extract with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (PE:EA=2:1) to obtain a brown oily liquid (310.0 mg). LC-MS: [M+H] + :423.3.
2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)吡啶-3-胺(5)的合成：Synthesis of 2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)pyridin-3-amine (5):
向N-(2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)吡啶-3-基)-1,1-二苯基甲烷亚胺(310.0mg,0.73mmol)的二氯甲烷(5.0mL)溶液中加入三氟乙酸(2.5mL)。反应体系在室温下搅拌2小时。反应液浓缩后经硅胶柱层析(DCM:MeOH＝10:1)纯化得到无色油状液体(80.0mg)。LC-MS:[M+H]+:259.1。To N-(2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1,1-diphenylmethaneimine (310.0 mg, 0.73 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (2.5 mL). The reaction system was stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain a colorless oily liquid (80.0 mg). LC-MS: [M+H] + :259.1.
5'-(2-((2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-139)的合成：5'-(2-((2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-fluoropyrimidin-4-yl) Synthesis of spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-139):
向2-(二氟甲氧基)-5-(4-甲基哌嗪-1-基)吡啶-3-胺(100.0mg,0.39mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(123.0mg,0.43mmol)的二氧六环(3.0mL)悬浮液中加入醋酸钯(9.0mg,0.04mmol)、1,1'-联萘-2,2'-双二苯膦(48.0mg,0.08mmol)和碳酸铯(252.0mg,0.77mmol)。反应体系在氮气保护下于90℃搅拌2小时。待反应完全后加水(10.0mL)稀释反应液，用乙酸乙酯萃取(20mL×3)。合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得到粗品。粗品经制备HPLC纯化得到黄色固体(17.0mg)。1H NMR(400MHz,DMSO)δ8.93(s,1H),8.81(d,J＝3.2Hz,1H),8.51(d,J＝2.8Hz,1H),8.41(s,1H),8.32(s,1H),8.26(d,J＝8.0Hz,1H),8.01(t,J＝59.6Hz,1H),7.52(d,J＝8.0Hz,1H),6.62(d,J＝2.4Hz,1H),2.96(t,J＝4.8Hz,4H),2.47(t,J＝4.8Hz,4H),2.22(s,3H),1.56(s,4H)；LC-MS:[M+H]+:512.2。To 2-(difluoromethoxy)-5-(4-methylpiperazin-1-yl)pyridin-3-amine (100.0 mg, 0.39 mmol), 5'-(2-chloro-5-fluoropyrimidine -4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (123.0 mg, 0.43 mmol) in dioxane (3.0 mL) suspension Palladium acetate (9.0 mg, 0.04 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (48.0 mg, 0.08 mmol) and cesium carbonate (252.0 mg, 0.77 mmol) were added. The reaction system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction is complete, add water (10.0 mL) to dilute the reaction solution, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by preparative HPLC to obtain a yellow solid (17.0 mg). 1 H NMR (400MHz, DMSO) δ8.93 (s, 1H), 8.81 (d, J = 3.2Hz, 1H), 8.51 (d, J = 2.8Hz, 1H), 8.41 (s, 1H), 8.32 ( s,1H),8.26(d,J＝8.0Hz,1H),8.01(t,J＝59.6Hz,1H),7.52(d,J＝8.0Hz,1H),6.62(d,J＝2.4Hz, 1H), 2.96 (t, J＝4.8Hz, 4H), 2.47 (t, J＝4.8Hz, 4H), 2.22 (s, 3H), 1.56 (s, 4H); LC-MS: [M+H] + :512.2.
实施例40.化合物DP-01-150的合成
Example 40. Synthesis of compound DP-01-150
4-溴-2-碘-1-乙烯基苯(2)的合成：Synthesis of 4-bromo-2-iodo-1-vinylbenzene (2):
将甲基三苯基碘化膦(468.0mg,1.16mmol)和碳酸钾(200.0mg,1.45mmol)溶解于二氧六环(10mL)中，加入4-溴-2-碘-苯甲醛(300.0mg,0.97mmol)，100℃反应18小时。冷却反应液，旋干，粗产品经硅胶柱层析(石油醚)得到无色油状物(230.0mg)。1H NMR(400MHz,DMSO)δ8.20(s,1H),7.92(d,J＝8.4Hz,1H),7.77(d,J＝8.4Hz,1H),6.92(dd,J＝17.2,11.1Hz,1H),5.97(d,J＝17.3Hz,1H),5.57(d,J＝11.1 Hz,1H)。Dissolve methyl triphenylphosphine iodide (468.0 mg, 1.16 mmol) and potassium carbonate (200.0 mg, 1.45 mmol) in dioxane (10 mL), and add 4-bromo-2-iodo-benzaldehyde (300.0 mg, 0.97mmol), react at 100°C for 18 hours. The reaction solution was cooled and spun to dryness. The crude product was subjected to silica gel column chromatography (petroleum ether) to obtain a colorless oil (230.0 mg). 1 H NMR (400MHz, DMSO) δ8.20 (s, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.77 (d, J = 8.4Hz, 1H), 6.92 (dd, J = 17.2, 11.1 Hz,1H),5.97(d,J＝17.3Hz,1H),5.57(d,J＝11.1 Hz,1H).
4-溴-1-(2,2-二氟环丙基)-2-碘苯(3)的合成：Synthesis of 4-bromo-1-(2,2-difluorocyclopropyl)-2-iodobenzene (3):
将碘化钠(148.0mg,0.99mmol)和4-溴-2-碘-1-乙烯基苯(700.0mg,2.27mmol)溶于四氢呋喃(3mL)中，加入(三氟甲基)三甲基硅烷(1.13g,7.95mmol)，氮气保护下，70℃反应24小时冷却反应。冷却反应液，旋干，粗产品经硅胶柱层析(石油醚)得到无色油状物(430.0mg)。1H NMR(400MHz,DMSO)δ8.10(s,1H),7.60(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),2.91(dd,J＝21.2,11.2Hz,1H),2.02–1.94(m,2H)。Dissolve sodium iodide (148.0mg, 0.99mmol) and 4-bromo-2-iodo-1-vinylbenzene (700.0mg, 2.27mmol) in tetrahydrofuran (3mL), add (trifluoromethyl)trimethyl Silane (1.13g, 7.95mmol), react under nitrogen protection at 70°C for 24 hours and cool the reaction. The reaction solution was cooled and spun to dryness. The crude product was subjected to silica gel column chromatography (petroleum ether) to obtain a colorless oil (430.0 mg). 1 H NMR (400MHz, DMSO) δ8.10 (s, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.24 (d, J = 8.0Hz, 1H), 2.91 (dd, J = 21.2, 11.2 Hz,1H),2.02–1.94(m,2H).
N-(5-溴-2-(2,2-二氟环丙基)苯基)-1,1-二苯基甲烷亚胺(4)的合成：Synthesis of N-(5-bromo-2-(2,2-difluorocyclopropyl)phenyl)-1,1-diphenylmethaneimine (4):
将4-溴-1-(2,2-二氟环丙基)-2-碘苯(430.0mg,1.20mmol)、二苯甲酮亚胺(218.0mg,1.20mmol)、叔丁醇钠(345.4mg,3.59mmol)、三(二亚苄基丙酮)二钯(109.7mg,0.12mmol)及4,5-双二苯基膦-9,9-二甲基氧杂蒽(138.6mg,0.24mmol)溶解于甲苯(6mL)中，60℃反应5小时。冷却反应液，旋干，粗产品经硅胶柱层析(石油醚:乙酸乙酯＝10:1)得到白色固体(370.0mg)。LC-MS:[M+H]+:412.0,414.0。4-Bromo-1-(2,2-difluorocyclopropyl)-2-iodobenzene (430.0 mg, 1.20 mmol), benzophenone imine (218.0 mg, 1.20 mmol), sodium tert-butoxide ( 345.4mg, 3.59mmol), tris(dibenzylideneacetone)dipalladium (109.7mg, 0.12mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (138.6mg, 0.24 mmol) was dissolved in toluene (6 mL) and reacted at 60°C for 5 hours. The reaction solution was cooled and spun to dryness. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (370.0 mg). LC-MS: [M+H] + :412.0, 414.0.
N-(2-(2,2-二氟环丙基)-5-(4-甲基哌嗪-1-基)苯基)-1,1-二苯基甲烷亚胺(5)的合成：Synthesis of N-(2-(2,2-difluorocyclopropyl)-5-(4-methylpiperazin-1-yl)phenyl)-1,1-diphenylmethane imine (5) :
将N-(5-溴-2-(2,2-二氟环丙基)苯基)-1,1-二苯基甲烷亚胺(350.0mg,0.85mmol)、N-甲基哌嗪(102.1mg,1.02mmol)、叔丁醇钠(244.8mg,2.55mmol)、三(二亚苄基丙酮)二钯(77.7mg,0.09mmol)及1,1'-联萘-2,2'-双二苯膦(105.7mg,0.17mmol)溶解于甲苯(8mL)中，110℃反应3小时。冷却反应液，旋干，粗产品经硅胶柱层析(二氯甲烷:甲醇＝10:1)得到棕色固体(350.0mg)。LC-MS:[M+H]+:432.7。N-(5-bromo-2-(2,2-difluorocyclopropyl)phenyl)-1,1-diphenylmethaneimine (350.0 mg, 0.85 mmol), N-methylpiperazine ( 102.1 mg, 1.02 mmol), sodium tert-butoxide (244.8 mg, 2.55 mmol), tris(dibenzylideneacetone) dipalladium (77.7 mg, 0.09 mmol) and 1,1'-binaphthyl-2,2'- Bisdiphenylphosphine (105.7 mg, 0.17 mmol) was dissolved in toluene (8 mL) and reacted at 110°C for 3 hours. The reaction solution was cooled and spun to dryness. The crude product was subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to obtain a brown solid (350.0 mg). LC-MS: [M+H] + :432.7.
2-(2,2-二氟环丙基)-5-(4-甲基哌嗪-1-基)苯胺(6)的合成：Synthesis of 2-(2,2-difluorocyclopropyl)-5-(4-methylpiperazin-1-yl)aniline (6):
将N-(2-(2,2-二氟环丙基)-5-(4-甲基哌嗪-1-基)苯基)-1,1-二苯基甲烷亚胺(100.0mg,0.23mmol)溶解于二氯甲烷(3mL)中，滴加三氟乙酸(1mL)，室温反应18小时。旋干反应液，粗产品经硅胶柱层析(二氯甲烷:甲醇:氨水＝100:10:1)得到白色色固体(60.0mg)。LC-MS:[M+H]+:268.3。N-(2-(2,2-difluorocyclopropyl)-5-(4-methylpiperazin-1-yl)phenyl)-1,1-diphenylmethaneimine (100.0 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added dropwise, and the reaction was carried out at room temperature for 18 hours. The reaction solution was spun to dryness, and the crude product was subjected to silica gel column chromatography (dichloromethane: methanol: ammonia = 100:10:1) to obtain a white solid (60.0 mg). LC-MS: [M+H] + :268.3.
5'-(2-((2-(2,2-二氟环丙基)-5-(4-甲基哌嗪-1-基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-150)的合成：5'-(2-((2-(2,2-difluorocyclopropyl)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl )Synthesis of spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-150):
将2-(2,2-二氟环丙基)-5-(4-甲基哌嗪-1-基)苯胺(60.0mg,0.22mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(65.0mg,0.22mmol)、三(二亚苄基丙酮)二钯(21.0mg,0.02mmol)、1,1'-联萘-2,2'-双二苯膦(28.0mg,0.045mmol)及碳酸铯(220.0mg,0.68mmol)溶解于甲苯(5mL)中，100℃反应18小时。反应液过滤，旋干，粗产品经中性制备得到白色固体(18.8mg)。1H NMR(400MHz,MeOD)δ8.51(s,1H),8.41(d,J＝3.6Hz,1H),8.33(d,J＝8.0Hz,1H),7.54(d,J＝2.4Hz,1H),7.37(d,J＝8.4Hz,1H),7.14(d,J＝8.4Hz,1H),6.76(dd,J＝8.8,2.8Hz,1H),3.24–3.21(m,4H),2.84–2.75(m,1H),2.62–2.59(m,4H),2.34(s,3H),1.83–1.80(m,1H),1.67–1.52(m,5H)；LC-MS:[M+H]+:521.8。2-(2,2-Difluorocyclopropyl)-5-(4-methylpiperazin-1-yl)aniline (60.0mg, 0.22mmol), 5'-(2-chloro-5-fluoropyrimidine -4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (65.0mg, 0.22mmol), tris(dibenzylideneacetone)dipalladium ( 21.0mg, 0.02mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (28.0mg, 0.045mmol) and cesium carbonate (220.0mg, 0.68mmol) were dissolved in toluene (5mL), 100 ℃ reaction for 18 hours. The reaction solution was filtered and spun to dryness. The crude product was neutralized to obtain a white solid (18.8 mg). 1 H NMR (400MHz, MeOD) δ8.51 (s, 1H), 8.41 (d, J = 3.6Hz, 1H), 8.33 (d, J = 8.0Hz, 1H), 7.54 (d, J = 2.4Hz, 1H),7.37(d,J＝8.4Hz,1H),7.14(d,J＝8.4Hz,1H),6.76(dd,J＝8.8,2.8Hz,1H),3.24–3.21(m,4H), 2.84–2.75(m,1H),2.62–2.59(m,4H),2.34(s,3H),1.83–1.80(m,1H),1.67–1.52(m,5H); LC-MS:[M+ H] + :521.8.
实施例41.化合物DP-01-149的合成
Example 41. Synthesis of compound DP-01-149
4-溴-1-(溴甲基)-2-碘苯(2)的合成：Synthesis of 4-bromo-1-(bromomethyl)-2-iodobenzene (2):
将化合物4-溴-2-碘-1-甲苯(9.0g,30.31mmol)、N-溴丁二酰亚胺(5.9g,33.15mmol)和偶氮二异丁腈(0.5g,3.04mmol)溶于四氯化碳(50mL)中，在80℃反应2小时。反应液过滤，滤液浓缩。粗品经硅胶柱层析(乙酸乙酯:石油醚＝0-30％)纯化得白色固体(2.5g)。1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝2.0Hz,1H),7.62(dd,J＝8.4,2.0Hz,1H),7.56(d,J＝8.4Hz,1H),4.70(s,2H)。Compound 4-bromo-2-iodo-1-toluene (9.0g, 30.31mmol), N-bromosuccinimide (5.9g, 33.15mmol) and azobisisobutyronitrile (0.5g, 3.04mmol) Dissolve in carbon tetrachloride (50 mL) and react at 80°C for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to obtain a white solid (2.5g). 1 H NMR (400MHz, DMSO-d6) δ8.09 (d, J = 2.0Hz, 1H), 7.62 (dd, J = 8.4, 2.0Hz, 1H), 7.56 (d, J = 8.4Hz, 1H), 4.70(s,2H).
4-溴-2-碘-1-(异氰甲基)苯(3)的合成：Synthesis of 4-bromo-2-iodo-1-(isocyanomethyl)benzene (3):
向4-溴-1-(溴甲基)-2-碘苯(2.4g,6.39mmol)的四氢呋喃(30mL)溶液中加入三甲基氰硅烷(1.3g,13.10mmol)。然后将反应液冷却至0℃后缓慢滴加1M四丁基氟化铵(12.8mL,12.8mmol)，滴加完毕后将反应升至室温搅拌3小时。反应液加入冰水混合物(30mL)淬灭，分离出有机相。水相用乙酸乙酯(30mL×2)萃取，合并有机相，分别用水(30mL)和饱和食盐水(30mL)洗涤，无水硫酸镁干燥，过滤浓缩。粗品经硅胶柱层析(石油醚：乙酸乙酯＝10:1)纯化得到白色固体(1.5g)。1HNMR(400MHz,DMSO-d6)δ8.13(d,J＝1.4Hz,1H),7.67(dd,J＝8.4,1.4Hz,1H),7.47(d,J＝8.4Hz,1H),4.03(s,2H)。To a solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (2.4 g, 6.39 mmol) in tetrahydrofuran (30 mL) was added trimethylsilyl cyanide (1.3 g, 13.10 mmol). Then the reaction solution was cooled to 0°C and 1M tetrabutylammonium fluoride (12.8 mL, 12.8 mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction was raised to room temperature and stirred for 3 hours. The reaction solution was quenched by adding ice-water mixture (30 mL), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (1.5 g). 1 HNMR (400MHz, DMSO-d6) δ8.13(d,J＝1.4Hz,1H),7.67(dd,J＝8.4,1.4Hz,1H),7.47(d,J＝8.4Hz,1H),4.03 (s,2H).
1-(4-溴-2-碘苯基)环丙烷-1-甲腈(4)的合成：Synthesis of 1-(4-bromo-2-iodophenyl)cyclopropane-1-carbonitrile (4):
氮气保护下，将4-溴-2-碘-1-(异氰甲基)苯(1.6g,4.97mmol)溶于N,N-二甲基甲酰胺(2mL)中，冷却至0℃后加入氢化钠(398.4mg,9.94mmol,60％w/w)。混合物在0℃搅拌1小时后加入1-氯-2-溴乙烷(0.82mL,9.94mmol)，升温至25℃后继续搅拌1小时。反应液加水(20mL)淬灭，用乙酸乙酯(20mL×3)萃取。合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝1:5)纯化得到白色固体(1.5g)。1H NMR(400MHz,DMSO-d6)δ8.15(d,J＝2.5Hz,1H),7.64(dd,J＝9.0,2.5Hz,1H),7.39(d,J＝9.0Hz,1H),1.80(q,J＝5.1Hz,2H),1.38(q,J＝5.0Hz,2H)。Under nitrogen protection, dissolve 4-bromo-2-iodo-1-(isocyanomethyl)benzene (1.6g, 4.97mmol) in N,N-dimethylformamide (2mL), and cool to 0°C. Sodium hydride (398.4 mg, 9.94 mmol, 60% w/w) was added. The mixture was stirred at 0°C for 1 hour, then 1-chloro-2-bromoethane (0.82 mL, 9.94 mmol) was added, the temperature was raised to 25°C, and stirring was continued for 1 hour. The reaction solution was quenched by adding water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain a white solid (1.5g). 1 H NMR (400MHz, DMSO-d6) δ8.15 (d, J＝2.5Hz, 1H), 7.64 (dd, J＝9.0, 2.5Hz, 1H), 7.39 (d, J＝9.0Hz, 1H), 1.80(q,J=5.1Hz,2H), 1.38(q,J=5.0Hz,2H).
1-(4-溴-2-((二苯基亚甲基)氨基)苯基)环丙烷-1-甲腈(5)的合成：Synthesis of 1-(4-bromo-2-((diphenylmethylene)amino)phenyl)cyclopropane-1-carbonitrile (5):
向1-(4-溴-2-碘苯基)环丙烷-1-甲腈(500.0mg,1.44mmol)和二苯基甲烷亚胺(312.5mg,1.72mmol)的1,4-二氧六环(10mL)溶液中依次加入1,1'-联萘-2,2'-双二苯膦(178.9mg,0.29mmol)、三(二亚苄基丙酮)二钯(263.2mg,0.29mmol)和碳酸铯(1.4g,4.31mmol)，并在氮气保护下于100℃搅拌2小时。将反应液冷却至室温后浓缩至干。粗品经硅胶柱层析(甲醇:二氯甲烷＝0-5％)纯化得到黄色固体(550.0mg)。LC-MS:[M+H]+:401.1。 1,4-dioxane to 1-(4-bromo-2-iodophenyl)cyclopropane-1-carbonitrile (500.0 mg, 1.44 mmol) and diphenylmethane imine (312.5 mg, 1.72 mmol) To the ring (10 mL) solution, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (178.9 mg, 0.29 mmol) and tris(dibenzylideneacetone)dipalladium (263.2 mg, 0.29 mmol) were added in sequence. and cesium carbonate (1.4g, 4.31mmol), and stirred at 100°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 0-5%) to obtain a yellow solid (550.0 mg). LC-MS: [M+H] + :401.1.
1-(2-((二苯基亚甲基)氨基)-4-(4-甲基哌嗪-1-基)苯基)环丙烷-1-甲腈(6)的合成：Synthesis of 1-(2-((diphenylmethylene)amino)-4-(4-methylpiperazin-1-yl)phenyl)cyclopropane-1-carbonitrile (6):
氮气保护下，向1-(4-溴-2-((二苯基亚甲基)氨基)苯基)环丙烷-1-甲腈(550mg,1.37mmol)、1-甲基哌嗪(206.3mg,2.06mmol)、2-双环己基膦-2',6'-二甲氧基-1,1'-二联苯(56.3mg,0.14mmol)、三(二亚苄基丙酮)二钯(125.6mg,0.14mmol)的1,4-二氧六环(20mL)溶液中加入碳酸铯(1340.1mg,4.11mmol。将混合物100℃搅拌2小时，直到原料完全消耗。反应液冷却至室温后真空浓缩，粗品经硅胶柱层析(0-5％的甲醇/二氯甲烷)纯化得到黄色固体(500.0mg)。LC-MS:[M+H]+:421.1。Under nitrogen protection, add 1-(4-bromo-2-((diphenylmethylene)amino)phenyl)cyclopropane-1-carbonitrile (550mg, 1.37mmol) and 1-methylpiperazine (206.3 mg, 2.06mmol), 2-bicyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl (56.3mg, 0.14mmol), tris(dibenzylideneacetone)dipalladium ( To a solution of 1,4-dioxane (125.6 mg, 0.14 mmol) in 20 mL, cesium carbonate (1340.1 mg, 4.11 mmol) was added. The mixture was stirred at 100°C for 2 hours until the raw materials were completely consumed. The reaction solution was cooled to room temperature and vacuumed After concentration, the crude product was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to obtain a yellow solid (500.0 mg). LC-MS: [M+H] + : 421.1.
1-(2-氨基-4-(4-甲基哌嗪-1-基)苯基)环丙烷-1-甲腈(7)的合成：Synthesis of 1-(2-amino-4-(4-methylpiperazin-1-yl)phenyl)cyclopropane-1-carbonitrile (7):
在室温下，向1-(2-((二苯基亚甲基)氨基)-4-(4-甲基哌嗪-1-基)苯基)环丙烷-1-甲腈(350.0mg,0.83mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(1.5mL)，反应液于室温搅拌2小时后减压浓缩，所得残余物加入饱和碳酸氢钠水溶液(5mL)中和，用二氯甲烷(10mL×2)萃取。合并有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤浓缩得棕色油状粗品产物(150.0mg)。粗品直接用于下一步反应。LC-MS:[M+H]+:257.3。To 1-(2-((diphenylmethylene)amino)-4-(4-methylpiperazin-1-yl)phenyl)cyclopropane-1-carbonitrile (350.0 mg, Trifluoroacetic acid (1.5 mL) was added to a solution of 0.83 mmol) in methylene chloride (3 mL). The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was neutralized by adding saturated aqueous sodium bicarbonate solution (5 mL). Extract with methyl chloride (10mL×2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a brown oily crude product (150.0 mg). The crude product was directly used in the next reaction. LC-MS: [M+H] + :257.3.
1-(2-((5-氟-4-(3'-氧代螺环[环丙烷-1,1'-异吲哚啉]-5'-基)嘧啶-2-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)环丙烷-1-甲腈(DP-01-149)的合成：1-(2-((5-fluoro-4-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyrimidin-2-yl)amino)- Synthesis of 4-(4-methylpiperazin-1-yl)phenyl)cyclopropane-1-carbonitrile (DP-01-149):
向1-(2-氨基-4-(4-甲基哌嗪-1-基)苯基)环丙烷-1-甲腈(200.0mg,0.78mmol)和5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(226.0mg,0.78mmol)的1,4-二氧六环(10mL)溶液中依次加入1,1'-联萘-2,2'-双二苯膦(48.6mg,0.08mmol)、三(二亚苄基丙酮)二钯(71.4mg,0.08mmol)和碳酸铯(762.0mg,2.34mmol)。氮气保护下，将混合物在100℃下搅拌2小时。将反应液冷却至室温，加水(20mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相，分别用水(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品。粗品经制备HPLC分离纯化得到黄色固体(8.9mg)。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),9.06(d,J＝3.1Hz,1H),8.95(s,1H),8.35(s,1H),8.28(d,J＝8.2Hz,1H),7.98(d,J＝1.8Hz,1H),7.56(d,J＝8.0Hz,1H),6.88(d,J＝8.3Hz,1H),6.70(d,J＝8.1Hz,1H),3.14–3.05(m,4H),2.43(d,J＝4.8Hz,4H),2.20(s,3H),1.57(s,4H),1.47(d,J＝12.8Hz,4H)；LC-MS:[M+H]+:510.3。To 1-(2-amino-4-(4-methylpiperazin-1-yl)phenyl)cyclopropane-1-carbonitrile (200.0 mg, 0.78 mmol) and 5'-(2-chloro-5- 1,4-dioxane of fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (226.0 mg, 0.78 mmol) 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (48.6mg, 0.08mmol), tris(dibenzylideneacetone)dipalladium (71.4mg, 0.08mmol) and carbonic acid were added to the solution in sequence. Cesium (762.0mg, 2.34mmol). Under nitrogen protection, the mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by preparative HPLC to obtain a yellow solid (8.9 mg). 1 H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 9.06 (d, J = 3.1 Hz, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 8.28 (d, J =8.2Hz,1H),7.98(d,J＝1.8Hz,1H),7.56(d,J＝8.0Hz,1H),6.88(d,J＝8.3Hz,1H),6.70(d,J＝8.1 Hz,1H),3.14–3.05(m,4H),2.43(d,J＝4.8Hz,4H),2.20(s,3H),1.57(s,4H),1.47(d,J＝12.8Hz,4H ); LC-MS: [M+H] + :510.3.
实施例42.化合物DP-01-164的合成
Example 42. Synthesis of compound DP-01-164
1-甲基-4-(3-硝基-4-(三氟甲基)苯基)哌嗪(2)的合成：Synthesis of 1-methyl-4-(3-nitro-4-(trifluoromethyl)phenyl)piperazine (2):
在室温下，将4-溴-2-硝基三氟甲基苯(1.0g,3.70mmol)溶解在甲苯(10mL)中，并依次加入1-甲基哌嗪(556.5mg,5.56mmol)、三(二亚苄基丙酮)二钯(169.6mg,0.19mmol)、2-双环己基膦-2',6'-二甲氧基 联苯(152.1mg,0.37mmol)和叔丁醇钠(1.1g,11.45mmol)。将反应液于90℃搅拌6小时，反应液冷却至室温后加水(10mL)稀释，用乙酸乙酯(15mL×3)萃取。合并有机相用无水硫酸钠干燥，过滤浓缩得到粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝1:1；Rf＝0.3)纯化得无色透明油状物(800.0mg)。LC-MS:[M+H]+:290.1。Dissolve 4-bromo-2-nitrotrifluoromethylbenzene (1.0g, 3.70mmol) in toluene (10mL) at room temperature, and add 1-methylpiperazine (556.5mg, 5.56mmol), Tris(dibenzylideneacetone)dipalladium (169.6mg, 0.19mmol), 2-bicyclohexylphosphine-2',6'-dimethoxy Biphenyl (152.1 mg, 0.37 mmol) and sodium tert-butoxide (1.1 g, 11.45 mmol). The reaction solution was stirred at 90°C for 6 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1:1; R f = 0.3) to obtain a colorless and transparent oil (800.0 mg). LC-MS: [M+H] + :290.1.
5-(4-甲基哌嗪-1-基)-2-(三氟甲基)苯胺(3)的合成：Synthesis of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)aniline (3):
将1-甲基-4-(3-硝基-4-(三氟甲基)苯基)哌嗪(40.0mg,0.14mmol)溶解在甲醇(3mL)中，加入Pd/C(14.9mg,10％w/w)，置换氢气三次。将混合物于室温搅拌6小时，直到原料完全消失。反应液经硅藻土过滤，滤液浓缩得黑色固体(30.0mg)。所得粗产物直接用于下一步反应。LC-MS:[M+H]+:260.1。Dissolve 1-methyl-4-(3-nitro-4-(trifluoromethyl)phenyl)piperazine (40.0 mg, 0.14 mmol) in methanol (3 mL), and add Pd/C (14.9 mg, 10% w/w), replacing hydrogen three times. The mixture was stirred at room temperature for 6 hours until the starting material disappeared completely. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a black solid (30.0 mg). The crude product obtained was directly used in the next reaction. LC-MS: [M+H] + :260.1.
5'-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-164)的合成：5'-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane Synthesis of -1,1'-isoindoline]-3'-one (DP-01-164):
将5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(25.0mg,0.09mmol)和5-(4-甲基哌嗪-1-基)-2-(三氟甲基)苯胺(29.1mg,0.11mmol)溶解在二氧六环(1mL)中，向溶液中加入醋酸钯(2.24mg,0.01mmol)、碳酸铯(84.4mg,0.26mmol)和1,1'-联萘-2,2'-双二苯膦(10.8mg,0.017mmol)。置换三次氮气后将混合物加热回流6小时。将反应液倒入水中(1mL)并用乙酸乙酯(4mL×3)萃取。合并有机相后用无水硫酸钠干燥，过滤浓缩得到粗品。粗品经碱性制备HPLC纯化得透明无色固体(3.2mg)。1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.75(s,1H),8.56(d,J＝3.6Hz,1H),8.25(s,1H),8.15(d,J＝8.0Hz,1H),7.49(d,J＝8.8Hz,1H),7.45(d,J＝8.8Hz,1H),7.27(s,1H),6.89(d,J＝8.4Hz,1H),3.28–3.22(m,4H),2.46–2.36(m,4H),2.20(s,3H),1.52(s,4H)；LC-MS:[M+H]+:513.3。5'-(2-Chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (common int-10) (25.0 mg, 0.09 mmol ) and 5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)aniline (29.1 mg, 0.11 mmol) were dissolved in dioxane (1 mL), and palladium acetate was added to the solution (2.24 mg, 0.01 mmol), cesium carbonate (84.4 mg, 0.26 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (10.8 mg, 0.017 mmol). After replacing nitrogen three times, the mixture was heated to reflux for 6 hours. The reaction solution was poured into water (1 mL) and extracted with ethyl acetate (4 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by alkaline preparative HPLC to obtain a transparent colorless solid (3.2 mg). 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.75(s,1H),8.56(d,J＝3.6Hz,1H),8.25(s,1H),8.15(d,J ＝8.0Hz,1H),7.49(d,J＝8.8Hz,1H),7.45(d,J＝8.8Hz,1H),7.27(s,1H),6.89(d,J＝8.4Hz,1H), 3.28–3.22(m,4H),2.46–2.36(m,4H),2.20(s,3H),1.52(s,4H); LC-MS: [M+H] + :513.3.
实施例43.化合物DP-01-206的合成
Example 43. Synthesis of compound DP-01-206
1-(4-甲氧基-3-硝基苯基)-4-甲基哌嗪(2)的合成：Synthesis of 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine (2):
将化合物4-溴-1-甲氧基-2-硝基苯(500.0mg,2.16mmol)、1-甲基哌嗪(280.6mg,2.80mmol)、2-二环己基膦-2′,6′-二甲氧基-联苯(88.5mg,0.22mmol)、碳酸铯(1404.2mg,4.31mmol)和三(二亚苄基丙酮)二钯(98.7mg,0.11mmol)溶于二氧六环(8mL)中，氮气置换三次，升温至90℃搅拌6小时，LCMS检测原料反应完全。反应液加水(15mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝0-34％,石油醚/乙酸乙酯＝1:1,Rf＝0.2)纯化得黄色油状物(230.0mg)。LC-MS:[M+H]+:252.1。Compound 4-bromo-1-methoxy-2-nitrobenzene (500.0mg, 2.16mmol), 1-methylpiperazine (280.6mg, 2.80mmol), 2-dicyclohexylphosphine-2′,6 '-Dimethoxy-biphenyl (88.5 mg, 0.22 mmol), cesium carbonate (1404.2 mg, 4.31 mmol) and tris(dibenzylideneacetone) dipalladium (98.7 mg, 0.11 mmol) were dissolved in dioxane (8 mL), replace with nitrogen three times, raise the temperature to 90°C and stir for 6 hours. LCMS detects that the reaction of the raw materials is complete. The reaction solution was diluted with water (15 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-34%, petroleum ether/ethyl acetate = 1:1, Rf = 0.2) to obtain a yellow oil (230.0 mg). LC-MS: [M+H] + :252.1.
2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(3)的合成：Synthesis of 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (3):
将化合物1-(4-甲氧基-3-硝基苯基)-4-甲基哌嗪(180.0mg,0.72mmol)和Pd/C(80mg,10％w/w)悬浮 于甲醇(5mL)中，氢气置换三次后室温搅拌反应4小时。LCMS监测反应完全后将反应液通过硅藻土过滤，滤饼用乙酸乙酯洗涤3次，滤液旋干后得黄色固体(150.0mg)。LC-MS:[M+H]+:222.2。Compound 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine (180.0 mg, 0.72 mmol) and Pd/C (80 mg, 10% w/w) were suspended In methanol (5 mL), hydrogen was substituted three times and the reaction was stirred at room temperature for 4 hours. After LCMS monitored that the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed three times with ethyl acetate, and the filtrate was spin-dried to obtain a yellow solid (150.0 mg). LC-MS: [M+H] + :222.2.
5'-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-206)的合成：5'-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1, Synthesis of 1'-isoindoline]-3'-one (DP-01-206):
将化合物2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(150.0mg,0.68mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(216.0mg,0.75mmol)、1,1'-联萘-2,2'-双二苯膦(84.4mg,0.14mmol)、醋酸钯(15.2mg,0.07mmol)和碳酸铯(441.7mg,1.36mmol)溶于1,4-二氧六环(4mL)中，置换氮气，升温至100℃搅拌6小时，LCMS监测到原料消失。反应液加水(5mL)稀释，用乙酸乙酯萃取(10mL×3)。合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(甲醇:二氯甲烷＝0-16％；二氯甲烷/甲醇＝10:1,Rf＝0.2)纯化得黑色固体粗品(111.0mg)，后者经制备HPLC进一步纯化得白色固体(27.3mg)。1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.44–8.33(m,3H),7.87(s,1H),7.33(s,1H),7.18(d,J＝8.4Hz,1H),6.83(d,J＝8.8Hz,1H),6.56(dd,J＝8.4,2.8Hz,1H),3.89(s,3H),3.29–3.10(m,4H),2.66–2.56(m,4H),2.37(s,3H),1.70–1.60(m,2H),1.56-1.52(m,2H)；LC-MS:[M+H]+:475.3。Compound 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (150.0mg, 0.68mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[ Cyclopropane-1,1'-isoindolin]-3'-one (common int-10) (216.0mg, 0.75mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ( 84.4mg, 0.14mmol), palladium acetate (15.2mg, 0.07mmol) and cesium carbonate (441.7mg, 1.36mmol) were dissolved in 1,4-dioxane (4mL), replaced with nitrogen, heated to 100°C and stirred for 6 Hours later, LCMS detected the disappearance of the starting material. The reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 0-16%; dichloromethane/methanol = 10:1, R f = 0.2) to obtain a black solid crude product (111.0 mg), which was further purified by preparative HPLC. A white solid (27.3 mg) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ8.65 (s, 1H), 8.44–8.33 (m, 3H), 7.87 (s, 1H), 7.33 (s, 1H), 7.18 (d, J = 8.4Hz, 1H),6.83(d,J＝8.8Hz,1H),6.56(dd,J＝8.4,2.8Hz,1H),3.89(s,3H),3.29–3.10(m,4H),2.66–2.56(m ,4H),2.37(s,3H),1.70–1.60(m,2H),1.56-1.52(m,2H); LC-MS: [M+H] + :475.3.
实施例44.化合物DP-01-221的合成
Example 44. Synthesis of compound DP-01-221
4-溴-1-乙氧基-2-硝基苯(2)的合成：Synthesis of 4-bromo-1-ethoxy-2-nitrobenzene (2):
在室温下，将4-溴-1-氟-2-硝基苯(1.0g,4.55mmol)溶解在N,N-二甲基甲酰胺(10mL)中，向溶液中加入乙醇钠(619.3mg,9.1mmol)。将混合物50℃下搅拌12小时，直到原料完全消耗。反应液冷却，加水(10mL)淬灭反应，用乙酸乙酯萃取(50mL×3)。合并有机相，再用饱和食盐水洗涤(15mL×3)，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(石油醚:乙酸乙酯＝3:1)得到白色固体(1.0g)。LC-MS:[M+H]+:246.2。Dissolve 4-bromo-1-fluoro-2-nitrobenzene (1.0g, 4.55mmol) in N,N-dimethylformamide (10mL) at room temperature, and add sodium ethoxide (619.3mg) to the solution ,9.1mmol). The mixture was stirred at 50°C for 12 hours until the starting materials were completely consumed. The reaction solution was cooled, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 3), and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Separate by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a white solid (1.0g). LC-MS: [M+H] + :246.2.
1-(4-乙氧基-3-硝基苯基)-4-甲基哌嗪(3)的合成：Synthesis of 1-(4-ethoxy-3-nitrophenyl)-4-methylpiperazine (3):
向4-溴-1-乙氧基-2-硝基苯(1.0g,4.08mmol)的二氧六环(10mL)溶液中依次加入1-甲基哌嗪(529.2 mg,5.28mmol)、三(二亚苄基丙酮)二钯(186.1mg,0.20mmol)、2-双环己基膦-2',6'-二甲氧基联苯(166.9mg,0.41mmol)和碳酸铯(2648.3mg,8.13mmol)。将所得混合物在氮气保护下于100℃搅拌6小时。待反应液冷却后加水(10mL)稀释，用乙酸乙酯萃取(15mL×3)。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(石油醚:乙酸乙酯＝3:1)得到白色固体(400.0mg)。LC-MS:[M+H]+:266.2。To a solution of 4-bromo-1-ethoxy-2-nitrobenzene (1.0g, 4.08mmol) in dioxane (10mL) was added 1-methylpiperazine (529.2 mg, 5.28mmol), tris(dibenzylideneacetone)dipalladium (186.1mg, 0.20mmol), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (166.9mg, 0.41mmol) and Cesium carbonate (2648.3mg, 8.13mmol). The resulting mixture was stirred at 100°C for 6 hours under nitrogen protection. After the reaction solution was cooled, water (10 mL) was added to dilute it, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (400.0 mg). LC-MS: [M+H] + :266.2.
2-乙氧基-5-(4-甲基哌嗪-1-基)苯胺(4)的合成：Synthesis of 2-ethoxy-5-(4-methylpiperazin-1-yl)aniline (4):
将1-(4-乙氧基-3-硝基苯基)-4-甲基哌嗪(200.0mg,0.75mmol)和钯碳(80.22mg,10％w/w)溶解在甲醇(3mL)中。插入氢气球并置换三次氢气。将混合物室温搅拌5小时，直到原料完全消耗。将反应液过滤浓缩得到黑色固体(120.0mg)。LC-MS:[M+H]+:236.2。Dissolve 1-(4-ethoxy-3-nitrophenyl)-4-methylpiperazine (200.0 mg, 0.75 mmol) and palladium on carbon (80.22 mg, 10% w/w) in methanol (3 mL) middle. Insert a hydrogen balloon and replace the hydrogen gas three times. The mixture was stirred at room temperature for 5 hours until the starting materials were completely consumed. The reaction solution was filtered and concentrated to obtain a black solid (120.0 mg). LC-MS: [M+H] + :236.2.
5'-(2-((2-乙氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-221)的合成：5'-(2-((2-ethoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1, Synthesis of 1'-isoindoline]-3'-one (DP-01-221):
在室温下，向5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(135.4mg,0.47mmol)和2-乙氧基-5-(4-甲基哌嗪-1-基)苯胺(100.0mg,0.43mmol)的二氧六环(2mL)溶液中依次加入碳酸铯(415.4mg,1.28mmol)、1,1'-联萘-2,2'-双二苯膦(52.9mg,0.085mmol)和三(二亚苄基丙酮)二钯(38.9mg,0.043mmol)。将反应液在氮气保护下加热回流6小时，直到原料完全消耗。反应液冷却后真空除去溶剂，加水(5mL)稀释，用乙酸乙酯萃取(15mL×3)。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到粗品。经碱性制备得到白色固体(20.7mg)。1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.48–8.28(m,3H),7.88(s,1H),7.18(d,J＝8.0Hz,1H),6.82(d,J＝8.8Hz,1H),6.54(dd,J＝8.8,2.8Hz,1H),6.45(s,1H),4.10(q,J＝7.2Hz,2H),3.28–3.09(m,4H),2.65–2.52(m,4H),2.37(s,3H),1.65(m,2H),1.54(m,2H),1.47(t,J＝6.8Hz,3H)；LC-MS:[M+H]+:489.2。To 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (135.4 mg, 0.47mmol) and 2-ethoxy-5-(4-methylpiperazin-1-yl)aniline (100.0mg, 0.43mmol) in dioxane (2mL) were added cesium carbonate (415.4 mg, 1.28 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (52.9 mg, 0.085 mmol), and tris(dibenzylideneacetone)dipalladium (38.9 mg, 0.043 mmol). The reaction solution was heated and refluxed under nitrogen protection for 6 hours until the raw materials were completely consumed. After the reaction solution was cooled, the solvent was removed in vacuo, diluted with water (5 mL), and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. A white solid (20.7 mg) was obtained by basic preparation. 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.48–8.28(m,3H),7.88(s,1H),7.18(d,J＝8.0Hz,1H),6.82(d ,J＝8.8Hz,1H),6.54(dd,J＝8.8,2.8Hz,1H),6.45(s,1H),4.10(q,J＝7.2Hz,2H),3.28–3.09(m,4H) ,2.65–2.52(m,4H),2.37(s,3H),1.65(m,2H),1.54(m,2H),1.47(t,J＝6.8Hz,3H); LC-MS:[M+ H] + :489.2.
实施例45.化合物DP-01-207的合成
Example 45. Synthesis of compound DP-01-207
4-溴-1-异丙氧基-2-硝基苯(2)的合成：Synthesis of 4-bromo-1-isopropoxy-2-nitrobenzene (2):
将化合物4-溴-2-硝基苯酚(2.0g,9.17mmol)和2-碘丙烷(1.1mL,11.01mmol)溶解在N,N-二甲基甲酰胺(20.0mL)中，向溶液中加入碳酸钾(1.9g,13.74mmol)。将混合物在110℃下搅拌6小时。待反应完全， 反应液冷却，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(石油醚:乙酸乙酯＝3:1)得到白色固体(1.8g)。LC-MS:[M+H]+:260.1,262.1。Compound 4-bromo-2-nitrophenol (2.0g, 9.17mmol) and 2-iodopropane (1.1mL, 11.01mmol) were dissolved in N,N-dimethylformamide (20.0mL). Potassium carbonate (1.9g, 13.74mmol) was added. The mixture was stirred at 110°C for 6 hours. When the reaction is complete, The reaction solution was cooled, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a white solid (1.8g). LC-MS: [M+H] + :260.1, 262.1.
1-(4-异丙氧基-3-硝基苯基)-4-甲基哌嗪(3)的合成：Synthesis of 1-(4-isopropoxy-3-nitrophenyl)-4-methylpiperazine (3):
将4-溴-1-异丙氧基-2-硝基苯(1.0g,3.83mmol)和N-甲基哌嗪(501.0mg,5.00mmol)溶解在二氧六环(10mL)中，向溶液中加入三(二亚苄基丙酮)二钯(176.0mg,0.19mmol)、2-双环己基膦-2',6'-二甲氧基联苯(157.9mg,0.38mmol)和碳酸铯(2505.4mg,7.69mmol)。将所得混合物于100℃搅拌6小时，待反应完全，反应液冷却，加水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)。合并有机相，用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(石油醚/乙酸乙酯＝3:1)得到白色固体(700.0mg)。LC-MS:[M+H]+:280.1。4-Bromo-1-isopropoxy-2-nitrobenzene (1.0g, 3.83mmol) and N-methylpiperazine (501.0mg, 5.00mmol) were dissolved in dioxane (10mL). Tris(dibenzylideneacetone)dipalladium (176.0mg, 0.19mmol), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (157.9mg, 0.38mmol) and cesium carbonate ( 2505.4 mg, 7.69 mmol). The resulting mixture was stirred at 100°C for 6 hours. When the reaction was complete, the reaction solution was cooled, water (10 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain a white solid (700.0 mg). LC-MS: [M+H] + :280.1.
2-异丙氧基-5-(4-甲基哌嗪-1-基)苯胺(4)的合成：Synthesis of 2-isopropoxy-5-(4-methylpiperazin-1-yl)aniline (4):
将1-(4-异丙氧基-3-硝基苯基)-4-甲基哌嗪(300.0mg,1.07mmol)和钯碳(114.3mg,10％w/w)溶解在甲醇(3mL)中。插入氢气球并置换三次氢气。将混合物搅拌5小时，直到原料完全消耗。将反应液过滤浓缩得到黑色固体(200.0mg)。LC-MS:[M+H]+:250.1。Dissolve 1-(4-isopropoxy-3-nitrophenyl)-4-methylpiperazine (300.0 mg, 1.07 mmol) and palladium on carbon (114.3 mg, 10% w/w) in methanol (3 mL )middle. Insert a hydrogen balloon and replace the hydrogen gas three times. Stir the mixture for 5 hours until the ingredients are completely consumed. The reaction solution was filtered and concentrated to obtain a black solid (200.0 mg). LC-MS: [M+H] + :250.1.
5'-(5-氟-2-((2-异丙氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-207)的合成：5'-(5-fluoro-2-((2-isopropoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1 ,Synthesis of 1'-isoindoline]-3'-one (DP-01-207):
将5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(100.0mg,0.35mmol)和2-异丙氧基-5-(4-甲基哌嗪-1-基)苯胺(111.9mg,0.45mmol)溶解在二氧六环(1mL)中，向溶液中加入三(二亚苄基丙酮)二钯(31.61mg,0.035mmol)，然后加入碳酸铯(337.4mg,1.04mmol)以及1,1'-联萘-2,2'-双二苯膦(43.0mg,0.07mmol)，置换三次氮气。将混合物回流6小时。待反应完全后真空下除去溶剂，加水(5mL)稀释，用乙酸乙酯萃取(5mL×3)。合并有机相，用饱和食盐水洗涤(5.0mL)，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经制备纯化得到白色固体(39.2mg)。1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.67(d,J＝3.5Hz,1H),8.30(s,1H),8.24(d,J＝8.3Hz,1H),8.16(s,1H),8.06(s,1H),8.03(d,J＝2.8Hz,1H),7.49(d,J＝8.1Hz,1H),6.95(d,J＝8.9Hz,1H),6.56(dd,J＝8.9,2.8Hz,1H),4.53–4.47(m,1H),3.08–3.05(m,4H),2.47(d,J＝4.6Hz,4H),2.22(s,3H),1.55(s,4H),1.28(d,J＝6.0Hz,6H)；LC-MS:[M+H]+:503.2。5'-(2-Chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (100.0 mg, 0.35 mmol ) and 2-isopropoxy-5-(4-methylpiperazin-1-yl)aniline (111.9 mg, 0.45 mmol) were dissolved in dioxane (1 mL), and tris(dioxane) was added to the solution. Benzyl acetone) dipalladium (31.61mg, 0.035mmol), then add cesium carbonate (337.4mg, 1.04mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.0mg, 0.07mmol) , replace nitrogen three times. The mixture was refluxed for 6 hours. After the reaction was complete, the solvent was removed under vacuum, diluted with water (5 mL), and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (5.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was preparatively purified to obtain a white solid (39.2 mg). 1 H NMR (400MHz, DMSO-d6) δ8.90 (s, 1H), 8.67 (d, J = 3.5Hz, 1H), 8.30 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.16(s,1H),8.06(s,1H),8.03(d,J＝2.8Hz,1H),7.49(d,J＝8.1Hz,1H),6.95(d,J＝8.9Hz,1H), 6.56(dd,J＝8.9,2.8Hz,1H),4.53–4.47(m,1H),3.08–3.05(m,4H),2.47(d,J＝4.6Hz,4H),2.22(s,3H) ,1.55(s,4H),1.28(d,J＝6.0Hz,6H); LC-MS: [M+H] + :503.2.
实施例46.化合物PR-01-116的合成
Example 46. Synthesis of compound PR-01-116
5'-(5-氟-2-((5-(1-甲基-4-氧代-1,4-氮杂膦-4-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(PR-01-116)的合成： 5'-(5-fluoro-2-((5-(1-methyl-4-oxo-1,4-azaphosphine-4-yl)-2-(trifluoromethoxy)phenyl) Synthesis of amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (PR-01-116):
将化合物1-甲基-1,4-氮杂膦-4-氧化物(40.0mg,0.30mmol)、5'-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-12)(152.8mg,0.30mmol)、三(二亚苄基丙酮)二钯(27.5mg,0.03mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(17.4mg,0.03mmol)、磷酸钾(127.2mg,0.6mmol)溶于N,N-二甲基甲酰胺(2mL)中，氮气保护下于100℃反应4小时。反应液冷却过滤，滤液加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取后浓缩得到类黑色油状物，通过制备HPLC纯化得白色固体(55mg)。1H NMR(400MHz,MeOD-d4)δ8.94–8.90(m,1H),8.56(d,J＝3.6Hz,1H),8.51(s,1H),8.40–8.38(m,1H),7.58–7.56(m,2H),7.45(d,J＝8.4Hz,1H),3.05–2.94(m,2H),2.90–2.80(m,2H),2.38–2.29(m,5H),2.17–2.08(m,2H),1.71–1.58(m,4H)；LC-MS:[M+H]+:562.2。Compound 1-methyl-1,4-azaphosphine-4-oxide (40.0 mg, 0.30 mmol), 5'-(2-((5-bromo-2-(trifluoromethoxy)phenyl) )Amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-12) (152.8mg, 0.30mmol), tris(di Benzylideneacetone) dipalladium (27.5mg, 0.03mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (17.4mg, 0.03mmol), potassium phosphate (127.2mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (2 mL), and reacted at 100°C for 4 hours under nitrogen protection. The reaction solution was cooled and filtered, and the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and concentrated to obtain an almost black oily substance, which was purified by preparative HPLC to obtain a white solid (55 mg). 1 H NMR(400MHz,MeOD-d4)δ8.94–8.90(m,1H),8.56(d,J＝3.6Hz,1H),8.51(s,1H),8.40–8.38(m,1H),7.58 –7.56(m,2H),7.45(d,J＝8.4Hz,1H),3.05–2.94(m,2H),2.90–2.80(m,2H),2.38–2.29(m,5H),2.17–2.08 (m,2H),1.71–1.58(m,4H); LC-MS: [M+H] + :562.2.
实施例47.化合物DP-01-160的合成
Example 47. Synthesis of compound DP-01-160
5'-(5-氟-2-((5-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(1)的合成：5'-(5-fluoro-2-((5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(trifluoromethoxy)phenyl)amino Synthesis of )pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (1):
向5'-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-12)(100.0mg,0.20mmol)、1-甲基-4-硼酸频哪醇酯-1,2,3,6-四氢吡啶(56.9mg,0.26mmol)的1,4-二氧六环(1.0mL)和水(0.1mL)的混合溶剂中加入1,1'-双(二苯膦基)二茂铁二氯化钯(14.4mg,0.02mmol)和磷酸钾(124.8mg,0.59mmol)。反应体系在氮气保护下于90℃搅拌反应2小时。待反应完全后加入水溶液(10.0mL)淬灭反应，用乙酸乙酯萃取三次(20mL×3)。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经制备分离得到黄色固体(8.8mg)。1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.91(s,1H),8.65(d,J＝3.6Hz,1H),8.30(s,1H),8.20(d,J＝8.4Hz,1H),8.02(s,1H),7.49(d,J＝8.0Hz,1H),7.36(d,J＝8.4Hz,1H),7.29(d,J＝8.4Hz,1H),6.21(s,1H),3.14(s,2H),2.69(s,2H),2.53(s,2H),2.36(s,3H),1.54(s,4H)；LC-MS:[M+H]+:526.4。To 5'-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole Phenoline]-3'-one (common int-12) (100.0mg, 0.20mmol), 1-methyl-4-boronic acid pinacol ester-1,2,3,6-tetrahydropyridine (56.9mg, 0.26 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (14.4 mg, 0.02) was added to a mixed solvent of 1,4-dioxane (1.0 mL) and water (0.1 mL). mmol) and potassium phosphate (124.8mg, 0.59mmol). The reaction system was stirred and reacted at 90°C for 2 hours under nitrogen protection. After the reaction was complete, aqueous solution (10.0 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was prepared and isolated to obtain a yellow solid (8.8 mg). 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.91 (s, 1H), 8.65 (d, J = 3.6Hz, 1H), 8.30 (s, 1H), 8.20 (d, J ＝8.4Hz,1H),8.02(s,1H),7.49(d,J＝8.0Hz,1H),7.36(d,J＝8.4Hz,1H),7.29(d,J＝8.4Hz,1H), 6.21(s,1H),3.14(s,2H),2.69(s,2H),2.53(s,2H),2.36(s,3H),1.54(s,4H); LC-MS:[M+H ] + :526.4.
5'-(5-氟-2-((5-(1-甲基哌啶-4-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-160)的合成：5'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)spiro[ring Synthesis of propane-1,1'-isoindoline]-3'-one (DP-01-160):
向5'-(5-氟-2-((5-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(20.0mg,0.04mmol)的甲醇溶液中(2.0mL)加入钯碳(10.0mg,10％w/w)。反应体系在氢气氛围中于室温搅拌24小时。待反应完全，过滤除去钯碳后真空浓缩。粗品经制备分离得到黄色固体(4.0mg)。1H NMR(400MHz,MeOD)δ8.66(s,1H),8.54(d,J＝4.0Hz,1H),8.52(d,J＝2.0Hz,1H),8.48(s,1H),8.36(d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(dd,J＝8.4,1.2Hz,1H),7.05(dd,J＝8.4,2.0Hz,1H),3.60(d,J＝12.4Hz,2H),3.19–3.12(m,2H),3.04–2.95(m,1H),2.92(s,3H),2.21–2.06(m,4H),1.70–1.61(m,4H)；LC-MS:[M+H]+:528.3。 To 5'-(5-fluoro-2-((5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(trifluoromethoxy)phenyl) Palladium on carbon (10.0 mg, 10% w/w). The reaction system was stirred at room temperature under a hydrogen atmosphere for 24 hours. When the reaction is complete, filter to remove palladium carbon and then concentrate in vacuum. The crude product was preparatively isolated to obtain a yellow solid (4.0 mg). 1 H NMR (400MHz, MeOD) δ8.66 (s, 1H), 8.54 (d, J = 4.0Hz, 1H), 8.52 (d, J = 2.0Hz, 1H), 8.48 (s, 1H), 8.36 ( d,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(dd,J＝8.4,1.2Hz,1H),7.05(dd,J＝8.4,2.0Hz,1H), 3.60(d,J＝12.4Hz,2H),3.19–3.12(m,2H),3.04–2.95(m,1H),2.92(s,3H),2.21–2.06(m,4H),1.70–1.61( m,4H); LC-MS: [M+H] + :528.3.
实施例48.化合物DP-01-163的合成
Example 48. Synthesis of compound DP-01-163
5'-(5-氟-2-((5-((1R,5S)-8-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-163)的合成：5'-(5-fluoro-2-((5-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(tri Synthesis of fluoromethoxy)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-163):
在室温下，将5'-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-12)(50.0mg,0.10mmol)溶在四氢呋喃(0.5mL)中，加入8-甲基-3,8-二氮杂-二环[3.2.1]辛烷盐酸盐(24.0mg,0.12mmol)、1M双三甲基硅基胺基锂(0.49mL,0.49mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(3.9mg,0.01mmol)和三(二亚苄基丙酮)二钯(9.2mg,0.01mmol)。将所得混合物在90℃下搅拌5小时，过滤旋干得到黑褐色固体，固体经过碱性制备得到白色固体(8.2mg)。1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.42(d,J＝3.2Hz,1H),8.36(d,J＝8.1Hz,1H),8.16(d,J＝2.9Hz,1H),7.44(s,1H),7.19(d,J＝8.1Hz,1H),7.13(d,J＝9.1Hz,1H),6.42(dd,J＝9.4,3.1Hz,2H),3.36(d,J＝10.9Hz,2H),3.27(s,2H),3.09(d,J＝10.2Hz,2H),2.37(s,3H),2.11–1.93(m,2H),1.77–1.54(m,6H)；LC-MS:[M+H]+:555.3。5'-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-Isoindolin]-3'-one (common int-12) (50.0 mg, 0.10 mmol) was dissolved in tetrahydrofuran (0.5 mL), and 8-methyl-3,8-diaza-bicyclo[ 3.2.1] Octane hydrochloride (24.0mg, 0.12mmol), 1M lithium bistrimethylsilylamide (0.49mL, 0.49mmol), 2-dicyclohexylphosphonyl-2'-(N,N -dimethylamine)-biphenyl (3.9 mg, 0.01 mmol) and tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.01 mmol). The resulting mixture was stirred at 90°C for 5 hours, filtered and spun dry to obtain a dark brown solid. The solid was prepared alkaline to obtain a white solid (8.2 mg). 1 H NMR (400MHz, CDCl 3 ) δ8.61 (s, 1H), 8.42 (d, J = 3.2Hz, 1H), 8.36 (d, J = 8.1Hz, 1H), 8.16 (d, J = 2.9Hz ,1H),7.44(s,1H),7.19(d,J＝8.1Hz,1H),7.13(d,J＝9.1Hz,1H),6.42(dd,J＝9.4,3.1Hz,2H),3.36 (d,J＝10.9Hz,2H),3.27(s,2H),3.09(d,J＝10.2Hz,2H),2.37(s,3H),2.11–1.93(m,2H),1.77–1.54( m,6H); LC-MS: [M+H] + :555.3.
实施例49.化合物DP-01-162的合成
Example 49. Synthesis of compound DP-01-162
6-甲基-3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯(2)的合成：Synthesis of 6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (2):
将3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯(400.0mg,2.02mmol)和甲醛(0.65mL,8.07mmol,37％甲醛水溶液)溶解于四氢呋喃(10mL)和乙酸(0.5mL)中，室温搅拌1小时，将醋酸硼氢化钠(2.1g,9.91mmol)加入到反应体系中，于室温继续搅拌17小时。反应液加水(8mL)稀释，加入碳酸钾调节溶液至pH＝9，用乙酸乙酯萃取(20mL×3)。合并有机相用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤浓缩得到白色固体(400.0mg)。LC-MS:[M+H]+:213.2。Dissolve 3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (400.0mg, 2.02mmol) and formaldehyde (0.65mL, 8.07mmol, 37% formaldehyde aqueous solution) in tetrahydrofuran (10mL ) and acetic acid (0.5 mL), stir at room temperature for 1 hour, add sodium acetate borohydride (2.1 g, 9.91 mmol) to the reaction system, and continue stirring at room temperature for 17 hours. The reaction solution was diluted with water (8 mL), potassium carbonate was added to adjust the solution to pH=9, and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid (400.0 mg). LC-MS: [M+H] + :213.2.
6-甲基-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐(3)的合成：Synthesis of 6-methyl-3,6-diazabicyclo[3.1.1]heptane dihydrochloride (3):
将6-甲基-3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯(270.0mg,1.27mmol)溶解于4M盐酸(5mL,20.00mmol)的1,4-二氧六环溶液中，室温搅拌6小时。加入甲基叔丁基醚(15mL)，有固体析出，过滤， 甲基叔丁基醚(20mL)洗涤，收集固体并干燥得到白色固体产物(230.0mg)。LC-MS:[M+H]+:113.2。6-Methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (270.0mg, 1.27mmol) was dissolved in 1,4 of 4M hydrochloric acid (5mL, 20.00mmol) - Dioxane solution, stir at room temperature for 6 hours. Add methyl tert-butyl ether (15mL), if solid precipitates, filter. Wash with methyl tert-butyl ether (20 mL), collect the solid and dry to obtain a white solid product (230.0 mg). LC-MS: [M+H] + :113.2.
5'-(5-氟-2-((5-(6-甲基-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-162)的合成：5'-(5-fluoro-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-(trifluoromethoxy) Synthesis of phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-162):
将化合物5'-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-12)(50.0mg,0.10mmol)、6-甲基-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐(21.8mg,0.19mmol)、三(二亚苄基丙酮)二钯(9.0mg,0.01mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(7.7mg,0.02mmol)及1M双三甲基硅基胺基锂(0.49mL,0.49mmol)溶解于四氢呋喃(0.5mL)中，氮气保护下，于70℃反应6小时。反应液冷却至室温，饱和氯化铵水溶液(1mL)淬灭，用乙酸乙酯(10mL×3)萃取。合并有机相干燥，过滤旋干。粗产品经反相甲酸制备得到白色固体(7.2mg)。1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.87(s,1H),8.65(d,J＝3.6Hz,1H),8.32(s,1H),8.21(s,1H),8.19(s,1H),7.47–7.45(m,2H),7.23(d,J＝8.0Hz,1H),6.51(dd,J＝8.8,2.8Hz,1H),3.60(d,J＝5.6Hz,2H),3.48(d,J＝10.8Hz,2H),3.31–3.28(m,2H),2.46–2.40(m,1H),2.04(s,3H),1.56–1.53(m,5H)；LC-MS:[M+H]+:541.4。The compound 5'-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole Dolin]-3'-one (common int-12) (50.0mg, 0.10mmol), 6-methyl-3,6-diazabicyclo[3.1.1]heptane dihydrochloride (21.8mg, 0.19mmol), tris(dibenzylideneacetone)dipalladium (9.0mg, 0.01mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (7.7mg, 0.02 mmol) and 1M lithium bistrimethylsilylamide (0.49 mL, 0.49 mmol) were dissolved in tetrahydrofuran (0.5 mL), and reacted at 70°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, filtered and spin-dried. The crude product was prepared by reverse phase formic acid to obtain a white solid (7.2 mg). 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.87(s,1H),8.65(d,J＝3.6Hz,1H),8.32(s,1H),8.21(s,1H ),8.19(s,1H),7.47–7.45(m,2H),7.23(d,J＝8.0Hz,1H),6.51(dd,J＝8.8,2.8Hz,1H),3.60(d,J＝ 5.6Hz,2H),3.48(d,J＝10.8Hz,2H),3.31–3.28(m,2H),2.46–2.40(m,1H),2.04(s,3H),1.56–1.53(m,5H ); LC-MS: [M+H] + :541.4.
实施例50.化合物PR-01-113、PR-01-113A、PR-01-113B的合成
Example 50. Synthesis of compounds PR-01-113, PR-01-113A, and PR-01-113B
5-(3-硝基-4-(三氟甲氧基)苯基)-2,5-二氮杂双环[4.1.0]庚烷-2-羧酸叔丁酯(2)的合成：Synthesis of 5-(3-nitro-4-(trifluoromethoxy)phenyl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (2):
将化合物2,5-二氮杂双环[4.1.0]庚烷-2-羧酸叔丁酯(250.0mg,1.26mmol)、4-溴-2-硝基三氟甲氧基苯(360.6mg,1.26mmol)、三(二亚苄基丙酮)钯(115.5mg,0.126mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(120.2mg,0.25mmol)及叔丁醇钠(363.5mg,3.78mmol)溶解于甲苯(8mL)中，氮气保护下，90℃反应2小时。反应液旋干，粗产品经硅胶柱层析(石油醚:乙酸乙酯＝3:1)得到棕色固体(210.0mg)。LC-MS:[M-tBu+H]+:348.0。The compound 2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (250.0mg, 1.26mmol) and 4-bromo-2-nitrotrifluoromethoxybenzene (360.6mg ,1.26mmol), tris(dibenzylideneacetone)palladium (115.5mg, 0.126mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (120.2mg, 0.25mmol) ) and sodium tert-butoxide (363.5 mg, 3.78 mmol) were dissolved in toluene (8 mL), and reacted at 90°C for 2 hours under nitrogen protection. The reaction liquid was spun to dryness, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a brown solid (210.0 mg). LC-MS: [M- tBu +H] + : 348.0.
2-(3-硝基-4-(三氟甲氧基)苯基)-2,5-二氮杂双环[4.1.0]庚烷二盐酸盐(3)的合成：Synthesis of 2-(3-nitro-4-(trifluoromethoxy)phenyl)-2,5-diazabicyclo[4.1.0]heptane dihydrochloride (3):
将5-(3-硝基-4-(三氟甲氧基)苯基)-2,5-二氮杂双环[4.1.0]庚烷-2-羧酸叔丁酯(210.0mg,0.52mmol)溶解于2N HCl(10mL,20.00mmol)乙酸乙酯中，室温反应18小时。反应液旋干得到黄色油状物质(195.0mg)。LC-MS:[M+H]+:304.2。 5-(3-Nitro-4-(trifluoromethoxy)phenyl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylic acid tert-butyl ester (210.0 mg, 0.52 mmol) was dissolved in 2N HCl (10 mL, 20.00 mmol) ethyl acetate, and reacted at room temperature for 18 hours. The reaction solution was spun to dryness to obtain a yellow oily substance (195.0 mg). LC-MS: [M+H] + :304.2.
2-甲基-5-(3-硝基-4-(三氟甲氧基)苯基)-2,5-二氮杂双环[4.1.0]庚烷(4)的合成：Synthesis of 2-methyl-5-(3-nitro-4-(trifluoromethoxy)phenyl)-2,5-diazabicyclo[4.1.0]heptane (4):
将2-(3-硝基-4-(三氟甲氧基)苯基)-2,5-二氮杂双环[4.1.0]庚烷二盐酸盐(190.0mg,0.63mmol)和37％甲醛(0.27mL,2.70mmol)水溶液溶解于四氢呋喃(10mL)和乙酸(0.5mL)中，室温搅拌1小时，将醋酸硼氢化钠(532.7mg,2.51mmol)加入到反应体系中，室温反应17小时。用水(8mL)稀释，碳酸钾固体调节pH＝9，用乙酸乙酯萃取(10mL×3),有机相用饱和氯化钠水溶液(10mL)洗涤，干燥，旋干得到粗产品经硅胶柱层析(二氯甲烷:甲醇＝10:1)棕色油状物质(140.0mg)。LC-MS:[M+H]+:318.2。2-(3-Nitro-4-(trifluoromethoxy)phenyl)-2,5-diazabicyclo[4.1.0]heptane dihydrochloride (190.0 mg, 0.63 mmol) and 37 % formaldehyde (0.27mL, 2.70mmol) aqueous solution was dissolved in tetrahydrofuran (10mL) and acetic acid (0.5mL), stirred at room temperature for 1 hour, sodium acetate borohydride (532.7mg, 2.51mmol) was added to the reaction system, and the reaction was carried out at room temperature for 17 Hour. Dilute with water (8 mL), adjust the pH to 9 with potassium carbonate solid, extract with ethyl acetate (10 mL (dichloromethane:methanol=10:1) brown oily substance (140.0 mg). LC-MS: [M+H] + :318.2.
5-(5-甲基-2,5-二氮杂双环[4.1.0]庚烷-2-基)-2-(三氟甲氧基)苯胺(5)的合成：Synthesis of 5-(5-methyl-2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-(trifluoromethoxy)aniline (5):
将2-甲基-5-(3-硝基-4-(三氟甲氧基)苯基)-2,5-二氮杂双环[4.1.0]庚烷(130.0mg,0.41mmol)溶于甲醇(10mL)中，加入七滴浓盐酸和10％钯碳(15.0mg)，氢气保护下，室温反应2小时。过滤，滤液旋干，得到棕色固体，加入饱和碳酸氢钠水溶液(10mL)，用乙酸乙酯萃取(10mL×3)，有机相干燥，旋干得到棕色固体(115.0mg)。LC-MS:[M+H]+:288.3。Dissolve 2-methyl-5-(3-nitro-4-(trifluoromethoxy)phenyl)-2,5-diazabicyclo[4.1.0]heptane (130.0 mg, 0.41 mmol) To methanol (10 mL), add seven drops of concentrated hydrochloric acid and 10% palladium on carbon (15.0 mg), and react at room temperature for 2 hours under hydrogen protection. Filter, and spin the filtrate to dryness to obtain a brown solid. Add saturated sodium bicarbonate aqueous solution (10 mL), extract with ethyl acetate (10 mL × 3), dry the organic phase, and spin to dryness to obtain a brown solid (115.0 mg). LC-MS: [M+H] + :288.3.
5'-(5-氟-2-((5-(5-甲基-2,5-二氮杂双环[4.1.0]庚烷-2-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(PR-01-113)的合成：5'-(5-fluoro-2-((5-(5-methyl-2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-(trifluoromethoxy) Synthesis of phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (PR-01-113):
将化合物5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(141.2mg,0.49mmol)、5-(5-甲基-2,5-二氮杂双环[4.1.0]庚烷-2-基)-2-(三氟甲氧基)苯胺(common int-10)(100.0mg,0.35mmol)、三(二亚苄基丙酮)钯(31.9mg,0.035mmol)、1,1'-联萘-2,2'-双二苯膦(43.4mg,0.07mmol)及碳酸铯(340.2mg,1.04mmol)溶解于甲苯(1mL)中，氮气保护下，100℃反应5小时。反应液过滤，滤液旋干。粗产品经甲酸制备得到白色固体(79.0mg)。1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.87(s,1H),8.63(d,J＝3.6Hz,1H),8.29(s,1H),8.19(d,J＝8.0Hz,1H),8.13(s,1H),7.50–7.46(m,2H),7.20(d,J＝8.4Hz,1H),6.61(dd,J＝9.2,2.8Hz,1H),3.36(s,1H),3.10(t,J＝8.4Hz,1H),2.64–2.61(m,2H),2.52(s,1H),2.40–2.32(m,4H),1.53(s,4H),0.58(d,J＝6.0Hz,1H),0.37(s,1H).LC-MS:[M+H]+:541.2。Compound 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (141.2 mg, 0.49 mmol), 5-( 5-Methyl-2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-(trifluoromethoxy)aniline (common int-10) (100.0mg, 0.35mmol), Tris(dibenzylideneacetone)palladium (31.9mg, 0.035mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.4mg, 0.07mmol) and cesium carbonate (340.2mg, 1.04mmol) ) was dissolved in toluene (1 mL), and reacted at 100°C for 5 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was spun dry. The crude product was prepared with formic acid to obtain a white solid (79.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.87(s,1H),8.63(d,J＝3.6Hz,1H),8.29(s,1H),8.19(d,J ＝8.0Hz,1H),8.13(s,1H),7.50–7.46(m,2H),7.20(d,J＝8.4Hz,1H),6.61(dd,J＝9.2,2.8Hz,1H),3.36 (s,1H),3.10(t,J＝8.4Hz,1H),2.64–2.61(m,2H),2.52(s,1H),2.40–2.32(m,4H),1.53(s,4H), 0.58 (d, J=6.0Hz, 1H), 0.37 (s, 1H). LC-MS: [M+H] + : 541.2.
消旋体PR-01-113经过SFC分离纯化(色谱柱：ChiralPak AD,250×30mm I.D.,5μm；流动相：A相：CO2；B相：IPA(0.1％7mol/L NH3in MeOH)；梯度：B％：30％；7min，120min)后得到白色固体PR-01-113A(13.0mg)和白色固体PR-01-113B(17.5mg)。Racemate PR-01-113 was separated and purified by SFC (chromatographic column: ChiralPak AD, 250×30mm ID, 5μm; mobile phase: Phase A: CO 2 ; Phase B: IPA (0.1% 7mol/L NH3in MeOH); gradient : B%: 30%; 7 min, 120 min), white solid PR-01-113A (13.0 mg) and white solid PR-01-113B (17.5 mg) were obtained.
PR-01-113A：PR-01-113A:
手性分析条件：色谱柱：CHIRALPAK C-IG 5μm 4.6*100mm，流动相：A相：CO2；B相：IPA(0.05％DEA v/v)；梯度：B％：30.0％，保留时间为4.477min，ee％＝100％。Chiral analysis conditions: chromatographic column: CHIRALPAK C-IG 5μm 4.6*100mm, mobile phase: A phase: CO 2 ; B phase: IPA (0.05% DEA v/v); gradient: B%: 30.0%, retention time: 4.477min,ee%=100%.
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.87(s,1H),8.63(d,J＝3.2Hz,1H),8.29(s,1H),8.19(d,J＝8.0Hz,1H),7.50–7.46(m,2H),7.20(d,J＝8.4Hz,1H),6.61(dd,J＝9.2,3.2Hz,1H),3.35(s,1H),3.09(t,J＝8.4,1H),2.67–2.59(m,2H),2.48–2.44(m,1H),2.37–2.32(m,4H),1.53(s,4H),0.56–0.53(m,1H),0.33–0.31(m,1H)；LC-MS:[M+H]+:541.1。 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.87(s,1H),8.63(d,J＝3.2Hz,1H),8.29(s,1H),8.19(d,J ＝8.0Hz,1H),7.50–7.46(m,2H),7.20(d,J＝8.4Hz,1H),6.61(dd,J＝9.2,3.2Hz,1H),3.35(s,1H),3.09 (t,J＝8.4,1H),2.67–2.59(m,2H),2.48–2.44(m,1H),2.37–2.32(m,4H),1.53(s,4H),0.56–0.53(m, 1H), 0.33–0.31(m,1H); LC-MS: [M+H] + :541.1.
PR-01-113B：PR-01-113B:
手性分析条件：色谱柱：CHIRALPAK C-IG 5μm 4.6*100mm，流动相：A相：CO2；B相：IPA(0.05％DEA v/v)；梯度：B％：30.0％，保留时间为5.334min，ee％＝97.37％。Chiral analysis conditions: chromatographic column: CHIRALPAK C-IG 5μm 4.6*100mm, mobile phase: A phase: CO 2 ; B phase: IPA (0.05% DEA v/v); gradient: B%: 30.0%, retention time: 5.334min,ee%=97.37%.
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.87(s,1H),8.63(d,J＝3.6Hz,1H),8.29(s,1H),8.19(d,J＝8.4Hz,1H),7.50–7.46(m,2H),7.20(d,J＝8.0Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),3.35(s,1H), 3.09(t,J＝8.4,1H),2.67–2.59(m,2H),2.48–2.44(m,1H),2.37–2.30(m,4H),1.53(s,4H),0.55(q,J＝4.8Hz,1H),0.32(q,J＝4.8Hz,1H)；LC-MS:[M+H]+:541.2。 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.87(s,1H),8.63(d,J＝3.6Hz,1H),8.29(s,1H),8.19(d,J ＝8.4Hz,1H),7.50–7.46(m,2H),7.20(d,J＝8.0Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),3.35(s,1H), 3.09(t,J＝8.4,1H),2.67–2.59(m,2H),2.48–2.44(m,1H),2.37–2.30(m,4H),1.53(s,4H),0.55(q,J =4.8Hz, 1H), 0.32 (q, J = 4.8Hz, 1H); LC-MS: [M+H] + : 541.2.
实施例51.化合物DP-01-203、DP-01-203A、DP-01-203B的合成
Example 51. Synthesis of compounds DP-01-203, DP-01-203A, and DP-01-203B
5'-(5-氟-2-((5-(5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-203)的合成：5'-(5-fluoro-2-((5-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(trifluoromethoxy) Synthesis of phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-203):
将化合物5'-(2-((5-溴-2-(三氟甲氧基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-12)(50.0mg,0.10mmol)、2-甲基-2,5-二氮杂双环[2.2.1]庚烷二盐酸盐(18.2mg,0.10mmol)、三(二亚苄基丙酮)二钯(9.0mg,0.01mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(7.7mg,0.02mmol)及1M双三甲基硅基胺基锂(0.5mL,0.50mmol)溶解于四氢呋喃(0.5mL)中，氮气保护下，70℃反应4小时。冷却反应体系，用饱和氯化铵水溶液(1mL)淬灭，乙酸乙酯(2mL)萃取。有机相干燥，旋干，粗产品经硅胶柱层析(二氯甲烷:甲醇＝7:1)得到粗产品，经反相甲酸制备得到白色固体(34.3mg)。1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.87(s,1H),8.63(d,J＝3.2Hz,1H),8.29(s,1H),8.19–8.18(m,2H),7.47(d,J＝8.4Hz,1H),7.23(d,J＝2.8Hz,1H),7.14(d,J＝8.8Hz,1H),6.36(dd,J＝8.8,2.8Hz,1H),4.26(s,1H),3.47(s,1H),3.38–3.35(s,1H),3.19(d,J＝9.2Hz,1H),2.76(d,J＝7.6Hz,1H),2.54(s,1H),2.27(s,3H),1.88(d,J＝8.8Hz,1H),1.79(d,J＝8.8Hz,1H),1.53(s,4H)；LC-MS:[M+H]+:541.2。The compound 5'-(2-((5-bromo-2-(trifluoromethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole Dolin]-3'-one (common int-12) (50.0mg, 0.10mmol), 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (18.2mg, 0.10mmol), tris(dibenzylideneacetone)dipalladium (9.0mg, 0.01mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (7.7mg, 0.02 mmol) and 1M lithium bistrimethylsilylamide (0.5 mL, 0.50 mmol) were dissolved in tetrahydrofuran (0.5 mL), and the reaction was carried out at 70°C for 4 hours under nitrogen protection. The reaction system was cooled, quenched with saturated aqueous ammonium chloride solution (1 mL), and extracted with ethyl acetate (2 mL). The organic phase was dried and spin-dried. The crude product was subjected to silica gel column chromatography (dichloromethane:methanol=7:1) to obtain the crude product. A white solid (34.3 mg) was obtained by using reversed-phase formic acid. 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.87(s,1H),8.63(d,J＝3.2Hz,1H),8.29(s,1H),8.19–8.18(m ,2H),7.47(d,J＝8.4Hz,1H),7.23(d,J＝2.8Hz,1H),7.14(d,J＝8.8Hz,1H),6.36(dd,J＝8.8,2.8Hz ,1H),4.26(s,1H),3.47(s,1H),3.38–3.35(s,1H),3.19(d,J＝9.2Hz,1H),2.76(d,J＝7.6Hz,1H) ,2.54(s,1H),2.27(s,3H),1.88(d,J＝8.8Hz,1H),1.79(d,J＝8.8Hz,1H),1.53(s,4H); LC-MS: [M+H] + :541.2.
消旋体DP-01-203经SFC分离纯化(色谱柱：ChiralPak C-IG,250×30mm I.D.,5μm；流动相：A相：CO2；B：MeOH+0.1％NH3-H2O；梯度：B％：40％；8.4min；180min)得白色固体DP-01-203A(6.4mg)和白色固体DP-01-203B(7.7mg)。Racemate DP-01-203 was separated and purified by SFC (chromatographic column: ChiralPak C-IG, 250×30mm ID, 5 μm; mobile phase: Phase A: CO 2 ; B: MeOH+0.1% NH 3 -H 2 O; Gradient: B%: 40%; 8.4min; 180min) to obtain white solid DP-01-203A (6.4mg) and white solid DP-01-203B (7.7mg).
DP-01-203A：DP-01-203A:
手性分析条件：色谱柱：CHIRALPAK C-IG 5μm 4.6*100mm，流动相：A相：CO2；B相：MeOH(0.05％DEA v/v)；梯度：B％：40.0％，保留时间为3.562min，ee％＝99.77％。Chiral analysis conditions: chromatographic column: CHIRALPAK C-IG 5μm 4.6*100mm, mobile phase: A phase: CO 2 ; B phase: MeOH (0.05% DEA v/v); gradient: B%: 40.0%, retention time: 3.562min, ee%=99.77%.
1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.87(s,1H),8.63(d,J＝3.6Hz,1H),8.33(s,1H),8.29(s,1H),8.19(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.23(d,J＝2.8Hz,1H),7.13(d,J＝8.8Hz,1H),6.35(dd,J＝8.8,2.8Hz,1H),4.23(d,J＝8.4Hz,1H),3.42(s,1H),3.36(s,1H),3.17(d,J＝8.8Hz,1H),2.74(d,J＝8.0Hz,1H),2.46(s,1H),2.24(s,3H),1.85(d,J＝9.2Hz,1H),1.77(d,J＝9.2Hz,1H),1.53(s,4H)；LC-MS:[M+H]+:541.1。 1 H NMR (400MHz, DMSO-d6) δ8.93 (s, 1H), 8.87 (s, 1H), 8.63 (d, J = 3.6Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H ),8.19(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.23(d,J＝2.8Hz,1H),7.13(d,J＝8.8Hz,1H), 6.35(dd,J＝8.8,2.8Hz,1H),4.23(d,J＝8.4Hz,1H),3.42(s,1H),3.36(s,1H),3.17(d,J＝8.8Hz,1H ),2.74(d,J＝8.0Hz,1H),2.46(s,1H),2.24(s,3H),1.85(d,J＝9.2Hz,1H),1.77(d,J＝9.2Hz,1H ), 1.53(s,4H); LC-MS: [M+H] + :541.1.
DP-01-203B：DP-01-203B:
手性分析条件：色谱柱：CHIRALPAK C-IG 5μm 4.6*100mm，流动相：A相：CO2；B相：MeOH(0.05％DEA v/v)；梯度：B％：40.0％，保留时间为4.436min，ee％＝90.05％。Chiral analysis conditions: chromatographic column: CHIRALPAK C-IG 5μm 4.6*100mm, mobile phase: A phase: CO 2 ; B phase: MeOH (0.05% DEA v/v); gradient: B%: 40.0%, retention time: 4.436min,ee%=90.05%.
1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.87(s,1H),8.63(d,J＝3.2Hz,1H),8.29(s,1H),8.19(d,J＝8.4Hz,1H),7.47(d,J＝8.0Hz,1H),7.23(d,J＝2.8Hz,1H),7.14(d,J＝8.0Hz,1H),6.35(dd,J＝ 9.2,2.8Hz,1H),4.24(s,1H),3.42(s,2H),3.17(d,J＝8.4Hz,1H),2.74(d,J＝7.6Hz,1H),2.46(s,1H),2.24(s,3H),1.85(d,J＝9.2Hz,1H),1.77(d,J＝9.6Hz,1H),1.53(s,4H)；LC-MS:[M+H]+:541.1。 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.87(s,1H),8.63(d,J＝3.2Hz,1H),8.29(s,1H),8.19(d,J ＝8.4Hz,1H),7.47(d,J＝8.0Hz,1H),7.23(d,J＝2.8Hz,1H),7.14(d,J＝8.0Hz,1H),6.35(dd,J＝ 9.2,2.8Hz,1H),4.24(s,1H),3.42(s,2H),3.17(d,J＝8.4Hz,1H),2.74(d,J＝7.6Hz,1H),2.46(s, 1H), 2.24 (s, 3H), 1.85 (d, J = 9.2Hz, 1H), 1.77 (d, J = 9.6Hz, 1H), 1.53 (s, 4H); LC-MS: [M+H] + :541.1.
实施例52.化合物DP-01-161、DP-01-161A、DP-01-161B的合成
Example 52. Synthesis of compounds DP-01-161, DP-01-161A, and DP-01-161B
3-(羟甲基)-4-甲基哌嗪-1-羧酸叔丁酯(2)的合成：Synthesis of 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (2):
将化合物3-(羟甲基)哌嗪-1-羧酸叔丁酯(2.0g,9.25mmol)和甲醛(2.3g,28.37mmol,37％)、冰醋酸(0.5mL)溶于甲醇(20mL)中，室温下搅拌1小时，随后降温至0℃，分批加入氰基硼氢化钠(1.16g,18.50mmol)，室温搅拌15小时，TLC监测原料已反应完全。反应液加入饱和碳酸氢钠(40mL)稀释，用二氯甲烷萃取(50mL×3)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(甲醇:二氯甲烷＝0-5％,二氯甲烷/甲醇＝10:1,Rf＝0.3)纯化得黄色油状物(1.5g)。LC-MS:[M+H]+:231.1。Compound 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (2.0g, 9.25mmol), formaldehyde (2.3g, 28.37mmol, 37%), and glacial acetic acid (0.5mL) were dissolved in methanol (20mL ), stir at room temperature for 1 hour, then cool to 0°C, add sodium cyanoborohydride (1.16g, 18.50mmol) in batches, and stir at room temperature for 15 hours. TLC monitors that the raw materials have reacted completely. The reaction solution was diluted with saturated sodium bicarbonate (40 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 0-5%, dichloromethane/methanol = 10:1, R f = 0.3) to obtain a yellow oil (1.5 g). LC-MS: [M+H] + :231.1.
3-(氟甲基)-4-甲基哌嗪-1-羧酸叔丁酯(3)的合成：Synthesis of 3-(fluoromethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (3):
将化合物3-(羟甲基)-4-甲基哌嗪-1-羧酸叔丁酯(1.5g,6.51mmol)溶于二氯甲烷(24mL)中，降温至0℃后将二乙胺基三氟化硫(1.2g,7.44mmol)的二氯甲烷(24mL)溶液滴加至上述溶液中，升温至40℃搅拌12小时，LCMS监测原料已反应完全。反应液加入饱和碳酸氢钠水溶液(20mL)淬灭，用二氯甲烷萃取(20mL×3)。合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(甲醇:二氯甲烷＝0-3％；二氯甲烷/甲醇＝20:1,Rf＝0.4)纯化得无色油状物(600.0mg)。LC-MS:[M+H]+:233.1。Dissolve compound 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (1.5g, 6.51mmol) in dichloromethane (24mL), cool to 0°C, and add diethylamine A solution of sulfur trifluoride (1.2g, 7.44mmol) in dichloromethane (24mL) was added dropwise to the above solution, and the temperature was raised to 40°C and stirred for 12 hours. LCMS monitored that the raw materials had reacted completely. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (20 mL), and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 0-3%; dichloromethane/methanol = 20:1, R f = 0.4) to obtain a colorless oil (600.0 mg). LC-MS: [M+H] + :233.1.
2-(氟甲基)-1-甲基哌嗪(4)的合成：Synthesis of 2-(fluoromethyl)-1-methylpiperazine (4):
室温下，将化合物3-(氟甲基)-4-甲基哌嗪-1-羧酸叔丁酯(500.0mg,2.15mmol)溶于甲醇(4mL)中，将2M盐酸/乙酸乙酯溶液(2.2mL)缓慢加入，升温至40℃搅拌6小时，LCMS检测原料反应完全。将反应液直接浓缩得粗品(250.0mg)，直接用于下一步反应。LC-MS:[M+H]+:133.2。At room temperature, compound 3-(fluoromethyl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (500.0 mg, 2.15 mmol) was dissolved in methanol (4 mL), and 2M hydrochloric acid/ethyl acetate solution was added. (2.2 mL) was added slowly, the temperature was raised to 40°C and stirred for 6 hours. LCMS detected that the raw material reaction was complete. The reaction solution was directly concentrated to obtain a crude product (250.0 mg), which was directly used in the next reaction. LC-MS: [M+H] + :133.2.
2-(氟甲基)-1-甲基-4-(3-硝基-4-(三氟甲氧基)苯基)哌嗪(5)的合成：Synthesis of 2-(fluoromethyl)-1-methyl-4-(3-nitro-4-(trifluoromethoxy)phenyl)piperazine (5):
氮气保护下，将化合物2-(氟甲基)-1-甲基哌嗪(250.0mg,1.89mmol)、4-溴-2-硝基-1-(三氟甲氧基)苯(450.0mg,1.57mmol)、三(二亚苄基丙酮)二钯(72.0mg,0.078mmol)、碳酸铯(1.5g,4.60mmol)和2- 二环己基膦-2′,6′-二甲氧基-联苯(64.6mg,0.16mmol)溶于1,4-二氧六环(5mL)中，混合物加热至90℃搅拌6小时，LCMS检测原料已反应完全。反应液用水(10mL)稀释，乙酸乙酯萃取(10mL×3)。合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，真空浓缩得粗品。粗品经硅胶柱层析(乙酸乙酯:石油醚＝0-70％,石油醚/乙酸乙酯＝1:1,Rf＝0.3)纯化得黄色油状物(120.0mg)。LC-MS:[M+H]+:338.1。Under nitrogen protection, the compounds 2-(fluoromethyl)-1-methylpiperazine (250.0mg, 1.89mmol) and 4-bromo-2-nitro-1-(trifluoromethoxy)benzene (450.0mg ,1.57mmol), tris(dibenzylideneacetone)dipalladium (72.0mg, 0.078mmol), cesium carbonate (1.5g, 4.60mmol) and 2- Dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (64.6 mg, 0.16 mmol) was dissolved in 1,4-dioxane (5 mL). The mixture was heated to 90°C and stirred for 6 hours. LCMS Check that the raw materials have reacted completely. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-70%, petroleum ether/ethyl acetate = 1:1, R f = 0.3) to obtain a yellow oil (120.0 mg). LC-MS: [M+H] + :338.1.
5-(3-(氟甲基)-4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(6)的合成：Synthesis of 5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (6):
将化合物2-(氟甲基)-1-甲基-4-(3-硝基-4-(三氟甲氧基)苯基)哌嗪(120.0mg,0.36mmol)和Pd/C(50mg,10％w/w)悬浮于甲醇(3mL)中。插入氢气球，置换三次后于40℃搅拌反应6小时。LCMS监测反应完全，将反应液通过硅藻土过滤，滤饼用乙酸乙酯洗涤3次，滤液旋干后得白色固体(100.0mg,92％)。LC-MS:[M+H]+:308.1。Compound 2-(fluoromethyl)-1-methyl-4-(3-nitro-4-(trifluoromethoxy)phenyl)piperazine (120.0 mg, 0.36 mmol) and Pd/C (50 mg , 10% w/w) was suspended in methanol (3 mL). A hydrogen balloon was inserted, replaced three times, and stirred for 6 hours at 40°C. LCMS monitored that the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filter cake was washed three times with ethyl acetate. The filtrate was spin-dried to obtain a white solid (100.0 mg, 92%). LC-MS: [M+H] + :308.1.
5'-(5-氟-2-((5-(3-(氟甲基)-4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-161)的合成：5'-(5-fluoro-2-((5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidine Synthesis of -4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-161):
氮气保护下，将化合物5-(3-(氟甲基)-4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(100.0mg,0.33mol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(105.2mg,0.36mmol)、1,1'-联萘-2,2'-双二苯膦(41.1mg,0.066mmol)、醋酸钯(7.4mg,0.033mmol)和碳酸铯(322.6mg,0.99mmol)溶于1,4-二氧六环(5mL)中，混合物加热至100℃后搅拌6小时，LCMS监测到原料已反应完全。反应液加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)。合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经制备纯化得白色固体(18.0mg)。1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.45–8.29(m,3H),7.48(s,1H),7.26-7.15(m,2H),7.04(s,1H),6.56(dd,J＝8.8,2.8Hz,1H),4.64–4.35(m,2H),3.55(t,J＝13.2Hz,2H),3.04–2.95(m,2H),2.87(t,J＝6.8Hz,1H),2.58–2.55(m,2H),2.47(s,3H),1.67(t,J＝6.8Hz,2H),1.56(t,J＝6.8Hz,2H)；LC-MS:[M+H]+:561.3。Under nitrogen protection, compound 5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (100.0mg, 0.33mol), 5'- (2-Chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (105.2 mg, 0.36 mmol), 1, 1'-binaphthyl-2,2'-bisdiphenylphosphine (41.1mg, 0.066mmol), palladium acetate (7.4mg, 0.033mmol) and cesium carbonate (322.6mg, 0.99mmol) were dissolved in 1,4-dioxy In six rings (5 mL), the mixture was heated to 100°C and stirred for 6 hours. LCMS detected that the raw materials had reacted completely. The reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was preparatively purified to obtain a white solid (18.0 mg). 1 H NMR (400MHz, CDCl 3 ) δ8.62(s,1H),8.45–8.29(m,3H),7.48(s,1H),7.26-7.15(m,2H),7.04(s,1H), 6.56(dd,J＝8.8,2.8Hz,1H),4.64–4.35(m,2H),3.55(t,J＝13.2Hz,2H),3.04–2.95(m,2H),2.87(t,J＝ 6.8Hz,1H),2.58–2.55(m,2H),2.47(s,3H),1.67(t,J＝6.8Hz,2H),1.56(t,J＝6.8Hz,2H); LC-MS: [M+H] + :561.3.
消旋体DP-01-161经过SFC分离纯化(色谱柱：ChiralCel OX,250×21.2mm I.D.,5μm；流动相：A相：CO2；B相：IPA+0.1％NH3-H2O；梯度：B％：30％，6.9min；180min)后得到白色固体DP-01-161A(5.0mg)和白色固体DP-01-161B(7.0mg)。Racemate DP-01-161 was separated and purified by SFC (chromatographic column: ChiralCel OX, 250×21.2mm ID, 5μm; mobile phase: phase A: CO 2 ; phase B: IPA+0.1% NH 3 -H 2 O; Gradient: B%: 30%, 6.9min; 180min), white solid DP-01-161A (5.0mg) and white solid DP-01-161B (7.0mg) were obtained.
DP-01-161A：DP-01-161A:
手性分析条件：色谱柱：ChiralCel OX,250×21.2mm I.D.,5μm，流动相：A相：CO2；B相：MeOH(0.05％DEA v/v)；梯度：B：30％，保留时间为3.938min；ee％＝100.0％。Chiral analysis conditions: Chromatographic column: ChiralCel OX, 250×21.2mm ID, 5μm, mobile phase: Phase A: CO 2 ; Phase B: MeOH (0.05% DEA v/v); Gradient: B: 30%, retention time It is 3.938min; ee%=100.0%.
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.43(d,J＝3.2Hz,1H),8.36(d,J＝8.6Hz,1H),8.31(d,J＝2.8Hz,1H),7.47(s,1H),7.22(d,J＝8.0Hz,1H),7.18–7.15(m,1H),6.56(dd,J＝9.2,2.8Hz,1H),6.29(s,1H),4.54(d,J＝3.6Hz,1H),4.43–4.41(m,1H),3.55(t,J＝12.8Hz,2H),3.06–2.89(m,2H),2.88–2.79(m,1H),2.53–2.48(m,2H),2.43(s,3H),1.65–1.62(m,2H),1.56–1.54(m,2H)；LC-MS:[M+H]+:561.1。DP-01-161B： 1 H NMR (400MHz, CDCl 3 ) δ8.62 (s, 1H), 8.43 (d, J = 3.2Hz, 1H), 8.36 (d, J = 8.6Hz, 1H), 8.31 (d, J = 2.8Hz ,1H),7.47(s,1H),7.22(d,J＝8.0Hz,1H),7.18–7.15(m,1H),6.56(dd,J＝9.2,2.8Hz,1H),6.29(s, 1H),4.54(d,J＝3.6Hz,1H),4.43–4.41(m,1H),3.55(t,J＝12.8Hz,2H),3.06–2.89(m,2H),2.88–2.79(m ,1H),2.53–2.48(m,2H),2.43(s,3H),1.65–1.62(m,2H),1.56–1.54(m,2H); LC-MS:[M+H] + :561.1 . DP-01-161B：
手性分析条件：色谱柱：ChiralCel OX,250×21.2mm I.D.,5μm，流动相：A相：CO2；B相：MeOH(0.05％DEA v/v)；梯度：B：30％，保留时间为4.659min；ee％＝96.3％。Chiral analysis conditions: Chromatographic column: ChiralCel OX, 250×21.2mm ID, 5μm, mobile phase: Phase A: CO 2 ; Phase B: MeOH (0.05% DEA v/v); Gradient: B: 30%, retention time It is 4.659min; ee%=96.3%.
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.43(d,J＝3.2Hz,1H),8.36(d,J＝8.0Hz,1H),8.31(d,J＝2.8Hz,1H),7.47(s,1H),7.22(d,J＝8.0Hz,1H),7.17(d,J＝8.8Hz,1H),6.56(dd,J＝9.2,3.2Hz,1H),6.33(s,1H),4.54(d,J＝4.0Hz,1H),4.3–4.41(m,1H),3.55(t,J＝12.8Hz,2H),3.04–2.97(m,1H),2.96 –2.77(m,2H),2.53–2.47(m,2H),2.43(s,3H),1.65–1.61(m,2H),1.55–1.53(m,2H)；LC-MS:[M+H]+:561.3。 1 H NMR (400MHz, CDCl 3 ) δ8.62 (s, 1H), 8.43 (d, J = 3.2Hz, 1H), 8.36 (d, J = 8.0Hz, 1H), 8.31 (d, J = 2.8Hz ,1H),7.47(s,1H),7.22(d,J＝8.0Hz,1H),7.17(d,J＝8.8Hz,1H),6.56(dd,J＝9.2,3.2Hz,1H),6.33 (s,1H),4.54(d,J＝4.0Hz,1H),4.3–4.41(m,1H),3.55(t,J＝12.8Hz,2H),3.04–2.97(m,1H),2.96 –2.77(m,2H),2.53–2.47(m,2H),2.43(s,3H),1.65–1.61(m,2H),1.55–1.53(m,2H); LC-MS:[M+H ] + :561.3.
实施例53.化合物DP-01-201-2的合成
Example 53. Synthesis of compound DP-01-201-2
5-溴-7-(2-羟乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(1)的合成：Synthesis of tert-butyl 5-bromo-7-(2-hydroxyethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (1):
将5-溴-1,1-二甲基-3-氧代-7-乙烯基异吲哚啉-2-羧酸叔丁酯(300.0mg,0.82mmol)溶于四氢呋喃(30mL)中，冰浴下加入1M硼烷(1.0mL)四氢呋喃溶液，室温反应1小时后，冰浴下加入甲醇(1mL)、氢氧化钠(65.5mg,1.64mmol)和30％双氧水(1.17mL)，室温继续搅拌2小时后用饱和硫代硫酸钠水溶液(15mL)淬灭反应，用乙酸乙酯萃取(15mL×3)。合并有机相后干燥，过滤浓缩得到粗产品。经硅胶柱层析(石油醚:乙酸乙酯＝3:1)纯化得到白色固(80.0mg)。LC-MS:[M-tBu+H]+:328.2,330.2。Dissolve 5-bromo-1,1-dimethyl-3-oxo-7-vinylisoindoline-2-carboxylic acid tert-butyl ester (300.0 mg, 0.82 mmol) in tetrahydrofuran (30 mL), ice Add 1M borane (1.0mL) tetrahydrofuran solution under the bath. After reacting at room temperature for 1 hour, add methanol (1mL), sodium hydroxide (65.5mg, 1.64mmol) and 30% hydrogen peroxide (1.17mL) under the ice bath, and continue stirring at room temperature. After 2 hours, the reaction was quenched with saturated aqueous sodium thiosulfate solution (15 mL), and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried, filtered and concentrated to obtain a crude product. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (80.0 mg). LC-MS: [M- tBu +H] + : 328.2, 330.2.
5-溴-7-(2-甲氧基乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(2)的合成：Synthesis of tert-butyl 5-bromo-7-(2-methoxyethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (2):
将5-溴-7-(2-羟乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(70.0mg,0.18mmol)溶解于四氢呋喃(8mL)中，-70℃下滴加1M双三甲基硅基胺基锂(0.2mL,0.20mmol)，在-70℃下搅拌半个小时。将碘甲烷(38.8mg,0.27mmol)滴加到反应体系中，反应升至室温并搅拌0.5小时。饱和氯化铵水溶液(10mL)淬灭反应，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到白色固体(28.0mg)。LC-MS:[M+H]+:398.0,400.0。5-Bromo-7-(2-hydroxyethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylic acid tert-butyl ester (70.0 mg, 0.18 mmol) was dissolved in tetrahydrofuran ( 8 mL), add 1 M lithium bistrimethylsilylamide (0.2 mL, 0.20 mmol) dropwise at -70°C, and stir at -70°C for half an hour. Methyl iodide (38.8 mg, 0.27 mmol) was added dropwise to the reaction system, and the reaction was raised to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a white solid (28.0 mg). LC-MS: [M+H] + :398.0, 400.0.
7-(2-甲氧基乙基)-1,1-二甲基-3-氧代-5-硼酸频那醇酯-异吲哚啉-2-羧酸叔丁酯(3)的合成：Synthesis of 7-(2-methoxyethyl)-1,1-dimethyl-3-oxo-5-boronic acid pinacol ester-isoindoline-2-carboxylic acid tert-butyl ester (3) :
将化合物5-溴-7-(2-甲氧基乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(28.0mg,0.07mmol)、联硼酸频那醇酯(19.6mg,0.077mmol)、乙酸钾(17.3mg,0.18mmol)及[1,1'-双(二苯基膦)二茂铁]二氯化钯(5.1mg,0.007mmol)悬浮在无水二氧六环(3mL)中，氮气保护下于100℃条件下反应5小时。反应液加水(5mL)稀释，用乙酸乙酯萃取(5mL×3)，合并有机相用无水硫酸钠干燥，过滤，浓缩得到粗品(30.0mg)。粗品直接用于下一步反应。LC-MS:[M+H]+:446.2。Compound 5-bromo-7-(2-methoxyethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylic acid tert-butyl ester (28.0 mg, 0.07mmol), Pinacol diborate (19.6mg, 0.077mmol), potassium acetate (17.3mg, 0.18mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.1mg, 0.007 mmol) was suspended in anhydrous dioxane (3 mL), and reacted at 100°C for 5 hours under nitrogen protection. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product (30.0 mg). The crude product was directly used in the next reaction. LC-MS: [M+H] + :446.2.
5-(2-氯-5-氟嘧啶-4-基)-7-(2-甲氧基乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(4)的合成：5-(2-chloro-5-fluoropyrimidin-4-yl)-7-(2-methoxyethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylic acid Synthesis of tert-butyl ester (4):
将化合物7-(2-甲氧基乙基)-1,1-二甲基-3-氧代-5-硼酸频那醇酯-异吲哚啉-2-羧酸叔丁酯(30.0mg,0.067mmol)、2,4-二氯-5-氟嘧啶(22.5mg,0.135mmol)、磷酸钾(42.9mg,0.20mmol)及[1,1'-双(二苯基膦)二茂铁]二氯化钯(4.9mg,0.0067mmol)悬浮在无水二氧六环(4mL)和水(0.8mL)中，氮气保护下于100℃ 下反应4小时。反应液浓缩所得粗产品经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化得到棕色固体(22.0mg)。LC-MS:[M+H]+:450.3,452.3。Compound 7-(2-methoxyethyl)-1,1-dimethyl-3-oxo-5-boronic acid pinacol ester-isoindoline-2-carboxylic acid tert-butyl ester (30.0 mg ,0.067mmol), 2,4-dichloro-5-fluoropyrimidine (22.5mg, 0.135mmol), potassium phosphate (42.9mg, 0.20mmol) and [1,1'-bis(diphenylphosphine)ferrocene ] Palladium dichloride (4.9 mg, 0.0067 mmol) was suspended in anhydrous dioxane (4 mL) and water (0.8 mL) at 100°C under nitrogen protection. The reaction was carried out for 4 hours. The reaction solution was concentrated and the crude product obtained was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a brown solid (22.0 mg). LC-MS: [M+H] + :450.3, 452.3.
5-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-7-(2-甲基乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(5)的合成：5-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-7-(2-methyl Synthesis of tert-butyl ethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (5):
将5-(2-氯-5-氟嘧啶-4-基)-7-(2-甲氧基乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(17.0mg,0.037mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(common int-16)(12.5mg,0.056mmol)、碳酸铯(36.9mg,0.11mmol)、1,1'-联萘-2,2'-双二苯膦(4.7mg,0.0075mmol)及醋酸钯(0.8mg,0.0035mmol)溶解在甲苯(1mL)中，氮气保护下，100℃反应5小时。反应液浓缩所得粗品经制备TLC(二氯甲烷:甲醇＝10:1)纯化得到白色固体(19.0mg)。LC-MS:[M+H]+:635.4。5-(2-Chloro-5-fluoropyrimidin-4-yl)-7-(2-methoxyethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylic Tert-butyl acid ester (17.0mg, 0.037mmol), 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (common int-16) (12.5mg, 0.056mmol), cesium carbonate ( 36.9mg, 0.11mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (4.7mg, 0.0075mmol) and palladium acetate (0.8mg, 0.0035mmol) were dissolved in toluene (1mL), nitrogen Under protection, react at 100°C for 5 hours. The crude product obtained by concentrating the reaction solution was purified by preparative TLC (dichloromethane:methanol=10:1) to obtain a white solid (19.0 mg). LC-MS: [M+H] + :635.4.
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-4-(2-甲基乙基)-3,3-二甲基异吲哚-1-酮(DP-01-210-2)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4-(2-methyl Synthesis of ethyl)-3,3-dimethylisoindol-1-one (DP-01-210-2):
将5-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-7-(2-甲基乙基)-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(17.0mg,0.027mmol)溶解在二氯甲烷(1mL)中，加入三氟乙酸(0.5mL)，室温反应1小时。反应液真空浓缩。粗品加入二氯甲烷(1mL)和固体碳酸钠(3mg)，搅拌1小时。有机相经制备TLC(二氯甲烷:甲醇＝10:1)纯化得到白色固体(11.1mg)。1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝3.2Hz,1H),8.24(s,1H),8.10(s,2H),7.84(d,J＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),4.94(s,1H),3.80(s,3H),3.71(t,J＝6.8Hz,2H),3.05(t,J＝6.8Hz,6H),2.96(s,3H),2.49–2.38(m,4H),2.23(s,3H),1.55(s,6H)；LC-MS:[M+H]+:535.2。5-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-7-(2-methyl Ethyl)-1,1-dimethyl-3-oxoisoindoline-2-carboxylic acid tert-butyl ester (17.0 mg, 0.027 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid was added (0.5mL), react at room temperature for 1 hour. The reaction solution was concentrated in vacuo. Dichloromethane (1 mL) and solid sodium carbonate (3 mg) were added to the crude product, and stirred for 1 hour. The organic phase was purified by preparative TLC (dichloromethane:methanol=10:1) to obtain a white solid (11.1 mg). 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J＝3.2Hz,1H),8.24(s,1H),8.10(s,2H),7.84(d,J＝2.8Hz,1H), 6.93(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),4.94(s,1H),3.80(s,3H),3.71(t,J＝6.8Hz,2H ),3.05(t,J＝6.8Hz,6H),2.96(s,3H),2.49–2.38(m,4H),2.23(s,3H),1.55(s,6H); LC-MS:[M +H] + :535.2.
实施例54.化合物DP-01-205的合成
Example 54. Synthesis of compound DP-01-205
(4-(3-溴-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲磺酸甲酯(1)的合成：Synthesis of (4-(3-bromo-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanesulfonate methyl ester (1):
氮气保护下，将甲基磺酰氯(139.7mg,1.22mmol)滴加到三乙胺(164.5mg,1.63mmol)和(4-(3-溴-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲醇(common int-14)(300.0mg,0.81mmol)的无水二氯甲烷(5mL)溶液中，并在室温下搅拌1小时。待反应完全，向反应液中加入饱和碳酸氢钠水溶液(10mL)，用二氯甲烷(20mL×2)萃取。合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(0-10％的甲醇/二氯甲烷)纯化得到黄色固体(300.0mg)。LC-MS:[M+H]+:446.9,448.9。 Under nitrogen protection, methylsulfonyl chloride (139.7mg, 1.22mmol) was added dropwise to triethylamine (164.5mg, 1.63mmol) and (4-(3-bromo-4-(trifluoromethoxy)phenyl) -1-methylpiperazin-2-yl)methanol (common int-14) (300.0 mg, 0.81 mmol) in anhydrous dichloromethane (5 mL) and stirred at room temperature for 1 hour. When the reaction is complete, add saturated aqueous sodium bicarbonate solution (10 mL) to the reaction solution, and extract with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (300.0 mg). LC-MS: [M+H] + :446.9, 448.9.
2-(4-(3-溴-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)乙腈(2)的合成：Synthesis of 2-(4-(3-bromo-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)acetonitrile (2):
向(4-(3-溴-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲磺酸甲酯(300.0mg,0.67mmol)的N,N-二甲基甲酰胺(5mL)溶液中依次加入氰化钠(92.6mg,1.90mmol)和碘化钾(21.6mg,0.13mmol)，于100℃搅拌反应16小时。待反应完全，反应液加入饱和碳酸氢钠水溶液(20mL)稀释，并用乙酸乙酯(20mL×2)萃取。合并有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(0-10％的甲醇/二氯甲烷)纯化得到黄色固体(180.0mg)。LC-MS:[M+H]+:377.9,379.9。To (4-(3-bromo-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanesulfonate methyl ester (300.0 mg, 0.67 mmol) N,N- Sodium cyanide (92.6 mg, 1.90 mmol) and potassium iodide (21.6 mg, 0.13 mmol) were added in sequence to the dimethylformamide (5 mL) solution, and the reaction was stirred at 100°C for 16 hours. When the reaction is complete, the reaction solution is diluted with saturated sodium bicarbonate aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (180.0 mg). LC-MS: [M+H] + :377.9,379.9.
2-(4-(3-(二苯基亚甲基)氨基)-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)乙腈(3)的合成：Synthesis of 2-(4-(3-(diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)acetonitrile (3):
氮气保护下，向2-(4-(3-溴-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)乙腈(180.0mg,0.48mmol)的1,4-二氧六环(3mL)溶液中依次加二苯甲酮亚胺(258.8mg,1.43mmol)、1,1'-联萘-2,2'-双二苯膦(59.3mg,0.095mmol)、三(二亚苄基丙酮)二钯(87.2mg,0.095mmol)和碳酸铯(465.2mg,1.43mmol)，并加热至100℃搅拌2小时。将反应物冷却至室温后真空浓缩，粗品经硅胶柱层析(0-10％的甲醇/二氯甲烷)纯化得到黄色固体(200.0mg)。LC-MS:[M+H]+:479.2。Under nitrogen protection, add 1, To the 4-dioxane (3mL) solution, benzophenone imine (258.8mg, 1.43mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (59.3mg, 0.095mmol) were added in sequence. ), tris(dibenzylideneacetone)dipalladium (87.2 mg, 0.095 mmol) and cesium carbonate (465.2 mg, 1.43 mmol), and heated to 100°C and stirred for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (200.0 mg). LC-MS: [M+H] + :479.2.
2-(4-(3-氨基-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)乙腈(4)的合成：Synthesis of 2-(4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)acetonitrile (4):
向2-(4-(3-(二苯基亚甲基)氨基)-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)乙腈(200.0mg,0.42mmol)的1,4-二氧六环(3.0mL)溶液中加入4M盐酸二氧六环溶液(3mL，12mmol)，将反应液在室温下搅拌1小时。反应结束后将反应液减压浓缩得到淡黄色油状物(105.0mg)。粗品直接用于下一步反应。LC-MS:[M+H]+:315.3。To 2-(4-(3-(diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)acetonitrile (200.0 mg, 0.42 mmol) of 1,4-dioxane (3.0 mL) was added to a 4M dioxane hydrochloride solution (3 mL, 12 mmol), and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a light yellow oil (105.0 mg). The crude product was directly used in the next reaction. LC-MS: [M+H] + :315.3.
2-(4-(3-((5-氟-4-(3'-氧代螺[环丙烷-1,1'-异吲哚啉]-5'-基)嘧啶-2-基)氨基)-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)乙腈(DP-01-205)的合成：2-(4-(3-((5-fluoro-4-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyrimidin-2-yl)amino Synthesis of )-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)acetonitrile (DP-01-205):
向2-(4-(3-氨基-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)乙腈(110.0mg,0.35mmol)的1,4-二氧六环(10mL)溶液中依次加入5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(153.5mg,0.53mmol)、1,1'-联萘-2,2'-双二苯膦(43.6mg,0.07mmol)、三(二亚苄基丙酮)二钯(32.1mg,0.035mmol)和碳酸铯(342.1mg,1.05mmol)，并加热至100℃搅拌4小时。将反应物冷却至室温后真空浓缩，粗品经制备HPLC纯化得到黄色固体(5.1mg)。1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.88(s,1H),8.63(d,J＝3.5Hz,1H),8.29(s,1H),8.21(d,J＝8.3Hz,1H),7.51–7.49(m,2H),7.24(d,J＝9.0Hz,1H),6.77(dd,J＝9.2,2.9Hz,1H),3.60(d,J＝11.2Hz,1H),3.47(d,J＝13.1Hz,1H),2.96–2.81(m,3H),2.75–2.63(m,2H),2.46(s,1H),2.34(t,J＝9.7Hz,1H),2.27(s,3H),1.54(s,4H)；LC-MS:[M+H]+:568.2。To 2-(4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)acetonitrile (110.0 mg, 0.35 mmol) 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int- 10) (153.5mg, 0.53mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.6mg, 0.07mmol), tris(dibenzylideneacetone)dipalladium (32.1mg, 0.035 mmol) and cesium carbonate (342.1 mg, 1.05 mmol), and heated to 100°C and stirred for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain a yellow solid (5.1 mg). 1 H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.88 (s, 1H), 8.63 (d, J = 3.5Hz, 1H), 8.29 (s, 1H), 8.21 (d, J ＝8.3Hz,1H),7.51–7.49(m,2H),7.24(d,J＝9.0Hz,1H),6.77(dd,J＝9.2,2.9Hz,1H),3.60(d,J＝11.2Hz ,1H),3.47(d,J＝13.1Hz,1H),2.96–2.81(m,3H),2.75–2.63(m,2H),2.46(s,1H),2.34(t,J＝9.7Hz, 1H), 2.27(s,3H), 1.54(s,4H); LC-MS: [M+H] + :568.2.
实施例55.化合物DP-01-208的合成
Example 55. Synthesis of compound DP-01-208
5'-(2-氯-5-氟-6-甲基嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(1)的合成：Synthesis of 5'-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (1):
室温下，向5'-硼酸频那醇酯螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-9)(300.0mg,1.05mmol)的二氧六环(5mL)和水(1mL)溶液中加入2,4-二氯-5-氟-6-甲基嘧啶(228.5mg,1.26mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(79.8mg,0.11mmol)、磷酸钾(669.9mg,3.16mmol)。置换三次氮气，将所得混合物在90℃下搅拌4小时。反应液冷却，加入水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)。合并有机相，用饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(石油醚:乙酸乙酯＝5:1)得到白色固体(200.0mg)。LC-MS:[M+H]+:304.2。Dioxane was added to 5'-pinacol borate ester spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-9) (300.0 mg, 1.05 mmol) at room temperature. (5mL) and water (1mL) were added with 2,4-dichloro-5-fluoro-6-methylpyrimidine (228.5mg, 1.26mmol), [1,1'-bis(diphenylphosphine)diocene Iron] palladium dichloride (79.8 mg, 0.11 mmol), potassium phosphate (669.9 mg, 3.16 mmol). Nitrogen was replaced three times, and the resulting mixture was stirred at 90°C for 4 hours. The reaction solution was cooled, water (10 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Separate by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (200.0 mg). LC-MS: [M+H] + :304.2.
5'-(5-氟-6-甲基-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-208)的合成：5'-(5-fluoro-6-methyl-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidine-4- Synthesis of spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-208):
室温下，向5'-(2-氯-5-氟-6-甲基嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(78.9mg,0.26mmol)和5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(common int-1)(88.1mg,0.32mmol)的1,4-二氧六环(1mL)溶液中加入碳酸铯(257.5mg,0.79mmol)、1,1'-联萘-2,2'-双二苯膦(32.8mg,0.053mmol)和三(二亚苄基丙酮)二钯(24.1mg,0.026mmol)。氮气置换三次后，将混合物于90℃反应6小时。待反应完全，真空下除去多余溶剂，加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)。合并有机相，用饱和食盐水洗涤(5mL)，无水硫酸钠干燥，过滤，浓缩得到粗品。经碱性制备纯化得到白色固体(11.8mg)。1H NMR(400MHz,DMSO-d6)δ8.87–8.85(m,2H),8.25(s,1H),8.17(d,J＝8.2Hz,1H),7.64(s,1H),7.46(d,J＝8.3Hz,1H),7.19(d,J＝8.0Hz,1H),6.79–6.63(m,1H),3.15(s,4H),2.45–2.42(m,7H),2.21(s,3H),1.53(s,4H)；LC-MS:[M+H]+:543.4。To 5'-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (78.9 mg, 0.26mmol) and 1,4-dioxane of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (common int-1) (88.1mg, 0.32mmol) Cesium carbonate (257.5 mg, 0.79 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (32.8 mg, 0.053 mmol) and tris(dibenzylideneacetone) were added to the ring (1 mL) solution. Dipalladium (24.1 mg, 0.026 mmol). After nitrogen replacement three times, the mixture was reacted at 90°C for 6 hours. When the reaction is complete, remove excess solvent under vacuum, dilute with water (10 mL), and extract with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Basic preparative purification gave a white solid (11.8 mg). 1 H NMR (400MHz, DMSO-d6) δ8.87–8.85 (m, 2H), 8.25 (s, 1H), 8.17 (d, J = 8.2Hz, 1H), 7.64 (s, 1H), 7.46 (d ,J＝8.3Hz,1H),7.19(d,J＝8.0Hz,1H),6.79–6.63(m,1H),3.15(s,4H),2.45–2.42(m,7H),2.21(s, 3H), 1.53 (s, 4H); LC-MS: [M+H] + : 543.4.
实施例56.化合物DP-01-219、DP-01-219A、DP-01-219B的合成
Example 56. Synthesis of compounds DP-01-219, DP-01-219A, and DP-01-219B
(4-(3-(二苯基亚甲基)氨基)-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲醇(1)的合成：Synthesis of (4-(3-(diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanol (1):
向(4-(3-溴-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲醇(common int-14)(210.0mg,0.57mmol)的1,4-二氧六环(3mL)溶液中依次加二苯甲酮亚胺(206.2mg,1.14mmol)、1,1'-联萘-2,2'-双二苯膦(68.5mg,0.11mmol)、三(二亚苄基丙酮)二钯(100.7mg,0.11mmol)和碳酸铯(556.0mg,1.71mmol)，并在氮气保护下加热至100℃搅拌2小时。将反应物冷却至室温后真空浓缩，粗品经硅胶柱层析(0-10％的甲醇/二氯甲烷)纯化得到黄色固体(160.0mg)。LC-MS:[M+H]+:470.1。To (4-(3-bromo-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanol (common int-14) (210.0 mg, 0.57 mmol) 1, To the 4-dioxane (3mL) solution, benzophenone imine (206.2mg, 1.14mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (68.5mg, 0.11mmol) were added in sequence. ), tris(dibenzylideneacetone)dipalladium (100.7 mg, 0.11 mmol) and cesium carbonate (556.0 mg, 1.71 mmol), and heated to 100°C under nitrogen protection and stirred for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (160.0 mg). LC-MS: [M+H] + :470.1.
(4-(3-氨基-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲醇(2)的合成：Synthesis of (4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanol (2):
将(4-(3-(二苯基亚甲基)氨基)-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲醇(160.0mg,0.34mmol)溶解在1,4-二氧六环(3mL)中，加入4M盐酸二氧六环溶液(3mL,12mmol)，将反应液在室温搅拌1小时。反应结束后，将反应液浓缩得到淡黄色油状物(50.0mg)。粗品直接用于下一步反应。LC-MS:[M+H]+:306.3。 (4-(3-(Diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanol (160.0 mg, 0.34 mmol) Dissolve in 1,4-dioxane (3 mL), add 4M dioxane hydrochloride solution (3 mL, 12 mmol), and stir the reaction solution at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain a light yellow oil (50.0 mg). The crude product was directly used in the next reaction. LC-MS: [M+H] + :306.3.
5'-(5-氟-2-((5-(3-(羟甲基)-4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-219)的合成：5'-(5-fluoro-2-((5-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidine Synthesis of -4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-219):
向(4-(3-氨基-4-(三氟甲氧基)苯基)-1-甲基哌嗪-2-基)甲醇(50.0mg,0.16mmol)的1,4-二氧六环(10mL)溶液中依次加入5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(57.0mg,0.20mmol)、1,1'-联萘-2,2'-双二苯膦(20.4mg,0.033mmol)、三(二亚苄基丙酮)二钯(15.0mg,0.016mmol)和碳酸铯(160.3mg,0.49mmol)，并加热至100℃搅拌4小时。将反应物冷却至室温后真空浓缩，粗品经制备纯化得到黄色固体(4.2mg)。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.88(s,1H),8.62(d,J＝3.4Hz,1H),8.28(s,1H),8.20(d,J＝8.4Hz,1H),7.52–7.44(m,2H),7.22(d,J＝9.1Hz,1H),6.75(d,J＝9.2Hz,1H),4.57(s,1H),3.64(d,J＝10.7Hz,2H),3.51(d,J＝10.8Hz,1H),3.39(s,1H),2.81(s,2H),2.61–2.54(m,1H),2.35–2.27(m,1H),2.25(s,3H),2.13(s,1H),1.54(s,4H)；LC-MS:[M+H]+:559.3。1,4-dioxane to (4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperazin-2-yl)methanol (50.0 mg, 0.16 mmol) (10mL) solution was added successively to 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (57.0mg, 0.20mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20.4mg, 0.033mmol), tris(dibenzylideneacetone)dipalladium (15.0mg, 0.016mmol) and cesium carbonate (160.3 mg, 0.49 mmol), and heated to 100°C and stirred for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was preparatively purified to obtain a yellow solid (4.2 mg). 1 H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.88 (s, 1H), 8.62 (d, J = 3.4Hz, 1H), 8.28 (s, 1H), 8.20 (d, J ＝8.4Hz,1H),7.52–7.44(m,2H),7.22(d,J＝9.1Hz,1H),6.75(d,J＝9.2Hz,1H),4.57(s,1H),3.64(d ,J＝10.7Hz,2H),3.51(d,J＝10.8Hz,1H),3.39(s,1H),2.81(s,2H),2.61–2.54(m,1H),2.35–2.27(m, 1H), 2.25(s,3H), 2.13(s,1H), 1.54(s,4H); LC-MS: [M+H] + :559.3.
消旋体DP-01-219经SFC分离纯化(色谱柱：CHIRALPAK C-IG 5μm 4.6*100mm I.D.,5μm；流动相：A相：CO2；B相：EtOH(0.05％DEA v/v)；梯度：B％：40.0％，8min)得白色固体DP-01-219A和白色固体DP-01-219B。Racemate DP-01-219 was separated and purified by SFC (chromatographic column: CHIRALPAK C-IG 5μm 4.6*100mm ID, 5μm; mobile phase: Phase A: CO 2 ; Phase B: EtOH (0.05% DEA v/v); Gradient: B%: 40.0%, 8 min) to obtain white solid DP-01-219A and white solid DP-01-219B.
DP-01-219A：DP-01-219A:
手性分析条件：色谱柱：CHIRALPAK C-IG 5μm 4.6*100mm.,5μm，流动相：A相：CO2；B相：EtOH(0.05％DEA v/v)；梯度：B％：40％，保留时间为2.727min；ee％＝100.0％。Chiral analysis conditions: Chromatographic column: CHIRALPAK C-IG 5μm 4.6*100mm., 5μm, mobile phase: Phase A: CO 2 ; Phase B: EtOH (0.05% DEA v/v); Gradient: B%: 40%, The retention time is 2.727min; ee%=100.0%.
1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.87(s,1H),8.62(d,J＝3.5Hz,1H),8.27(s,1H),8.20(d,J＝8.1Hz,1H),7.46(dd,J＝11.1,5.5Hz,2H),7.21(d,J＝8.6Hz,1H),6.74(dd,J＝9.1,2.8Hz,1H),4.56(t,J＝5.4Hz,1H),3.63(d,J＝11.0Hz,2H),3.50(d,J＝11.8Hz,1H),3.36(s,1H),2.80(s,2H),2.60–2.53(m,1H),2.26–2.22(m,4H),2.12(s,1H),1.53(s,4H)；LC-MS:[M+H]+:559.2。 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.87 (s, 1H), 8.62 (d, J = 3.5Hz, 1H), 8.27 (s, 1H), 8.20 (d, J ＝8.1Hz,1H),7.46(dd,J＝11.1,5.5Hz,2H),7.21(d,J＝8.6Hz,1H),6.74(dd,J＝9.1,2.8Hz,1H),4.56(t ,J＝5.4Hz,1H),3.63(d,J＝11.0Hz,2H),3.50(d,J＝11.8Hz,1H),3.36(s,1H),2.80(s,2H),2.60–2.53 (m,1H),2.26–2.22(m,4H),2.12(s,1H),1.53(s,4H); LC-MS: [M+H] + :559.2.
DP-01-219B：DP-01-219B:
手性分析条件：色谱柱：CHIRALPAK C-IG 5μm 4.6*100mm.,5μm，流动相：A相：CO2；B相：EtOH(0.05％DEA v/v)；梯度：B％：40％，保留时间为3.532min；ee％＝97.6％。Chiral analysis conditions: Chromatographic column: CHIRALPAK C-IG 5μm 4.6*100mm., 5μm, mobile phase: Phase A: CO 2 ; Phase B: EtOH (0.05% DEA v/v); Gradient: B%: 40%, The retention time is 3.532min; ee%=97.6%.
1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.87(s,1H),8.62(d,J＝3.5Hz,1H),8.27(s,1H),8.20(d,J＝8.4Hz,1H),7.46(dd,J＝11.3,5.4Hz,2H),7.21(d,J＝8.6Hz,1H),6.74(dd,J＝9.1,2.8Hz,1H),4.56(t,J＝5.5Hz,1H),3.63(d,J＝10.9Hz,2H),3.50(d,J＝11.2Hz,1H),3.36(s,1H),2.80(s,2H),2.60–2.53(m,1H),2.31–2.22(m,4H),2.12(s,1H),1.53(s,4H)；LC-MS:[M+H]+:559.2。 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.87 (s, 1H), 8.62 (d, J = 3.5Hz, 1H), 8.27 (s, 1H), 8.20 (d, J ＝8.4Hz,1H),7.46(dd,J＝11.3,5.4Hz,2H),7.21(d,J＝8.6Hz,1H),6.74(dd,J＝9.1,2.8Hz,1H),4.56(t ,J＝5.5Hz,1H),3.63(d,J＝10.9Hz,2H),3.50(d,J＝11.2Hz,1H),3.36(s,1H),2.80(s,2H),2.60–2.53 (m,1H),2.31–2.22(m,4H),2.12(s,1H),1.53(s,4H); LC-MS: [M+H] + :559.2.
实施例57.化合物DP-01-229的合成
Example 57. Synthesis of compound DP-01-229
(E)-6-溴-4-(2-乙氧基乙烯基)-3-甲基-1-异吲哚啉-2-羧酸叔丁酯(1)的合成：Synthesis of (E)-6-bromo-4-(2-ethoxyvinyl)-3-methyl-1-isoindoline-2-carboxylic acid tert-butyl ester (1):
将化合物6-溴-4-碘-3-甲基-1-氧代异吲哚-2-羧酸叔丁酯(common int-15)(700.0mg,1.55mmol)、(E)-1-乙氧乙烯基-2-硼酸频那醇酯(337.3mg,1.56mmol)、磷酸钾(657.3mg,3.10mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(113.3mg,0.156mmol)置于二氧六环(10mL)和水(1mL)中，氮气保护下于100℃反应3小时。反应液浓缩后经硅胶柱层析纯化(石油醚:乙酸乙酯＝100:1-50:1)得到白色油状化合物(350.0mg)。1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.60(s,1H),7.48(d,J＝12.8Hz,1H),5.89(d,J＝12.8Hz,1H),5.23(d,J＝6.4Hz,1H),4.04–3.95(m,2H),1.53(d,J＝1.2Hz,9H),1.50–1.47(m,3H),1.32–1.26(m,3H).Compound 6-bromo-4-iodo-3-methyl-1-oxoisoindole-2-carboxylic acid tert-butyl ester (common int-15) (700.0 mg, 1.55 mmol), (E)-1- Ethoxyvinyl-2-boronic acid pinacol ester (337.3mg, 1.56mmol), potassium phosphate (657.3mg, 3.10mmol), [1,1'-bis(diphenylphosphine)ferrocene] dichloride Palladium (113.3 mg, 0.156 mmol) was placed in dioxane (10 mL) and water (1 mL), and reacted at 100°C for 3 hours under nitrogen protection. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1-50:1) to obtain a white oily compound (350.0 mg). 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.60 (s, 1H), 7.48 (d, J = 12.8Hz, 1H), 5.89 (d, J = 12.8Hz, 1H), 5.23(d,J＝6.4Hz,1H),4.04–3.95(m,2H),1.53(d,J＝1.2Hz,9H),1.50–1.47(m,3H),1.32–1.26(m,3H) .
2-(6-溴-3-甲基-1-氧代异吲哚-4-基)乙醛(2)的合成：Synthesis of 2-(6-bromo-3-methyl-1-oxoisoindol-4-yl)acetaldehyde (2):
将化合物(E)-6-溴-4-(2-乙氧基乙烯基)-3-甲基-1-异吲哚啉-2-羧酸叔丁酯(310.0mg,0.78mmol)溶于甲酸中(1.5mL)，加热至50℃搅拌1小时。反应液加水(10mL)稀释，用饱和碳酸氢钠溶液调至弱碱性，用乙酸乙酯萃取(3×10mL)。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得白色固体(120.0mg)。粗品直接用于下一步反应。LC-MS:[M+H+]:268.0,270.0。Compound (E)-6-bromo-4-(2-ethoxyvinyl)-3-methyl-1-isoindoline-2-carboxylic acid tert-butyl ester (310.0 mg, 0.78 mmol) was dissolved in (1.5 mL) in formic acid, heated to 50°C and stirred for 1 hour. The reaction solution was diluted with water (10 mL), adjusted to weak alkalinity with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid (120.0 mg). The crude product was directly used in the next reaction. LC-MS: [M+H + ]: 268.0, 270.0.
6-溴-4-(2-羟乙基)-3-甲基异吲哚-1-酮(3)的合成：Synthesis of 6-bromo-4-(2-hydroxyethyl)-3-methylisoindol-1-one (3):
将化合物2-(6-溴-3-甲基-1-氧代异吲哚-4-基)乙醛(115.0mg,0.43mmol)溶于乙醇中(1mL)，0℃下加硼氢化钠(24.5mg,0.65mmol)后，室温条件下反应1.5小时。加5mL水稀释反应液，用乙酸乙酯萃取(3×10mL)。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得粗品白色固体(60.0mg)。LC-MS:[M+H+]:269.9,271.9。Compound 2-(6-bromo-3-methyl-1-oxoisoindol-4-yl)acetaldehyde (115.0 mg, 0.43 mmol) was dissolved in ethanol (1 mL), and sodium borohydride was added at 0°C. (24.5 mg, 0.65 mmol), react at room temperature for 1.5 hours. Add 5 mL of water to dilute the reaction solution, and extract with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude white solid (60.0 mg). LC-MS: [M+H + ]: 269.9, 271.9.
4-(2-羟乙基)-3-甲基-6-硼酸频那醇酯异吲哚-1-酮(4)的合成：Synthesis of 4-(2-hydroxyethyl)-3-methyl-6-boronic acid pinacol ester isoindol-1-one (4):
将化合物6-溴-4-(2-羟乙基)-3-甲基异吲哚-1-酮(55.0mg,0.20mmol)、联硼酸频那醇酯(60.9mg,0.24mmol)、醋酸钾(59.9mg,0.61mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(14.8mg,0.02mmol)置于无水二氧六环(1mL)中。氮气保护下于100℃搅拌反应3小时。反应液浓缩后经硅胶柱层析纯化(二氯甲烷:甲醇＝50:1～20:1)得到白色固体化合物(37.0mg)。LC-MS:[M+H]+:318.1。Compound 6-bromo-4-(2-hydroxyethyl)-3-methylisoindol-1-one (55.0 mg, 0.20 mmol), pinacol diborate (60.9 mg, 0.24 mmol), acetic acid Potassium (59.9 mg, 0.61 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (14.8 mg, 0.02 mmol) were placed in dry dioxane (1 mL). The reaction was stirred at 100°C for 3 hours under nitrogen protection. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=50:1~20:1) to obtain a white solid compound (37.0 mg). LC-MS: [M+H] + :318.1.
6-(2-氯-5-氟嘧啶-4-基)-4-(2-羟乙基)-3-甲基异吲哚-1-酮(5)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3-methylisoindol-1-one (5):
将化合物4-(2-羟乙基)-3-甲基-6-硼酸频那醇酯异吲哚-1-酮(30.1mg,0.095mmol)、2,4-二氯-5-氟嘧啶(18.4mg,0.11mmol)、磷酸钾(41.0mg,0.19mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(6.9mg,0.0095mmol)置于二氧六环(1mL)和水(0.2mL)中，氮气保护下于100℃搅拌反应3小时。反应液浓缩后经硅胶 柱层析纯化(二氯甲烷:甲醇＝30:1～10:1)得到白色固体(20.0mg)。LC-MS:[M+H]+:322.0。Compound 4-(2-hydroxyethyl)-3-methyl-6-boronic acid pinacol ester isoindol-1-one (30.1 mg, 0.095 mmol) and 2,4-dichloro-5-fluoropyrimidine (18.4mg, 0.11mmol), potassium phosphate (41.0mg, 0.19mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (6.9mg, 0.0095mmol) were placed in dioxygen Six rings (1 mL) and water (0.2 mL) were stirred and reacted at 100°C for 3 hours under nitrogen protection. The reaction solution was concentrated and passed through silica gel Purification by column chromatography (dichloromethane:methanol=30:1~10:1) gave a white solid (20.0 mg). LC-MS: [M+H] + :322.0.
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-4-(2-羟乙基)-3-甲基异吲哚-1-酮(DP-01-229)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4-(2-hydroxyethyl Synthesis of -3-methylisoindol-1-one (DP-01-229):
将化合物6-(2-氯-5-氟嘧啶-4-基)-4-(2-羟乙基)-3-甲基异吲哚-1-酮(16.1mg,0.05mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(common int-16)(12.9mg,0.06mmol)、1,1'-联萘-2,2'-双二苯膦(6.6mg,0.01mmol)、醋酸钯(2.2mg,0.01mmol)和碳酸铯(32.5mg,0.10mmol)置于无水二氧六环(0.5mL)中，氮气保护下于90℃搅拌反应3小时。加5mL水稀释反应液，并用乙酸乙酯萃取(3×5mL)。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩后经制备分离纯化得黄色固体(2.1mg)。1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.65(d,J＝3.6Hz,1H),8.21(s,1H),8.09(s,2H),7.87(d,J＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),4.93–4.78(m,2H),3.81(s,3H),3.76–3.66(m,2H),3.06–3.01(m,4H),2.99–2.89(m,2H),2.47–2.42(m,4H),2.20(s,3H),1.44(d,J＝6.6Hz,3H)；LC-MS:[M+H]+:507.2。Compound 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3-methylisoindol-1-one (16.1 mg, 0.05 mmol), 2- Methoxy-5-(4-methylpiperazin-1-yl)aniline (common int-16) (12.9mg, 0.06mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (6.6mg, 0.01mmol), palladium acetate (2.2mg, 0.01mmol) and cesium carbonate (32.5mg, 0.10mmol) were placed in anhydrous dioxane (0.5mL), and stirred at 90°C under nitrogen protection for reaction 3 Hour. Add 5 mL of water to dilute the reaction solution, and extract with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid (2.1 mg) through preparative separation and purification. 1 H NMR (400MHz, DMSO-d6) δ8.78 (s, 1H), 8.65 (d, J = 3.6 Hz, 1H), 8.21 (s, 1H), 8.09 (s, 2H), 7.87 (d, J ＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),4.93–4.78(m,2H),3.81(s,3H),3.76 –3.66(m,2H),3.06–3.01(m,4H),2.99–2.89(m,2H),2.47–2.42(m,4H),2.20(s,3H),1.44(d,J＝6.6Hz ,3H); LC-MS: [M+H] + :507.2.
实施例58.化合物DP-01-146的合成
Example 58. Synthesis of compound DP-01-146
4-(3-氨基-4-(三氟甲氧基)苯基)哌嗪-1-羧酸叔丁酯(2)的合成：Synthesis of tert-butyl 4-(3-amino-4-(trifluoromethoxy)phenyl)piperazine-1-carboxylate (2):
将化合物5-溴-2-(三氟甲氧基)苯胺(2.0g,7.81mmol)、三(二亚苄基丙酮)二钯(0.7g,0.76mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(0.6g,1.52mmol)溶于四氢呋喃(20mL)，氮气置换三次，滴加1M双三甲基硅基胺基锂(18.8mL,18.80mmol)，再加入哌嗪-1-羧酸叔丁酯(2.3g,12.35mmol)，升温至70℃搅拌4小时，LCMS检测反应完全，向反应液加入水(50mL)，用乙酸乙酯萃取(50mL×3)，合并有机相用饱和食盐水洗一次，无水硫酸钠干燥，过滤、旋蒸、得到粗品，经反向柱层析(乙腈:水＝5-60％)得红色固体(998.0mg)。LC-MS:[M+H]+:362.2。The compound 5-bromo-2-(trifluoromethoxy)aniline (2.0g, 7.81mmol), tris(dibenzylideneacetone)dipalladium (0.7g, 0.76mmol), 2-dicyclohexylphosphine- 2'-(N,N-dimethylamine)-biphenyl (0.6g, 1.52mmol) was dissolved in tetrahydrofuran (20mL), replaced with nitrogen three times, and 1M lithium bistrimethylsilylamide (18.8mL, 18.80 mmol), then add piperazine-1-carboxylic acid tert-butyl ester (2.3g, 12.35mmol), raise the temperature to 70°C and stir for 4 hours. LCMS detects that the reaction is complete. Add water (50mL) to the reaction solution and extract with ethyl acetate. (50mL mg). LC-MS: [M+H] + :362.2.
4-(3-((5-氟-4-(3'-氧代螺[环丙烷-1,1'-异吲哚啉]-5'-基)嘧啶-2-基)氨基)-4-(三氟甲氧基)苯基)哌嗪-1-羧酸叔丁酯(3)的合成：4-(3-((5-fluoro-4-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyrimidin-2-yl)amino)-4 Synthesis of -(trifluoromethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (3):
将4-(3-氨基-4-(三氟甲氧基)苯基)哌嗪-1-羧酸叔丁酯(74.9mg,0.21mmol)和5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(common int-10)(50.0mg,0.17mmol)溶于1,4-二氧六环中，再将碳酸铯(168.7mg,0.52mmol)、1,1'-联萘-2,2'-双二苯膦(24.9mg,0.04mmol)和三(二亚苄基丙酮)二钯(18.3mg,0.02mmol)加入反应瓶中，氮气鼓泡1分钟。反应液在100℃反应16小时。LCMS检测反应完全。反应液冷却室温倒入水中(10mL)，用乙酸乙酯萃取(10mL×3)。合并有机相，无水硫酸钠干燥、浓缩，柱层析纯化(石油醚:乙酸乙酯＝1:1)得黄色固体(30.0mg)。LC-MS:[M+H]+:615.2。4-(3-Amino-4-(trifluoromethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (74.9 mg, 0.21 mmol) and 5'-(2-chloro-5-fluoropyrimidine -4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (common int-10) (50.0mg, 0.17mmol) dissolved in 1,4-dioxane, Then add cesium carbonate (168.7mg, 0.52mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (24.9mg, 0.04mmol) and tris(dibenzylideneacetone)dipalladium (18.3mg ,0.02mmol) was added to the reaction flask, and nitrogen was bubbled for 1 minute. The reaction solution was reacted at 100°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was cooled to room temperature, poured into water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (30.0 mg). LC-MS: [M+H] + :615.2.
5'-(5-氟-2-((5-(哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮 (DP-01-146)的合成：5'-(5-fluoro-2-((5-(piperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1, 1'-isoindoline]-3'-one Synthesis of (DP-01-146):
将4-(3-((5-氟-4-(3'-氧代螺[环丙烷-1,1'-异吲哚啉]-5'-基)嘧啶-2-基)氨基)-4-(三氟甲氧基)苯基)哌嗪-1-羧酸叔丁酯(30.0mg,0.05mmol)溶于二氯甲烷(1mL)中，再将三氟乙酸(0.5mL)加入反应液中，室温搅拌10小时。LCMS检测反应完全。反应液减压浓缩，制备分离纯化得黄色固体(6.1mg)。1H NMR(400MHz,DMSO)δ9.05(s,1H),8.86(s,1H),8.63(s,1H),8.29(s,1H),8.19(d,J＝9.2Hz,1H),7.54(s,1H),7.49–7.46(m,1H),7.20–7.18(m,1H),6.73–7.71(m,1H),3.05(s,4H),2.82(s,4H),1.53(s,4H),1.23(s,1H)；LC-MS:[M+H]+:515.2。4-(3-((5-Fluoro-4-(3'-oxospiro[cyclopropane-1,1'-isoindolin]-5'-yl)pyrimidin-2-yl)amino)- 4-(Trifluoromethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (30.0mg, 0.05mmol) was dissolved in dichloromethane (1mL), and then trifluoroacetic acid (0.5mL) was added to the reaction solution and stirred at room temperature for 10 hours. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and a yellow solid (6.1 mg) was obtained by separation and purification. 1 H NMR (400MHz, DMSO) δ9.05 (s, 1H), 8.86 (s, 1H), 8.63 (s, 1H), 8.29 (s, 1H), 8.19 (d, J = 9.2Hz, 1H), 7.54(s,1H),7.49–7.46(m,1H),7.20–7.18(m,1H),6.73–7.71(m,1H),3.05(s,4H),2.82(s,4H),1.53( s, 4H), 1.23 (s, 1H); LC-MS: [M+H] + : 515.2.
实施例59.化合物DP-01-200-2的合成
Example 59. Synthesis of compound DP-01-200-2
5-溴-7-甲酰基-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(1)的合成：Synthesis of tert-butyl 5-bromo-7-formyl-1,1-dimethyl-3-oxoisoindole-2-carboxylate (1):
将5-溴-1,1-二甲基-3-氧代-7-乙烯基异吲哚-2-羧酸叔丁酯(common int-17)(200.0mg,0.55mmol)溶于异丙醇(5mL)中，加入溶于高碘酸钠(233.6mg,1.08mmol)，再加入锇酸钾二水合物(8.50mg,0.023mmol)。反应液室温搅拌4小时。将反应液倒入冰水(10mL)中，用乙酸乙酯萃取(10mL×3)，有机相干燥，浓缩得到白色固体(190.0mg)。LC-MS:[M-t-Bu+H]+:312.1,314.1。Dissolve 5-bromo-1,1-dimethyl-3-oxo-7-vinylisoindole-2-carboxylic acid tert-butyl ester (common int-17) (200.0 mg, 0.55 mmol) in isopropyl In alcohol (5 mL), add sodium periodate (233.6 mg, 1.08 mmol) dissolved in it, and then add potassium osmate dihydrate (8.50 mg, 0.023 mmol). The reaction solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was dried and concentrated to obtain a white solid (190.0 mg). LC-MS: [Mt-Bu+H] + :312.1, 314.1.
5-溴-7-(羟甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(2)的合成：Synthesis of 5-bromo-7-(hydroxymethyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (2):
将5-溴-7-甲酰基-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(170.0mg,0.46mmol)溶于乙醇(5mL)中，冰浴下加入硼氢化钠(26.2mg,0.69mmol)，室温反应1小时。反应液旋干，加入水(10mL)，用乙酸乙酯萃取(10mL×3)，有机相干燥，旋干得到白色固体(90.0mg)。LC-MS:[M-t-Bu+H]+:314.2,316.2。Dissolve 5-bromo-7-formyl-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (170.0 mg, 0.46 mmol) in ethanol (5 mL) and keep in ice bath Add sodium borohydride (26.2 mg, 0.69 mmol) at room temperature and react for 1 hour at room temperature. The reaction solution was spun to dryness, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was dried and spun to dryness to obtain a white solid (90.0 mg). LC-MS: [Mt-Bu+H] + :314.2, 316.2.
5-溴-7-(甲氧基甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(3)的合成：Synthesis of 5-bromo-7-(methoxymethyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (3):
将5-溴-7-(羟甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(70.0mg,0.19mmol)溶解于四氢呋喃(5mL)中，-70℃下滴加1M双三甲基硅基胺基锂(0.3mL,0.30mmol)，在-70℃下搅拌半个小时。将碘甲烷(53.7mg,0.38mmol)滴加到反应体系中，反应升到室温并搅拌0.5小时，用饱和氯化铵水溶液(10mL)淬灭反应，用乙酸乙酯(10mL×3)萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，干燥，旋干，粗产品经柱层析(石油醚:乙酸乙酯＝3:1)得到白色固体(30.0mg)，LC-MS:[M+H]+:384.2,386.2。Dissolve 5-bromo-7-(hydroxymethyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (70.0 mg, 0.19 mmol) in tetrahydrofuran (5 mL) , add 1M lithium bistrimethylsilylamide (0.3 mL, 0.30 mmol) dropwise at -70°C, and stir at -70°C for half an hour. Methyl iodide (53.7 mg, 0.38 mmol) was added dropwise to the reaction system. The reaction was raised to room temperature and stirred for 0.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried, and spin-dried. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (30.0 mg), LC-MS: [M +H] + :384.2,386.2.
7-(甲氧基甲基)-1,1-二甲基-3-氧代-5-硼酸频那醇酯异吲哚-2-羧酸叔丁酯(4)的合成：Synthesis of 7-(methoxymethyl)-1,1-dimethyl-3-oxo-5-boronic acid pinacol ester isoindole-2-carboxylic acid tert-butyl ester (4):
将化合物5-溴-7-(甲氧基甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(30.0mg,0.078mmol)、联硼酸频那醇酯(21.8mg,0.086mmol)、乙酸钾(19.2mg,0.20mmol)及[1,1'-双(二苯基膦)二茂铁]二氯化钯(5.71mg,0.0079mmol)悬浮在无水二氧六环(3mL)中，氮气保护下于95℃条件下反应18小时，向体系 中加入水(5mL)，然后用乙酸乙酯萃取(5mL×3)，合并乙酸乙酯相，用无水硫酸钠干燥，过滤，浓缩得到粗品(30.0mg)。LC-MS:[M-t-Bu+H]+:432.3。Compound 5-bromo-7-(methoxymethyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (30.0 mg, 0.078 mmol), diboronic acid Nathenol ester (21.8mg, 0.086mmol), potassium acetate (19.2mg, 0.20mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.71mg, 0.0079mmol) were suspended In anhydrous dioxane (3 mL), react at 95°C for 18 hours under nitrogen protection. Water (5 mL) was added, and then extracted with ethyl acetate (5 mL × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product (30.0 mg). LC-MS: [Mt-Bu+H] + :432.3.
5-(2-氯-5-氟嘧啶-4-基)-7-(甲氧基甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(5)的合成：5-(2-Chloro-5-fluoropyrimidin-4-yl)-7-(methoxymethyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester Synthesis of (5):
将化合物7-(甲氧基甲基)-1,1-二甲基-3-氧代-5-硼酸频那醇酯异吲哚-2-羧酸叔丁酯(30.0mg,0.069mmol)、2,4-二氯-5-氟嘧啶(25.0mg,0.15mmol)、磷酸钾(44.3mg,0.21mmol)及[1,1'-双(二苯基膦)二茂铁]二氯化钯(17.0mg,0.023mmol)悬浮在无水二氧六环(4mL)和水(0.8mL)中，氮气保护下于100℃条件下反应4小时。反应液旋干，粗产品经硅胶柱层析(二氯甲烷:甲醇＝10:1)得到棕色固体(30.0mg)。LC-MS:[M+H]+:436.3。Compound 7-(methoxymethyl)-1,1-dimethyl-3-oxo-5-boronic acid pinacol ester isoindole-2-carboxylic acid tert-butyl ester (30.0 mg, 0.069 mmol) , 2,4-dichloro-5-fluoropyrimidine (25.0mg, 0.15mmol), potassium phosphate (44.3mg, 0.21mmol) and [1,1'-bis(diphenylphosphine)ferrocene] dichloride Palladium (17.0 mg, 0.023 mmol) was suspended in anhydrous dioxane (4 mL) and water (0.8 mL), and reacted at 100°C for 4 hours under nitrogen protection. The reaction liquid was spun to dryness, and the crude product was subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to obtain a brown solid (30.0 mg). LC-MS: [M+H] + :436.3.
5-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-7-(甲氧基甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(6)的合成：5-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-7-(methoxymethyl Synthesis of 1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (6):
将5-(2-氯-5-氟嘧啶-4-基)-7-(甲氧基甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(20.0mg,0.046mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(common int-16)(15.2mg,0.068mmol)、碳酸铯(44.8mg,0.14mmol)、1,1'-联萘-2,2'-双二苯膦(5.7mg,0.009mmol)及醋酸钯(1.6mg,0.007mmol)溶解在1,4-二氧六环(1mL)中，氮气保护下，100℃反应5小时，反应液旋干，粗产品经硅胶板制备(二氯甲烷:甲醇＝10:1)得到白色固体(9.0mg)。LC-MS:[M+H]+:621.2。tert-butyl 5-(2-chloro-5-fluoropyrimidin-4-yl)-7-(methoxymethyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylate Ester (20.0mg, 0.046mmol), 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (common int-16) (15.2mg, 0.068mmol), cesium carbonate (44.8mg, 0.14mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (5.7mg, 0.009mmol) and palladium acetate (1.6mg, 0.007mmol) were dissolved in 1,4-dioxane (1mL ) under nitrogen protection, react at 100°C for 5 hours, spin the reaction liquid to dryness, and prepare the crude product on a silica gel plate (dichloromethane:methanol=10:1) to obtain a white solid (9.0 mg). LC-MS: [M+H] + :621.2.
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-4-(甲氧基甲基)-3,3-二甲基异吲哚-1-酮(DP-01-200-2)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4-(methoxymethyl Synthesis of 3,3-dimethylisoindol-1-one (DP-01-200-2):
将5-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-7-(甲氧基甲基)-1,1-二甲基-3-氧代异吲哚-2-羧酸叔丁酯(9.0mg,0.015mmol)溶解在二氯甲烷(1mL)中，加入三氟乙酸(0.5mL,6.53mmol)，室温反应1小时，反应液旋干。加入二氯甲烷(1mL)和碳酸钠(3mg)，搅拌1小时，有机相经硅胶制备板(二氯甲烷:甲醇＝10:1)制备得到白色固体(5.3mg)。1H NMR(400MHz,DMSO)δ8.66(d,J＝3.2Hz,1H),8.37(s,1H),8.23(s,1H),8.18(s,1H),7.87(d,J＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),5.61(s,1H),4.83(s,2H),3.81(s,3H),3.05(s,4H),2.96(s,3H),2.50(s,4H),2.25(s,3H),1.53(s,6H)；LC-MS:[M+H]+:521.3。5-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-7-(methoxy Methyl)-1,1-dimethyl-3-oxoisoindole-2-carboxylic acid tert-butyl ester (9.0 mg, 0.015 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL, 6.53 mmol), react at room temperature for 1 hour, and spin the reaction solution to dryness. Add dichloromethane (1 mL) and sodium carbonate (3 mg), stir for 1 hour, and pass the organic phase through a silica gel preparation plate (dichloromethane:methanol=10:1) to prepare a white solid (5.3 mg). 1 H NMR (400MHz, DMSO) δ8.66 (d, J = 3.2 Hz, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 2.8 Hz,1H),6.93(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),5.61(s,1H),4.83(s,2H),3.81(s,3H ),3.05(s,4H),2.96(s,3H),2.50(s,4H),2.25(s,3H),1.53(s,6H); LC-MS: [M+H] + :521.3.
实施例60.化合物DP-01-223的合成
Example 60. Synthesis of compound DP-01-223
6-溴-3,3-二甲基-4-(S-甲基磺酰亚胺基)异吲哚啉-1-酮(1)的合成：Synthesis of 6-bromo-3,3-dimethyl-4-(S-methylsulfonylimido)isoindolin-1-one (1):
将化合物6-溴-3,3-二甲基-4-(甲硫基)异吲哚啉-1-酮(200.0mg,0.70mmol)、碘苯二乙酸(563.0mg,1.75mmol)、氨基甲酸铵(109.0mg,1.40mmol)溶于甲醇(2.0mL)中。反应液在室温下搅拌12小时。待反应完全，真空除去多余溶剂。粗品经柱层析分离(二氯甲烷:甲醇＝20:1)纯化得到黄色油状液体(107.0mg)。LC-MS:[M+H]+:317.0,319.0。Compound 6-bromo-3,3-dimethyl-4-(methylthio)isoindolin-1-one (200.0 mg, 0.70 mmol), iodophenylacetic acid (563.0 mg, 1.75 mmol), amino Ammonium formate (109.0 mg, 1.40 mmol) was dissolved in methanol (2.0 mL). The reaction solution was stirred at room temperature for 12 hours. When the reaction is complete, remove excess solvent in vacuo. The crude product was separated by column chromatography (dichloromethane: methanol = 20:1) and purified to obtain a yellow oily liquid (107.0 mg). LC-MS: [M+H] + :317.0, 319.0.
(1,1-二甲基-7-(S-甲基磺酰亚胺基)-3-氧代异吲哚啉-5-基)硼酸(2)的合成：Synthesis of (1,1-dimethyl-7-(S-methylsulfonimido)-3-oxoisoindolin-5-yl)boronic acid (2):
将化合物6-溴-3,3-二甲基-4-(S-甲基磺酰亚胺基)异吲哚啉-1-酮(107.0mg,0.34mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(24.9mg,0.034mmol)、联硼酸频那醇酯(111.3mg,0.44mmol)、醋酸钾(99.2mg,1.01mmol)置于1,4-二氧六环(2.0mL)中。反应体系在氮气保护下于80℃搅拌2小时。待反应完全，反应液直接浓缩得到黑色固体(95.9mg)。LC-MS:[M+H]+:283.0。Compound 6-bromo-3,3-dimethyl-4-(S-methylsulfonylimido)isoindolin-1-one (107.0 mg, 0.34 mmol), [1,1'-bis (Diphenylphosphine)ferrocene]palladium (II) dichloride (24.9 mg, 0.034 mmol), pinacol diborate (111.3 mg, 0.44 mmol), and potassium acetate (99.2 mg, 1.01 mmol) were placed in 1,4-dioxane (2.0 mL). The reaction system was stirred at 80°C for 2 hours under nitrogen protection. When the reaction was complete, the reaction solution was directly concentrated to obtain a black solid (95.9 mg). LC-MS: [M+H] + :283.0.
6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基-4-(S-甲基磺酰亚胺基)异吲哚啉-1-酮(3)的合成：6-(2-Chloro-5-fluoropyrimidin-4-yl)-3,3-dimethyl-4-(S-methylsulfonylimido)isoindolin-1-one (3) synthesis:
将(1,1-二甲基-7-(S-甲基磺酰亚胺基)-3-氧代异吲哚啉-5-基)硼酸(95.9mg,0.34mmol)、2,4-二氯-5-氟嘧啶(67.5mg,0.40mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(24.7mg,0.034mmol)、磷酸钾(214.6mg,1.01mmol)置于1,4-二氧六环和水的混合溶液中(2.2mL,1,4-二氧六环:水＝10:1,v/v)。反应体系在氮气保护下于90℃搅拌2小时。待反应完全后加水(10.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(二氯甲烷:甲醇＝10:1)得到棕黄色固体(98.5mg)。LC-MS:[M+H]+:369.0。(1,1-Dimethyl-7-(S-methylsulfonylimido)-3-oxoisoindolin-5-yl)boronic acid (95.9 mg, 0.34 mmol), 2,4- Dichloro-5-fluoropyrimidine (67.5 mg, 0.40 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (24.7 mg, 0.034 mmol), potassium phosphate ( 214.6 mg, 1.01 mmol) was placed in a mixed solution of 1,4-dioxane and water (2.2 mL, 1,4-dioxane: water = 10:1, v/v). The reaction system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction was complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (dichloromethane:methanol=10:1) to obtain a brown solid (98.5 mg). LC-MS: [M+H] + :369.0.
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-3,3-二甲基-4(S-甲基磺酰亚胺基)异吲哚啉-1-酮(DP-01-223)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethyl Synthesis of -4(S-methylsulfonylimido)isoindolin-1-one (DP-01-223):
将2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(75.5mg,0.34mmol)、6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基-4-(S-甲基磺酰亚胺基)异吲哚啉-1-酮(98.5mg,0.27mmol)、三(二亚苄基丙酮)二钯(28.4mg,0.031mmol)、1,1'-联萘-2,2'-双二苯膦(38.6mg,0.062mmol)、碳酸铯(202.0mg,0.62mmol)置于1,4-二氧六环中(1.0mL)。反应体系在氮气保护下于100℃搅拌2小时。待反应完全后加水(10.0mL)淬灭，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经制备高效液相色谱分离得到黄色固体(4.3mg)。1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.80(s,1H),8.46(s,1H),8.32(s,1H),7.90(s,1H),6.84(d,J＝8.4Hz,1H),6.59(d,J＝8.0Hz,1H),6.40(s,1H),3.91(s,3H),3.21(s,4H),3.16(s,3H),2.79(s,4H),2.47(s,3H),1.93–1.90(m,6H)；LC-MS:[M+H]+:554.2。2-Methoxy-5-(4-methylpiperazin-1-yl)aniline (75.5mg, 0.34mmol), 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3 -Dimethyl-4-(S-methylsulfonylimido)isoindolin-1-one (98.5mg, 0.27mmol), tris(dibenzylideneacetone)dipalladium (28.4mg, 0.031mmol) ), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (38.6mg, 0.062mmol), cesium carbonate (202.0mg, 0.62mmol) were placed in 1,4-dioxane (1.0mL ). The reaction system was stirred at 100°C for 2 hours under nitrogen protection. After the reaction was complete, add water (10.0 mL) to quench, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. A yellow solid (4.3 mg) was obtained by preparative high-performance liquid chromatography. 1 H NMR (400MHz, CDCl 3 ) δ9.12(s,1H),8.80(s,1H),8.46(s,1H),8.32(s,1H),7.90(s,1H),6.84(d, J＝8.4Hz,1H),6.59(d,J＝8.0Hz,1H),6.40(s,1H),3.91(s,3H),3.21(s,4H),3.16(s,3H),2.79( s,4H),2.47(s,3H),1.93–1.90(m,6H); LC-MS: [M+H] + :554.2.
实施例61.化合物DP-01-225的合成
Example 61. Synthesis of compound DP-01-225
6-溴-3,3-二甲基-4-(甲基磺酰基)异吲哚啉-1-酮(1)的合成：Synthesis of 6-bromo-3,3-dimethyl-4-(methylsulfonyl)isoindolin-1-one (1):
将化合物6-溴-3,3-二甲基-4-(甲硫基)异吲哚啉-1-酮(500.0mg,1.75mmol)、过氧硫酸氢钾复合盐(3.22g,9.30mmol)置于四氢呋喃和水的混合溶液中(20mL,四氢呋喃:水＝1:1)。反应体系在室温下搅拌12小时。待反应完全后加水(50.0mL)淬灭反应，用乙酸乙酯萃取(50mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经硅胶柱层析(二氯甲烷:甲醇＝20:1)纯化得到黄色固体(200.0mg)。LC-MS:[M+H]+:318.0,319.9。Compound 6-bromo-3,3-dimethyl-4-(methylthio)isoindolin-1-one (500.0mg, 1.75mmol) and potassium hydrogen peroxysulfate complex salt (3.22g, 9.30mmol) ) was placed in a mixed solution of tetrahydrofuran and water (20 mL, tetrahydrofuran:water=1:1). The reaction system was stirred at room temperature for 12 hours. After the reaction is complete, add water (50.0 mL) to quench the reaction, and extract with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a yellow solid (200.0 mg). LC-MS: [M+H] + :318.0,319.9.
(1,1-二甲基-7-(甲基磺酰基)-3-氧代异吲哚啉-5-基)硼酸(2)的合成：Synthesis of (1,1-dimethyl-7-(methylsulfonyl)-3-oxoisoindolin-5-yl)boronic acid (2):
将化合物6-溴-3,3-二甲基-4-(甲基磺酰基)异吲哚啉-1-酮(24.0mg,0.075mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(5.5mg,0.0075mmol)、联硼酸频那醇酯(24.9mg,0.098mmol)、醋酸钾(22.2mg,0.23mmol)置于1,4-二氧六环(1.0mL)中。反应体系在氮气保护下于80℃搅拌2小时。待反应完全，反应液直接浓缩得到黑色固体粗品(46.3mg)，直接用于下一步反应。LC-MS:[M+H]+:284.1。Compound 6-bromo-3,3-dimethyl-4-(methylsulfonyl)isoindolin-1-one (24.0 mg, 0.075 mmol), [1,1'-bis(diphenylphosphine) ) Ferrocene] Palladium (II) dichloride (5.5 mg, 0.0075 mmol), pinacol diborate (24.9 mg, 0.098 mmol), and potassium acetate (22.2 mg, 0.23 mmol) were placed in 1,4-bis Oxyhexanes (1.0 mL). The reaction system was stirred at 80°C for 2 hours under nitrogen protection. When the reaction is complete, the reaction solution is directly concentrated to obtain a crude black solid product (46.3 mg), which is directly used in the next step of the reaction. LC-MS: [M+H] + :284.1.
6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基-4-(甲基磺酰基)异吲哚啉-1-酮(3)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-3,3-dimethyl-4-(methylsulfonyl)isoindolin-1-one (3):
将(1,1-二甲基-7-(甲基磺酰基)-3-氧代异吲哚啉-5-基)硼酸(22.6mg,0.08mmol)、2,4-二氯-5-氟嘧啶(15.1mg,0.09mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(5.5mg,0.0075mmol)、磷酸钾(48.0mg,0.23mmol)置于1,4-二氧六环和水的混合溶液中(1.1mL,1,4-二氧六环:水＝10:1)。反应体系在氮气保护下于90℃搅拌2小时。待反应完全，加水(10.0mL)淬灭反应，用乙酸乙酯萃取(10mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(二氯甲烷:甲醇＝10:1)得到黄色固体(14.8mg)。LC-MS:[M+H]+:370.0,372.0。(1,1-Dimethyl-7-(methylsulfonyl)-3-oxoisoindolin-5-yl)boronic acid (22.6 mg, 0.08 mmol), 2,4-dichloro-5- Fluoropyrimidine (15.1mg, 0.09mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (5.5mg, 0.0075mmol), potassium phosphate (48.0mg, 0.23mmol) ) was placed in a mixed solution of 1,4-dioxane and water (1.1 mL, 1,4-dioxane:water=10:1). The reaction system was stirred at 90°C for 2 hours under nitrogen protection. When the reaction is complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (dichloromethane:methanol=10:1) to obtain a yellow solid (14.8 mg). LC-MS: [M+H] + :370.0, 372.0.
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-3,3-二甲基-4-(甲基磺酰基)异吲哚啉-1-酮(DP-01-225)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethyl Synthesis of -4-(methylsulfonyl)isoindolin-1-one (DP-01-225):
将6-(2-氯-5-氟嘧啶-4-基)-3,3-二甲基-4-(甲基磺酰基)异吲哚啉-1-酮(15.0mg,0.04mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(9.90mg,0.04mmol)、三(二亚苄基丙酮)二钯(7.4mg,0.008mmol)、1,1'-联萘-2,2'-双二苯膦(10.1mg,0.016mmol)、碳酸铯(52.8mg,0.16mmol)置于1,4-二氧六环(1.0mL)中。反应体系在氮气保护下于100℃搅拌2小时。待反应完全，加水(10.0mL)淬灭反应，用乙酸乙酯萃取(20mL× 3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经制备分离纯化得到黄色固体(7.0mg)。1H NMR(400MHz,MeOD)δ8.91(s,1H),8.73(s,1H),8.56(d,J＝3.2Hz,1H),8.17(d,J＝2.4Hz,1H),6.93(d,J＝8.8Hz,1H),6.64(dd,J＝8.8,2.4Hz,1H),3.89(s,3H),3.23(s,3H),3.16–3.09(m,4H),2.66–2.56(m,4H),2.32(s,3H),1.86(s,6H)；LC-MS:[M+H]+:555.2。6-(2-Chloro-5-fluoropyrimidin-4-yl)-3,3-dimethyl-4-(methylsulfonyl)isoindolin-1-one (15.0 mg, 0.04 mmol), 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (9.90mg, 0.04mmol), tris(dibenzylideneacetone)dipalladium (7.4mg, 0.008mmol), 1,1 '-Binaphthyl-2,2'-bisdiphenylphosphine (10.1 mg, 0.016 mmol) and cesium carbonate (52.8 mg, 0.16 mmol) were placed in 1,4-dioxane (1.0 mL). The reaction system was stirred at 100°C for 2 hours under nitrogen protection. When the reaction is complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. After preparation, isolation and purification, a yellow solid (7.0 mg) was obtained. 1 H NMR (400MHz, MeOD) δ8.91 (s, 1H), 8.73 (s, 1H), 8.56 (d, J = 3.2Hz, 1H), 8.17 (d, J = 2.4Hz, 1H), 6.93 ( d,J＝8.8Hz,1H),6.64(dd,J＝8.8,2.4Hz,1H),3.89(s,3H),3.23(s,3H),3.16–3.09(m,4H),2.66–2.56 (m,4H),2.32(s,3H),1.86(s,6H); LC-MS: [M+H] + :555.2.
实施例62.化合物DP-01-239的合成
Example 62. Synthesis of compound DP-01-239
1-(4-溴-2-硝基苯氧基)-2-甲基丙-2-醇(2)的合成：Synthesis of 1-(4-bromo-2-nitrophenoxy)-2-methylpropan-2-ol (2):
将化合物4-溴-1-氟-2-硝基苯(500.0mg,2.27mmol)、2-甲基丙烷-1,2-二醇(266.3mg,2.95mmol)和碳酸铯(1.5g,4.60mmol)置于N,N-二甲基甲酰胺(10mL)中，置换氮气，升温至80℃搅拌6小时。反应液加入水(20mL)稀释，用乙酸乙酯萃取(30mL×3)。合并有机相用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤浓缩。粗品经硅胶柱纯化(乙酸乙酯:石油醚＝0-25％)得黄色油状物(461.0mg)。1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝2.4Hz,1H),7.80(dd,J＝9.0,2.4Hz,1H),7.34(d,J＝9.0Hz,1H),4.70(s,1H),3.89(s,2H),1.19(s,6H)。The compound 4-bromo-1-fluoro-2-nitrobenzene (500.0mg, 2.27mmol), 2-methylpropane-1,2-diol (266.3mg, 2.95mmol) and cesium carbonate (1.5g, 4.60 mmol) was placed in N,N-dimethylformamide (10 mL), replaced with nitrogen, and the temperature was raised to 80°C and stirred for 6 hours. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column (ethyl acetate: petroleum ether = 0-25%) to obtain yellow oil (461.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.10 (d, J = 2.4Hz, 1H), 7.80 (dd, J = 9.0, 2.4Hz, 1H), 7.34 (d, J = 9.0Hz, 1H), 4.70(s,1H),3.89(s,2H),1.19(s,6H).
2-甲基-1-(4-(4-甲基哌嗪-1-基)-2-硝基苯氧基)丙烷-2-醇(3)的合成：Synthesis of 2-methyl-1-(4-(4-methylpiperazin-1-yl)-2-nitrophenoxy)propan-2-ol (3):
将化合物1-(4-溴-2-硝基苯氧基)-2-甲基丙-2-醇(200.0mg,0.69mmol)、1-甲基哌嗪(82.9mg,0.83mmol)、2-二环己基膦-2′,6′-二甲氧基-联苯(56.6mg,0.14mmol)、碳酸铯(449.3mg,1.38mmol)和三(二亚苄基丙酮)二钯(63.1mg,0.069mmol)置于1,4-二氧六环(5mL)中，氮气置换三次，升温至90℃搅拌6小时。反应液加入水(20mL)稀释，用乙酸乙酯萃取(30mL×3)。合并有机相用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩得粗品。经硅胶柱层析(甲醇:二氯甲烷＝0-5％)纯化得黄色油状物(160.0mg)。LC-MS:[M+H]+:310.2。Compound 1-(4-bromo-2-nitrophenoxy)-2-methylpropan-2-ol (200.0mg, 0.69mmol), 1-methylpiperazine (82.9mg, 0.83mmol), 2 -Dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (56.6 mg, 0.14 mmol), cesium carbonate (449.3 mg, 1.38 mmol) and tris(dibenzylideneacetone)dipalladium (63.1 mg ,0.069mmol) was placed in 1,4-dioxane (5mL), replaced with nitrogen three times, and the temperature was raised to 90°C and stirred for 6 hours. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. Purify through silica gel column chromatography (methanol: dichloromethane = 0-5%) to obtain a yellow oil (160.0 mg). LC-MS: [M+H] + :310.2.
1-(2-氨基-4-(4-甲基哌嗪-1-基)苯氧基)-2-甲基丙-2-醇(4)的合成：Synthesis of 1-(2-amino-4-(4-methylpiperazin-1-yl)phenoxy)-2-methylpropan-2-ol (4):
将化合物2-甲基-1-(4-(4-甲基哌嗪-1-基)-2-硝基苯氧基)丙烷-2-醇(150.0mg,0.48mmol)和钯碳(50.0mg,10％w/w)悬浮于甲醇(4mL)中，氢气置换三次后，室温搅拌反应4小时。LCMS监测反应完全后， 将反应液通过硅藻土过滤，滤饼用乙酸乙酯洗涤3次，滤液旋干后得黄色固体(128.0mg)。LC-MS:[M+H]+:280.4。Compound 2-methyl-1-(4-(4-methylpiperazin-1-yl)-2-nitrophenoxy)propan-2-ol (150.0 mg, 0.48 mmol) and palladium on carbon (50.0 mg, 10% w/w) was suspended in methanol (4 mL), and after hydrogen replacement three times, the reaction was stirred at room temperature for 4 hours. After LCMS monitoring of the complete reaction, The reaction solution was filtered through diatomaceous earth, the filter cake was washed three times with ethyl acetate, and the filtrate was spin-dried to obtain a yellow solid (128.0 mg). LC-MS: [M+H] + :280.4.
5'-(5-氟-2-((2-(2-羟基-2-甲基丙氧基)-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-239)的合成：5'-(5-fluoro-2-((2-(2-hydroxy-2-methylpropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-4 -Synthesis of spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-239):
将化合物1-(2-氨基-4-(4-甲基哌嗪-1-基)苯氧基)-2-甲基丙-2-醇(128.0mg,0.46mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(159.3mg,0.55mmol)、1,1'-联萘-2,2'-双二苯膦(57.0mg,0.092mmol)、碳酸铯(298.5mg,0.92mmol)和三(二亚苄基丙酮)二钯(41.9mg,0.046mmol)置于1,4-二氧六环(5mL)中，置换氮气，升温至100℃搅拌6小时。反应液加入水(20mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩得粗品。经制备纯化得黄色固体(41.1mg)。1H NMR(400MHz,CDCl3)δ8.57(s,1H),8.37–8.27(m,3H),7.95(s,1H),7.66(s,1H),7.25(d,J＝8.4Hz,1H),7.14(d,J＝8.0Hz,1H),6.85(d,J＝8.4Hz,1H),6.57–6.47(m,1H),3.90–3.79(m,2H),3.19(s,4H),2.60(s,4H),2.35(s,3H),1.70–1.63(m,2H),1.55–1.46(m,2H),1.39(s,6H)；LC-MS:[M+H]+:533.8。Compound 1-(2-amino-4-(4-methylpiperazin-1-yl)phenoxy)-2-methylpropan-2-ol (128.0 mg, 0.46mmol), 5'-(2 -Chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (159.3 mg, 0.55 mmol), 1,1'-binaphthyl-2, 2'-Bisdiphenylphosphine (57.0mg, 0.092mmol), cesium carbonate (298.5mg, 0.92mmol) and tris(dibenzylideneacetone)dipalladium (41.9mg, 0.046mmol) were placed in 1,4-dioxy Six rings (5 mL) were replaced with nitrogen, and the temperature was raised to 100°C and stirred for 6 hours. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. After preparation and purification, a yellow solid (41.1 mg) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ8.57 (s, 1H), 8.37–8.27 (m, 3H), 7.95 (s, 1H), 7.66 (s, 1H), 7.25 (d, J = 8.4Hz, 1H),7.14(d,J＝8.0Hz,1H),6.85(d,J＝8.4Hz,1H),6.57–6.47(m,1H),3.90–3.79(m,2H),3.19(s,4H ),2.60(s,4H),2.35(s,3H),1.70–1.63(m,2H),1.55–1.46(m,2H),1.39(s,6H); LC-MS:[M+H] + :533.8.
实施例63.化合物DP-01-242的合成
Example 63. Synthesis of compound DP-01-242
1-甲基-4-(4-甲基-3-硝基苯基)哌嗪(2)的合成：Synthesis of 1-methyl-4-(4-methyl-3-nitrophenyl)piperazine (2):
氮气保护下，将化合物4-溴-1-甲基-2-硝基苯(300.0mg,1.39mmol)、1-甲基哌嗪(166.9mg,1.67mmol)、2-二环己基膦-2′,6′-二甲氧基-联苯(114.0mg,0.28mmol)、碳酸铯(905.0mg,2.78mmol)和三(二亚苄基丙酮)二钯(127.2mg,0.14mmol)置于1,4-二氧六环(6mL)中，升温至90℃搅拌6小时。LCMS检测原料已反应完。反应液加水(30mL)稀释，用乙酸乙酯萃取(40mL×3)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩得粗品。粗品经硅胶柱层析纯化(甲醇:二氯甲烷＝0-5％)得黄色油状物(216.0mg)。LC-MS:[M+H]+:236.1。Under nitrogen protection, compound 4-bromo-1-methyl-2-nitrobenzene (300.0mg, 1.39mmol), 1-methylpiperazine (166.9mg, 1.67mmol), 2-dicyclohexylphosphine-2 ′,6′-dimethoxy-biphenyl (114.0 mg, 0.28 mmol), cesium carbonate (905.0 mg, 2.78 mmol) and tris(dibenzylideneacetone) dipalladium (127.2 mg, 0.14 mmol) were placed in 1 , 4-dioxane (6 mL), raise the temperature to 90°C and stir for 6 hours. LCMS detects that the raw materials have reacted completely. The reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 0-5%) to obtain a yellow oil (216.0 mg). LC-MS: [M+H] + :236.1.
2-甲基-5-(4-甲基哌嗪-1-基)苯胺(3)的合成：Synthesis of 2-methyl-5-(4-methylpiperazin-1-yl)aniline (3):
将化合物1-甲基-4-(4-甲基-3-硝基苯基)哌嗪(200.0mg,0.85mmol)和钯碳(80.0mg,10％w/w)悬浮于甲醇(4mL)中，氢气置换三次后，室温搅拌反应4小时。LCMS监测反应完全后，将反应液通过硅藻土过滤，滤饼用乙酸乙酯洗涤3次，滤液浓缩得白色固体(170.0mg)。LC-MS:[M+H]+:206.2。Compound 1-methyl-4-(4-methyl-3-nitrophenyl)piperazine (200.0 mg, 0.85 mmol) and palladium on carbon (80.0 mg, 10% w/w) were suspended in methanol (4 mL) , after replacing with hydrogen three times, the reaction was stirred at room temperature for 4 hours. After LCMS monitored that the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed three times with ethyl acetate, and the filtrate was concentrated to obtain a white solid (170.0 mg). LC-MS: [M+H] + :206.2.
5'-(5-氟-2-((2-甲基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-242)的合成：5'-(5-fluoro-2-((2-methyl-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1 Synthesis of '-isoindoline]-3'-one (DP-01-242):
将化合物2-甲基-5-(4-甲基哌嗪-1-基)苯胺(120.0mg,0.58mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(203.2mg,0.70mmol)、碳酸铯(380.9mg,1.17mmol)、1,1'-联萘-2,2'-双二苯膦(72.8mg,0.12mmol)和三(二亚苄基丙酮)二钯(53.5mg,0.06mmol)置于1,4-二氧六环(4mL)，置换氮气，升温 至100℃搅拌6小时。反应液加水(30mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩得粗品。经制备得淡黄色固体(122.9mg)。1H NMR(400MHz,DMSO-d6)δ8.85–8.82(m,2H),8.54(d,J＝3.6Hz,1H),8.27(s,1H),8.17(d,J＝8.0Hz,1H),7.45(d,J＝8.4Hz,1H),7.16(d,J＝2.0Hz,1H),7.05(d,J＝8.4Hz,1H),6.67(dd,J＝8.0,2.4Hz,1H),3.11–3.03(m,4H),2.46–2.39(m,4H),2.20(s,3H),2.14(s,3H),1.52(s,4H)；LC-MS:[M+H]+:459.6。Compound 2-methyl-5-(4-methylpiperazin-1-yl)aniline (120.0mg, 0.58mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[ring Propane-1,1'-isoindolin]-3'-one (203.2mg, 0.70mmol), cesium carbonate (380.9mg, 1.17mmol), 1,1'-binaphthyl-2,2'-bisdi Phenylphosphine (72.8mg, 0.12mmol) and tris(dibenzylideneacetone)dipalladium (53.5mg, 0.06mmol) were placed in 1,4-dioxane (4mL), replaced with nitrogen, and heated Stir to 100°C for 6 hours. The reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. A pale yellow solid (122.9 mg) was prepared. 1 H NMR (400MHz, DMSO-d6) δ8.85–8.82(m,2H),8.54(d,J＝3.6Hz,1H),8.27(s,1H),8.17(d,J＝8.0Hz,1H ),7.45(d,J＝8.4Hz,1H),7.16(d,J＝2.0Hz,1H),7.05(d,J＝8.4Hz,1H),6.67(dd,J＝8.0,2.4Hz,1H ),3.11–3.03(m,4H),2.46–2.39(m,4H),2.20(s,3H),2.14(s,3H),1.52(s,4H); LC-MS:[M+H] + :459.6.
实施例64.化合物DP-01-252的合成
Example 64. Synthesis of compound DP-01-252
2-(4-溴-2-硝基苯氧基)乙烷-1-醇(2)的合成：Synthesis of 2-(4-bromo-2-nitrophenoxy)ethane-1-ol (2):
将化合物4-溴-1-氟-2-硝基苯(500.0mg,2.27mmol)、乙二醇(423.4mg,6.82mmol)、碳酸铯(2.96g,9.08mmol)置于N,N-二甲基甲酰胺(10.0mL)中。反应液升至80℃搅拌反应12小时。待反应完全后加水(10.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(PE:EA＝2:1)得到黄色油状液体(360.0mg)。Compound 4-bromo-1-fluoro-2-nitrobenzene (500.0mg, 2.27mmol), ethylene glycol (423.4mg, 6.82mmol), and cesium carbonate (2.96g, 9.08mmol) were placed in N,N-di Methylformamide (10.0 mL). The reaction solution was raised to 80°C and stirred for 12 hours. After the reaction was complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Separate by column chromatography (PE:EA=2:1) to obtain a yellow oily liquid (360.0 mg).
2-(4-(4-甲基哌嗪-1-基)-2-硝基苯氧基)乙烷-1-醇(3)的合成：Synthesis of 2-(4-(4-methylpiperazin-1-yl)-2-nitrophenoxy)ethane-1-ol (3):
氮气保护下，将化合物2-(4-溴-2-硝基苯氧基)乙烷-1-醇(360.0mg,1.37mmol)溶于无水1,4-二氧六环(6mL)中，依次加入2-双环己基膦-2',6'-二甲氧基联苯(56.4mg,0.14mmol)、三(二亚苄基丙酮)二钯(63.2mg,0.069mmol)、碳酸铯(895.4mg,2.75mmol)和N-甲基哌嗪(206.5mg,2.06mmol)，反应液升至90℃搅拌反应12小时。待反应完全后加水(10.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝20:1)得到绿色油状液体(102.0mg)。LC-MS:[M+H]+:282.2。Under nitrogen protection, compound 2-(4-bromo-2-nitrophenoxy)ethane-1-ol (360.0 mg, 1.37 mmol) was dissolved in anhydrous 1,4-dioxane (6 mL) , add 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (56.4mg, 0.14mmol), tris(dibenzylideneacetone)dipalladium (63.2mg, 0.069mmol), cesium carbonate ( 895.4 mg, 2.75 mmol) and N-methylpiperazine (206.5 mg, 2.06 mmol). The reaction solution was raised to 90°C and stirred for 12 hours. After the reaction was complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Separate by column chromatography (DCM:MeOH=20:1) to obtain a green oily liquid (102.0 mg). LC-MS: [M+H] + :282.2.
2-(2-氨基-4-(4-甲基哌嗪-1-基)苯氧基)乙烷-1-醇(4)的合成：Synthesis of 2-(2-amino-4-(4-methylpiperazin-1-yl)phenoxy)ethane-1-ol (4):
将化合物2-(4-(4-甲基哌嗪-1-基)-2-硝基苯氧基)乙烷-1-醇(102.0mg,0.36mmol)、钯碳(35.0mg,10％w/w)置于甲醇(5mL)中，氢气氛围下在室温搅拌反应2小时。待反应完全，反应液垫硅藻土过滤，滤饼用少量甲醇洗涤两次，浓缩滤液得到棕黄固体(98.3mg)。LC-MS:[M+H]+:252.2。Compound 2-(4-(4-methylpiperazin-1-yl)-2-nitrophenoxy)ethane-1-ol (102.0 mg, 0.36 mmol), palladium on carbon (35.0 mg, 10% w/w) was placed in methanol (5 mL), and the reaction was stirred at room temperature for 2 hours under a hydrogen atmosphere. When the reaction is complete, the reaction solution is filtered through diatomaceous earth, the filter cake is washed twice with a small amount of methanol, and the filtrate is concentrated to obtain a brown solid (98.3 mg). LC-MS: [M+H] + :252.2.
5'-(5-氟-2-((2-(2-羟基乙氧基)-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-252)的合成： 5'-(5-fluoro-2-((2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)spiro[ Synthesis of cyclopropane-1,1'-isoindolin]-3'-one (DP-01-252):
将2-(2-氨基-4-(4-甲基哌嗪-1-基)苯氧基)乙烷-1-醇(98.3mg,0.39mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(113.3mg,0.39mmol)、三(二亚苄基丙酮)二钯(32.5mg,0.035mmol)、1,1'-联萘-2,2'-双二苯膦(44.2mg,0.07mmol)、碳酸铯(231.3mg,0.71mmol)置于1,4-二氧六环(2.0mL)中。反应体系在氮气保护下于100℃搅拌2小时。待反应完全后加水(10.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经制备分离得到黄色固体(29.4mg)。1H NMR(400MHz,MeOD)δ8.52(s,1H),8.50(d,J＝3.6Hz,1H),8.40–8.32(m,2H),7.42(d,J＝8.0Hz,1H),6.94(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),4.17–4.05(m,2H),3.99–3.86(m,2H),3.21–3.09(m,4H),2.71–2.58(m,4H),2.36(s,3H),1.74–1.52(m,4H)；LC-MS:[M+H]+:505.3。2-(2-Amino-4-(4-methylpiperazin-1-yl)phenoxy)ethan-1-ol (98.3 mg, 0.39 mmol), 5'-(2-chloro-5- Fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (113.3 mg, 0.39 mmol), tris(dibenzylideneacetone) dipalladium (32.5 mg, 0.035 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (44.2mg, 0.07mmol), cesium carbonate (231.3mg, 0.71mmol) were placed in 1,4-dioxane (2.0mL )middle. The reaction system was stirred at 100°C for 2 hours under nitrogen protection. After the reaction was complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. A yellow solid (29.4 mg) was isolated after preparation. 1 H NMR (400MHz, MeOD) δ8.52 (s, 1H), 8.50 (d, J = 3.6Hz, 1H), 8.40–8.32 (m, 2H), 7.42 (d, J = 8.0Hz, 1H), 6.94(d,J＝8.8Hz,1H),6.61(dd,J＝8.8,2.8Hz,1H),4.17–4.05(m,2H),3.99–3.86(m,2H),3.21–3.09(m, 4H), 2.71–2.58 (m, 4H), 2.36 (s, 3H), 1.74–1.52 (m, 4H); LC-MS: [M+H] + : 505.3.
实施例65.化合物DP-01-258的合成
Example 65. Synthesis of compound DP-01-258
6-(2-((2-乙氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)-5-氟嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(DP-01-258)的合成：6-(2-((2-ethoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl Synthesis of 3,3-dimethylisoindol-1-one (DP-01-258):
将6-(2-氯-5-氟嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(50.0mg,0.15mmol)、2-乙氧基-5-(4-甲基哌嗪-1-基)苯胺(45.6mg,0.19mmol)、碳酸铯(145.6mg,0.45mmol)、1,1'-联萘-2,2'-双二苯膦(18.6mg,0.03mmol)及醋酸钯(3.3mg,0.015mmol)置于1,4-二氧六环(1mL)中，氮气保护下，于100℃反应18小时。反应液冷却至室温后减压浓缩得粗品。粗品经酸性制备得到黄色固体(19.5mg)。1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.66(d,J＝3.2Hz,1H),8.18–8.15(m,2H),8.08–8.06(m,2H),7.90(d,J＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.59(dd,J＝8.8,2.8Hz,1H),4.06(q,J＝7.2Hz,2H),3.70(t,J＝7.2Hz,2H),3.07–2.99(m,6H),2.48–2.43(m,4H),2.21(s,3H),1.58(s,6H),1.34(t,J＝6.8Hz,3H)；LC-MS:[M+H]+:535.2。6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (50.0 mg, 0.15 mmol), 2-Ethoxy-5-(4-methylpiperazin-1-yl)aniline (45.6mg, 0.19mmol), cesium carbonate (145.6mg, 0.45mmol), 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine (18.6 mg, 0.03 mmol) and palladium acetate (3.3 mg, 0.015 mmol) were placed in 1,4-dioxane (1 mL), and reacted at 100°C for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain crude product. The crude product was prepared by acidification to give a yellow solid (19.5 mg). 1 H NMR (400MHz, DMSO-d6) δ8.82 (s, 1H), 8.66 (d, J = 3.2Hz, 1H), 8.18–8.15 (m, 2H), 8.08–8.06 (m, 2H), 7.90 (d,J＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.59(dd,J＝8.8,2.8Hz,1H),4.06(q,J＝7.2Hz,2H),3.70 (t,J＝7.2Hz,2H),3.07–2.99(m,6H),2.48–2.43(m,4H),2.21(s,3H),1.58(s,6H),1.34(t,J＝6.8 Hz, 3H); LC-MS: [M+H] + :535.2.
实施例66.化合物DP-01-259的合成
Example 66. Synthesis of compound DP-01-259
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮 (DP-01-259)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4-(2-hydroxyethyl methyl)-3,3-dimethylisoindol-1-one Synthesis of (DP-01-259):
将6-(2-氯-5-氟嘧啶-4-基)-4-(2-羟乙基)-3,3-二甲基异吲哚-1-酮(50.0mg,0.15mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(49.4mg,0.22mmol)、碳酸铯(145.6mg,0.45mmol)、1,1'-联萘-2,2'-双二苯膦(18.6mg,0.03mmol)及醋酸钯(3.3mg,0.015mmol)悬浮在1,4-二氧六环(1mL)中，氮气保护下于100℃反应18小时，反应液冷却后浓缩。粗产品经酸性制备得到黄色固体(21.5mg)。1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.66(d,J＝3.2Hz,1H),8.33(s,2H),8.22(s,1H),8.09(s,1H),8.07(s,1H),7.86(d,J＝2.8Hz,1H),6.94(d,J＝9.2Hz,1H),6.62(dd,J＝9.2,2.8Hz,1H),3.81(s,3H),3.70(t,J＝6.8Hz,2H),3.07–2.98(m,6H),2.49–2.40(m,4H),2.21(s,3H),1.58(s,6H)；LC-MS:[M+H]+:521.2。6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-(2-hydroxyethyl)-3,3-dimethylisoindol-1-one (50.0 mg, 0.15 mmol), 2-Methoxy-5-(4-methylpiperazin-1-yl)aniline (49.4mg, 0.22mmol), cesium carbonate (145.6mg, 0.45mmol), 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine (18.6 mg, 0.03 mmol) and palladium acetate (3.3 mg, 0.015 mmol) were suspended in 1,4-dioxane (1 mL), and reacted at 100°C for 18 hours under nitrogen protection. The reaction solution Cool and concentrate. The crude product was prepared by acidification to give a yellow solid (21.5 mg). 1 H NMR (400MHz, DMSO-d6) δ8.82 (s, 1H), 8.66 (d, J = 3.2Hz, 1H), 8.33 (s, 2H), 8.22 (s, 1H), 8.09 (s, 1H ),8.07(s,1H),7.86(d,J＝2.8Hz,1H),6.94(d,J＝9.2Hz,1H),6.62(dd,J＝9.2,2.8Hz,1H),3.81(s ,3H),3.70(t,J＝6.8Hz,2H),3.07–2.98(m,6H),2.49–2.40(m,4H),2.21(s,3H),1.58(s,6H); LC- MS:[M+H] + :521.2.
实施例67.化合物DP-01-261的合成
Example 67. Synthesis of compound DP-01-261
(1R,5S)-3-(4-甲氧基-3-硝基苯基)-8-甲基-3,8-二氮杂双环[3.2.1]辛烷(3)的合成：Synthesis of (1R,5S)-3-(4-methoxy-3-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (3):
将化合物4-溴-1-甲氧基-2-硝基苯(258.0mg,1.11mmol)溶于无水1,4-二氧六环(3mL)中，依次加入2-双环己基膦-2',6'-二甲氧基联苯(41.5mg,0.10mmol)和三(二亚苄基丙酮)二钯(92.5mg,0.10mmol)。氮气保护条件下加入叔丁醇钠(194.1mg,2.02mmol)和8-甲基-3,8-二氮杂-二环[3.2.1]辛烷盐酸盐(200.0mg,1.00mmol)，反应液升至100℃搅拌2小时。待反应完全，将反应液加水(20mL)稀释，用乙酸乙酯萃取(30mL×3)。合并有机相用无水硫酸钠干燥，过滤，浓缩至干。经硅胶柱层析(二氯甲烷:甲醇＝10:1)纯化得到棕色油状物(197.0mg)。LC-MS:[M+H]+:278.1。Compound 4-bromo-1-methoxy-2-nitrobenzene (258.0 mg, 1.11 mmol) was dissolved in anhydrous 1,4-dioxane (3 mL), and 2-bicyclohexylphosphine-2 was added successively ',6'-dimethoxybiphenyl (41.5 mg, 0.10 mmol) and tris(dibenzylideneacetone)dipalladium (92.5 mg, 0.10 mmol). Under nitrogen protection, add sodium tert-butoxide (194.1 mg, 2.02 mmol) and 8-methyl-3,8-diaza-bicyclo[3.2.1]octane hydrochloride (200.0 mg, 1.00 mmol). The reaction solution was raised to 100°C and stirred for 2 hours. When the reaction is complete, dilute the reaction solution with water (20 mL) and extract with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Purified by silica gel column chromatography (dichloromethane:methanol=10:1), a brown oily substance (197.0 mg) was obtained. LC-MS: [M+H] + :278.1.
2-甲氧基-5-((1R,5S)-8-甲基-3,8-二氮杂双环[3.2.1]辛烷-3-基)苯胺(4)的合成：Synthesis of 2-methoxy-5-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)aniline (4):
将化合物(1R,5S)-3-(4-甲氧基-3-硝基苯基)-8-甲基-3,8-二氮杂双环[3.2.1]辛烷(197.0mg,0.71mmol)溶于甲醇(5mL)中，氮气保护下加入钯碳(30.0mg,10％w/w)，并用氢气置换3次。将反应液于常温搅拌4个小时后垫硅藻土过滤，滤饼用少量甲醇洗涤两次，浓缩滤液得到棕黄色固体(160.0mg)。LC-MS:[M+H]+:248.2。Compound (1R,5S)-3-(4-methoxy-3-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (197.0 mg, 0.71 mmol) was dissolved in methanol (5 mL), palladium on carbon (30.0 mg, 10% w/w) was added under nitrogen protection, and replaced with hydrogen three times. The reaction solution was stirred at room temperature for 4 hours and then filtered through diatomaceous earth. The filter cake was washed twice with a small amount of methanol. The filtrate was concentrated to obtain a brown solid (160.0 mg). LC-MS: [M+H] + :248.2.
5'-(5-氟-2-((2-甲氧基-5-((1R,5S)-8-甲基-3,8-二氮杂双环[3.2.1]辛烷-3-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-261)的合成：5'-(5-fluoro-2-((2-methoxy-5-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane-3- Synthesis of base)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-261):
将化合物2-甲氧基-5-((1R,5S)-8-甲基-3,8-二氮杂双环[3.2.1]辛烷-3-基)苯胺(150.0mg,0.61mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚]-3'-酮(175.7mg,0.61mmol)、三(二亚苄基丙酮)二钯(55.5mg,0.06mmol)和1,1'-联萘-2,2'-双二苯膦(75.5mg,0.12mmol)置于无水1,4-二氧六环(5mL)中，氮气保护下加入碳酸铯(494.0mg,1.52mmol)，反应液升至100℃搅拌4小时。待反应完全，将反应液加水(20mL)稀释，用二氯甲烷萃取(30mL×3)。合并有机相用无水硫酸钠干燥，过滤，浓缩至干。经制备分离纯化得到黄色固体(32.6mg)。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.65(d,J＝3.2Hz,1H),8.30(s, 1H),8.23(d,J＝8.0Hz,1H),8.18(s,1H),7.85(d,J＝2.8Hz,1H),7.48(d,J＝8.0Hz,1H),6.91(d,J＝8.8Hz,1H),6.47(dd,J＝8.8,2.8Hz,1H),3.79(s,3H),3.28–3.25(m,4H),2.85(d,J＝8.8Hz,2H),2.27(s,3H),1.94(d,J＝8.8Hz,2H),1.68–1.66(m,2H),1.55(s,4H)；LC-MS:[M+H]+:501.1。Compound 2-methoxy-5-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)aniline (150.0 mg, 0.61 mmol) , 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole]-3'-one (175.7mg, 0.61mmol), tris(dibenzylidene) Acetone) dipalladium (55.5 mg, 0.06 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (75.5 mg, 0.12 mmol) were placed in anhydrous 1,4-dioxane ( 5 mL), add cesium carbonate (494.0 mg, 1.52 mmol) under nitrogen protection, and the reaction solution was raised to 100°C and stirred for 4 hours. When the reaction is complete, dilute the reaction solution with water (20 mL) and extract with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. After preparation, isolation and purification, a yellow solid (32.6 mg) was obtained. 1 H NMR (400MHz, DMSO-d6) δ8.91 (s, 1H), 8.65 (d, J = 3.2Hz, 1H), 8.30 (s, 1H),8.23(d,J＝8.0Hz,1H),8.18(s,1H),7.85(d,J＝2.8Hz,1H),7.48(d,J＝8.0Hz,1H),6.91(d, J＝8.8Hz,1H),6.47(dd,J＝8.8,2.8Hz,1H),3.79(s,3H),3.28–3.25(m,4H),2.85(d,J＝8.8Hz,2H), 2.27 (s, 3H), 1.94 (d, J = 8.8Hz, 2H), 1.68–1.66 (m, 2H), 1.55 (s, 4H); LC-MS: [M+H] + : 501.1.
实施例68.化合物DP-01-222的合成
Example 68. Synthesis of compound DP-01-222
4-(二甲基磷酰基)-6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-3-甲基-1-氧代异吲哚啉-2-羧酸叔丁酯(1)的合成：4-(dimethylphosphoryl)-6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-4- Synthesis of tert-butyl)-3-methyl-1-oxoisoindoline-2-carboxylate (1):
氮气保护下，将化合物6-(2-氯-5-氟嘧啶-4-基)-4-(二甲基磷酰基)-3-甲基-1-氧代异吲哚啉-2-羧酸叔丁酯(200.0mg,0.44mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(97.0mg,0.44mmol)、醋酸钯(9.0mg,0.04mmol)、1,1'-联萘-2,2'-双二苯膦(24.0mg,0.04mmol)、碳酸铯(429.0mg,1.32mmol)置于1,4-二氧六环(3ml)中，加热至100℃反应16小时。反应液冷却至室温后，反应液加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取。合并有机相用饱和食盐水洗涤(80mL×2)，无水硫酸钠干燥，过滤浓缩得黄色油状粗品。粗品经反向色谱柱(10％甲醇/二氯甲烷)纯化得黄色固体(120.0mg)。LC-MS:[M+H]+:639.2。Under nitrogen protection, compound 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-(dimethylphosphoryl)-3-methyl-1-oxoisoindoline-2-carboxylic Tert-butyl acid ester (200.0mg, 0.44mmol), 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (97.0mg, 0.44mmol), palladium acetate (9.0mg, 0.04mmol) , 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (24.0mg, 0.04mmol), cesium carbonate (429.0mg, 1.32mmol) were placed in 1,4-dioxane (3ml), Heat to 100°C and react for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily crude product. The crude product was purified by reverse reverse chromatography column (10% methanol/dichloromethane) to obtain a yellow solid (120.0 mg). LC-MS: [M+H] + :639.2.
4-(二甲基磷酰基)-6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-3-甲基异吲哚-1-酮(DP-01-222)的合成：4-(dimethylphosphoryl)-6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-4- Synthesis of 3-methylisoindol-1-one (DP-01-222):
将化合物4-(二甲基磷酰基)-6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-3-甲基-1-氧代异吲哚啉-2-羧酸叔丁酯(100.0mg,0.16mmol)，三氟乙酸(0.3ml)溶于二氯甲烷(1mL)中，室温下反应1小时。反应液直接浓缩后通过制备高效液相色谱纯化得到黄色固体(45.0mg)。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.68(d,J＝3.2Hz,1H),8.33–8.32(m,3H),7.74(d,J＝2.4Hz,1H),6.93(d,J＝8.8Hz,1H),6.63(dd,J＝8.8,2.4Hz,1H),5.08(q,J＝6.4Hz,1H),3.79(s,3H),3.01(s,4H),2.44(s,4H),2.20(s,3H),1.80(dd,J＝13.2,3.2Hz,6H),1.59(d,J＝6.4Hz,3H)；LC-MS:[M+H]+:539.3。Compound 4-(dimethylphosphoryl)-6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine- 4-yl)-3-Methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (100.0 mg, 0.16 mmol), trifluoroacetic acid (0.3 ml) dissolved in dichloromethane (1 mL) , react at room temperature for 1 hour. The reaction solution was directly concentrated and purified by preparative high-performance liquid chromatography to obtain a yellow solid (45.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.68(d,J＝3.2Hz,1H),8.33–8.32(m,3H),7.74(d,J＝2.4Hz,1H ),6.93(d,J＝8.8Hz,1H),6.63(dd,J＝8.8,2.4Hz,1H),5.08(q,J＝6.4Hz,1H),3.79(s,3H),3.01(s ,4H),2.44(s,4H),2.20(s,3H),1.80(dd,J＝13.2,3.2Hz,6H),1.59(d,J＝6.4Hz,3H); LC-MS:[M +H] + :539.3.
实施例69.化合物DP-01-224的合成
Example 69. Synthesis of compound DP-01-224
7-(苄硫基)-5-溴-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(1)的合成：Synthesis of tert-butyl 7-(benzylthio)-5-bromo-1,1-dimethyl-3-oxoisoindoline-2-carboxylate (1):
将5-溴-7-碘-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(500.0mg,1.07mmol)和苄硫醇(146.6mg,1.18mmol)溶于1,4-二氧六环(10mL)中，依次加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(124.1mg,0.21mmol)、三(二亚苄基丙酮)二钯(196.5mg,0.21mmol)和三乙胺(0.45mL)。在50℃下搅拌2小时。将反应液冷却至室温后浓缩至干。粗品经硅胶柱层析(0-5％甲醇/二氯甲烷)纯化得到黄色油状物(350.0mg)。LC-MS:[M-tBu+H]+:406.1。5-Bromo-7-iodo-1,1-dimethyl-3-oxoisoindoline-2-carboxylic acid tert-butyl ester (500.0mg, 1.07mmol) and benzylthiol (146.6mg, 1.18mmol) ) was dissolved in 1,4-dioxane (10 mL), and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (124.1 mg, 0.21 mmol), tris(dioxane) were added in sequence. Benzyl acetone) dipalladium (196.5 mg, 0.21 mmol) and triethylamine (0.45 mL). Stir at 50°C for 2 hours. The reaction solution was cooled to room temperature and concentrated to dryness. The crude product was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to obtain a yellow oil (350.0 mg). LC-MS: [M- tBu +H] + :406.1.
5-溴-1,1-二甲基-3-氧代-7-氨磺酰基异吲哚啉-2-羧酸叔丁酯(2)的合成：Synthesis of 5-bromo-1,1-dimethyl-3-oxo-7-sulfamoylisoindoline-2-carboxylic acid tert-butyl ester (2):
将7-(苄硫基)-5-溴-1,1-二甲基-3-氧代异吲哚啉-2-羧酸叔丁酯(350.0mg,0.76mmol)溶于乙腈(5mL)中，并加入乙酸(0.1mL)和水(0.2mL)，然后分批次加入1,3-二氯-5,5-二甲基乙内酰脲(298.2mg,1.51mmol)。反应在室温搅拌30分钟。然后将反应液慢慢滴加到25％的氨水(2mL)中，然后在室温下继续搅拌0.5小时。反应结束后用水(20mL)稀释反应液，然后用二氯甲烷(20mL×3)萃取。合并有机相，用饱和盐水洗涤，无水硫酸钠干燥，过滤浓缩。粗产物通过硅胶柱层析(0-50％的乙酸乙酯/石油醚)纯化得到黄色固体(260.0mg)。LC-MS:[M-tBu+H]+:363.2。Dissolve 7-(benzylthio)-5-bromo-1,1-dimethyl-3-oxoisoindoline-2-carboxylic acid tert-butyl ester (350.0 mg, 0.76 mmol) in acetonitrile (5 mL) , and add acetic acid (0.1 mL) and water (0.2 mL), and then add 1,3-dichloro-5,5-dimethylhydantoin (298.2 mg, 1.51 mmol) in batches. The reaction was stirred at room temperature for 30 minutes. The reaction solution was then slowly added dropwise to 25% ammonia water (2 mL), and then stirring was continued at room temperature for 0.5 hours. After the reaction, the reaction solution was diluted with water (20 mL), and then extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether) to give a yellow solid (260.0 mg). LC-MS: [M- tBu +H] + :363.2.
1,1-二甲基-3-氧代-7-氨磺酰基-5-硼酸频那醇酯异吲哚啉-2-羧酸叔丁酯(3)的合成：Synthesis of 1,1-dimethyl-3-oxo-7-sulfamoyl-5-boronic acid pinacol ester isoindoline-2-carboxylic acid tert-butyl ester (3):
将化合物5-溴-1,1-二甲基-3-氧代-7-氨磺酰基异吲哚啉-2-羧酸叔丁酯(190.0mg,0.45mmol)、联硼酸频那醇酯(138.0mg,0.54mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(33.2mg,0.046mmol)及乙酸钾(66.7mg,0.68mmol)悬浮在无水二氧六环(5mL)中，氮气保护下于90℃搅拌1小时。反应结束，向体系中加入水(10mL)，然后用乙酸乙酯(50mL×3)萃取。合并有机相后用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经硅胶柱层析(0-5％的甲醇/二氯甲烷)纯化得到灰色固体(150.0mg)。LC-MS:[M-tBu+H]+:411.1。Compound 5-bromo-1,1-dimethyl-3-oxo-7-sulfamoylisoindoline-2-carboxylic acid tert-butyl ester (190.0 mg, 0.45 mmol) and pinacol diborate (138.0mg, 0.54mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (33.2mg, 0.046mmol) and potassium acetate (66.7mg, 0.68mmol) were suspended in in water dioxane (5 mL), and stirred at 90°C for 1 hour under nitrogen protection. After the reaction was completed, water (10 mL) was added to the system, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to give a gray solid (150.0 mg). LC-MS: [M- tBu +H] + :411.1.
5-(2-氯-5-氟嘧啶-4-基)-1,1-二甲基-3-氧代-7-磺酰异吲哚啉-2-羧酸叔丁酯(4)的合成：5-(2-Chloro-5-fluoropyrimidin-4-yl)-1,1-dimethyl-3-oxo-7-sulfonylisoindoline-2-carboxylic acid tert-butyl ester (4) synthesis:
将化合物1,1-二甲基-3-氧代-7-氨磺酰基-5-硼酸频那醇酯异吲哚啉-2-羧酸叔丁酯(150.0mg,0.32mmol)、2,4-二氯-5-氟嘧啶(80.6mg,0.48mmol)、磷酸钾(204.8mg,0.97mmol)及[1,1'-双(二苯基膦基)二茂铁]二氯化钯(47.1mg,0.06mmol)悬浮在无水1,4-二氧六环(3mL)和水(0.3mL)中，氮气保护下于100℃搅拌反应1小时。反应结束后将反应液直接浓缩得粗品。粗品经硅胶柱层析(0-5％甲醇/二氯甲烷)纯化得到棕色固体(35.0mg)。LC-MS:[M-tBu+H]+:415.1。 Compound 1,1-dimethyl-3-oxo-7-sulfamoyl-5-boronic acid pinacol ester isoindoline-2-carboxylic acid tert-butyl ester (150.0 mg, 0.32 mmol), 2, 4-Dichloro-5-fluoropyrimidine (80.6mg, 0.48mmol), potassium phosphate (204.8mg, 0.97mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 47.1 mg, 0.06 mmol) was suspended in anhydrous 1,4-dioxane (3 mL) and water (0.3 mL), and the reaction was stirred at 100°C for 1 hour under nitrogen protection. After the reaction is completed, the reaction solution is directly concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to obtain a brown solid (35.0 mg). LC-MS: [M- tBu +H] + : 415.1.
5-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-1,1-二甲基-3-氧代-7-磺酰异吲哚啉-2-羧酸叔丁酯(5)的合成：5-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1,1-dimethyl Synthesis of -3-oxo-7-sulfonylisoindoline-2-carboxylic acid tert-butyl ester (5):
向5-(2-氯-5-氟嘧啶-4-基)-1,1-二甲基-3-氧代-7-磺酰异吲哚啉-2-羧酸叔丁酯(35.0mg,0.07mmol)的1,4-二氧六环(2mL)溶液中依次加入2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(22.6mg,0.10mmol)、1,1'-联萘-2,2'-双二苯膦(42.3mg,0.07mmol)、三(二亚苄基丙酮)二钯(62.2mg,0.07mmol)和碳酸铯(66.4mg,0.20mmol)，并加热至100℃搅拌1小时。将反应物冷却至室温后真空浓缩，粗产品经硅胶柱层析(0-20％的甲醇/二氯甲烷)得到黑色固体(20.0mg)。LC-MS:[M+H]+:656.2。To 5-(2-chloro-5-fluoropyrimidin-4-yl)-1,1-dimethyl-3-oxo-7-sulfonylisoindoline-2-carboxylic acid tert-butyl ester (35.0 mg ,0.07mmol) to a solution of 1,4-dioxane (2mL), 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (22.6mg, 0.10mmol), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (42.3mg, 0.07mmol), tris(dibenzylideneacetone)dipalladium (62.2mg, 0.07mmol) and cesium carbonate (66.4mg, 0.20mmol) ), and heat to 100°C and stir for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was subjected to silica gel column chromatography (0-20% methanol/dichloromethane) to obtain a black solid (20.0 mg). LC-MS: [M+H] + :656.2.
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-3,3-二甲基-1-氧代异吲哚啉-4-磺酰胺(DP-01-224)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3,3-dimethyl Synthesis of -1-oxoisoindoline-4-sulfonamide (DP-01-224):
将5-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-1,1-二甲基-3-氧代-7-磺酰异吲哚啉-2-羧酸叔丁酯(20.0mg,0.03mmol)溶解在二氯甲烷(2mL)中，然后再加入三氟乙酸(1mL)，室温下反应1小时。反应结束，将反应混合物在真空中浓缩，粗品用制备色谱纯化得到白色固体(5.0mg)。1HNMR(400MHz,DMSO-d6)δ9.13(s,1H),8.78(s,1H),8.73(d,J＝3.2Hz,1H),8.42(s,1H),8.30(s,1H),7.83(d,J＝2.9Hz,1H),6.94(d,J＝8.9Hz,1H),6.62(dd,J＝8.9,2.8Hz,1H),3.81(s,3H),3.05–3.02(m,4H),2.45–2.43(m,4H),2.20(s,3H),1.72(s,6H)；LC-MS:[M+H]+:556.3。5-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1,1-dimethyl Tert-butyl-3-oxo-7-sulfonylisoindoline-2-carboxylate (20.0 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. React at room temperature for 1 hour. At the end of the reaction, the reaction mixture was concentrated in vacuo, and the crude product was purified by preparative chromatography to obtain a white solid (5.0 mg). 1 HNMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 8.78 (s, 1H), 8.73 (d, J = 3.2Hz, 1H), 8.42 (s, 1H), 8.30 (s, 1H) ,7.83(d,J＝2.9Hz,1H),6.94(d,J＝8.9Hz,1H),6.62(dd,J＝8.9,2.8Hz,1H),3.81(s,3H),3.05–3.02( m,4H),2.45–2.43(m,4H),2.20(s,3H),1.72(s,6H); LC-MS: [M+H] + :556.3.
实施例70.化合物DP-01-228的合成
Example 70. Synthesis of compound DP-01-228
4-(二甲基磷酰基)-6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3-甲基-1-氧代异吲哚啉-2-羧酸叔丁酯(1)的合成：4-(dimethylphosphoryl)-6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino) Synthesis of tert-butyl pyrimidin-4-yl)-3-methyl-1-oxoisoindoline-2-carboxylate (1):
将化合物6-(2-氯-5-氟嘧啶-4-基)-4-(二甲基磷酰基)-3-甲基-1-氧代异吲哚啉-2-羧酸叔丁酯(200.0mg,0.44mmol)、5-(4-甲基哌嗪-1-基)-2-三氟甲氧基苯胺(146.0mg,0.53mmol)、醋酸钯(9.0mg,0.04mmol)、1,1'-联萘-2,2'-双二苯膦(25.0mg,0.04mmol)、碳酸铯(429.0mg,1.32mmol)溶于1,4-二氧六环(3ml)中，氮气保护下，升温至100℃反应3小时。反应液冷却后，通过色谱柱(0％-10％甲醇/二氯甲烷)纯化样品，得到黄色固体(130.0mg)。LC-MS:[M+H]+:693.3。Compound 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-(dimethylphosphoryl)-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (200.0mg, 0.44mmol), 5-(4-methylpiperazin-1-yl)-2-trifluoromethoxyaniline (146.0mg, 0.53mmol), palladium acetate (9.0mg, 0.04mmol), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (25.0mg, 0.04mmol) and cesium carbonate (429.0mg, 1.32mmol) were dissolved in 1,4-dioxane (3ml), protected by nitrogen Then, the temperature was raised to 100°C for 3 hours. After the reaction solution was cooled, the sample was purified through a chromatography column (0%-10% methanol/dichloromethane) to obtain a yellow solid (130.0 mg). LC-MS: [M+H] + :693.3.
4-(二甲基磷酰基)-6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3-甲基异吲哚-1-酮(DP-01-228)的合成：4-(dimethylphosphoryl)-6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino) Synthesis of pyrimidin-4-yl)-3-methylisoindol-1-one (DP-01-228):
将化合物4-(二甲基磷酰基)-6-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-3-甲基-1-氧代异吲哚啉-2-羧酸叔丁酯(100.0mg,0.14mmol)、三氟乙酸(0.3ml)溶于二氯甲烷(1ml)中后，室温反应1小时。反应液旋干后，通过制备纯化得到(42.0mg)。1H NMR(400MHz,DMSO)δ9.21(s,1H),8.90(s,1H),8.66(d,J＝3.2Hz,1H),8.31–8.28(m,2H),7.33(d,J＝2.8Hz,1H),7.21(d,J＝8.8Hz,1H), 6.78(dd,J＝8.8,2.8Hz,1H),5.06(q,J＝6.4Hz,1H),3.17–3.10(m,4H),2.46–2.40(m,4H),2.20(s,3H),1.77(dd,J＝13.2,2.0Hz,6H),1.57(d,J＝6.4Hz,3H)；LC-MS:[M+H]+:593.3。Compound 4-(dimethylphosphoryl)-6-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl) Amino)pyrimidin-4-yl)-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (100.0mg, 0.14mmol), trifluoroacetic acid (0.3ml) were dissolved in dichloromethane (1ml), react at room temperature for 1 hour. After the reaction solution was spun to dryness, the product (42.0 mg) was obtained through preparative purification. 1 H NMR (400MHz, DMSO) δ9.21 (s, 1H), 8.90 (s, 1H), 8.66 (d, J = 3.2Hz, 1H), 8.31–8.28 (m, 2H), 7.33 (d, J ＝2.8Hz,1H),7.21(d,J＝8.8Hz,1H), 6.78(dd,J＝8.8,2.8Hz,1H),5.06(q,J＝6.4Hz,1H),3.17–3.10(m,4H),2.46–2.40(m,4H),2.20(s,3H) , 1.77 (dd, J=13.2, 2.0Hz, 6H), 1.57 (d, J=6.4Hz, 3H); LC-MS: [M+H] + : 593.3.
实施例71.化合物DP-01-235的合成
Example 71. Synthesis of compound DP-01-235
1-(叔丁基)3-甲基-4-甲基哌嗪-1,3-二甲酸酯(2)的合成：Synthesis of 1-(tert-butyl)3-methyl-4-methylpiperazine-1,3-dicarboxylate (2):
将化合物1-(叔丁基)3-甲基哌嗪-1,3-二甲酸酯(1.0g,4.09mmol)、甲醛水溶液(647.4mg,8.20mmol,38％)溶于乙腈(10ml)和水(2ml)中，向反应液中缓慢加入氰基硼氢化钠(516.6mg,8.22mmol)，于室温搅拌2小时。反应液加水(100mL)稀释，用乙酸乙酯(100mL×3)萃取。合并有机相用饱和食盐水(80mL×2)洗涤，无水硫酸钠干燥，过滤浓缩得无色油状粗品。粗品经柱层析(0-10％乙酸乙酯/石油醚)纯化得到无色油状(560.0mg)。LC-MS:[M+H]+:259.3。Compound 1-(tert-butyl)3-methylpiperazine-1,3-dicarboxylate (1.0g, 4.09mmol) and formaldehyde aqueous solution (647.4mg, 8.20mmol, 38%) were dissolved in acetonitrile (10ml) and water (2 ml), slowly added sodium cyanoborohydride (516.6 mg, 8.22 mmol) to the reaction solution, and stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a colorless oily crude product. The crude product was purified by column chromatography (0-10% ethyl acetate/petroleum ether) to obtain a colorless oil (560.0 mg). LC-MS: [M+H] + :259.3.
3-(2-羟基丙-2-基)-4-甲基哌嗪-1-羧酸叔丁酯(3)的合成：Synthesis of 3-(2-hydroxyprop-2-yl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (3):
将化合物1-(叔丁基)3-甲基-4-甲基哌嗪-1,3-二甲酸酯(540.0mg,2.09mmol)溶于二氯甲烷(10mL)，反应液冷却至-65℃后缓慢滴入甲基溴化镁(4.6mL,4.60mmol,1mol/L)。滴加完毕后，反应液升至室温反应2小时。加50mL氯化铵水溶液稀释反应液，用二氯甲烷(50mL×2)萃取。合并有机相用饱和食盐水洗涤(100mL×2)，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝2:1)纯化得到无色油状(390.0mg)。1H NMR(400MHz,DMSO)δ4.26(s,1H),3.75(d,J＝11.2Hz,1H),3.60(d,J＝12.8Hz,1H),2.92(s,1H),2.80–2.74(m,1H),2.38(s,3H),2.34–2.30(m,1H),2.03(dd,J＝9.2,4.0Hz,1H),1.40(s,9H),1.09(d,J＝8.4Hz,6H)。Compound 1-(tert-butyl)3-methyl-4-methylpiperazine-1,3-dicarboxylate (540.0 mg, 2.09 mmol) was dissolved in dichloromethane (10 mL), and the reaction solution was cooled to - After 65°C, slowly add methylmagnesium bromide (4.6mL, 4.60mmol, 1mol/L) dropwise. After the dropwise addition was completed, the reaction solution was raised to room temperature and reacted for 2 hours. Add 50 mL of ammonium chloride aqueous solution to dilute the reaction solution, and extract with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain colorless oil (390.0 mg). 1 H NMR (400MHz, DMSO) δ4.26 (s, 1H), 3.75 (d, J = 11.2Hz, 1H), 3.60 (d, J = 12.8Hz, 1H), 2.92 (s, 1H), 2.80– 2.74(m,1H),2.38(s,3H),2.34–2.30(m,1H),2.03(dd,J＝9.2,4.0Hz,1H),1.40(s,9H),1.09(d,J＝ 8.4Hz, 6H).
2-(1-甲基哌嗪-2-基)丙-2-醇(4)的合成：Synthesis of 2-(1-methylpiperazin-2-yl)propan-2-ol (4):
将化合物3-(2-羟基丙-2-基)-4-甲基哌嗪-1-羧酸叔丁酯(370.0mg,1.43mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(1mL)，室温搅拌1小时后，反应液旋干。甲基叔丁基醚打浆后过滤得白色粗品(200.0mg)，直接用于下一步反应。LC-MS:[M+H]+:159.1。Compound 3-(2-hydroxyprop-2-yl)-4-methylpiperazine-1-carboxylic acid tert-butyl ester (370.0 mg, 1.43 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid was added (1 mL). After stirring at room temperature for 1 hour, the reaction solution was spun to dryness. Methyl tert-butyl ether was pulped and filtered to obtain a white crude product (200.0 mg), which was directly used in the next reaction. LC-MS: [M+H] + :159.1.
2-(4-(4-甲氧基-3-硝基苯基)-1-甲基哌嗪-2-基)丙-2-醇(5)的合成：Synthesis of 2-(4-(4-methoxy-3-nitrophenyl)-1-methylpiperazin-2-yl)propan-2-ol (5):
将化合物2-(1-甲基哌嗪-2-基)丙-2-醇(150.0mg,0.95mmol)、4-溴-1-甲氧基-2-硝基苯(263.2mg,1.13mmol)、三(二亚苄基丙酮)二钯(91.5mg,0.10mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(47.6mg,0.10mmol)、叔丁醇钠(182.4mg,1.90mmol)溶于甲苯(3mL)，于90℃反应5小时。反应液冷却后加水(30mL) 稀释，用乙酸乙酯(30mL×3)萃取。合并有机相用饱和氯化钠水溶液洗涤(50mL)，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化得到无色油状物(45.0mg)。LC-MS:[M+H]+:310.1。Compound 2-(1-methylpiperazin-2-yl)propan-2-ol (150.0mg, 0.95mmol) and 4-bromo-1-methoxy-2-nitrobenzene (263.2mg, 1.13mmol) ), tris(dibenzylideneacetone)dipalladium (91.5mg, 0.10mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (47.6mg, 0.10mmol), Sodium tert-butoxide (182.4 mg, 1.90 mmol) was dissolved in toluene (3 mL) and reacted at 90°C for 5 hours. After cooling the reaction solution, add water (30mL) Dilute and extract with ethyl acetate (30mL×3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a colorless oil (45.0 mg). LC-MS: [M+H] + :310.1.
2-(4-(3-氨基-4-甲氧基苯基)-1-甲基哌嗪-2-基)丙-2-醇(6)的合成：Synthesis of 2-(4-(3-amino-4-methoxyphenyl)-1-methylpiperazin-2-yl)propan-2-ol (6):
将化合物2-(4-(4-甲氧基-3-硝基苯基)-1-甲基哌嗪-2-基)丙-2-醇(40.0mg,0.13mmol)、铁粉(36.2mg,0.65mmol)、氯化铵(34.8mg,0.65mmol)溶于甲醇(1mL)和水(0.2mL)，80℃反应3小时，反应液冷却后，过滤后浓缩得到棕色固体(35.0mg)。LC-MS:[M+H]+:280.1。Compound 2-(4-(4-methoxy-3-nitrophenyl)-1-methylpiperazin-2-yl)propan-2-ol (40.0 mg, 0.13 mmol), iron powder (36.2 mg, 0.65mmol) and ammonium chloride (34.8mg, 0.65mmol) were dissolved in methanol (1mL) and water (0.2mL), and reacted at 80°C for 3 hours. After the reaction solution was cooled, filtered and concentrated to obtain a brown solid (35.0mg) . LC-MS: [M+H] + :280.1.
5'-(5-氟-2-((5-(3-(2-羟基丙-2-基)-4-甲基哌嗪-1-基)-2-甲氧基苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-235)的合成：5'-(5-fluoro-2-((5-(3-(2-hydroxyprop-2-yl)-4-methylpiperazin-1-yl)-2-methoxyphenyl)amino) Synthesis of pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (DP-01-235):
将化合物2-(4-(3-氨基-4-甲氧基苯基)-1-甲基哌嗪-2-基)丙-2-醇(30.0mg,0.11mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(31.8mg,0.11mmol)、三(二亚苄基丙酮)二钯(9.6mg,0.01mmol)、1,1'-联萘-2,2'-双二苯膦(6.9mg,0.011mmol)、碳酸铯(71.5mg,0.22mmol)溶于1,4-二氧六环(1mL)中，氮气保护下加热至100℃反应16小时。反应液冷却后加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取。合并有机相用饱和食盐水洗涤(80mL×2)，无水硫酸钠干燥，过滤浓缩得粗品。粗品通过制备纯化得到白色固体(14.1mg)。1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.64(d,J＝3.6Hz,1H),8.28(s,1H),8.22–8.21(m,2H),7.84(d,J＝2.8Hz,1H),7.49(d,J＝8.0Hz,1H),6.93(d,J＝8.8Hz,1H),6.55(dd,J＝8.8,2.8Hz,1H),4.29(s,1H),3.80(s,3H),3.37(s,2H),2.85(d,J＝12.0Hz,1H),2.73–2.70(m,1H),2.46(d,J＝4.8Hz,2H),2.40(s,3H),2.19(dd,J＝9.6,3.2Hz,1H),1.54(s,4H),1.10(s,3H),1.02(s,3H).LC-MS:[M+H]+:533.3。Compound 2-(4-(3-amino-4-methoxyphenyl)-1-methylpiperazin-2-yl)propan-2-ol (30.0 mg, 0.11 mmol), 5'-(2 -Chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (31.8 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (9.6mg, 0.01mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (6.9mg, 0.011mmol), cesium carbonate (71.5mg, 0.22mmol) dissolved in 1,4-dioxy Six rings (1 mL), heated to 100°C under nitrogen protection for 16 hours. After cooling, the reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified preparatively to give a white solid (14.1 mg). 1 H NMR (400MHz, DMSO-d6) δ8.89 (s, 1H), 8.64 (d, J = 3.6Hz, 1H), 8.28 (s, 1H), 8.22–8.21 (m, 2H), 7.84 (d ,J＝2.8Hz,1H),7.49(d,J＝8.0Hz,1H),6.93(d,J＝8.8Hz,1H),6.55(dd,J＝8.8,2.8Hz,1H),4.29(s ,1H),3.80(s,3H),3.37(s,2H),2.85(d,J＝12.0Hz,1H),2.73–2.70(m,1H),2.46(d,J＝4.8Hz,2H) ,2.40(s,3H),2.19(dd,J＝9.6,3.2Hz,1H),1.54(s,4H),1.10(s,3H),1.02(s,3H).LC-MS:[M+ H] + :533.3.
实施例72.化合物DP-01-240、DP-01-240A、DP-01-240B的合成
Example 72. Synthesis of compounds DP-01-240, DP-01-240A, and DP-01-240B
4-(3-溴-4-甲氧基苯基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(2)的合成：Synthesis of tert-butyl 4-(3-bromo-4-methoxyphenyl)-2-(hydroxymethyl)piperazine-1-carboxylate (2):
向2-溴-4-碘-1-甲氧基苯(4.1g,13.10mmol)的二甲基亚砜(20mL)溶液中加入2-(羟甲基)哌嗪-1-羧酸叔丁酯(3.4g,15.72mmol)、碳酸铯(5.1g,15.65mmol)、碘化亚铜(0.5g,2.63mmol)和L-脯氨酸(0.3g,2.61mmol)，在90℃氮气下搅拌1小时。反应结束后，反应液加200mL水稀释，用乙酸乙酯(200mL×3)萃取。合并有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。粗品经(石油醚/乙酸乙酯＝8:1)柱层 析纯化得到黄色油状液体(1.2g)。LC-MS:[M+H]+:401.1,403.1。To a solution of 2-bromo-4-iodo-1-methoxybenzene (4.1 g, 13.10 mmol) in dimethyl sulfoxide (20 mL) was added tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate Ester (3.4g, 15.72mmol), cesium carbonate (5.1g, 15.65mmol), copper iodide (0.5g, 2.63mmol) and L-proline (0.3g, 2.61mmol), stirred under nitrogen at 90°C 1 hour. After the reaction, the reaction solution was diluted with 200 mL of water, and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was passed through (petroleum ether/ethyl acetate=8:1) column layer After analytical purification, a yellow oily liquid (1.2g) was obtained. LC-MS: [M+H] + :401.1, 403.1.
(4-(3-溴-4-甲氧基苯基)哌嗪-2-基)甲醇(3)的合成：Synthesis of (4-(3-bromo-4-methoxyphenyl)piperazin-2-yl)methanol (3):
将4-(3-溴-4-甲氧基苯基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(1.1g,2.74mmol)溶解在二氯甲烷(20mL)中，并向溶液中加入三氟乙酸(4mL)，添加完毕，将反应液室温搅拌2小时。反应结束后将反应液直接浓缩得到油状物(815.0mg)，直接用于下一步反应。LC-MS:[M+H]+:301.1,303.1。Dissolve 4-(3-bromo-4-methoxyphenyl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.1g, 2.74mmol) in dichloromethane (20mL) , and add trifluoroacetic acid (4 mL) to the solution. After the addition is completed, the reaction solution is stirred at room temperature for 2 hours. After the reaction, the reaction solution was directly concentrated to obtain an oil (815.0 mg), which was directly used in the next reaction. LC-MS: [M+H] + :301.1, 303.1.
(4-(3-溴-4-甲氧基苯基)-1-甲基哌嗪-2-基)甲醇(4)的合成：Synthesis of (4-(3-bromo-4-methoxyphenyl)-1-methylpiperazin-2-yl)methanol (4):
将(4-(3-溴-4-甲氧基苯基)哌嗪-2-基)甲醇(330.0mg,1.10mmol)溶于水(2mL)和乙腈(5mL)，然后将38％甲醛水溶液(0.5mL)和乙酸(30.0mg,0.5mmol)加入反应液，室温搅拌1小时后加入三乙酰氧基硼氢化钠(694.9mg,3.28mmol)。然后将悬浮液搅拌3小时，用饱和碳酸氢钠水溶液(20mL)淬灭反应，用乙酸乙酯(100mL×2)萃取。有合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得粗品。粗品经硅胶柱层析(0-10％甲醇/二氯甲烷)纯化得到黄色固体(238.0mg)。LC-MS:[M+H]+:315.1,317.1。Dissolve (4-(3-bromo-4-methoxyphenyl)piperazin-2-yl)methanol (330.0 mg, 1.10 mmol) in water (2 mL) and acetonitrile (5 mL), and then add 38% formaldehyde aqueous solution (0.5 mL) and acetic acid (30.0 mg, 0.5 mmol) were added to the reaction solution, stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (694.9 mg, 3.28 mmol) was added. The suspension was then stirred for 3 hours, the reaction was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (238.0 mg). LC-MS: [M+H] + :315.1, 317.1.
(4-(3-((二苯基亚甲基)氨基)-4-甲氧基苯基)-1-甲基哌嗪-2-基)甲醇(5)的合成：Synthesis of (4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperazin-2-yl)methanol (5):
向(4-(3-溴-4-甲氧基苯基)-1-甲基哌嗪-2-基)甲醇(500.0mg,1.59mmol)的1,4-二氧六环(3mL)溶液中依次加二苯甲酮亚胺(575.0mg,3.17mmol)、1,1'-联萘-2,2'-双二苯膦(197.6mg,0.32mmol)、三(二亚苄基丙酮)二钯(290.5mg,0.32mmol)和碳酸铯(1550.5mg,4.76mmol)，并在氮气保护下加热至100℃搅拌2小时。将反应物冷却至室温后真空浓缩，粗品经硅胶柱层析(0-10％甲醇/二氯甲烷)纯化得到黄色固体(320.0mg)。LC-MS:[M+H]+:416.3。To a solution of (4-(3-bromo-4-methoxyphenyl)-1-methylpiperazin-2-yl)methanol (500.0 mg, 1.59 mmol) in 1,4-dioxane (3 mL) Add benzophenone imine (575.0mg, 3.17mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (197.6mg, 0.32mmol), and tris(dibenzylideneacetone) in sequence. Dipalladium (290.5 mg, 0.32 mmol) and cesium carbonate (1550.5 mg, 4.76 mmol) were heated to 100°C under nitrogen protection and stirred for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (320.0 mg). LC-MS: [M+H] + :416.3.
(4-(3-氨基-4-甲氧基苯基)-1-甲基哌嗪-2-基)甲醇(6)的合成：Synthesis of (4-(3-amino-4-methoxyphenyl)-1-methylpiperazin-2-yl)methanol (6):
将(4-(3-((二苯基亚甲基)氨基)-4-甲氧基苯基)-1-甲基哌嗪-2-基)甲醇(320.0mg,0.77mmol)溶解在1,4-二氧六环(3mL)中并加入2M盐酸二氧六环溶液(3mL)，将反应液在室温下搅拌1小时。反应结束后将反应液真空浓缩得到淡黄色油状物(110.0mg)，直接用于下一步反应。LC-MS:[M+H]+:252.3。Dissolve (4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperazin-2-yl)methanol (320.0 mg, 0.77 mmol) in 1 , 2M dioxane hydrochloride solution (3 mL) was added to 4-dioxane (3 mL), and the reaction solution was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated in vacuo to obtain a light yellow oil (110.0 mg), which was directly used in the next reaction. LC-MS: [M+H] + :252.3.
5'-(5-氟-2-((5-(3-(羟甲基)-4-甲基哌嗪-1-基)-2-甲氧基苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-240)的合成：5'-(5-fluoro-2-((5-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl )Synthesis of spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-240):
向(4-(3-氨基-4-甲氧基苯基)-1-甲基哌嗪-2-基)甲醇(100.0mg,0.40mmol)的1,4-二氧六环(5mL)溶液中依次加入5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(138.1mg,0.48mmol)、1,1'-联萘-2,2'-双二苯膦(49.6mg,0.08mmol)、三(二亚苄基丙酮)二钯(36.4mg,0.04mmol)和碳酸铯(388.9mg,1.19mmol)，并加热至100℃搅拌4小时。将反应物冷却至室温后真空浓缩，粗品经制备HPLC纯化得到黄色固体(22.8mg)。1HNMR(400MHz,DMSO-d6)δ8.90(s,1H),8.65(d,J＝3.6Hz,1H),8.30(s,1H),8.27–8.24(m,2H),7.88(s,1H),7.51(d,J＝8.2Hz,1H),6.95(d,J＝8.8Hz,1H),6.61(d,J＝8.8Hz,1H),4.57(s,1H),3.81(s,3H),3.62(s,1H),3.52(d,J＝10.8Hz,1H),3.42–3.38(m,1H),3.28–3.27(m,1H),2.84(s,1H),2.73(s,1H),2.49–2.42(m,1H),2.33–2.28(m,5H),1.55(s,4H)；LC-MS:[M+H]+:505.2。To a solution of (4-(3-amino-4-methoxyphenyl)-1-methylpiperazin-2-yl)methanol (100.0 mg, 0.40 mmol) in 1,4-dioxane (5 mL) 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (138.1mg, 0.48mmol), 1, 1'-binaphthyl-2,2'-bisdiphenylphosphine (49.6mg, 0.08mmol), tris(dibenzylideneacetone)dipalladium (36.4mg, 0.04mmol) and cesium carbonate (388.9mg, 1.19mmol) , and heated to 100°C and stirred for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain a yellow solid (22.8 mg). 1 HNMR(400MHz, DMSO-d6)δ8.90(s,1H),8.65(d,J＝3.6Hz,1H),8.30(s,1H),8.27–8.24(m,2H),7.88(s, 1H),7.51(d,J＝8.2Hz,1H),6.95(d,J＝8.8Hz,1H),6.61(d,J＝8.8Hz,1H),4.57(s,1H),3.81(s, 3H),3.62(s,1H),3.52(d,J＝10.8Hz,1H),3.42–3.38(m,1H),3.28–3.27(m,1H),2.84(s,1H),2.73(s ,1H),2.49–2.42(m,1H),2.33–2.28(m,5H),1.55(s,4H); LC-MS: [M+H] + :505.2.
消旋体DP-01-240经SFC分离纯化(色谱柱：CHIRALPAK AD 100*4.6mm 5μm；流动相：A相：50％n-Hexane(0.05％DEA)；B相：EtOH；梯度：B％：50％，10min)得白色固体DP-01-240A和白色固体DP-01-240B。Racemate DP-01-240 was separated and purified by SFC (chromatographic column: CHIRALPAK AD 100*4.6mm 5μm; mobile phase: phase A: 50% n-Hexane (0.05% DEA); phase B: EtOH; gradient: B% :50%, 10min) to obtain white solid DP-01-240A and white solid DP-01-240B.
DP-01-240A： DP-01-240A:
手性分析条件：色谱柱：CHIRALPAK AD 100*4.6mm 5μm，流动相：A相：50％(0.05％DEA n-Hexane)，B相：EtOH；梯度：B％：50％，保留时间为6.084分钟，ee％＝98.65％。Chiral analysis conditions: Chromatographic column: CHIRALPAK AD 100*4.6mm 5μm, mobile phase: Phase A: 50% (0.05% DEA n-Hexane), Phase B: EtOH; Gradient: B%: 50%, retention time is 6.084 minutes, ee%=98.65%.
1H NMR(400MHz,DMSO)δ8.96(s,1H),8.71(d,J＝3.5Hz,1H),8.36(s,1H),8.31–8.30(m,2H),7.93(d,J＝2.9Hz,1H),7.57(d,J＝8.0Hz,1H),7.00(d,J＝8.9Hz,1H),6.66(dd,J＝8.9,3.0Hz,1H),4.60(s,1H),3.87(s,3H),3.66(s,1H),3.57(d,J＝11.9Hz,1H),3.45–3.44(m,2H),2.86(d,J＝11.2Hz,1H),2.75(d,J＝14.0Hz,1H),2.50(s,1H),2.38(d,J＝13.2Hz,1H),2.31(s,3H),2.21(s,1H),1.61(s,4H)；LC-MS:[M+H]+:505.3。 1 H NMR (400MHz, DMSO) δ8.96 (s, 1H), 8.71 (d, J = 3.5 Hz, 1H), 8.36 (s, 1H), 8.31–8.30 (m, 2H), 7.93 (d, J ＝2.9Hz,1H),7.57(d,J＝8.0Hz,1H),7.00(d,J＝8.9Hz,1H),6.66(dd,J＝8.9,3.0Hz,1H),4.60(s,1H ),3.87(s,3H),3.66(s,1H),3.57(d,J＝11.9Hz,1H),3.45–3.44(m,2H),2.86(d,J＝11.2Hz,1H),2.75 (d,J＝14.0Hz,1H),2.50(s,1H),2.38(d,J＝13.2Hz,1H),2.31(s,3H),2.21(s,1H),1.61(s,4H) ; LC-MS: [M+H] + :505.3.
DP-01-240B：DP-01-240B：
手性分析条件：色谱柱：CHIRALPAK AD 100*4.6mm 5μm，流动相：A相：50％(0.05％DEA n-Hexane)，B相：EtOH；梯度：B％：50％，保留时间为7.531分钟，ee％＝94.29％。Chiral analysis conditions: Chromatographic column: CHIRALPAK AD 100*4.6mm 5μm, mobile phase: Phase A: 50% (0.05% DEA n-Hexane), Phase B: EtOH; Gradient: B%: 50%, retention time is 7.531 minutes, ee%=94.29%.
1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.65(d,J＝3.6Hz,1H),8.30(s,1H),8.28–8.24(m,2H),7.87(d,J＝2.7Hz,1H),7.51(d,J＝8.1Hz,1H),6.94(d,J＝8.9Hz,1H),6.60(dd,J＝8.8,2.9Hz,1H),4.53(s,1H),3.81(s,3H),3.62(d,J＝10.2Hz,1H),3.51(d,J＝11.3Hz,1H),3.41–3.36(m,2H),2.80(d,J＝11.3Hz,1H),2.70(d,J＝14.3Hz,1H),2.45(d,J＝11.2Hz,1H),2.34–2.29(m,1H),2.25(s,3H),2.15(s,1H),1.55(s,4H)；LC-MS:[M+H]+:505.2。 1 H NMR (400MHz, DMSO-d6) δ8.90 (s, 1H), 8.65 (d, J = 3.6Hz, 1H), 8.30 (s, 1H), 8.28–8.24 (m, 2H), 7.87 (d ,J＝2.7Hz,1H),7.51(d,J＝8.1Hz,1H),6.94(d,J＝8.9Hz,1H),6.60(dd,J＝8.8,2.9Hz,1H),4.53(s ,1H),3.81(s,3H),3.62(d,J＝10.2Hz,1H),3.51(d,J＝11.3Hz,1H),3.41–3.36(m,2H),2.80(d,J＝ 11.3Hz,1H),2.70(d,J＝14.3Hz,1H),2.45(d,J＝11.2Hz,1H),2.34–2.29(m,1H),2.25(s,3H),2.15(s, 1H), 1.55 (s, 4H); LC-MS: [M+H] + : 505.2.
实施例73.化合物DP-01-243的合成
Example 73. Synthesis of compound DP-01-243
4-溴-1-环丙基-2-硝基苯(2)的合成：Synthesis of 4-bromo-1-cyclopropyl-2-nitrobenzene (2):
将化合物4-溴-1-碘-2-硝基苯(2.5g,7.62mmol)、环丙基硼酸(1.0g,11.64mmol)、醋酸钯(172.9mg,0.77mmol)、三环己基膦(215.9mg,0.77mmol)、磷酸钾(4.9g,23.08mmol)溶于甲苯(30ml)和水(3ml)中，氮气保护下，升温至100℃反应3小时。反应液冷却后，反应液加水(300mL)稀释，用乙酸乙酯(300mL×2)萃取。有机相用饱和氯化钠溶液洗涤(200mL)，无水硫酸钠干燥，过滤浓缩。粗品经硅胶柱层析(0％-15％乙酸乙酯/石油醚)纯化得到黄色固体(730.0mg)。1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝2.0Hz,1H),7.78(dd,J＝8.4,2.0Hz,1H),7.20(d,J＝8.4Hz,1H),2.14(tt,J＝8.4,5.2Hz,1H),1.05–0.99(m,2H),0.79–0.71(m,2H)。Compound 4-bromo-1-iodo-2-nitrobenzene (2.5g, 7.62mmol), cyclopropylboronic acid (1.0g, 11.64mmol), palladium acetate (172.9mg, 0.77mmol), tricyclohexylphosphine ( 215.9 mg, 0.77 mmol) and potassium phosphate (4.9 g, 23.08 mmol) were dissolved in toluene (30 ml) and water (3 ml). Under nitrogen protection, the temperature was raised to 100°C and the reaction was carried out for 3 hours. After the reaction liquid was cooled, the reaction liquid was diluted with water (300 mL), and extracted with ethyl acetate (300 mL × 2). The organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0%-15% ethyl acetate/petroleum ether) to obtain a yellow solid (730.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.09 (d, J＝2.0Hz, 1H), 7.78 (dd, J＝8.4, 2.0Hz, 1H), 7.20 (d, J＝8.4Hz, 1H), 2.14(tt,J＝8.4,5.2Hz,1H),1.05–0.99(m,2H),0.79–0.71(m,2H).
1-(4-环丙基-3-硝基苯基)-4-甲基哌嗪(3)的合成：Synthesis of 1-(4-cyclopropyl-3-nitrophenyl)-4-methylpiperazine (3):
将化合物4-溴-1-环丙基-2-硝基苯(700.0mg,2.89mmol)、N-甲基哌嗪(433.0mg,4.32mmol)、三(二 亚苄基丙酮)二钯(265.0mg,0.29mmol)、2-二环己基膦-2′,6′-二甲氧基联苯(237.0mg,0.58mmol)、碳酸铯(2.8g,8.59mmol)溶于1,4-二氧六环(7ml)中，于100℃反应6小时。反应液加水(100mL)稀释，用乙酸乙酯(100mL×2)萃取。有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤浓缩。粗品通过硅胶柱层析(0-40％乙酸乙酯/石油醚)纯化得到黄色油状物(330.0mg)。LC-MS:[M+H]+:262.1。Compound 4-bromo-1-cyclopropyl-2-nitrobenzene (700.0mg, 2.89mmol), N-methylpiperazine (433.0mg, 4.32mmol), tris(di Benzylidene acetone) dipalladium (265.0mg, 0.29mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (237.0mg, 0.58mmol), cesium carbonate (2.8g, 8.59mmol) ) was dissolved in 1,4-dioxane (7 ml) and reacted at 100°C for 6 hours. The reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-40% ethyl acetate/petroleum ether) to obtain a yellow oil (330.0 mg). LC-MS: [M+H] + :262.1.
2-环丙基-5-(4-甲基哌嗪-1-基)苯胺(4)的合成：Synthesis of 2-cyclopropyl-5-(4-methylpiperazin-1-yl)aniline (4):
将化合物1-(4-环丙基-3-硝基苯基)-4-甲基哌嗪(100.0mg,0.38mmol)、铁粉(63.0mg,1.13mmol)、氯化铵(161.0mg,3.01mmol)溶于甲醇(1mL)和水(0.2mL)中，80℃反应3小时后，反应液冷却，过滤，使用甲醇泡洗超声过滤滤饼3次，合并滤液浓缩，得到黑色粗品(80.0mg)，直接用于下一步。LC-MS:[M+H]+:232.1。Compound 1-(4-cyclopropyl-3-nitrophenyl)-4-methylpiperazine (100.0mg, 0.38mmol), iron powder (63.0mg, 1.13mmol), ammonium chloride (161.0mg, 3.01 mmol) was dissolved in methanol (1 mL) and water (0.2 mL). After reacting at 80°C for 3 hours, the reaction solution was cooled and filtered. The filter cake was washed with methanol and ultrasonic filtered 3 times. The filtrate was combined and concentrated to obtain a black crude product (80.0 mg) and used directly in the next step. LC-MS: [M+H] + :232.1.
5'-(2-((2-环丙基-5-(4-甲基哌嗪-1-基)苯基)氨基)-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-243)的合成：5'-(2-((2-cyclopropyl-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1, Synthesis of 1'-isoindoline]-3'-one (DP-01-243):
将化合物2-环丙基-5-(4-甲基哌嗪-1-基)苯胺(70.0mg,0.30mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(87.0mg,0.30mmol)、三(二亚苄基丙酮)二钯(28.8mg,0.03mmol)、1,1'-联萘-2,2'-双二苯膦(37.3mg,0.06mmol)、碳酸铯(293.0mg,0.90mmol)置于1,4-二氧六环(1mL)中，氮气保护下加热至100℃反应16小时。反应液冷却后加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取。有机相用饱和食盐水(80mL×2)洗涤，无水硫酸钠干燥，过滤浓缩。粗品经制备高效液相色谱纯化得到白色固体(15.2mg)。1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.70(s,1H),8.60(d,J＝3.6Hz,1H),8.30(s,1H),8.21(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.41(s,1H),6.88(d,J＝8.4Hz,1H),6.65(d,J＝8.4Hz,1H),3.10(s,4H),2.47(s,4H),2.23(s,3H),1.94–1.86(m,1H),1.54(s,4H),0.82(d,J＝8.0Hz,2H),0.52(d,J＝4.4Hz,2H)；LC-MS:[M+H]+:485.3。Compound 2-cyclopropyl-5-(4-methylpiperazin-1-yl)aniline (70.0mg, 0.30mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[ Cyclopropane-1,1'-isoindolin]-3'-one (87.0mg, 0.30mmol), tris(dibenzylideneacetone)dipalladium (28.8mg, 0.03mmol), 1,1'- Naphthalene-2,2'-bisdiphenylphosphine (37.3 mg, 0.06 mmol) and cesium carbonate (293.0 mg, 0.90 mmol) were placed in 1,4-dioxane (1 mL), and heated to 100°C under nitrogen protection. Reaction time is 16 hours. After cooling, the reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (80 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to obtain a white solid (15.2 mg). 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.70(s,1H),8.60(d,J＝3.6Hz,1H),8.30(s,1H),8.21(d,J ＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.41(s,1H),6.88(d,J＝8.4Hz,1H),6.65(d,J＝8.4Hz,1H), 3.10(s,4H),2.47(s,4H),2.23(s,3H),1.94–1.86(m,1H),1.54(s,4H),0.82(d,J＝8.0Hz,2H),0.52 (d, J=4.4Hz, 2H); LC-MS: [M+H] + : 485.3.
实施例74.化合物DP-01-256的合成
Example 74. Synthesis of compound DP-01-256
6-溴-3-甲基-4-(甲硫基)-1-氧代异吲哚啉-2-羧酸叔丁酯(1)的合成：Synthesis of tert-butyl 6-bromo-3-methyl-4-(methylthio)-1-oxoisoindoline-2-carboxylate (1):
将化合物6-溴-4-碘-3-甲基-1-氧代异吲哚啉-2-羧酸叔丁酯(1.6g,3.54mmol)、甲硫醇钠(744.2mg,10.62mmol)、碘化亚铜(67.4mg,0.35mmol)和L-脯氨酸钠盐(98.5mg,0.72mmol)溶于二甲基亚砜(16.0mL)中。反应体系在氮气保护下于90℃搅拌3小时。待反应完全后加入水(20.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝20:1)得到黄色固体(900.0mg)。LC-MS:[M+H-Boc]+:272.9,274.9。 Compound 6-bromo-4-iodo-3-methyl-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (1.6g, 3.54mmol) and sodium methylmercaptide (744.2mg, 10.62mmol) , copper iodide (67.4 mg, 0.35 mmol) and L-proline sodium salt (98.5 mg, 0.72 mmol) were dissolved in dimethyl sulfoxide (16.0 mL). The reaction system was stirred at 90°C for 3 hours under nitrogen protection. After the reaction was complete, water (20.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (DCM:MeOH=20:1) to obtain a yellow solid (900.0 mg). LC-MS: [M+H-Boc] + :272.9, 274.9.
6-溴-3-甲基-4-(甲硫基)异吲哚啉-1-酮(2)的合成：Synthesis of 6-bromo-3-methyl-4-(methylthio)isoindolin-1-one (2):
将化合物6-溴-3-甲基-4-(甲硫基)-1-氧代异吲哚啉-2-羧酸叔丁酯(900.0mg,2.42mmol)溶于二氯甲烷(10.0mL)中，缓慢滴加三氟乙酸(1.0mL)。反应体系在室温下搅拌1小时后浓缩得到粗品。经柱层析分离纯化(DCM:MeOH＝20:1)得到黄色固体(530.0mg)。LC-MS:[M+H]+:272.0,274.0。Compound 6-bromo-3-methyl-4-(methylthio)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (900.0 mg, 2.42 mmol) was dissolved in dichloromethane (10.0 mL ), slowly add trifluoroacetic acid (1.0 mL) dropwise. The reaction system was stirred at room temperature for 1 hour and then concentrated to obtain crude product. The product was separated and purified by column chromatography (DCM:MeOH=20:1) to obtain a yellow solid (530.0 mg). LC-MS: [M+H] + :272.0, 274.0.
6-溴-3-甲基-4-(甲基磺酰基)异吲哚啉-1-酮(3)的合成：Synthesis of 6-bromo-3-methyl-4-(methylsulfonyl)isoindolin-1-one (3):
将化合物6-溴-3-甲基-4-(甲硫基)异吲哚啉-1-酮(528.0mg,1.94mmol)、过氧硫酸氢钾复合盐(3.58g,10.34mmol)溶于四氢呋喃(5mL)和水(5mL)中，反应体系于室温搅拌12小时。待反应完全后加水(20.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝20:1)纯化得到黄色固体(300.0mg)。LC-MS:[M+H]+:303.9,305.9。Compound 6-bromo-3-methyl-4-(methylthio)isoindolin-1-one (528.0 mg, 1.94 mmol) and potassium peroxyhydrogen sulfate complex salt (3.58 g, 10.34 mmol) were dissolved in The reaction system was stirred in tetrahydrofuran (5 mL) and water (5 mL) at room temperature for 12 hours. After the reaction is complete, add water (20.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Purified by column chromatography (DCM:MeOH=20:1) to obtain a yellow solid (300.0 mg). LC-MS: [M+H] + :303.9, 305.9.
(1-甲基-7-(甲基磺酰基)-3-氧代异吲哚啉-5-基)硼酸(4)的合成：Synthesis of (1-methyl-7-(methylsulfonyl)-3-oxoisoindolin-5-yl)boronic acid (4):
将化合物6-溴-3-甲基-4-(甲基磺酰基)异吲哚啉-1-酮(300.0mg,0.99mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(72.0mg,0.10mmol)、联硼酸频那醇酯(325.2mg,1.28mmol)、醋酸钾(289.8mg,2.95mmol)置于1,4-二氧六环(3.0mL)中。反应体系在氮气保护下于80℃搅拌1小时。待反应完全，反应液真空浓缩得到黑色固体(266.4mg)，直接用于下一步反应。LC-MS:[M+H]+:270.1。Compound 6-bromo-3-methyl-4-(methylsulfonyl)isoindolin-1-one (300.0mg, 0.99mmol), [1,1'-bis(diphenylphosphine)diocene Iron] palladium dichloride (72.0mg, 0.10mmol), pinacol diborate (325.2mg, 1.28mmol), potassium acetate (289.8mg, 2.95mmol) were placed in 1,4-dioxane (3.0mL )middle. The reaction system was stirred at 80°C for 1 hour under nitrogen protection. When the reaction was complete, the reaction solution was concentrated in vacuum to obtain a black solid (266.4 mg), which was directly used in the next reaction. LC-MS: [M+H] + :270.1.
6-(2-氯-5-氟嘧啶-4-基)-3-甲基-4-(甲基磺酰基)异吲哚啉-1-酮(5)的合成：Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-4-(methylsulfonyl)isoindolin-1-one (5):
将(1-甲基-7-(甲基磺酰基)-3-氧代异吲哚啉-5-基)硼酸(266.4mg,0.99mmol)、2,4-二氯-5-氟嘧啶(197.4mg,1.18mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(72.0mg,0.10mmol)、磷酸钾(626.4mg,2.95mmol)溶于1,4-二氧六环和水的混合溶液中(3.3mL,1,4-二氧六环:水＝10:1)。反应体系在氮气保护下于90℃搅拌2小时。待反应完全后加水(10.0mL)淬灭反应，用乙酸乙酯萃取(10mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离(DCM:MeOH＝10:1)得到黄色固体(280.0mg)。LC-MS:[M+H]+:356.1,358.0。(1-Methyl-7-(methylsulfonyl)-3-oxoisoindolin-5-yl)boronic acid (266.4 mg, 0.99 mmol), 2,4-dichloro-5-fluoropyrimidine ( 197.4mg, 1.18mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (72.0mg, 0.10mmol), potassium phosphate (626.4mg, 2.95mmol) were dissolved in In a mixed solution of 1,4-dioxane and water (3.3 mL, 1,4-dioxane:water=10:1). The reaction system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction is complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separate by column chromatography (DCM:MeOH=10:1) to obtain a yellow solid (280.0 mg). LC-MS: [M+H] + :356.1, 358.0.
6-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-3-羟基-3-甲基-4-(甲基磺酰基)异吲哚啉-1-酮(DP-01-256)的合成：6-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-3-hydroxy-3-methyl Synthesis of base-4-(methylsulfonyl)isoindolin-1-one (DP-01-256):
将2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(34.2mg,0.15mmol)、6-(2-氯-5-氟嘧啶-4-基)-3-甲基-4-(甲基磺酰基)异吲哚啉-1-酮(50.0mg,0.14mmol)、三(二亚苄基丙酮)二钯(12.9mg,0.014mmol)、1,1'-联萘-2,2'-双二苯膦(17.6mg,0.028mmol)、碳酸铯(91.9mg,0.28mmol)置于1,4-二氧六环中(1.0mL)。反应体系在氮气保护下于90℃搅拌2小时。待反应完全后加水(10.0mL)淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得到粗品。经制备分离得到黄色固体(14.0mg)。1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.86(s,1H),8.48(d,J＝2.8Hz,1H),8.24(d,J＝2.4Hz,1H),7.90(s,1H),6.84(d,J＝8.8Hz,1H),6.58(dd,J＝8.8,2.8Hz,1H),3.91(s,3H),3.33(s,3H),3.26–3.16(m,4H),2.69–2.56(m,4H),2.28(s,3H),2.13(s,3H)；LC-MS:[M+H]+:557.1。2-Methoxy-5-(4-methylpiperazin-1-yl)aniline (34.2mg, 0.15mmol), 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl 4-(methylsulfonyl)isoindolin-1-one (50.0mg, 0.14mmol), tris(dibenzylideneacetone)dipalladium (12.9mg, 0.014mmol), 1,1'- Naphthalene-2,2'-bisdiphenylphosphine (17.6 mg, 0.028 mmol) and cesium carbonate (91.9 mg, 0.28 mmol) were placed in 1,4-dioxane (1.0 mL). The reaction system was stirred at 90°C for 2 hours under nitrogen protection. After the reaction was complete, add water (10.0 mL) to quench the reaction, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. A yellow solid (14.0 mg) was isolated after preparation. 1 H NMR (400MHz, CDCl 3 ) δ8.90 (s, 1H), 8.86 (s, 1H), 8.48 (d, J = 2.8Hz, 1H), 8.24 (d, J = 2.4Hz, 1H), 7.90 (s,1H),6.84(d,J＝8.8Hz,1H),6.58(dd,J＝8.8,2.8Hz,1H),3.91(s,3H),3.33(s,3H),3.26–3.16( m,4H),2.69–2.56(m,4H),2.28(s,3H),2.13(s,3H); LC-MS: [M+H] + :557.1.
实施例75.化合物DP-01-267的合成
Example 75. Synthesis of compound DP-01-267
5-乙酰基-2-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(2)的合成：5-acetyl-2-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-6, Synthesis of 6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (2):
氮气保护下，将化合物2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(214.9mg,0.97mmol)、5-乙酰基-2-(2-氯-5-氟嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(300.0mg,0.88mmol)、三(二亚苄基丙酮)二钯(80.9mg,0.088mmol)、1,1'-联萘-2,2'-双二苯膦(110.0mg,0.18mmol)、碳酸铯(575.4mg,1.77mmol)置于1,4-二氧六环(3.0mL)中，加热至100℃反应2小时。待反应完全，将反应冷却至室温。反应液加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)。合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤。有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。经柱层析分离纯化(二氯甲烷:甲醇＝10:1)得到黄色固体(65.4mg)。LC-MS:[M+H]+:525.1。Under nitrogen protection, the compounds 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (214.9mg, 0.97mmol) and 5-acetyl-2-(2-chloro-5-fluoro Pyrimidin-4-yl)-6,6-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (300.0mg, 0.88mmol), tris(dimethyl) Benzyl acetone) dipalladium (80.9 mg, 0.088 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (110.0 mg, 0.18 mmol), and cesium carbonate (575.4 mg, 1.77 mmol) were placed 1,4-dioxane (3.0 mL), heated to 100°C and reacted for 2 hours. When the reaction is complete, cool the reaction to room temperature. The reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. Separation and purification by column chromatography (dichloromethane:methanol=10:1) gave a yellow solid (65.4 mg). LC-MS: [M+H] + :525.1.
2-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(DP-01-267)的合成：2-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-6,6-dimethyl Synthesis of -5,6-dihydro-4H-thieno[2,3-c]pyrrole-4-one (DP-01-267):
将化合物5-乙酰基-2-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-6,6-二甲基-5,6-二氢-4H-噻吩并[2,3-c]吡咯-4-酮(50.0mg,0.095mmol)，氢氧化钠(11.4mg,0.28mmol)溶于四氢呋喃(1.0mL)与水(1.0mL)的混合溶液中，室温搅拌反应2小时。待反应完全，反应液加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)。合并有机相依次用水(10mL)和饱和氯化钠水溶液(10mL)洗涤。有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经制备分离得黄色固体(8.0mg)。1H NMR(400MHz,DMSO-d6)δ8.38(dd,J＝4.8,2.8Hz,2H),8.01(d,J＝1.2Hz,1H),7.87(s,1H),6.84(d,J＝8.8Hz,1H),6.58(dd,J＝8.8,2.8Hz,1H),6.23(s,1H),3.90(s,3H),3.36–3.22(m,4H),2.71–2.63(m,4H),2.40(s,3H),1.70(s,6H)；LCMS:[M+H]+:483.0。Compound 5-acetyl-2-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)- 6,6-Dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (50.0mg, 0.095mmol), dissolved in sodium hydroxide (11.4mg, 0.28mmol) The mixture was stirred in a mixed solution of tetrahydrofuran (1.0 mL) and water (1.0 mL) at room temperature for 2 hours. When the reaction is complete, the reaction solution is diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was prepared and isolated to obtain a yellow solid (8.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.38(dd,J＝4.8,2.8Hz,2H),8.01(d,J＝1.2Hz,1H),7.87(s,1H),6.84(d,J ＝8.8Hz,1H),6.58(dd,J＝8.8,2.8Hz,1H),6.23(s,1H),3.90(s,3H),3.36–3.22(m,4H),2.71–2.63(m, 4H), 2.40 (s, 3H), 1.70 (s, 6H); LCMS: [M+H] + : 483.0.
实施例76.化合物DP-01-269的合成
Example 76. Synthesis of compound DP-01-269
5'-(2,5-二氯嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(1)的合成：Synthesis of 5'-(2,5-dichloropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (1):
将化合物5'-硼酸频那醇酯螺环[1,1'-异吲哚]-3'-酮(200.0mg,0.70mmol)、碳酸铯(455.0mg,1.40 mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(56.7mg,0.07mmol)、2,4,5-三氯嘧啶(127.0mg,0.69mmol)溶于1,4-二氧六环和水(10mL,5:1)中，氮气保护下于100℃搅拌6小时。反应液冷却至室温，倒入水(20mL)中，用乙酸乙酯(15mL×3)萃取。有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、浓缩后经硅胶柱层析(乙酸乙酯:石油醚＝2:1)纯化得到黄色固体(150.0mg)。LC-MS:[M+H]+:306.2,308.1。The compound 5'-pinacol borate spiro[1,1'-isoindole]-3'-one (200.0mg, 0.70mmol) and cesium carbonate (455.0mg, 1.40 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (56.7mg, 0.07mmol), 2,4,5-trichloropyrimidine (127.0mg ,0.69mmol) was dissolved in 1,4-dioxane and water (10mL, 5:1), and stirred at 100°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1) to obtain a yellow solid (150.0 mg). LC-MS: [M+H] + :306.2, 308.1.
5'-(5-氯-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-269)的合成：5'-(5-chloro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1, Synthesis of 1'-isoindoline]-3'-one (DP-01-269):
将化合物5'-(2,5-二氯嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(150.0mg,0.49mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(109.0mg,0.49mmol)、碳酸铯(478.0mg,1.47mmol)、三(二亚苄基丙酮)二钯(47.4mg,0.052mmol)、1,1'-联萘-2,2'-双二苯膦(64.5mg,0.10mmol)溶于甲苯(10mL)中，氮气保护下于100℃搅拌6小时。反应液冷却至室温，倒入水(20mL)中，用乙酸乙酯(15mL×3)萃取。合并有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、浓缩后经硅胶柱层析(二氯甲烷:甲醇＝10:1)得到粗品。粗品经制备纯化得白色固体(28.5mg)。1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.62(s,1H),8.37(s,1H),8.11(d,J＝1.0Hz,1H),8.03(dd,J＝8.0,1.6Hz,1H),7.84(d,J＝2.2Hz,1H),7.45(d,J＝8.1Hz,1H),6.92(d,J＝8.9Hz,1H),6.60(dd,J＝8.9,2.9Hz,1H),3.79(s,3H),3.01–2.98(m,4H),2.43–2.41(m,4H),2.20(s,3H),1.53(d,J＝2.1Hz,4H).LC-MS:[M+H]+:491.5。Compound 5'-(2,5-dichloropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (150.0 mg, 0.49 mmol), 2-methoxy 5-(4-methylpiperazin-1-yl)aniline (109.0mg, 0.49mmol), cesium carbonate (478.0mg, 1.47mmol), tris(dibenzylideneacetone)dipalladium (47.4mg, 0.052 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (64.5 mg, 0.10 mmol) were dissolved in toluene (10 mL), and stirred at 100°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the crude product. The crude product was preparatively purified to obtain a white solid (28.5 mg). 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.62(s,1H),8.37(s,1H),8.11(d,J＝1.0Hz,1H),8.03(dd,J ＝8.0,1.6Hz,1H),7.84(d,J＝2.2Hz,1H),7.45(d,J＝8.1Hz,1H),6.92(d,J＝8.9Hz,1H),6.60(dd,J ＝8.9,2.9Hz,1H),3.79(s,3H),3.01–2.98(m,4H),2.43–2.41(m,4H),2.20(s,3H),1.53(d,J＝2.1Hz, 4H).LC-MS: [M+H] + :491.5.
实施例77.化合物DP-01-245的合成
Example 77. Synthesis of compound DP-01-245
5-氯-2-(氯甲基)烟酸甲酯(2)的合成：Synthesis of 5-chloro-2-(chloromethyl)nicotinic acid methyl ester (2):
将化合物5-氯-2-甲基烟酸甲酯(3.1g,16.70mmol)、三氯异氰尿酸(11.6g,49.91mmol)、苯甲酰胺(0.2g,1.65mmol)溶于三氯甲烷中(50mL)，65℃条件下搅拌40小时。向反应液中加入50mL饱和碳酸钠溶液并搅拌20分钟，用二氯甲烷(20mL×3)萃取。合并有机相并用无水硫酸钠干燥，过滤浓缩后经柱层析(石油醚:乙酸乙酯＝150:1～80:1)纯化得到无色油状物(2.1g)。LCMS:[M+H]+:220.0,222.0。Dissolve the compounds 5-chloro-2-methylnicotinic acid methyl ester (3.1g, 16.70mmol), trichloroisocyanuric acid (11.6g, 49.91mmol), and benzamide (0.2g, 1.65mmol) in chloroform (50 mL) and stirred at 65°C for 40 hours. 50 mL of saturated sodium carbonate solution was added to the reaction solution, stirred for 20 minutes, and extracted with dichloromethane (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 150:1 to 80:1) to obtain a colorless oil (2.1g). LCMS: [M+H] + :220.0,222.0.
3-氯-6-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(3)的合成：Synthesis of 3-chloro-6-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (3):
将化合物5-氯-2-(氯甲基)烟酸甲酯(2.0g,9.09mmol)、4-甲氧基苄胺(1.5g,10.93mmol)溶于乙腈中(10mL)，缓慢滴加N,N-二异丙基乙胺(2.35g,18.18mmol)，室温条件下搅拌16小时。反应液加水(20mL) 稀释，用二氯甲烷(20mL×3)萃取。合并有机相并用无水硫酸钠干燥，过滤浓缩。粗品经柱层析(石油醚:乙酸乙酯＝4:1～2:1)纯化得到白色固体化合物(1.2g)。1H NMR(400MHz,DMSO)δ8.79(d,J＝2.4Hz,1H),8.24(d,J＝2.0Hz,1H),7.25(d,J＝8.8Hz,2H),6.91(d,J＝8.4Hz,2H),4.68(s,2H),4.40(s,2H),3.73(s,3H)。Dissolve the compounds 5-chloro-2-(chloromethyl)nicotinic acid methyl ester (2.0g, 9.09mmol) and 4-methoxybenzylamine (1.5g, 10.93mmol) in acetonitrile (10mL), and slowly add dropwise N,N-diisopropylethylamine (2.35g, 18.18mmol), stirred at room temperature for 16 hours. Add water (20mL) to the reaction solution Dilute and extract with dichloromethane (20mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=4:1~2:1) to obtain a white solid compound (1.2g). 1 H NMR (400MHz, DMSO) δ8.79 (d, J = 2.4Hz, 1H), 8.24 (d, J = 2.0Hz, 1H), 7.25 (d, J = 8.8Hz, 2H), 6.91 (d, J＝8.4Hz,2H),4.68(s,2H),4.40(s,2H),3.73(s,3H).
3-氯-6-(4-甲氧基苄基)-7,7-二甲基-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(4)的合成：3-Chloro-6-(4-methoxybenzyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (4) Synthesis:
将化合物3-氯-6-(4-甲氧基苄基)-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(1.2g,4.16mmol)溶于无水四氢呋喃中(20mL)，0℃条件下缓慢滴加双三甲基硅基胺基锂(16.6mL,16.6mmol,1mol/L)并于室温搅拌1小时，缓慢滴加碘甲烷(2.36g,16.63mmol)继续搅拌反应1小时。加10mL饱和氯化铵淬灭反应，用乙酸乙酯(15mL×3)萃取。合并有机相并用无水硫酸钠干燥，过滤浓缩。粗品经柱层析(石油醚:乙酸乙酯＝100:1～30:1)纯化得到白色固体化合物(580.0mg)。LCMS:[M+H]+:317.1,319.1。Compound 3-chloro-6-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (1.2g, 4.16mmol) was dissolved in In anhydrous tetrahydrofuran (20mL), slowly add lithium bistrimethylsilylamide (16.6mL, 16.6mmol, 1mol/L) at 0°C and stir at room temperature for 1 hour. Add methyl iodide (2.36g) slowly. ,16.63mmol) and continue stirring for 1 hour. Add 10 mL saturated ammonium chloride to quench the reaction, and extract with ethyl acetate (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:1 ~ 30:1) to obtain a white solid compound (580.0 mg). LCMS: [M+H] + :317.1,319.1.
(6-(4-甲氧基苄基)-7,7-二甲基-5-氧代-6,7-二氢-5H-吡咯并[3,4-b]吡啶-3-基)硼酸(5)的合成：(6-(4-methoxybenzyl)-7,7-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl) Synthesis of boric acid (5):
将化合物3-氯-6-(4-甲氧基苄基)-7,7-二甲基-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(580.0mg,1.83mmol)、联硼酸频那醇酯(781.6mg,3.08mmol)、2-双环己基膦-2',4',6'-三异丙基联苯(195.6mg,0.41mmol)、甲磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(173.7mg,0.21mmol)、醋酸钾(604.1mg,6.16mmol)溶于二氧六环中(10mL)，80℃氮气保护下反应5小时。反应液冷却后加水(10mL)稀释，用乙酸乙酯(15mL×3)萃取。合并有机相并用无水硫酸钠干燥，过滤浓缩得到黑色粗品(350.0mg)，直接用于下一步反应。LCMS:[M+H]+:327.1。Compound 3-chloro-6-(4-methoxybenzyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one ( 580.0mg, 1.83mmol), pinacol diborate (781.6mg, 3.08mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (195.6mg, 0.41mmol), Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2 -Palladium (II) (173.7 mg, 0.21 mmol) and potassium acetate (604.1 mg, 6.16 mmol) were dissolved in dioxane (10 mL) and reacted at 80°C under nitrogen protection for 5 hours. After cooling, the reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a black crude product (350.0 mg), which was directly used in the next reaction. LCMS:[M+H] + :327.1.
3-(2-氯-5-氟嘧啶-4-基)-6-(4-甲氧基苄基)-7,7-二甲基-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(6)的合成：3-(2-Chloro-5-fluoropyrimidin-4-yl)-6-(4-methoxybenzyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3 ,Synthesis of 4-b]pyridin-5-one (6):
将化合物(6-(4-甲氧基苄基)-7,7-二甲基-5-氧代-6,7-二氢-5H-吡咯并[3,4-b]吡啶-3-基)硼酸(350.0mg,1.07mmol)、2,4-二氯-5-氟嘧啶(268.8mg,1.61mmol)、磷酸钾(683.3mg,3.22mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(78.5mg,0.11mmol)溶于二氧六环(8mL)和水(2mL)中。80℃氮气保护下反应5小时。反应液加水(10mL)稀释，用乙酸乙酯(10mL×3)萃取。合并有机相并用无水硫酸钠干燥，过滤浓缩所得粗品经柱层析(石油醚:乙酸乙酯＝5:1～3:1)纯化得到白色固体(250.0mg)。LCMS:[M+H]+:413.1,415.1。Compound (6-(4-methoxybenzyl)-7,7-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3- (350.0mg, 1.07mmol), 2,4-dichloro-5-fluoropyrimidine (268.8mg, 1.61mmol), potassium phosphate (683.3mg, 3.22mmol), [1,1'-bis(diphenyl) Phosphoferrocene]palladium(II) dichloride (78.5 mg, 0.11 mmol) was dissolved in dioxane (8 mL) and water (2 mL). React under nitrogen protection at 80°C for 5 hours. The reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain a white solid (250.0 mg). LCMS: [M+H] + :413.1,415.1.
3-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-6-(4-甲氧基苄基)-7,7-二甲基-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(7)的合成：3-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-6-(4-methoxy Synthesis of (benzyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (7):
将化合物3-(2-氯-5-氟嘧啶-4-基)-6-(4-甲氧基苄基)-7,7-二甲基-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(250.0mg,0.61mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(147.5mg,0.67mmol)、1,1'-联萘-2,2'-双二苯膦(75.9mg,0.12mmol)、三(二亚苄基丙酮)二钯(55.9mg,0.061mmol)、碳酸铯(589.3mg,1.81mmol)溶于二氧六环中，并于100℃氮气保护下反应5小时。反应液加水(10mL)稀释，用乙酸乙酯(10mL×3)萃取。合并有机相并用无水硫酸钠干燥，过滤浓缩后经柱层析(二氯甲烷:甲醇＝100:1～40:1)纯化得到白色固体(240.0mg)。LCMS:[M+H]+:598.4。Compound 3-(2-chloro-5-fluoropyrimidin-4-yl)-6-(4-methoxybenzyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one (250.0mg, 0.61mmol), 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (147.5mg, 0.67mmol), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (75.9mg, 0.12mmol), tris(dibenzylideneacetone)dipalladium (55.9mg, 0.061mmol), cesium carbonate (589.3mg, 1.81mmol) ) was dissolved in dioxane and reacted at 100°C under nitrogen protection for 5 hours. The reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (dichloromethane:methanol=100:1~40:1) to obtain a white solid (240.0 mg). LCMS: [M+H] + :598.4.
3-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-7,7-二甲基-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(DP-01-245)的合成：3-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-7,7-dimethyl Synthesis of -6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (DP-01-245):
将化合物3-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-6-(4-甲氧基苄基)-7,7-二甲 基-6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮(240.0mg,0.40mmol)溶于三氟乙酸(3mL)和三氟甲磺酸(1mL)中，60℃条件下反应2.5小时。反应完全溶液浓缩，加10mL水并用氨水调节溶液的pH值为碱性。用二氯甲烷(15mL×3)萃取,合并有机相并用无水硫酸钠干燥，过滤浓缩。粗品经制备纯化得到黄色固体化合物(40.2mg)。1H NMR(400MHz,DMSO)δ9.31(s,1H),9.07(s,1H),8.70(d,J＝3.2Hz,1H),8.50(s,1H),8.32(s,1H),7.86(d,J＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.60(dd,J＝9.2,3.2Hz,1H),3.79(s,3H),3.07–3.00(m,4H),2.46–2.41(m,4H),2.20(s,3H),1.51(s,6H).LCMS:[M+H]+:478.2。Compound 3-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-6-(4- Methoxybenzyl)-7,7-dimethyl Benzyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (240.0 mg, 0.40 mmol) was dissolved in trifluoroacetic acid (3 mL) and trifluoromethanesulfonic acid (1 mL) , reacted at 60°C for 2.5 hours. After the reaction is complete, the solution is concentrated, 10 mL of water is added and ammonia is used to adjust the pH value of the solution to alkaline. Extract with dichloromethane (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The crude product was preparatively purified to obtain a yellow solid compound (40.2 mg). 1 H NMR (400MHz, DMSO) δ9.31 (s, 1H), 9.07 (s, 1H), 8.70 (d, J = 3.2Hz, 1H), 8.50 (s, 1H), 8.32 (s, 1H), 7.86(d,J＝2.8Hz,1H),6.93(d,J＝8.8Hz,1H),6.60(dd,J＝9.2,3.2Hz,1H),3.79(s,3H),3.07–3.00(m ,4H),2.46–2.41(m,4H),2.20(s,3H),1.51(s,6H).LCMS:[M+H] + :478.2.
实施例78.化合物DP-01-246的合成
Example 78. Synthesis of compound DP-01-246
3-(溴甲基)-6-氯吡啶甲酸甲酯(2)的合成：Synthesis of methyl 3-(bromomethyl)-6-chloropicolinate (2):
将6-氯-3-甲基吡啶甲酸甲酯(2.9g,15.62mmol)溶解在四氯化碳(50mL)中，并在氮气保护下加入偶氮二异丁腈(257.5mg,1.57mmol)和N-溴代丁二酰亚胺(2.8g,15.73mmol)。反应于80℃搅拌16小时，反应结束后将反应液减压浓缩，粗品经(石油醚/乙酸乙酯＝8:1)柱层析纯化得到白色固体(2.2g)。LC-MS:[M+H]+:264.1,266.1。Dissolve 6-chloro-3-methylpicolinate methyl ester (2.9g, 15.62mmol) in carbon tetrachloride (50mL), and add azobisisobutyronitrile (257.5mg, 1.57mmol) under nitrogen protection. and N-bromosuccinimide (2.8g, 15.73mmol). The reaction was stirred at 80°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The crude product was purified by (petroleum ether/ethyl acetate = 8:1) column chromatography to obtain a white solid (2.2g). LC-MS: [M+H] + :264.1, 266.1.
2-氯-6-(4-甲氧基苄基)-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(3)的合成：Synthesis of 2-chloro-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (3):
将3-(溴甲基)-6-氯吡啶甲酸甲酯(2.2g,8.32mmol)和(4-甲氧基苯基)甲胺(1.4g,10.20mmol)溶解在四氢呋喃(30mL)中，缓慢加入N,N-二异丙基乙胺(1.6g,12.38mmol后在室温搅拌6小时。用饱和氯化铵水溶液(100mL)淬灭反应，用乙酸乙酯(200mL×2)萃取。合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝2:1)纯化得到白色固体(1.8g)。LC-MS:[M+H]+:289.1,291.1。Dissolve 3-(bromomethyl)-6-chloropicolinate methyl ester (2.2g, 8.32mmol) and (4-methoxyphenyl)methanamine (1.4g, 10.20mmol) in tetrahydrofuran (30mL). N,N-diisopropylethylamine (1.6g, 12.38mmol) was slowly added and stirred at room temperature for 6 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100mL), and extracted with ethyl acetate (200mL×2). Combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain a white solid (1.8g). LC-MS: [ M+H] + :289.1,291.1.
2-氯-6-(4-甲氧基苄基)-5,5-二甲基-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(4)的合成：2-Chloro-6-(4-methoxybenzyl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (4) Synthesis:
将2-氯-6-(4-甲氧基苄基)-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(1.8g,6.23mmol)、氢化钠(550.0mg,13.75mmol,60％w/w)加入四氢呋喃(50mL)中，室温搅拌1小时，再加入碘甲烷(2.0g,14.09mmol)，继续在室温下搅拌1小时。反应液加水(100mL)稀释，用乙酸乙酯(150mL×2)萃取。合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩得到粗产物。粗品经柱层析纯化(石油醚/乙酸乙酯＝1:1)得到白色固体(1.2g)。LC-MS:[M+H]+:317.1。Combine 2-chloro-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (1.8g, 6.23mmol), sodium hydride (550.0 mg, 13.75 mmol, 60% w/w) was added to tetrahydrofuran (50 mL), stirred at room temperature for 1 hour, then methyl iodide (2.0 g, 14.09 mmol) was added, and stirring continued at room temperature for 1 hour. The reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 1:1) to obtain a white solid (1.2g). LC-MS: [M+H] + :317.1.
6-(4-甲氧基苄基)-5,5-二甲基-2-(三甲基锡基)-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(5)的合成： 6-(4-methoxybenzyl)-5,5-dimethyl-2-(trimethyltinyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine- Synthesis of 7-keto(5):
将2-氯-6-(4-甲氧基苄基)-5,5-二甲基-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(310.0mg,0.98mmol)、四(三苯基膦)钯(116.0mg,0.10mmol)和六甲基二锡(490.0mg,1.50mmol)溶解在1,4-二氧六环(10mL)中，并在氮气保护下加热至100℃搅拌2小时。反应结束后将反应液减压浓缩，粗品经柱层析(石油醚/乙酸乙酯＝1:1)纯化得到灰色固体(360.0mg)。LC-MS:[M+H]+:447.1。2-Chloro-6-(4-methoxybenzyl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (310.0 mg, 0.98mmol), tetrakis(triphenylphosphine)palladium (116.0mg, 0.10mmol) and hexamethyldisin (490.0mg, 1.50mmol) were dissolved in 1,4-dioxane (10mL), and Heat to 100°C under nitrogen protection and stir for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate = 1:1) to obtain a gray solid (360.0 mg). LC-MS: [M+H] + :447.1.
2-(2-氯-5-氟嘧啶-4-基)-6-(4-甲氧基苄基)-5,5-二甲基-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(6)的合成：2-(2-Chloro-5-fluoropyrimidin-4-yl)-6-(4-methoxybenzyl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3 ,Synthesis of 4-b]pyridin-7-one (6):
向6-(4-甲氧基苄基)-5,5-二甲基-2-(三甲基锡基)-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(360.0mg,0.81mmol)的1,4-二氧六环(5mL)溶液中依次加碘化亚铜(30.4mg,0.16mmol)、2,4-二氯-5-氟嘧啶(203.7mg,1.22mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(117.1mg,0.16mmol)，并在氮气保护下加热至100℃搅拌2小时。将反应物冷却至室温后减压浓缩，粗品经硅胶柱层析(0-10％的甲醇/二氯甲烷)纯化得到黄色固体(280.0mg)。LC-MS:[M+H]+:413.2,415.2。To 6-(4-methoxybenzyl)-5,5-dimethyl-2-(trimethyltinyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine To a solution of -7-one (360.0 mg, 0.81 mmol) in 1,4-dioxane (5 mL), copper iodide (30.4 mg, 0.16 mmol) and 2,4-dichloro-5-fluoropyrimidine were added successively (203.7 mg, 1.22 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (117.1 mg, 0.16 mmol), and heated to 100°C under nitrogen protection and stirred for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain a yellow solid (280.0 mg). LC-MS: [M+H] + :413.2, 415.2.
2-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-6-(4-甲氧基苄基)-5,5-二甲基-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(7)的合成：2-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-6-(4-methoxy Synthesis of (benzyl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (7):
向2-(2-氯-5-氟嘧啶-4-基)-6-(4-甲氧基苄基)-5,5-二甲基-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(260.0mg,0.63mmol)的1,4-二氧六环(10mL)溶液中依次加入2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(199.0mg,0.90mmol)、1,1'-联萘-2,2'-双二苯膦(40.8mg,0.066mmol)、三(二亚苄基丙酮)二钯(45.0mg,0.049mmol)和碳酸铯(617.5mg,1.90mmol)，并加热至100℃搅拌16小时。将反应液冷却至室温后真空浓缩，粗品经硅胶柱层析(0-20％的甲醇/二氯甲烷)纯化得到黄色固体(70.0mg)。LC-MS:[M+H]+:598.3。To 2-(2-chloro-5-fluoropyrimidin-4-yl)-6-(4-methoxybenzyl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[ To a solution of 3,4-b]pyridin-7-one (260.0 mg, 0.63 mmol) in 1,4-dioxane (10 mL) was added 2-methoxy-5-(4-methylpiperazine- 1-yl)aniline (199.0mg, 0.90mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (40.8mg, 0.066mmol), tris(dibenzylideneacetone)dipalladium (45.0 mg, 0.049mmol) and cesium carbonate (617.5mg, 1.90mmol), and heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-20% methanol/dichloromethane) to obtain a yellow solid (70.0 mg). LC-MS: [M+H] + :598.3.
2-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-5,5-二甲基-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(DP-01-246)的合成：2-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5,5-dimethyl Synthesis of -5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (DP-01-246):
向2-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-6-(4-甲氧基苄基)-5,5-二甲基-5,6-二氢-7H-吡咯并[3,4-b]吡啶-7-酮(60.0mg,0.10mmol)的三氟乙酸(2mL)溶液中加入三氟甲磺酸(1mL)并加热至60℃搅拌2小时。将反应物冷却至室温后真空浓缩，粗品经制备纯化得到黄色固体(5.1mg)。1HNMR(400MHz,DMSO)δ9.22(s,1H),8.72(d,J＝3.1Hz,1H),8.36(d,J＝8.0Hz,1H),8.27–8.20(m,2H),8.17(s,1H),7.94(d,J＝2.8Hz,1H),6.92(d,J＝8.9Hz,1H),6.59(dd,J＝8.9,2.9Hz,1H),3.80(s,3H),3.06–3.02(m,4H),2.47–2.43(m,4H),2.22(s,3H),1.53(s,6H)；LC-MS:[M+H]+:478.3。To 2-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-6-(4-methyl Oxybenzyl)-5,5-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (60.0 mg, 0.10 mmol) in trifluoroacetic acid (2 mL ) solution was added trifluoromethanesulfonic acid (1 mL) and heated to 60°C and stirred for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was preparatively purified to obtain a yellow solid (5.1 mg). 1 HNMR (400MHz, DMSO) δ9.22 (s, 1H), 8.72 (d, J = 3.1Hz, 1H), 8.36 (d, J = 8.0Hz, 1H), 8.27–8.20 (m, 2H), 8.17 (s,1H),7.94(d,J＝2.8Hz,1H),6.92(d,J＝8.9Hz,1H),6.59(dd,J＝8.9,2.9Hz,1H),3.80(s,3H) ,3.06–3.02(m,4H),2.47–2.43(m,4H),2.22(s,3H),1.53(s,6H); LC-MS: [M+H] + :478.3.
实施例79.化合物DP-01-266、DP-01-266A、DP-01-266B的合成
Example 79. Synthesis of compounds DP-01-266, DP-01-266A, and DP-01-266B
2-(4-甲氧基-3-硝基苯基)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷(2)的合成：Synthesis of 2-(4-methoxy-3-nitrophenyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (2):
将4-溴-1-甲氧基-2-硝基苯(300.0mg,1.29mmol)、2-甲基-2,5-二氮杂双环[2.2.1]庚烷二盐酸盐(239.3 mg,1.29mmol)、叔丁醇钠(621.3mg,6.47mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(123.3mg,0.26mmol)及三(二亚苄基丙酮)二钯(118.4mg,0.13mmol)溶解在甲苯(7mL)中，氮气保护下，于90℃反应3小时。反应液旋干所得粗品经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化得到黄色固体(290.0mg)。LC-MS:[M+H]+:263.9。4-Bromo-1-methoxy-2-nitrobenzene (300.0 mg, 1.29 mmol), 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (239.3 mg, 1.29mmol), sodium tert-butoxide (621.3mg, 6.47mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (123.3mg, 0.26mmol) and tris( Dibenzylideneacetone) dipalladium (118.4 mg, 0.13 mmol) was dissolved in toluene (7 mL), and reacted at 90°C for 3 hours under nitrogen protection. The reaction solution was spin-dried and the crude product obtained was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (290.0 mg). LC-MS: [M+H] + :263.9.
2-甲氧基-5-(5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)苯胺(3)的合成：Synthesis of 2-methoxy-5-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)aniline (3):
将化合物2-(4-甲氧基-3-硝基苯基)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷(290.0mg,1.10mmol)溶解于甲醇(10mL)中，加入10％钯碳(30.0mg)，氢气保护下于室温反应18小时。反应液用硅藻土过滤，滤液旋干得到棕色固体(250.0mg)。LC-MS:[M+H]+:233.9。Compound 2-(4-methoxy-3-nitrophenyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (290.0 mg, 1.10 mmol) was dissolved in methanol ( 10 mL), add 10% palladium on carbon (30.0 mg), and react at room temperature for 18 hours under hydrogen protection. The reaction solution was filtered through diatomaceous earth, and the filtrate was spun to dryness to obtain a brown solid (250.0 mg). LC-MS: [M+H] + :233.9.
5'-(5-氟-2-((2-甲氧基-5-(5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-266)的合成：5'-(5-fluoro-2-((2-methoxy-5-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino Synthesis of )pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-266):
将2-甲氧基-5-(5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)苯胺(250.0mg,1.07mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(310.4mg,1.07mmol)、碳酸铯(1047.4mg,3.21mmol)、1,1'-联萘-2,2'-双二苯膦(133.5mg,0.21mmol)及醋酸钯(24.1mg,0.11mmol)溶解在二氧六环(5mL)中，氮气保护下，于100℃反应18小时。反应液浓缩所得粗品经酸性反相制备得到棕色固体(192.9mg)。1H NMR(400MHz,MeOD)δ8.55(s,1H),8.53(s,1H),8.43(d,J＝3.6Hz,1H),8.27(d,J＝8.0Hz,1H),8.01(d,J＝2.8Hz,1H),7.36(d,J＝8.0Hz,1H),6.89(d,J＝8.8Hz,1H),6.26(dd,J＝8.8,2.8Hz,1H),4.45(s,1H),4.11(s,1H),3.86(s,3H),3.71(dd,J＝10.8,2.4Hz,1H),3.49(t,J＝12.0Hz,2H),3.17(d,J＝9.6Hz,1H),2.79(s,3H),2.23(q,J＝9.6Hz,2H),1.67–1.57(m,4H)；LC-MS:[M+H]+:487.5。2-Methoxy-5-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)aniline (250.0mg, 1.07mmol), 5'-(2- Chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (310.4 mg, 1.07 mmol), cesium carbonate (1047.4 mg, 3.21 mmol), 1 , 1'-binaphthyl-2,2'-bisdiphenylphosphine (133.5mg, 0.21mmol) and palladium acetate (24.1mg, 0.11mmol) were dissolved in dioxane (5mL), under nitrogen protection, at 100 ℃ reaction for 18 hours. The crude product obtained by concentrating the reaction solution was prepared by acidic reverse phase to obtain a brown solid (192.9 mg). 1 H NMR (400MHz, MeOD) δ8.55(s,1H),8.53(s,1H),8.43(d,J＝3.6Hz,1H),8.27(d,J＝8.0Hz,1H),8.01( d,J＝2.8Hz,1H),7.36(d,J＝8.0Hz,1H),6.89(d,J＝8.8Hz,1H),6.26(dd,J＝8.8,2.8Hz,1H),4.45( s,1H),4.11(s,1H),3.86(s,3H),3.71(dd,J＝10.8,2.4Hz,1H),3.49(t,J＝12.0Hz,2H),3.17(d,J =9.6Hz, 1H), 2.79 (s, 3H), 2.23 (q, J = 9.6Hz, 2H), 1.67–1.57 (m, 4H); LC-MS: [M+H] + : 487.5.
消旋体DP-01-266经SFC分离纯化(色谱柱：ChiralPak IH,150*20mm I.D.,5μm；流动相：A相：CO2；B相MEOH+0.1％NH3H2O；梯度：B％：50％；20min，3h)得白色固体DP-01-266A和白色固体DP-01-266B。Racemate DP-01-266 was separated and purified by SFC (chromatographic column: ChiralPak IH, 150*20mm ID, 5μm; mobile phase: phase A: CO 2 ; phase B MEOH+0.1% NH 3 H 2 O; gradient: B %: 50%; 20min, 3h) to obtain white solid DP-01-266A and white solid DP-01-266B.
DP-01-266A：DP-01-266A:
手性分析条件：色谱柱：CHIRALPAK IH 5μm 4.6*100mm，流动相：A相：CO2；B相：MeOH；梯度：B％：50.0％，保留时间为6.736分钟，ee％＝100％。Chiral analysis conditions: Chromatographic column: CHIRALPAK IH 5μm 4.6*100mm, mobile phase: A phase: CO 2 ; B phase: MeOH; gradient: B%: 50.0%, retention time is 6.736 minutes, ee%=100%.
1H NMR(400MHz,MeOD)δ8.53(s,1H),8.46(d,J＝3.6Hz,1H),8.31(d,J＝8.0Hz,1H),8.01(d,J＝2.8Hz,1H),7.38(d,J＝8.0Hz,1H),6.88(d,J＝8.8Hz,1H),6.24(dd,J＝8.8,2.8Hz,1H),4.25(s,1H),3.86(s,3H),3.56–3.51(m,2H),3.33(s,1H),2.84–2.81(m,2H),2.38(s,3H),1.98(q,J＝8.4Hz,2H),1.66–1.59(m,4H)；LC-MS:[M+H]+:487.5。 1 H NMR (400MHz, MeOD) δ8.53 (s, 1H), 8.46 (d, J = 3.6Hz, 1H), 8.31 (d, J = 8.0Hz, 1H), 8.01 (d, J = 2.8Hz, 1H),7.38(d,J＝8.0Hz,1H),6.88(d,J＝8.8Hz,1H),6.24(dd,J＝8.8,2.8Hz,1H),4.25(s,1H),3.86( s,3H),3.56–3.51(m,2H),3.33(s,1H),2.84–2.81(m,2H),2.38(s,3H),1.98(q,J＝8.4Hz,2H),1.66 –1.59(m,4H); LC-MS: [M+H] + :487.5.
DP-01-266B：DP-01-266B:
手性分析条件：色谱柱：CHIRALPAK IH 5μm 4.6*100mm，流动相：A相CO2；B相：MeOH；梯度：B％：50.0％，保留时间为20.346分钟，ee％＝100％。Chiral analysis conditions: Chromatographic column: CHIRALPAK IH 5μm 4.6*100mm, mobile phase: phase A CO 2 ; phase B: MeOH; gradient: B%: 50.0%, retention time is 20.346 minutes, ee%=100%.
1H NMR(400MHz,MeOD)δ8.54(s,1H),8.47(d,J＝3.6Hz,1H),8.32(d,J＝8.0Hz,1H),8.02(d,J＝2.8Hz,1H),7.39(d,J＝8.0Hz,1H),6.88(d,J＝8.8Hz,1H),6.24(dd,J＝8.8,2.8Hz,1H),4.25(s,1H),3.86(s,3H),3.55–3.50(m,2H),3.33(s,1H),2.85–2.78(m,2H),2.37(s,3H),1.98(q,J＝8.0Hz,2H),1.68–1.58(m,4H)；LC-MS:[M+H]+:487.5。 1 H NMR (400MHz, MeOD) δ8.54 (s, 1H), 8.47 (d, J = 3.6Hz, 1H), 8.32 (d, J = 8.0Hz, 1H), 8.02 (d, J = 2.8Hz, 1H),7.39(d,J＝8.0Hz,1H),6.88(d,J＝8.8Hz,1H),6.24(dd,J＝8.8,2.8Hz,1H),4.25(s,1H),3.86( s,3H),3.55–3.50(m,2H),3.33(s,1H),2.85–2.78(m,2H),2.37(s,3H),1.98(q,J＝8.0Hz,2H),1.68 –1.58(m,4H); LC-MS: [M+H] + :487.5.
实施例80.化合物DP-01-270的合成
Example 80. Synthesis of compound DP-01-270
7-(4-甲氧基-3-硝基苯基)-9-甲基-3-氧-7,9-二氮杂双环[3.3.1]壬烷(2)的合成：Synthesis of 7-(4-methoxy-3-nitrophenyl)-9-methyl-3-oxo-7,9-diazabicyclo[3.3.1]nonane (2):
氮气保护下，将4-溴-1-甲氧基-2-硝基苯(118.7mg,0.51mmol)、9-甲基-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷二盐酸盐(100.0mg,0.46mmol)、三(二亚苄基丙酮)二钯(42.6mg,0.047mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(44.4mg,0.093mmol)和碳酸铯(606.2mg,1.86mmol)溶于甲苯(3mL)中，于90℃搅拌反应5小时。LCMS检测反应完全。反应液冷却至室温后加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)。合并有机相，无水硫酸钠干燥，过滤浓缩。粗品经硅胶柱层析纯化(二氯甲烷:乙酸乙酯＝20:1)得黄色油状物(110.0mg)。LC-MS:[M+H]+:294.2。Under nitrogen protection, 4-bromo-1-methoxy-2-nitrobenzene (118.7 mg, 0.51 mmol), 9-methyl-3-oxa-7,9-diazabicyclo [3.3.1 ] Nonane dihydrochloride (100.0mg, 0.46mmol), tris(dibenzylideneacetone)dipalladium (42.6mg, 0.047mmol), 2-dicyclohexylphosphine-2',4',6'-tris Cumene (44.4 mg, 0.093 mmol) and cesium carbonate (606.2 mg, 1.86 mmol) were dissolved in toluene (3 mL), and the mixture was stirred and reacted at 90°C for 5 hours. LCMS detection showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate=20:1) to obtain a yellow oil (110.0 mg). LC-MS: [M+H] + :294.2.
2-甲氧基-5-(9-甲基-3-氧-7,9-二氮杂双环[3.3.1]壬-7-基)苯胺(3)的合成：Synthesis of 2-methoxy-5-(9-methyl-3-oxo-7,9-diazabicyclo[3.3.1]non-7-yl)aniline (3):
将7-(4-甲氧基-3-硝基苯基)-9-甲基-3-氧-7,9-二氮杂双环[3.3.1]壬烷(110.0mg,0.38mmol)溶于甲醇(2mL)和四氢呋喃(1mL)中，将10％钯碳(39.9mg)加入反应体系，氢气置换三次后于常压、室温反应18小时。LCMS检测反应完全。反应液过滤浓缩得黄色油状物(80.0mg)。LC-MS:[M+H]+:264.3。Dissolve 7-(4-methoxy-3-nitrophenyl)-9-methyl-3-oxo-7,9-diazabicyclo[3.3.1]nonane (110.0 mg, 0.38 mmol) In methanol (2 mL) and tetrahydrofuran (1 mL), 10% palladium on carbon (39.9 mg) was added to the reaction system. After three replacements with hydrogen, the reaction was carried out at normal pressure and room temperature for 18 hours. LCMS detection showed that the reaction was complete. The reaction solution was filtered and concentrated to obtain yellow oil (80.0 mg). LC-MS: [M+H] + :264.3.
5'-(5-氟-2-((2-甲氧基-5-(9-甲基-3-氧-7,9-二氮杂双环[3.3.1]壬-7-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(DP-01-270)的合成：5'-(5-fluoro-2-((2-methoxy-5-(9-methyl-3-oxo-7,9-diazabicyclo[3.3.1]nonan-7-yl)benzene Synthesis of methyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-270):
将2-甲氧基-5-(9-甲基-3-氧-7,9-二氮杂双环[3.3.1]壬-7-基)苯胺(80.0mg,0.30mmol)、5'-(2-氯-5-氟嘧啶-4-基)螺[环丙烷-1,1'-异吲哚啉]-3'-酮(88.0mg,0.30mmol)、三(二亚苄基丙酮)二钯(27.8mg,0.03mmol)、1,1'-联萘-2,2'-双二苯膦(18.9mg,0.03mmol)和碳酸铯(296.9mg,0.91mmol)置于1,4-二氧六环(2mL)中，氮气置换三次，反应液于90℃搅拌5小时。LCMS检测反应完全，反应液冷却至室温后加水(10mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相后用无水硫酸钠干燥，过滤浓缩。柱层析纯化(二氯甲烷:甲醇＝20:1)后再制备纯化得黄色固体(2.5mg)。1H NMR(400MHz,DMSO)δ8.90(s,1H),8.65(d,J＝3.2Hz,1H),8.30(s,1H),8.23(d,J＝8.0Hz,1H),8.18(s,1H),7.90(d,J＝2.4Hz,1H),7.47(d,J＝8.4Hz,1H),6.95(d,J＝8.8Hz,1H),6.48(dd,J＝8.8,2.8Hz,1H),3.83-3.80(m,5H),3.71(d,J＝10.4Hz,2H),3.36–3.34(m,1H),3.30–3.29(m,1H),3.23(dd,J＝11.6,2.8Hz,2H),2.78(s,2H),2.46(s,3H),1.54(d,J＝2.9Hz,4H)；LCMS:[M+H]+:517.3。2-Methoxy-5-(9-methyl-3-oxo-7,9-diazabicyclo[3.3.1]non-7-yl)aniline (80.0 mg, 0.30 mmol), 5'- (2-Chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (88.0 mg, 0.30 mmol), tris(dibenzylideneacetone) Dipalladium (27.8mg, 0.03mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (18.9mg, 0.03mmol) and cesium carbonate (296.9mg, 0.91mmol) were placed in 1,4- Dioxane (2 mL) was replaced with nitrogen three times, and the reaction solution was stirred at 90°C for 5 hours. LCMS detected that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (dichloromethane:methanol=20:1) was followed by preparation and purification to obtain a yellow solid (2.5 mg). 1 H NMR (400MHz, DMSO) δ8.90 (s, 1H), 8.65 (d, J = 3.2Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 8.0Hz, 1H), 8.18 ( s,1H),7.90(d,J＝2.4Hz,1H),7.47(d,J＝8.4Hz,1H),6.95(d,J＝8.8Hz,1H),6.48(dd,J＝8.8,2.8 Hz,1H),3.83-3.80(m,5H),3.71(d,J＝10.4Hz,2H),3.36–3.34(m,1H),3.30–3.29(m,1H),3.23(dd,J＝ 11.6, 2.8Hz, 2H), 2.78 (s, 2H), 2.46 (s, 3H), 1.54 (d, J = 2.9Hz, 4H); LCMS: [M+H] + : 517.3.
实施例81.化合物PR-01-073的合成
Example 81. Synthesis of compound PR-01-073
2-氰基-6-甲基苯甲酸甲酯(2)的合成：Synthesis of methyl 2-cyano-6-methylbenzoate (2):
将化合物2-溴-6-甲基苯甲酸甲酯(3.0g,13.10mmol)、氰化亚铜(1.4g,15.63mmol)及碘化亚铜(0.25g,1.31mmol)悬浮于N,N-二甲基甲酰胺(20mL)中，氮气保护下130℃搅拌反应18小时后冷却至室温。旋除溶剂后粗产品经硅胶柱层析(乙酸乙酯:石油醚＝1:10)得到白色固体(1.1g)。1H NMR(400MHz,CDCl3)δ7.58(dd,J＝7.2,1.2Hz,1H),7.51–7.40(m,2H),4.01(s,3H),2.48(s,3H)。The compounds 2-bromo-6-methylbenzoic acid methyl ester (3.0g, 13.10mmol), copper cyanide (1.4g, 15.63mmol) and copper iodide (0.25g, 1.31mmol) were suspended in N, N -In dimethylformamide (20 mL), stir the reaction at 130°C for 18 hours under nitrogen protection and then cool to room temperature. After the solvent was removed, the crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain a white solid (1.1g). 1 H NMR (400MHz, CDCl 3 ) δ7.58 (dd, J=7.2, 1.2Hz, 1H), 7.51–7.40 (m, 2H), 4.01 (s, 3H), 2.48 (s, 3H).
7-甲基异吲哚啉-1-酮(3)的合成：Synthesis of 7-methylisoindolin-1-one (3):
将化合物2-氰基-6-甲基苯甲酸甲酯(1.0g,5.71mmol)溶解在乙醇(80mL)中，加入雷尼镍合金(100.0mg)。在150psi氢气压力下，室温反应18小时。反应液经硅藻土过滤，滤液旋干，得到白色固体(800.0mg)。产物直接用于下一步反应。LCMS:[M+H]+:148.3。Compound 2-cyano-6-methylbenzoic acid methyl ester (1.0 g, 5.71 mmol) was dissolved in ethanol (80 mL), and Raney nickel alloy (100.0 mg) was added. React at room temperature for 18 hours under 150 psi hydrogen pressure. The reaction solution was filtered through diatomaceous earth, and the filtrate was spun dry to obtain a white solid (800.0 mg). The product was directly used in the next reaction. LCMS: [M+H] + :148.3.
6-碘-7-甲基异吲哚啉-1-酮(4)的合成：Synthesis of 6-iodo-7-methylisoindolin-1-one (4):
在冰水浴中，将化合物7-甲基异吲哚啉-1-酮(800.0mg,5.44mmol)溶解在浓硫酸(8mL)中搅拌0.5小时，将N-碘代丁二酰亚胺(2.29g,10.18mmol)加入反应体系，冰水浴搅拌反应2小时后将反应液倒入冰水中淬灭。用乙酸乙酯萃取(10mL×3)，有机相用饱和亚硫酸钠水溶液(15mL)和水(15mL)洗，无水硫酸钠干燥，浓缩粗产品，经柱层析纯化得(石油醚:乙酸乙酯＝1:1)得到白色固体化合物(300.0mg)。1HNMR(400MHz,DMSO-d6)δ8.57(s,1H),7.98(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),4.24(s,2H),2.70(s,3H)。In an ice-water bath, compound 7-methylisoindolin-1-one (800.0 mg, 5.44 mmol) was dissolved in concentrated sulfuric acid (8 mL) and stirred for 0.5 hours. N-iodosuccinimide (2.29 g, 10.18 mmol) was added to the reaction system, stirred in an ice water bath for 2 hours, and then the reaction solution was poured into ice water to quench. Extract with ethyl acetate (10mL =1:1) to obtain a white solid compound (300.0 mg). 1 HNMR (400MHz, DMSO-d6) δ8.57(s,1H),7.98(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),4.24(s,2H),2.70 (s,3H).
7-甲基-6-硼酸频那醇酯异吲哚啉-1-酮(5)的合成：Synthesis of 7-methyl-6-boronic acid pinacol ester isoindolin-1-one (5):
将化合物6-碘-7-甲基异吲哚啉-1-酮(100.0mg,0.37mmol)、频那醇硼烷(100.0mg,0.78mmol)、三乙胺(150.0mg,1.48mmol)、2-(二环己基膦基)联苯(26.0mg,0.074mmol)及醋酸钯(5.0mg,0.022mmol)悬浮于二氧六环(2mL)中，氮气保护下，80℃反应1小时。冷却反应，加入水(8mL)稀释，用乙酸乙酯(8mL×3)萃取。合并有机相后无水硫酸钠干燥，旋干得到粗产品(70.0mg,纯度:40％)，直接用于下一步反应。LCMS:[M+H]+:274.3。Compound 6-iodo-7-methylisoindolin-1-one (100.0mg, 0.37mmol), pinacolborane (100.0mg, 0.78mmol), triethylamine (150.0mg, 1.48mmol), 2-(Dicyclohexylphosphino)biphenyl (26.0 mg, 0.074 mmol) and palladium acetate (5.0 mg, 0.022 mmol) were suspended in dioxane (2 mL), and reacted at 80°C for 1 hour under nitrogen protection. The reaction was cooled, water (8 mL) was added to dilute, and extracted with ethyl acetate (8 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spun to dryness to obtain a crude product (70.0 mg, purity: 40%), which was directly used in the next reaction. LCMS: [M+H] + :274.3.
7-甲基-6-(2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)异吲哚啉-1-酮(PR-01-073)的合成：7-Methyl-6-(2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)isoindole Synthesis of lin-1-one (PR-01-073):
将化合物7-甲基-6-硼酸频那醇酯异吲哚啉-1-酮(70.0mg,0.10mmol,纯度:40％)、4-氯-N-(5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)嘧啶-2-胺(50.0mg,0.13mmol)、碳酸钾(45.5mg,0.33mmol)以及[1,1'-双 (二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(8.1mg,0.01mmol)溶于二氧六环(5mL)和水(1mL)中，氮气保护下在100℃下反应3小时后直接浓缩至干。经酸性制备纯化得为白色固体(24.7mg)。1H NMR(400MHz,MeOD)δ8.55(d,J＝5.2Hz,1H),8.21(s,1H),7.68(d,J＝7.6Hz,1H),7.51(d,J＝8.0Hz,1H),7.25(d,J＝9.2Hz,1H),7.09–7.07(m,1H),6.76(dd,J＝9.2,2.8Hz,1H),4.45(s,2H),3.82(d,J＝12.4Hz,2H),3.60–3.54(m,2H),3.27–3.24(m,2H),3.13–3.05(m,2H),2.96(s,3H),2.77(s,3H)；LC-MS:[M+H]+:499.5。Compound 7-methyl-6-boronic acid pinacol ester isoindolin-1-one (70.0 mg, 0.10 mmol, purity: 40%), 4-chloro-N-(5-(4-methylpiperdine) Azin-1-yl)-2-(trifluoromethoxy)phenyl)pyrimidin-2-amine (50.0 mg, 0.13 mmol), potassium carbonate (45.5 mg, 0.33 mmol) and [1,1'-bis (Diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (8.1 mg, 0.01 mmol) was dissolved in dioxane (5 mL) and water (1 mL) at 100°C under nitrogen protection. After reacting for 3 hours, it was directly concentrated to dryness. After acidic preparation and purification, a white solid (24.7 mg) was obtained. 1 H NMR (400MHz, MeOD) δ8.55(d,J＝5.2Hz,1H),8.21(s,1H),7.68(d,J＝7.6Hz,1H),7.51(d,J＝8.0Hz, 1H),7.25(d,J＝9.2Hz,1H),7.09–7.07(m,1H),6.76(dd,J＝9.2,2.8Hz,1H),4.45(s,2H),3.82(d,J ＝12.4Hz,2H),3.60–3.54(m,2H),3.27–3.24(m,2H),3.13–3.05(m,2H),2.96(s,3H),2.77(s,3H); LC- MS: [M+H] + :499.5.
实施例82.化合物DP-01-274的合成
Example 82. Synthesis of compound DP-01-274
2'-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(1)的合成：2'-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4'-oxospiro Synthesis of [cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid tert-butyl ester (1):
将2'-(2-氯-5-氟嘧啶-4-基)-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(50.0mg,0.13mmol)、2-甲氧基-5-(4-甲基哌嗪-1-基)苯胺(28.0mg,0.13mmol)、碳酸铯(123.0mg,0.38mmol)、三(二亚苄基丙酮)二钯(12.0mg,0.013mmol)以及1,1'-联萘-2,2'-双二苯膦(16.0mg,0.026mmol)置于无水二氧六环(1mL)中，于氮气保护下100℃反应3小时。LCMS监测反应完全。反应液浓缩后经硅胶柱层析(二氯甲烷:甲醇＝10:1)纯化得到黄色固体(50.0mg)。LC-MS:[M+H]+:581.5。2'-(2-Chloro-5-fluoropyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4 'H)-tert-butylcarboxylate (50.0mg, 0.13mmol), 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (28.0mg, 0.13mmol), cesium carbonate (123.0 mg, 0.38mmol), tris(dibenzylideneacetone)dipalladium (12.0mg, 0.013mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (16.0mg, 0.026mmol) were placed in anhydrous dioxane (1 mL), and reacted at 100°C for 3 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain a yellow solid (50.0 mg). LC-MS: [M+H] + :581.5.
2'-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-4'(5'H)-酮(DP-01-274)的合成：2'-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1, Synthesis of 6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (DP-01-274):
将2'-(5-氟-2-((2-甲氧基-5-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(50.0mg,0.086mmol)溶于二氯甲烷(1mL)中，冰浴冷却下缓慢加入三氟乙酸(0.2mL)，反应在室温下搅拌1小时。LCMS监测反应完全。反应液浓缩后经碳酸氢铵制备纯化得到黄色固体(30.4mg)。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.65(d,J＝3.2Hz,1H)8.10(s,1H),7.96(d,J＝2.8Hz,1H),7.80(s,1H),6.92(d,J＝8.8Hz,1H),6.58(dd,J＝8.8,2.8Hz,1H),3.81(s,3H),3.10–3.07(m,4H),2.49–2.46(m,4H),2.24(s,3H),1.69–1.67(m,2H),1.56–1.54(m,2H)；LC-MS:[M+H]+:481.2。2'-(5-fluoro-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-4'-oxo Spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid tert-butyl ester (50.0mg, 0.086mmol) was dissolved in dichloromethane (1mL) , trifluoroacetic acid (0.2 mL) was slowly added while cooling in an ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated and purified through ammonium bicarbonate to obtain a yellow solid (30.4 mg). 1 H NMR (400MHz, DMSO-d6) δ8.71 (s, 1H), 8.65 (d, J = 3.2Hz, 1H) 8.10 (s, 1H), 7.96 (d, J = 2.8Hz, 1H), 7.80 (s,1H),6.92(d,J＝8.8Hz,1H),6.58(dd,J＝8.8,2.8Hz,1H),3.81(s,3H),3.10–3.07(m,4H),2.49– 2.46(m,4H),2.24(s,3H),1.69–1.67(m,2H),1.56–1.54(m,2H); LC-MS: [M+H] + :481.2.
实施例83.化合物DP-01-275的合成
Example 83. Synthesis of compound DP-01-275
2'-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(1)的合成：2'-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-4' -Synthesis of oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid tert-butyl ester (1):
将2'-(2-氯-5-氟嘧啶-4-基)-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(40.0mg,0.10mmol)、5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯胺(28.0mg,0.10mmol)、碳酸铯(99.0mg,0.30mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.010mmol)和1,1'-联萘-2,2'-双二苯膦(13.5mg,0.022mmol)置于无水二氧六环(1mL)中，于氮气保护下100℃反应3小时。LCMS监测反应完全。反应液浓缩后经硅胶柱层析(二氯甲烷:甲醇＝10:1)纯化得到黄色固体(50.0mg)。LC-MS:[M+H]+:635.5。2'-(2-Chloro-5-fluoropyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4 'H)-tert-butylcarboxylate (40.0mg, 0.10mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (28.0mg, 0.10mmol), Cesium carbonate (99.0mg, 0.30mmol), tris(dibenzylideneacetone)dipalladium (9.2mg, 0.010mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (13.5mg, 0.022 mmol) was placed in anhydrous dioxane (1 mL), and reacted at 100°C for 3 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain a yellow solid (50.0 mg). LC-MS: [M+H] + :635.5.
2'-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-4'(5'H)-酮(DP-01-275)的合成：2'-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)spiro[ring Synthesis of propane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (DP-01-275):
将2'-(5-氟-2-((5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-4'-氧代螺[环丙烷-1,6'-噻吩并[2,3-c]吡咯]-5'(4'H)-羧酸叔丁酯(50.0mg,0.079mmol)溶于二氯甲烷(1mL)中，冰浴冷却后缓慢加入三氟乙酸(0.2mL)，反应在室温下搅拌1小时。LCMS监测反应完全。反应液浓缩后经碳酸氢铵制备纯化得到淡黄色固体(28.2mg)。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.69(s,1H),8.62(d,J＝3.2Hz,1H),7.78(s,1H),7.53(d,J＝2.8Hz,1H),7.20(d,J＝9.2Hz,1H),6.74(dd,J＝9.2,2.8Hz,1H),3.20–3.18(m,4H),2.49–2.47(m,4H),2.25(s,3H),1.66–1.64(m,2H),1.55–1.53(m,2H)；LC-MS:[M+H]+:535.1。2'-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-4 '-Oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylic acid tert-butyl ester (50.0mg, 0.079mmol) was dissolved in dichloro To methane (1 mL), trifluoroacetic acid (0.2 mL) was slowly added after cooling in an ice bath, and the reaction was stirred at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated and purified through ammonium bicarbonate to obtain a light yellow solid (28.2 mg). 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.69 (s, 1H), 8.62 (d, J = 3.2Hz, 1H), 7.78 (s, 1H), 7.53 (d, J ＝2.8Hz,1H),7.20(d,J＝9.2Hz,1H),6.74(dd,J＝9.2,2.8Hz,1H),3.20–3.18(m,4H),2.49–2.47(m,4H) ,2.25(s,3H),1.66–1.64(m,2H),1.55–1.53(m,2H); LC-MS:[M+H] + :535.1.
实施例84Example 84
按照实施例1的方法制备得到如下化合物：
The following compounds were prepared according to the method of Example 1:
实施例85Example 85
按照实施例13的方法制备得到如下化合物：
The following compounds were prepared according to the method of Example 13:
实施例86Example 86
按照实施例7的方法制备得到如下化合物：
The following compounds were prepared according to the method of Example 7:
实施例87Example 87
按照实施例12的方法制备得到如下化合物：
The following compounds were prepared according to the method of Example 12:
实施例88Example 88
按照方法III制备得到如下化合物：
The following compounds were prepared according to method III:
实施例89Example 89
按照实施例12的方法制备得到如下化合物：
The following compounds were prepared according to the method of Example 12:
实施例90.化合物对PLK1抑制活性测试Example 90. Test of compound’s inhibitory activity against PLK1
在384孔稀释板中用DMSO将待测化合物进行3倍梯度稀释，将稀释好的化合物用ECHO转移25nL在384孔反应板中，确保DMSO含量为0.5％。转移2.5μL 2X PLK1酶溶液到384孔反应板中，1000rpm离心1min，25℃孵育10min。转移2.5μL 2X ATP&PLK tide混合溶液到384孔反应板中，1000rpm离心1min，25℃孵育60min。转移4μL ADP-Glo Reagent试剂到384孔反应板中，1000rpm离心1min，25℃孵育40min。转移8μL ADP-Glo Detection试剂到384孔反应板中，1000rpm离心1min，25℃孵育40min。使用BMG酶标仪读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。利用GraphPad软件非线性拟合公式(1)计算阳性药IC50：Use DMSO to perform a 3-fold gradient dilution of the compound to be tested in a 384-well dilution plate. Use ECHO to transfer 25 nL of the diluted compound into a 384-well reaction plate to ensure that the DMSO content is 0.5%. Transfer 2.5 μL of 2X PLK1 enzyme solution to a 384-well reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min. Transfer 2.5 μL of 2X ATP&PLK tide mixed solution into a 384-well reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min. Transfer 4 μL of ADP-Glo Reagent reagent to the 384-well reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 40 min. Transfer 8 μL of ADP-Glo Detection reagent to the 384-well reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 40 min. Use a BMG microplate reader to read the RLU (Relative luminescence unit) signal. Signal intensity is used to characterize the degree of kinase activity. Use the nonlinear fitting formula (1) of GraphPad software to calculate the IC 50 of the positive drug:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))(1)Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))(1)
其中，X代表化合物浓度log值，Y代表抑制率(％inhibition)。Among them, X represents the log value of the compound concentration, and Y represents the inhibition rate (%inhibition).
结果表明，本发明的化合物具有良好的PLK1抑制活性，IC50小于100nM，优选小于10nM，代表性化合物的IC50如下表1所示：The results show that the compound of the present invention has good PLK1 inhibitory activity, with an IC50 of less than 100 nM, preferably less than 10 nM. The IC50 of representative compounds is shown in Table 1 below:
表1.代表性化合物对PLK1的抑制活性


Table 1. Inhibitory activity of representative compounds against PLK1


以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。 The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiment. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (10)

  1. 如下式(I)所示化合物，
    A compound represented by the following formula (I),
    或其药学上可接受的盐、氘代物，其中：Or its pharmaceutically acceptable salts or deuterated products, wherein:
    E独立地选自C、N、O；E is independently selected from C, N, O;
    T、M、Q独立地选自N、CR3；T, M, Q are independently selected from N, CR3;
    X、Y、Z独立地选自N、CR5；X, Y and Z are independently selected from N and CR5;
    A环选自苯基、含有1-3个独立地选自N、O、S的5-11元杂芳基；Ring A is selected from phenyl and contains 1-3 5-11-membered heteroaryl groups independently selected from N, O, and S;
    B环与A环的环碳原子或环氮原子相连；Ring B is connected to the ring carbon atom or ring nitrogen atom of A ring;
    R1独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R1 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy base, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
    当R1独立地为C1-4烷基时，两个R1连同其所连接的C一起可形成3-7元环烷基，该环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R1 is independently C 1-4 alkyl, two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which is optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substitution, the alkyl, Alkenyl, alkynyl, and alkoxy groups are optionally selected from one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, C 1-4 alkoxy group substituted;
    R2独立地选自H、F、Cl、Br、OH、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基所取代；R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, containing Substituted with 1-3 3-7-membered heterocycloalkyl groups independently selected from N, O, and S, and 1-3 5-11-membered heteroaryl groups independently selected from N, O, S;
    R3独立地选自H、F、Cl、Br、OH、CN、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、 -NR8C(O)R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、-NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-11元杂芳基所取代；R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9、 -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or more independently is selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-11-membered heteroaryl containing 1-3 independently selected from N, O, S replaced;
    R4选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
    R5独立地选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
    R6选自NR8R9、NR8C(O)R9、C(O)NR8R9、C1-4烷基、哌嗪基、桥环哌嗪基、螺环哌嗪基，所述烷基、哌嗪基、桥环哌嗪基、螺环哌嗪基任选地被一个或多个R7取代；R6 is selected from NR8R9, NR8C(O)R9, C(O)NR8R9, C 1-4 alkyl, piperazinyl, bridged piperazinyl, spiropiperazinyl, the alkyl, piperazinyl, bridged piperazinyl Base, spiropiperazinyl is optionally substituted by one or more R7;
    或R6与其连接的环C原子、环Y原子、及该环C原子和环Y原子之间的键一起形成含有1-3个独立地选自N、O、S的5-7元杂环烷基，该环可任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；Or R6, together with its connected ring C atom, ring Y atom, and the bond between the ring C atom and ring Y atom, forms a 5-7 membered heterocycloalkane containing 1-3 independently selected from N, O, and S group, the ring may be optionally replaced by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy group substituted, the alkyl, alkenyl, alkynyl, alkoxy group optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2. Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
    R7独立地选自H、F、Cl、Br、OH、CN、NR8R9、＝O、C1-4烷基、C1-4烷氧基、C3-7环烷基，所述烷基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R7 is independently selected from H, F, Cl, Br, OH, CN, NR8R9, =O, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, Alkoxy and cycloalkyl are optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
    R8和R9独立地选自H、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基，所述烷基、烯基、炔基、烷氧基任选地被一个或多个选自F、Cl、Br、OH、CN、NH2的基团所取代；R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 ;
    当R8和R9连接在同一原子上时，R8和R9连同其所连接的原子一起可形成含有1-3个独立地选自N、O、S的3-7元杂环烷基，该杂环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R8 and R9 are connected on the same atom, R8 and R9 together with the atoms to which they are connected can form a 3-7-membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S. The heterocyclic ring The alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
    m为0、1、2或3。m is 0, 1, 2 or 3.
    w为0、1、2。w is 0, 1, 2.
  2. 如权利要求1所述的化合物，其特征在于，结构如下式(IA)所示：
    The compound according to claim 1, characterized in that its structure is represented by the following formula (IA):
    其中：in:
    T、M、Q独立地选自N、CR3；T, M, Q are independently selected from N, CR3;
    X、Y、Z独立地选自N、CR5；X, Y, Z are independently selected from N, CR5;
    R1独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R1 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy base, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
    当R1独立地为C1-4烷基时，两个R1连同其所连接的C一起可形成3-7元环烷基，该环烷基可任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R1 is independently C 1-4 alkyl, the two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group substituted, the alkyl group , alkenyl, alkynyl, alkoxy is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C Substituted with 2-4 alkynyl and C 1-4 alkoxy groups;
    R2独立地选自H、F、Cl、Br、OH、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基所取代；R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered heteroaryl containing 1-3 independently selected from N, O, S , -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally one or more independently selected from F , Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, containing Substituted with 1-3 3-7-membered heterocycloalkyl groups independently selected from N, O, and S, and 1-3 5-6-membered heteroaryl groups independently selected from N, O, S;
    R3独立地选自H、F、Cl、Br、OH、CN、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-NR8C(O)R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、-NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基所取代； R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, -NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Substituted by heteroaryl;
    R4选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R4 is selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3- 7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups substituted;
    R5独立地选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , Substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
    R7独立地选自H、F、Cl、Br、OH、CN、NR8R9、＝O、C1-4烷基、C3-7环烷基，所述烷基和环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R7 is independently selected from H, F, Cl, Br, OH, CN, NR8R9, =O, C 1-4 alkyl, C 3-7 cycloalkyl, the alkyl and cycloalkyl are optionally replaced by one Or substituted by multiple groups independently selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
    R8和R9独立地选自H、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基，所述烷基、烯基、炔基、烷氧基任选地被一个或多个选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R8 and R9 are independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, the alkyl, alkenyl , Alkynyl and alkoxy groups are optionally substituted by one or more groups selected from F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl;
    当R8和R9连接在同一原子上时，R8和R9连同其所连接的原子一起可形成含有1-3个独立地选自N、O、S的3-7元杂环烷基，该杂环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团取代，所述烷基、烯基、炔基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基的基团所取代；When R8 and R9 are connected on the same atom, R8 and R9 together with the atom to which they are connected can form a 3-7 membered heterocycloalkyl group containing 1-3 independently selected from N, O, and S. The heterocyclic ring The alkyl group is optionally one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkoxy groups substituted, the alkyl, alkenyl, alkynyl, alkoxy groups optionally by one or more independently selected from F, Cl, Br, OH, CN, NH 2 , C Substituted with 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy groups;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    n为0、1、2、3、4、5、6、7或8。n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
    优选地：Preferably:
    T为N，M、Q独立地选自CR3；T is N, M and Q are independently selected from CR3;
    X、Y、Z独立地选自CR5；X, Y, Z are independently selected from CR5;
    R1独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基，所述烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2的基团所取代；R1 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, the alkyl group is optionally selected from one or more independently selected from F, Cl, Substituted by Br, OH, CN, NH 2 groups;
    当R1独立地为C1-4烷基时，两个R1连同其所连接的C一起可形成3-7元环烷基，该环烷基可任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；When R1 is independently C 1-4 alkyl, two R1 together with the C to which they are attached may form a 3-7 membered cycloalkyl group, which may optionally be one or more independently selected from Substituted with F, Cl, Br, OH, CN, NH 2 and C 1-4 alkyl groups;
    R2独立地选自H、F、Cl、Br、OH、CN、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基的基团所取代；R2 is independently selected from H, F, Cl, Br, OH, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 Cycloalkyl, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl groups are optionally one or more independently selected from F, Cl, Br, OH, CN, Substituted with NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl groups;
    R3独立地选自H、F、Cl、Br、OH、CN、NO2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基、含有1-3个独立地选自N、O、S的3-7元杂环烷基、含有1-3个独立地选自N、O、S的5-6元杂芳基、-C(O)R8、-C(O)NR8R9、-S(O)2R8、-S(O)2NR8R9、-NR8R9、-NR8C(O)R9、-P(O)R8R9，所述烷基、烯基、炔基、烷氧基、环烷基、杂环烷基、杂芳基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-7环烷基的基团所取代；R3 is independently selected from H, F, Cl, Br, OH, CN, NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-7 cycloalkyl, 3-7-membered heterocycloalkyl containing 1-3 independently selected from N, O, S, 5-6-membered containing 1-3 independently selected from N, O, S Heteroaryl, -C(O)R8, -C(O)NR8R9, -S(O) 2 R8, -S(O) 2 NR8R9, -NR8R9, -NR8C(O)R9, -P(O)R8R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally replaced by one or Multiple independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3 -7 cycloalkyl group substituted;
    R4选自C1-4烷氧基，所述烷氧基任选地被一个或多个独立地选自F、Cl、Br的基团所取代； R4 is selected from C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br;
    R5独立地选自H、F、Cl、Br、OH、CN、NH2、C1-4烷基，所述烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2的基团所取代；R5 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl, and the alkyl group is optionally selected from one or more independently selected from F, Cl, Br, OH , CN, NH 2 groups substituted;
    R7独立地选自H、F、Cl、Br、OH、CN、NH2、＝O、C1-4烷基、C3-7环烷基，所述烷基和环烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R7 is independently selected from H, F, Cl, Br, OH, CN, NH 2 , =O, C 1-4 alkyl, C 3-7 cycloalkyl, the alkyl and cycloalkyl are optionally replaced by Substituted with one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 , C 1-4 alkyl;
    R8和R9独立地选自H、OH、C1-4烷基、C1-4烷氧基，所述烷基、烷氧基任选地被一个或多个独立地选自F、Cl、Br、OH、CN、NH2、C1-4烷基的基团所取代；R8 and R9 are independently selected from H, OH, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy groups are optionally one or more independently selected from F, Cl, Substituted by Br, OH, CN, NH 2 and C 1-4 alkyl groups;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.
  3. 如权利要求1或2所述的化合物，其特征在于，结构如下式(IC)所示：
    The compound according to claim 1 or 2, characterized in that its structure is represented by the following formula (IC):
    其中，in,
    X、Y独立地选自N、CR5；X and Y are independently selected from N and CR5;
    R1独立地选自H、OH、＝O、C1-4烷基；R1 is independently selected from H, OH, =O, C 1-4 alkyl;
    当R1均为甲基时，两个R1连同其所连接的C一起可形成环丙烷基；When R1 is both methyl, the two R1 together with the C to which they are connected can form a cyclopropyl group;
    R2独立地选自H、C1-4烷基、-S(O)2R8、-P(O)R8R9，所述烷基任选地被一个或多个独立地选自OH、C1-4烷氧基的基团所取代；R2 is independently selected from H, C 1-4 alkyl, -S(O) 2 R8, -P(O)R8R9, the alkyl group is optionally substituted by one or more groups independently selected from OH, C 1-4 alkoxy;
    R3选自H、F、Cl、Br、CN、C1-4烷基；R3 is selected from H, F, Cl, Br, CN, C 1-4 alkyl;
    R4选自C1-4烷基、C1-4烷氧基、环丙烷基，所述烷基、烷氧基、环丙烷基任选地被一个或多个独立地选自F、Cl、Br、CN、OH的基团所取代；R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Substituted by Br, CN, OH groups;
    R5独立地选自H、CN；R5 is independently selected from H, CN;
    R7独立地选自H、C1-4烷基，所述烷基任选地被一个或多个独立地选自F、Cl、Br、OH、CN的基团所取代；R7 is independently selected from H, C 1-4 alkyl, the alkyl is optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN;
    R8和R9独立地选自NH2、C1-4烷基。R8 and R9 are independently selected from NH 2 and C 1-4 alkyl.
    优选地，结构如下式(ID)所示：
    Preferably, the structure is as shown in the following formula (ID):
    其中，in,
    R1独立地选自H、＝O、甲基；R1 is independently selected from H, =O, methyl;
    当R1均为甲基时，两个R1连同其所连接的C一起可形成环丙烷基；When R1 is both methyl, the two R1 together with the C to which they are connected can form a cyclopropyl group;
    R3选自H、F、Cl、Br、CN、甲基；R3 is selected from H, F, Cl, Br, CN, methyl;
    R4选自C1-4烷基、C1-4烷氧基、环丙烷基，所述烷基、烷氧基、环丙烷基任选地被一个或多个独立地选自F、Cl、Br、CN、OH的基团所取代。R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and the alkyl, alkoxy, cyclopropyl is optionally one or more independently selected from F, Cl, Replaced by Br, CN, OH groups.
    更优选地，结构如下式(IB)所示：
    More preferably, the structure is as shown in the following formula (IB):
    其中：in:
    R1独立地选自H、甲基；R1 is independently selected from H, methyl;
    R3选自H、F、Cl、Br、甲基。R3 is selected from H, F, Cl, Br, methyl.
    或者，更优选地，结构如下式(IF)所示：
    Or, more preferably, the structure is as shown in the following formula (IF):
    其中，in,
    R3选自H、F、Cl、Br、甲基；R3 is selected from H, F, Cl, Br, methyl;
    R4选自C1-4烷基、C1-4烷氧基，所述烷基、烷氧基任选地被一个或多个独立地选自F、Cl、Br的基团所取代；优选甲氧基、三氟甲氧基；R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br; preferably Methoxy, trifluoromethoxy;
    R6选自 R6 is selected from
  4. 如权利要求1所述的化合物，其特征在于，结构如下式(IE)所示：
    The compound according to claim 1, characterized in that its structure is represented by the following formula (IE):
    其中，in,
    R1独立地选自H、甲基；R1 is independently selected from H, methyl;
    当R1均为甲基时，两个R1连同其所连接的C一起可形成环丙烷基；When R1 is both methyl, the two R1 together with the C to which they are connected can form a cyclopropyl group;
    R3选自H、F、Cl、Br、甲基；R3 is selected from H, F, Cl, Br, methyl;
    R4选自C1-4烷基、C1-4烷氧基，所述烷基、烷氧基任选地被一个或多个独立地选自F、Cl、Br的基团所取代。R4 is selected from C 1-4 alkyl, C 1-4 alkoxy, which is optionally substituted by one or more groups independently selected from F, Cl, Br.
  5. 如权利要求1所述的化合物，其特征在于，所述化合物选自：



    The compound of claim 1, wherein the compound is selected from:



  6. 一种药物组合物，其特征在于，含有如权利要求1-5中任一项所述的化合物和药学上可接受的载体。A pharmaceutical composition, characterized by containing the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
  7. 一种抑制PLK1的方法，其特征在于，使用如权利要求1-5中任一项所述的化合物。A method for inhibiting PLK1, characterized by using the compound according to any one of claims 1-5.
  8. 一种预防和/或治疗PLK1相关疾病的方法，其特征在于，给予有需要的个体治疗和/或预防有效量的如权利要求1-5中任一项所述的化合物和如权利要求6所述的药物组合物。A method for preventing and/or treating PLK1-related diseases, characterized by administering to an individual in need a therapeutically and/or preventively effective amount of a compound as claimed in any one of claims 1-5 and a compound as claimed in claim 6 the pharmaceutical composition described above.
    优选地，所述PLK1相关疾病为癌症。Preferably, the PLK1-related disease is cancer.
    更优选地，所述癌症选自直肠癌、肺癌、乳腺癌、前列腺癌、胰腺癌、胃癌、头颈癌、卵巢癌、子宫癌、胶质瘤、肝癌、食管癌、膀胱癌、肾癌、淋巴瘤、黑色素瘤、骨肉瘤、白血病、骨髓增生异常综合征。More preferably, the cancer is selected from rectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, glioma, liver cancer, esophageal cancer, bladder cancer, kidney cancer, lymphoma tumors, melanoma, osteosarcoma, leukemia, myelodysplastic syndrome.
  9. 如权利要求1-5中任一项所述的化合物和如权利要求6所述的药物组合物在制备PLK1抑制剂中的 用途。The use of the compound according to any one of claims 1 to 5 and the pharmaceutical composition according to claim 6 in the preparation of PLK1 inhibitors use.
  10. 如权利要求1-5中任一项所述的化合物和如权利要求6所述的药物组合物在制备用于预防和/或治疗PLK1相关疾病的药物中的用途。Use of a compound according to any one of claims 1 to 5 and a pharmaceutical composition according to claim 6 in the preparation of a medicament for preventing and/or treating PLK1-related diseases.
    优选地，所述PLK1相关疾病为癌症。Preferably, the PLK1-related disease is cancer.
    更优选地，所述癌症选自直肠癌、肺癌、乳腺癌、前列腺癌、胰腺癌、胃癌、头颈癌、卵巢癌、子宫癌、胶质瘤、肝癌、食管癌、膀胱癌、肾癌、淋巴瘤、黑色素瘤、骨肉瘤、白血病、骨髓增生异常综合征。 More preferably, the cancer is selected from rectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, glioma, liver cancer, esophageal cancer, bladder cancer, kidney cancer, lymphoma tumors, melanoma, osteosarcoma, leukemia, myelodysplastic syndrome.
PCT/CN2023/117138 2022-09-08 2023-09-06 Compound as plk1 inhibitor, and preparation method therefor and use thereof WO2024051717A1 (en)

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CN1860104A (en) * 2003-07-30 2006-11-08 西克拉塞尔有限公司 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors
CN101044137A (en) * 2004-08-20 2007-09-26 贝林格尔·英格海姆国际有限公司 2,4-di(aminophenyl)pyrimidine derivatives as plk inhibitors
WO2009040399A1 (en) * 2007-09-28 2009-04-02 Nerviano Medical Sciences S.R.L. Substituted pyrrolo-pyrimidine derivatives, process for their preparation and their use as kinase inhibitors
CN106810536A (en) * 2015-11-30 2017-06-09 甘李药业股份有限公司 A kind of kinases inhibitor and preparation method thereof and medical usage
WO2022061273A1 (en) * 2020-09-21 2022-03-24 Prelude Therapeutics, Incorporated Cdk inhibitors and their use as pharmaceuticals
WO2022133215A1 (en) * 2020-12-18 2022-06-23 Prelude Therapeutics Incorporated Cdk inhibitors and their use as pharmaceuticals
CN115819418A (en) * 2023-02-14 2023-03-21 山东绿叶制药有限公司 PLK1 kinase inhibitor and preparation method and application thereof
WO2023087027A1 (en) * 2021-11-15 2023-05-19 Erasca, Inc. Thiophene ulk1/2 inhibitors and their use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1860104A (en) * 2003-07-30 2006-11-08 西克拉塞尔有限公司 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors
CN101044137A (en) * 2004-08-20 2007-09-26 贝林格尔·英格海姆国际有限公司 2,4-di(aminophenyl)pyrimidine derivatives as plk inhibitors
WO2009040399A1 (en) * 2007-09-28 2009-04-02 Nerviano Medical Sciences S.R.L. Substituted pyrrolo-pyrimidine derivatives, process for their preparation and their use as kinase inhibitors
CN106810536A (en) * 2015-11-30 2017-06-09 甘李药业股份有限公司 A kind of kinases inhibitor and preparation method thereof and medical usage
WO2022061273A1 (en) * 2020-09-21 2022-03-24 Prelude Therapeutics, Incorporated Cdk inhibitors and their use as pharmaceuticals
WO2022133215A1 (en) * 2020-12-18 2022-06-23 Prelude Therapeutics Incorporated Cdk inhibitors and their use as pharmaceuticals
WO2023087027A1 (en) * 2021-11-15 2023-05-19 Erasca, Inc. Thiophene ulk1/2 inhibitors and their use thereof
CN115819418A (en) * 2023-02-14 2023-03-21 山东绿叶制药有限公司 PLK1 kinase inhibitor and preparation method and application thereof

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