WO2018233684A1 - 7-位取代吡咯并三嗪类化合物或其药学上可用的盐，及其制备方法和用途 - Google Patents

7-位取代吡咯并三嗪类化合物或其药学上可用的盐，及其制备方法和用途 Download PDF

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WO2018233684A1
WO2018233684A1 PCT/CN2018/092419 CN2018092419W WO2018233684A1 WO 2018233684 A1 WO2018233684 A1 WO 2018233684A1 CN 2018092419 W CN2018092419 W CN 2018092419W WO 2018233684 A1 WO2018233684 A1 WO 2018233684A1
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alkyl
group
substituted
substituent
pharmaceutically acceptable
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PCT/CN2018/092419
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French (fr)
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杨春皓
蒙凌华
向皞月
李京
王祥
谭村
贺茜
丁健
陈奕
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中国科学院上海药物研究所
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Priority to SG11201912827TA priority Critical patent/SG11201912827TA/en
Priority to CN201880042091.1A priority patent/CN110869371B/zh
Priority to EP18820615.5A priority patent/EP3643717B1/en
Priority to ES18820615T priority patent/ES2887629T3/es
Priority to KR1020207002152A priority patent/KR102413943B1/ko
Priority to AU2018287971A priority patent/AU2018287971B9/en
Priority to CA3068114A priority patent/CA3068114C/en
Priority to JP2019571243A priority patent/JP6852199B2/ja
Priority to US16/626,254 priority patent/US11214572B2/en
Priority to RU2020101594A priority patent/RU2745548C1/ru
Priority to BR112019027545-2A priority patent/BR112019027545A2/pt
Publication of WO2018233684A1 publication Critical patent/WO2018233684A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a 7-position substituted pyrrolotriazine compound or a pharmaceutically usable salt thereof, and a process for the preparation thereof and use thereof.
  • the PI3K-Akt-mTOR signaling pathway is one of the major pathways that transmit signals from receptor tyrosine kinases and G-protein coupled receptors and plays an important role in a variety of cellular functions. Recent studies have found that in a variety of human tumors, multiple key nodal proteins in the PI3K-Akt-mTOR signaling pathway are over-activated by mutation or amplification of the coding gene [Vivancod et al., Nat Rev Cancer 2 (2002) , pp. 489-501]. PI3K, a bridge molecule that links extracellular signals and cellular responses, is a key factor regulating cell growth, metabolism, and survival. Its overactivation is closely related to the occurrence of multiple tumors in humans [Sabbah et al., Curr Med Chem 18 (2011). ), pp. 5528-5544].
  • PI3K belongs to intracellular phosphatidylinositol kinase with phosphatidylinositol kinase activity and silk/threonine kinase activity. According to gene family homology, substrate specificity and function, PI3K superfamily is mainly divided into three types: type I, type II, type III [Engelman et al., Nat Rev Genet 7 (2006), pp. 606-619. ]. Type I PI3K is the most widely studied class to date, and this type of PI3K can be divided into four subtypes of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ .
  • Type I PI3K is a heterodimeric enzyme consisting of a 110 kDa catalytic subunit and an 85 kDa regulatory subunit. Due to the difference in regulatory subunits and activation mechanisms, these four subtypes can be grouped into two categories: Class IA, Class IB. Among them, PI3K ⁇ , PI3K ⁇ and PI3K ⁇ belong to Class IA and are activated by receptor tyrosine kinase (RTKs); PI3K ⁇ belongs to Class IB and is activated by G-protein coupled receptor.
  • RTKs receptor tyrosine kinase
  • Type I PI3K phosphorylates the 3rd position of phosphatidylinositol-4,5-phosphate (PIP2) to form phosphatidylinositol-3,4,5-triphosphate ( Phosphatidylinositol-3,4,5-phosphate, PIP3).
  • PIP3 can bind and activate a variety of intracellular target proteins (such as AKT and PDK1) to form a signal cascade complex that ultimately regulates cell proliferation, differentiation, survival and migration.
  • Type II PI3K is a monomeric structure, lacks regulatory subunits, and is divided into three subtypes of PI3KC2 ⁇ , PI3KC2 ⁇ , and PI3KC2 ⁇ ; it is mainly involved in the transport of intracellular substances, cell survival, and internalization of membrane receptor proteins.
  • Type III PI3K has only one subtype, Vps34 (vacuole protein sorting defective 34), which is well known for its endocytosis and Golgi vesicle transport functions [Backer, Biochem J 410 (2008), pp. 1-17 ]. Recent studies have shown that Vps34 plays an important role in autophagy [Ma et al, Cell Res 24 (2014), pp. 912-924].
  • PI3K inhibitors there are dozens of PI3K inhibitors in clinical research, which can be roughly divided into three categories: non-selective PI3K inhibitors, type I PI3K selective inhibitors and subtype-selective type I PI3K inhibitors. From the analysis of existing clinical data, although non-selective PI3K inhibitors first entered clinical studies, they progressed slowly due to dose limitation and toxicity. Subtype-selective PI3K inhibitors have the fastest progress, especially PI3K ⁇ inhibitors, of which the first marketed PI3K inhibitor, Idelalisib, is a PI3K ⁇ inhibitor, and another ⁇ / ⁇ selective inhibitor, Duvelisib, is already in phase III clinical [Winkler et al.
  • the catalytic subunit p110 ⁇ of PI3K ⁇ is different from P110 ⁇ and P110 ⁇ widely expressed in various tissues of the whole body, and is mainly selectively expressed in the immune system, such as B cells, T cells, etc., and hematological malignancies. It is closely related to diseases such as inflammation and immunity [Fruman et al., N Engl J Med 370 (2014), pp. 1061-1062].
  • Idelalisib is approved by the US FDA as a drug for the treatment of recurrent chronic lymphocytic leukemia (CLL), recurrent follicular B-cell non-Hodgkin's lymphoma (FL) and recurrent small lymphocytic lymphoma. . This highlights the significance of PI3K ⁇ inhibitors in the treatment of hematological malignancies.
  • R 1 is halogen, or a C 1-6 alkyl group or a C 3-8 cycloalkyl group which is unsubstituted or substituted with at least one substituent, the substituent being a halogen;
  • R 2 is -C(OH)R 5 R 6 , -COC 1-6 alkyl, -CN, unsubstituted or substituted with at least one substituent: C 1-6 alkyl, -CH 2 NH- C 1-6 alkyl, -CH 2 N(C 1-6 alkyl)(C 1-6 alkyl), -CH 2 - (saturated heterocyclic group containing 1-2 hetero atoms and 3-6 carbon atoms) ), -CH 2 - (containing a 1-2 hetero atom and a saturated heterocyclic group of 3 to 6 carbon atoms) - (containing a 1-2 hetero atom and a saturated heterocyclic group of 3 to 6 carbon atoms), -CH 2 - (containing a 1-2 hetero atom and a saturated spiro group of 4 to 12 carbon atoms), -CH 2 - (a saturated bridged ring group containing 1-2 hetero atoms and 3 to 12 carbon atoms) - (including 1-2 hetero a saturated hetero
  • the hetero atom is selected from at least one of N, O and S,
  • the R 5 and R 6 are each independently hydrogen or C 1-6 alkyl
  • R 3 is Wherein R 7 , R 8 , R 9 , R 10 are each independently hydrogen or C 1-6 alkyl which is unsubstituted or substituted with at least one substituent, the substituent being a halogen or a hydroxy group;
  • R 4 is -NH 2 , -NHCONHR 11 or -NHCO 2 R 12 , wherein R 11 and R 12 are each independently a C 1-6 alkyl group, a C 3-8 cycloalkane which is unsubstituted or substituted with at least one substituent. Or a phenyl group, the substituent being selected from at least one of halogen and -C(O)OR 13 , wherein R 13 is a C 1-6 alkyl group which is unsubstituted or substituted with at least one substituent, said R The substituent in 13 is a halogen.
  • the R 1 is halogen, or C 1-4 alkyl or C 3-6 cycloalkyl, unsubstituted or substituted with at least one substituent.
  • the R 1 is -Cl, -F, methylalkyl, trifluoromethyl or difluoromethylalkyl.
  • the R 2 is -C(OH)R 5 R 6 , -COC 1-4 alkyl, -CN, unsubstituted or substituted with at least one substituent: C 1 -4 alkyl, -CH 2 NH-C 1-4 alkyl, -CH 2 N(C 1-4 alkyl)(C 1-4 alkyl), -X- (saturation containing 1-2 heteroatoms) Four to six-membered heterocyclic group), -X- (saturated four to six-membered heterocyclic group containing 1-2 hetero atoms) - (saturated four to six-membered heterocyclic group containing 1-2 hetero atoms), -X- (including 1-2 heteroatoms and saturated bicyclospirocyclyl groups of 4-8 carbon atoms), -X- (saturated bicyclic bridged ring groups containing 1-2 heteroatoms and 3-8 carbon atoms)-(including 1-2 a saturated tetra- to six-membere
  • the R 5 and R 6 are each independently hydrogen, methyl or ethyl.
  • the substituent in R 2 is -F, -Cl, -Br, -I, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -C(CH 3 )(CF 3 )OH, -C(CF 3 ) 2 OH, -C(CH 3 ) 2 OCH 3 , -C(CH 3 2 NH 2 , -CH 2 C(CH 3 ) 2 OH, -CH(OH)CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 OH, -C(CH 3 ) 2 CH 2 OCH 3 , -C(CH
  • the R 2 is Rx and Ry are each -N(CH 3 ) 2 , -S(O) 2 CH 3 or a C 1-4 alkyl group which is unsubstituted or substituted with at least one substituent which is halogen, hydroxy, -CONH 2 , -CF 3 , amino or -OCH 3 .
  • the R 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 3 is wherein R 7 , R 8 , R 9 and R 10 are each independently hydrogen or C 1-4 alkyl.
  • the R 7 , R 8 , R 9 , R 10 are each independently H or methyl.
  • the R 3 is morpholinyl or (S)-3-methylmorpholinyl.
  • the R 4 is -NH 2 , -NHCONHR 11 or -NHCO 2 R 12 , wherein R 11 and R 12 are each independently C 1 - unsubstituted or substituted with at least one substituent a 4- alkyl group, a C 3-6 cycloalkyl group or a phenyl group, the substituent being selected from at least one of fluorine, chlorine, bromine and -C(O)OR 13 , wherein R 13 is a C 1-4 alkyl group .
  • the R 11 and R 12 are each independently methyl, ethyl, isopropyl, cyclopropyl, phenyl, -Ph-CO 2 Et-p or 4-fluorophenyl .
  • the pharmaceutically acceptable salts include organic acid salts and inorganic acid salts including, but not limited to, maleate, succinate, citrate, tartrate, fumarate, acetate, methanesulfonate, Hydrochloride, phosphate, nitrate or sulfate.
  • Another object of the present invention is to provide a process for the preparation of a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by the general formula I, which is prepared by the following route:
  • reagents and conditions required for each step include:
  • Step a dropwise adding chlorosulfonyl isocyanate to a solution of the compound Aa1', dimethylformamide (DMF) in anhydrous acetonitrile to obtain the compound Aa2', or step b: dissolving the compound Aa1" in chloroform, and adding N-chlorosuccinimide is reacted to obtain compound Aa2";
  • Step c adding 5% by mass of sodium hypochlorite solution to the solution of the compound Aa2', K 2 CO 3 , NH 4 Cl, concentrated aqueous ammonia, methyl trioctyl ammonium chloride in methyl tert-butyl ether, and reacting Compound Aa3, or step d: the compound Aa2" is dissolved in anhydrous dimethylformamide, NaH is added, and after stirring, O-(2,4-dinitrophenyl)-hydroxylamine is added to obtain the compound Aa3;
  • Step e the compound Aa3 is dissolved in a saturated ammonia methanol solution or ammonia in methanol to obtain a compound Aa4;
  • Step f mixing compound Aa4 with aldehyde, anhydrous copper chloride, dimethyl sulfoxide, the reaction to obtain compound Aa5;
  • Step g adding phosphorus oxychloride to a mixture of compound Aa5 and N,N-dimethylaminopyridine or dimethylaminopyridine to obtain compound Aa6;
  • Step h to the compound Aa6, the addition of anhydrous tetrahydrofuran and morpholine, the reaction to obtain the compound Aa7;
  • Step i adding Raney nickel to the acetic acid/water/pyridine suspension of the compound Aa7 and sodium hypophosphite, the reaction gives the compound Aa8;
  • Step j suspending the compound Aa8, sodium cyanoborohydride and an amine in methanol, adding acetic acid to obtain a product; or step j: adding methyl magnesium bromide to a solution of the compound Aa8 in anhydrous tetrahydrofuran to obtain a product; Or step j: adding diethylaminosulfur trifluoride (DAST) to a solution of the compound Aa8 in anhydrous dichloromethane to obtain a product.
  • DAST diethylaminosulfur trifluoride
  • compound P-28 is prepared by the following route:
  • Step 1 Compound P-28-1 was dissolved in a mixture of dichloromethane and water, followed by sodium trifluoromethylsulfinate, and the system was cooled and a 70% aqueous solution of t-butoxyethanol was slowly added dropwise, followed by Adding dimethyl sulfoxide and raising the temperature to obtain compound P-28-2;
  • Step 2 The compound P-28-2 and phosphorus oxychloride are added to toluene, followed by the addition of N,N-dimethylaniline, and the reaction is carried out under reflux to obtain a crude chloro compound, and the crude chloro compound is dissolved in anhydrous tetrahydrofuran. Add morpholine at 0 ° C, stir at room temperature until the reaction of the starting material is complete, and concentrate to obtain the crude product directly in the next reaction;
  • Step 3 The crude product obtained in Step 2 is added to methanol to dissolve, then water and sodium hydroxide are added, and the reaction is carried out under reflux until the starting material completely disappears, concentrated, water is added, the pH is adjusted to precipitate a solid, and dried, and the next reaction is directly carried out;
  • Step 4 The crude product of Step 3, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), triethylamine and 2-(4-piperidinyl) 2-propanol is added to N,N-dimethylformamide (DMF) to give the compound P-28-5;
  • HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DMF N,N-dimethylformamide
  • Step 5 Dissolve P-28-5 in anhydrous tetrahydrofuran, then slowly add borane/tetrahydrofuran (BH 3 /THF) dropwise. After the addition is completed, the reaction system is heated to carry out the reaction, then the reaction system is cooled and slowly added dropwise. Concentrated hydrochloric acid was added dropwise, and the temperature was raised to give the compound P-28.
  • borane/tetrahydrofuran BH 3 /THF
  • Another object of the present invention is to provide a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by the formula I or a pharmaceutically acceptable salt thereof for preparing a PI3K activity inhibitor Use in.
  • the PI3K activity inhibitor has a selective inhibitory effect on PI3K ⁇ .
  • the PI3K activity inhibitor is for use in a medicament for treating a disease associated with a PI3K channel.
  • the diseases associated with the PI3K channel include tumors, leukemias, and autoimmune diseases.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by Formula I or a pharmaceutical thereof
  • a useful salt for the treatment of a disease associated with the PI3K channel is a 7-substituted pyrrole [2,1-f][1,2,4]-triazine compound represented by Formula I or a pharmaceutical thereof.
  • the inventors of the present invention have obtained a novel class of 7-substituted pyrrole [2,1-f][1,2,4]-triazine compounds by rational design and comprehensive consideration of the pharmacokinetic factors of the compounds.
  • the compounds exhibit better PI3K inhibitory activity, can effectively inhibit PI3K kinase activity, and have greatly improved and improved pharmacokinetic properties such as bioavailability due to the introduction of the 7-position group;
  • the compounds exhibit unpredictable high selectivity and strong inhibitory activity against PI3K ⁇ , and thus these compounds can be used to treat diseases associated with the PI3K channel, particularly for anti-cancer or for the treatment of tumors, leukemias and autoimmune diseases. After further optimization and screening, it is expected to develop into a new type of anti-tumor drugs.
  • alkyl refers to a straight or branched alkyl group.
  • substituted refers to the replacement of one or more hydrogen atoms.
  • the halogen herein may be selected from at least one of F, Cl, Br and I, preferably at least one of F and Cl.
  • Step a Preparation of ethyl 4-cyano-5-methyl-1H-pyrrole-2-carboxylate (Aa2')
  • Step c Preparation of ethyl 1-amino-4-cyano-5-methyl-1H-pyrrole-2-carboxylate (Aa3')
  • the compound Aa3' (800 mg, 4.1 mmol) was dissolved in 100 mL of a saturated ammonia methanol solution or a methanol solution of ammonia, and the mixture was sealed at 80 ° C for 2 days, cooled to room temperature, and concentrated to give a yellow solid (680 mg, 100%).
  • Step b Preparation of ethyl 4-cyano-5-chloro-1H-pyrrole-2-carboxylate (Aa2")
  • Step d Preparation of ethyl 1-amino-4-cyano-5-chloro-1H-pyrrole-2-carboxylate (Aa3")
  • Phosphorus oxychloride was added to a mixture of Compound Aa5 (1.0 equiv.), 4-dimethylaminopyridine (2.0 equiv.), and refluxed for 10 hours. After cooling, phosphorus oxychloride was removed under reduced pressure, and anhydrous tetrahydrofuran and morpholine were added in that order and refluxed for 2 hours. The tetrahydrofuran was evaporated under reduced pressure, and the mixture was evaporated. EtOAcjjjjjjjjjj .
  • Step j Synthesis of the compounds P-(1-9), 12, (29-32), (34-35), (38-43), (45-46)
  • Methanesulfonic acid (370 ⁇ L, 0.3 mmol) was added to a solution of the compound P-9 (160 mg, 0.3 mmol) in chloroform (10 mL), and the mixture was reacted at room temperature for 2 hours, then diluted with anhydrous diethyl ether (50 mL), filtered and dried. Yellow compound P-9 methanesulfonate (145 mg, 77%).
  • Step j Synthesis of compound P-33, 36, 37
  • the obtained product was dissolved in methanol (15 mL), and 10 equivalents of a 1M potassium hydroxide solution was added and refluxed. After completion of the reaction, it was concentrated and purified by column chromatography (dichloromethane / methanol: 40/1).
  • the obtained product was dissolved in concentrated hydrochloric acid (10 mL) and refluxed for 7 days. After completion of the reaction, it was neutralized and purified by column chromatography (dichloromethane / methanol: 10/1).
  • the obtained product was dissolved in methanol (15 mL), and 10 equivalents of a 1M potassium hydroxide solution was added and refluxed. After completion of the reaction, it was concentrated and purified by column chromatography (dichloromethane / methanol: 40/1).
  • the obtained product was dissolved in methanol (15 mL), and 10 equivalents of a 1M potassium hydroxide solution was added and refluxed. After completion of the reaction, it was concentrated and purified by column chromatography (dichloromethane / methanol: 40/1).
  • a method for preparing a methanesulfonate of the reference compound P-9 was used to give the yellow compound P-17 methanesulfonate (190 mg, 81%).
  • a method for preparing a methanesulfonate of the reference compound P-9 was used to give yellow compound P-21 methanesulfonate (70 mg, 81%).
  • Step 1 P-28-1 (437.0 mg, 1.0 mmol, preparation method see CN201210177980.3) was dissolved in a mixture of dichloromethane:water (10:1, 20 mL), followed by the addition of trifluoromethyl Sodium sulfonate (936.0 mg, 6 mmol), the above system was cooled to 0 ° C, and a 70% aqueous solution of t-butoxy-butanol (1.4 mL, 10.0 mmol) was slowly added dropwise. After the addition was completed, stirring was continued for 30 min; Sulfoxide (4.0 mL) was heated to 40 ° C overnight, and the end of the reaction was analyzed by LC-MS.
  • Step 2 P-28-2 (300 mg, 0.6 mmol) and phosphorus oxychloride (1.85 g, 11.9 mmol) were added to toluene (20 mL) followed by N,N-dimethylaniline (215.6 mg, 18.0) Methyl) was reacted overnight under reflux. The reaction was completed by TCL, and the reaction mixture was concentrated, then ethyl acetate and iced water were added and stirred, and the ethyl acetate phase was separated, and the ethyl acetate phase was dried and concentrated to give crude chlorobenzene. The crude chloroform was dissolved in anhydrous tetrahydrofuran (10 mL), and morpholine (155.0 mg, 1.8 mmol) was added at 0 ° C and stirred at room temperature until the reaction was completed.
  • Step 3 The crude product obtained in Step 2 was dissolved in methanol (20 mL), then water (1 mL) and sodium hydroxide (237.6 mg) were added and reacted under reflux until the starting material disappeared completely, concentrated, water was added, and the pH was adjusted to 5-6. Solid, dry, directly next.
  • Step 4 The crude product from Step 3, HBTU (455.0mg, 1.2mmol), triethylamine (121mg, 1,2mmol) and 2-(4-piperidinyl)-2-propanol (Aa9, 93.2mg, 0.65 mmol) was added to DMF (10 mL) and allowed to react at room temperature overnight, and the reaction was completed by LC-MS. The reaction mixture was poured into EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • test compound was dissolved in DMSO (dimethyl sulfoxide) to 100 ⁇ M or 10 ⁇ M as a stock solution, and each 2 ⁇ L was added to 48 ⁇ L of 1 ⁇ reaction buffer (1 ⁇ Reaction Buffer) to obtain 1 ⁇ M or 100 nM.
  • 1 ⁇ reaction buffer 1 ⁇ Reaction Buffer
  • a 4% DMSO solution of the compound was mixed and diluted with 4% DMSO in 1 time reaction buffer (in 1 ⁇ Reaction Buffer) to obtain a 100 nM or 20 nM compound solution.
  • IC 50 assay concentration setting 10 ⁇ M and 100 ⁇ M were selected for the starting concentrations for different enzymes. Dissolve in DMSO to 1 mM or 10 mM as a working solution, and add 1 ⁇ L to 24 ⁇ l of 1X Kinase Buffer A (1 ⁇ Kinase Buffer A) to obtain 40 ⁇ M or 400 ⁇ M compound solution containing 4% DMSO, and serially dilute by 4 times. At 10 dilutions, 2.5 ⁇ L of each diluted solution was added to a 384-well plate such that the final concentration of the compound in the final 10 ⁇ L of the kinase reaction system was 10 ⁇ M, 2.5 ⁇ M, 0.625 ⁇ M and contained 1% DMSO.
  • Emission Ratio(ER) 665nM Emission signal/620nm Emission signal
  • the inhibition rate is calculated using the following formula:
  • Inhibition rate (ER sample - ER 0% ) / (ER 100% - ER 0% ) ⁇ 100%
  • the compounds in the table all showed a good inhibitory effect on PI3K kinase, and in particular, the compound P-5/6/7 showed an inhibitory effect on the selectivity of PI3K ⁇ .
  • GDC0941 is a positive compound, the chemical name is 2-(1H-carbazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-? Phenyl)thieno[3,2-D]pyrimidine(4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d ]pyrimidin-4-yl]morpholine).
  • Administration by intragastric administration 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h and 24 h after administration.
  • Intravenous administration 5 min after administration, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h and 24 h.
  • venous blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the concentration of the compound in rat plasma was determined by LC/MS/MS.
  • the pharmacokinetic parameters after administration were calculated using a non-compartmental model of Phoenix 1.3 software (Pharsight, USA).

Abstract

本发明涉7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，及其制备方法和用途。该类化合物显示较好的PI3K抑制活性，能有效地抑制PI3K激酶活性，并且由于7-位基团的引入，生物利用度等药代动力学性质有较大提高和改善；此外，本发明中的化合物表现出了对PI3Kδ不可预期的高选择性和强抑制活性，因此这些化合物能用来治疗与PI3K通道相关的疾病，尤其是用来抗癌或者治疗肿瘤、白血病及自身免疫性疾病。经过进一步的优化和筛选后，有望研发成为新型的抗肿瘤药物。

Description

7-位取代吡咯并三嗪类化合物或其药学上可用的盐，及其制备方法和用途 技术领域
本发明涉及药物化学领域，特别是涉及7-位取代吡咯并三嗪类化合物或其药学上可用的盐，及其制备方法和用途。
背景技术
PI3K-Akt-mTOR信号通路是传递来自于受体酪氨酸激酶和G蛋白偶联受体信号的主要通路之一，在多种细胞功能中扮演着重要的角色。近年来的研究发现，在多种人类肿瘤中，PI3K-Akt-mTOR信号通路中的多个关键节点蛋白因编码基因存在突变或扩增而过度激活[Vivancod等人，Nat Rev Cancer 2(2002)，第489-501页]。其中PI3K作为联系细胞外信号与细胞应答效应的桥梁分子，是调节细胞生长、代谢和存活的关键因子，其过度激活与人类多种肿瘤的发生密切相关[Sabbah等人，Curr Med Chem 18(2011)，第5528-5544页]。
PI3K属于细胞内的磷脂酰肌醇激酶，具有磷脂酰肌醇激酶活性以及丝/苏氨酸激酶活性。根据基因系列同源性、底物特异性及功能不同，PI3K超家族主要分为三类：I型、II型、III型[Engelman等人，Nat Rev Genet 7(2006)，第606-619页]。I型PI3K是到目前为止研究最为广泛的一类，该类PI3K又可分为PI3Kα，PI3Kβ，PI3Kδ，PI3Kγ四个亚型。I型PI3K是由一个110kDa的催化亚基和一个85kDa的调节亚基构成的异二聚体酶。由于调节亚基和激活机理的不同，这四个亚型又可以归为两类：Class IA,Class IB。其中PI3Kα，PI3Kβ，PI3Kδ属于Class IA，由受体酪氨酸激酶(receptor tyrosine kinase,RTKs)激活；而PI3Kγ属于Class IB，由G-蛋白偶联受体激活。I型PI3K可以将磷脂酰肌醇-4,5-二磷酸酯(phosphatidylinositol-4,5-phosphate,PIP2)的3位磷酸化，生成磷脂酰肌醇-3,4,5-三磷酸酯(phosphatidylinositol-3,4,5-phosphate,PIP3)。PIP3作为重要的第二信使，可以结合并激活多种细胞内的靶蛋白(如AKT和PDK1)，形成一个信号级联复合物，最终调节细胞的增殖、分化、存活和迁移等。II、III型PI3K与I型
PI3K的激酶区具有高度的同源性并且拥有相似的磷酸化功能，但其具体的生理作用知之甚少。II型PI3K为单体结构，缺少调节亚基，分为PI3KC2α，PI3KC2β，PI3KC2γ三个亚型；主要参与细胞内物质的运输，细胞存活和膜受体蛋白的内化过程。III型PI3K，只有一种亚型即Vps34(vacuole protein sorting defective 34)，其关于胞吞作用和高尔基体的囊泡的运输功能已经广为人知[Backer，Biochem J 410(2008)，第1-17页]。近年的研究表明Vps34在细胞自噬过程中扮演了重要角色[Ma等人，Cell Res 24(2014)，第912-924页]。
目前，已经有数十个PI3K抑制剂处于临床研究阶段，它们大致可分为三类：非选择性PI3K抑制剂，I型PI3K选择性抑制剂和亚型选择性I型PI3K抑制剂。从现有的临床数据分析来看，虽然非选择性的PI3K抑制剂最早进入临床研究，但由于剂量限制性和毒性进展较慢。亚型选择性PI3K抑制剂进展最快，尤其是PI3Kδ抑制剂，其中首个上市的PI3K抑制剂Idelalisib就是PI3Kδ抑制剂，另一个γ/δ选择性抑制剂Duvelisib已经处于III期临床[Winkler等人，Chem Biol 20(2013)，第1362-1372页]。在Class IA的催化亚基中，PI3Kδ的催化亚基p110δ不同于广泛表达于全身各组织的P110α和P110β，主要在免疫系统中选择性高表达，如B细胞、T细胞等，与血液恶性肿瘤和炎症、免疫等疾病密切相关[Fruman等人，N Engl J Med 370(2014)，第1061-1062页]。Idelalisib正是作为治疗复发的慢性淋巴细胞白血病(CLL)、复发性滤泡B细胞非霍奇金淋巴瘤(FL)和复发性小淋巴细胞淋巴瘤三种血液瘤的药物被美国的FDA批准上市。这彰显了PI3Kδ抑制剂在血液恶性肿瘤治疗中的重大意义。
目前针对PI3Kδ的抑制剂的骨架大都集中在Idelalisib母核类似物上，例如US20140121224A1。而相比之下，以三嗪为母核的化合物就已有的数据来看，较Idelalisib毒性明显降低。另一类研究较多的结构是噻吩并嘧啶母核，其代表化合物是PI3K泛抑制剂GDC-0941[Folkes等人，J Med Chem 51(2008)，第5522-5532页]。这类化合物虽然也有PI3Kδ选择性的报道[Murray等人，J Med Chem 55(2012)，第7686-7695页]，但是其母核与吡咯并三嗪性质差异很大。而基于吡咯并三嗪为母核的PI3K抑制剂报到目前只有少数几例，例如CN102675323A，并且至今未有关于PI3Kδ抑制活性的报道。
发明内容
基于此，本发明的目的是提供一种通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐：
Figure PCTCN2018092419-appb-000001
其中，
R 1为卤素，或未取代或被至少一个取代基取代的C 1-6烷基或C 3-8环烷基，所述取代基为卤素；
R 2为-C(OH)R 5R 6、-COC 1-6烷基、-CN、未取代或被至少一个取代基取代的如下基团：C 1-6烷基、-CH 2NH-C 1-6烷基、-CH 2N(C 1-6烷基)(C 1-6烷基)、-CH 2-(含1-2杂原子及3-6碳原子的饱和杂环基)、-CH 2-(含1-2杂原子及3-6碳原子的饱和杂环基)-(含1-2杂原子及3-6碳原子的饱和杂环基)、-CH 2-(含1-2杂原子及4-12碳原子的饱和螺环基)、-CH 2-(含1-2杂原子及3-12碳原子的饱和桥环基)-(含1-2杂原子及3-6碳原子的饱和杂环基)，或-CH 2-(含1-2杂原子及3-12碳原子的饱和桥环基)，所述取代基为卤素、-N(C 1-4烷基)(C 1-4烷基)、-O-C 1-4烷基、-CN、-COOH、-CHO、-NHS(O) 2-C 1-4烷基、-N(C 1-4烷基)C(C 1-4烷基)(C 1-4烷基)-CONH 2、＝O、-OH、-S(O) 2N(C 1-4烷基)(C 1-4烷基)、-S-C 1-4烷基、-S(O) 2-C 1-4烷基、-CO-C 3-6环烷基、氧杂环丁烷基、吗啉基、C 3-6环烷基、-C 1-4烷基-N(C 1-4烷基)(C 1-4烷基)、未取代或被至少一个甲基取代的C 1-4烷基-O-C 1-4烷基、未取代或被至少一个甲基取代的-CONH 2、未取代或被至少一个甲基取代的C 1-4烷基-CONH 2、未取代或被至少一个甲基取代的-COO-C 1-4烷基、未取代或被至少一个甲基取代的-NH 2、未取代或被至少一个甲基取代的-NHCO-C 1-4烷基、未取代或被至少一个取代基A取代的-CO-C 1-4烷基，所述取代基A为羟基或甲基，或者未取代或被至少一个取代基B取代的C 1-4烷基，所述取代基B为-NH 2、-OCH 3、-CONH 2、-OH或-CF 3。
所述R 2中，所述杂原子选自N、O和S中的至少一种，
所述R 5和R 6各自独立地为氢或C 1-6烷基；
R 3为
Figure PCTCN2018092419-appb-000002
其中R 7，R 8，R 9，R 10各自独立地为氢或未取代或被至少一个取代基取代的C 1-6烷基，所述取代基为卤素或羟基；
R 4为-NH 2、-NHCONHR 11或-NHCO 2R 12，其中R 11和R 12各自独立地为未取代或被至少一个取代基取代的C 1-6烷基、C 3-8环烷基或苯基，所述取代基选自卤素和-C(O)OR 13中的至少一种，其中R 13为未取代或被至少一个取代基取代的C 1-6烷基，所述R 13中的所述取代基为卤素。
在其中的一个实施例中，所述R 1为卤素，或未取代或被至少一个取代基取代的C 1-4烷基或C 3-6环烷基。
在其中的一个实施例中，所述R 1为-Cl、-F、甲烷基、三氟甲烷基或二氟甲烷基。
在其中的一个实施例中，所述R 2为-C(OH)R 5R 6、-COC 1-4烷基、-CN、未取代或被至少一个取代基取代的如下基团：C 1-4烷基、-CH 2NH-C 1-4烷基、-CH 2N(C 1-4烷基)(C 1-4烷基)、-X-(含1-2杂原子的饱和四至六元杂环基)、-X-(含1-2杂原子的饱和四至六元杂环基)-(含1-2杂原子的饱和四至六元杂环基)、-X-(含1-2杂原子及4-8碳原子的饱和二环螺环基)、-X-(含1-2杂原子及3-8碳原子的饱和二环桥环基)-(含1-2杂原子的饱和四至六元杂环基)，或-X-(含1-2杂原子及3-8碳原子的饱和二环桥环基)，其中X为CH 2，所述杂环基、螺环基和桥环基以N原子与X相连，所述R 5和R 6各自独立地为氢或C 1-4烷基。
在其中的一个实施例中，所述R 5和R 6各自独立地为氢，甲基或乙基。
在其中的一个实施例中，所述R 2中的所述取代基为-F、-Cl、-Br、-I、-CH 3、-CH 2CH 3、-CH 2CH(CH 3) 2、-CH 2NH 2、-CH 2N(CH 3) 2、-CH 2CH 2NH 2、-CH 2CH 2N(CH 3) 2、-CH 2OH、-CH 2OCH 3、-CH 2CH 2OH、-C(CH 3) 2OH、-C(CH 3)(CF 3)OH、-C(CF 3) 2OH、-C(CH 3) 2OCH 3、-C(CH 3) 2NH 2、-CH 2C(CH 3) 2OH、-CH(OH)CH(CH 3) 2、-C(CH 3) 2CH 2OH、-C(CH 3) 2CH 2OCH 3、-CN、-CF 3、-CO 2H、-CHO、-COCH 3、-CO 2CH 3、-CO 2C(CH 3) 3、-COCH 2OH、-COC(OH)(CH 3) 2、-COCH(OH)CH 3、-CONH 2、-CONHCH 3、-CON(CH 3) 2、-CH 2CONH 2、-CH 2CON(CH 3) 2、 -C(CH 3) 2CONH 2、-NH 2、-NHCH 3、-N(CH 3) 2、-NHCOCH 3、-N(CH 3)COCH 3、-NHS(O) 2CH 3、-N(CH 3)C(CH 3) 2CONH 2、＝O、-OH、-OCH 3、-S(O) 2N(CH 3) 2、-SCH 3、-S(O) 2CH 3、-C(O)-环丙基、环丙基、环丁基、氧杂环丁烷基或吗啉基取代。
在其中的一个实施例中，所述R 2为
Figure PCTCN2018092419-appb-000003
Rx和Ry分别为-N(CH 3) 2、-S(O) 2CH 3或未取代或被至少一个取代基取代的C 1-4烷基，所述取代基为卤素、羟基、-CONH 2、-CF 3、氨基或-OCH 3。
在其中的一个实施例中，所述R 2为
Figure PCTCN2018092419-appb-000004
Figure PCTCN2018092419-appb-000005
在其中的一个实施例中，所述R 3为
Figure PCTCN2018092419-appb-000006
其中R 7，R 8，R 9，R 10各自独立地为氢或C 1-4烷基。
在其中的一个实施例中，所述R 7，R 8，R 9，R 10各自独立地为H或甲基。
在其中的一个实施例中，所述R 3为吗啉基或(S)-3-甲基吗啉基。
在其中的一个实施例中，所述R 4为-NH 2、-NHCONHR 11或-NHCO 2R 12，其中R 11和R 12各自独立地为未取代或被至少一个取代基取代的C 1-4烷基、C 3-6环烷基或苯基，所述取代基选自氟、氯、溴和-C(O)OR 13中的至少一种，其中R 13为C 1-4烷基。
在其中的一个实施例中，所述R 11和R 12各自独立地为甲基、乙基、异丙基、环丙基、苯基、-Ph-CO 2Et-p或4-氟苯基。
所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，例如具有如下述通式中的一种表示的结构：
Figure PCTCN2018092419-appb-000007
Figure PCTCN2018092419-appb-000008
Figure PCTCN2018092419-appb-000009
所述药学可接受的盐包括有机酸盐和无机酸盐，包括但不限于马来酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、富马酸盐、乙酸盐、甲磺酸盐、盐酸盐、磷酸盐、硝酸盐或硫酸盐。
本发明的另一目的是提供通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物的制备方法，通过以下路线进行制备：
Figure PCTCN2018092419-appb-000010
进一步来讲，各步骤所需试剂和条件包括：
步骤a：向化合物Aa1'、二甲基甲酰胺(DMF)的无水乙腈溶液中，滴加氯磺酰异氰酸酯，反应得到化合物Aa2'，或者步骤b：将化合物Aa1”溶解于氯仿中，加入N-氯代丁二酰亚胺进行反应，得到化合物Aa2”；
步骤c：向化合物Aa2'、K 2CO 3、NH 4Cl、浓氨水、甲基三辛基氯化铵的甲基叔丁基醚溶液中，滴加5％质量百分比的次氯酸钠溶液，反应得到化合物Aa3，或者步骤d：将化合物Aa2”溶解于无水二甲基甲酰胺中，加入NaH，搅拌后加入O-(2,4-二硝基苯基)-羟胺，反应得到化合物Aa3；
步骤e：将化合物Aa3溶于饱和氨甲醇溶液或氨的甲醇溶液中，反应得到化合物Aa4；
步骤f：将化合物Aa4与醛、无水氯化铜、二甲亚砜混合，反应得到化合物Aa5；
步骤g：向化合物Aa5和N,N-二甲基氨基吡啶或二甲基氨基吡啶的混合物中加入三氯氧磷，反应得到化合物Aa6；
步骤h：向化合物Aa6中，加入无水四氢呋喃和吗啉，反应得到化合物Aa7；
步骤i：向化合物Aa7和一水次亚磷酸钠的醋酸/水/吡啶悬浮液中，加入雷尼镍，反应得到化合物Aa8；和
步骤j：将化合物Aa8、氰基硼氢化钠和胺悬浮于甲醇中，加入醋酸，反应得到产物；或者步骤j：向化合物Aa8的无水四氢呋喃溶液中加入甲基溴化镁，反应得到产物；或者步骤j：向化合物Aa8的无水二氯甲烷溶液中加入二乙胺基三氟化硫(DAST)，反应得到产物。
在其中一个实施例中，化合物P-28通过以下路线进行制备：
Figure PCTCN2018092419-appb-000011
具体包括以下步骤：
步骤1：将化合物P-28-1溶于二氯甲烷与水的混合液中，随后加入三氟甲基亚磺酸钠，冷却上述体系并缓慢滴加70％过氧叔丁醇水溶液，随后加入二甲基亚砜，升温反应得到化合物P-28-2；
步骤2：将化合物P-28-2和三氯氧磷加入到甲苯中，随后加入N,N-二甲基苯胺，于回流状态下反应得到氯代物粗品，将氯代物粗品溶于无水四氢呋喃中，0℃下加入吗啉，于室温下搅拌直到原料反应完全，浓缩得粗品直接下一步反应；
步骤3：将步骤2所得粗品加入甲醇溶解，随后加入水和氢氧化钠，于回流下反应直到原料完全消失，浓缩，加入水，调pH值析出固体，干燥，直接下一步反应；
步骤4：将步骤3的粗品、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、三乙胺和2-(4-哌啶基)-2-丙醇加入N，N-二甲基甲酰胺(DMF)中，反应得到化合物P-28-5；和
步骤5：将P-28-5溶于无水四氢呋喃中，随后缓慢滴加甲硼烷/四氢呋喃(BH 3/THF)，滴加完毕，升温反应体系进行反应，随后冷却反应体系并缓慢滴加浓盐酸，滴加完毕，升温反应得到化合物P-28。
本发明的另一个目的是提供通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途。
在其中一个实施例中，所述PI3K活性抑制剂对PI3Kδ具有选择性抑制作用。
在其中一个实施例中，所述PI3K活性抑制剂用在治疗与PI3K通道相关的疾病的药物中。
优选的，所述与PI3K通道相关的疾病包括肿瘤、白血病和自身免疫性疾病。
另外，本发明提供了一种药物组合物，其包含治疗有效量的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三 嗪类化合物或其药学上可用的盐，所述药物组合物用于治疗与PI3K通道相关的疾病。
本发明的发明人通过合理设计，综合考虑化合物的药代动力学因素，得到了一类新型的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物。该类化合物显示较好的PI3K抑制活性，能有效地抑制PI3K激酶活性，并且由于7-位基团的引入，生物利用度等药代动力学性质有较大提高和改善；此外，本发明中的化合物表现出了对PI3Kδ不可预期的高选择性和强抑制活性，因此这些化合物能用来治疗与PI3K通道相关的疾病，尤其是用来抗癌或者治疗肿瘤、白血病及自身免疫性疾病。经过进一步的优化和筛选后，有望研发成为新型的抗肿瘤药物。
具体实施方式
本文中所述的“烷基”指的是直链烷基或支链烷基。
本文中所述的“取代”指的是取代一个或多个氢原子。本文中的卤素可以选自F,Cl,Br和I中的至少一种，优选为F和Cl中的至少一种。
下面结合实施例对本发明作进一步阐述，但这些实施例绝对不是对本发明的任何限制。所有实施例中， 1H NMR由BrucherAM-400型和GEMINI-300型核磁共振仪记录，化学位移以δ(ppm)表示；质谱由MAT-95型质谱仪记录；分离用硅胶为200-300目。
步骤a：4-氰基-5-甲基-1H-吡咯-2-甲酸乙酯(Aa2')的制备
Figure PCTCN2018092419-appb-000012
冰浴下，向化合物Aa1'(1.0g,6.5mmol)、DMF(1.3mL)的无水乙腈(20mL)溶液中，滴加氯磺酰异氰酸酯(0.7mL，8.0mmol)，移至室温，反应过夜。用饱和碳酸钠溶液(20mL)淬灭，加水稀释，乙酸乙酯(50mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，减压浓缩得到粗产品，色谱柱纯化(石油醚/乙酸乙酯：3/1)，得白色化合物(980mg，84％)。
1H NMR(300MHz,CDCl 3)δ10.07(br s 1H),7.03(d,J＝2.53Hz,1H),4.34(q,J＝7.13Hz,2H),2.47(s,3H),1.37(t,J＝7.13Hz,3H)。
步骤c：1-氨基-4-氰基-5-甲基-1H-吡咯-2-甲酸乙酯(Aa3')的制备
Figure PCTCN2018092419-appb-000013
冰盐浴下，向化合物Aa2'(200mg，1.1mmol)，K 2CO 3(840mg,6.0mmol)，NH 4Cl(385mg,7.2mmol)，浓氨水(1.2mL)，甲基三辛基氯化铵(0.010mL)的甲基叔丁基醚(50mL)溶液中，经恒压滴液漏斗滴加5％(质量百分比)的次氯酸钠溶液(12mL)，移至室温反应4小时。饱和硫代硫酸钠淬灭，分出甲基叔丁基醚层，水层用乙酸乙酯(50mL)萃取一次，合并有机层，水洗三次，无水硫酸钠干燥，减压浓缩得到粗产品，色谱柱纯化(石油醚/乙酸乙酯：4/1)，得无色液体(183mg，86％)，放置后固化。
1H NMR(300MHz,CDCl 3)δ7.01(s,1H),5.46(s,2H),4.30(q,J＝7.13Hz,2H),2.42(s,3H),1.35(t,J＝7.13Hz,3H)。
步骤e：1-氨基-4-氰基-5-甲基-1H-吡咯-2-甲酰胺(Aa4')的制备
Figure PCTCN2018092419-appb-000014
将化合物Aa3'(800mg，4.1mmol)溶于100mL饱和的氨甲醇溶液或氨的甲醇溶液，80℃封管反应2天，冷却至室温，浓缩得黄色固体(680mg，100％)。
1H NMR(300MHz,DMSO-d 6)δ8.01(br s,1H),7.39br(s,1H),7.02(s,1H),6.70(br s,2H),2.27(s,3H)。
步骤b：4-氰基-5-氯-1H-吡咯-2-甲酸乙酯(Aa2”)的制备
Figure PCTCN2018092419-appb-000015
将化合物Aa1”(2.0g，12.2mmol)溶解于氯仿中，加入N-氯代丁二酰亚胺(2.0g，15.0mmol)，室温搅拌过夜；加水(100mL)稀释，分出有机层，水层用氯仿(100mL)萃取两次，合并有机相，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，减压浓缩得到粗产品，色谱柱纯化(石油醚/乙酸乙酯：20/1)得白色固体(510mg，22％)。
1H NMR(300MHz,CDCl 3)δ10.68(s,1H),7.09(d,J＝2.8Hz,1H),4.39(q,J＝7.1Hz,2H),1.39(t,J＝7.2Hz,3H)。
步骤d：1-氨基-4-氰基-5-氯-1H-吡咯-2-甲酸乙酯(Aa3”)的制备
Figure PCTCN2018092419-appb-000016
将化合物Aa2”(300mg，1.5mmol)溶解于无水DMF(10mL)中，冰浴下，加入NaH(60％，分散于矿物油中，75mg，1.9mmol)，继续搅拌30分钟，加入O-(2,4-二硝基苯基)-羟胺(360mg，1.8mmol)，室温下搅拌6小时，将反应液倒入水(50mL)中，用乙酸乙酯(50mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙酸乙酯：10/1)得到白色固体(305mg，95％)。
1H NMR(300MHz,CDCl 3)δ7.09(s,1H),5.80(s,2H),4.34(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H)。
步骤e：1-氨基-4-氰基-5-氯-1H-吡咯-2-甲酰胺(Aa4”)的制备
Figure PCTCN2018092419-appb-000017
以化合物Aa3”(350mg，1.6mmol)为原料，参照化合物Aa4'的制备过程得黄色固体(290mg，100％)。
1H NMR(300MHz,DMSO-d 6)δ8.12(br s,1H),7.63(br s,1H),7.19(s,1H),6.86(br s,2H)。
步骤f：化合物Aa5的合成
Figure PCTCN2018092419-appb-000018
化合物Aa4(1.0equiv.)，N-(5-甲酰基-4-(三氟甲基)吡啶基-2-)特戊酰胺(1.2equiv.，课题组制备)，无水氯化铜(1.0equiv.)的二甲亚砜溶液，升温至100℃反应。反应完毕后，冷却，倒入水中，乙酸乙酯萃取三次，合并有机层，饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：50/1)纯化得黄色固体。
Figure PCTCN2018092419-appb-000019
化合物Aa4'(600mg，3.7mmol)，对应的醛(1.2g，4.4mmol)，无水氯化铜(490mg，3.7mmol)，二甲亚砜(25mL)；得黄色固体(1.3g,85％)。
1H NMR(300MHz,CDCl 3)δ8.82(s,1H),8.62(s,1H),8.43(br s,1H),7.27(s,1H),2.60(s,3H),1.38(s,9H)。
Figure PCTCN2018092419-appb-000020
化合物Aa4”(200mg，1.1mmol)，对应的醛(362mg，1.3mmol)，无水氯化铜(150mg，1.1mmol)，二甲亚砜(15mL)；得黄色固体(408mg,85％)。
1H NMR(300MHz,CDCl 3)δ8.80(s,1H),8.62(s,1H),8.41(s,1H),7.36(s,1H),1.38(s,9H)。
步骤g和h：化合物Aa7的合成
Figure PCTCN2018092419-appb-000021
向化合物Aa5(1.0equiv.)，4-二甲氨基吡啶(2.0equiv.)的混合物中加入三氯氧磷，回流10小时。冷却后，减压除掉三氯氧磷，依次加入无水四氢呋喃，吗啉，回流2小时。减压蒸掉四氢呋喃，加水，乙酸乙酯萃取，依次用饱和食盐水、水洗涤一次，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙酸乙酯：4/1)纯化得白色固体。
Figure PCTCN2018092419-appb-000022
化合物Aa5'(1.0g，2.4mmol)，4-二甲氨基吡啶(583mg，4.8mmol)，三氯氧磷(20mL)，四氢呋喃(100mL)，吗啉(5mL)；得白色固体(980mg，84％)。
1H NMR(300MHz,CDCl 3)δ8.76(s,1H),8.72(s,1H),8.24(br s,1H),6.99(s,1H),4.06(t,J＝4.77Hz,4H),3.84(t,J＝4.73Hz,4H),2.65(s,3H),1.36(s,9H)。
Figure PCTCN2018092419-appb-000023
化合物Aa5”(360mg，0.8mmol)，4-二甲氨基吡啶(200mg，1.6mmol)，三氯氧磷(5mL)，四氢呋喃(50mL)，吗啉(2mL)；得白色固体(370mg，88％)。
1H NMR(300MHz,CDCl 3)δ8.75(s,1H),8.72(s,1H),8.24(s,1H),7.09(s,1H),4.07(t,J＝4.8Hz,4H),3.86(t,J＝4.8Hz,4H),1.36(s,9H)。
Figure PCTCN2018092419-appb-000024
化合物Aa5'(800mg，1.9mmol)，4-二甲氨基吡啶(466mg，3.8mmol)，三氯氧磷(15mL)，四氢呋喃(100mL)，(S)-3-甲基吗啉(5mL)；得黄色固体(720mg，76％)。
步骤i：化合物Aa8的合成
Figure PCTCN2018092419-appb-000025
往化合物Aa7(1.0equiv.)，一水次亚磷酸钠(6.7equiv.)的醋酸/水/吡啶(v/v/v：1/1/2)悬浮液中，加入雷尼镍，升温至60℃反应。冷却至室温，过滤，乙酸乙酯萃取，3N盐酸洗涤3次，浓缩，柱层析(二氯甲烷/甲醇：50/1)纯化得黄色固体。
Figure PCTCN2018092419-appb-000026
化合物Aa7'(1.0g，1.0mmol)，一水次亚磷酸钠(710mg，6.7mmol)，醋酸/水/吡啶(v/v/v：1/1/2)(50mL)，雷尼镍(750mg)，得黄色固体(232mg，47％)。
1H NMR(300MHz,CDCl 3)δ10.15(s,1H),8.78(br s,1H),8.72(s,1H),8.25(s,1H),7.17(s,1H),4.10(t,J＝4.8Hz,8H),3.84(t,J＝4.8Hz,8H),2.79(s,3H),1.36(s,9H)。
Figure PCTCN2018092419-appb-000027
化合物Aa7”(300mg，0.6mmol)，一水次亚磷酸钠(426mg，4.0mmol)，醋酸/水/吡啶(v/v/v：1/1/2)(25mL)，雷尼镍(450mg)，得黄色固体(130mg，42％)。
Figure PCTCN2018092419-appb-000028
化合物Aa7”'(600mg，1.2mmol)，一水次亚磷酸钠(852mg，8.0mmol)，醋酸/水/吡啶(v/v/v：1/1/2)(50mL)，雷尼镍(900mg)，得黄色色固体(420mg，83％)。
步骤j：化合物P-(1-9)，12，(29-32)，(34-35)，(38-43)，(45-46)的合成
Figure PCTCN2018092419-appb-000029
化合物Aa8(0.2mmol)、氰基硼氢化钠(0.4mmol)和对应的胺(0.24mmol)悬浮于甲醇(20mL)中，加入醋酸(0.05mL)，室温搅拌。反应完毕后，加水(50mL)稀释，用乙酸乙酯(100mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：40/1)得产物。
将所得产物溶解于甲醇(15mL)中，加入10个当量的1M氢氧化钾溶液，回流反应。反应完毕后，浓 缩，柱层析(二氯甲烷/甲醇：40/1)纯化。
Figure PCTCN2018092419-appb-000030
黄色固体(38mg，两步总收率：44％)。 1H NMR(300MHz,CDCl 3)δ8.62(s,1H),6.80(s,1H),6.73(s,1H),4.90(br s,2H),4.03(t,J＝4.5Hz,4H),3.81(t,J＝4.5Hz,4H),3.50(s,2H),2.48(s,3H),2.28(s,6H)。
Figure PCTCN2018092419-appb-000031
黄色固体(44mg，两步总收率：45％)。 1H NMR(300MHz,CDCl 3)δ8.63(s,1H),6.80(s,1H),6.77(s,1H),4.89(br s,2H),4.04(br s,4H),3.87(s,2H),3.82(br s,4H),2.77(t,J＝3.3Hz,2H),2.49(s,3H),2.35(t,J＝6.3Hz,2H),2.23(s,6H),1.80–1.64(m,2H)。
Figure PCTCN2018092419-appb-000032
黄色固体(49mg，两步总收率：52％)。 1H NMR(300MHz,CDCl 3)δ8.62(s,1H),6.79(s,1H),6.72(s,1H),4.88(br s,2H),4.04(t,J＝3.9Hz,4H),3.91–3.73(m,6H),3.46(t,J＝6.7Hz,2H),3.32(s,3H),2.77(t,J＝6.8Hz,2H),2.49(s,3H),1.89–1.72(m,2H). 13C NMR(126MHz,CDCl 3)δ158.83,153.94,151.95,151.83,138.11(q,J＝32.4Hz),126.24,122.95(q,J＝274.3Hz),122.44,121.65,111.79,105.21(q,J＝5.5Hz),103.35,71.40,66.81,58.71,47.06,45.94,45.66,29.90,9.24。
Figure PCTCN2018092419-appb-000033
黄色固体(38mg，两步总收率：38％)。 1H NMR(400MHz,CDCl 3)δ8.63(s,1H),6.80(s,1H),6.76(s,1H),4.84(br s,2H),4.03(t,J＝4.9Hz,4H),3.82(t,J＝4.8Hz,4H),3.63(s,2H),3.53(t,J＝5.6Hz,2H),3.35(s,3H),2.63(t,J＝5.6Hz,2H),2.48(s,3H),2.33(s,3H). 13C NMR(101MHz,CDCl 3)δ158.77,153.94,151.95,151.77,138.13(q,J＝32.8Hz),127.07,122.28(q,J＝275.7Hz),121.72,120.25,111.93,105.22(q,J＝5.6Hz),104.45,70.60,66.81,58.92,56.06,54.13,45.91,42.68,9.36。
Figure PCTCN2018092419-appb-000034
黄色固体(68mg，两步总收率：64％)。 1H NMR(500MHz,CDCl 3)δ8.65(s,1H),6.82(s,1H),6.74(s,1H),4.94–4.88(m,2H),4.06(t,J＝4.6Hz,4H),3.84(t,J＝4.8Hz,4H),3.59(s,2H),3.06(d,J＝10.7Hz,2H),2.51(s,3H),1.97(t,J＝11.3Hz,2H),1.81–1.67(m,2H),1.35–1.25(m,3H),1.19(s,6H). 13C NMR(126MHz,CDCl 3)δ158.79,153.93,151.95,151.77,138.12(q,J＝32.3Hz),127.33,122.95(q,J＝274.5Hz),121.68,120.06,111.82,105.23(q,J＝6.2Hz),104.54,72.47,66.81,54.58,54.06,47.40,45.93,27.00,26.84,9.48。
Figure PCTCN2018092419-appb-000035
黄色固体(58mg，两步总收率：58％)。 1H NMR(300MHz,CDCl 3)δ8.62(s,1H),6.80(s,1H),6.69(s,1H),4.84(br s,2H),4.03(t,J＝4.8Hz,4H),3.82(t,J＝4.8Hz,4H),3.57(s,2H),2.68–2.45(m,8H),2.41(q,J＝7.2Hz,2H),1.07(t,J＝7.2Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.78,153.94,151.93,151.79,138.15(q,J＝32.5Hz,CF 3C),127.42,122.94(q,J＝274.4Hz,CF 3),121.71,119.89,111.77,105.23(q,J＝5.5Hz,CF 3CCH),104.57,66.81,54.42,52.97,52.83,52.28,45.94,12.01,9.45。
Figure PCTCN2018092419-appb-000036
黄色固体(55mg，两步总收率：53％)。 1H NMR(500MHz,CDCl 3)δ8.64(s,1H),6.80(s,1H),6.71(s,1H),4.99(br s,2H),4.04(t,J＝4.8Hz,4H),3.83(t,J＝4.8Hz,4H),3.56(s,2H),3.09–2.86(m,2H),2.50(s,3H),2.29(s,6H),2.21–2.07(m,1H),2.05–1.93(m,2H),1.87–1.75(m,2H),1.65–1.44(m,2H). 13C NMR(126MHz,CDCl 3)δ158.88,153.92,151.93,151.77,138.07(q,J＝32.5Hz),127.26,122.95(q,J＝274.6Hz),121.58,120.29,111.78,105.21(q,J＝5.7Hz),104.45,66.80,62.32,54.34,52.93,45.92,41.72,28.29,9.45。
Figure PCTCN2018092419-appb-000037
黄色固体(46mg，两步总收率：47％)。 1H NMR(400MHz,CDCl 3)δ8.62(s,1H),6.81(s,2H),4.87(br s,2H),4.05(t,J＝4.8Hz,4H),3.83(t,J＝4.8Hz,4H),3.70(s,2H),2.85(s,4H),2.78(s,4H),2.49(s,3H). 13C NMR(126MHz,CDCl 3)δ158.82,153.96,152.08,151.89,138.16(q,J＝32.3Hz),127.58,122.93(q,J＝274.6Hz),121.55,112.14,105.29(q,J＝5.4Hz),105.03,66.80,54.99,54.49,45.96,27.36,9.47。
Figure PCTCN2018092419-appb-000038
黄色固体(79mg，两步总收率：72％)。 1H NMR(300MHz,CDCl 3)δ8.62(s,1H),6.81(s,1H),6.64(s,1H),4.84(br s,2H),4.03(t,J＝4.5Hz,4H),3.82(t,J＝4.9Hz,4H),3.60(s,2H),3.24(t,J＝5.0Hz,4H),2.77(s,3H),2.58(t,J＝4.9Hz,4H),2.49(s,3H). 13C NMR(126MHz,CDCl 3)δ158.83,153.95,151.99,151.95,138.12(q,J＝32.4Hz,CF 3C),127.42,122.95(q,J＝274.4Hz,CF 3),121.57,119.23,111.90,105.25(q,J＝5.5Hz,CF 3CCH), 104.48,66.79,54.26,52.19,45.95,45.84,34.28,9.44。
Figure PCTCN2018092419-appb-000039
往化合物P-9(160mg，0.3mmol)的氯仿(10mL)溶液中，加入甲烷磺酸(370μL，0.3mmol)，室温反应2小时后，加入无水乙醚(50mL)稀释，过滤，干燥，得黄色化合物P-9甲烷磺酸盐(145mg，77％)。
1H NMR(500MHz,DMSO-d 6)δ9.89(br s,1H),8.51(s,1H),7.25(s,1H),7.23(s,1H),4.47(br s,2H),4.02(t,J＝5.0Hz,4H),3.76(t,J＝4.9Hz,,4H),3.73(s,2H),3.57–3.47(m,2H),3.30–3.09(m,4H),3.01(s,3H),2.52(br s,2H),2.43(br s,6H). 13C NMR(126MHz,DMSO-d 6)δ157.47,153.93,151.45,145.46,138.57(q,J＝33.3Hz),129.45,122.77(q,J＝275.06Hz),118.65,112.36,111.92,110.13,107.64,66.42,51.32,50.27,46.01,42.96,40.23,35.51,9.65。
Figure PCTCN2018092419-appb-000040
黄色固体(63mg，两步总收率：53％)。 1H NMR(400MHz,CDCl 3)δ8.63(s,1H),6.83(s,1H),6.70(s,1H),4.99(br s,2H),4.24–3.98(m,4H),3.96–3.78(m,4H),3.60(s,2H),3.46(br s,4H),2.51(s,3H),2.44(br s,4H),1.47(s,9H). 13C NMR(126MHz,CDCl 3)δ158.91,154.77,153.94,151.85,151.72,138.18(q,J＝32.6Hz),127.40,122.93(q,J＝274.1Hz),121.50,119.51,111.85,105.39(q,J＝5.6Hz),104.52,79.65,66.79,54.45,52.74,45.93,28.43,9.45。
Figure PCTCN2018092419-appb-000041
黄色固体(45mg两步总收率：43％)。 1H NMR(500MHz,Chloroform-d)δ8.62(s,1H),6.80(s,1H),6.70(s,1H),4.84(d,J＝7.5Hz,2H),4.06–4.00(m,4H),3.95(d,J＝11.4Hz,2H),3.83–3.80(m,4H),3.65(s,2H),3.47(t,J＝7.5Hz,2H),3.36(t,J＝11.7Hz,2H),2.88(t,J＝7.3Hz,2H),2.32–2.16(m,2H),1.71–1.57(m,2H),1.52(ddd,J＝13.2,3.8,1.9Hz,2H)。
Figure PCTCN2018092419-appb-000042
黄色固体(40mg两步总收率：41％)。 1H NMR(500MHz,Chloroform-d)δ8.62(s,1H),6.81(s,1H),6.65(s,1H),4.85(d,J＝5.3Hz,2H),4.75(s,4H),4.05–4.00(m,4H),3.82(t,J＝4.9Hz,4H),3.61(s,2H),3.42(s,3H),2.48(s,4H)。
Figure PCTCN2018092419-appb-000043
黄色固体(36mg两步总收率：32％)。 1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),6.79(s,1H),6.72(s,1H),4.90(d,J＝5.8Hz,2H),4.02(t,J＝4.7Hz,4H),3.81(t,J＝4.8Hz,5H),3.73–3.68(m,4H),3.57(s,2H),3.00(d,J＝11.1Hz,2H),2.58–2.46(m,8H),2.18(dq,J＝11.2,5.9,4.2Hz,1H),2.01(t,J＝11.1Hz,2H),1.82(d,J＝13.4Hz,2H),1.58(td,J＝12.1,3.6Hz,2H)。
Figure PCTCN2018092419-appb-000044
对应的胺的合成参考WO2010138589(A1)，黄色固体(20mg两步总收率：18％)。 1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),7.74–7.50(m,1H),6.81(s,1H),4.84(s,2H),4.67–4.60(m,2H),4.59–4.51(m,2H),4.32–4.13(m,2H),4.10–3.98(m,4H),3.83(t,J＝4.9Hz,4H),2.92–2.74(m,1H),2.50(s,3H),2.21(d,J＝7.7Hz,2H),2.06–1.97(m,4H),1.00–0.84(m,6H)。
Figure PCTCN2018092419-appb-000045
黄色固体(52mg两步总收率：52％)。 1H NMR(300MHz,Chloroform-d)δ8.62(s,1H),6.80(s,1H),6.67(d,J＝1.3Hz,1H),4.84(d,J＝4.0Hz,2H),4.08–3.98(m,4H),3.81(t,J＝4.8Hz,4H),3.62(s,2H),3.37(dd,J＝4.3，1.5Hz，8H)，2.47(d，J＝1.5Hz，3H)，2.32(d，J＝1.5Hz，3H)。
Figure PCTCN2018092419-appb-000046
对应的胺的合成参考WO2010138589(A1)，黄色固体(75mg两步总收率：67％)。 1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),7.14(d,J＝5.3Hz,1H),6.80(s,1H),6.68(s,1H),5.54(d,J＝5.3Hz,1H),4.93(s,2H),4.03(dd,J＝5.7,4.0Hz,4H),3.82(dd,J＝5.7,4.0Hz,4H),3.58(s,2H),2.59–2.52(m,6H),2.49(s,3H),1.20(s,8H)。
Figure PCTCN2018092419-appb-000047
黄色固体(49mg两步总收率：47％)。 1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),6.85(s,1H),6.81(s,1H),4.86(s,2H),4.04(t,J＝4.9Hz,4H),3.82(q,J＝4.8,3.6Hz,8H),3.58(t,J＝5.3Hz,4H),3.28–3.25(m,2H),2.51(s,3H),1.81(t,J＝5.6Hz,4H)。
Figure PCTCN2018092419-appb-000048
对应的胺的合成参考WO2010138589(A1)，黄色固体(47mg两步总收率：44％)。 1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),6.80(s,1H),6.77(s,1H),4.88(s,2H),4.03(dd,J＝5.7,4.1Hz,4H),3.82(dd,J＝5.6,4.0Hz,4H),3.75(d,J＝1.5Hz,2H),3.47(s,2H),3.42(d,J＝12.1Hz,2H),3.32(d,J＝10.1Hz,1H),3.20(d,J＝10.2Hz,1H),3.01(s,1H),2.78(dd,J＝9.2,2.4Hz,1H),2.66(d,J＝2.4Hz,2H),2.50(s,3H),2.24–2.14(m,1H),1.75(d,J＝9.7Hz,1H),1.51(d,J＝9.7Hz,1H)。
Figure PCTCN2018092419-appb-000049
黄色固体(56mg两步总收率：51％)。 1H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.62(s,1H),6.82(s,1H),4.97(s,2H),4.74(t,J＝6.3Hz,1H),4.67(d,J＝6.4Hz,1H),4.55–4.44(m,2H),4.26–4.14(m,2H),4.07(dd,J＝5.7,4.0Hz,4H),4.03–3.87(m,2H),3.86–3.80(m,4H),3.49(s,1H),3.35(d,J＝11.7Hz,1H),2.82–2.62(m,1H),2.51(s,3H),2.21(t,J＝7.6Hz,1H),2.04–1.97(m,2H),0.90–0.82(m,1H)。
Figure PCTCN2018092419-appb-000050
对应的胺的合成参考WO2010138589(A1)，黄色固体(53mg两步总收率：47％)。 1H NMR(400MHz,Chloroform-d)δ8.62(s,1H),6.81(s,1H),6.77(s,1H),4.81(s,2H),4.03(dd,J＝5.7,4.1Hz,4H),3.83–3.81(m,4H),3.72(d,J＝4.7Hz,4H),3.60(s,2H),3.04(s,3H),2.50(s,3H),2.32(d,J＝5.3Hz,4H),1.70(s,6H)。
Figure PCTCN2018092419-appb-000051
对应的胺的合成参考WO2010138589(A1)，黄色固体(52mg两步总收率：48％)。 1H NMR(400MHz,Chloroform-d)δ8.61(d,J＝3.7Hz,1H),6.81(s,1H),6.71(s,1H),4.88(s,2H),4.03(dq,J＝6.3,2.8,2.3Hz,4H),3.85–3.79(m,4H),3.59(s,2H),3.34(s,2H),2.67–2.42(m,15H),1.04(s,6H)。
Figure PCTCN2018092419-appb-000052
对应的胺的合成参考WO2010138589(A1)，黄色固体(52mg两步总收率：48％)。 1H NMR(400MHz,Chloroform-d)δ8.62(s,1H),6.80(s,1H),4.86(s,2H),4.04(dd,J＝5.7,4.1Hz,4H),3.84–3.79(m,4H),3.62(s,2H),3.16(d,J＝1.4Hz,2H),3.09–3.04(m,2H),2.48(d,J＝1.5Hz,3H),2.02(d,J＝13.2Hz,2H),1.67(d,J＝ 8.8Hz,2H),1.45(s,2H),1.08(s,6H)。
Figure PCTCN2018092419-appb-000053
对应的胺合成参考WO2013134226，黄色固体(50mg两步总收率：43％)。LC-MS m/z：[M+H] +＝588.0。
Figure PCTCN2018092419-appb-000054
对应的胺合成参考WO2013134226，黄色固体(61mg两步总收率：48％)。LC-MS m/z：[M+H] +＝641.9。
步骤j：化合物P-33，36，37的合成
Figure PCTCN2018092419-appb-000055
化合物Aa8(0.2mmol)、氰基硼氢化钠(0.4mmol)和对应的Boc保护的胺(0.24mmol)悬浮于甲醇(20mL)中，加入醋酸(0.05mL)，室温搅拌。反应完毕后，加水(50mL)稀释，用乙酸乙酯(100mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：40/1)得产物。
产物溶于二氯甲烷(10mL)中，加入10倍当量的三氟乙酸，室温搅拌2天。反应结束后直接旋干。
将所得产物溶解于甲醇(15mL)中，加入10个当量的1M氢氧化钾溶液，回流反应。反应完毕后，浓缩，柱层析(二氯甲烷/甲醇：40/1)纯化。
Figure PCTCN2018092419-appb-000056
黄色固体(52mg两步总收率：50％)。 1H NMR(400MHz,Chloroform-d)δ8.62(s,1H),6.81(s,1H),6.68(d,J＝3.4Hz,1H),4.83(s,2H),4.03(t,J＝4.8Hz,4H),3.82(t,J＝5.0Hz,4H),3.49(d,J＝3.3Hz,2H),3.36(s,2H),2.47(d,J＝3.4Hz,3H),2.34(s,2H),1.93(s,4H),1.79(t,J＝5.3Hz,4H)。
Figure PCTCN2018092419-appb-000057
黄色固体(50mg两步总收率：48％)。 1H NMR(400MHz,Chloroform-d)δ8.60(s,1H),6.79(s,1H),6.67(s,1H),4.90(s,2H),4.02(dd,J＝5.7,4.1Hz,4H),3.84–3.77(m,4H),3.67(s,2H),3.05(s,4H),2.77(dd,J＝6.6,4.0Hz,4H),2.49(s,3H),1.76–1.69(m,4H)。
Figure PCTCN2018092419-appb-000058
黄色固体(45mg两步总收率：46％)。 1H NMR(400MHz,Chloroform-d)δ8.62(d,J＝2.0Hz,1H),6.81(s,1H),6.65(d,J＝3.8Hz,1H),4.80(s,2H),4.03(q,J＝4.1,3.2Hz,4H),3.82(t,J＝4.8Hz,4H),3.74(s,2H),3.60(d,J＝2.5Hz,2H),3.35(s,3H),3.30(d,J＝8.3Hz,2H),2.51–2.46(m,4H)。
步骤j：化合物P-44的合成
Figure PCTCN2018092419-appb-000059
化合物Aa8(0.2mmol)、氰基硼氢化钠(0.4mmol)和N-乙酰基-2-(4-哌啶基)-2-丙胺(0.24mmol)悬浮于甲醇(20mL)中，加入醋酸(0.05mL)，室温搅拌。反应完毕后，加水(50mL)稀释，用乙酸乙酯(100mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：40/1)得产物。
将所得产物溶解于浓盐酸(10mL)中，回流反应7天。反应完毕后，中和，柱层析(二氯甲烷/甲醇：10/1)纯化。
Figure PCTCN2018092419-appb-000060
N-乙酰基-2-(4-哌啶基)-2-丙胺的合成参考WO2014043068，黄色固体(12mg，两步总产率11％)。LC-MS m/z：[M+H] +＝533.0。
步骤j：化合物P-10的合成
Figure PCTCN2018092419-appb-000061
化合物Aa8``(0.2mmol)、氰基硼氢化钠(0.4mmol)和对应的胺(0.24mmol)悬浮于甲醇(20mL)中，加入醋酸(0.05mL)，室温搅拌。反应完毕后，加水(50mL)稀释，用乙酸乙酯(100mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：40/1)得产物。
将所得产物溶解于甲醇(15mL)中，加入10个当量的1M氢氧化钾溶液，回流反应。反应完毕后，浓缩，柱层析(二氯甲烷/甲醇：40/1)纯化。
Figure PCTCN2018092419-appb-000062
黄色固体(55mg，两步总收率：48％)。 1H NMR(300MHz,Chloroform-d)δ8.63(d,J＝3.1Hz,1H),6.82(d,J＝3.1Hz,1H),6.65(s,1H),4.93(br s,1H),4.83(s,2H),4.56(d,J＝11.3Hz,1H),4.09–3.97(m,1H),3.89–3.74(m,2H),3.72–3.53(m,4H),3.26(s,4H),2.78(s,3H),2.60(s,4H),2.49(s,3H),1.45(d,J＝6.8Hz,3H). 13C NMR(126MHz,Chloroform-d)δ158.81,153.66,152.06,151.91,138.12(q,J＝32.3Hz),127.41,122.94(d,J＝274.5Hz).,121.65,111.92,105.26(d,J＝6.7Hz),104.58,71.03,66.98,54.26,52.16,45.83,34.28,15.27,9.49。
步骤j：化合物P-11，(25-27)的合成
Figure PCTCN2018092419-appb-000063
化合物Aa8```(0.2mmol)、氰基硼氢化钠(0.4mmol)和对应的胺(0.24mmol)悬浮于甲醇(20mL)中，加入醋酸(0.05mL)，室温搅拌。反应完毕后，加水(50mL)稀释，用乙酸乙酯(100mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：40/1)得产物。
将所得产物溶解于甲醇(15mL)中，加入10个当量的1M氢氧化钾溶液，回流反应。反应完毕后，浓缩，柱层析(二氯甲烷/甲醇：40/1)纯化。
Figure PCTCN2018092419-appb-000064
黄色固体(34mg，两步总收率：30％)。 1H NMR(300MHz,CDCl 3)δ8.59(s,1H),6.80(s,1H),6.74(s,1H),4.87(br s,2H),4.04(t,J＝4.6Hz,4H),3.83(t,J＝4.7Hz,4H),3.67(s,2H),3.27(t,J＝4.9Hz,4H),2.78(s,2H),2.64(t,J＝5.1Hz,4H). 13C NMR(126MHz,CDCl 3)δ159.02,153.50,153.30,151.82,138.25(q,J＝32.8Hz),122.85(q,J＝274.3Hz),120.96,118.53,115.86,112.74,105.24(q,J＝6.1Hz),104.61,66.69,53.04,52.06,46.00,45.79,34.38。
Figure PCTCN2018092419-appb-000065
白色固体(35mg，收率：45％)。 1H NMR(400MHz,CD 3OD)δ8.31(s,1H),7.00(s,1H),6.82(s,1H),3.97(m,4H),3.72(m,4H),3.68(s,2H),3.23(s,2H),3.06(d,2H),2.16(t,2H),1.72(d,2H),1.33(m,4H),1.05(s,6H)。
Figure PCTCN2018092419-appb-000066
白色固体(30mg，收率：40％)。 1H NMR(400MHz,CD 3OD)δ8.32(s,1H),6.94(s,1H),6.83(s,1H),3.97(m,4H),3.72(m,4H),3.55(br，s,1H),3.22(d,2H),2.92(d,2H),2.23(s,6H),2.03(d,2H),1.78(d,2H),1.47(d,2H),1.18(d,2H)。
Figure PCTCN2018092419-appb-000067
白色固体(38mg，收率：42％)。 1H NMR(400MHz,CD 3OD)δ8.30(s,1H),6.97(s,1H),6.83(s,1H),4.00(m,4H),3.73(m,4H),3.65(s,2H),3.23(d,2H),2.66(m,4H),1.16(t,3H)。
化合物P-13，14的合成
Figure PCTCN2018092419-appb-000068
将化合物P-12(500mg,)溶解于40mL二氯甲烷中，加入2.5mL三氟乙酸，室温搅拌2小时。反应完毕后，减压除掉溶剂，得油状物，加10mL甲醇溶解，加入乙醚(80mL)有固体析出，过滤得脱Boc产物的三氟乙酸盐420mg。
将上述所得盐(按含一分子三氟乙酸计算，114mg，0.2mmol)，对应的酸(1.5equiv.)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)(1.5equiv.)，1-羟基苯并三唑(HOBT)(1.5equiv.)，N,N-二异丙基乙胺(DIPEA)(3equiv.)悬浊于DMF中，室温下反应。反应完毕后，加入水稀释，乙酸乙酯萃取三次，合并有机层，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：20/1)纯化得产品。
Figure PCTCN2018092419-appb-000069
黄色固体(67mg，60％)。 1H NMR(500MHz,CDCl 3)δ8.65(s,1H),6.84(s,1H),6.68(s,1H),4.91(s,2H),4.53(br s,1H),4.06(t,J＝4.8Hz,4H),3.85(t,J＝4.8Hz,4H),3.79–3.65(m,4H),3.60(s,2H),2.51(s,7H),1.50(s,6H). 13C NMR(126MHz,CDCl 3)δ174.93,158.85,153.94,151.94,151.92,138.12(q,J＝32.6Hz),127.36,122.90(q,J＝274.06Hz),121.55,119.38,111.87,105.27(q,J＝6.3Hz),104.42,71.53,66.79,54.40,52.96,45.94,27.83,9.44。
Figure PCTCN2018092419-appb-000070
黄色固体(55mg，50％)。 1H NMR(500MHz,CDCl 3)δ8.66(s,1H),6.84(s,1H),6.68(s,1H),4.87(s,2H),4.47(t,J＝6.7Hz,1H),4.07(t,J＝4.8Hz,4H),3.90(d,J＝7.3Hz,1H),3.86(t,J＝4.8Hz,4H),3.82–3.71(m,1H),3.69–3.62(m,1H),3.61(s,1H),3.43(d,J＝5.2Hz,2H),2.58–2.35(m,7H),1.34(d,J＝6.6Hz,3H). 13C NMR(126MHz,CDCl 3)δ173.50,158.83,153.95,151.97,138.26,138.13(d,J＝32.8Hz),127.37,122.95(q,J＝274.6Hz),121.59,119.28,111.89,105.27,104.41,66.79,64.02,54.42,52.70,52.56,45.94,44.87,42.53,21.50,9.44。
化合物P-15的合成
Figure PCTCN2018092419-appb-000071
氮气保护、冰浴下，往化合物Aa8'(600mg，1.2mmol)的无水四氢呋喃(40mL)溶液中、加入1M甲基溴化镁(4.8mL，4.8mmol)，移至室温下反应。待反应完毕后，加水50mL稀释，用乙酸乙酯(100mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇＝40/1)得黄色化合物(520mg，86％)。
将上述所得产物(400mg，0.8mmol)溶解于15mL甲醇中，加入10个当量的1M氢氧化钾溶液(8mL)，回流反应。反应完毕后，浓缩，柱层析(二氯甲烷/甲醇＝40/1)纯化得黄色化合物(270mg，80％)。
1H NMR(300MHz,CDCl 3)。δ8.59(s,1H),6.80(s,1H),6.75(s,1H),5.14(q,J＝4.8Hz,1H),4.82(s,2H),4.04(t,J＝4.8Hz,4H),3.82(t,J＝4.8Hz,4H),2.53(s,3H),1.99(br s,1H),1.58(d,J＝6.4Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.78,154.14,152.05,151.93,128.13,125.24,111.85,105.25(q,J＝5.5Hz),100.27,66.80,63.82,45.97,24.52,9.38。
化合物P-16的合成
Figure PCTCN2018092419-appb-000072
氮气保护、冰浴下，往化合物Aa8'(100mg，0.2mmol)的无水二氯甲烷(20mL)溶液中、加入1mL二乙胺基三氟化硫(DAST)，移至室温下反应。待反应完毕后，缓慢加冰水10mL淬灭，加水(50mL)稀释，用二氯甲烷(50mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，直接用于下一步反应。
将上述所得产物溶解于15mL甲醇中，加入10个当量的1M氢氧化钾溶液(2mL)，回流反应。反应完毕后，浓缩，柱层析(二氯甲烷/甲醇＝40/1)纯化得黄色化合物(38mg，两步总收率：：44％)。
1H NMR(300MHz,CDCl 3)。δ8.63(s,1H),6.86(t,J＝56.4Hz,1H),6.85(s,1H),6.82(s,1H),4.85(br s,2H),4.06(t,J＝4.9Hz,4H),3.84(t,J＝4.8Hz,4H),2.58(s,3H). 13C NMR(101MHz,CDCl 3)δ158.98,154.52,152.94,151.96,138.17(q,J＝32.6Hz),127.09(t,J＝6.3Hz),122.88(q,J＝274.3Hz),121.13,117.39(t,J＝25.8Hz),112.40(t,J＝233.7Hz),112.24,105.29(q,J＝6.1Hz),101.21(t,J＝5.0Hz),66.71,45.96,9.46。
化合物P-17，18的合成
Figure PCTCN2018092419-appb-000073
-30℃下，向化合物P-9(110mg，0.2mmol)的无水氯仿(10mL)溶液中，加入无水三乙胺(30μL，0.25mmol)，滴加对应的氯甲酸酯(0.6mmol)的氯仿(5mL)溶液，维持在该温度下反应。待反应完毕后，缓慢加冰水10mL淬灭，加二氯甲烷(40mL)稀释，分出有机层，饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：50/1)纯化得黄色固体。
Figure PCTCN2018092419-appb-000074
黄色固体(55mg，45％)。 1H NMR(400MHz,CDCl 3)δ9.18(br s,1H),8.84(s,1H),8.45(s,1H),6.68(s,1H),4.05(t,J＝4.5Hz,4H),3.86(s,3H),3.84–3.78(m,4H),3.62(s,2H),3.25(s,4H),2.78(s,3H),2.59(s,4H),2.50(s,3H). 13C NMR(101MHz,CDCl 3)δ153.87,153.54,152.67,151.39,150.80,138.69(q,J＝32.9Hz,CF 3C),127.50,126.60,122.72(q,J＝275.83Hz,CF 3),119.55,111.79,109.21(q,J＝5.2Hz,CF 3CCH),104.69,66.70,54.19,52.72,52.18,45.89,45.84,34.22,9.40。
Figure PCTCN2018092419-appb-000075
参照化合物P-9的甲烷磺酸盐的制备方法。以化合物P-17(200mg，0.3mmol)为原料，得黄色化合物P-17甲烷磺酸盐(190mg，81％)。
1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),9.83(br s,1H),8.79(s,1H),8.31(s,1H),7.23(s,1H),4.46(s,2H),4.01(t,J＝4.8Hz,4H),3.82–3.68(m,7H),3.62–3.41(m,4H),3.28–3.04(m,4H),3.00(s,3H),2.50(s,3H),2.38(s,3H). 13C NMR(126MHz,DMSO-d 6)δ154.58,154.11,153.99,152.04,151.38,136.87(q,J＝31.6Hz,CF 3C),129.53,125.47,123.08(q,J＝274.9Hz,CF 3),112.40,112.00,108.63(q,J＝6.9Hz,CF 3CCH),107.63,66.41,52.76,51.36,50.31,46.02,42.98,40.23,35.54,9.69。
Figure PCTCN2018092419-appb-000076
黄色固体(55mg，74％)。 1H NMR(300MHz,CDCl 3)δ9.69(s,1H),8.96(s,1H),8.51(s,1H),7.41(t,J＝7.2Hz,2H),7.36–7.19(m,3H),6.67(s,1H),4.13–3.91(m,4H),3.79(s,4H),3.61(s,2H),3.25(s,4H),2.78(s,3H),2.58(s,4H),2.41(s,3H)。
化合物P-19的合成
Figure PCTCN2018092419-appb-000077
10mL微波反应管中，加入化合物P-17(122mg，0.2mmol)，无水氯化钙(10mg，mmol)，甲胺醇溶液(2mL)，微波100℃反应30分钟，浓缩，薄层层析(二氯甲烷/甲醇：20/1)纯化得白色固体(30mg，33％)。
1H NMR(400MHz,CDCl 3)。δ9.37(s,1H),9.06(br s,1H),8.74(s,1H),7.28(s,1H),6.68(s,1H),4.05(t,J＝4.6Hz,4H),3.84(t,J＝4.9Hz,4H),3.61(s,2H),3.25(br s,4H),3.01(d,J＝4.6Hz,3H),2.78(s,3H),2.59(br s,4H),2.50(s,3H). 13C NMR(126MHz,CDCl 3)δ156.42,153.99(q,J＝13.5Hz),151.34,149.71,138.66,138.39,127.59,124.36,122.56(q,J＝274.93Hz),119.56,111.84,109.33(q,J＝5.4Hz),104.70,66.78,54.26,52.23,45.95,45.90,34.27,26.54,9.45。
化合物P-20的合成
Figure PCTCN2018092419-appb-000078
往化合物P-18(75mg，0.1mmol)的DMF(3mL)溶液中，加入环丙胺(1mL),升温至60℃反应。反应完毕，加水(30mL)稀释，用乙酸乙酯(50mL)萃取两次，合并有机层，饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩，薄层层析(二氯甲烷/甲醇：40/1)得黄色化合物(26mg，40％)。
1H NMR(400MHz,CDCl 3)。δ9.47(br s,1H),9.09(br s,1H),8.73(s,1H),7.40(s,1H),6.67(s,1H),4.05(t,J＝4.7Hz,4H),3.84(t,J＝4.8Hz,4H),3.61(s,2H),3.25(t,J＝4.7Hz,4H),2.78(br s,4H),2.59(s,4H),2.49(s,3H),0.95–0.78(m,2H),0.71–0.61(m,2H). 13C NMR(126MHz,CDCl 3)δ156.70,153.93,153.85,151.32,149.81,138.53(q,J＝33.2Hz),127.59,124.65,122.57(q,J＝274.7Hz),119.57,111.83,109.48(q,J＝6.6Hz),104.69,66.77,54.26,52.23,45.95,45.90,34.27,22.58,9.45,6.80。
化合物P-(21-24)的合成
Figure PCTCN2018092419-appb-000079
往化合物P-9(1equiv.)和1，8-二氮环[5.4.0]十一-7-烯(DBU，6equiv)的二氯甲烷溶液中加入对应的异氰酸酯(6equiv)，室温下反应。反应完毕，加水稀释，二氯甲烷萃取一次，饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩，柱层析(二氯甲烷/甲醇：50/1)纯化得黄色固体。
Figure PCTCN2018092419-appb-000080
以化合物P-9(160mg，0.3mmol)为起始原料，得黄色固体(54mg，29％)。 1H NMR(300MHz,DMSO-d 6)δ9.62(s,1H),8.71(s,1H),8.08(s,1H),7.45(d,J＝5.7Hz,1H),6.92(s,1H),3.96(t,J＝4.8Hz,4H),3.73(t,J＝4.8Hz,4H),3.56(s,2H),3.18(t,J＝6.8Hz,2H),3.08(s,4H),2.85(s,3H),2.48(s,4H),2.42(s,3H),1.09(t,J＝7.1Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ154.81,154.58,153.78,151.31,150.88,136.71(q,J＝31.8Hz),127.20,124.08,123.23(q,J＝274.81Hz),120.27,111.34,108.29(q,J＝6.2Hz),106.21,66.46,53.80,52.14,45.94,34.44,34.06,15.69,9.67。
Figure PCTCN2018092419-appb-000081
参照化合物P-9的甲烷磺酸盐的制备方法。以化合物P-21(75mg，0.31mmol)为原料，得黄色化合物P-21甲烷磺酸盐(70mg，81％)。
1H NMR(300MHz,DMSO-d 6)δ9.80(br s,1H),9.65(s,1H),8.72(s,1H),8.11(s,1H),7.44(br s,1H),7.20(s,1H),4.45(s,2H),4.13(s,2H),4.01(t,J＝4.9Hz,4H),3.75(s,6H),3.49(s,2H),3.27–3.03(m,7H),3.00(s,3H),2.37(s,3H),1.09(t,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ155.00,154.56,153.98,152.13,150.91,136.74(q,J＝31.4Hz),129.46,123.69,123.29(q,J＝274.3Hz),112.39,111.93,108.36(q,J＝6.4Hz),107.53,66.41,51.36,40.24,50.30,46.00,42.99,35.51,34.45,15.68,9.69。
Figure PCTCN2018092419-appb-000082
以化合物P-9(160mg，0.3mmol)为起始原料，得黄色固体(128mg，67％)。 1H NMR(300MHz,CDCl 3)δ9.45(s,1H),8.93(br s,1H),8.74(s,1H),7.30(s,1H),6.67(s,1H),4.10-4.16(m,1H),4.05(t,J＝4.4Hz,4H),3.84(t,J＝4.3Hz,4H),3.61(s,2H),3.25(t,J＝4.5Hz,4H),2.78(s,3H),2.59(t,J＝4.7Hz,4H),2.50(s,3H),1.30(d,J＝6.4Hz,6H). 13C NMR(126MHz,CDCl 3)δ155.16,154.33,153.93,151.41,149.67,138.39(q,J＝32.9Hz),127.55,124.19,122.61(q,J＝274.4Hz),119.53,111.83,109.53(q,J＝5.6Hz),104.66,66.78,54.26,52.23,45.95,45.91,42.21,34.25,23.08,9.45。
Figure PCTCN2018092419-appb-000083
以化合物P-9(110mg，0.2mmol)为起始原料，得黄色固体(40mg，29％)。 1H NMR(300MHz,CDCl 3)δ11.45(s,1H),9.44(s,1H),8.85(s,1H),7.60(dd,J＝8.9,4.7Hz,2H),7.35(s,1H),7.07(t,J＝8.2Hz,2H),6.69(s,1H),4.07(br s,4H),3.86(t,J＝5.1Hz,4H),3.63(s,2H),3.26(s,4H),2.79(s,3H),2.60(s,4H),2.52(s,3H). 13C NMR(126MHz,CDCl 3)δ159.29(d,J＝242.9Hz),153.74(d,J＝54.9Hz),153.50,151.09,149.67,138.93(q,J＝32.9Hz),133.94(q,J＝2.9Hz),127.67,125.13,122.05(q,J＝7.8Hz),119.69,115.66(q,J＝22.6Hz),111.82,109.78,104.83,66.78,54.27,52.25,45.96,45.91,34.28,9.47。
Figure PCTCN2018092419-appb-000084
以化合物P-9(110mg，0.2mmol)为起始原料，得黄色固体(46mg，31％)。 1H NMR(300MHz,DMSO-d 6)δ10.04(s,1H),9.92(s,1H),8.82(s,1H),8.22(s,1H),7.91(d,J＝8.7Hz,,2H),7.65(d,J＝8.8Hz,,2H),6.94(s,1H),4.27(q,J＝6.9Hz,2H),3.97(t,J＝4.9Hz,4H),3.82–3.66(m,4H),3.57(s,2H),3.08(s,4H),2.85(s,3H),2.48-2.43(m,7H),1.30(t,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ165.79,153.90,153.79,152.07,151.17,143.65,136.95(q,J＝32.2Hz),130.89,127.27,125.30,123.23(q,J＝274.93Hz),124.16,120.35,118.45,111.35,108.74,106.31,66.47,60.89,53.80,52.14,45.94,34.07,14.71,9.68。
化合物P-28的合成
Figure PCTCN2018092419-appb-000085
步骤1：将P-28-1(437.0mg,1.0mmol,其制备方法参见CN201210177980.3)溶于二氯甲烷:水(10:1,20mL)的混合液中，随后加入三氟甲基亚磺酸钠(936.0mg,6mmol),将上述体系冷却到0℃并缓慢滴加70％过氧叔丁醇水溶液(1.4mL,10.0mmol)，滴加完毕，继续搅拌30min；随后加入二甲基亚砜(4.0mL)并升温到40℃反应过夜，LC-MS检测分析反应结束。加入二氯甲烷和水搅拌，静止，分液的有机相，干燥，浓缩得到粗品。用石油醚：乙酸乙酯(10:1～4:1)过柱得到P-28-2(300mg)。LC-MS:506.2(M+1)。
步骤2：将P-28-2(300mg,0.6mmol)和三氯氧磷(1.85g,11.9mmol)加入到甲苯(20mL)中，随后加入N,N-二甲基苯胺(215.6mg,18.0mmol)于回流状态下反应过夜。TCL分析反应完全，将反应体系浓缩，随后加入乙酸乙酯和冰水进行搅拌，分液得到乙酸乙酯相，对乙酸乙酯相进行干燥，浓缩得到氯代物粗品。将氯代物粗品溶于无水四氢呋喃(10mL)中，0℃下加入吗啉(155.0mg,1.8mmol)于室温下搅拌直到原料反应完全，浓缩得粗品直接下一步反应。
步骤3：将步骤2所得粗品加入甲醇(20mL)溶解，随后加入水(1mL)和氢氧化钠(237.6mg)与回流下反应直到原料完全消失，浓缩，加入水，调PH到5-6析出固体，干燥，直接下一步。LC-MS:477.2(M+H) +。
步骤4：将步骤3的粗品、HBTU(455.0mg,1.2mmol)、三乙胺(121mg,1,2mmol)和2-(4-哌啶基)-2-丙醇(Aa9`,93.2mg,0.65mmol)加入DMF(10mL)中于室温下反应过夜，LC-MS分析反应结束。将反应体系倒入到冰水中用乙酸乙酯萃取，有机相干燥，浓缩，过柱(DCM:MeOH＝100:1～40:1)得到浅色固体P-28-5(140mg)。
1H NMR(300MHz,CD 3OD)δ8.48(s,1H),7.79(d,1H),7.65(d,1H),7.34～7.42(brs,2H),6.81(s,1H),6.70(s,1H),5.26(s,1H),4.76(d,1H),4.02(s,4H),3.80(s,4H),1.82～1.95(m,2H),1.47～1.69(m,2H),1.24(s,6H).LC-MS:602.3(M+1)。
步骤5：N 2保护下将P-28-5(100mg,0.17mmol)溶于无水四氢呋喃(10mL)中冷却到-20℃,随后缓慢滴加BH 3/THF(1N,1.7mL,1.7mmol)，滴加完毕，将反应体系升温到60℃反应1h，随后将反应体系冷却到-20℃缓慢滴加浓盐酸(0.8mL),滴加完毕，随后升温到60℃反应，LC-MS检测中间体全部转化为目标化合物。冷 却，加入乙酸乙酯和水进行分液的水。水相用氢氧化钠调pH到10左右，用DCM进行萃取，干燥浓缩，快速过柱(DCM:MeOH＝100:1～40:1)得到P-28(20mg)。
1H NMR(300MHz,CD 3OD)δ:8.36(s,1H),7.09(s,1H),6.84(s,1H),5.42(s,1H),4.05(t,4H),3.99(s,2H),3.77(t,4H),3.50(brs,1H),2.39(t,2H),1.80(t,2H),1.36～1.52(m,4H),1.08(s,6H),LC-MS:588.2(M+1)。
活性测试实验
初筛浓度设定：待测化合物用DMSO(二甲基亚砜)溶解至100μM或10μM作为储存液，各取2μL加入48μL 1倍反应缓冲液(1×Reaction Buffer)中，得到1μM或100nM含4％DMSO的化合物溶液，混匀后用4％DMSO在1倍反应缓冲液中(in 1×Reaction Buffer)稀释得到100nM或20nM化合物溶液。每个稀释溶液各取5μL加入384孔板中，这样在最后的20μL激酶反应体系中化合物的终浓度就分别是1μM和100nM或者100nM和20nM并含有1％DMSO。
IC 50测定浓度设定：针对不同酶，起始浓度选择10μM和100μM。用DMSO溶解至1mM或10mM作为工作液，各取1μL加入24μl 1倍激酶缓冲液A(1×Kinase Buffer A)中，得到40μM或400μM含4％DMSO的化合物溶液，依次4倍倍比梯度稀释，10个稀释浓度，每个稀释溶液各取2.5μL加入384孔板中，这样在最后的10μL激酶反应体系中化合物的终浓度就依次是10μM，2.5μM，0.625μM并含有1％DMSO。
实验步骤：室温下，PI3K激酶反应30分钟后终止，向各孔加入检测液，充分混合，室温孵育2小时，多功能酶标仪(2104
Figure PCTCN2018092419-appb-000086
Multilabel Reader(Cat:2104-0010,PerkinElmer))检测，记录测试结果。
实验结果:
计算各孔的激发光比值(Emission Ratio)
Emission Ratio(ER)＝665nM Emission signal/620nm Emission signal
100％抑制对照的平均Emission Ratio记为：ER 100％
0％抑制对照的平均Emission Ratio记为：ER 0％
计算抑制率
抑制率用以下公式计算：
抑制率＝(ER sample-ER 0％)/(ER 100％-ER 0％)×100％
如表1和表2所示，表中化合物均显示出了对PI3K激酶较好的抑制作用，尤其是化合物P-5/6/7显示出了对PI3Kδ选择性的抑制作用。
表1 部分化合物在指定浓度下对PI3K激酶各个亚型的抑制作用
Figure PCTCN2018092419-appb-000087
表2 部分化合物对PI3K激酶各个亚型的抑制作用
Figure PCTCN2018092419-appb-000088
从表中可以看出，化合物P-5，P-6，P-7等对PI3Kδ有很好的选择性。GDC0941为阳性化合物,化学名称为2-(1H-吲唑-4-基)-6-[[4-(甲基磺酰基)-1-哌嗪基]甲基]-4-(4-吗啉基)噻吩并[3,2-D]嘧啶(4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine)。
初步药代动力学测试实验
1.取健康SD大鼠14只，雄性，体重200-220g，随机分成4组，每组3-4只,分别灌胃(10mg/kg)和静脉注射(5mg/kg)给予被试化合物P-17和化合物CYH33(与化合物P-17相比，缺失一个7-位甲基)，具体安排见下表3：
Figure PCTCN2018092419-appb-000089
试验前禁食12h，自由饮水。给药后2h统一进食。
2.采血时间点及样品处理
灌胃给药：给药后0.25h，0.5h，1.0h，2.0h，3.0h，4.0h，6.0h，8.0h和24h。
静脉给药：给药后5min，0.25h，0.5h，1.0h，2.0h，4.0h，6.0h，8.0h和24h。
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.3ml，置肝素化试管中，11000rpm离心5min，分离血浆，于-20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中化合物的浓度。
采用Phoenix 1.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
Figure PCTCN2018092419-appb-000090
Figure PCTCN2018092419-appb-000091
Figure PCTCN2018092419-appb-000092
(ID为动物编号，Tmax为达峰时间，Cmax为血药峰浓度，AUC为药时曲线下面积，MRT为平均驻留时间，T1/2，Cl为药物清除率，Vss为稳态分布容积，F为绝对生物利用度)
从上表中可以看出，P-17尽管和CYH33相差一个甲基，其稳态分布容积Vss、平均驻留时间MRT、半衰期T1/2、绝对生物利用度F都有所改善，尤其是绝对生物利用度有大幅度提高(测试化合物为CYH33和P17的单甲磺酸盐，化合物结构如下)。
Figure PCTCN2018092419-appb-000093
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (17)

  1. 一种通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐：
    Figure PCTCN2018092419-appb-100001
    其中，
    R 1为卤素，或未取代或被至少一个取代基取代的C 1-6烷基或C 3-8环烷基，所述取代基为卤素；
    R 2为-C(OH)R 5R 6、-COC 1-6烷基、-CN、未取代或被至少一个取代基取代的如下基团：C 1-6烷基、-CH 2NH-C 1-6烷基、-CH 2N(C 1-6烷基)(C 1-6烷基)、-CH 2-(含1-2杂原子及3-6碳原子的饱和杂环基)、-CH 2-(含1-2杂原子及3-6碳原子的饱和杂环基)-(含1-2杂原子及3-6碳原子的饱和杂环基)、-CH 2-(含1-2杂原子及4-12碳原子的饱和螺环基)、-CH 2-(含1-2杂原子及3-12碳原子的饱和桥环基)-(含1-2杂原子及3-6碳原子的饱和杂环基)，或-CH 2-(含1-2杂原子及3-12碳原子的饱和桥环基)，所述取代基为卤素、-N(C 1-4烷基)(C 1-4烷基)、-O-C 1-4烷基、-CN、-COOH、-CHO、-NHS(O) 2-C 1-4烷基、-N(C 1-4烷基)C(C 1-4烷基)(C 1-4烷基)-CONH 2、＝O、-OH、-S(O) 2N(C 1-4烷基)(C 1-4烷基)、-S-C 1-4烷基、-S(O) 2-C 1-4烷基、-CO-C 3-6环烷基、氧杂环丁烷基、吗啉基、C 3-6环烷基、-C 1-4烷基-N(C 1-4烷基)(C 1-4烷基)、未取代或被至少一个甲基取代的C 1-4烷基-O-C 1-4烷基、未取代或被至少一个甲基取代的-CONH 2、未取代或被至少一个甲基取代的C 1-4烷基-CONH 2、未取代或被至少一个甲基取代的-COO-C 1-4烷基、未取代或被至少一个甲基取代的-NH 2、未取代或被至少一个甲基取代的-NHCO-C 1-4烷基、未取代或被至少一个取代基A取代的-CO-C 1-4烷基，所述取代基A为羟基或甲基，或者未取代或被至少一个取代基B取代的C 1-4烷基，所述取代基B为-NH 2、-OCH 3、-CONH 2、-OH或-CF 3；
    所述R 2中，所述杂原子选自N、O和S中的至少一种，
    所述R 5和R 6各自独立地为氢或C 1-6烷基；
    R 3为
    Figure PCTCN2018092419-appb-100002
    其中R 7，R 8，R 9，R 10各自独立地为氢或未取代或被至少一个取代基取代的C 1-6烷基，所述取代基为卤素或羟基；
    R 4为-NH 2、-NHCONHR 11或-NHCO 2R 12，其中R 11和R 12各自独立地为未取代或被至少一个取代基取代的C 1-6烷基、C 3-8环烷基或苯基，所述取代基选自卤素和-C(O)OR 13中的至少一种，其中R 13为未取代或被至少一个取代基取代的C 1-6烷基，所述R 13中的所述取代基为卤素。
  2. 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 1为卤素，或未取代或被至少一个取代基取代的C 1-4烷基或C 3-6环烷基。
  3. 根据权利要求2所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 1为-Cl、-F、甲烷基、三氟甲烷基或二氟甲烷基。
  4. 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 2为-C(OH)R 5R 6、-COC 1-4烷基、-CN、未取代或被至少一个取代基取代的如下基团：C 1-4烷基、-CH 2NH-C 1-4烷基、-CH 2N(C 1-4烷基)(C 1-4烷基)、-X-(含1-2杂原子的饱和四至六元杂环基)、-X-(含1-2杂原子的饱和四至六元杂环基)-(含1-2杂原子的饱和四至六元杂环基)、-X-(含1-2杂原子及4-8碳原子的饱和二环螺环基)、-X-(含1-2杂原子及3-8碳原子的饱和二环桥环基)-(含1-2杂原子的饱和四至六元杂环基)，或-X-(含1-2杂原子及3-8碳原子的饱和二环桥环基)，其中X为CH 2，所述杂环基、螺环基和桥环基 以N原子与X相连，所述R 5和R 6各自独立地为氢或C 1-4烷基。
  5. 根据权利要求4所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 2中的所述取代基为-F、-Cl、-Br、-I、-CH 3、-CH 2CH 3、-CH 2CH(CH 3) 2、-CH 2NH 2、-CH 2N(CH 3) 2、-CH 2CH 2NH 2、-CH 2CH 2N(CH 3) 2、-CH 2OH、-CH 2OCH 3、-CH 2CH 2OH、-C(CH 3) 2OH、-C(CH 3)(CF 3)OH、-C(CF 3) 2OH、-C(CH 3) 2OCH 3、-C(CH 3) 2NH 2、-CH 2C(CH 3) 2OH、-CH(OH)CH(CH 3) 2、-C(CH 3) 2CH 2OH、-C(CH 3) 2CH 2OCH 3、-CN、-CF 3、-CO 2H、-CHO、-COCH 3、-CO 2CH 3、-CO 2C(CH 3) 3、-COCH 2OH、-COC(OH)(CH 3) 2、-COCH(OH)CH 3、-CONH 2、-CONHCH 3、-CON(CH 3) 2、-CH 2CONH 2、-CH 2CON(CH 3) 2、-C(CH 3) 2CONH 2、-NH 2、-NHCH 3、-N(CH 3) 2、-NHCOCH 3、-N(CH 3)COCH 3、-NHS(O) 2CH 3、-N(CH 3)C(CH 3) 2CONH 2、＝O、-OH、-OCH 3、-S(O) 2N(CH 3) 2、-SCH 3、-S(O) 2CH 3、-C(O)-环丙基、环丙基、环丁基、氧杂环丁烷基或吗啉基取代。
  6. 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 2为
    Figure PCTCN2018092419-appb-100003
    Rx和Ry分别为-N(CH 3) 2、-S(O) 2CH 3或未取代或被至少一个取代基取代的C 1-4烷基，所述取代基为卤素、羟基、-CONH 2、-CF 3、氨基或-OCH 3。
  7. 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 2为
    Figure PCTCN2018092419-appb-100004
    Figure PCTCN2018092419-appb-100005
  8. 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 3为
    Figure PCTCN2018092419-appb-100006
    其中R 7，R 8，R 9，R 10各自独立地为氢或C 1-4烷基。
  9. 根据权利要求8所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 3为吗啉基或(S)-3-甲基吗啉基。
  10. 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 4为-NH 2、-NHCONHR 11或-NHCO 2R 12，其中R 11和R 12各自独立地为未取代或被至少一个取代基取代的C 1-4烷基、C 3-6环烷基或苯基，所述取代基选自氟、氯、溴和-C(O)OR 13中的至少一种，其中R 13为C 1-4烷基。
  11. 根据权利要求10所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，所述R 11和R 12各自独立地为甲基、乙基、异丙基、环丙基、苯基、-Ph-CO 2Et-p或4-氟苯基。
  12. 根据权利要求1所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐，其特征在于，具有如下述通式中的一种表示的结构：
    Figure PCTCN2018092419-appb-100007
    Figure PCTCN2018092419-appb-100008
    Figure PCTCN2018092419-appb-100009
  13. 一种权利要求1至12中任意一项所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途。
  14. 根据权利要求13所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途，其特征在于，所述PI3K活性抑制剂对PI3Kδ具有选择性抑制作用。
  15. 根据权利要求13所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途，其特征在于，所述PI3K活性抑制剂用在治疗与PI3K通道相关的疾病的药物中。
  16. 根据权利要求15所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐在制备PI3K活性抑制剂中的用途，其特征在于，所述与PI3K通道相关的疾病为肿瘤、白血病及自身免疫性疾病中的至少一种。
  17. 一种用于治疗与PI3K通道相关的疾病的药物组合物，其特征在于，该组合物包含治疗有效量的根据权利要求1至12中任意一项所述的通式I表示的7-位取代吡咯[2,1-f][1,2,4]并三嗪类化合物或其药学上可用的盐。
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