WO2019170050A1 - 一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用 - Google Patents

一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用 Download PDF

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WO2019170050A1
WO2019170050A1 PCT/CN2019/076841 CN2019076841W WO2019170050A1 WO 2019170050 A1 WO2019170050 A1 WO 2019170050A1 CN 2019076841 W CN2019076841 W CN 2019076841W WO 2019170050 A1 WO2019170050 A1 WO 2019170050A1
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group
branched
cyclohexyl
straight
substituted
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PCT/CN2019/076841
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English (en)
French (fr)
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何严萍
张洪彬
郑永唐
武玉萌
唐成润
芮若梅
杨柳萌
王江远
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云南大学
中国科学院昆明动物研究所
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Priority to US16/977,775 priority Critical patent/US11447470B2/en
Publication of WO2019170050A1 publication Critical patent/WO2019170050A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to the field of chemical synthesis and pharmaceutical technology, and in particular to a 2-thiomethylpyrazinium pyrimidine compound, a preparation method thereof, a pharmaceutical composition and use thereof.
  • AIDS Acquired immunodeficiency syndrome
  • HIV human immunodeficied cytovirus
  • RT Reverse transcriptase
  • NNRTIs Non-nucleoside reverse transcriptase inhibitors
  • cART highly active antiretroviral therapy
  • the existing drugs can not eliminate the virus, need to take life, drug resistance and serious side effects such as dyslipidemia, insulin resistance, fat malnutrition Heart disease and other related diseases are the main causes of cART failure.
  • NNRTIs There are more than 60 types of NNRTIs that have been reported. Although they have different structures, they are all bound to the RT catalytic center. In the combined pocket (NNBP), the combined pocket is more flexible, making it possible to design a variety of NNRTIs.
  • first-generation NNRTIs (Nevirapine, Delavirdine) are widely used in clinically to produce resistant mutations such as L100A, H103N, Y181C and Y181C+K103N.
  • Second-generation NNRTIs (evreline (ETV) and rivivirin (RPV)) have high inhibitory activity against multiple drug-resistant strains, but generally poor water solubility and membrane permeability lead to their bioavailability.
  • Low, oral doses increase, causing problems such as toxic side effects and cross-resistance. If etravirine has a severe skin allergic reaction, rivivirin has side effects such as depression, insomnia, acute respiratory distress syndrome, rash and headache.
  • the technical problem to be solved by the present invention is to overcome the ubiquitous defects in water solubility and membrane permeability of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) existing in the prior art, thereby leading to bioavailability thereof.
  • NRTIs non-nucleoside HIV-1 reverse transcriptase inhibitors
  • Low, oral dosage is increased, further causing toxic side effects and cross-resistance, etc., thus providing a 2-thiomethylpyrazinium pyrimidine compound different from the prior art, a preparation method thereof, a pharmaceutical composition and application thereof .
  • the 2-thiomethylpyrazinium compounds of the present invention are useful as HIV-1 inhibitors and for the preparation of a medicament for the treatment and/or prevention of immunodeficiency virus (HIV).
  • HIV immunodeficiency virus
  • the present invention solves the above technical problems by the following technical solutions.
  • the present invention provides a 2-thiomethylpyrazinium compound represented by Formula I, an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph thereof. Or a pharmaceutically acceptable salt thereof or a prodrug thereof:
  • A is S, O, NH or NCH 3 ;
  • R 1 is H, a C 1 -C 6 branched or linear alkyl group, or a C 3 -C 6 cycloalkyl group;
  • R 2 is H or halogen
  • the ⁇ ring is a cyclohexyl group or a phenyl group substituted by n identical or different R 4 , wherein n is 0, 1, 2, 3 or 4; and R 4 is halogen, hydroxy, cyano, nitro, amino, C branched or straight-chain 1 -C 6 alkyl or C branched or linear alkoxy of 1 -C 6.
  • R 1 is a C 1 -C 6 branched or linear alkyl group
  • the C 1 -C 6 branched or linear alkyl group is preferably a C 1 -C 3 branch or a linear alkyl group, further preferably an isopropyl group, a n-propyl group, an ethyl group or a methyl group;
  • R 1 is a C 3 -C 6 cycloalkyl group
  • the C 1 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • R 2 is a halogen
  • the halogen is preferably fluorine, chlorine, bromine or iodine, further preferably chlorine;
  • R 3 when R 3 is a C 1 -C 12 branched or linear alkyl group, the C 1 -C 12 branched or linear alkyl group is preferably a C 1 -C 6 branch or
  • the linear alkyl group is further preferably a C 1 -C 4 branched or linear alkyl group, and still more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a sec-butyl group. Or tert-butyl;
  • R 3 is a C 3 -C 6 cycloalkyl group
  • the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
  • R 3 is a C 6 -C 20 aryl group substituted by one or more R 3a
  • the C 6 -C 20 aryl group is preferably a C 6 -C 10 aryl group, further preferably a phenyl group.
  • the C 2 -C 10 heteroaryl group is preferably a C 2 -C 6 heteroaryl group, further preferably Is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinone, oxadiazole Base, pyridone, or triazolyl.
  • R 3a or R 3b is a halogen
  • the halogen is preferably fluorine, chlorine, bromine or iodine
  • the C 1 -C 6 branched or linear alkyl group is preferably C. a branched or linear alkyl group of 1 - C 3 , further preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group;
  • R 3a or R 3b is a C 1 -C 6 branched or linear alkyl group
  • the C 1 -C 6 branched or linear alkyl group is preferably a C 1 -C 3 branch or straight
  • An alkyl group further preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group;
  • R 3a or R 3b is a C 1 -C 6 branched or linear alkoxy group
  • the C 1 -C 6 branched or linear alkoxy group is preferably a C 1 -C 3 branch.
  • a linear alkoxy group further preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group;
  • R 3a or R 3b is a C 1 -C 6 branched or straight-chain alkylthio group
  • the C 1 -C 6 branched or straight-chain alkylthio group is preferably a C 1 -C 3 branch.
  • a linear alkoxy group further preferably a methylthio group, an ethylthio group, a propylthio group or an isopropylthio group;
  • R 3a or R 3b is a C 1 -C 6 branched or straight-chain haloalkyl group
  • the C 1 -C 6 linear or branched haloalkyl group is one or more of the same or different halogen atoms.
  • said C 1 -C 6 linear or branched haloalkyl group being preferably C
  • a linear or branched haloalkyl group of 1 - C 3 is further preferably a trifluoromethyl group, a difluoromethyl group or a 1,2-difluoroethyl group.
  • R 3 is a phenyl group substituted by one or more R 3a
  • the substitution is preferably a mono- or di-substitution, and the mono-substitution is preferably a 3-position or a 4-position substitution
  • the double substitution is preferably a 2,4-position double substitution or a 3,4-position double substitution.
  • R 4 is a halogen
  • the halogen is preferably fluorine, chlorine, bromine or iodine
  • R 4 is a C 1 -C 6 branched or linear alkyl group
  • the C 1 -C 6 branched or linear alkyl group is preferably a C 1 -C 3 branched or straight chain alkyl group. Further preferred is methyl, ethyl, n-propyl or isopropyl;
  • R 4 is a C 1 -C 6 branched or straight chain alkoxy group
  • the C 1 -C 6 branched or straight chain alkoxy group is preferably a C 1 -C 3 branched or straight chain
  • the alkoxy group is more preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.
  • n is preferably 2
  • R 4 is preferably a branched or linear alkyl group which is simultaneously halogen or C 1 -C 6 ; It is further preferred that it is simultaneously fluorine, both chlorine, or both methyl; the R 4 is preferably substituted at the 2-position and the 6-position, or the 3-position and the 5-position of the phenyl group.
  • n is preferably 2, preferably a branched or linear alkoxy group in which two R 4 are each a C 1 - C 6 group; Further, it is further preferred that two R 4 groups may be bonded to form a ring, that is, together form an oxygen-containing hetero ring which is a ring structure with the phenyl group.
  • two R 4 together form an oxygen-containing heterocyclic ring having a cis-ring structure with the phenyl group it is preferably an oxygen-containing 5-7 membered heterocyclic ring having a cis-ring structure with the phenyl group, for example,
  • A is S.
  • the alpha ring is
  • R 1 is H, methyl, ethyl or isopropyl.
  • R 2 is H or Cl.
  • R 3 is a C 6 -C 20 aryl group, a C 2 -C 10 heteroaryl group, one or more (for example 1-6, preferably 1-3 or 1) - 2) R 3a substituted C 6 -C 20 aryl or C 2 -C 10 substituted by one or more (for example 1-6, preferably 1-3 or 1-2) R 3b Heteroaryl.
  • A is S and the alpha ring is R 1 is ethyl or isopropyl; R 2 is H or Cl; R 3 is C 6 -C 20 aryl, C 2 -C 10 heteroaryl, by one or more (for example 1-6 , preferably 1-3 or 1-2) R 3a substituted C 6 -C 20 aryl or one or more (for example 1-6, preferably 1-3 or 1-2) R 3b Substituted C 2 -C 10 heteroaryl.
  • A is S, the ⁇ ring is cyclohexyl, R 1 is ethyl or isopropyl; R 2 is H or Cl; R 3 is C 6 -C 20 aryl, C 2 -C 10 heteroaryl, C 6 -C 20 aryl substituted by one or more (for example 1-6, preferably 1-3 or 1-2) R 3a or by one or more ( For example, 1-6, preferably 1-3 or 1-2) R 3b substituted C 2 -C 10 heteroaryl.
  • R 3 is a C 6 -C 20 aryl group substituted by one or more (for example 1-6, preferably 1-3 or 1-2) R 3a , wherein The C 6 -C 20 aryl group is a phenyl group; R 3a is a hydroxyl group, a halogen, a C 1 -C 6 branched or linear alkyl group, a C 1 -C 6 branched or linear alkoxy group; , C branched or straight-chain alkylthio, C branched or unbranched haloalkyl of 1 -C 6 alkyl of 1 -C 6.
  • A is S and the alpha ring is R 1 is ethyl or isopropyl; R 2 is H or Cl; R 3 is phenyl or phenyl substituted by one R 3a , wherein R 3a is a hydroxy group, a halogen, a C 1 -C 6 branch or a linear alkoxy group or a C 1 -C 6 branched or linear alkylthio group; the substitution is a 4-position substitution.
  • A is S, the alpha ring is cyclohexyl, R 1 is ethyl or isopropyl; R 2 is H or Cl; and R 3 is phenyl or phenyl substituted by one R 3a
  • R 3a is a hydroxyl group, a halogen, a C 1 -C 6 branched or straight chain alkoxy group or a C 1 -C 6 branched or straight chain alkylthio group; the substitution is a 4-position substitution.
  • A is S, the alpha ring is cyclohexyl, R 1 is ethyl or isopropyl; R 2 is H or Cl; and R 3 is phenyl or phenyl substituted by one R 3a Wherein R 3a is hydroxy, F, Cl, methoxy or methylthio; the substitution is a 4-position substitution.
  • the structural unit of the 2-thiomethylpyrazinium pyridinone compound of formula I is Is any of the following structure fragments:
  • the 2-thiomethylpyrazolidine compound represented by Formula I is further preferably a compound having any of the following structures:
  • the 2-thiomethylpyrazolidine compound represented by Formula I may further preferably be a compound having any of the following structures:
  • the present invention further provides a process for the preparation of a 2-thiomethylpyrazinium pyridine ketone compound of the formula I, which comprises the steps of: intermediate 6 in the presence of a base in the presence of a base
  • the substrate 7 is subjected to an alkylation reaction as shown below;
  • A, n, R 1 , R 2 , R 3 , R 4 and the ⁇ ring are all defined as described above, and X is a halogen.
  • the alkylation reaction is carried out according to such an alkylation reaction mechanism in the art, and can be carried out using conditions and parameters conventionally used in such alkylation reactions in the art.
  • X is preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine.
  • the solvent may be used conventionally in the field for such reactions, and does not participate in or interfere with the reaction; the present invention preferably is one of DMF, THF, CH 3 CN, dioxane, pyridine. Or more, more preferably DMF.
  • the amount of the solvent to be used may be conventionally used in such reactions in the art to be capable of completely dissolving the reactants and ensuring that the reaction proceeds smoothly.
  • the base may be conventionally used for such reactions in the art; the present invention preferably is selected from the group consisting of DMAP, Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaH, Et 3 N Or more, more preferably K 2 CO 3 .
  • the amount of the base can be used conventionally in the field for such reactions; in the present invention, it is preferred that the molar ratio of the intermediate 6 to the base is from 1:1 to 1:2, such as 3:4. .
  • the molar ratio of the intermediate 6 to the intermediate 7 can be a conventionally used ratio for such a reaction in the art, and it is preferably 1:1 to 1:1.2 in the present invention.
  • the reaction temperature of the alkylation reaction can be conventionally used for such reactions in the art; the present invention is preferably controlled between 20 and 80 ° C, such as room temperature (20 to 25 ° C).
  • the progress of the alkylation reaction can be monitored by conventional test methods in the art (e.g., TLC, HPLC or NMR), generally with the disappearance or discontinuation of the starting material as the end of the reaction.
  • the reaction time of the alkylation reaction is preferably from 3 to 24 h, more preferably from 8 to 12 h.
  • the preparation method of the 2-thiomethylpyrazinium pyridine compound of the formula I preferably comprises the steps of dissolving the intermediate 7 in a part of the solvent, and adding the After stirring at room temperature, a solution of the intermediate 6 and a part of the solvent is added, and stirring is continued.
  • the preparation method of the 2-thiomethylpyrazolidine compound represented by Formula I is preferably after the alkylation reaction is completed, and further includes the following post-treatment step: After the alkylation is completed, the reaction liquid is poured into ice water to precipitate a white solid, which is filtered or extracted with ethyl acetate to obtain a crude product. The crude product is purified by column chromatography or recrystallized to obtain the objective product.
  • the corresponding intermediate 7 can be prepared by a method well known to those skilled in the art of organic chemistry, and specific reference can be made to Yan-Ping He, Jin Long, et al. Bioorg. &Med. Chem. 2011, 21, 694-697, page 695, paragraph 3), the specific synthetic route of which is shown below (the contents of which are hereby incorporated by reference):
  • R 1 is as described above.
  • the ⁇ ring is a phenyl group substituted by n identical or different R 4
  • the corresponding intermediate 7 can be prepared by a method well known to those skilled in the art of organic chemistry, and specific reference can be made to Maxim B in the present invention. .Nawrozkij, Dante Rotili, et al. J. Med. Chem. 2008, 51, 4641-4652), the specific synthetic route of which is shown below (the contents of which are hereby incorporated by reference):
  • R 1 , R 4 and n are as defined above.
  • the 2-thiomethylpyrazolidine compound represented by Formula I preferably further comprises the step of halogenating the intermediate 5 with a halogenating reagent in a solvent to obtain an intermediate. 6 can;
  • R 2 and R 3 are as defined above, and X is a halogen.
  • the halogenation reaction is carried out according to such a halogenation reaction mechanism in the art, and can be carried out using conditions and parameters conventionally used in the halogenation reaction of the art.
  • X is preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine.
  • the solvent may be used conventionally in the field for such reactions, and does not participate in or interfere with the reaction; the present invention preferably is one or more of THF, CH 3 CN, dioxane, pyridine. More preferably, it is CH 3 CN.
  • the amount of the solvent to be used may be conventionally used in such reactions in the art to be capable of completely dissolving the reactants and ensuring that the reaction proceeds smoothly.
  • the halogenating agent may be conventionally used in such reactions in the art; preferably, the present invention is selected from one or more of Br 2 , PBr 3 , CBr 4 , NBS, NCS, POCl 3 or I 2 . Further, it is preferably PBr 3 .
  • the amount of the halogenating agent used in the field can be conventionally used in the field; in the present invention, the molar ratio of the intermediate 5 to the halogenating agent is preferably 1:1 to 1:2. Such as 1:1.2.
  • the reaction temperature of the halogenation reaction can be conventionally used for such reactions in the art; the present invention is preferably controlled between 0 and 85 ° C, for example, between 70 and 85 ° C.
  • the progress of the halogenation reaction can be monitored by conventional test methods (e.g., TLC, HPLC or NMR) in the art, generally with the disappearance or discontinuation of the starting material as the end of the reaction.
  • the reaction time of the halogenation reaction is preferably from 8 to 24 h, more preferably from 0.5 to 3 h.
  • the preparation method of the 2-thiomethylpyrazinium pyridine ketone compound represented by Formula I preferably comprises the step of dissolving the intermediate 5 in the solvent in an ice bath condition.
  • the halogenated reagent is added dropwise, and after the dropwise addition is completed, the halogenation reaction is carried out by stirring.
  • the preparation method of the 2-thiomethylpyrazinium pyridine ketone compound represented by Formula I is preferably after the halogenation reaction is completed, and further includes the following post-treatment step: After the end of the halogenation, the reaction mixture was poured into ice water, the solvent was evaporated under reduced pressure, and the mixture was evaporated to dryness with saturated NaHCO 3 and filtered, and the filtrate was extracted with ethyl acetate. Drying over anhydrous sodium sulfate, concentrating under reduced pressure and recrystallization to give the intermediate 6. Among them, the recrystallization is preferably carried out using ethyl acetate/petroleum ether (1:3, v/v).
  • the 2-thiomethylpyrazolidine compound represented by Formula I preferably further comprises the step of: subjecting Intermediate 4 to reduction in a solvent in the presence of a reducing agent. , the intermediate 5 can be obtained;
  • R 2 and R 3 are as defined above.
  • the reduction reaction is carried out in accordance with such a reduction reaction mechanism in the art, and can be carried out using conditions and parameters conventionally used in the reduction reaction of the art.
  • the reduction reaction is preferably carried out under the protection of an inert gas such as nitrogen.
  • the solvent may be conventionally used in such reactions in the art, and does not participate in or interfere with the reaction; the present invention preferably is one of CH 3 CN, THF, DMF, DMSO, dioxane. Or more, more preferably the solvent is subjected to anhydrous treatment prior to carrying out the reaction.
  • the amount of the solvent to be used may be conventionally used in such reactions in the art to be capable of completely dissolving the reactants and ensuring that the reaction proceeds smoothly.
  • the reducing agent may be conventionally used in the reaction of the art; it is preferably selected from one or more of NaBH 4 , LiAlH 4 and KBH 4 , and further preferably LiAlH 4 .
  • the amount of the reducing agent used in the field can be conventionally used in the field; in the present invention, the molar ratio of the intermediate 4 to the reducing agent is preferably 1:1 - 1:2, such as 1 :1.5.
  • the reaction temperature of the reduction reaction can be conventionally used for such a reaction in the art; the present invention is preferably controlled at a temperature of from 0 to 45 ° C, more preferably at room temperature.
  • the progress of the reduction reaction can be monitored by conventional test methods in the art (e.g., TLC, HPLC or NMR), generally with the disappearance or discontinuation of the starting material as the end of the reaction.
  • the reaction time of the reduction reaction is preferably from 2 to 12 hours.
  • the preparation method of the 2-thiomethylpyrazinium pyridine ketone compound of the formula I preferably comprises the step of: in the mixture of the intermediate 4 and the solvent,
  • the reducing agent may be added in portions under ice bath and nitrogen protection, and the reduction reaction may be carried out by stirring.
  • the preparation method of the 2-thiomethylpyrazolidine compound represented by Formula I preferably after the completion of the reduction reaction further comprises the following post-treatment step: in the reduction After completion, the reaction was quenched with EtOAc EtOAc EtOAc. Intermediate 5 is available. Among them, the recrystallization is preferably carried out using ethyl acetate/petroleum ether (1:3, v/v).
  • the 2-thiomethylpyrazolidine compound represented by Formula I preferably further comprises the step of halogenating the intermediate 3 with a halogenating reagent in a solvent to obtain a middle portion.
  • Body 4 can be;
  • R 2 and R 3 are as defined above.
  • the halogenation reaction is carried out according to such a halogenation reaction mechanism in the art, and can be carried out using conditions and parameters conventionally used in the halogenation reaction of the art.
  • the solvent may be used conventionally in the field for such reactions, and does not participate in or interfere with the reaction; the present invention preferably is one or more of CH 3 CN, THF, DMF and dioxane. kind.
  • the amount of the solvent to be used may be conventionally used in such reactions in the art to be capable of completely dissolving the reactants and ensuring that the reaction proceeds smoothly.
  • the halogenating agent can be conventionally used in such reactions in the art; it is preferred in the present invention to be selected from one or more of NBS, NCS and NIS.
  • the amount of the halogenating agent can be used conventionally in the field for such reactions; in the present invention, it is preferred that the molar ratio of the intermediate 3 to the halogenating agent is 1:1 to 1:6. Such as 1:1.2.
  • the reaction temperature of the halogenation reaction can be conventionally used for such reactions in the art; the present invention is preferably controlled between 40 and 80 ° C, for example, 60 ° C.
  • the progress of the halogenation reaction can be monitored by conventional test methods (e.g., TLC, HPLC or NMR) in the art, generally with the disappearance or discontinuation of the starting material as the end of the reaction.
  • the reaction time of the halogenation reaction is preferably from 8 to 24 h, more preferably from 10 to 15 h.
  • the preparation method of the 2-thiomethylpyrazolidine compound represented by Formula I preferably comprises the steps of dissolving the intermediate 3 in the solvent and adding it at room temperature.
  • the halogenated reagent described above may be stirred and subjected to the halogenation reaction after completion of the dropwise addition.
  • the preparation method of the 2-thiomethylpyrazinium pyridine ketone compound represented by Formula I is preferably after the halogenation reaction is completed, and further includes the following post-treatment step: After the end of the halogenation, the solvent is evaporated under reduced pressure, and ethyl acetate is evaporated. The organic phase is combined, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. .
  • the column chromatography purification eluent is preferably ethyl acetate/petroleum ether (1:4, v/v).
  • the 2-thiomethylpyrazolidine compound represented by Formula I preferably further comprises the steps of: subjecting Intermediate 2 to hydrazine hydrate in a solvent to obtain Intermediate 3 Yes;
  • R 3 is the same as described above.
  • the condensation reaction is carried out in accordance with such a condensation reaction mechanism in the art, and can be carried out using conditions and parameters conventionally used in the condensation reaction of the art.
  • the solvent may be conventionally used in such reactions in the art, and does not participate in or interfere with the reaction; the present invention preferably is MeOH, EtOH, THF, dioxane, CH 3 CN and H 2 O. One or more of them is further preferably EtOH.
  • the amount of the solvent to be used may be conventionally used in such reactions in the art to be capable of completely dissolving the reactants and ensuring that the reaction proceeds smoothly.
  • the amount of the hydrazine hydrate can be used conventionally in the field for such reactions; in the present invention, it is preferred that the molar ratio of the intermediate 5 to the hydrazine hydrate is from 1:1 to 1:2.
  • the reaction temperature of the condensation reaction can be conventionally used for such reactions in the art; the present invention is preferably controlled between 30 and 85 °C.
  • the progress of the condensation reaction can be monitored by conventional test methods in the art (e.g., TLC, HPLC or NMR), generally with the disappearance or discontinuation of the starting material as the end of the reaction.
  • the reaction time of the condensation reaction is preferably from 3 to 24 hours.
  • the preparation method of the 2-thiomethylpyrazolidine compound represented by Formula I preferably comprises the step of: in the mixture of the intermediate 2 and the solvent, The hydrazine hydrate is added dropwise at room temperature, and the condensation reaction is carried out by refluxing after completion of the dropwise addition.
  • the preparation method of the 2-thiomethylpyrazolidine compound represented by Formula I preferably after the end of the condensation reaction further comprises the following post-treatment step: in the condensation After completion, it was cooled to room temperature, and the solvent was evaporated to dryness.
  • the intermediate 3 was obtained by concentration under reduced pressure and recrystallization.
  • the recrystallization is preferably carried out using ethyl acetate/petroleum ether (1:5, v/v).
  • the 2-thiomethylpyrazinium compound represented by Formula I preferably further comprises the steps of: Intermediate 1 and oxalic acid in a solvent in the presence of a base
  • the diethyl ester is subjected to a nucleophilic substitution reaction to obtain an intermediate 2;
  • R 3 is the same as described above.
  • the nucleophilic substitution reaction is carried out according to such a nucleophilic substitution reaction mechanism in the art, and can be carried out using conditions and parameters conventionally used in such a nucleophilic substitution reaction in the art.
  • the solvent may be conventionally used in such reactions in the art, and does not participate in or interfere with the reaction; the present invention preferably is in the form of MeOH, EtOH, THF, CH 3 CN, dioxane and toluene. One or more, further preferably it is EtOH.
  • the amount of the solvent to be used may be conventionally used in such reactions in the art to be capable of completely dissolving the reactants and ensuring that the reaction proceeds smoothly.
  • the base may be conventionally used in the field for such reactions; the present invention preferably is selected from the group consisting of DMAP, Cs 2 CO 3 , K 2 CO 3 , C 2 H 5 ONa, CH 3 ONa, Na 2 CO 3 .
  • C 2 H 5 ONa when used as a base, it can be obtained by in situ preparation of sodium metal and ethanol.
  • the amount of the base used may be conventionally used in the reaction of the art; in the present invention, it is preferred that the molar ratio of the intermediate 1 to the base is from 1:1 to 1:2.
  • the amount of the diethyl oxalate can be used conventionally in the field for such a reaction; in the present invention, it is preferred that the molar ratio of the intermediate 1 to the diethyl oxalate is 1: 1-1:2.
  • the reaction temperature of the nucleophilic substitution reaction can be conventionally used for such reactions in the art; the present invention is preferably controlled at a temperature between 20 and 80 ° C, for example, at room temperature.
  • the progress of the nucleophilic substitution reaction can be monitored by conventional test methods (e.g., TLC, HPLC or NMR) in the art, generally at the end of the reaction in which the starting material disappears or is no longer reacted.
  • the reaction time of the nucleophilic substitution reaction is preferably from 3 to 24 h, for example 8 h.
  • the preparation method of the 2-thiomethylpyrazolidine compound represented by Formula I preferably comprises the steps of: the intermediate 1, the base and the solvent. To the mixture, diethyl oxalate is added and the reaction is carried out at room temperature.
  • the method for preparing a 2-thiomethylpyrazinium pyridine compound of the formula I preferably after the end of the nucleophilic substitution reaction further comprises the following post-treatment step: After the end of the nucleophilic substitution reaction, the pH is adjusted to 8 by the addition of dilute hydrochloric acid, and the solvent is evaporated to dryness, and the organic phase is combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the preparation method of the 2-thiomethylpyrazolidine compound represented by Formula I is preferably prepared by the following synthetic route:
  • n R 1 , R 2 , R 3 , R 4 , ⁇ ring and X are the same as described above, and the specific reaction conditions and parameters of each step are the same as described above.
  • the present invention further provides a 2-thiomethylpyrazinium compound represented by Formula I, an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, and the like.
  • a crystalline form, a pharmaceutically acceptable salt thereof or a prodrug thereof for the preparation of a non-nucleoside HIV-1 inhibitor, preferably a non-nucleoside HIV-1 IIIB inhibitor Agent.
  • the present invention further provides a 2-thiomethylpyrazinium compound represented by Formula I, an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, and the like.
  • a crystalline form, a pharmaceutically acceptable salt thereof or a prodrug thereof for the preparation of an anti-HIV-1 drug.
  • the present invention further provides a 2-thiomethylpyrazinium compound represented by Formula I, an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph thereof. And a pharmaceutically acceptable salt thereof or a prodrug thereof for use in the manufacture of a medicament for the treatment and/or prevention of human immunodeficiency virus (HIV) infection.
  • a 2-thiomethylpyrazinium compound represented by Formula I an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph thereof.
  • a pharmaceutically acceptable salt thereof or a prodrug thereof for use in the manufacture of a medicament for the treatment and/or prevention of human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a 2-thiomethylpyrazinium compound of the formula I, an N-oxide, a tautomer thereof, an optical difference A construct, hydrate, solvate, polymorph, pharmaceutically acceptable salt thereof or prodrug thereof, and at least one pharmaceutical excipient.
  • the 2-thiomethylpyrazolidine compound represented by Formula I, an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph thereof, or the like The mass percentage of the pharmaceutically acceptable salt or prodrug thereof in the pharmaceutical composition is from 0.1% to 99.9%, and the mass percentage means the 2-thiomethylpyrazolpyrimidin as shown in Formula I a compound, an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph, a pharmaceutically acceptable salt thereof, or a prodrug thereof, as a percentage of the total mass of the pharmaceutical composition .
  • the 2-thiomethylpyrazolidine compound represented by Formula I an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph thereof, or the like
  • the sum of the mass fractions of the pharmaceutically acceptable salt or its prodrug and the pharmaceutically acceptable excipient is 100%.
  • the choice of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrating agent, a lubricant, an emulsifier or a suspending agent.
  • the invention further provides a method of treating a human immunodeficiency virus (HIV) infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of 2-thiomethylpyrazolone as shown in Formula I. a compound, an N-oxide, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph, a pharmaceutically acceptable salt thereof or a prodrug thereof.
  • HIV human immunodeficiency virus
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • the chemical formulae of the present invention may exhibit tautomerism, structural isomerism, and stereoisomerism.
  • the invention includes any interconversion or structural or stereoisomeric forms thereof, and mixtures thereof, the ability of which is not limited to any one or a mixture thereof.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the compounds of the invention are either by hand or Software naming, commercially available compounds using the supplier catalog name.
  • the positive progress of the present invention is that the present invention provides a novel 2-thiomethylpyrazinium pyrimidine compound, a preparation method thereof, a pharmaceutical composition and use thereof. It has been proved by experiments that the 2-thiomethylpyrazolidine compound of the present invention can be applied as an HIV-1 inhibitor and has high application value. Specifically, it can be used as an HIV-1 inhibitor for the preparation of anti-AIDS drugs.
  • the synthetic route of the target compound I-1 is as follows:
  • Step (1) Preparation of 2,4-dioxo-4-phenylbutanoic acid ethyl ester (Intermediate 2-1)
  • Step (2) Preparation of ethyl 5-phenyl-1H-pyrazole-3-carboxylate (intermediate 3-1)
  • Step (3) Preparation of ethyl 4-chloro-5-phenyl-1H-pyrazole-3-carboxylate (intermediate 4-1)
  • 6-Cyclohexylmethyl-5-ethyl-thiopyrimidinone 7-1 (0.003 mol, 0.728 g) was placed in 9 mL of DMF, stirred and dissolved, and anhydrous K 2 CO 3 (0.004 mol, 0.553 g) was added. After stirring at room temperature for 30 min, 5 mL of a solution of Intermediate 6-1 (0.681 g, 0.003 mol) in DMF was added and stirring was continued for 3 h until the reaction was completed. The reaction mixture was poured into 10 mL of ice water to precipitate a white solid. Filtration or extraction with ethyl acetate afforded the crude product.
  • the method of the preparation of the target compound I-1 was carried out except that the operation of the step (3) was omitted.
  • step (1) used 1-(4-methoxyphenyl)-acetophenone as the starting material 1, and the operation of the step (3) was omitted.
  • step (1) used 1-(4-methylphenyl)-acetophenone as the starting material 1, and the operation of the step (3) was omitted.
  • step (1) used 1-(2,4-dimethylphenyl)-acetophenone as the starting material 1, and the operation of the step (3) was omitted.
  • the preparation was carried out by the method of the object compound I-1 except that the step (1) used acetaldehyde as the starting material 1, and the operation of the step (3) was omitted.
  • the preparation was carried out by the method of the object compound I-1 except that the step (1) used acetone as the starting material 1, and the operation of the step (3) was omitted.
  • step (1) uses 1-(4-chlorophenyl)-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is omitted.
  • the sulfalkylation reaction was carried out using 6-cyclohexylmethyl-5-isopropyl-thiouracil A.
  • step (1) uses 1-(4-fluorophenyl)-acetophenone as starting material 1, and step (6) uses 6-cyclohexylmethyl group.
  • step (6) uses 6-cyclohexylmethyl group.
  • -5-Isopropyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 1-(4-hydroxyphenyl)-acetophenone as the starting material 1, and the operation of the step (3) is omitted, in the step (6)
  • the sulfalkylation reaction was carried out using 6-cyclohexylmethyl-5-isopropyl-thiouracil A.
  • step (1) uses 1-(4-fluorophenyl)-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is omitted.
  • the sulfalkylation reaction was carried out using 6-cyclohexylmethyl-5-isopropyl-thiouracil A.
  • step (1) uses 1-(4-methoxyphenyl)-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6)
  • the sulfalkylation reaction is carried out using 6-cyclohexylmethyl-5-isopropyl-thiouracil A.
  • step (1) uses 1-(4-fluorophenyl)-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is omitted.
  • the sulfalkylation reaction is carried out using 6-cyclohexylmethyl-5-methyl-thiopyrimidine A.
  • the preparation is carried out by the method of the object compound I-1 except that the step (3) is omitted, and the cycloalkylation reaction is carried out using the 6-cyclohexylmethylthiouracil A in the step (6).
  • step (1) uses 1-(4-fluorophenyl)-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is omitted.
  • the sulfalkylation reaction is carried out using 6-cyclohexylmethylthiouracil A.
  • step (1) uses 4'-hydroxy-acetophenone as starting material 1, step (3) is omitted, and step 6 (6) is used.
  • step (3) is omitted, and step 6 (6) is used.
  • Methyl-5-methyl-thiouracil A is subjected to a sulfation reaction.
  • the method of the preparation of the target compound I-1 was carried out except that the cycloalkylation reaction was carried out using the 6-cyclohexylmethyl-thiouracil A in the step (6).
  • step (1) uses 4'-fluoro-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the 6-benzyl group is used in the step (6).
  • -5-Ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1
  • step (3) is omitted
  • step (6) is used 6-(1) ',3'-Benzodioxy)-5-methyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1, step (3) is omitted, and step (6) is used 6-(2) ',6'-Dichlorobenzyl)-5-ethyl-thiouracil A was subjected to a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1, step (3) is omitted, and step (6) is used 6-(3).
  • step (1) uses 4'-fluoro-acetophenone as starting material 1
  • step (3) is omitted
  • step (6) is used 6-(3).
  • ',5'-Difluorobenzyl)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as starting material 1
  • step (6) uses 6-benzyl-5- Ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as starting material 1
  • step (6) uses 6-cyclohexylmethyl group- Thiourop A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as starting material 1
  • step (6) uses 6-(2',6 '-Dichlorobenzyl)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as starting material 1
  • step (6) uses 6-cyclohexylmethyl group- 5-Methyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as starting material 1
  • step (6) uses 6-(3',5 '-Difluorobenzyl)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is used.
  • 6-Benzyl-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is used.
  • 6-Cyclohexylmethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is used.
  • 6-(2',6'-Dichlorobenzyl)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is used.
  • 6-(3',5'-Difluorobenzyl)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 3',4'-difluoro-acetophenone as the starting material 1, the operation of the step (3) is omitted, and the step (6) is used.
  • 6-(1',3'-benzodioxy)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1
  • step (6) uses 6-(3',5'-difluoro Benzyl)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1
  • step (6) uses 6-(2',6'-dichloro Benzyl)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1
  • step (6) uses 6-(1',3'-benzoic acid.
  • Dioxy)-5-ethyl-thiouracil A is subjected to a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1
  • step (6) uses 6-benzyl-5-ethyl-sulfur.
  • Uracil A undergoes a sulfation reaction.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1
  • step (6) uses 6-cyclohexylmethyl-thiouracil A.
  • a sulfur alkylation reaction is carried out.
  • step (1) uses 4'-fluoro-acetophenone as starting material 1, and step (6) uses 6-cyclohexylmethyl-5-methyl group.
  • step (6) uses 6-cyclohexylmethyl-5-methyl group.
  • - Thiuracil A is subjected to a sulfation reaction.
  • step (6) is carried out by using 6-(2',6'-dichlorobenzyl)-5-ethyl-thiouracil A for the sulfation reaction. .
  • step (6) is carried out using 6-(1',3'-benzodioxy)-5-ethyl-thiouracil A for sulfation. reaction.
  • Cytotoxicity assay The toxicity of the compound to C8166 cells was determined by the MTT assay. The compound was diluted five-fold in a 96-well cell culture plate, and 100 ⁇ L of 4 ⁇ 10 5 /mL C8166 cell suspension was added to each well. Three replicate holes were set for each concentration. A drug-free cell control and drug Zidovudine (AZT) and Nevirapine (NVP) controls were also set. Incubate for three days at 37 ° C in a 15% CO 2 incubator, and incubate for 4 hours at 37 ° C with MTT solution per well. An additional 10% SDS-50% DMF was added to each well and incubated overnight at 37 ° C in a 5% CO 2 incubator.
  • the OD value (measurement wavelength: 570 nm; reference wavelength: 630 nm) was measured by a BIO-TEK ELx800 ELISA instrument, and a measurement reaction curve was drawn based on the experimental results to calculate a CC 50 (concentration of the compound when 50% of cells were virulent).
  • the present invention uses AZT and NVP as control substances, and the results of the inhibitory activity of the target compound against HIV-1 IIIB are shown in Table 1:
  • the compounds of the present invention are a novel class of 2-thiomethylpyrazopyrimidinone compounds. As can be seen from Table 1, the compounds have significant anti-HIV activity, and some of the preferred compounds have an EC 50 value of nanomolar. level. And the compounds of this type are less toxic, and the samples of I-01, 10, 13, 15, 16, 22, 25, 40, 49, 52, 53, 55, 62-72 have a CC 50 value of more than 200 ⁇ M in vitro. Therefore, the 2-thiomethylpyrazinium compound of the present invention is characterized by high efficiency and low toxicity as a novel structure of HIV-RT inhibitor.

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Abstract

本发明公开了一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用。本发明所述的2-硫甲基吡唑嘧啶酮类化合物的结构如式I所示，其中：A为S、O、NH或NCH3；R1为H、C1-C6的支链或直链烷基、或C3-C6环烷基；R2为H或卤素；R3为H、C1-C12的支链或直链烷基、C3-C6环烷基、C6-C20的芳基、C2-C10的杂芳基、被一个或多个R3a取代的C6-C20的芳基或被一个或多个R3b取代的C2-C10的杂芳基；α环为环己基或被n个相同或不同的R4取代的苯基，R4为卤素、羟基、氰基、硝基、氨基、C1-C6的支链或直链烷基、或C1-C6的支链或直链烷氧基。本发明所述的2-硫甲基吡唑嘧啶酮类化合物可作为HIV-1抑制剂并用于制备治疗和/或预防免疫缺陷病毒的药物。

Description

一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用
本申请要求申请日为2018年3月6日的中国专利申请CN201810183285.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及化学合成和药物技术领域，具体涉及一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用。
背景技术
获得性免疫缺陷综合征(Acquired immunodeficiency syndrome,AIDS)即艾滋病，是由于人体受免疫缺陷病毒(Human immunodeficiedcy virus,HIV)的感染而引发的疾病。逆转录酶(Reverse transcriptase,RT)作为催化病毒RNA向DNA转化的关键酶，是抗艾滋病药物设计的关键靶标。
非核苷类逆转录酶抑制剂(non-nucleoside reverse transcriptase inhibitors，NNRTIs)具有高效、低毒、选择性好等诸多优点，是当前治疗艾滋病高效抗逆转录病毒疗法(cART)的重要组成部分。尽管cART的出现极大地降低了艾滋病患者的死亡率和提高了生活质量，但现有药物不能清除病毒，需终生服用，药物抵抗性和严重的毒副作用，如血脂异常、胰岛素抵抗、脂肪营养不良、心脏病和其他相关疾病，是cART失败的主要原因。现已报道的NNRTIs有60多类，尽管结构各异，但它们都结合于距RT催化中心约
Figure PCTCN2019076841-appb-000001
的结合口袋(NNBP)中，该结合口袋较大的柔性，为结构多样的NNRTIs的设计提供了可能。
目前，经美国FDA批准上市的抗HIV逆转录酶抑制剂有五种，即：奈韦拉平(Nevirapine)、地拉韦啶(Delavirdine)、依非韦伦(Efavirenz)、依曲韦林(Etravirine)和利匹韦林(Rilpivirine)。由于HIV-1病毒的高变异性，第一代NNRTIs(奈韦拉平(Nevirapine)、地拉韦啶(Delavirdine))广泛用于临床后产生了L100A、H103N、Y181C和Y181C+K103N等耐药突变。第二代NNRTIs(依曲韦林(ETV)及利匹韦林(RPV))虽然对多种耐药株具有较高抑制活性，但普遍较差的水溶性和透膜性导致其生物利用度低、口服剂量加大，从而引起毒副作用和交叉耐药等问题。如依曲韦林有严重的皮肤过敏反应，利匹韦林存在抑郁、失眠、急性呼吸窘迫综合症、皮疹及头痛等毒副作用。
因此，新型高效、低毒、广谱抗耐药以及具有良好药代动力学性质的NNRTIs的研究 仍是当前抗HIV药物研发的热点领域。
发明内容
本发明所要解决的技术问题是为了克服现有技术中已有的非核苷类HIV-1逆转录酶抑制剂(NNRTIs)普遍存在水溶性和透膜性较差的缺陷，从而导致其生物利用度低、口服剂量加大，进一步引起毒副作用和交叉耐药等问题，因而提供了一种与现有技术不同的2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用。本发明的2-硫甲基吡唑嘧啶酮类化合物可作为HIV-1抑制剂并用于制备治疗和/或预防免疫缺陷病毒(HIV)的药物。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药：
Figure PCTCN2019076841-appb-000002
其中：
A为S、O、NH或NCH 3；
R 1为H、C 1-C 6的支链或直链烷基、或C 3-C 6环烷基；
R 2为H或卤素；
R 3为H、C 1-C 12的支链或直链烷基、C 3-C 6环烷基、C 6-C 20的芳基、C 2-C 10的杂芳基、被一个或多个(例如1-6个，优选1-3个或1-2个)R 3a取代的C 6-C 20的芳基或被一个或多个(例如1-6个，优选1-3个或1-2个)R 3b取代的C 2-C 10的杂芳基；其中，R 3a和R 3b各自独立地选自羟基、硝基、卤素、氨基、氰基、HOS(＝O) 2-、CH 3S(＝O) 2-、C 1-C 6的支链或直链烷基-S(＝O) 2NH-、C 1-C 6的支链或直链烷基、C 1-C 6的支链或直链烷氧基、C 1-C 6的支链或直链烷硫基、C 1-C 6的支链或直链卤代烷基，当R 3a或R 3b为多个时，每个R 3a或每个R 3b相同或不同。
α环为环己基或被n个相同或不同的R 4取代的苯基，其中，n为0、1、2、3或4；R 4为卤素、羟基、氰基、硝基、氨基、C 1-C 6的支链或直链烷基、或C 1-C 6的支链或直链烷氧基。
本发明中，当R 1为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基优选为C 1-C 3的支链或直链烷基，进一步优选为异丙基、正丙基、乙基或甲基；
当R 1为C 3-C 6环烷基时，所述的C 1-C 6环烷基优选为环丙基、环丁基、环戊基或环己基。
本发明中，当R 2为卤素时，所述的卤素优选为氟、氯、溴或碘，进一步优选为氯；
本发明中，当R 3为C 1-C 12的支链或直链烷基时，所述的C 1-C 12的支链或直链烷基优选为C 1-C 6的支链或直链烷基，进一步优选为C 1-C 4的支链或直链烷基，更进一步优选为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
当R 3为C 3-C 6环烷基时，所述的C 3-C 6环烷基优选为环丙基、环丁基、环戊基或环己基；
当R 3为被一个或多个R 3a取代的C 6-C 20的芳基时，所述的C 6-C 20的芳基优选为C 6-C 10的芳基，进一步优选为苯基；所述的被一个或多个R 3a取代的C 6-C 20的芳基优选
Figure PCTCN2019076841-appb-000003
当R 3为被一个或多个R 3b取代的C 2-C 10的杂芳基时，所述的C 2-C 10的杂芳基优选为C 2-C 6的杂芳基，进一步优选为吡啶基、哒嗪基、嘧啶基、吡嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、嘧啶酮基、噁二唑基、吡啶酮基、或三氮唑基。
本发明中，当R 3a或R 3b为卤素时，所述的卤素优选为氟、氯、溴或碘；
当R 3a或R 3b为C 1-C 6的支链或直链烷基-S(＝O) 2NH-时，所述的C 1-C 6的支链或直链烷基优选为C 1-C 3的支链或直链烷基，进一步优选为甲基、乙基、正丙基或异丙基；
当R 3a或R 3b为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基优选为C 1-C 3的支链或直链烷基，进一步优选为甲基、乙基、正丙基或异丙基；
当R 3a或R 3b为C 1-C 6的支链或直链烷氧基时，所述的C 1-C 6的支链或直链烷氧基优 选为C 1-C 3的支链或直链烷氧基，进一步优选为甲氧基、乙氧基、丙氧基或异丙氧基；
当R 3a或R 3b为C 1-C 6的支链或直链烷硫基时，所述的C 1-C 6的支链或直链烷硫基优选为C 1-C 3的支链或直链烷氧基，进一步优选为甲硫基、乙硫基、丙硫基或异丙硫基；
当R 3a或R 3b为C 1-C 6的支链或直链卤代烷基时，所述的C 1-C 6的直链或支链卤代烷基为被一个或多个相同或不同的卤素原子取代的C 1-C 6的直链或支链烷基，所述的卤代可在相同或不同的碳原子上；所述的C 1-C 6的直链或支链卤代烷基优选为C 1-C 3的直链或支链卤代烷基，进一步优选为三氟甲基、二氟甲基、1,2-二氟乙基。
本发明中，当R 3为被一个或多个R 3a取代的苯基时，所述的取代优选为单取代或双取代，所述的单取代优选为3-位或4-位取代；所述的双取代优选为2,4-位双取代或3,4-位双取代。
本发明中，当R 4为卤素时，所述的卤素优选为氟、氯、溴或碘；
当R 4为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基优选为C 1-C 3的支链或直链烷基，进一步优选为甲基、乙基、正丙基或异丙基；
当R 4为C 1-C 6的支链或直链烷氧基时，所述的C 1-C 6的支链或直链烷氧基优选为C 1-C 3的支链或直链烷氧基，进一步优选为甲氧基、乙氧基、丙氧基或异丙氧基。
本发明中，当α环为被n个相同或不同的R 4取代的苯基时，n优选为2，R 4优选为同时为卤素或C 1-C 6的支链或直链烷基；进一步优选其同时为氟、同时为氯、或同时为甲基；所述的R 4优选取代在所述苯基的2-位和6-位，或3-位和5-位。
本发明中，当α环为被n个相同或不同的R 4取代的苯基时，n优选为2，优选其中两个R 4分别为C 1-C 6的支链或直链烷氧基，进一步优选两个R 4可连接成环，即共同构成一个与所述苯基为并环结构的含氧杂环。当两个R 4共同构成一个与所述苯基为并环结构的含氧杂环时，优选其为与所述苯基为并环结构的含氧5-7元杂环，例如
Figure PCTCN2019076841-appb-000004
在本发明一优选实施方案中，A为S。
在本发明一优选实施方案中，α环为
Figure PCTCN2019076841-appb-000005
Figure PCTCN2019076841-appb-000006
在本发明一优选实施方案中，R 1为H、甲基、乙基或异丙基。
在本发明一优选实施方案中，R 2为H或Cl。
在本发明一优选实施方案中，R 3为C 6-C 20的芳基、C 2-C 10的杂芳基、被一个或多个(例如1-6个，优选1-3个或1-2个)R 3a取代的C 6-C 20的芳基或被一个或多个(例如1-6个，优选1-3个或1-2个)R 3b取代的C 2-C 10的杂芳基。
在本发明一优选实施方案中，A为S，α环为
Figure PCTCN2019076841-appb-000007
Figure PCTCN2019076841-appb-000008
R 1为乙基或异丙基；R 2为H或Cl；R 3为C 6-C 20的芳基、C 2-C 10的杂芳基、被一个或多个(例如1-6个，优选1-3个或1-2个)R 3a取代的C 6-C 20的芳基或被一个或多个(例如1-6个，优选1-3个或1-2个)R 3b取代的C 2-C 10的杂芳基。
在本发明一优选实施方案中，A为S，α环为环己基，R 1为乙基或异丙基；R 2为H或Cl；R 3为C 6-C 20的芳基、C 2-C 10的杂芳基、被一个或多个(例如1-6个，优选1-3个或1-2个)R 3a取代的C 6-C 20的芳基或被一个或多个(例如1-6个，优选1-3个或1-2个)R 3b取代的C 2-C 10的杂芳基。
在本发明一优选实施方案中，R 3为被一个或多个(例如1-6个，优选1-3个或1-2个)R 3a取代的C 6-C 20的芳基，其中，所述的C 6-C 20的芳基为苯基；R 3a为羟基、卤素、C 1-C 6的支链或直链烷基、C 1-C 6的支链或直链烷氧基、C 1-C 6的支链或直链烷硫基、C 1-C 6的支链或直链卤代烷基。
在本发明一优选实施方案中，A为S，α环为
Figure PCTCN2019076841-appb-000009
Figure PCTCN2019076841-appb-000010
R 1为乙基或异丙基；R 2为H或Cl；R 3为苯基或被一个R 3a取代的苯基，其 中，R 3a为羟基、卤素、C 1-C 6的支链或直链烷氧基或C 1-C 6的支链或直链烷硫基；所述的取代为4-位取代。
在本发明一优选实施方案中，A为S，α环为环己基，R 1为乙基或异丙基；R 2为H或Cl；R 3为苯基或被一个R 3a取代的苯基，其中，R 3a为羟基、卤素、C 1-C 6的支链或直链烷氧基或C 1-C 6的支链或直链烷硫基；所述的取代为4-位取代。
在本发明一优选实施方案中，A为S，α环为环己基，R 1为乙基或异丙基；R 2为H或Cl；R 3为苯基或被一个R 3a取代的苯基，其中，R 3a为羟基、F、Cl、甲氧基或甲硫基；所述的取代为4-位取代。
在本发明一优选实施方案中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物中的结构单元
Figure PCTCN2019076841-appb-000011
为如下任一结构片段：
Figure PCTCN2019076841-appb-000012
Figure PCTCN2019076841-appb-000013
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物进一步优选为具有以下任一结构的化合物：
Figure PCTCN2019076841-appb-000014
Figure PCTCN2019076841-appb-000015
Figure PCTCN2019076841-appb-000016
Figure PCTCN2019076841-appb-000017
Figure PCTCN2019076841-appb-000018
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物进一步还可优选为具有以下任一结构的化合物：
Figure PCTCN2019076841-appb-000019
Figure PCTCN2019076841-appb-000020
本发明进一步提供了一种如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法，其包括以下步骤：在溶剂中，在碱存在的条件下，将中间体6与中间体7进行如下所示的烷基化反应，即可；
Figure PCTCN2019076841-appb-000021
其中，A、n、R 1、R 2、R 3、R 4和α环的定义均同前所述，X为卤素。
本发明中，所述的烷基化反应按照本领域此类烷基化反应机理进行反应，可采用本领域此类烷基化反应常规所用的条件和参数进行。
本发明中，X优选为氟、氯、溴或碘，进一步优选为氯。
本发明中，所述的溶剂可为本领域此类反应常规所用，以不参与或干扰反应为准；本发明优选其为DMF、THF、CH 3CN、二氧六环、吡啶中的一种或多种，进一步优选为DMF。
本发明中，所述的溶剂的用量可为本领域此类反应常规所用，以能够完全溶解反应物且保证反应顺利进行为准。
本发明中，所述的碱可为本领域此类反应常规所用；本发明优选其选自DMAP、Cs 2CO 3、K 2CO 3、Na 2CO 3、NaH、Et 3N中的一种或多种，进一步优选为K 2CO 3。
本发明中，所述的碱的用量可为本领域此类反应常规所用；本发明优选所述的中间体6与所述的碱的摩尔比为1:1-1:2，如3:4。
本发明中，所述的中间体6与中间体7的摩尔比可为本领域此类反应常规所用配比，本发明优选其为1:1-1:1.2。
本发明中，所述的烷基化反应的反应温度可为本领域此类反应常规所用；本发明优选控制在20-80℃之间，如室温条件(20-25℃)。
本发明中，所述的烷基化反应的进程可以采用本领域中的常规测试方法(例如TLC、HPLC或NMR)进行监测，一般以原料消失或不再反应为反应的终点。所述的烷基化反应的反应时间优选为3-24h，更优选8-12h。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选包括下述步骤：将所述的中间体7溶解于部分所述溶剂，加入所述的碱，室温搅拌后加入中间体6与部分所述溶剂的溶液，继续搅拌，即可。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选在所述的烷基化反应结束后，还包括下述后处理步骤：在所述的烷基化结束后，将反应液倒入冰水中，析出白色固体，过滤或者用乙酸乙酯萃取得粗产物，粗产物经柱层析纯化或者重结晶即可得目标产物纯品。其中，所述的柱层析纯化的展开剂优选为乙酸乙酯与石油醚的混合溶剂，如乙酸乙酯/石油醚＝1:4(v/v))。
本发明中，当α环为环己基时，对应的中间体7可采用有机化学领域普通技术人员熟知的方法制备得到，本发明中具体可参考Yan-Ping He,Jin Long,et al.Bioorg.&Med.Chem.2011,21,694-697，其中第695页第3段)，其具体合成路线如下所示(该文献的内容通过引用的方式并入本文)：
Figure PCTCN2019076841-appb-000022
Figure PCTCN2019076841-appb-000023
其中，R 1的定义同前所述。
本发明中，当α环为被n个相同或不同的R 4取代的苯基时，对应的中间体7可采用有机化学领域普通技术人员熟知的方法制备得到，本发明中具体可参考Maxim B.Nawrozkij，Dante Rotili，et al.J.Med.Chem.2008,51,4641-4652)，其具体合成路线如下所示(该文献的内容通过引用的方式并入本文)：
Figure PCTCN2019076841-appb-000024
其中，R 1、R 4和n的定义均同前所述。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物优选还包括下述步骤：在溶剂中，将中间体5与卤化试剂进行卤代反应，得到中间体6即可；
Figure PCTCN2019076841-appb-000025
其中，R 2和R 3的定义均同前所述，X为卤素。
本发明中，所述的卤代反应按照本领域此类卤代反应机理进行反应，可采用本领域此类卤代反应常规所用的条件和参数进行。
本发明中，X优选为氟、氯、溴或碘，进一步优选为氯。
本发明中，所述的溶剂可为本领域此类反应常规所用，以不参与或干扰反应为准；本发明优选其为THF、CH 3CN、二氧六环、吡啶中的一种或多种，进一步优选其为CH 3CN。
本发明中，所述的溶剂的用量可为本领域此类反应常规所用，以能够完全溶解反应物且保证反应顺利进行为准。
本发明中，所述的卤代试剂可为本领域此类反应常规所用；本发明优选其选自Br 2、PBr 3、CBr 4、NBS、NCS、POCl 3或I 2中的一种或多种，进一步优选其为PBr 3。
本发明中，所述的卤代试剂的用量可为本领域此类反应常规所用；本发明优选所述的中间体5与所述的卤代试剂的摩尔比为1:1-1:2，如1:1.2。
本发明中，所述的卤代反应的反应温度可为本领域此类反应常规所用；本发明优选控制在0～85℃之间，例如70～85℃之间。
本发明中，所述的卤代反应的进程可以采用本领域中的常规测试方法(例如TLC、HPLC或NMR)进行监测，一般以原料消失或不再反应为反应的终点。所述的卤代反应的反应时间优选为8-24h，更优选0.5-3h。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选包括下述步骤：将所述的中间体5溶解于所述溶剂，在冰浴条件下滴加入所述的卤代试剂，滴加完毕后搅拌进行所述卤代反应，即可。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选在所述的卤代反应结束后，还包括下述后处理步骤：在所述的卤代结束后，将反应液倒入冰水中，减压蒸去溶剂，用饱和NaHCO 3调pH至弱碱性，抽滤，将滤液用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥，减压浓缩，重结晶即可得所述中间体6。其中，所述的重结晶优选采用乙酸乙酯/石油醚(1:3,v/v)进行。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物优选还包括下述步骤：在溶剂中，在还原剂存在的条件下，将中间体4进行还原反应，得到中间体5即可；
Figure PCTCN2019076841-appb-000026
其中，R 2和R 3的定义均同前所述。
本发明中，所述的还原反应按照本领域此类还原反应机理进行反应，可采用本领域此类还原反应常规所用的条件和参数进行。
本发明中，所述的还原反应优选在惰性气体如氮气保护下进行。
本发明中，所述的溶剂可为本领域此类反应常规所用，以不参与或干扰反应为准；本发明优选其为CH 3CN、THF、DMF、DMSO、二氧六环中的一种或多种，更优选所述溶剂在进行反应前经无水处理。
本发明中，所述的溶剂的用量可为本领域此类反应常规所用，以能够完全溶解反应物且保证反应顺利进行为准。
本发明中，所述的还原剂可为本领域此类反应常规所用；本发明优选其选自NaBH 4、LiAlH 4和KBH 4中的一种或多种，进一步优选其为LiAlH 4。
本发明中，所述的还原剂的用量可为本领域此类反应常规所用；本发明优选所述的中间体4与所述的还原剂的摩尔比为1:1-1:2，如1:1.5。
本发明中，所述的还原反应的反应温度可为本领域此类反应常规所用；本发明优选控制在0～45℃之间，进一步优选为室温条件。
本发明中，所述的还原反应的进程可以采用本领域中的常规测试方法(例如TLC、HPLC或NMR)进行监测，一般以原料消失或不再反应为反应的终点。所述的还原反应的反应时间优选为2-12h。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选包括下述步骤：在所述的中间体4与所述溶剂的混合液中，在冰浴和氮气保护条件下分批加入所述的还原剂，加毕搅拌进行所述还原反应，即可。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选在所述的还原反应结束后，还包括下述后处理步骤：在所述的还原结束后，在冰浴下滴加饱和氯化铵水溶液猝灭反应，抽滤，滤液用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥，减压浓缩，重结晶即可得中间体5。其中，所述的重结晶优选采用乙酸乙酯/石油醚(1:3,v/v)进行。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物优选还包括下述步骤：在溶剂中，将中间体3与卤代试剂进行卤代反应，得到中间体4即可；
Figure PCTCN2019076841-appb-000027
其中，R 2和R 3的定义均同前所述。
本发明中，所述的卤代反应按照本领域此类卤代反应机理进行反应，可采用本领域此类卤代反应常规所用的条件和参数进行。
本发明中，所述的溶剂可为本领域此类反应常规所用，以不参与或干扰反应为准；本发明优选其为CH 3CN、THF、DMF和二氧六环中的一种或多种。
本发明中，所述的溶剂的用量可为本领域此类反应常规所用，以能够完全溶解反应物且保证反应顺利进行为准。
本发明中，所述的卤代试剂可为本领域此类反应常规所用；本发明优选其选自NBS、NCS和NIS中的一种或多种。
本发明中，所述的卤代试剂的用量可为本领域此类反应常规所用；本发明优选所述的中间体3与所述的卤代试剂的摩尔比为1:1-1:6，如1:1.2。
本发明中，所述的卤代反应的反应温度可为本领域此类反应常规所用；本发明优选控制在40～80℃之间，例如60℃。
本发明中，所述的卤代反应的进程可以采用本领域中的常规测试方法(例如TLC、HPLC或NMR)进行监测，一般以原料消失或不再反应为反应的终点。所述的卤代反应的反应时间优选为8-24h，更优选10-15h。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选包括下述步骤：将所述的中间体3溶解于所述溶剂，室温下加入所述的卤代试剂，滴加完毕后搅拌进行所述卤代反应，即可。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选在所述的卤代反应结束后，还包括下述后处理步骤：在所述的卤代结束后，减压蒸去溶剂，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥，减压浓缩，粗产物经柱层析纯化即可得所述中间体4。其中，所述的柱层析纯化的洗脱剂优选采用乙酸乙酯/石油醚(1:4,v/v)。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物优选还包括下述步骤：在溶剂中，将中间体2与水合肼进行缩合反应，得到中间体3即可；
Figure PCTCN2019076841-appb-000028
其中，R 3的定义同前所述。
本发明中，所述的缩合反应按照本领域此类缩合反应机理进行反应，可采用本领域此类缩合反应常规所用的条件和参数进行。
本发明中，所述的溶剂可为本领域此类反应常规所用，以不参与或干扰反应为准；本发明优选其为MeOH、EtOH、THF、二氧六环、CH 3CN和H 2O中的一种或多种，进一步优选为EtOH。
本发明中，所述的溶剂的用量可为本领域此类反应常规所用，以能够完全溶解反应物且保证反应顺利进行为准。
本发明中，所述的水合肼的用量可为本领域此类反应常规所用；本发明优选所述的中间体5与所述的水合肼的摩尔比为1:1-1:2。
本发明中，所述的缩合反应的反应温度可为本领域此类反应常规所用；本发明优选控制在30～85℃之间。
本发明中，所述的缩合反应的进程可以采用本领域中的常规测试方法(例如TLC、HPLC或NMR)进行监测，一般以原料消失或不再反应为反应的终点。所述的缩合反应的反应时间优选为3-24h。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选包括下述步骤：在所述的中间体2与所述溶剂的混合液中，在室温条件下滴加入水合肼，滴加完毕后回流搅拌进行所述缩合反应，即可。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选在所述的缩合反应结束后，还包括下述后处理步骤：在所述的缩合结束后，冷却到室温，蒸干溶剂，加水和乙酸乙酯萃取，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥。减压浓缩后重结晶即可得所述中间体3。其中，所述的重结晶优选采用乙酸乙酯/石油醚(1:5,v/v)进行。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物优选还包括下述步骤： 在溶剂中，在碱存在的条件下，将中间体1与乙二酸二乙酯进行亲核取代反应，得到中间体2即可；
Figure PCTCN2019076841-appb-000029
其中，R 3的定义同前所述。
本发明中，所述的亲核取代反应按照本领域此类亲核取代反应机理进行反应，可采用本领域此类亲核取代反应常规所用的条件和参数进行。
本发明中，所述的溶剂可为本领域此类反应常规所用，以不参与或干扰反应为准；本发明优选其为MeOH、EtOH、THF、CH 3CN、二氧六环和甲苯中的一种或多种，进一步优选其为EtOH。
本发明中，所述的溶剂的用量可为本领域此类反应常规所用，以能够完全溶解反应物且保证反应顺利进行为准。
本发明中，所述的碱可为本领域此类反应常规所用；本发明优选其选自DMAP、Cs 2CO 3、K 2CO 3、C 2H 5ONa、CH 3ONa、Na 2CO 3、NaHCO 3和Et 3N中的一种或多种，进一步优选其为C 2H 5ONa。
本发明中，当使用C 2H 5ONa为碱时，可采用金属钠与乙醇原位制备而得。
本发明中，所述的碱的用量可为本领域此类反应常规所用；本发明优选所述的中间体1与所述的碱的摩尔比为1:1-1:2。
本发明中，所述的乙二酸二乙酯的用量可为本领域此类反应常规所用；本发明优选所述的中间体1与所述的乙二酸二乙酯的摩尔比为1:1-1:2。
本发明中，所述的亲核取代反应的反应温度可为本领域此类反应常规所用；本发明优选控制在20～80℃之间，例如室温条件下。
本发明中，所述的亲核取代反应的进程可以采用本领域中的常规测试方法(例如TLC、HPLC或NMR)进行监测，一般以原料消失或不再反应为反应的终点。所述的亲核取代反应的反应时间优选为3-24h，例如8h。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选包括下述步骤：在所述的中间体1、所述的碱和所述的溶剂的混合物中，加入乙二酸二乙酯，室温反应即可。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选在所 述的亲核取代反应结束后，还包括下述后处理步骤：在所述的亲核取代反应结束后，加入稀盐酸调pH至8，蒸干所述溶剂，用水和乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩即可。
本发明中，所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法优选采用下述合成路线制备：
Figure PCTCN2019076841-appb-000030
其中，n、R 1、R 2、R 3、R 4、α环和X的定义均同前所述，其中各步骤的具体反应条件和参数均同前所述。
根据本发明公开的上述制备方法，本领域技术人员可采用与之相同或相似的原理和方法，制得本发明的如式I所示的2-硫甲基吡唑嘧啶酮类化合物中所涉及的各具体化合物。
本发明进一步还提供了一种如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药在制备非核苷类HIV-1抑制剂中的应用，所述的非核苷类HIV-1抑制剂优选为非核苷类HIV-1 ⅢB抑制剂。
本发明进一步还提供了一种如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药在制备抗HIV-1药物中的应用。
本发明进一步提供了如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药在制备治疗和/或预防人类免疫缺陷病毒(HIV)感染药物中的应用。
本发明进一步还提供了一种药物组合物，其包括治疗有效量的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药，和至少一种药用辅料。所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药在药物组合物中的质量百分比为0.1％-99.9％，所述的质量百分比是指所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药占药物组合物总质量的百分比。所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药与所述的药用辅料的质量分数之和为100％。所述的药用辅料的选择因施用途径和作用特点而异，通常是填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂或助悬剂。
本发明进一步还提供了一种治疗人类免疫缺陷病毒(HIV)感染疾病的方法，所述的方法包括给予需要其的个体治疗有效量的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸 加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)，该文献的内容通过引用的方式并入本文)。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一 般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120.1985年,62:114-120，该文献的内容通过引用的方式并入本文。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明涉及的化学通式可以表现出互变异构、结构异构和立体异构现象。本发明包括其任意互变或结构或立体异构形式及其混合物，他们的能力不限于任何一种异构或其混合物的形式。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体 以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
除非另有规定，本发明所用试剂和原料均市售可得。
除非另有规定，本发明的化合物经手工或者
Figure PCTCN2019076841-appb-000031
软件命名，市售化合物采用供应商目录名称。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明的积极进步效果在于：本发明提供了一种结构新颖的2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用。经试验证明，本发明的2-硫甲基吡唑嘧啶酮类化合物可作为HIV-1抑制剂应用，并具有较高的应用价值。具体地说，可作为HIV-1抑制剂用于制备抗艾滋病药物。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。原料可以从商业途径获得，或者通过本领域已知的方法制备，或根据本文所述方法制备。
下列实施例中制得的各化合物的结构通过核磁共振( 1H NMR或 13C NMR)或质谱(MS)来确定，其中NMR测定使用BrukerAV-300型核磁共振仪，测定溶剂为氘代二甲亚砜 (DMSO-D 6)或氘代氯仿(CDCl 3)，TMS为内标。
制备实施例1：目标化合物I的制备
目标化合物I-1合成路线如下式所示：
Figure PCTCN2019076841-appb-000032
步骤(1)：2，4-二氧代-4-苯基丁酸乙酯(中间体2-1)的制备
取40mL乙醇置于200mL圆底烧瓶中，室温搅拌下分批加入钠(2g,0.083mol)，待冷却到室温后，加入苯乙酮(5g,0.042mol)，然后加入乙二酸二乙酯(7.4g,0.046mol)，室温反应8h,加入1mol/L的盐酸调pH至8，蒸干乙醇，加水10mL,用20mL乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。过滤、浓缩得到9.3g中间体2-1，可不经纯化直接用于下一步反应。
步骤(2)：5-苯基-1H-吡唑-3-甲酸乙酯(中间体3-1)的制备
将上述中间体2-1(9.3g,0.042mol)置于装有50mL乙醇的圆底烧瓶中，室温搅拌下滴加入水合肼(2.1g,0.042mol)，加毕，回流3h后冷却到室温，蒸干乙醇，加水10mL，乙酸乙酯萃取(3×20mL)，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥。减压浓缩后，用乙酸乙酯/石油醚(1:5)重结晶，得到8.68g中间体3-1，产率95.6％。
步骤(3)：4-氯-5-苯基-1H-吡唑-3-甲酸乙酯(中间体4-1)的制备
取中间体3-1(2g,9.20mmol)置于100mL的圆底烧瓶中，加入CH 3CN与DMF共12mL(CH 3CN：DMF＝5:1)，室温搅拌下加入NCS，加毕，升温至60℃反应10h至反应完全。减压蒸去乙腈，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥。减压蒸去溶剂得中间体4粗产物，经柱层析(乙酸乙酯：石油醚＝1:4)分离得中间体4-1纯品1.16g，产率50.5％。
步骤(4)：4-氯-5-苯基-1H-吡唑-3-甲醇(中间体5-1)的制备
取中间体4-1(1.16g,4.64mmol)置于100mL圆底烧瓶中,加入10mL无水THF，在冰浴、氮气保护下分批加入LiAlH 4(0.277g,6.96mmol),室温搅拌2h至反应完全，冰浴下滴加饱和的氯化铵水溶液猝灭反应。抽滤，滤液用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥，减压浓缩，用乙酸乙酯/石油醚(1:3)重结晶得中间体5-1纯品0.768g，产率79.6％。
步骤(5)：3-溴甲基-4-氯-5-苯基-1H-吡唑(中间体6-1)的制备
取上述中间体5-1(0.768g，3.69mmol)置于50mL圆底烧瓶中,加入乙腈15mL，在冰浴下缓慢滴加PBr 3(1.20g,4.43mmol),加毕，升温至80℃反应1h。反应毕，将反应液倒入冰水中，减压蒸去乙腈，用饱和NaHCO 3调pH至弱碱性，抽滤，将滤液用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤后无水硫酸钠干燥，减压浓缩，用乙酸乙酯/石油醚(1:3)重结晶得中间体6-1纯品0.681g，产率89.6％。
步骤(6)：目标化合物I-1的制备
将6-环己甲基-5-乙基-硫嘧啶酮7-1(0.003mol,0.728g)置于9mL DMF中，搅拌溶解后，加入无水K 2CO 3(0.004mol,0.553g)，室温搅拌30min，加入5mL溶有中间体6-1(0.681g,0.003mol)的DMF溶液，继续搅拌3h至反应完全后，将反应液倒入10mL冰水中，析出白色固体。过滤或者用乙酸乙酯萃取得粗产物，粗产物经柱层析乙酸乙酯/石油醚(1:4)纯化得到目标产物I-1。
Figure PCTCN2019076841-appb-000033
产物为白色晶体，产率86％。 1H NMR(DMSO-d6,300MHz)δ0.94-0.97(t,3H,J＝7.2Hz,CH 3),0.99(m,2H,Cyclohexyl-H),1.06-1.08(m,3H,Cyclohexyl-H),1.56-1.59(m,5H,Cyclohexyl-H),1.81(m,1H,Cyclohexyl-H),2.32-2.34(d,2H,J＝6.0Hz,CH 2-Cyclohexyl),2.36-2.38(m,2H,CH 2CH 3),4.44(s,2H,CH 2-S),7.40-7.51(m,3H,Ph-H),7.77-7.79(m,2H,Ph-H),10.88(br,1H,NH),13.19(br,1H,NH)； 13C NMR(DMSO-d6,75MHz)δ13.19,18.01,25.00(2C),25.73(2C),25.87,32.63,36.53,40.76,105.07,121.05,126.42,126.42,126.42,128.67(3C),140.28，141.02，155.86,161.05,162.92.
Figure PCTCN2019076841-appb-000034
如目标化合物I-1的方法制备，所不同的是步骤(3)操作省略。
产物为白色固体，收率87％。 1H NMR(CDCl 3,300MHz)δ0.85-0.88(t,3H,J＝8.1Hz,CH 3),0.97-1.00(m,2H,Cyclohexyl-H),1.07-1.12(m,3H,Cyclohexyl-H),1.65-1.69(m,5H,Cyclohexyl-H),1.82(m,1H,Cyclohexyl-H),2.46-2.48(d,2H,J＝6.9Hz,C H 2-Cyclohexyl),2.51-2.53(m,2H,C H 2 CH 3),4.42(s,2H,C H 2-S),6.52(s,1H,pyrazole),7.34-7.36(m,3H,Ph-H),7.67-7.69(m,2H,Ph-H),10.24-10.73(br,1H,NH),13.19(br,1H,NH)； 13C NMR(CDCl 3,75MHz)δ13.37,18.75,26.31(2C),26.40,26.90(2C),33.36,37.50,41.80,102.28,122.74,125.71(2C),128.32,128.86(2C),130.56,146.29,146.99,156.37,163.11,164.73.
Figure PCTCN2019076841-appb-000035
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-溴苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，收率74％。 1H NMR(CDCl 3,300MHz)δ0.89-0.91(t,3H,J＝6.0Hz,CH 3),1.04(m,2H,Cyclohexyl-H),1.13(m,3H,Cyclohexyl-H),1.69(m,5H,Cyclohexyl-H),1.84(m,1H,Cyclohexyl-H),2.53(m,2H,C H 2-Cyclohexyl),2.53(m,2H,CH 2),4.45(s,2H,C H 2S),6.53(s,1H,pyrazole-H),7.23-7.25(m,1H,Ph-H),7.41-7.44(m,1H,Ph-H),7.63-7.65(m,1H,Ph-H),7.90(m,1H,Ph-H),12.36(br,1H,NH),13.19(br,1H,NH)； 13C NMR(CDCl 3,75MHz)δ13.38,18.75,26.32(5C),33.38,37.58,41.90,102.64,122.64,122.92,124.29,128.73,130.29,131.00,133.49,144.90,147.13,156.42,163.40,164.88.
Figure PCTCN2019076841-appb-000036
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-溴苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率89％。 1H NMR(DMSO-d 6,300MHz)δ0.93-0.95(t,3H,J＝7.2Hz,CH 3),0.98(m,2H,Cyclohexyl-H),1.02-1.04(m,3H,Cyclohexyl-H),1.52-1.55(m,5H,Cyclohexyl-H),1.71(m,1H,Cyclohexyl-H),2.33-2.35(m,2H,C H 2-Cyclohexyl),2.33-2.35(m,2H,CH 2),4.43(s,2H,C H 2-S),7.42-7.45(m,1H,Ph-H),7.55-7.58(m,1H,Ph-H),7.80-7.82(m,1H,Ph-H),7.95(m,1H,Ph-H),13.01(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.58,18.26,23.13,25.77(4C),32.73,36.87,40.65,104.93,119.02,121.85,125.25,128.74,130.77(2C),132.99,140.95,141.24,160.40,161.32,168.14.
Figure PCTCN2019076841-appb-000037
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-氯苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体；产率85％。 1H NMR(CDCl 3,300MHz)δ0.97-1.01(m,2H,Cyclohexyl-H),1.01-1.12(t,3H,J＝7.2Hz,CH 3),1.17-1.21(m,3H,Cyclohexyl-H),1.65-1.69(m,5H,Cyclohexyl-H),1.80(m,1H,Cyclohexyl-H),2.47-2.49(d,2H,J＝6.6Hz,C H 2-Cyclohexyl),2.51-2.54(m,2H,CH 2),4.41(s,2H,C H 2-S),6.50(s,1H,pyrazole-H),7.25-7.30(m,2H,Ph-H),7.56(m,1H,Ph-H),7.58-7.70(m,1H,Ph-H),12.56(br,1H,NH)； 13C NMR(CDCl 3,75MHz)δ13.36,18.74,26.13(5C),33.37,37.61,41.92,102.60,122.69,123.82,125.86,128.12,130.05,133.19,134.73,144.98,147.21,156.52,163.40,164.88.
Figure PCTCN2019076841-appb-000038
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-氯苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率90％。 1H NMR(DMSO-d 6,300MHz)δ0.88(m,2H,Cyclohexyl-H),0.93-0.98(t,3H,J＝7.2Hz,CH 3),1.03-1.05(m,3H,Cyclohexyl-H),1.53-1.56(m,5H,Cyclohexyl-H),1.72(m,1H,Cyclohexyl-H),2.34-2.36(m,2H,C H 2-Cyclohexyl),2.34-2.36(m,2H,CH 2),4.43(s,2H,C H 2-S),7.44-7.53(m,2H,Ph-H),7.76-7.81(m,2H,Ph-H),12.50(br,2H,2NH)； 13CNMR(DMSO-d 6,75MHz)δ13.26,18.05,23.37,25.72(2C),25.86(2C),32.62,36.62,40.65,105.34,120.48,124.85,125.89,128.02,130.52,131.97,133.39,140.52,141.12,157.09,161.09,164.33.
Figure PCTCN2019076841-appb-000039
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氯苯基)-苯乙酮为起始原 料1，步骤(3)操作省略。
产物为白色晶体，产率88％。 1H NMR(DMSO-d 6,300MHz)δ0.97-0.99(t,3H,J＝7.2Hz,CH 3),1.09(m,2H,Cyclohexyl-H),1.18(m,3H,Cyclohexyl-H),1.57(m,5H,Cyclohexyl-H),1.75(m,1H,Cyclohexyl-H),2.35-2.39(m,2H,C H 2-Cyclohexyl),2.35-2.39(m,2H,C H 2 CH 3),4.39(s,2H,C H 2-S),6.58-6.61(s,1H,pyrazole-H),7.28-7.45(m,2H,Ph-H),7.69-7.45(m,2H,Ph-H),12.78(br,1H,NH)； 13C NMR(DMSO-d 6,75MHz)δ13.21,18.03,25.73(2C),25.86(3C),32.65,36.58,40.76,101.71,121.98,124.93,126.61,127.66,128.68,131.86,132.08,145.91,156.29,160.85,163.02.
Figure PCTCN2019076841-appb-000040
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氟苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率89％。 1H NMR(DMSO-d 6,300MHz)δ0.90(m,2H,Cyclohexyl-H),0.95-0.99(t,3H,J＝7.5Hz,CH 3),1.06-1.09(m,3H,Cyclohexyl-H),1.56-1.60(m,5H,Cyclohexyl-H),1.75(m,1H,Cyclohexyl-H),2.36-2.38(m,2H,C H 2-Cyclohexyl),2.36-2.38(m,2H,CH 2),4.39(s,2H,C H 2-S),6.57(s,1H,pyrazole-H),7.18-7.24(m,2H,Ph-H),7.73-7.77(m,2H,Ph-H),12.78(br,1H,NH)； 13C NMR(DMSO-d 6,75MHz)δ13.18,18.02,25.40,25.40,25.72,25.85(2C),32.65,36.58,40.71,101.55,115.39,115.68,121.07,126.90,127.00,127.99,144.42,145.63,156.32,160.62,161.56,163.26.
Figure PCTCN2019076841-appb-000041
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氟苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率71％。 1H NMR(DMSO-d 6,300MHz)δ0.96-0.98(m,2H,Cyclohexyl-H),1.04-1.06(t,3H,J＝7.8Hz,CH 3),1.13-1.15(m,3H,Cyclohexyl-H),1.50-1.58(m,5H,Cyclohexyl-H),1.75(m,1H,Cyclohexyl-H),2.35-2.37(m,2H,C H 2-Cyclohexyl),2.35-2.37(m,2H,CH 2),4.43(s,2H,C H 2-S),7.29-7.35(m,2H,Ph-H),7.79-7.84(m,2H,Ph-H),12.96(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.17,17.99,23.69,25.72(2C),25.86(2C),32.61,36.51,40.75,101.97,115.53,115.82,121.11,128.54,128.65(2C),140.42,141.63,155.92,161.08,161.96,162.95.
Figure PCTCN2019076841-appb-000042
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-甲氧基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率50％。 1H NMR(DMSO-d 6,300MHz)δ0.95-1.00(t,3H,J＝7.2Hz,CH 3),1.02-1.12(m,2H,Cyclohexyl-H),1.16-1.20(m,3H,Cyclohexyl-H),1.59-1.62(m,5H,Cyclohexyl-H),1.78(m,1H,Cyclohexyl-H),2.36-2.38(m,2H,C H 2-Cyclohexyl),2.40(m,2H,CH 2),3.76(s,3H,OCH 3),4.37(s,2H,C H 2-S),6.49(s,1H,pyrazole-H),6.95-6.98(m,2H,Ph-H),7.62-7.65(m,2H,Ph-H),12.07-13.10(br,1H,NH)； 13C NMR(DMSO-d 6,75MHz)δ13.23,18.02,25.74(2C),25.88(3C),32.66,36.58,40.71,55.06,100.85,114.11(2C),121.10,123.45,126.31(2C),142.23,145.48,156.39,158.90,160.65,163.03.
Figure PCTCN2019076841-appb-000043
Figure PCTCN2019076841-appb-000044
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-氯-4-甲氧基苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率53％。 1H NMR(DMSO-d 6,300MHz)δ0.88(m,2H,Cyclohexyl-H),0.93-0.98(t,3H,J＝6.9Hz,CH 3),1.04-1.07(m,3H,Cyclohexyl-H),1.54-1.57(m,5H,Cyclohexyl-H),1.74(m,1H,Cyclohexyl-H),2.34-2.36(m,2H,C H 2-Cyclohexyl),2.34-2.36(m,2H,CH 2),3.89(s,3H,OCH 3),4.42(s,2H,C H 2-S),7.24-7.27(s,1H,Ph-H),7.72-7.81(m,2H,Ph-H),12.52-13.21(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.18,17.99,23.71,25.72(2C),25.86(2C),32.61,36.52,40.24,56.15,104.76,112.91,121.29,123.5,126.41,127.59,127.81,154.49,141.36,142.55,155.96,160.95,162.96.
Figure PCTCN2019076841-appb-000045
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3，4-二氯苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率51％。 1H NMR(DMSO-d 6,300MHz)δ0.94(m,2H,Cyclohexyl-H),0.96-0.99(t,3H,J＝7.2Hz,CH 3),1.05-1.08(m,3H,Cyclohexyl-H),1.55-1.58(m,5H,Cyclohexyl-H),1.72(m,1H,Cyclohexyl-H),2.35-2.37(m,2H,C H 2-Cyclohexyl),2.35-2.37(m,2H,CH 2),4.39(s,2H,C H 2-S),6.68(s,1H,pyrazole-H),7.59-7.62(m,1H,Ph-H),7.68-7.72(m,1H,Ph-H),7.94-7.95(m,1H,Ph-H),12.81(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.19,18.02,24.90,25.72(2C),25.86(2C),32.63,36.58,40.82,102.26,121.06,124.96,126.47(2C),129.78,130.82,131.53,141.48,144.69,156.09,161.07,162.99.
Figure PCTCN2019076841-appb-000046
Figure PCTCN2019076841-appb-000047
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3，4-二氯苯基)-苯乙酮为起始原料1。
产物为白色晶体；产率82％。 1H NMR(DMSO-d 6,300MHz)δ0.93-0.98(t,3H,J＝7.2Hz,CH 3),1.04(m,2H,Cyclohexyl-H),1.04(m,3H,Cyclohexyl-H),1.53-1.55(m,5H,Cyclohexyl-H),1.70(m,1H,Cyclohexyl-H),2.33-2.36(m,2H,C H 2-Cyclohexyl),2.33-2.36(m,2H,CH 2),4.42(s,2H,C H 2S),7.46-7.55(m,2H,Ph-H),7.98-7.99(m,1H,Ph-H),12.72-13.36(br,2H,2NH)； 13CNMR(DMSO-d 6,75MHz)δ13.17,17.99,23.17,25.70(2C),25.84(2C),32.59,36.52,40.76,105.57,121.09,124.86,126.07,128.73,130.91,131.49,133.42,140.68,141.77,155.74,161.08,162.96.
Figure PCTCN2019076841-appb-000048
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-氟苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率74％。 1H NMR(DMSO-d 6,300MHz)δ0.97-1.00(m,2H,Cyclohexyl-H),1.06-1.10(t,3H,J＝7.2Hz,CH 3),1.13-1.16(m,3H,Cyclohexyl-H),1.64-1.68(m,5H,Cyclohexyl-H),1.80(m,1H,Cyclohexyl-H),2.45-2.47(m,2H,C H 2-Cyclohexyl),2.45-2.47(m,2H,CH 2),4.39(s,2H,C H 2-S),6.49(s,1H,pyrazole-H),6.96(m,1H,Ph-H),7.28-7.46(m,3H,Ph-H),12.40(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.32,18.72,26.30(5C),33.37,37.56,41.90,102.63,112.64,114.98,121.33,122.75,130.36,133.35,145.29,147.05,156.25,161.46,163.32,164.73.
Figure PCTCN2019076841-appb-000049
Figure PCTCN2019076841-appb-000050
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-氟苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率89％。 1H NMR(DMSO-d 6,300MHz)δ0.95(m,3H,CH 3),1.04(m,2H,Cyclohexyl-H),1.04(m,3H,Cyclohexyl-H),1.53(m,5H,Cyclohexyl-H),1.72(m,1H,Cyclohexyl-H),2.34(m,2H,C H 2-Cyclohexyl),2.34(m,2H,CH 2),4.43(s,2H,C H 2-S),7.22(m,1H,Ph-H),7.55-7.65(m,3H,Ph-H),12.98-13.05(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.15,17.99,23.55,25.70(2C),25.84(2C),32.59,36.52,40.76,105.46,112.89,115.10,121.10,122.35(2C),130.77,140.68,141.54,155.95,161.11,162.13,162.95.
Figure PCTCN2019076841-appb-000051
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氯苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率90％。 1H NMR(DMSO-d 6,300MHz)δ0.88(m,2H,Cyclohexyl-H),0.93-0.98(t,3H,J＝7.2Hz,CH 3),1.03-1.05(m,3H,Cyclohexyl-H),1.53-1.56(m,5H,Cyclohexyl-H),1.74(m,1H,Cyclohexyl-H),2.34-2.36(m,2H,C H 2-Cyclohexyl),2.34-2.36(m,2H,CH 2),4.43(s,2H,C H 2-S),7.52-7.55(m,2H,Ph-H),7.79-7.81(m,2H,Ph-H),13.01(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.18,17.99,23.53,25.71(2C),25.85(2C),32.60,36.52,40.75,105.26,121.09,128.03(3C),128.76(2C),133.06,140.46,141.02,155.78,161.11,162.93.
Figure PCTCN2019076841-appb-000052
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-羟基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率54％。 1H NMR(DMSO-d 6,300MHz)δ0.96-1.00(t,3H,J＝7.2Hz,CH 3),1.09-1.12(m,2H,Cyclohexyl-H),1.09-1.12(m,3H,Cyclohexyl-H),1.59-1.62(m,5H,Cyclohexyl-H),1.79(m,1H,Cyclohexyl-H),2.36-2.40(m,2H,C H 2-Cyclohexyl),2.36-2.40(m,2H,CH 2),4.36(s,2H,C H 2-S),6.42(s,1H,pyrazole-H),6.78-6.81(m,2H,Ph-H),7.50-7.53(m,2H,Ph-H),9.62(br,1H,OH),12.67(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.22,18.04,25.75,25.88(2C),26.07(2C),32.67,36.59,40.76,100.49,115.48(2C),121.42,126.40(2C),128.38,145.64,156.39,157.25,157.25,160.82,162.98.
Figure PCTCN2019076841-appb-000053
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3，4-二氟苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率89％。 1H NMR(DMSO-d 6,300MHz)δ0.94-0.99(t,3H,J＝7.2Hz,CH 3),1.05-1.08(m,2H,Cyclohexyl-H),1.05-1.08(m,3H,Cyclohexyl-H),1.55-1.59(m,5H,Cyclohexyl-H),1.72(m,1H,Cyclohexyl-H),2.32-2.38(m,2H,C H 2-Cyclohexyl),2.32-2.38(m,2H,CH 2),4.38(s,2H,C H 2-S),6.64(s,1H,pyrazole-H),7.38-7.45(m,1H,Ph-H),7.48-7.59(m,1H,Ph-H),7.71-7.78(m,1H,Ph-H),11.81-12.97(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.16,18.01,24.98,25.70(2C),25.84(2C),32.62,36.59,40.71,102.03,113.8,117.78,121.04,121.63,129.61,143.99,145.48,149.06,149.47,156.27,160.66,163.12.
Figure PCTCN2019076841-appb-000054
Figure PCTCN2019076841-appb-000055
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3,4-二氟苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率68％。 1H NMR(DMSO-d 6,300MHz)δ0.92-0.97(t,3H,J＝7.2Hz,CH 3),1.02-1.04(m,2H,Cyclohexyl-H),1.12-1.16(m,3H,Cyclohexyl-H),1.52-1.55(m,5H,Cyclohexyl-H),1.72(m,1H,Cyclohexyl-H),2.33-2.35(m,2H,C H 2-Cyclohexyl),2.33-2.35(m,2H,CH 2),4.42(s,2H,C H 2-S),7.51-7.57(m,1H,Ph-H),7.64-7.73(m,1H,Ph-H),7.73-7.80(m,1H,Ph-H),13.00(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.12,17.98,23.26,25.70(2C),25.83(2C),32.59,36.52,40.75,105.29,115.24,117.78,121.10,123.29(2C),140.50,141.28,149.31,149.23,155.79,161.07,162.95.
Figure PCTCN2019076841-appb-000056
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(2,4-二氟苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率75％。 1H NMR(CDCl 3,300MHz)δ1.07-1.10(m,2H,Cyclohexyl-H),1.12-1.17(t,3H,J＝6.9Hz,CH 3),1.22-1.26(m,3H,Cyclohexyl-H),1.66-1.70(m,5H,Cyclohexyl-H),1.82(m,1H,Cyclohexyl-H),2.48-2.56(m,2H,C H 2-Cyclohexyl),2.48-2.56(m,2H,CH 2),4.44(s,2H,C H 2-S),6.64(s,1H,pyrazole-H),6.85-6.92(m,2H,Ph-H),7.76-7.7(m,1H,Ph-H),12.09-12.42(br,2H,2NH)； 13C NMR(CDCl 3,75MHz)δ13.33,18.72,26.29(3C),26.38(2C),33.36,37.54,41.90,104.66,111.90,115.45,115.62,122.75,129.12,141.28,145.26,159.5,162.76,156.33,163.22,164.79.
Figure PCTCN2019076841-appb-000057
Figure PCTCN2019076841-appb-000058
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-甲基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率82％。 1H NMR(DMSO-d 6,300MHz)δ0.96-1.00(t,3H,J＝6.9Hz,CH 3),1.11(m,2H,Cyclohexyl-H),1.11(m,3H,Cyclohexyl-H),1.59(m,5H,Cyclohexyl-H),1.80(m,1H,Cyclohexyl-H),2.28(s,3H,C H 3-Ph),2.37(m,2H,Cyclohexyl-H),2.37(m,2H,CH 2),4.39(s,2H,C H 2-S),6.53(s,1H,pyrazole-H),7.17-7.19(m,2H,Ph-H),7.58-7.61(m,2H,Ph-H),12.77(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.21,18.05,20.70,25.77(3C),25.88(2C),32.70,36.59,40.89,101.20,121.16,124.86(2C),128.09,129.23(2C),137.01,142.32,145.67,156.31,160.94,162.89.
Figure PCTCN2019076841-appb-000059
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-甲基苯基)-苯乙酮为起始原料1。
产物为白色晶体,产率63％。 1H NMR(DMSO-d 6,300MHz)δ0.97-0.99(m,2H,Cyclohexyl-H),1.06-1.12(t,3H,J＝7.8Hz,CH 3),1.17(m,3H,Cyclohexyl-H),1.52-1.59(m,5H,Cyclohexyl-H),1.79(m,1H,Cyclohexyl-H),2.31(s,3H,C H 3-Ph),2.35-2.37(m,2H,CH 2-Cyclohexyl),2.35-2.37(m,2H,CH 2),4.44(s,2H,C H 2-S),7.25-7.28(m,2H,Ph-H),7.65-7.6(m,2H,Ph-H),12.94(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.17,18.00,20.76,24.04,25.76(2C),25.89(2C),32.66,36.51,40.76,104.82,121.10,126.68(3C),129.22(2C),137.95,140.17,141.01,156.00,161.02,162.93.
Figure PCTCN2019076841-appb-000060
Figure PCTCN2019076841-appb-000061
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-甲基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率74％。 1H NMR(DMSO-d 6,300MHz)δ0.92(m,2H,Cyclohexyl-H),0.96-1.01(t,3H,J＝6.9Hz,CH 3),1.08-1.14(m,3H,Cyclohexyl-H),1.53-1.60(m,5H,Cyclohexyl-H),1.80(m,1H,Cyclohexyl-H),2.30(s,3H,C H 3-Ph),2.37-2.39(m,2H,CH 2-Cyclohexyl),2.37-2.39(m,2H,CH 2),4.41(s,2H,C H 2-S),6.55(s,1H,pyrazole-H),7.06-7.09(m,1H,Ph-H),7.23-7.28(m,1H,Ph-H),7.50-7.54(m,2H,Ph-H),12.79(br,2H,2NH)； 13CNMR(DMSO-d 6,75MHz)δ13.18,18.07,20.92,25.78(3C),25.89(2C),32.70,36.62,40.91,101.48,121.17,122.11,125.55,128.31,128.53,130.87,137.77,145.19,145.93,156.32,160.94,162.91.
Figure PCTCN2019076841-appb-000062
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-甲基苯基)-苯乙酮为起始原料1。
产物为白色晶体，产率66％。 1H NMR(DMSO-d 6,300MHz)δ0.89(m,2H,Cyclohexyl-H),0.95-0.99(t,3H,J＝7.2Hz,CH 3),1.08(m,3H,Cyclohexyl-H),1.56-1.59(m,5H,Cyclohexyl-H),1.79(m,1H,Cyclohexyl-H),2.30(s,3H,C H 3-Ph),2.33-2.37(m,2H,CH 2-Cyclohexyl),2.33-2.37(m,2H,CH 2),4.45(s,2H,C H 2-S),7.17-7.19(m,1H,Ph-H),7.31-7.36(m,1H,Ph-H),7.57-7.59(m,2H,Ph-H),12.95(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.16,18.02,20.97,23.97,25.76(2C),25.90(2C),32.67,36.52,40.79,105.08,121.10,123.60,126.98(2C),128.52,129.03,137.81,141.98,142.53,156.03,161.03,162.94.
Figure PCTCN2019076841-appb-000063
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-甲硫基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率53％。 1H NMR(DMSO-d 6,300MHz)δ0.96-1.00(t,3H,J＝7.2Hz,CH 3),1.08-1.10(m,2H,Cyclohexyl-H),1.15(m,3H,Cyclohexyl-H),1.58(m,5H,Cyclohexyl-H),1.78(m,1H,Cyclohexyl-H),2.37(s,3H,C H 3S),2.46-2.50(m,2H,CH 2-Cyclohexyl),2.46-2.50(m,2H,CH 2),4.40(s,2H,C H 2-S),6.55(CH,pyrazole),7.25-7.28(m,2H,Ph-H),7.64-7.67(m,2H,Ph-H),12.78(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.22,14.52,18.05,25.77(3C),25.89(2C),32.69,36.58,40.88,101.32,121.15,125.41(2C),125.99(2C),127.65,137.69,145.61,156.25,160.98,162.90.
Figure PCTCN2019076841-appb-000064
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-三氟甲基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率68％。 1H NMR(DMSO-d 6,300MHz)δ0.75(m,2H,Cyclohexyl-H),0.96-0.98(t,3H,J＝6.6Hz,CH 3),1.06(m,3H,Cyclohexyl-H),1.54(m,5H,Cyclohexyl-H),1.72(m,1H,Cyclohexyl-H),2.34-2.36(m,2H,Cyclohexyl-H),2.34-2.36(m,2H,CH 2),4.42(s,2H,C H 2-S),6.72(CH,pyrazole-H),7.59-7.60(m,2H,Ph-H),8.01-8.0(m,2H,Ph-H),12.58(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.12,18.00,24.94,25.68(2C),25.79(2C),32.61,36.56,40.70,102.09,121.10,122.28,123.83,125.88,128.74,129.56,130.24,132.89,144.05,146.06,156.22,160.68,163.11.
Figure PCTCN2019076841-appb-000065
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(3-三氟甲基苯基)-苯乙酮为起始原料1。
产物为白色晶体；产率63％。 1H NMR(DMSO-d 6,300MHz)δ1.68-1.81(m,2H,Cyclohexyl-H),1.85-1.90(t,3H,J＝6.9Hz,CH 3),1.93(m,3H,Cyclohexyl-H),2.06-2.45(m,5H,Cyclohexyl-H),2.62(m,1H,Cyclohexyl-H),3.25-3.27(m,2H,Cyclohexyl-H),3.25-3.27(m,2H,C H 2CH 3),5.37(s,2H,C H 2-S),8.52-8.64(m,2H,Ph-H),8.93-9.04(m,2H,Ph-H),13.94(br,2H,2NH)； 13C NMR(DMSO-d 6,75MHz)δ13.10,17.98,23.36,25.66(2C),25.79(2C),32.58,36.51,40.76,105.54,121.09(2C),122.58,123.95,124.66,128.96,129.33,129.92,140.58,141.26,155.81,161.05,162.56.
Figure PCTCN2019076841-appb-000066
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-异丙基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率71％。 1H NMR(DMSO-d 6,300MHz)δ0.92(m,2H,Cyclohexyl-H),0.96-1.01(t,3H,J＝7.5Hz,CH 3),1.08-1.10(d,6H,J＝7.5Hz,2CH 3),1.15-1.17(m,3H,Cyclohexyl-H),1.59(m,5H,Cyclohexyl-H),1.80(m,1H,Cyclohexyl-H),2.37-2.39(m,2H,CH 2-Cyclohexyl),2.37-2.39(m,2H,CH 2),2.81-2.85(m,1H,CHMe 2),4.41(s,2H,C H 2-S),6.53(CH,pyrazole-H),7.21-7.24(m,2H,Ph-H),7.60-7.63(m,2H,Ph-H),12.78(br,1H,NH)； 13C NMR(DMSO-d 6,75MHz)δ13.19,18.06,23.62(2),25.77(3),25.89,25.89,32.71,33.16,36.59, 40.92,101.29,121.15,125.00(2C),126.53(2C),126.53,128.49,145.66,147.92,156.35,160.92,162.90.
Figure PCTCN2019076841-appb-000067
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(2，4-二甲基苯基)-苯乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率65％。 1H NMR(DMSO-d 6,300MHz)δ0.96-1.00(m,2H,Cyclohexyl-H),1.04-1.09(t,3H,J＝7.2Hz,CH 3),1.17-1.25(m,3H,Cyclohexyl-H),1.65(m,5H,Cyclohexyl-H),1.84(m,1H,Cyclohexyl-H),2.31(s,3H,C H 3-Ph),2.35(s,3H,C H 3-Ph),2.44-2.50(m,2H,C H 2-Cyclohexyl),2.44-2.50(m,2H,CH 2),4.46(s,2H,C H 2-S),6.35(CH,pyrazole-H),6.97-7.03(m,2H,Ph-H),7.30-7.32(m,2H,Ph-H),12.54(br,2H,NH)； 13C NMR(DMSO-d 6,75MHz)δ13.40,18.77,20.86,21.23,26.37,26.50(2C),27.51(2C),33.43,37.43,41.86,105.16,122.78,126.82,127.29,129.03,131.70,135.80,138.29,145.35,146.58,156.26,163.03,164.67.
Figure PCTCN2019076841-appb-000068
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3,3-二甲基丁烷-2-酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率45％。 1H NMR(CDCl 3,300MHz)δ0.85(m,2H,Cyclohexyl-H),1.02(s,9H,3×CH 3),1.07-1.12(t,3H,J＝7.5Hz,CH 3),1.34(m,1H,Cyclohexyl-H),1.67-1.71(m,7H,Cyclohexyl-H),1.84(m,1H,Cyclohexyl-H),2.44-2.47(d,2H,J＝6.9Hz,CH 2-Cyclohexyl), 2.51-2.56(m,2H,CH 2),4.38(s,2H,C H 2-S),6.05(CH,pyrazole-H)； 13C NMR(CDCl 3,75MHz)δ13.32,18.70,26.34(2C),26.44,28.01(2C),30.26(3C),31.23,33.35,37.35,41.76,100.91,122.76,142.18,146.33,155.36,156.21,162.80,164.32.
Figure PCTCN2019076841-appb-000069
如目标化合物I-1的方法制备，所不同的是步骤(1)使用乙醛为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率51％。 1H NMR(CDCl 3,300MHz)δ1.05(m,2H,Cyclohexyl-H),1.07-1.12(t,3H,J＝7.5Hz,CH 3),1.17-1.26(m,3H,Cyclohexyl),1.66-1.70(m,5H,Cyclohexyl-H),1.80-1.85(m,1H,Cyclohexyl-H),2.45-2.47(d,2H,J＝7.2Hz,CH 2-Cyclohexyl),2.51-2.53(m,2H,CH 2),4.44(s,2H,C H 2-S),6.27-6.28(d,1H,J＝7.5Hz,pyrazole-H),7.52-7.53(d,J＝7.5Hz,1H,pyrazole-H)； 13C NMR(CDCl 3,75MHz)δ13.28,18.71,26.31(2C),26.41,27.19(2C),33.34,37.36,41.74,104.76,122.66,131.71,140.92,145.81,156.11,163.09,164.65.
Figure PCTCN2019076841-appb-000070
如目标化合物I-1的方法制备，所不同的是步骤(1)使用丙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率49％。 1H NMR(CDCl 3,300MHz)δ1.04(m,2H,Cyclohexyl-H),1.07-1.12(t,3H,J＝7.5Hz,CH 3),1.16-1.23(m,3H,Cyclohexyl-H),1.66-1.69(m,5H,Cyclohexyl-H),1.80-1.85(m,1H,Cyclohexyl-H),2.30(s,3H,C H 3-pyrazole),2.44-2.46(d,2H,J＝7.2Hz,CH 2-Cyclohexyl),2.50-2.53(m,2H,C H 2 CH 3),4.37(s,2H,C H 2-S),6.02(CH,pyrazole-H),11.01-11.45(br,2H,NH)； 13C NMR(CDCl 3,75MHz)δ11.48,13.30,18.68,26.31,26.31(2C),27.33 (2C),33.33,37.33,41.72,104.13,122.59,141.94,146.81,156.33,163.02,164.63.
Figure PCTCN2019076841-appb-000071
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-环丙基乙酮为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率38％。 1H NMR(CDCl 3,300MHz)δ1.04(m,2H,Cyclohexyl-H),1.07-1.12(t,3H,J＝7.5Hz,CH 3),1.17-1.20(m,4H,2×CH 2),1.23-1.26(m,3H,Cyclohexyl-H),1.66-1.69(m,5H,Cyclohexyl-H),1.82(m,1H,Cyclohexyl-H),1.87-1.94(m,1H,cyclopropyl-H),2.43-2.50(d,2H,J＝7.5Hz,CH 2-Cyclohexyl),2.53-2.55(m,2H,C H 2 CH 3),4.36(s,2H,C H 2-S),5.88(CH,pyrazole),11.72(br,2H,NH)； 13C NMR(CDCl 3,75MHz)δ7.37,7.87(2C),13.31,18.69,26.32(2C),26.43,27.26(2C),33.34,37.36,41.75,100.94,122.59,146.25,149.44,156.37,163.01,164.63.
Figure PCTCN2019076841-appb-000072
如目标化合物I-1的方法制备，所不同的是步骤(1)使用2-乙酰吡啶为起始原料1，步骤(3)操作省略。
产物为白色晶体，产率30％。 1H NMR(CDCl 3,300MHz)δ1.00-1.04(m,2H,Cyclohexyl-H),1.07-1.12(t,3H,J＝7.5Hz,CH 3),1.16-1.26(m,3H,Cyclohexyl-H),1.63-1.69(m,5H,Cyclohexyl-H),1.80-1.83(m,1H,Cyclohexyl-H),2.45-2.47(d,2H,J＝6.9Hz,CH 2-Cyclohexyl),2.51-2.54(m,2H,C H 2 CH 3),4.49(s,2H,C H 2-S),6.75(s,1H,pyrazole-H),7.20-7.21(m,1H,pyridine-H),7.69(m,2H,pyridine-H),8.63-8.64(m,1H,pyridine-H),10.27-10.67(br,2H,2NH)； 13C NMR(CDCl 3,75MHz)δ13.32,18.67,26.28(2C),26.39,27.08,27.08,33.35,37.38,41.76,101.19,120.31,122.69,122.92,137.01,145.22,147.74,148.91,149.41,156.10,161.87,164.82.
Figure PCTCN2019076841-appb-000073
如目标化合物I-1的方法制备，所不同的是步骤(3)操作省略,步骤(6)中反应物A使用6-环己甲基-5-异丙基-硫嘧啶酮进行硫烷基化反应。
产物为白色晶体；产率78％。 1H NMR(CDCl 3,300MHz)δ0.76-0.78(m,2H,Cyclohexyl-H),0.97-1.00(m,2H,Cyclohexyl-H),1.07-1.12(m,3H,Cyclohexyl-H),1.26-1.29(d,6H,2CH 3)1.65-1.69(m,3H,Cyclohexyl-H),1.83(m,1H,Cyclohexyl-H),2.41-2.43(d,2H,J＝7.0Hz,C H 2-Cyclohexyl),2.86-3.23(m,1H,C HMe 2),4.43(s,2H,C H 2-S),6.51(s,1H,pyrazole-H),7.32-7.34(m,3H,Ph-H),7.66-7.71(m,2H,Ph-H),10.36(br,1H,NH),13.19(br,1H,NH).
Figure PCTCN2019076841-appb-000074
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氯苯基)-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-环己甲基-5-异丙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率80％。 1H NMR(DMSO-d 6,300MHz)δ1.01-1.08(m,2H,Cyclohexyl-H),1.18(m,3H,Cyclohexyl-H),1.53(m,5H,Cyclohexyl-H),1.76(m,1H,Cyclohexyl-H),2.35-2.39(m,2H,C H 2-Cyclohexyl),2.86-3.19(m,1H,CHMe 2),4.35(s,2H,C H 2-S),6.57-6.60(s,1H,pyrazole-H),7.26-7.43(m,2H,Ph-H),7.67-7.73(m,2H,Ph-H),12.77(br,1H,2NH).
Figure PCTCN2019076841-appb-000075
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氟苯基)-苯乙酮为起始原料1,步骤(6)中使用6-环己甲基-5-异丙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率82％。 1H NMR(DMSO-d 6,300MHz)δ0.98-1.01(m,2H,Cyclohexyl-H),1.15-1.17(m,3H,Cyclohexyl-H),1.26-1.29(d,6H,2CH 3),1.51-1.57(m,5H,Cyclohexyl-H),1.76(m,1H,Cyclohexyl-H),2.33-2.36(m,2H,C H 2-Cyclohexyl),2.86-3.24(m,1H,CHMe 2),4.41(s,2H,C H 2-S),7.29-7.34(m,2H,Ph-H),7.79-7.82(m,2H,Ph-H),12.96(br,2H,2NH).
Figure PCTCN2019076841-appb-000076
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-羟基苯基)-苯乙酮为起始原料1，步骤(3)操作省略,步骤(6)中使用6-环己甲基-5-异丙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率64％。 1H NMR(DMSO-d 6,300MHz)δ0.96-1.10(m,5H,Cyclohexyl-H),1.58-1.60(m,5H,Cyclohexyl-H),1.79(m,1H,Cyclohexyl-H),2.36-2.40(m,2H,CH 2-Cyclohexyl)2.86-3.28(m,1H,CHMe 2),4.42(s,2H,CH 2-S),6.41(s,1H,pyrazole-H),6.77-6.80(m,2H,Ph-H),7.51-7.54(m,2H,Ph-H),9.22(br,1H,OH),12.13(br,2H,2NH).
Figure PCTCN2019076841-appb-000077
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氟苯基)-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-环己甲基-5-异丙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率87％。 1H NMR(DMSO-d 6,300MHz)δ0.88-0.92(m,2H,Cyclohexyl-H),1.04-1.06(m,3H,Cyclohexyl-H),1.26-1.29(d,6H,2CH 3),1.53-1.58(m,5H,Cyclohexyl-H),1.75(m,1H,Cyclohexyl-H),2.26-2.28(m,2H,C H 2-Cyclohexyl),2.86-3.26(m,1H,CHMe 2),4.41(s,2H,C H 2-S),6.56(s,1H,pyrazole-H),7.17-7.22(m,2H,Ph-H),7.68-7.72(m,2H,Ph-H),12.68(br,1H,2NH).
Figure PCTCN2019076841-appb-000078
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-甲氧基苯基)-苯乙酮为起始原料1,步骤(3)操作省略，步骤(6)中使用6-环己甲基-5-异丙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率50％。 1H NMR(DMSO-d 6,300MHz)δ0.96-0.98(m,2H,Cyclohexyl-H),1.16-1.21(m,3H,Cyclohexyl-H),1.58-1.62(m,5H,Cyclohexyl-H),1.81(m,1H,Cyclohexyl-H),2.34-2.36(m,2H,C H 2-Cyclohexyl),2.84-3.26(m,1H,CHMe 2),3.86(s,3H,OCH 3),4.39(s,2H,C H 2-S),6.47(s,1H,pyrazole-H),6.94-6.97(m,2H,Ph-H),7.61-7.64(m,2H,Ph-H),12.10(br,1H,NH).
Figure PCTCN2019076841-appb-000079
如目标化合物I-1的方法制备，所不同的是步骤(3)骤操作省略,步骤(6)中反应物A使用6-环己甲基-5-甲基-硫尿嘧啶进行硫烷基化反应。
产物为白色晶体；产率85％。 1H NMR(DMSO-d6,300MHz)δ0.94-1.00(m,2H,cyclohexyl-H),1.08-1.11(m,3H,Cyclohexyl-H),1.58-1.73(m,6H,Cyclohexyl-H),1.87(s,3H,CH 3),2.39-2.41(d,2H,CH 2-Cyclohexyl),4.38(s,2H,CH 2-S),6.59(s,1H,pyrazole-H),7.28-7.30(m,1H,Ph-H),7.36-7.41(t,2H,J＝7.23Hz,Ph-H),7.70-7.72(d,2H,Ph-H),12.84(br,2H,2NH).
Figure PCTCN2019076841-appb-000080
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氟苯基)-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-环己甲基-5-甲基-硫嘧啶A进行硫烷基化反应。
产物为白色晶体；产率87％。 1H NMR(DMSO-d 6,300MHz),δ0.93-0.97(m,2H,Cyclohexyl-H),1.07-1.10(m,3H,Cyclohexyl-H),1.57-1.60(m,6H,Cyclohexyl-H),1.88(s,3H,CH 3),2.38-2.41(d,2H,CH 2-Cyclohexyl),4.38(s,2H,CH 2-S),6.58(s,1H,pyrazole-H),7.20-7.26(m,2H,J＝8.8Hz,Ph-H),7.73-7.77(m,2H,Ph-H),12.77(br,1H,NH).
Figure PCTCN2019076841-appb-000081
Figure PCTCN2019076841-appb-000082
如目标化合物I-1的方法制备，所不同的是使用1-(4-甲氧基苯基)-苯乙酮为起始原料1，步骤(3)操作省略,步骤(6)中使用6-环己甲基-5-甲基-硫嘧啶A进行硫烷基化反应。
产物为白色晶体；产率62％。 1H NMR(DMSO-d 6,300MHz)δ0.95-0.99(m,2H,Cyclohexyl-H),1.11-1.13(m,3H,Cyclohexyl-H),1.59-1.63(m,6H,Cyclohexyl-H),1.88(s,3H,CH 3),2.39-2.42(m,2H,C H 2-Cyclohexyl),3.77(s,3H,OCH 3),4.36(s,2H,C H 2-S),6.49(s,1H,pyrazole-H),6.95-6.98(m,2H,Ph-H),7.62-7.65(m,2H,Ph-H),12.70(br,2H,2NH).
Figure PCTCN2019076841-appb-000083
如目标化合物I-1的方法制备，所不同的是步骤(3)骤操作省略,步骤(6)中使用6-环己甲基硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体；产率83％。 1H NMR(DMSO-d 6,300MHz)δ0.89-0.97(m,2H,Cyclohexyl-H),1.09-1.17(m,3H,Cyclohexyl-H),1.58-1.62(m,6H,Cyclohexyl-H),2.32-2.34(d,2H,C H 2-Cyclohexyl),4.40(s,2H,C H 2-S),5.96(s,1H,Pyrimidone-H),6.61(s,1H,pyrazole-H),7.27-7.32(t,1H,J＝7.30Hz,Ph-H),7.37-7.42(t,2H,J＝7.47Hz,Ph-H),7.70-7.72(d,2H,Ph-H),12.80(br,2H,2NH).
Figure PCTCN2019076841-appb-000084
如目标化合物I-1的方法制备，所不同的是步骤(1)使用1-(4-氟苯基)-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-环己甲基硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体；产率89％。 1H NMR(DMSO-d 6,300MHz)δ0.88-0.92(m,2H, Cyclohexyl-H),1.08-1.11(m,3H,Cyclohexyl-H),1.57-1.61(m,6H,Cyclohexyl-H),2.32-2.34(d,2H,C H 2-Cyclohexyl),4.40(s,2H,C H 2-S),5.96(s,1H,Pyrimidone-H),6.59(s,1H,pyrazole-H),7.20-7.26(m,2H,Ph-H),7.73-7.78(m,2H,Ph-H),12.79(br,1H,NH).
Figure PCTCN2019076841-appb-000085
如目标化合物I-1的方法制备，所不同的是使用1-(4-甲氧基苯基)-苯乙酮为起始原料1，步骤(3)操作省略,步骤(6)中使用6-环己甲基硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体；产率47％。 1H NMR(DMSO-d 6,300MHz)δ0.90-0.97(m,2H,Cyclohexyl-H),1.10-1.17(m,3H,Cyclohexyl),1.59-1.72(m,6H,Cyclohexyl),2.32-2.3 4(d,2H,CH 2-Cyclohexyl),3.77(s,3H,OCH3),4.38(s,2H,CH2-S),5.96(s,1H,Pyrimidone-H),6.50(s,1H,pyrazole-H),6.95-6.98(d,2H,Ph-H),7.62-7.65(m,2H,Ph-H),12.72(br,2H,NH).
Figure PCTCN2019076841-appb-000086
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-羟基-苯乙酮为起始原料1,步骤(3)操作省略，步骤(6)中使用6-环己甲基-5-甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率65％。 1H NMR(DMSO-d 6,400MHz)δ0.94-1.02(m,2H,Cyclohexyl-H),1.08-1.22(m,4H,Cyclohexyl-H),1.56-1.63(m,5H,Cyclohexyl-H),1.89(s,3H,CH 3),2.40-2.42(d,2H,J＝6.88Hz,C H 2-Cyclohexyl),4.35(s,2H,C H 2-S),6.43(s,1H,pyrazole-H),6.78-6.80(d,2H,J＝8.52Hz,Ph-H),7.50-7.52(d,2H,J＝8.52Hz,Ph-H),9.61(s,1H,OH),12.67(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz)δ10.99,26.19(3C),26.38(2C),33.11,37.18,42.02,101.03,115.97(2C),122.27,126.90(2C),131.69,137.35,145.92,156.77,157.72, 162.04,163.75.
Figure PCTCN2019076841-appb-000087
如目标化合物I-1的方法制备，所不同的是步骤(6)中使用6-环己甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率44％。 1H NMR(DMSO-d 6,400MHz),δ0.85-0.93(m,2H,Cyclohexyl-H),1.01-1.18(m,3H,Cyclohexyl-H),1.53-1.58(m,5H,Cyclohexyl-H),1.67-1.71(m,1H,Cyclohexyl-H),2.30-2.32(d,2H,J＝7.00Hz,C H 2-Cyclohexyl),4.46(s,2H,C H 2-S),5.96(s,1H,Pyrimidone-H),7.39-7.43(t,1H,J＝7.32Hz,Ph-H),7.47-7.51(t,2H,J＝7.44Hz,Ph-H),7.78-7.80(d,2H,J＝7.56Hz,Ph-H),13.19(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz)δ26.03(3C),26.37(2C),32.89,36.60,44.70,105.66,107.62,126.96(2C),128.96,129.22,132.95,138.53,141.39,152.49,157.05,162.06,164.69.
Figure PCTCN2019076841-appb-000088
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1,步骤(3)操作省略，步骤(6)中使用6-苄基-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率83％。 1H NMR(DMSO-d 6,400MHz),δ0.93-0.96(t,3H,J＝7.3Hz,CH 2-C H 3),2.44-2.47(m,2H,C H 2-CH 3),3.92(s,2H,C H 2-Ph),4.36(s,2H,C H 2-S),6.41(s,1H,pyrazole-H),7.17-7.30(m,7H,Ph-H),7.69-7.73(m,2H,Ph-H),12.80(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz)δ13.57,18.71,25.70,40.15,102.15,116.09(2C),121.68,126.70, 127.50(2C),128.80(2C),129.33(2C),133.41,138.99,141.63,145.36,148.50,157.30,160.94,163.37.
Figure PCTCN2019076841-appb-000089
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1,步骤(3)操作省略，步骤(6)中使用6-(1’,3’-苯并二氧基)-5-甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率76％。 1H NMR(DMSO-d 6,400MHz),δ0.93-0.97(t,3H,J＝7.3Hz,CH 2-C H 3),2.43-2.48(m,2H,C H 2-CH 3),3.83(s,2H,C H 2-Ph),4.38(s,2H,C H 2-S),5.90(s,2H,O-C H 2-O),6.45(s,1H,pyrazole-H),6.74-6.80(m,2H,Ph-H),6.87(s,1H,Ph-H),7.22-7.26(t,2H,J＝8.8Hz,Ph-H),7.70-7.73(m,2H,Ph-H),12.77(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz)δ13.62,18.63,25.43,39.67,101.16,102.11,108.57,109.77,116.07(2C),121.52,122.23,127.47,129.38,132.63,135.07,140.08,143.08,146.07,147.61,154.08,157.17,160.93,163.36.
Figure PCTCN2019076841-appb-000090
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1,步骤(3)操作省略，步骤(6)中使用6-(2’,6’-二氯苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率62％。 1H NMR(DMSO-d 6,400MHz),δ1.09-1.13(t,3H,J＝7.0 Hz,CH 2-C H 3),2.56-2.58(m,2H,C H 2-CH 3),3.98(s,2H,C H 2-Ph),4.26(s,2H,C H 2-S),6.00(s,1H,pyrazole-H),7.18-7.29(m,3H,Ph-H),7.42-7.44(d,2H,J＝7.96Hz,Ph-H),7.67-7.71(m,2H,Ph-H),12.80(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz)δ13.06,18.39,35.24,43.13,101.62,116.14(2C),127.48(2C),128.48(2C),129.52,135.05,136.12(2C),139.48,140.40,142.88,149.36,151.11,157.83,160.93,163.36.
Figure PCTCN2019076841-appb-000091
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1,步骤(3)操作省略，步骤(6)中使用6-(3’,5’-二氟苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率78％。 1H NMR(DMSO-d 6,400MHz),δ0.93-0.97(t,3H,J＝7.3Hz,CH 2-C H 3),2.45-2.49(m,2H,C H 2-CH 3),3.96(s,2H,C H 2-Ph),4.34(s,2H,C H 2-S),6.41(s,1H,pyrazole-H),7.01-7.06(m,3H,Ph-H),7.21-7.26(t,2H,J＝8.8Hz,Ph-H),7.67-7.71(m,2H,Ph-H),12.80(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz)δ13.55,18.60,25.76,39.42,102.01,102.39,112.56(2C),115.98(2C),121.97,127.45(2C),139.46,143.50,149.37,154.05,157.54,159.39,160.93,161.46,163.36,163.90.
Figure PCTCN2019076841-appb-000092
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(6)中使用6-苄基-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率72％。 1H NMR(DMSO-d 6,400MHz),δ0.89-0.92(t,3H,J＝7.3Hz,CH 2-C H 3),2.41-2.47(m,2H,C H 2-CH 3),3.90(s,2H,C H 2-Ph),4.43(s,2H,C H 2-S),7.14-7.17(m,1H,Ph-H),7.21-7.27(m,4H,Ph-H),7.54-7.65(m,2H,Ph-H),7.75-7.80(m,1H,Ph-H),13.06(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.46,18.67,24.01,40.12,105.95,116.04,118.56,121.68,124.01,126.64,128.73(2C),129.20(2C),136.42,138.98,143.77,146.08,148.68,151.12,156.83,160.89,163.76.
Figure PCTCN2019076841-appb-000093
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(6)中使用6-环己甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率67％。 1H NMR(DMSO-d 6,400MHz),δ0.84-0.92(m,2H,Cyclohexyl-H),1.06-1.19(m,3H,Cyclohexyl-H),1.54-1.66(m,6H,Cyclohexyl-H),2.30-2.32(d,2H,J＝6.9Hz,C H 2-Cyclohexyl),4.45(s,2H,C H 2-S),5.97(s,1H,Pyrimidone-H),7.55-7.61(m,1H,Ph-H),7.66-7.68(m,1H,Ph-H),7.76-7.82(m,1H,Ph-H),13.48(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ26.00(3C),26.35(2C),32.86,36.61,44.73,105.89,107.67,115.87,118.55,123.96,131.36,136.14,140.00,148.68,151.12,155.79,161.40,164.00.
Figure PCTCN2019076841-appb-000094
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(6)中使用6-(2’,6’-二氯苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率79％。 1H NMR(DMSO-d 6,400MHz),δ1.09-1.13(m,3H,CH 2- C H 3),2.56-2.57(m,2H,C H 2-CH 3),3.96(s,2H,C H 2-Ph),4.23(s,2H,C H 2-S),7.22-7.26(m,1H,Ph-H),7.39-7.42(m,2H,Ph-H),7.58-7.62(m,2H,Ph-H),7.74-7.79(m,1H,Ph-H),13.12(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.06,18.36,24.59,35.16,105.76,115.97,118.70,124.04,128.37(2C),129.39,131.39,134.95,136.04(2C),138.15,144.28,148.76,149.88,151.08,155.79,159.86,163.23.
Figure PCTCN2019076841-appb-000095
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(6)中使用6-环己甲基-5-甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率54％。 1H NMR(DMSO-d 6,400MHz),δ0.92-0.94(m,2H,Cyclohexyl-H),1.05-1.07(m,3H,Cyclohexyl-H),1.54-1.67(m,6H,Cyclohexyl-H),1.87(s,3H,CH 3),2.37-2.39(d,2H,J＝6.9Hz,C H 2-Cyclohexyl),4.43(s,2H,C H 2-S),7.56-7.61(m,1H,Ph-H),7.67-7.69(m,1H,Ph-H),7.78-7.83(m,1H,Ph-H),13.28(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ10.94,26.14(3C),26.35(2C),33.01,37.16,41.87,105.78,115.86,118.53,123.93,130.67,137.17,141.50,145.16,148.66,151.04,155.40,161.08,163.99.
Figure PCTCN2019076841-appb-000096
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(6)中使用6-(3’,5’-二氟苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率62％。 1H NMR(DMSO-d 6,400MHz),δ0.89-0.93(t,3H,J＝7.4Hz,CH 2-C H 3),2.40-2.46(m,2H,C H 2-CH 3),3.95(s,2H,C H 2-Ph),4.39(s,2H,C H 2-S),6.95-7.03 (m,3H,Ph-H),7.53-7.65(t,2H,Ph-H),7.74-7.78(m,1H,Ph-H),13.31(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.49,18.58,23.69,39.98,102.18,105.82,112.37(2C),115.88,118.51,123.93,128.26,132.09,135.06,137.44,143.50(2C),146.51,148.59,151.04,157.69,161.41,163.86.
Figure PCTCN2019076841-appb-000097
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-苄基-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率76％。 1H NMR(DMSO-d 6,400MHz),δ0.92-0.96(t,3H,J＝7.3Hz,CH 2-C H 3),2.43-2.47(m,2H,C H 2-CH 3),3.92(s,2H,C H 2-Ph),4.37(s,2H,C H 2-S),6.49(s,1H,pyrazole-H),7.16-7.19(m,1H,Ph-H),7.23-7.29(m,4H,Ph-H),7.44-7.54(m,2H,Ph-H),7.70-7.75(m,1H,Ph-H),12.83(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.55,18.70,24.32,40.14,102.62,114.35,118.36,122.23,126.69,128.78(2C),129.33(2C),131.66,139.01,142.37,148.10,148.91,150.48,151.34,156.80,160.86,163.55.
Figure PCTCN2019076841-appb-000098
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-环己甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率82％。 1H NMR(DMSO-d 6,400MHz),δ0.83-0.94(m,2H,Cyclohexyl-H),1.05-1.18(m,3H,Cyclohexyl-H),1.54-1.67(m,6H,Cyclohexyl-H),2.31-2.33(d,2H,J＝6.9Hz,C H 2-Cyclohexyl),4.40(s,2H,C H 2-S),5.96(s,1H,Pyrimidone-H),6.67(s,1H, pyrazole-H),7.42-7.49(m,1H,Ph-H),7.57-7.60(m,1H,Ph-H),7.74-7.79(m,1H,Ph-H),12.80(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ26.02(3C),26.35(2C),32.90,36.65,44.87,102.69,107.73,114.35,118.34,112.17,130.37,136.04,139.42,148.51,150.95,155.06,164.34,167.35.
Figure PCTCN2019076841-appb-000099
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-(2’,6’-二氯苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率73％。 1H NMR(DMSO-d 6,400MHz),δ1.09-1.13(t,3H,J＝7.1Hz,CH 2-C H 3),2.54-2.59(m,2H,C H 2-CH 3),3.99(s,2H,C H 2-Ph),4.24-4.26(m,2H,C H 2-S),6.08(s,1H,pyrazole-H),7.20-7.24(m,1H,Ph-H),7.40-7.43(m,2H,Ph-H),7.49-7.50(m,2H,Ph-H),7.66-7.71(m,1H,Ph-H),12.81(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.04,18.38,24.43,35.22,102.11,114.28,118.41,122.25,128.46(2C),129.52,135.03,136.10(2C),141.49,144.77,148.11,148.91,150.58,151.34,157.94,160.84,163.30.
Figure PCTCN2019076841-appb-000100
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-(3’,5’-二氟苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率82％。 1H NMR(DMSO-d 6,400MHz),δ0.92-0.96(t,3H,J＝7.3 Hz,CH 2-C H 3),2.42-2.48(m,2H,C H 2-CH 3),3.96(s,2H,C H 2-Ph),4.35(s,2H,C H 2-S),6.49(s,1H,pyrazole-H),6.99-7.03(m,3H,Ph-H),7.42-7.49(m,1H,Ph-H),7.52-7.55(m,1H,Ph-H),7.69-7.74(m,1H,Ph-H),12.86(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.51,18.59,25.23,39.44,102.24,102.51,112.53(2C),114.33,118.29,122.15,130.72,134.39,137.46,140.05,143.51,145.42,148.49,150.93,159.52,161.44,163.88(2C).
Figure PCTCN2019076841-appb-000101
如目标化合物I-1的方法制备，所不同的是步骤(1)使用3’,4’-二氟-苯乙酮为起始原料1，步骤(3)操作省略，步骤(6)中使用6-(1’,3’-苯并二氧基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率85％。 1H NMR(DMSO-d 6,400MHz),δ0.92-0.96(t,3H,J＝7.3Hz,CH 2-C H 3),2.42-2.47(m,2H,C H 2-CH 3),3.83(s,2H,C H 2-Ph),4.38(s,2H,C H 2-S),5.89(s,2H,O-C H 2-O),6.53(s,1H,pyrazole-H),6.73-6.79(m,2H,Ph-H),6.85(s,1H,Ph-H),7.43-7.53(m,2H,Ph-H),7.71-7.76(m,1H,Ph-H),12.81(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.59,18.62,25.54,39.66,101.15,102.60,108.54,109.75,114.36,118.32,122.22(2C),132.63,136.00,138.70,142.21,146.05,147.60,148.13,148.91,150.47,151.34,161.01,163.70.
Figure PCTCN2019076841-appb-000102
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1，步骤(6)中使用6-(3’,5’-二氟苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率77％。 1H NMR(DMSO-d 6,400MHz),δ0.91-0.94(t,3H,J＝7.3Hz,CH 2-C H 3),2.42-2.47(m,2H,C H 2-CH 3),3.95(s,2H,C H 2-Ph),4.39(s,2H,C H 2-S),6.97-7.04(m,3H,Ph-H),7.31-7.36(t,2H,J＝8.6Hz,Ph-H),7.78-7.82(m,2H,Ph-H),12.98(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.50,18.58,24.50,39.40,102.20,105.50,112.44(2C),116.21(2C),122.14,129.17(2C),138.96,143.46,149.22,152.52,156.05,159.35,161.26,161.43,163.71,163.87.
Figure PCTCN2019076841-appb-000103
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1，步骤(6)中使用6-(2’,6’-二氯苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率72％。 1H NMR(DMSO-d 6,400MHz),δ1.08-1.12(t,3H,J＝7.3Hz,CH 2-C H 3),2.54-2.59(m,2H,C H 2-CH 3),3.95(s,2H,C H 2-Ph),4.22(s,2H,C H 2-S),7.22-7.26(t,1H,J＝8.2Hz,Ph-H),7.33-7.45(m,4H,Ph-H),7.77-7.81(m,2H,Ph-H),12.91(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.06,18.37,24.31,35.56,105.40,116.31(2C),128.37(2C),129.23(2C),129.38,134.98,136.06(2C),138.83,139.55,142.29,148.66,151.76,158.26,161.31,163.75.
Figure PCTCN2019076841-appb-000104
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1，步骤(6)中使用6-(1’,3’-苯并二氧基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率83％。 1H NMR(DMSO-d 6,400MHz),δ0.90-0.94(t,3H,J＝7.3Hz,CH 2-C H 3),2.41-2.46(m,2H,C H 2-CH 3),3.81(s,2H,C H 2-Ph),4.44(s,2H,C H 2-S),5.92(s,2H,O-C H 2-O),6.73-6.80(m,2H,Ph-H),6.83(s,1H,Ph-H),7.32-7.36(m,2H,Ph-H),7.80-7.84(m,2H,Ph-H),13.06(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.53,18.62,24.09,39.66,101.16,105.59,108.48,109.61,116.22(2C),121.38,122.15,126.59,129.21(2C),132.60,139.72,142.56,146.06,147.59,153.95,157.36,161.27,163.71.
Figure PCTCN2019076841-appb-000105
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1，步骤(6)中使用6-苄基-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率79％。 1H NMR(DMSO-d 6,400MHz),δ0.90-0.93(t,3H,J＝7.3Hz,CH 2-C H 3),2.42-2.48(m,2H,C H 2-CH 3),3.90(s,2H,C H 2-Ph),4.43(s,2H,C H 2-S),7.14-7.17(t,1H,J＝7.0Hz,Ph-H),7.22-7.25(t,2H,J＝7.6Hz,Ph-H),7.27-7.29(d,2H,J＝7.2Hz,Ph-H),7.32-7.36(t,2H,J＝8.7Hz,Ph-H),7.81-7.84(m,2H,Ph-H),12.97(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.48,18.69,24.30,40.17,105.60,116.25(2C),121.49,126.64,128.73(2C),129.25(4C),133.92,138.97,140.12,144.11,148.84,156.97,161.28,163.72.
Figure PCTCN2019076841-appb-000106
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1，步骤(6)中使用6-环己甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率68％。 1H NMR(DMSO-d 6,400MHz),δ0.84-0.92(m,2H, Cyclohexyl-H),1.03-1.11(m,3H,Cyclohexyl-H),1.55-1.69(m,6H,Cyclohexyl-H),2.30-2.32(d,2H,J＝7.0Hz,C H 2-Cyclohexyl),4.45(s,2H,C H 2-S),5.96(s,1H,Pyrimidone-H),7.32-7.36(t,2H,J＝8.8Hz,Ph-H),7.81-7.84(m,2H,Ph-H),13.09(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ26.02(3C),26.35,32.87,36.59,44.71,105.56,107.69,116.21(2C),126.33,129.15(2C),138.01,142.77,148.11,158.68,161.25,163.70,167.53,
Figure PCTCN2019076841-appb-000107
如目标化合物I-1的方法制备，所不同的是步骤(1)使用4’-氟-苯乙酮为起始原料1，步骤(6)中使用6-环己甲基-5-甲基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率86％。 1H NMR(DMSO-d 6,400MHz),δ0.92-0.97(m,2H,Cyclohexyl-H),1.06-1.07(m,3H,Cyclohexyl-H),1.51-1.58(m,5H,Cyclohexyl-H),1.70(s,1H,Cyclohexyl-H),1.87(s,3H,CH 3),2.37-2.39(d,2H,J＝6.9Hz,C H 2-Cyclohexyl),4.43(s,2H,C H 2-S),7.32-7.36(t,2H,J＝8.7Hz,Ph-H),7.80-7.84(m,2H,Ph-H),12.87(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ24.13,26.16(3C),26.36(2C),33.04,37.12,41.87,105.50,116.20(2C),129.13(2C),139.22,146.53,152.02,156.28,159.55,161.24,162.22,163.69.
Figure PCTCN2019076841-appb-000108
如目标化合物I-1的方法制备，所不同的是步骤(6)中使用6-(3’,5’-二氟苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率82％。 1H NMR(DMSO-d 6,400MHz),δ0.92-0.95(t,3H,J＝7.3Hz,CH 2-C H 3),2.42-2.48(m,2H,C H 2-CH 3),3.95(s,2H,C H 2-Ph),4.40(s,2H,C H 2-S),6.99-7.04 (m,3H,Ph-H),7.39-7.43(t,1H,J＝7.2Hz,Ph-H),7.47-7.51(t,2H,J＝7.4Hz,Ph-H),7.75-7.77(d,2H,J＝7.5Hz,Ph-H),12.94(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.53,18.58,24.45,39.41,102.21,105.61,112.48(2C),122.13,126.90(2C),129.02,129.23(2C),133.45,138.70,143.46,149.82,154.63,156.71,159,40,161.44,163.68,
Figure PCTCN2019076841-appb-000109
如目标化合物I-1的方法制备，所不同的是步骤(6)中使用6-(2’,6’-二氯苄基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率75％。 1H NMR(DMSO-d 6,400MHz),δ1.09-1.12(t,3H,J＝7.3Hz,CH 2-C H 3),2.54-2.59(m,2H,C H 2-CH 3),3.96(s,2H,C H 2-Ph),4.22(s,2H,C H 2-S),7.22-7.26(t,1H,J＝8.0Hz,Ph-H),7.40-7.43(m,3H,Ph-H),7.48-7.52(t,2H,J＝7.5Hz,Ph-H),7.74-7.76(d,2H,J＝7.6Hz,Ph-H),12.99(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.06,18.38,24.49,35.17,105.52,121.20,126.98(2C),128.37(2C),129.09,129.29(2C),129.37,135.00,136.08,139.24,143.40,147.65,153.06,157.87,160.77,163.28.
Figure PCTCN2019076841-appb-000110
如目标化合物I-1的方法制备，所不同的是步骤(6)中使用6-苄基-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率86％。 1H NMR(DMSO-d 6,400MHz),δ0.90-0.93(t,3H,J＝7.3Hz,CH 2-C H 3),2.42-2.48(m,2H,C H 2-CH 3),3.90(s,2H,C H 2-Ph),4.43(s,2H,C H 2-S),7.14-7.18(t,1H,J＝7.0Hz,Ph-H),7.23-7.26(t,2H,J＝7.3Hz,Ph-H),7.28-7.30(d,2H,J＝7.2Hz,Ph-H), 7.40-7.44(t,1H,J＝7.2Hz,Ph-H),7.48-7.52(t,2H,J＝7.4Hz,Ph-H),7.77-7.79(d,2H,J＝7.6Hz,Ph-H),12.86-13.43(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.50,18.68,24.48,40.13,105.67,121.54,126.65,127.01(2C),128.74(2C),129.03,129.27(4C),138.96,143.47,146.32,152.34,156.96,160.95,163.79.
Figure PCTCN2019076841-appb-000111
如目标化合物I-1的方法制备，所不同的是步骤(6)中使用6-(1’,3’-苯并二氧基)-5-乙基-硫尿嘧啶A进行硫烷基化反应。
产物为白色晶体，产率85％。 1H NMR(DMSO-d 6,400MHz),δ0.91-0.94(t,3H,J＝7.2Hz,CH 2-C H 3),2.41-2.47(m,2H,C H 2-CH 3),3.81(s,2H,C H 2-Ph),4.44(s,2H,C H 2-S),5.92(s,2H,O-C H 2-O),6.74-6.79(m,2H,Ph-H),6.85(s,1H,Ph-H),7.40-7.44(t,1H,J＝7.2Hz,Ph-H),7.48-7.52(t,2H,J＝7.4Hz,Ph-H),7.77-7.79(d,2H,J＝7.5Hz,Ph-H),12.83-13.43(br,2H,NH)； 13C NMR(DMSO-d 6,100MHz),δ13.55,18.61,24.49,39.69,101.16,105.18,108.50,109.65,122.18,127.02(2C),129.02,129.24(2C),131.14,132.62,144.38,146.07,147.60,151.33,157.02,160.58,161.19,163.59.
效果实施例1：抗HIV-1活性测试
采用HIV-1感染的C8166细胞进行细胞水平抗HIV生物活性测试，具体方法描述如下。
细胞毒性实验：化合物对C8166细胞的毒性采用MTT法测定。在96孔细胞培养板中，将化合物进行五倍倍比稀释，每孔加入100μL 4×10 5/mL C8166细胞悬液。每个浓度设置3个复孔。同时设置不含药物的细胞对照及药物Zidovudine(AZT)和Nevirapine(NVP)对照。37℃，15％CO 2培养箱中培养三天，每孔加MTT溶液37℃孵育4小时。每孔再加入10％SDS-50％DMF，37℃，5％CO 2培养箱中孵育过夜。混匀后用BIO-TEK ELx800ELISA仪测定OD值(测定波长：570nm；参考波长：630nm)，根据实验结果绘制计量反应曲线， 计算CC 50(50％细胞产生毒性时的化合物浓度)。
合胞体抑制实验：将4×10 5/mL C8166细胞悬液100μL接种到含化合物五倍倍比稀释的96孔细胞培养板中，加入HIV-1 ⅢB稀释上清(MOI＝0.04)，每个浓度梯度设3个复孔。同时设置不含化合物的HIV-1 ⅢB感染的阴性对照孔和含药物Zidovudine(AZT)和Nevirapine(NVP)的阳性对照孔。37℃，5％CO 2培养箱中培养三天，倒置显微镜下(100×)，选取5个不重叠的视野，计数合胞体数目。根据实验结果绘制计量反应曲线，按Reed&Muench法计算出化合物抑制病毒的50％有效浓度(EC 50，50％有效浓度)。计算公式：致细胞病变抑制率(％)＝(1-实验孔合胞体数/对照孔合胞体数)×100％
本发明用AZT及NVP作对照品，目标化合物对HIV-1 IIIB的抑制活性结果见表1：
表1目标化合物对HIV-1 IIIB的抑制活性数据
Figure PCTCN2019076841-appb-000112
Figure PCTCN2019076841-appb-000113
Figure PCTCN2019076841-appb-000114
Figure PCTCN2019076841-appb-000115
本发明所述的化合物为一类结构新颖的2-硫甲基吡唑嘧啶酮类化合物，由表1可见，该类化合物具有显著的抗HIV活性，其中部分优选化合物EC 50值达到了纳摩尔级。且该类化合物毒性较小，其中I-01、10、13、15、16、22、25、40、49、52、53、55、62-72等样品体外对C8166的CC 50值均大于200μM；因此，本发明所述的2-硫甲基吡唑嘧啶酮类化合物作为一类结构新颖的HIV-RT抑制剂，具有高效低毒的特点。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (18)

  1. 一种如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药：
    Figure PCTCN2019076841-appb-100001
    其中：
    A为S、O、NH或NCH 3；
    R 1为H、C 1-C 6的支链或直链烷基、或C 3-C 6环烷基；
    R 2为H或卤素；
    R 3为H、C 1-C 12的支链或直链烷基、C 3-C 6环烷基、C 6-C 20的芳基、C 2-C 10的杂芳基、被一个或多个R 3a取代的C 6-C 20的芳基或被一个或多个R 3b取代的C 2-C 10的杂芳基；其中，R 3a和R 3b各自独立地选自羟基、硝基、卤素、氨基、氰基、HOS(＝O) 2-、CH 3S(＝O) 2-、C 1-C 6的支链或直链烷基-S(＝O) 2NH-、C 1-C 6的支链或直链烷基、C 1-C 6的支链或直链烷氧基、C 1-C 6的支链或直链烷硫基、C 1-C 6的支链或直链卤代烷基，当R 3a或R 3b为多个时，每个R 3a或每个R 3b相同或不同；
    α环为环己基或被n个相同或不同的R 4取代的苯基，其中，n为0、1、2、3或4；
    R 4为卤素、羟基、氰基、硝基、氨基、C 1-C 6的支链或直链烷基、或C 1-C 6的支链或直链烷氧基。
  2. 如权利要求1所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物，其特征在于，其中，
    当R 1为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基为C 1-C 3的支链或直链烷基；
    当R 1为C 3-C 6环烷基时，所述的C 1-C 6环烷基为环丙基、环丁基、环戊基或环己基；
    当R 2为卤素时，所述的卤素为氟、氯、溴或碘；
    当R 3为C 1-C 12的支链或直链烷基时，所述的C 1-C 12的支链或直链烷基为C 1-C 6的支链或直链烷基；
    当R 3为C 3-C 6环烷基时，所述的C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基；
    当R 3为被一个或多个R 3a取代的C 6-C 20的芳基时，所述的C 6-C 20的芳基为C 6-C 10的芳基；
    当R 3为被一个或多个R 3b取代的C 2-C 10的杂芳基时，所述的C 2-C 10的杂芳基为C 2-C 6的杂芳基；
    当R 3a或R 3b为卤素时，所述的卤素为氟、氯、溴或碘；
    当R 3a或R 3b为C 1-C 6的支链或直链烷基-S(＝O) 2NH-时，所述的C 1-C 6的支链或直链烷基为C 1-C 3的支链或直链烷基；
    当R 3a或R 3b为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基为C 1-C 3的支链或直链烷基；
    当R 3a或R 3b为C 1-C 6的支链或直链烷氧基时，所述的C 1-C 6的支链或直链烷氧基为C 1-C 3的支链或直链烷氧基；
    当R 3a或R 3b为C 1-C 6的支链或直链烷硫基时，所述的C 1-C 6的支链或直链烷硫基为C 1-C 3的支链或直链烷氧基；
    当R 3a或R 3b为C 1-C 6的支链或直链卤代烷基时，所述的C 1-C 6的直链或支链卤代烷基为C 1-C 3的直链或支链卤代烷基；
    当R 3为被一个或多个R 3a取代的苯基时，所述的取代为单取代或双取代；
    当R 4为卤素时，所述的卤素为氟、氯、溴或碘；
    当R 4为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基为C 1-C 3的支链或直链烷基；
    当R 4为C 1-C 6的支链或直链烷氧基时，所述的C 1-C 6的支链或直链烷氧基为C 1-C 3的支链或直链烷氧基；
    当α环为被n个相同或不同的R 4取代的苯基时，n为2，R 4为同时为卤素或C 1-C 6的支链或直链烷基；或者，n为2，其中两个R 4分别为C 1-C 6的支链或直链烷氧基。
  3. 如权利要求1或2所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物，其特征在于，其中，
    当R 1为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基为异丙基、正丙基、乙基或甲基；
    当R 2为卤素时，所述的卤素为氯；
    当R 3为C 1-C 12的支链或直链烷基时，所述的C 1-C 12的支链或直链烷基为C 1-C 4的支 链或直链烷基；
    当R 3为被一个或多个R 3a取代的C 6-C 20的芳基时，所述的C 6-C 20的芳基为苯基；
    当R 3为被一个或多个R 3b取代的C 2-C 10的杂芳基时，所述的C 2-C 10的杂芳基为吡啶基、哒嗪基、嘧啶基、吡嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、嘧啶酮基、噁二唑基、吡啶酮基、或三氮唑基；
    当R 3a或R 3b为C 1-C 6的支链或直链烷基-S(＝O) 2NH-时，所述的C 1-C 6的支链或直链烷基为甲基、乙基、正丙基或异丙基；
    当R 3a或R 3b为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基为甲基、乙基、正丙基或异丙基；
    当R 3a或R 3b为C 1-C 6的支链或直链烷氧基时，所述的C 1-C 6的支链或直链烷氧基为甲氧基、乙氧基、丙氧基或异丙氧基；
    当R 3a或R 3b为C 1-C 6的支链或直链烷硫基时，所述的C 1-C 6的支链或直链烷硫基为甲硫基、乙硫基、丙硫基或异丙硫基；
    当R 3a或R 3b为C 1-C 6的支链或直链卤代烷基时，所述的C 1-C 6的直链或支链卤代烷基为三氟甲基、二氟甲基、1,2-二氟乙基；
    当R 3为被一个或多个R 3a取代的苯基，所述的取代为单取代时，所述的单取代为3-位或4-位取代；所述的取代为双取代时，所述的双取代为2,4-位双取代或3,4-位双取代；
    当R 4为C 1-C 6的支链或直链烷基时，所述的C 1-C 6的支链或直链烷基为甲基、乙基、正丙基或异丙基；
    当R 4为C 1-C 6的支链或直链烷氧基时，所述的C 1-C 6的支链或直链烷氧基为甲氧基、乙氧基、丙氧基或异丙氧基；
    当α环为被n个相同或不同的R 4取代的苯基，n为2，R 4为同时为卤素或C 1-C 6的支链或直链烷基时，R 4为同时为氟、同时为氯、或同时为甲基；或者，n为2，两个R 4分别为C 1-C 6的支链或直链烷氧基时，两个R 4连接成环，即共同构成一个与所述苯基为并环结构的含氧杂环。
  4. 如权利要求1～3中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物，其特征在于，其中，
    当R 3为C 1-C 12的支链或直链烷基时，所述的C 1-C 12的支链或直链烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    当R 3为被一个或多个R 3a取代的C 6-C 20的芳基时，所述的被一个或多个R 3a取代的 C 6-C 20的芳基为
    Figure PCTCN2019076841-appb-100002
    Figure PCTCN2019076841-appb-100003
    当α环为被n个相同或不同的R 4取代的苯基，n为2时，所述的R 4取代在所述苯基的2-位和6-位，或3-位和5-位；
    当α环为被n个相同或不同的R 4取代的苯基，n为2，两个R 4共同构成一个与所述苯基为并环结构的含氧杂环时，其为与所述苯基为并环结构的含氧5-7元杂环。
  5. 如权利要求1～4中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物，其特征在于，其中，
    A为S；
    和/或，α环为
    Figure PCTCN2019076841-appb-100004
    和/或，R 1为H、甲基、乙基或异丙基；
    和/或，R 2为H或Cl；
    和/或，R 3为C 6-C 20的芳基、C 2-C 10的杂芳基、被一个或多个R 3a取代的C 6-C 20的芳基或被一个或多个R 3b取代的C 2-C 10的杂芳基。
  6. 如权利要求1～5中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物，其特征在于，其中，
    当R 3为被一个或多个R 3a取代的C 6-C 20的芳基或被一个或多个R 3b取代的C 2-C 10的杂芳基时，所述的一个或多个为1-6个、1-3个或1-2个。
  7. 如权利要求1～6中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物，其特征在于，其中，
    A为S，α环为
    Figure PCTCN2019076841-appb-100005
    R 1为乙基或异丙基；R 2为H或Cl；R 3为C 6-C 20的芳基、C 2-C 10的杂芳基、被一个或多个R 3a取代的C 6-C 20的芳基或被一个或多个R 3b取代的C 2-C 10的杂芳基；
    或，A为S，α环为
    Figure PCTCN2019076841-appb-100006
    R 1为乙基或异丙基；R 2为H或Cl；R 3为苯基或被一个R 3a取代的苯基，其中，R 3a为羟基、卤素、C 1-C 6的支链或直链烷氧基或C 1-C 6的支链或直链烷硫基；所述的取代为4-位取代；
    或，A为S，α环为环己基，R 1为乙基或异丙基；R 2为H或Cl；R 3为苯基或被一个R 3a取代的苯基，其中，R 3a为羟基、F、Cl、甲氧基或甲硫基；所述的取代为4-位取代。
  8. 如权利要求1～7中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物，其特征在于，其中，
    所述的如式I所示的2-硫甲基吡唑嘧啶酮化合物中的结构单元
    Figure PCTCN2019076841-appb-100007
    为如下任一结构片段：
    Figure PCTCN2019076841-appb-100008
    Figure PCTCN2019076841-appb-100009
  9. 如权利要求1～8中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮化合物类，其特征在于，其为如下任一化合物：
    Figure PCTCN2019076841-appb-100010
    Figure PCTCN2019076841-appb-100011
    Figure PCTCN2019076841-appb-100012
    Figure PCTCN2019076841-appb-100013
    Figure PCTCN2019076841-appb-100014
  10. 一种如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法，其包括以下步骤：在溶剂中，在碱存在的条件下，将中间体6与中间体7进行如下所示的烷基化反应，即可；
    Figure PCTCN2019076841-appb-100015
    其中，A、n、R 1、R 2、R 3、R 4和α环的定义均同权利要求1～9中至少一项所述，X为卤素。
  11. 一种如权利要求10所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法，其还包括以下步骤：在溶剂中，将中间体5与卤化试剂进行卤代反应，得到中间体6即可；
    Figure PCTCN2019076841-appb-100016
    其中，R 2和R 3的定义均同权利要求1～9中至少一项所述，X为卤素。
  12. 一种如权利要求11所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法，其还包括以下步骤：在溶剂中，在还原剂存在的条件下，将中间体4进行还原反应，得到中间体5即可；
    Figure PCTCN2019076841-appb-100017
    其中，R 2和R 3的定义均同权利要求1～9中至少一项所述。
  13. 一种如权利要求12所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物的制备方法，其还包括以下步骤：在溶剂中，将中间体3与卤代试剂进行卤代反应，得到中间体4即可；
    Figure PCTCN2019076841-appb-100018
    其中，R 2和R 3的定义均同权利要求1～9中至少一项所述。
  14. 一种如权利要求1～9中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药在制备非核苷类HIV-1抑制剂中的应用。
  15. 如权利要求14所述的应用，其中，所述的非核苷类HIV-1抑制剂为非核苷类HIV-1 ⅢB抑制剂。
  16. 一种如权利要求1～9中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药在制备治疗和/或预防人类免疫缺陷病毒感染药物中的应用。
  17. 一种药物组合物，其包括治疗有效量的如权利要求1～9中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药，和至少一种药用辅料。
  18. 一种治疗人类免疫缺陷病毒感染疾病的方法，所述的方法包括给予需要其的个体治疗有效量的如权利要求1～9中至少一项所述的如式I所示的2-硫甲基吡唑嘧啶酮类化合物、其N-氧化物、互变异构体、光学异构体、水合物、溶剂化物、多晶型物、其药学上可接受的盐或其前药。
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