WO2014194667A1 - Composé alkynyle hétérocyclique et ses utilisations - Google Patents

Composé alkynyle hétérocyclique et ses utilisations Download PDF

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Publication number
WO2014194667A1
WO2014194667A1 PCT/CN2014/000557 CN2014000557W WO2014194667A1 WO 2014194667 A1 WO2014194667 A1 WO 2014194667A1 CN 2014000557 W CN2014000557 W CN 2014000557W WO 2014194667 A1 WO2014194667 A1 WO 2014194667A1
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Prior art keywords
group
substituted
fluorenyl
halogen
ring
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PCT/CN2014/000557
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English (en)
Chinese (zh)
Inventor
胡有洪
耿美玉
刘杨
丁健
艾菁
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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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    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and particularly relates to a novel class of alkynyl heterocyclic compounds and their use in preparing antitumor drugs. Background technique
  • Receptor tyrosine kinases are involved in the regulation of cell proliferation, migration, differentiation, apoptosis and a series of cell biological events. Overexpression or overactivation is closely related to tumor development and is a key target for tumor therapy. point.
  • Fibroblast growth factor receptors FGFRs
  • the FGFR family mainly includes four subtypes of FGFR1, FGFR2, FGFR3 and FGFR4. (Turner N., Grose R., Fibroblast growth factor signalling: from development to cancer, Nature Reviews Cancer. (2010) 10: 116-129.
  • FGFR members are continuously activated due to gene amplification, mutation, fusion or ligand induction. Induces tumor cell proliferation, invasion, migration, and promotes angiogenesis.
  • FGFRs are highly expressed or abnormally activated in various tumors, and are closely related to poor prognosis of tumor patients, such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, and uterus.
  • Endometrial cancer prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratinoma, myeloma, rhabdomyosarcoma, etc.
  • Died MV, Arnedos M, Andre F, Soria JC Fibroblast growth factor receptor inhibitors as a cancer treatment : from a biologic rationale to medical perspectives. Cancer discovery, 2013, 3, 264-79; Turner N , Grose R: Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer, 2010, 10, 116-29.
  • FGFR and its ligand FGFs of various subtypes in hepatocarcinoma have abnormal expression and activation, such as FGFR2, FGFR3, FGFR4, FGF19, FGF2, FGF5, FGFS, FGF9 and so on.
  • FGF/FGFR axis in liver cancer (Chen AL, Shen YC, Zhu AX: Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma. Oncology-Basel, 2011, 81, 372 -80. ).
  • FGFR3 mutations account for 50%-60% of non-invasive bladder cancers, and FGFR3 mutations account for 10%-15% of invasive bladder cancers.
  • FGFR3t(4;14)(pl6.3;q32) gene rearrangement accounts for 15-20% in multiple myeloma, this fusion gene can lead to high expression and sustained activation of FGFR3, leading to clonal plasma cells in bone And a large amount of accumulation in the bone marrow affects the normal hematopoietic function.
  • the present invention targets FGFR1 and FGFR2, and synthesizes a series of novel alkynyl heterocycles having excellent FGFR1 and FGFR2 inhibitory activities. Compounds, and this series of compounds showed good inhibitory activity against FGFR2-dependent gastric cancer cell lines. Summary of the invention
  • the inventors of the present invention synthesized a series of novel alkynyl heterocyclic compounds, and determined that these compounds have good inhibitory activities at the molecular level of FGFR1 and FGFR2, and can effectively inhibit FGFR2-dependent at the nM level.
  • the growth of gastric cancer cell lines has significant anti-tumor activity. This is important for the development of new anti-tumor drugs.
  • Another object of the present invention is to provide the use of the above novel alkynyl heterocyclic compounds for the preparation of antitumor drugs.
  • a further object of the present invention is to provide a pharmaceutical composition having antitumor activity comprising a therapeutically effective amount of one or more of the above novel alkynyl heterocyclic compounds and a pharmaceutically acceptable excipient.
  • the present invention provides a class of alkynyl heterocyclic compounds represented by the general formula I,
  • M and Y are each independently CH or N;
  • W is C or N; wherein, when W is N, it does not exist;
  • L is -C(0)NH- or -NHC(O)-;
  • R 2 is selected from:
  • R 2 and an adjacent atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the heteroaryl
  • the ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C r C 6 fluorenyl group, halogen-substituted C r C 6 fluorenyl group, CrC 6 fluorenyloxy group;
  • R 2 and an adjacent N atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein, the heteroaryl
  • the ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C r C 6 fluorenyl group, halogen-substituted C r C 6 fluorenyl group, CrC 6 fluorenyloxy group;
  • R 3 is selected from:
  • R 5 and R 6 are each independently selected from:
  • n 0 or 1
  • R 7 and R 8 are each independently:
  • R 7 and 11 8 and the attached N atom may form a ring Het 1 , wherein Het 1 is a 5-8 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S; a 4-10 membered heterocyclic ring selected from the group consisting of hetero atoms in N, 0 and S; wherein The heteroaryl ring or heterocyclic ring may be substituted with a substituent selected from a halogen, an oxo group, a CrC 6 fluorenyl group, a halogen-substituted CrC 6 fluorenyl group, and a CrC 6 fluorenyloxy group;
  • ( ⁇ and each independently are hydrogen; C r C 6 fluorenyl; C 3 -C 6 cyclodecyl; C r C 6 decanoyl; unsubstituted or 1-5 selected from 3 ⁇ 4, CrC 6 ⁇ a phenyl group substituted with a substituent in the CrC 6 fluorenyl group and the CrC 6 fluorenyl group;
  • the B ring is a benzene ring; or a 5-6 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S.
  • M and Y are each independently CH or N;
  • W is C or N; wherein, when W is N, it does not exist;
  • L is -C(0)NH- or -NHC(O)-;
  • a phenyl group which is unsubstituted or substituted with from 1 to 5 substituents selected from halogen, C r C 4 fluorenyl, halogen-substituted C r C 4 fluorenyl, C r C 4 fluorenyloxy;
  • the Y ring of the A ring may form a benzene ring, a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the benzene
  • R 2 is selected from the group consisting of
  • a phenyl group which is unsubstituted or substituted with from 1 to 5 substituents selected from halogen, C r C 4 fluorenyl, halogen-substituted C r C 4 fluorenyl, C r C 4 fluorenyloxy;
  • Q n 3 ⁇ 4 are each independently hydrogen; C r C 4 fluorenyl; C 3 -C 6 cyclodecyl; C r C 4 decanoyl; unsubstituted or a phenyl group substituted with 1-5 substituents selected from the group consisting of halogen, C r C 4 fluorenyl, halogen-substituted C r C 4 fluorenyl, and C r C 4 fluorenyloxy;
  • R 2 and an adjacent atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein The ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C r C 4 fluorenyl group, 3 ⁇ 4 cyano substituted C r C 4 fluorenyl group, C r C 4 fluorenyloxy group;
  • R 2 and an adjacent N atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein The heterocyclic ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C r C 4 fluorenyl group, halogen-substituted dC 4 fluorenyl group, and C r C 4 fluorenyloxy group;
  • R is selected from the group consisting of
  • the Y ring with the A ring may form an anthracene ring with the following structure of the A ring:
  • R r , R r , and R 2 are each independently selected from:
  • R 2 is selected from the group consisting of
  • R 2 and adjacent atoms may form an anthracene ring with the following structure of the A ring:
  • R 2 and adjacent atoms may form an anthracene ring of the following structure with the A ring:
  • R 2 and an adjacent N atom may form an anthracene ring of the following structure with the A ring:
  • R 3 is:
  • the B ring is a divalent group of the following structure: And when the B ring is a benzene ring, 1 ⁇ and 1 2 form a ring E, and the ring of the ring formed by the ring E and the ring A The following structure:
  • R 4 , R 5 and Re are selected from:
  • n 0 or 1
  • R 7 and R 8 are each independently:
  • R 7 and Rg and the attached N atom may form a ring Het 1 , wherein Het 1 is a 5-6 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S; 3 4-10 membered heterocyclic rings selected from heteroatoms in N, 0 and S; wherein the heteroaryl ring or heterocyclic ring may be substituted by a halogen, an oxo group, a dC 4 fluorenyl group, a halogen Substituent substitution in C r C 4 fluorenyl, C r C 4 methoxy;
  • R 4 , R 5 and Re are selected from:
  • n is Het 1 is the following structure:
  • the c-ring is of the following structure:
  • Another object of the present invention is to provide a process for producing an alkynyl heterocyclic compound represented by the general formula I, which comprises an alkyne-containing hetero
  • the preparation method of the cyclic compound includes any one selected from the following synthetic routes I, II and III.
  • Synthetic route I includes the following steps:
  • Step 1 adding the compound 1-1, NBS, AIBN and CC1 4 to the round bottom flask, and reacting with an oil bath, the reaction temperature is 70-120 ° C; after the reaction is completed, the compound 1-2 can be obtained by purification;
  • the equivalent ratio of the compound 1-1, NBS and AIBN was 1:1.1:0.2; the heating method was an oil bath; the temperature was 100 ° C ; and the reaction time was 36 hours.
  • Step 2 Add compound 1-2, 1-3, CH 2 C1 2 and Et 3 N to the round bottom flask, and carry out the reaction at room temperature; after the reaction is completed, the compound 1-4 can be obtained by purification; Compound 1-2, The equivalent ratio of the compound 1-3 to Et 3 N was 1:1.1:1.2; the temperature was room temperature; and the reaction time was 12 hours.
  • Step 3 Add compound 1-4, reduced Fe powder, EtOH and NH 4 C1 to the round bottom flask, and heat the reaction in an oil bath at a reaction temperature of 70-120 ° C. After the reaction is completed, the compound 1 can be obtained by purification. -5;
  • the equivalent ratio of the compound 1-4, the reduced Fe powder and the NH 4 C1 is 1:4:2; the heating method is an oil bath; the temperature is 100 ° C ; and the reaction time is 10 hours.
  • Step 4 Adding compound 1-6, S0C1 2 and DMF to a round bottom flask, and heating the reaction in an oil bath at a reaction temperature of 80 to 120 ° C; after completion of the reaction, purification is carried out to obtain a compound 1-7; -6, DMF equivalent ratio is 1:0.05, S0C1 2 is solvent; heating method is oil bath; temperature is 100 ° C ; reaction time is 8 hours.
  • Step 5 Add the compound 1-5, 1-7, DMF and Et 3 N to the round bottom flask, and carry out the reaction at room temperature; after the reaction is completed, the compound 1-8 can be obtained by purification; Compound 1-5, Compound 1- The equivalent ratio of 7 to Et 3 N is 1:1:1.1; the temperature is room temperature; the reaction time is 4 hours.
  • Step 6 Add compound 1-8, trimethylsilylacetylene, Pd(PPh 3 ) 4 , CuI, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° C; after completion of the reaction, purification to give compound 1-9; compounds 1-8, trimethylsilyl acetylene, Pd (PPh 3) 4, Cul, DIPEA, and the equivalent ratio of 1: 1.5: 0.05: 0.1 :3;
  • the heating method is microwave irradiation, the power is 150 watts, the time is 20 minutes; the reaction temperature is 80 °C.
  • Step 7 A compound 1-9, potassium carbonate and methanol are added to a round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound 1-10 is obtained by purification.
  • the equivalent ratio of the compound 1-9 to potassium carbonate was 1:10, methanol was the solvent, and the chamber temperature was room temperature; the reaction time was 3 hours.
  • Step 8 Add compound 1-10, compound 1-1-1, Pd(PPh 3 ) 4 , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° C. ; after the reaction, purification to give compound 1-12.
  • the equivalent ratio of compound 1-10, compound 1-1-1, Pd(PPh 3 ) 4 , Cul and DIPEA is 1:1.5:0.05:0.1:3;
  • Synthetic route ⁇ Synthetic Route II includes the following steps:
  • Step 1 The compound 11-1, PBr 3 and toluene are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ⁇ -2 is obtained by purification; the equivalent ratio of the compound II-1 and PBr 3 is 1: 2, toluene is the solvent; the temperature is room temperature; the reaction time is 12 hours.
  • Step 2 The compound 11-2, 11-3, CH 2 C1 2 and Et 3 N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ⁇ -4 is obtained by purification; the compound 11-2, The equivalent ratio of the compound ⁇ -3 to Et 3 N was 1:1:1.1; the temperature was room temperature; and the reaction time was 12 hours.
  • Step 3 Adding compound 11-4, reducing Fe powder, EtOH and NH 4 C1 to a round bottom flask, and heating the reaction in an oil bath at a reaction temperature of 70 to 120 ° C; after completion of the reaction, the compound is obtained by purification. -5;
  • the equivalent ratio of the compound 11-4, the reduced Fe powder and the NH 4 C1 is 1:4:2; the heating method is an oil bath; the temperature is 100 ° C; and the reaction time is 10 hours.
  • Step 4 Adding compound 11-6, SOCl 2 and DMF to a round bottom flask, and reacting with an oil bath, the reaction temperature is 80 to 120 ° C; after completion of the reaction, the compound ⁇ -7 can be obtained by purification;
  • the equivalent ratio of -6 to DMF is 1:0.05, SOCl 2 is a solvent; the heating method is an oil bath; the temperature is 100 ° C ; and the reaction time is 8 hours.
  • Step 5 The compound 11-5, 11-7, DMF and Et 3 N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ⁇ -8 is obtained by purification; the compound 11-5, the compound ⁇ - The equivalent ratio of 7 to Et 3 N is 1:1:1.1; the temperature is room temperature; the reaction time is 4 hours.
  • Step 6 Add compound 11-8, trimethylsilylacetylene, Pd(PPh 3 ) 4 , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120. After completion of the reaction, the compound ⁇ -9 is obtained by purification; the equivalent ratio of compound 11-8, trimethylsilylacetylene, Pd(PPh 3 ) 4 , Cul, and DIPEA is 1:1.5:0.05:0.1 :3; The heating method is microwave irradiation, the power is 150 watts, the time is 20 minutes; the reaction temperature is 80 ⁇ . C.
  • Step 7 A compound 11-9, potassium carbonate and methanol are added to a round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound 11-10 is obtained by purification.
  • the equivalent ratio of the compound ⁇ -9 to potassium carbonate was 1:10, methanol was the solvent, the chamber temperature was room temperature, and the reaction time was 3 hours.
  • Step 8 Add compound 11-10, compound 11-11, Pd(PPh 3 ) 4 , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° C. ; after the reaction, purification to give compound 11-12.
  • the equivalent ratio of compound 11-10, compound 11-11, Pd(PPh 3 ) 4 , Cul and DIPEA is 1:1.5:0.05:0.1:3; the heating method is microwave irradiation, the power is 150 watts, and the time is 20 minutes;
  • the reaction temperature was 90 °C.
  • Synthetic route III includes the following steps:
  • Step 1 The compound 111-1, NaBr0 3 , NaHS0 3 , H 2 0 and EtOAc were added to a round bottom flask, and the reaction was carried out at room temperature; after completion of the reaction, the compound ⁇ -2 was obtained by purification; Compound 111-1, NaBr0 The equivalent ratio of 3 to NaHS0 3 was 1:3:3, the solvent ratio of solvent H 2 0 to EtOAc was 1:1; the temperature was room temperature; and the reaction time was 12 hours.
  • Step 2 The compound 111-2, 111-3, CH 2 C1 2 and Et 3 N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ⁇ -4 is obtained by purification; the compound 111-2, The equivalent ratio of the compound ⁇ -3 to Et 3 N was 1:1:1.1, the temperature was room temperature; and the reaction time was 12 hours.
  • Step 3 The compound 111-4, 111-5, DMF and Et 3 N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ⁇ -6 is obtained by purification; the compound 111-4, the compound ⁇ - The equivalent ratio of 5 to Et 3 N is 1:1:1.1, the temperature is room temperature; and the reaction time is 4 hours.
  • Step 4 Add compound 111-6, trimethylsilylacetylene, Pd(PPh 3 ) 4 , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120. After completion of the reaction, the compound ⁇ -7 is obtained by purification; the equivalent ratio of the compound 111-6, trimethylsilylacetylene, Pd(PPh 3 ) 4 , Cul and DIPEA is 1:1.5:0.05:0.1: 3; The heating method is microwave irradiation, the power is 150 watts, the time is 20 minutes; the reaction temperature is 80 ⁇ . C.
  • Step 5 The compound 111-7, potassium carbonate and methanol are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ⁇ -8 is obtained by purification; the equivalent ratio of the compound ⁇ -7 to potassium carbonate is 1: 10, methanol is the solvent, the chamber temperature is room temperature; the reaction time is 3 hours.
  • Step 6 Add compound 111-8, compound 111-9, Pd(PPh 3 ) 4 , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° C. ; after the reaction, purification to give compound 111-10.
  • the equivalent ratio of compound 111-9, compound 111-8, Pd(PPh 3 ) 4 , Cul and DIPEA is 1:1.5:0.05:0.1:3; the heating method is microwave irradiation, the power is 150 watts, and the time is 20 minutes;
  • the reaction temperature was 90 °C.
  • M, Y, W, Ri ⁇ R 2 , R 3 , R 7 , Rg and B are as defined above.
  • the present invention provides the use of the alkynyl heterocyclic compound represented by the above formula (I) for the preparation of an antitumor drug.
  • the present invention provides a pharmaceutical composition having antitumor activity comprising a therapeutically effective amount of one or more alkynyl heterocyclic compounds represented by the above formula (I) and A pharmaceutically acceptable excipient.
  • the tumor is non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, gastric cancer, skin cancer, epithelial cell carcinoma, nasopharyngeal carcinoma, lymphoma, gastrointestinal Any of the stromal tumors, leukemia, and the like.
  • NBS N-bromosuccinimide
  • AIBN azobisisobutyronitrile
  • Fe iron
  • NaBr0 3 sodium bromate
  • NaHS0 3 sodium bisulfite
  • Pd(PPh 3 ) 4 tetrakistriphenylphosphine palladium
  • DIPEA Diisopropylethylamine
  • the synthesis method is as in the following except that 4-bromo-1-isopropyl-1 hydrogen-pyrrole [2,3-c]pyridine is used instead of 4-bromoisoquinoline.
  • the synthesis method is as in the following except that 4-bromo-7-methoxy-1 hydrogen-pyrrole [2,3-c]pyridine is used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 1-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 4-bromoisoquinoline 1 (2H)-one was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 4-bromo-6,7-dimethoxyisoquinoline 1 (2H)-one was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 1-chloro-4-bromoisoquinoline was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 1-chloro-4-bromo-6,7-dimethoxyisoquinoline was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 1-methoxy-4-bromoisoquinoline was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 6-chloro-1,2,4-triazolium [4,3-B]pyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-chloro-7H-pyrrole [2,3-C]pyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-hydroxypyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-methoxypyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-aminopyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-methylaminopyridine was used in place of 4-bromoisoquinoline.
  • Example 36 The synthesis was carried out as in Example 1, except that 3-bromo-5-cyclopropylaminopyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-phenylpyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-(4-trifluoromethylphenyl)pyridine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-carboxypyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-ethylaminocarbonylpyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that dichloropyridazine was used in place of 4-bromoisoquinoline.
  • Example 55 The synthesis method was as in Example 1, except that 3-hydroxy-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-methoxy-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-amino-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-methylamino-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-cyclopropylamino-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-anilino-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-(2,6-dichloro-3,5-dimethoxyanilino)-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-acetamido-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-phenyl-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-(4-methoxyphenyl)-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-(3-trifluoromethyl-4-chlorophenyl)-6-chloropyridazine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-iodobenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-iodo-4-ethylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • Example 73 The synthesis method was as in Example 1, except that 3-iodo-4-cyclopropylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-iodo-4-fluorobenzoic acid was used instead of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-iodo-4-chlorobenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-iodo-4-bromobenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-iodo-4-methoxybenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-iodo-4-trifluoromethylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 6-chloropyridine-2-carboxylic acid was used instead of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 5-bromonicotinic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 2-bromoisonicotinic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 6-bromonicotinic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 4-chloropyrimidine-2-carboxylic acid was used instead of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 6-chloropyrimidine-4-carboxylic acid was used instead of 3-iodo-4-methylbenzoic acid.
  • the synthesis method is as in Example 1, except that 5-bromo-7-azaphosphorium is used instead of 4-bromoisoquinoline, and 2-chloropyrimidine-4-carboxylic acid is used instead of 3-iodo-4-methylbenzoic acid. .
  • the synthesis method was as in Example 1, except that 2-bromothiazole-5-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.
  • the synthesis method is as follows except that 3-iodobenzoic acid is used instead of 3-iodo-4-methylbenzoic acid, and 4-bromo-1 hydrogen-pyrrole [2,3-c]pyridine is used instead of 4-bromoisoquinoline. example 1.
  • the synthesis method was as in Example 1, except that morpholine was used instead of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that hexahydropyridine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that 1H-1,2,3-triazole was used in place of N-methylpiperazine.
  • Example 103 The synthesis method was as in Example 1, except that tetrahydropyrrole was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that pyrrole was used instead of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that imidazole was used instead of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that pyrazole was used instead of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that 4-methylpyrazole was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that high piperidine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that azetidinium was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that thiomorpholine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that thiomorpholine-U-dioxide was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that isothiazolium ruthenium 1,1-dioxide was used instead of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that tetrahydroisoquinoline was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that iso-porphyrin was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that 4-methylimidazole was used instead of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that N-methylhomopiperazine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 130 except that 2-amino-5-bromothiazole was used instead of 3-iodo-4-methylaniline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-methylpyridine was used in place of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that 3-bromo-5-isopropylpyridine was used instead of 4-bromoisoquinoline.
  • the synthesis method was as in Example 1, except that dimethylamine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that isopropylamine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that cyclopentylamine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that cyclopropylamine was used in place of N-methylpiperazine.
  • the synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodo-4-chlorobenzoic acid instead of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodo-4-fluorobenzoic acid instead of 3-iodo-4-methylbenzoic acid.
  • the synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodobenzoic acid instead of 3-iodo-4-methylbenzoic acid.
  • Test Example 1 Molecular level receptor tyrosine kinase FGFR activity inhibition experiment
  • Enzyme reaction substrate Poly(Glu, Tyr) 4 1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 2 ( ⁇ g/ml, 125 ⁇ 1/well) The plate was coated with an enzyme and reacted at 37 ° C for 12-16 hours. The liquid in the well was discarded. The plate was washed and washed three times with 200 ⁇ l/well of T-PBS (PBS containing 0.1% Tween-20 in potassium free). 5 minutes each time. The enzyme plate was dried in an oven at 37 °C for 1-2 hours.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 V0 4 , 1 mM DTT
  • 50 ⁇ M compound 1% DMSO dissolved
  • 50 ⁇ l of FGFR tyrosine kinase protein diluted in reaction buffer was added. The reaction was carried out for 1 hour at 37 ° C in a shaker (100 rpm). For each experiment, two wells without ATP control wells and corresponding DMSO solvent control wells (negative control wells) were required.
  • the liquid in the well was discarded and the plate was washed three times with T-PBS.
  • the antibody PY99 ⁇ /well was added (the antibody was diluted with BSA 5 mg/ml in T-PBS at a concentration of 0.4 g/ml), 37. C shaker reaction for 0.5 hours. The liquid in the well was discarded and the plate was washed three times with T-PBS.
  • reaction was stopped by adding 2 M H 2 S0 4 50 ⁇ l/well, and read at VERSAmax using a tunable wavelength microplate reader with a wavelength of 490 nm.
  • the supernatant was taken for SDS-PAGE electrophoresis (Mini-PROTEAN 3 Cell, Bio-Rad, Hercules, CA, USA), and after electrophoresis, the protein was transferred to a nitrocellulose membrane using a semi-dry electrotransfer system (Amersham Life Sciences, Arlington Heights, IL, USA), the nitrocellulose membrane was placed in a blocking solution (5% skimmed milk powder diluted in TBS containing 1 mM sodium vanadate) for 2 hours at room temperature, and then the membrane was placed in anti-p-FGFR (Cell Sinaling) Technology ) (1 : 1000) or anti-GAPDH (Kangcheng Bio) (1:6000) antibody at 4 ° C overnight.
  • a blocking solution 5% skimmed milk powder diluted in TBS containing 1 mM sodium vanadate
  • A21 615 Route I 100-200 100-200 500-1000
  • A126 531 route ⁇ ⁇ 50 ⁇ 50 ⁇ 100

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Abstract

La présente invention concerne un composé alkynyle hétérocyclique tel que représenté par la formule (I), un procédé de préparation de celui-ci, et ses utilisations dans la préparation de médicaments antitumoraux.
PCT/CN2014/000557 2013-06-05 2014-06-04 Composé alkynyle hétérocyclique et ses utilisations Ceased WO2014194667A1 (fr)

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WO2016123391A1 (fr) * 2015-01-29 2016-08-04 Genentech, Inc. Composés thérapeutiques et leurs utilisations
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WO2018068739A1 (fr) * 2016-10-13 2018-04-19 深圳市塔吉瑞生物医药有限公司 Composé hétérocyclique d'alcynyle pour inhiber l'activité de la protéine kinase
US10150767B2 (en) 2014-11-10 2018-12-11 Genentech, Inc. Therapeutic compounds and uses thereof
US10183009B2 (en) 2014-11-10 2019-01-22 Genentech, Inc. Therapeutic compounds and uses thereof
US10258603B2 (en) 2014-11-10 2019-04-16 Genentech, Inc. Therapeutic compounds and uses thereof
US10538520B2 (en) 2013-12-24 2020-01-21 Oncotartis Inc. Benzamide and nicotinamide compounds and methods of using same
EP3584239A4 (fr) * 2017-02-20 2020-08-26 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Composé contenant un alcynyle o-aminohétéroaryle, son procédé de préparation et son utilisation
WO2020176501A1 (fr) * 2019-02-25 2020-09-03 Albert Einstein College Of Medicine Composés utiles pour l'inhibition de dimères de raf
JP2022169721A (ja) * 2017-10-30 2022-11-09 シンブリア セラピューティクス インク Ｉｒａｋ４阻害剤およびその使用
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CN107226809A (zh) * 2016-03-23 2017-10-03 浙江大德药业集团有限公司 酪氨酸激酶抑制剂
JP7474752B2 (ja) * 2018-09-12 2024-04-25 パデュー リサーチ ファウンデイション キナーゼ阻害剤としてのアルキニルニコチンアミド化合物
WO2020206583A1 (fr) * 2019-04-08 2020-10-15 Qilu Regor Therapeutics Inc. Inhibiteurs de kinase et leurs utilisations
CN116730978B (zh) * 2022-03-11 2025-11-18 中国科学院上海药物研究所 一类含杂芳环炔基化合物及其制备方法和用途
CN115947693B (zh) * 2022-12-18 2024-11-05 重庆医科大学 一种fgfr4抑制剂及其制备与应用

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US10538520B2 (en) 2013-12-24 2020-01-21 Oncotartis Inc. Benzamide and nicotinamide compounds and methods of using same
WO2015108490A3 (fr) * 2014-01-17 2015-11-26 Agency For Science, Technology And Research Dérivés hétéroarylalcyne et leurs utilisations
US10258603B2 (en) 2014-11-10 2019-04-16 Genentech, Inc. Therapeutic compounds and uses thereof
US10150767B2 (en) 2014-11-10 2018-12-11 Genentech, Inc. Therapeutic compounds and uses thereof
US10183009B2 (en) 2014-11-10 2019-01-22 Genentech, Inc. Therapeutic compounds and uses thereof
WO2016123391A1 (fr) * 2015-01-29 2016-08-04 Genentech, Inc. Composés thérapeutiques et leurs utilisations
CN107531692A (zh) * 2015-01-29 2018-01-02 基因泰克公司 治疗化合物及其用途
CN107531692B (zh) * 2015-01-29 2020-12-25 基因泰克公司 治疗化合物及其用途
US10202378B2 (en) 2015-01-29 2019-02-12 Genentech, Inc. Therapeutic compounds and uses thereof
EP3496717A4 (fr) * 2016-08-15 2020-01-15 Purdue Research Foundation Dérivés d'aminoisoquinoléine substitués en position 4
EP4011882A1 (fr) * 2016-08-15 2022-06-15 Purdue Research Foundation Dérivés d'aminoisoquinoléine substitués en position 4
JP2019527725A (ja) * 2016-08-15 2019-10-03 パデュー リサーチ ファウンデイション ４位置換アミノイソキノリン誘導体
JP7562256B2 (ja) 2016-08-15 2024-10-07 パデュー リサーチ ファウンデイション ４位置換アミノイソキノリン誘導体
CN109843294A (zh) * 2016-08-15 2019-06-04 普渡研究基金会 4-取代的氨基异喹啉衍生物
US11001559B2 (en) 2016-08-15 2021-05-11 Purdue Research Foundation 4-substituted aminoisoquinoline derivatives
WO2018035072A1 (fr) 2016-08-15 2018-02-22 Purdue Research Foundation Dérivés d'aminoisoquinoléine substitués en position 4
CN108473476B (zh) * 2016-10-13 2021-02-19 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白激酶活性的炔基杂环类化合物
WO2018068739A1 (fr) * 2016-10-13 2018-04-19 深圳市塔吉瑞生物医药有限公司 Composé hétérocyclique d'alcynyle pour inhiber l'activité de la protéine kinase
CN108473476A (zh) * 2016-10-13 2018-08-31 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白激酶活性的炔基杂环类化合物
EP3584239A4 (fr) * 2017-02-20 2020-08-26 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Composé contenant un alcynyle o-aminohétéroaryle, son procédé de préparation et son utilisation
US11891382B2 (en) 2017-04-26 2024-02-06 Basilea Pharmaceutica International AG Processes for the preparation of furazanobenzimidazoles and crystalline forms thereof
JP2022169721A (ja) * 2017-10-30 2022-11-09 シンブリア セラピューティクス インク Ｉｒａｋ４阻害剤およびその使用
WO2020176501A1 (fr) * 2019-02-25 2020-09-03 Albert Einstein College Of Medicine Composés utiles pour l'inhibition de dimères de raf
US12440494B2 (en) 2019-02-25 2025-10-14 Albert Einstein College Of Medicine Compounds useful for inhibiting RAF dimers

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