WO2017162156A1 - 丙啶磺酰胺类化合物及其使用方法 - Google Patents

丙啶磺酰胺类化合物及其使用方法 Download PDF

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WO2017162156A1
WO2017162156A1 PCT/CN2017/077611 CN2017077611W WO2017162156A1 WO 2017162156 A1 WO2017162156 A1 WO 2017162156A1 CN 2017077611 W CN2017077611 W CN 2017077611W WO 2017162156 A1 WO2017162156 A1 WO 2017162156A1
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amino
chlorophenyl
mmol
fluorophenyl
oxoethyl
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PCT/CN2017/077611
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English (en)
French (fr)
Inventor
祝力
杨艳青
戴丽光
段小伟
杨钊
张慧
胡远东
彭勇
韩永信
赵锐
田心
王善春
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
北京赛林泰医药技术有限公司
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Application filed by 正大天晴药业集团股份有限公司, 连云港润众制药有限公司, 北京赛林泰医药技术有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to US16/087,396 priority Critical patent/US11203586B2/en
Priority to EP17769433.8A priority patent/EP3444237B1/en
Priority to CN201780018417.2A priority patent/CN109071429B/zh
Publication of WO2017162156A1 publication Critical patent/WO2017162156A1/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
    • C07D403/02—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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/22—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C07D203/24—Sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present application relates to propidium sulfonamides for use in the treatment of cancer and methods of use thereof.
  • IDH isocitrate dehydrogenase
  • NAD(+) as an electron acceptor
  • NADP(+) as an electron acceptor
  • IDHs There are five IDHs reported, three of which are NAD(+)-dependent isocitrate dehydrogenases, which are located in the mitochondrial matrix; and two are NADP(+)-dependent isocitrate dehydrogenases, one Located in the mitochondria and the other in the cytoplasm.
  • IDH1mutations At residue p.R132(IDH1(R132))occur frequently in high-grade gliomas but not in other solid tumers.Hum Mutat.30:7-11.].
  • IDH1 mutations are also present in acute myeloid leukemia, prostate cancer, paraganglioma, etc. [Green et al., 2010, Somatic mutations of IDH1 and IDH2in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 362:369-370.]. Bleeker et al found that R132H accounted for 86.9% of the IDH1 mutations.
  • the IDH1m inhibitor AG-120 (ie, ivosidenib) developed by Agios Pharmaceuticals has significant effects on acute myeloid erythroid leukemia, and studies on other malignant solid tumors such as cholangiocarcinoma, chondrosarcoma, and glioma are also underway.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof:
  • W is -(X 1 ) p -(X 2 ) q -(X 3 ) r -;
  • X 1 is selected from C 1-6 alkylene, which may be optionally substituted by one or more groups independently selected from R 5 ;
  • X 2 is selected from C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, which may be optionally substituted by one or more groups independently selected from R 6 ;
  • X 3 is selected from -NR 7 -;
  • p is 0 or 1;
  • q is 0 or 1
  • r is 0 or 1;
  • R 1 is selected from C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, which may be optionally substituted by one or more groups independently selected from R 8 ;
  • R 2 is selected from phenyl or contains from 1 to 2, 5-6 membered heteroaryl selected from N, O or S atoms, which may be optionally substituted by one or more groups independently selected from R 9 ;
  • R 3 and R 4 is independently selected from halogen, amino, hydroxy, halo C 1-3 alkyl or C 1-6 alkyl;
  • R 5 , R 6 and R 8 are each independently selected from halogen, amino, hydroxy, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 cycloalkyl;
  • R 7 is selected from hydrogen, C 1-3 alkyl or an amino protecting group
  • R 9 is selected from the group consisting of halogen, amino, hydroxy, cyano, halo C 1-3 alkyl or aminosulfonyl;
  • n 0 or 1
  • n 0 or 1.
  • each R 4 is independently selected from fluoro, chloro, bromo or trifluoromethyl.
  • the application provides a compound of Formula I-1, or a pharmaceutically acceptable salt, solvate or hydrate thereof:
  • the application provides a compound of Formula I-2, or a pharmaceutically acceptable salt, solvate or hydrate thereof:
  • a compound of the formula II or a pharmaceutically acceptable salt, solvate or hydrate thereof is provided:
  • W is -(X 1 ) p -(X 2 ) q -(X 3 ) r -;
  • X 1 is selected from C 1-6 alkylene, which may be optionally substituted by one or more groups independently selected from R 5 ;
  • X 2 is selected from C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, which may be optionally substituted by one or more groups independently selected from R 6 ;
  • X 3 is selected from -NR 7 -;
  • p is 0 or 1;
  • q is 0 or 1
  • r is 0 or 1;
  • R 1 is selected from C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, which may be optionally substituted by one or more groups independently selected from R 8 ;
  • R 2 is selected from phenyl or contains from 1 to 2, 5-6 membered heteroaryl selected from N, O or S atoms, which may be optionally substituted by one or more groups independently selected from R 9 ;
  • Each R 3 is independently selected from halogen, amino, hydroxy, halo C 1-3 alkyl or C 1-6 alkyl;
  • R 5 , R 6 and R 8 are each independently selected from halogen, amino, hydroxy, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 cycloalkyl;
  • R 7 is selected from hydrogen, C 1-3 alkyl or an amino protecting group
  • R 9 is selected from the group consisting of halogen, amino, hydroxy, cyano, halo C 1-3 alkyl or aminosulfonyl;
  • n 0 or 1.
  • X 1 is selected from C 1-6 alkylene.
  • X 1 is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 CH 2 -, -CH (CH 3 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 ) CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 CH 2
  • X 1 is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - or -CH (CH 3 )-.
  • X 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • X 2 is selected from pyrrolidinyl, cyclobutyl, or azetidinyl.
  • X 2 is selected from
  • X 3 is selected from -NH -, - N (CH 3 ) - or -N (Boc) -.
  • X 1 is selected from C 1-6 alkylene
  • X 2 is selected from pyrrolidinyl, cyclobutyl, or azetidinyl
  • X 3 is selected from -NR 7 -.
  • X 1 is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - or -CH (CH 3 )-;
  • X 2 is selected from X 3 is selected from -NR 7 -.
  • W is -CH 2 NR 7 -, CH(CH 3 )NR 7 -, -CH 2 CH 2 NR 7 -, -CH 2 CH 2 CH 2 NR 7 ,- CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -,
  • W is -CH 2 -, - CH 2 NH -, - CH 2 N (CH 3) -, - CH 2 N (Boc) -, - CH (CH 3) NH-, -CH 2 CH 2 -, -CH 2 CH 2 NH-, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 NH-, -CH 2 CH 2 CH 2 CH 2 -,
  • R 1 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Or pyrrolidinyl or piperidinyl, which may be optionally substituted by one or more groups independently selected from R 8 ; R 8 is selected from halogen. Further R 1 is selected from cyclobutyl or cyclohexyl, which may be optionally substituted by 1 or 2 independently fluoro groups; further R 1 is
  • R ⁇ 1> is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl, which may be optionally separated by one or more Substituted from a group selected from R 8 .
  • R ⁇ 1> is selected from cyclobutyl or cyclohexyl, which may be optionally substituted with 1 or 2 separate fluoro groups.
  • R 1 is selected from
  • R 1 is selected from
  • R 8 is selected from halo.
  • R 2 is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, pyrazole Or imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, which may optionally be Or a plurality of groups independently selected from R 9 ; R 9 is selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoro Ethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl
  • R 2 is selected from phenyl or pyridyl, which may be optionally substituted by one or more groups independently selected from R 9 ;
  • R 9 is selected from halogen, cyano, trifluoromethyl or -SO 2 NH 2 .
  • R 2 is selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazole group, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, which may be optionally substituted with one or more groups independently selected from R 9 substituents.
  • R 2 is selected from phenyl or pyridinyl, which may optionally be substituted with one or more substituents independently selected from R 9 in group.
  • R 9 is selected from halo, cyano, fluoromethyl, difluoromethyl, trifluoromethyl group, a fluoroethyl, difluoroethyl, trifluoroethyl , tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl or aminosulfonyl.
  • R 9 is selected from halogen, cyano, trifluoromethyl, or -SO 2 NH 2.
  • R 2 is selected from
  • each R 3 is independently selected from methyl, ethyl, propyl, isopropyl or t-butyl.
  • each R 3 is independently selected from methyl or isopropyl.
  • R 7 is selected from hydrogen, methyl, ethyl, t-butoxycarbonyl, benzyloxycarbonyl, tosyl, trityl, formyl, 2-biphenyl Keto-2-propoxycarbonyl or trifluoroacetyl.
  • R 7 is selected from hydrogen, methyl, tert-butoxycarbonyl group or benzyloxycarbonyl group.
  • a compound of the formula II-1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is provided:
  • the present application is preferably the following compounds and pharmaceutically acceptable salts, solvates or hydrates thereof:
  • the present invention preferably comprises the following compounds and pharmaceutically acceptable salts, solvates or hydrates thereof:
  • compositions of the present application provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more pharmaceutically acceptable Carrier or excipient.
  • the pharmaceutical compositions of the present application may further comprise one or more additional therapeutic agents.
  • Another aspect of the present application provides a method of treating a cancer induced by an IDH1 mutation having a R132X mutation; in some embodiments, the R132X mutation is selected from the group consisting of R132H, R132C, R132L, R132V, R132S, and R132G; In some preferred embodiments, the R132X mutation is selected from the group consisting of R132H; the method comprising administering a therapeutically effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof.
  • Another aspect of the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a cancer induced by an IDH1 mutation.
  • Another aspect of the present application provides a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof, for treating cancer induced by an IDH1 mutation.
  • the cancer induced by the IDH1 mutation is selected from the group consisting of: glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN) Acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma or vascular immunoblastic non-Hodgkin's lymphoma (NHL).
  • glioblastoma glioma
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML Acute myeloid leukemia
  • sarcoma melanoma
  • non-small cell lung cancer chondrosarcoma
  • cholangiocarcinoma cholangiocarcinoma
  • vascular immunoblastic non-Hodgkin's lymphoma NDL
  • the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN), acute myeloid leukemia (AML), cholangiocarcinoma, chondrosarcoma Or angioimmunoblastic non-Hodgkin's lymphoma (NHL) or the like, preferably including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), glioma, cholangiocarcinoma or chondrosarcoma.
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • cholangiocarcinoma chondrosarcoma
  • NDL angioimmunoblastic non-Hodgkin's lymphoma
  • AML acute myeloid leukemia
  • MDS myelodysplastic
  • the compound of Formula I or Formula II provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, has a very good inhibitory activity against IDH1 enzyme, and its activity is comparable to or better than AG-120 activity, and has very good
  • the in vivo metabolic level and very long half-life in vivo are expected to be more suitable for the treatment of cancers induced by IDH1 mutations.
  • the pharmaceutical composition of the present application can be prepared by combining a compound of the present application, or a pharmaceutically acceptable salt, solvate or hydrate thereof, with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid state.
  • a suitable pharmaceutically acceptable carrier for example, it can be formulated into a solid, semi-solid, liquid state.
  • gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administration of a compound of the present application, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation , parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers such carriers.
  • pharmaceutically acceptable carriers such carriers.
  • These carriers enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, solutions, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the sugar coating agent can be optionally selected according to methods generally known in the practice of pharmaceuticals.
  • the core is coated, especially with an enteric coating.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compound of Formula I or Formula II described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, can be administered by any suitable route and method, for example by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically effective amount of a compound of Formula I or Formula II is from about 0.0001 to 20 mg/Kg body weight per day, such as from 0.001 to 10 mg/Kg body weight per day.
  • the dosage frequency of the compound of Formula I or Formula II is determined by the needs of the individual patient, for example, one or two times per day, or more times per day. Administration can be intermittent, for example, wherein the patient receives a daily dose of a compound of Formula I or Formula II over a period of several days, followed by a patient not receiving Formula I or Formula II over a period of several days or more The daily dose of the compound.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn means having mn carbon atoms in this moiety.
  • C 3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.
  • C 0-6 alkylene group means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond.
  • C 1-10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.
  • the group herein is not limited to the loss of one hydrogen atom to form a monovalent group; in some cases, two hydrogen atoms may be lost to form a divalent group.
  • -X 1 -X 2 -X 3 - wherein X 2 is a divalent group formed after the loss of two hydrogen atoms, in which case the group of X 2 is defined as a common substituent, and should also be understood as A divalent group.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), that is, an atom other than carbon and hydrogen or an atomic group containing the same, and the hetero atom is independently selected from the group consisting of oxygen, nitrogen, sulfur, Phosphorus, silicon, germanium, aluminum, boron.
  • the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • halogen refers to any group of fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • amino refers to -NH 2 , -NH(alkyl) and -N(alkyl) 2 , and specific examples of the amino group include, but are not limited to, -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , - N(CH 3 ) 2 , -NHC 2 H 5 , -N(CH 3 )C 2 H 5 and the like.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, ⁇ , ⁇ , etc.
  • the specific alkyl group includes all of its isomeric forms, for example, the propyl group includes -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , for example, butyl includes -CH 2 CH 2 CH 2 CH 3 ,- CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 .
  • C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having from 1 to 3 carbon atoms.
  • the "alkyl”, “C 1-8 alkyl”, “C 1-6 alkyl” or “C 1-3 alkyl” may be unsubstituted or selected from one or more selected from the group consisting of hydroxyl, halogen or Substituent substitution of an amino group.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl; for example, the term “halo C 1-3 alkyl” is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl. And 3-bromopropyl and the like.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkylene refers to a divalent alkyl group, e.g. -CH 2 -, - CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, the alkylene group may be unsubstituted or substituted with one or more Substituents substituted from halogen, amino, hydroxy, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 cycloalkyl.
  • cycloalkyl refers to an all-carbon monocyclic saturated hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as a C 3-20 cycloalkyl group, preferably a C 3-6 cycloalkyl group, such as a cyclopropyl group, a ring. Butyl, cyclopentyl, cyclohexyl and the like.
  • the cycloalkyl group may be unsubstituted or substituted, and the substituent includes, but is not limited to, an alkyl group, an alkyloxy group, a cyano group, a carboxyl group, an aryl group, a heteroaryl group, an amino group, a halogen, a sulfonyl group. , sulfinyl, phosphoryl and hydroxy.
  • heteromatic ring refers to a monocyclic or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or Four ring atoms selected from N, O, and S, the remaining ring atoms are C, and have a fully conjugated ⁇ -electron system.
  • heteroaryl refers to a group remaining after the "heteroaryl ring" molecule has one hydrogen atom removed, and the heteroaryl group may be unsubstituted or substituted, including but not limited to alkyl, alkyl. Oxyl, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and heteroalicyclic.
  • Non-limiting examples of non-substituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazinyl.
  • heteroalicyclic refers to a monocyclic or fused ring having from 3 to 12 ring atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1 or The two ring atoms are heteroatoms selected from N, O, S(O) n (where n is 0, 1, or 2), and the remaining ring atoms are C.
  • Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • Examples of 3-membered saturated heteroalicyclic rings include, but are not limited to Examples of 4-membered saturated heteroalicyclic rings include, but are not limited to, Examples of 5-membered saturated heteroalicyclic rings include, but are not limited to Examples of 6-membered saturated heteroalicyclic rings include, but are not limited to Examples of 7-membered saturated heteroalicyclic rings include, but are not limited to Examples of 5-membered unsaturated heteroalicyclic rings include, but are not limited to Examples of 6-membered unsaturated heteroalicyclic rings include, but are not limited to
  • heterocycloalkyl refers to a group remaining after the "heteroalicyclic" molecule has one hydrogen atom removed, and the heterocycloalkyl group may be unsubstituted or the hydrogen atom therein may be optionally substituted with a substituent.
  • amino protecting group means that the amino hydrogen is substituted by one or two protecting groups including, but not limited to, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyl.
  • Ethoxycarbonyl methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, pivaloyl, benzoyl, Trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl.
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • DCM dichloromethane
  • Boc- means a tert-butoxycarbonyl group.
  • DIAD means diisopropyl azodicarboxylate.
  • TFA trifluoroacetic acid
  • DIEA N,N-diisopropylethylamine
  • TAA triethylamine
  • m-CPBA means m-chloroperoxybenzoic acid.
  • PE petroleum ether
  • EA means ethyl acetate
  • Dess-Martin oxidant means (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodo-3(1H)-one.
  • Ugi reaction refers to a multicomponent reaction in which a molecule of an aldehyde or a ketone, a molecule of an amine, a molecule of an isonitrile, and a molecule of a carboxylic acid condense to form an a-amidoamide.
  • Mitsunobu reaction means that the alcoholic hydroxyl group is replaced by a nucleophile by the action of diethyl azodicarboxylate (DEAD) and triphenylphosphine, while the carbon atom configuration attached to the hydroxyl group is reversed.
  • DEAD diethyl azodicarboxylate
  • triphenylphosphine triphenylphosphine
  • pharmaceutically acceptable is in the sense of those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • the pharmaceutically acceptable salts of the present application 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.
  • Certain compounds of the present application may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present application. Certain compounds of the present application may exist in polycrystalline or amorphous form.
  • Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and individual isomers are included within the scope of this application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present application, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixture thereof Mixtures and other mixtures, such as enantiomeric or diastereomeric enriched mixtures, all of which are within the scope of the present application. 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 this application.
  • 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 one enantiomer of a compound of the present application 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 purity. 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 application 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). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • pharmaceutically acceptable carrier refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, including, but not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like.
  • 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.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • W, R 1 , R 2 , R 3 and n are as defined for the compound of formula II.
  • the isonitrile compound 1, o-chlorobenzaldehyde 2, amino compound 3, and propidium sulfonamide carboxylic acid compound 7 are directly subjected to Ugi reaction to obtain a propidium sulfonamide compound of formula II.
  • Figure 1 is a graph showing the binding mode analysis of the compound of Example 10 and IDH1 (R132H).
  • the temperature is Celsius.
  • the reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing Belling Technology Co., Ltd., and these reagents can be used directly without further purification unless otherwise stated.
  • reaction vessel is provided with a rubber septum to add substrate and reagents via a syringe; glassware is dried and/or Heat and dry.
  • the column chromatography was performed using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; the thin layer chromatography was used to separate the thin layer chromatography silica gel prefabricated panels (HSGF254) produced by Yantai Chemical Industry Research Institute; the measurement of MS was performed by Thermo LCQ.
  • Nuclear magnetic data ( 1 H-NMR) was run at 400 MHz using a Varian apparatus unless otherwise stated.
  • the solvent used for the nuclear magnetic data is CDCl 3 , CD 3 OD, D 2 O, DMSO-d 6 , etc., based on tetramethylsilane (0.00 ppm) or based on residual solvent (CDCl 3 : 7.26 ppm; CD 3 OD : 3.31 ppm; D 2 O: 4.79 ppm; DMSO-d 6 : 2.50 ppm).
  • Example 1 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-( 3-fluorophenyl)acetamide
  • Step B 2-(2-Chlorophenyl)-N-cyclohexyl-2-(2-(1,3-dioxoisoindol-2-yl)-N-(3-fluorophenyl) Acetylamino)acetamide
  • O-chlorobenzaldehyde (187.4 ⁇ L, 1.66 mmol) was added to a solution of 3-fluoroaniline (160 ⁇ L, 1.66 mmol) in methanol under stirring at room temperature. After 15 min, N-phthaloylglycine (341.4 mg, 1.66 mmol), after the reaction was continued for 30 minutes, cyclohexyl isocyanide (207 ⁇ L, 1.66 mmol) was added, and the mixture was reacted at room temperature overnight, concentrated by distillation under reduced pressure, and purified by column chromatography on silica gel column to give 2-(2-chlorophenyl)-N. -cyclohexyl-2-(2-(1,3-dioxoisoindol-2-yl)-N-(3-fluorophenyl)acetamido)acetamide (708 mg, yield 78%).
  • Step C 2-Amino-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3-fluorophenyl)acetamide
  • reaction solution is then heated to 90 ° C overnight, filtered, concentrated in vacuo, and purified by column chromatography on silica gel column to give 2-amino-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2- Oxoethyl)-N-(3-fluorophenyl)acetamide (290 mg, yield 95%).
  • Step D 2-((N-(2-Chloroethyl)aminosulfonyl)amino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl )-N-(3-fluorophenyl)acetamide
  • Step E 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3 -fluorophenyl)acetamide
  • Step A (2S)-1-((1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)(3-fluorophenyl)amino)-1-oxo Propane-2-yl-carbamic acid tert-butyl ester
  • Step B (2S)-2-Amino-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3-fluorophenyl)propene Amide
  • (2S)-1-((1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)(3-fluorophenyl)amino) -1-oxopropane To a solution of tert-butyl-2-carbamic acid (1.14 g, 2.141 mmol) in EtOAc. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc.
  • Step C (2S)-2-((N-(2-chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2- Oxoethyl)-N-(3-fluorophenyl)propanamide
  • Step D (2S)-2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)- N-(3-fluorophenyl)propanamide
  • (2S)-2-((N-(2-chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino) To a solution of 2-oxoethyl)-N-(3-fluorophenyl)propanamide (110 mg, 0.192 mmol) in EtOAc. After completion of the reaction, water was added, and the mixture was evaporated.
  • Step A (2R)-1-((1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)(3-fluorophenyl)amino)-1-oxo Propane-2-yl-carbamic acid tert-butyl ester
  • Step B (2R)-2-Amino-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3-fluorophenyl)propene Amide
  • Step C (2R)-2-((N-(2-chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2- Oxoethyl)-N-(3-fluorophenyl)propanamide
  • Step D (R)-2-(Aziridine-1-sulfonylamino)-N-((R)-1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxo Ethyl)-N-(3-fluorophenyl)propanamide (Example 3)
  • EtOAcjjjjjjjjjjjjjj Amido)-N-((R)-1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3-fluorophenyl)propanamide (46mg , yield 48%) and (R)-2-(aziridine-1-sulfonylamino)-N-((S)-1-(2-chlorophenyl)-2-(cyclohexylamino)- 2-oxoethyl)-N-(3-fluorophenyl)propanamide (46 mg, yield 48%).
  • Step A 3-((1-(2-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)(3-fluorophenyl)amino)-3-oxopropyl)amino Tert-butyl formate
  • Step B 3-Amino-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3-fluorophenyl)propanamide
  • Step C 3-((N-(2-Chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl )-N-(3-fluorophenyl)propanamide
  • Step D 3-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3 -fluorophenyl)propionamide
  • Step B Methyl 3-(N-(2-chloroethyl)aminosulfonyl)propanoate
  • Step C 3-(Aziridine-1-ylsulfonyl)propionic acid
  • Step D 3-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3 -fluorophenyl)propionamide
  • Example 7 2-((1-(2-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)(3-fluorophenyl)amino)-2-oxoethyl) (((R)-2-Isopropylaziridine-1-yl)sulfonyl)carbamic acid tert-butyl ester
  • Step A (R)-N-(1-Hydroxy-3-methylbutan-2-yl)sulfamoylcarbamic acid tert-butyl ester
  • Boc-sulfamoyl chloride (1.15 g, 5.33 mmol) was added dropwise to a solution of D-prolinol (500 mg, 4.85 mmol) and triethylamine (1.35 mL, 9.69 mmol) in dichloromethane (15 mL). The dichloromethane solution was then allowed to warm to room temperature for 1 hour. After completion of the reaction, the reaction was neutralized with 1N HCl, and then the organic layer was separated, and the solid product (R)-N-(1-hydroxy-3-methylbut-2-yl)sulfamoylcarbamic acid tert-butyl ester was precipitated. 750 mg, yield 55%).
  • Step B tert-butyl (R)-2-isopropylaziridine-1-ylsulfonylcarbamate
  • Step C 2-((1-(2-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)(3-fluorophenyl)amino)-2-oxoethyl) ((R)-2-Isopropylaziridine-1-yl)sulfonyl)carbamic acid tert-butyl ester
  • Example 8 3-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- Oxoethyl)-N-(3-fluorophenyl)propanamide
  • Step A 3-((1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3-fluorophenyl)amino) Tert-butyl 3-oxopropyl]carbamate
  • 1,1-difluoro-3-isocyanocyclobutane (prepared by the method described in the patent CN201180043254.6) (1.0 g, 8.54 mmol) gave 3-((1- (2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3-fluorophenyl)amino)-3-oxopropyl]amino Tert-butyl formate (2.33 g, yield 62%).
  • Step B 3-Amino-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3- Fluorophenyl)propionamide
  • step B in Example 5 from 3-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)) -Fluorophenyl)amino)-3-oxopropyl]carbamic acid tert-butyl ester (2.33 g, 4.32 mmol) gave 3-amino-N-(1-(2-chlorophenyl)-2-(3 , 3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)propanamide (900 mg, yield 47%).
  • Step C 3-((N-(2-Chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)) Amino)-2-oxoethyl)-N-(3-fluorophenyl)propanamide
  • Step D 3-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo Alkenyl)-N-(3-fluorophenyl)propanamide
  • Example 10 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- Oxoethyl ⁇ -N-(3-fluorophenyl)acetamide
  • Step A 2-((N-(2-Chloroethyl)sulfonylamino)amino)acetic acid tert-butyl ester
  • Step B 2-((N-(2-chloroethyl)aminosulfonyl)amino)acetic acid
  • Step C 2-((N-(2-Chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)) Amino)-2-oxoethyl)-N-(3-fluorophenyl)acetamide
  • Step D 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo Alkenyl ⁇ -N-(3-fluorophenyl) Acetamide
  • Example 11 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- Oxoethyl)-N-(5-fluoropyridin-3-yl)acetamide
  • Step A 2-((N-(2-Chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutane) Amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)acetamide
  • Step B 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo Alkenyl)-N-(5-fluoropyridin-3-yl)acetamide
  • the synthesis procedure was the same as in the step E of Example 1, from 2-((N-(2-chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-(3 ,3-difluorocyclobutane)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)acetamide (46 mg, 0.081 mmol) Sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridine -3-yl)acetamide (4 mg, 9.3% yield).
  • Step B 2-(2-oxazolidinone-3-sulfonylamino)acetic acid tert-butyl ester
  • 2-Oxoxazolidinone-3-sulfonyl chloride (3.68 g, 19.83 mmol), glycine tert-butyl ester (2.60 g, 19.82 mmol) and triethylamine (2.00 g, 39.64) were added to 200 mL of dichloromethane at 0 °C. (mmol), warmed to room temperature and stirred overnight.
  • Step C 2-(N-Methyl-2-oxazolidinone-3-sulfonylamino)acetic acid tert-butyl ester
  • Step D 2-(N-Methyl-2-oxazolidinone-3-sulfonylamino)acetic acid
  • Step E 2-(2-Chlorophenyl)-N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(N-methyl-2-oxazolidinone-3-sulfonamide Acetylamino)acetamide
  • O-chlorobenzaldehyde (69 ⁇ L, 0.61 mmol) and m-fluoroaniline (59 ⁇ L, 0.61 mmol) were added to 10 mL of methanol at room temperature. After stirring for 10 minutes, 2-(N-methyl-2-oxazolidinone-3- was added. The sulfonylamino)acetic acid (145 mg, 0.61 mmol) was stirred for ten minutes then cyclohexyl isocyanide (67 mg, 0.61 mmol) was added and stirred at room temperature overnight.
  • Step F 2-(2-Chlorophenyl)-N-cyclohexyl-2-(N-(3-fluorophenyl)-2-((N-(2-hydroxyethyl))sulfonamide) Amino)acetamido)acetamide
  • Step G 2-(2-Chlorophenyl)-N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(N-methylaziridine-1-sulfonylamino)acetamido Acetamide
  • Example 13 4-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- Oxoethyl)-N-(3-fluorophenyl)butanamide
  • Step A Methyl 4-((N-(2-chloroethyl)aminosulfonyl)amino)butanoate
  • Step B 4-(Aziridine-1-sulfonylamino)butyric acid
  • Step C 4-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo Alkenyl)-N-(3-fluorophenyl)butanamide
  • O-chlorobenzaldehyde 46 ⁇ L, 0.405 mmol was added to a solution of 3-fluoroaniline (39 ⁇ L, 0.405 mmol) in methanol under stirring at room temperature. After reacting for 15 minutes, 4-(aziridine-1-sulfonylamino) was added. Butyric acid (90 mg, 0.432 mmol), and the reaction was continued for 30 minutes. Then, 1,1-difluoro-3-isocyanocyclobutane (47 mg, 0.405 mmol) was added, and the mixture was reacted at room temperature overnight, and concentrated under reduced pressure.
  • Example 14 3-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- Oxoethyl)-N-(3-fluorophenyl)propanamide
  • Step B Methyl 2-(N-(2-chloroethyl)aminosulfonyl)acetate
  • Methyl 2-(N-(2-chloroethyl)aminosulfonyl)acetate (3.22 g) was obtained from ethyl 2-(chlorosulfonyl)acetate (14.7 g, 85.2 mmol). , yield 18%).
  • Step D 2-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3 -fluorophenyl)acetamide
  • Example 16 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-( 3,5-difluorophenyl)acetamide
  • Step A 2-((N-(2-Chloroethyl)aminosulfonyl)amino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl )-N-(3,5-difluorophenyl)acetamide
  • Step B 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3 ,5-difluorophenyl)acetamide
  • Example 17 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-( 5-fluoropyridin-3-yl)acetamide
  • Step A 2-((N-(2-Chloroethyl)aminosulfonyl)amino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl )-N-(5-fluoropyridin-3-yl)acetamide
  • Step B 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(5 -fluoropyridin-3-yl)acetamide
  • Example 18 (S)-1-(Aziridine-1-ylsulfonyl)-N-((R)-1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxo Ethyl ethyl)-N-(3-fluorophenyl)pyrrolidine-2-carboxamide
  • Step A (S)-1-(N-(2-Chloroethyl)aminosulfonyl)pyrrolidine-2-carboxylic acid tert-butyl ester
  • Step B (S)-1-(N-(2-chloroethyl)aminosulfonyl)pyrrolidine-2-carboxylic acid
  • Step C (S)-1-(N-(2-chloroethyl)aminosulfonyl)-N-((R)-1-(2-chlorophenyl)-2-cyclohexylamino-2-oxo Alkenyl)-N-(3-fluorophenyl)pyrrolidine-2-carboxamide (C1)
  • Step D (S)-1-(aziridine-1-ylsulfonyl)-N-((R)-1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxo Ethyl)-N-(3-fluorophenyl)pyrrolidine-2-carboxamide (Example 18)
  • (S)-1-(aziridine-1-ylsulfonyl)-N-((S)-1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl) -N-(3-Fluorophenyl)pyrrolidine-2-carboxamide can be prepared from C2 by the same method.
  • Step B Methyl 5-(N-(2-chloroethyl)aminosulfonyl)pentanoate
  • Methyl 5-(N-(2-chloroethyl)aminosulfonyl)pentanoate (335 mg) was obtained from methyl 5-(chlorosulfonyl)pentanoate (700 mg, 3.26 mmol). , yield 40%).
  • Step D 5-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3 -fluorophenyl)pentanamide
  • Example 21 4-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-( 3-fluorophenyl)butanamide
  • Step A a mixture of ethyl 4-(chlorosulfonyl)butanoate and ethyl 4-(bromosulfonyl)butanoate
  • Step B ethyl 4-(N-(2-chloroethyl)aminosulfonyl)butanoate
  • Step C 4-(Aziridine-1-ylsulfonyl)butyric acid
  • Step D 4-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-(3 -fluorophenyl)butanamide
  • Step C N-(1-(2-Chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-3-(1,3-dioxoisoindol-2-yl)- N-(3-fluorophenyl)cyclobutylformamide
  • Step D 3-Amino-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-(3-fluorophenyl)cyclobutylcarboxamide
  • Step E 3-((N-(2-Chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)- N-(3-fluorophenyl)-cyclobutylformamide
  • Step F 3-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-(3-fluoro Phenyl)cyclobutylformamide
  • Step A 2-((N-(2-Chloroethyl)sulfonylamino)amino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)) Amino)-2-oxoethyl)-N-(3-trifluoromethylphenyl)acetamide
  • Step B 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo Ethyl ethyl)-N-(3-trifluoromethylphenyl)acetamide
  • Example 24 1-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-(3- Fluorophenyl)azetidin-3-carboxamide
  • Step A 3-((1-(2-Chlorophenyl))-2-(cyclohexylamino)-2-oxoethyl)(3-fluorophenyl)carbamoyl)azetidine- 1-carboxylic acid tert-butyl ester
  • Step B N-(1-(2-Chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-(3-fluorophenyl)azetidin-3-carboxamide
  • Step C 1-(N-(2-Chloroethyl)aminosulfonyl)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-( 3-fluorophenyl)-azetidine-3-carboxamide
  • Step D 1-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-(3-fluoro Phenyl)azetidin-3-carboxamide
  • Example 25 (S)-2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino group )-2-oxoethyl)-N-(3-fluorophenyl)acetamide
  • Step B (S)-2-[(1-(4-Methoxyphenyl)ethyl)amino]acetic acid benzyl acetate
  • Step C (S)-2-(N-(1-(4-Methoxyphenyl)ethyl)-2-oxazolidinone-3-sulfonylamino)acetic acid benzyl acetate
  • EtOAc EtOAc
  • EtOAc Benzyl 1-(4-methoxyphenyl)ethyl)-2-oxazolidinone-3-sulfonylamino)acetate (2.1 g, yield 64%).
  • Step D (S)-2-(N-(1-(4-methoxyphenyl)ethyl)-2-oxazolidinone-3-sulfonylamino)acetic acid
  • Step E (S)-2-(2-Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-(N-( (S)-1-(4-methoxyphenyl)ethyl)-2-oxazolidinone-3-sulfonylamino)acetamido)acetamide
  • Step F (S)-2-(2-Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-((N- (2-hydroxyethyl)aminosulfonyl)((S)-1-(4-methoxyphenyl)ethyl)amino)acetamido)acetamide
  • EtOAc Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-((N-(2-hydroxyethyl)aminosulfonyl) ( (S)-1-(4-Methoxyphenyl)ethyl)amino)acetamido)acetamide (41 mg, yield 72%).
  • Step G (S)-2-(2-Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-((N- (2-hydroxyethyl)aminosulfonyl)amino)acetamido)acetamide
  • Step H (S)-2-((N-(2-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo) (3-fluorophenyl)amino)-2-oxoethyl)sulfamoyl)amino)ethyl 4-methylbenzenesulfonate
  • Step I (S)-2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino) -2-oxoethyl)-N-(3-fluorophenyl)acetamide
  • Example 26 (R)-2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino group )-2-oxoethyl)-N-(3-fluorophenyl)acetamide
  • Step A (R)-2-(2-Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-(N-( (S)-1-(4-methoxyphenyl)ethyl)-2-oxazolidinone-3-sulfonylamino)acetamido)acetamide
  • Step B (R)-2-(2-Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-((N- (2-hydroxyethyl)aminosulfonyl)((S)-1-(4-methoxyphenyl)ethyl)amino)acetamido)acetamide
  • EtOAc Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-((N-(2-hydroxyethyl)aminosulfonyl) ( (S)-1-(4-Methoxyphenyl)ethyl)amino)acetamido)acetamide (32 mg, yield 76%).
  • Step C (R)-2-(2-Chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-(N-(3-fluorophenyl)-2-((N- (2-hydroxyethyl)aminosulfonyl)amino)acetamido)acetamide
  • Step D (R)-2-((N-(2-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo) (3-fluorophenyl)amino)-2-oxoethyl)aminosulfonyl)amino)ethyl 4-methylbenzenesulfonate
  • Step E (R)-2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino) -2-oxoethyl)-N-(3-fluorophenyl)acetamide
  • Example 27 1-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-(3- Fluorophenyl)pyrrolidine-3-carboxamide
  • Step A 3-((1-(2-Chlorophenyl)-2-cyclohexylamino-2-oxoethyl)(3-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step B 1-(N-(2-Chloroethyl)sulfamoyl)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-( 3-fluorophenyl)pyrrolidine-3-carboxamide
  • Step C 1-(Aziridine-1-ylsulfonyl)-N-(1-(2-chlorophenyl)-2-cyclohexylamino-2-oxoethyl)-N-(3-fluoro Phenyl)pyrrolidine-3-carboxamide
  • Example 28 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- Oxoethyl)-N-(3-aminosulfonylphenyl)acetamide
  • Step A 2-((N-(2-Chloroethyl)aminosulfonyl)amino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)) Amino)-2-oxoethyl)-N-(3-aminosulfonylphenyl)acetamide
  • Step B 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo Alkenyl)-N-(3-aminosulfonylphenyl)acetamide
  • Example 29 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- Oxoethyl)-N-(3,4-difluorophenyl)acetamide
  • Step A 2-((N-(2-Chloroethyl)aminosulfonyl)amino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)) Amino)-2-oxoethyl)-N-(3,4-difluorophenyl)acetamide
  • Step B 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo Alkenyl)-N-(3,4-difluorophenyl)acetamide
  • Example 30 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoethyl -N-(3-fluorophenyl)acetamide
  • Step A tert-Butyl 4-oxocyclohexylcarbamate
  • Dess-Martin oxidant 29.0 g, 68.3 mmol was added dropwise to a solution of N-4-Boc-aminocyclohexanol (9.8 g, 45.52 mmol) in dichloromethane (200 mL). The temperature was raised to room temperature and the reaction mixture was stirred overnight. Cautiously quenched with aq. EtOAc EtOAc EtOAc. Tert-butyl cyclohexylcarbamate (7.96 g, yield 82.1%).
  • Step B tert-butyl (4,4-difluorocyclohexyl)carbamate
  • Diethylaminosulfur trifluoride (8.54 g, 52.981 mmol) was added dropwise to a solution of tert-butyl 4-oxocyclohexylcarbamate (7.96 g, 37.323 mmol) in dichloromethane with stirring. (200 mL) solution was slowly warmed to room temperature and the reaction mixture was stirred overnight. Cautiously quenched with aq. aq. EtOAc EtOAc (EtOAc m. Tert-butyl difluorocyclohexyl)carbamate (about 70%) and tert-butyl 4-fluorocyclohexyl-3 alkenylcarboxylate (about 30%).
  • Step F 2-(N-(2-Chloroethyl)aminosulfonylamino)-N-(1-(2-chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2- Oxoethyl)-N-(3-fluorophenyl)acetamide
  • Step G 2-(Aziridine-1-sulfonylamino)-N-(1-(2-chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoethyl )-N-(3-fluorophenyl)acetamide
  • Step B Methyl (R)-2-(2-methylaziridine-1-sulfonylamino)acetate
  • Step D 2-(2-Chlorophenyl)-N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(((R)-2-methylaziridine)-1- Sulfonamide)acetamido)acetamide
  • 2-(2-Chlorophenyl)-N was obtained from (R)-2-(2-methylaziridine-1-sulfonylamino)acetic acid (20 mg, 0.103 mmol). -cyclohexyl-2-(N-(3-fluorophenyl)-2-(((R)-2-methylaziridine)-1-sulfonamido)acetamido)acetamide (45 mg, yield 81%).
  • Example 32 2-(2-Chlorophenyl)-N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(((S)-2-methylaziridine)-1 -sulfonamido)acetamido)acetamide
  • Step A (S)-methyl 2-(2-methylaziridine-1-sulfonylamino)acetate
  • Step B (S)-2-(2-Methylaziridine-1-sulfonylamino)acetic acid
  • (S)-2-(2-) was obtained from methyl (S)-2-(2-methylaziridine-1-sulfonylamino)acetate (95 mg, 0.457 mmol). Methyl aziridine-1-sulfonylamino)acetic acid (80 mg, yield 90%).
  • Step C 2-(2-Chlorophenyl)-N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(((S)-2-methylaziridine)-1- Sulfonamide)acetamido)acetamide
  • 2-(2-Chlorophenyl)-N was obtained from (S)-2-(2-methylaziridine-1-sulfonylamino)acetic acid (39 mg, 0.20 mmol). -cyclohexyl-2-(N-(3-fluorophenyl)-2-(((S)-2-methylaziridine)-1-sulfonamido)acetamido)acetamide (60 mg, yield 56%).
  • Example 33 2-(2-Chlorophenyl)-2-(N-(3-cyano-5-fluorophenyl)-2-(((S)-2-methylaziridine)-1 -sulfonylamino)acetamido)-N-(3,3-difluorocyclobutyl)acetamide
  • Step A (S)-3-((1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3-fluorobenzene) Tert-butyl carbamoyl pyrrolidine-1-carboxylate
  • Step B (3S)-1-(N-(2-chloroethyl)aminosulfonyl)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl) Amino)-2-oxoethyl)-N-(3-fluorophenyl)pyrrolidine-3-carboxamide
  • Step C (S)-1-(Aziridine-1-ylsulfonyl)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutane) Amino)-2-oxoethyl)-N-(3-fluorophenyl)pyrrolidine-3-carboxamide (Example 34)
  • Example 36 (R)-1-(Aziridine-1-ylsulfonyl)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclo) Butyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)pyrrolidine-3-carboxamide
  • Examples 36 and 37 were prepared by reference to the preparation of Examples 34 and 35, substituting (R)-1-Boc-pyrrolidine-3-carboxylic acid for (S)-1-Boc-pyrrolidine-3-carboxylic acid.
  • Resazurin is a traditional redox dye that can be reduced from a blue azurite without fluorescence to a pink fluorescent substance, resorufin.
  • resazurin is widely used for the determination of the viability of bacteria, cells and the enzyme activity of oxidoreductase.
  • We determined the inhibitory activity of the compound against IDHm by detecting the subtraction of the cofactor NADPH, and the inhibitory activity of the compound against IDH WT was determined by detecting the production of the cofactor NADPH.
  • the compound was pre-incubated with IDHm and NADPH, and then the reaction was initiated by adding ⁇ -KG. After a certain period of time under linear conditions, Diaphorase (lipoamide dehydrogenase) and the corresponding substrate Resazurin (Resazurin) were added for detection. .
  • the lipoamide dehydrogenase terminates the IDH2m reaction by attenuating the available cofactor NADPH, which oxidizes NADPH to NADP and reduces resazurin to a highly fluorescent resorufin, quantified by readily detectable fluorophores. The amount of cofactor NADPH remaining after a specific reaction time.
  • the compound was pre-incubated with IDH-WT and NADP, and then the reaction was initiated by the addition of isocitrate, Diaphorase (lipoamide dehydrogenase) and the corresponding substrate Resazurin (Resazurin). After a certain period of time under linear conditions, The amount of fluorescent substance is detected.
  • NADP was reduced to NADPH, which reduced the resazurin to a highly fluorescent resorufin under the action of lipoamide dehydrogenase.
  • the detected fluorophore was used to quantify the cofactors generated after a specific reaction time. The amount of NADPH, thereby calculating the inhibitory effect of the compound on IDH-WT.
  • the specific mode of operation was as follows: 2.5 ⁇ L of 3 ⁇ gradient diluted compound was added to a 384-well plate, followed by the addition of 5 ⁇ L of reaction buffer containing 40 nM IDH1 (R132H/R132C) and 20 ⁇ M NADPH (20 mM Tris-HCl, pH 7.5; 150 mM). NaCl; 10 mM MgCl 2 ; 0.4 mg/mL BSA (bovine serum albumin) and 2 mM DTT (dithiothreitol). The test mixture was then incubated at 23 ° C for 16 hours, after which 2.5 ⁇ L of reaction buffer containing 4 mM ⁇ -KG was added to initiate the reaction.
  • mice Male Sprague-Dawley rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into groups of 3, and the test sample suspension (5 mg/kg) was administered orally by a single oral administration. Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with a small animal anesthesia machine, 0.3 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube.
  • the compound of Example 10 has unique pharmacokinetic properties, The concentration of the drug in the body decreased with time. This trend is in good agreement with the slow binding mode of the drug and IDH1m, indicating that the drug gradually binds to IDH1m with time, and the concentration of the drug in plasma gradually decreases.

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Abstract

具有异柠檬酸脱氢酶1（IDH1）抑制活性的丙啶磺酰胺类化合物，其药学上可接受的盐、溶剂化物或水合物、药物组合物，以及上述化合物或其药学上可接受的盐、溶剂化物或水合物和其药物组合物在治疗IDH1突变诱发的癌症中的用途。

Description

丙啶磺酰胺类化合物及其使用方法
相关申请的引用
本申请要求于2016年03月22日向中华人民共和国国家知识产权局提交的第201610166113.8号中国申请专利申请的权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请涉及用于治疗癌症的丙啶磺酰胺类化合物及其使用方法。
背景技术
IDH(isocitrate dehydrogenase)全称异柠檬酸脱氢酶，是细胞内三羧酸循环过程中最主要的关键酶，它们能够催化异柠檬酸氧化脱羧生成2-氧化戊二酸(即，α-酮戊二酸)。IDH有两个不同的亚型，其中一个亚型利用NAD(+)作为电子受体，另一个亚型利用NADP(+)作为电子受体。已经报道的IDH有五种，其中3种为NAD(+)依赖型异柠檬酸脱氢酶，它们位于线粒体基质；还有两种为NADP(+)依赖型异柠檬酸脱氢酶，一种位于线粒体，另一种位于胞质。
研究发现多种肿瘤(如神经胶质瘤、肉瘤、急性粒细胞白血病等)存在IDH突变，突变位点是位于催化中心的精氨酸残基(IDH1/R132H、IDH2/R140Q、IDH2/R172K)。2009年，Bleeker等对672例不同来源的肿瘤和84个不同的肿瘤细胞系进行了IDH1突变的检测，发现这种突变特异性集中发生在脑胶质瘤中[Bleeker et al.,2009.IDH1mutations at residue p.R132(IDH1(R132))occur frequently in high-grade gliomas but not in other solid tumers.Hum Mutat.30:7-11.]。但后续的文献报道显示，急性髓细胞白血病、前列腺癌、副神经节瘤等也存在IDH1的突变[Green et al.,2010,Somatic mutations of IDH1and IDH2in the leukemic transformation of myeloproliferative neoplasms.N Engl J Med.362:369-370.]。Bleeker等发现在IDH1突变的病例中，R132H占了86.9％。其他类型如R132C、R132G、R132L、R132V、R132S占比例较小[Bleeker et al.,2009.IDH1mutations at residue p.R132(IDH1(R132))occur frequently in high-grade gliomas but not in other solid tumers.Hum Mutat.30:7-11.]。突变后的IDH获得一种新的能力，即催化α-酮戊二酸(α-KG)转化为2-羟基戊二酸(2-HG)。研究表明，α-酮戊二酸与2-羟基戊二酸的结构相似，2-HG与α-KG竞争，由此降低了α-KG依赖性酶的活性，导致染色质高度甲基化，这种超甲基化被认为干扰了正常的细胞分化，导致未成熟细胞过度增殖，从而引发癌症。
Agios Pharmaceuticals开发的IDH1m抑制剂AG-120(即ivosidenib)，对急性髓性红细胞白血病有显著药效，同时针对胆管癌、软骨肉瘤、神经胶质瘤等其他恶性固体肿瘤研究也在进行中。
发明内容
一方面，本申请提供通式I的化合物或其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000001
其中，
W为-(X1)p-(X2)q-(X3)r-；
X1选自C1-6亚烷基，其可任选地被一个或多个独立地选自R5的基团取代；
X2选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R6的基团取代；
X3选自-NR7-；
p为0或1；
q为0或1；
r为0或1；
且p、q、r不同时为0；
R1选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R8的基团取代；
R2选自苯基或含有1-2个选自N、O或S原子的5-6元杂芳基，其可任选地被一个或多个独立地选自R9的基团取代；
每个R3和R4分别独立地选自卤素、氨基、羟基、卤代C1-3烷基或C1-6烷基；
R5、R6和R8分别独立地选自卤素、氨基、羟基、氰基、卤代C1-3烷基、C1-6烷基或C3-6环烷基；
R7选自氢、C1-3烷基或氨基保护基；
R9选自卤素、氨基、羟基、氰基、卤代C1-3烷基或氨基磺酰基；
m为0或1；
n为0或1。
在本申请式I化合物的一个实施方案中，每个R4分别独立地选自氟、氯、溴或三氟甲基。
另一方面，本申请提供通式I-1所示的化合物或其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000002
其中，取代基定义如通式I化合物所述。
另一方面，本申请提供通式I-2所示的化合物或其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000003
其中，取代基定义如通式I化合物所述。
作为本申请的一个实施方式，提供通式II所示的化合物或其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000004
其中，
W为-(X1)p-(X2)q-(X3)r-；
X1选自C1-6亚烷基，其可任选地被一个或多个独立地选自R5的基团取代；
X2选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R6的基团取代；
X3选自-NR7-；
p为0或1；
q为0或1；
r为0或1；
且p、q、r不同时为0；
R1选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R8的基团取代；
R2选自苯基或含有1-2个选自N、O或S原子的5-6元杂芳基，其可任选地被一个或多个独立地选自R9的基团取代；
每个R3独立地选自卤素、氨基、羟基、卤代C1-3烷基或C1-6烷基；
R5、R6和R8分别独立地选自卤素、氨基、羟基、氰基、卤代C1-3烷基、C1-6烷基或C3-6环烷基；
R7选自氢、C1-3烷基或氨基保护基；
R9选自卤素、氨基、羟基、氰基、卤代C1-3烷基或氨基磺酰基；
n为0或1。
在本申请式II化合物的一个实施方案中，X1选自C1-6亚烷基。
在本申请式II化合物的一个实施方案中，X1选自-CH2-、-CH2CH2-、-CH(CH3)-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH2CH2CH2-、-CH(CH3)CH2CH2CH2-、-CH2CH(CH3)CH2CH2-、-CH2CH2CH2CH2CH2CH2-、-CH(CH3)CH2CH2CH2CH2-、-CH2CH(CH3)CH2CH2CH2-或-CH2CH2CH(CH3)CH2CH2-。
在本申请式II化合物的一个实施方案中，X1选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-或-CH(CH3)-。
在本申请式II化合物的一个实施方案中，X2选自环丙基、环丁基、环戊基、环己基、
Figure PCTCN2017077611-appb-000005
Figure PCTCN2017077611-appb-000006
在本申请式II化合物的一个实施方案中，X2选自吡咯烷基、环丁基、或氮杂环丁基。
在本申请式II化合物的一个实施方案中，X2选自
Figure PCTCN2017077611-appb-000007
在本申请式II化合物的一个实施方案中，X3选自-NH-、-N(CH3)-或-N(Boc)-。
在本申请式II化合物的一个实施方案中，X1选自C1-6亚烷基；X2选自吡咯烷基、环丁基、或氮杂环丁基；X3选自-NR7-。
在本申请式II化合物的一个实施方案中，X1选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2- 或-CH(CH3)-；X2选自
Figure PCTCN2017077611-appb-000008
X3选自-NR7-。
在本申请式II化合物的一个实施方案中，W为-CH2NR7-、CH(CH3)NR7-、-CH2CH2NR7-、-CH2CH2CH2NR7、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、
Figure PCTCN2017077611-appb-000009
Figure PCTCN2017077611-appb-000010
在本申请式II化合物的一个实施方案中，W为-CH2-、-CH2NH-、-CH2N(CH3)-、-CH2N(Boc)-、-CH(CH3)NH-、-CH2CH2-、-CH2CH2NH-、-CH2CH2CH2-、-CH2CH2CH2NH-、-CH2CH2CH2CH2-、
Figure PCTCN2017077611-appb-000011
Figure PCTCN2017077611-appb-000012
作为本发明一个优选的特定实施方式，式II所示的化合物或其药学上可接受的盐、溶剂化物或水合物中，R1选自环丙基、环丁基、环戊基、环己基、吡咯烷基或哌啶基，其可任选地被一个或多个独立地选自R8的基团取代；R8选自卤素。进一步的R1选自环丁基或环己基，其可任选地被1个或2个独立地氟基团取代；再进一步的R1为
Figure PCTCN2017077611-appb-000013
在本申请式II化合物的一个实施方案中，R1选自环丙基、环丁基、环戊基、环己基、吡咯烷基或哌啶基，其可任选地被一个或多个独立地选自R8的基团取代。
在本申请式II化合物的一个实施方案中，R1选自环丁基或环己基，其可任选地被1个或2个独立的氟基团取代。
在本申请式II化合物的一个实施方案中，R1选自
Figure PCTCN2017077611-appb-000014
在本申请式II化合物的一个实施方案中，R1选自
Figure PCTCN2017077611-appb-000015
在本申请式II化合物的一个实施方案中，R8选自卤素。
作为本发明一个优选的特定实施方式，式II所示的化合物或其药学上可接受的盐、溶剂化物或水合物中，R2选自苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基，其可任选地被一个或多个独立地选自R9的基团取代；R9选自卤素、氰基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、一氯甲基、二氯甲基、三氯甲基或氨基磺酰基。进一步的，R2选自苯基或吡啶基，其可任选地被一个或多个独立地选自R9的基团取代；R9选自卤素、氰基、三氟甲基或-SO2NH2。
在本申请式II化合物的一个实施方案中，R2选自苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基，其可任选地被一个或多个独立地选自R9的基团取代。
在本申请式II化合物的一个实施方案中，R2选自苯基或吡啶基，其可任选地被一个或多个独立地选自R9的基团取代。
在本申请式II化合物的一个实施方案中，R9选自卤素、氰基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、一氯甲基、二氯甲基、三氯甲基或氨基磺酰基。
在本申请式II化合物的一个实施方案中，R9选自卤素、氰基、三氟甲基或-SO2NH2。
在本申请式II化合物的一个实施方案中，R2选自
Figure PCTCN2017077611-appb-000016
Figure PCTCN2017077611-appb-000017
在本申请式II化合物的一个实施方案中，每个R3独立地选自甲基、乙基、丙基、异丙基或叔丁基。
在本申请式II化合物的一个实施方案中，每个R3独立地选自甲基或异丙基。
在本申请式II化合物的一个实施方案中，R7选自氢、甲基、乙基、叔丁氧羰基、苄氧羰基、对甲苯磺酰基、三苯甲基、甲酰基、2-联苯基-2-丙氧羰基或三氟乙酰基。
在本申请式II化合物的一个实施方案中，R7选自氢、甲基、叔丁氧羰基或苄氧羰基。
作为本申请的一个实施方式，提供通式II-1的化合物或其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000018
其中，取代基定义如通式II所述。
作为本申请的一个实施方式，提供通式II-2的化合物或其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000019
其中，取代基定义如通式II所述。
本申请优选下述化合物及其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000020
Figure PCTCN2017077611-appb-000021
Figure PCTCN2017077611-appb-000022
Figure PCTCN2017077611-appb-000023
Figure PCTCN2017077611-appb-000024
Figure PCTCN2017077611-appb-000025
Figure PCTCN2017077611-appb-000026
Figure PCTCN2017077611-appb-000027
进一步优选地，本发明优选下述化合物及其药学上可接受的盐、溶剂化物或水合物：
Figure PCTCN2017077611-appb-000028
Figure PCTCN2017077611-appb-000029
Figure PCTCN2017077611-appb-000030
Figure PCTCN2017077611-appb-000031
Figure PCTCN2017077611-appb-000032
本申请的另一方面提供了一种药物组合物，其包含治疗有效量的式Ⅰ或式Ⅱ化合物或其药学上可接受的盐、溶剂化物或水合物和一种或多种药学上可接受的载体或赋形剂。本申请的药物组合物可以进一步含有一种或多种额外的治疗剂。
本申请另一方面提供了一种治疗由IDH1突变诱发的癌症的方法，所述IDH1突变具有R132X突变；在一些实施方案中，R132X突变选自R132H、R132C、R132L、R132V、R132S和R132G；在一些优选的实施方案中，R132X突变选自R132H；所述方法包括给予治疗有效量的式I或式II化合物或其药学上可接受的盐、溶剂化物或水合物或其药物组合物。
本申请的另一方面提供了式I或式II化合物或其药学上可接受的盐、溶剂化物或水合物或其药物组合物在制备用于治疗由IDH1突变诱发的癌症的药物中的用途。
本申请的另一方面提供了治疗由IDH1突变诱发的癌症的式I或式II化合物或其药学上可接受的盐、溶剂化物或水合物或其药物组合物。
本申请的一些实施方案中，所述的由IDH1突变诱发的癌症选自：成胶质细胞瘤(神经胶质瘤)、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)。在更具体的实施方案中，待治疗的癌症是神经胶质瘤、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、胆管癌、软骨肉瘤、或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)等，优选地包括急性骨髓性白血病(AML)、骨髓增生异常综合征(MDS)、神经胶质瘤、胆管癌或软骨肉瘤。
本申请提供的式I或式II化合物或其药学上可接受的盐、溶剂化物或水合物具有非常好的IDH1酶的抑制活性，其活性与AG-120活性相当或更优，并且具有非常好的体内代谢水平和非常长的体内半衰期，有望成为更适合治疗由IDH1突变诱发的癌症的药物。
本申请的药物组合物可通过将本申请的化合物或其药学上可接受的盐、溶剂化物或水合物与适宜的药学上可接受的载体组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请的化合物或其药学上可接受的盐、溶剂化物或水合物或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合来配制该药物组合物。这些载体能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、溶液剂、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预胶化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂 的核心进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本文所述的式Ⅰ或式Ⅱ化合物或其药学上可接受的盐、溶剂化物或水合物可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。式Ⅰ或式Ⅱ化合物的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
式Ⅰ或式Ⅱ化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受式Ⅰ或式Ⅱ化合物的每日剂量，接着在若干天或更多天的期间，患者不接受式Ⅰ或式Ⅱ化合物的每日剂量。
有关定义：
除非另有说明，本文所用的下列术语和短语具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代对应的商品或其活性成分。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文所用的Cm-n指该部分中具有m-n个碳原子。例如，“C3-10环烷基”指该环烷基具有3-10个碳原子。“C0-6亚烷基”指该亚烷基具有0-6个碳原子，当亚烷基具有0个碳原子时，该基团为键。
本文中的数字范围，是指给定范围中的各个整数。例如“C1-10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
本文中的基团不局限于失去1个氢原子，形成1价基团；在某种情况下，可以失去两个氢原子，形成2价基团。例如-X1-X2-X3-，其中X2即为失去两个氢原子后形成的2价基团，此时X2的基团定义若为常见的取代基，也应被理解为2价基团。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代，酮取代不会发生在芳香基上。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，即碳和氢以外的原子或含有这些原子的原子团，杂原子独立地选自氧、氮、硫、磷、硅、锗、铝、硼。在出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的部分或全部彼此不同。
术语“卤素”或“卤代”是指氟、氯、溴或碘的任何基团。
术语“羟基”指-OH。
术语“氰基”指-CN。
术语“氨基”是指-NH2、-NH(烷基)和-N(烷基)2，氨基的具体例子包括但不限于-NH2、-NHCH3、-NHCH(CH3)2、-N(CH3)2、-NHC2H5、-N(CH3)C2H5等。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和脂肪烃基团，例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基等。所述特定烷基包括其所有同分异构体形式，例如丙基包括 -CH2CH2CH3、-CH(CH3)2，例如丁基包括-CH2CH2CH2CH3、-CH(CH3)(CH2CH3)、-C(CH3)3、-CH2CH(CH3)2。术语“C1-6烷基”指具有1-6个碳原子的烷基。术语“C1-4烷基”指具有1-4个碳原子的烷基。术语“C1-3烷基”指具有1-3个碳原子的烷基。所述“烷基”、“C1-8烷基”、“C1-6烷基”或“C1-3烷基”可以是非取代的或是被一个或多个选自羟基、卤素或氨基的取代基取代。
术语“卤代烷基”意在包括单卤代烷基和多卤代烷基；例如，术语“卤代C1-3烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基和3-溴丙基等等。卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基和五氯乙基。
术语“亚烷基”是指二价烷基，例如-CH2-、-CH2CH2-或-CH2CH2CH2-，所述亚烷基可以是非取代的或是被一个或多个选自卤素、氨基、羟基、氰基、卤代C1-3烷基、C1-6烷基或C3-6环烷基的取代基取代。
术语“环烷基”是指由碳原子和氢原子组成的全碳单环的饱和烃基团，如C3-20环烷基，优选为C3-6环烷基，例如环丙基、环丁基、环戊基、环己基等。所述环烷基可以是非取代的或是被取代的，所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基。
术语“杂芳环”是指5-12个环原子的单环或稠合环，具有5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。
术语“杂芳基”是指“杂芳环”分子去掉1个氢原子后余下的基团，杂芳基可以是非取代的或取代的，所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基。
术语“杂脂环”是指具有3-12个环原子的单环或稠合环，具有3、4、5、6、7、8、9、10、11或12个环原子，其中1或2个环原子是选自N、O、S(O)n(其中n为0、1或2)的杂原子，其余环原子为C。这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。3元饱和杂脂环的实例包括但不限于
Figure PCTCN2017077611-appb-000033
4元饱和杂脂环的实例包括但不限于
Figure PCTCN2017077611-appb-000034
5元饱和杂脂环的实例包括但不限于
Figure PCTCN2017077611-appb-000035
Figure PCTCN2017077611-appb-000036
6元饱和杂脂环的实例包括但不限于
Figure PCTCN2017077611-appb-000037
Figure PCTCN2017077611-appb-000038
7元饱和杂脂环的实例包括但不限于
Figure PCTCN2017077611-appb-000039
Figure PCTCN2017077611-appb-000040
5元不饱和杂脂环的实例包括但不限于
Figure PCTCN2017077611-appb-000041
Figure PCTCN2017077611-appb-000042
6元不饱和杂脂环的实例包括但不限于
Figure PCTCN2017077611-appb-000043
Figure PCTCN2017077611-appb-000044
术语“杂环烷基”是指“杂脂环”分子去掉1个氢原子后余下的基团，杂环烷基可以是非取代的或者其中的氢原子任选地被取代基取代，所述的取代基包括但不限于烷基、烷氧基、＝O、芳基、芳烷基、-COOH、-CN、氨基、卤素或羟基。
术语“氨基保护基”是指氨基氢被一个或两个保护基取代，所述保护基包括但不限于苄氧羰基、叔丁氧羰基、芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻硝基苯磺酰基、对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4-二甲氧基苄基、对甲氧基苄基或苄基。
“DMF”是指N,N-二甲基甲酰胺。
“THF”是指四氢呋喃。
“DCM”是指二氯甲烷。
“Boc-”是指叔丁氧羰基。
“DIAD”是指偶氮二甲酸二异丙酯。
“TFA”是指三氟乙酸。
“DIEA”是指N,N-二异丙基乙胺。
“TEA”是指三乙胺。
“m-CPBA”是指间氯过氧苯甲酸。
“PE”是指石油醚。
“EA”是指乙酸乙酯。
“戴斯-马丁氧化剂”是指(1,1,1-三乙酰氧基)-1,1-二氢-1,2-苯碘酰-3(1H)-酮。
术语“Ugi反应”是指一分子醛或酮、一分子胺、一分子异腈以及一分子羧酸缩合生成α-酰氨基酰胺的多组分反应。
术语“Mitsunobu反应”是指醇羟基在偶氮二羧酸二乙酯(DEAD)和三苯基膦的作用下被亲核试剂取代，同时跟羟基所连的碳原子构型发生翻转。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
本申请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。
本申请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，都包含在本申请的范围之内。本申请的某些化合物可以以多晶或无定形形式存在。
本申请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申请的范围之内。
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。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申请的范围之内。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-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申请的范围之内。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，均包括在本申请的范围之内。
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。如果想得到本申请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)。
本申请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)。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。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。对于本申请中的口服剂型，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。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本申请通式II的化合物可以由有机合成领域技术人员通过如下路线用本领域的标准方法来制备：
Figure PCTCN2017077611-appb-000045
其中，
W、R1、R2、R3和n的定义与式II化合物相同。
Figure PCTCN2017077611-appb-000046
异腈化合物1、邻氯苯甲醛2、氨基化合物3和丙啶磺酰胺羧酸化合物7直接进行Ugi反应即可得到丙啶磺酰胺式II化合物。
化合物1、2、3和羟基羧酸化合物4进行Ugi反应得到中间体5；中间体5与丙啶磺酰胺中间体6进行Mitsunobu反应得到式II化合物。
化合物1、2、3和氯乙氨基磺酰基羧酸化合物8进行Ugi反应得到中间体9；中间体9经分子内环化得到式II化合物。
化合物1、2、3和氨基保护(PG)的羧酸化合物10进行Ugi反应得到中间体11；中间体11经氨基脱保护(PG)得到中间体12；中间体12与氯乙基氨基磺酰氯13反应得到式II化合物。
附图说明
图1为实施例10化合物与IDH1(R132H)结合模式分析图。
图2为实施例10化合物的PK曲线图。
具体实施方式
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。本领域技术人员应该理解：还有形成本申请化合物的其它合成途径，下面提供的是非限制性的实施例。
除非另有说明，温度是摄氏温度。试剂购自国药集团化学试剂北京有限公司，阿法埃莎(Alfa Aesar)，或北京百灵威科技有限公司等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。
除非另有说明，下列反应在无水溶剂中，氮气或氩气的正压下或使用干燥管进行；反应瓶上装有橡胶隔膜，以便通过注射器加入底物和试剂；玻璃器皿烘干和/或加热干燥。
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱分离使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用Thermo LCQ Fleet型(ESI)液相色谱-质谱联用仪；旋光测定使用上海申光仪器仪表有限公司的SGW-3自动旋光仪。
除非另有说明，核磁数据(1H-NMR)使用Varian设备于400MHz运行。核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMSO-d6等，以四甲基硅烷(0.00ppm)为基准或以残留溶剂为基准(CDCl3：7.26ppm；CD3OD：3.31ppm；D2O：4.79ppm；DMSO-d6：2.50ppm)。当标明峰形多样性时，以下简写表示不同峰 形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以Hertz(Hz)为单位。
除非另有说明，本申请中部分实施例标题化合物未标明手性中心的绝对构型或环上取代基的相对位置，此部分化合物在制备过程中得到的是所有异构体的混合物，普通柱层析法未能将异构体进行分离，但并不表示该部分化合物不存在异构体。
实施例1：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000047
步骤A：(2-氯乙基)磺酰氯
Figure PCTCN2017077611-appb-000048
向2-氯乙胺盐酸盐(2.0g,17.2mmol)的乙腈溶液中，加入氯磺酸(8.4mL,103.4mmol)。然后将反应液加热至80℃反应18小时，冷却至室温，减压旋去溶剂，残余物加入乙醚稀释，滤去不溶物，滤液减压浓缩得(2-氯乙基)磺酰氯(1.22g,收率40％)。
1H-NMR(400MHz,CDCl3):δ＝6.13(s,1H),3.81(t,J＝5.2Hz,2H),3.72-3.68(m,2H)。
步骤B：2-(2-氯苯基)-N-环己基-2-(2-(1,3-二氧代异吲哚啉-2-基)-N-(3-氟苯基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000049
室温搅拌下，向3-氟苯胺(160μL,1.66mmol)的甲醇溶液中加入邻氯苯甲醛(187.4μL,1.66mmol)，反应15分钟后，加入N-邻苯二甲酰甘氨酸(341.4mg,1.66mmol)，继续反应30分钟后，加入环己基异氰(207μL,1.66mmol)，室温反应过夜，经减压蒸馏浓缩，柱层析硅胶柱分离得到2-(2-氯苯基)-N-环己基-2-(2-(1,3-二氧代异吲哚啉-2-基)-N-(3-氟苯基)乙酰氨基)乙酰胺(708mg,收率78％)。
1H-NMR(400MHz,CDCl3):δ＝7.86-7.83(m,2H),7.73-7.68(m,2H),7.35(d,J＝7.9Hz,1H),7.19-7.05(m,3H),7.00-6.92(m,3H),6.87-6.62(m,1H),6.42(s,1H),5.68(d,J＝7.8Hz,1H),4.18(d,J＝2.0Hz,2H),3.94-3.74(m,1H),1.97(d,J＝12.2Hz,1H),1.88(d,J＝12.6Hz,1H),1.75-1.54(m,4H),1.42-0.94(m,4H)。
m/z＝548[M+H]+。
步骤C：2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000050
向盛有2-(2-氯苯基)-N-环己基-2-(2-(1,3-二氧代异吲哚啉-2-基)-N-(3-氟苯基)乙酰氨基)乙酰胺(400mg,0.731mmol)的乙醇溶液中，加入水合联氨(222μL,3.656mmol)。然后将反应液加热至90℃反应过夜，过滤并真空浓缩，柱层析硅胶柱分离得到2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(290mg,收率95％)。
1H-NMR(400MHz,CDCl3):δ＝7.33(dd,J＝8.0,1.0Hz,1H),7.18-7.04(m,3H),7.05-6.92(m,2H),6.89-6.84(m,1H),6.79(s,1H),6.42(s,1H),5.55(d,J＝7.6Hz,1H),3.93-3.76(m,1H),3.15(d,J＝5.5Hz,2H),2.07-1.93(m,3H),1.87(d,J＝10.8Hz,1H),1.78-1.55(m,4H),1.42-1.06(m,4H)。
m/z＝418[M+H]+。
步骤D：2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000051
冰浴搅拌下，向盛有2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(100mg,0.239mmol)的二氯甲烷溶液中，加入三乙胺(66μL,0.478mmol)，然后滴加(2-氯乙基氨基)磺酰氯(59mg,0.33mmol)，滴加完毕，将反应液升至室温搅拌过夜，向反应液中加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(109mg,收率82％)。
1H-NMR(400MHz,CDCl3):δ＝7.34(d,J＝7.9Hz,1H),7.22-7.05(m,3H),7.03-6.87(m,4H),6.42(s,1H),5.46(d,J＝8.1Hz,1H),5.32(t,J＝5.2Hz,1H),4.89(t,J＝6.4Hz,1H),3.88-3.81(m,1H),3.67(t,J＝5.9Hz,2H),3.59-3.57(m,2H),3.45-3.30(m,2H),1.99(d,J＝10.5Hz,1H),1.88(d,J＝10.5Hz,1H),1.78-1.50(m,4H),1.48-0.95(m,4H)。
m/z＝559[M+H]+。
步骤E：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000052
将碳酸钾(36mg,0.258mmol)加入2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨 基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(72mg,0.129mmol)的DMF溶液中，室温搅拌反应过夜，加水淬灭，用乙酸乙酯萃取，合并的有机相用盐水洗涤3次，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(30mg,收率44％)。
1H-NMR(400MHz,CDCl3):δ＝7.86-7.48(m,1H),7.36(d,J＝8.0Hz,1H),7.24-7.09(m,2H),7.06-6.88(m,4H),6.43(s,1H),5.50-5.48(m,2H),3.95-3.66(m,3H),2.31(s,4H),2.01(d,J＝12.5Hz,1H),1.89(d,J＝11.8Hz,1H),1.82-1.47(m,4H),1.47-0.96(m,4H)。
m/z＝523[M+H]+。
实施例2：(2S)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000053
步骤A：(2S)-1-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-1-氧代丙烷-2-基-氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000054
室温搅拌下将2-氯-苯甲醛(400mg,2.846mmol)和3-氟苯胺(317mg,2.846mmol)加入MeOH(12mL)中，30分钟后添加Boc-L-丙氨酸(540mg,2.846mmol)并搅拌反应混合物10分钟。然后添加环己基异腈(311mg,2.846mmol)并且在室温下搅拌反应混合物过夜。真空除去溶剂，柱层析硅胶柱分离得到(2S)-1-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-1-氧代丙烷-2-基-氨基甲酸叔丁酯(1.15g，收率76％)。
1H-NMR(400MHz,CDCl3):δ＝7.36(d,J＝7.9Hz,1H),7.28(d,J＝8.1Hz,1H),7.16-7.10(m,3H),7.01-6.96(m,3H),6.44(s,1H),6.12(s,1H),5.52(d,J＝7.9Hz,1H),5.18(d,J＝34.2Hz,1H),4.24(s,1H),2.03-1.87(m,4H),1.79-1.56(m,4H),1.48-1.39(m,12H),1.38-0.98(m,2H)。
m/z＝532[M+H]+。
步骤B：(2S)-2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000055
冰浴搅拌下，向盛有(2S)-1-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-1-氧代丙烷 -2-基-氨基甲酸叔丁酯(1.14g,2.141mmol)的THF溶液中，慢慢滴加浓盐酸(2.0mL)，反应物室温搅拌过夜。反应完毕，饱和碳酸氢钠水溶液淬灭中和，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(2S)-2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(900mg，收率97.2％)。
1H-NMR(400MHz,CDCl3):δ＝7.34(dd,J＝17.6,8.0Hz,2H),7.24-6.81(m,7H),6.43(d,J＝39.0Hz,1H),5.59(d,J＝7.7Hz,1H),3.93-3.77(m,1H),3.43-3.33(m,1H),2.01(d,J＝10.7Hz,1H),1.95-1.83(m,2H),1.78-1.58(m,4H),1.42-1.25(m,2H),1.20-1.11(m,5H)。
m/z＝432[M+H]+。
步骤C：(2S)-2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000056
冰浴搅拌下，将2-氯乙基氨基磺酰氯(452mg,2.775mmol)加入(2S)-2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(400mg,0.925mmol)、吡啶(366mg,4.625mmol)和DCM(20mL)的混合物中，反应物升温到室温搅拌过夜。加水淬灭，用DCM萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(2S)-2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(111mg，收率21％)。
m/z＝573[M+H]+。
步骤D：(2S)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000057
室温搅拌下，向盛有(2S)-2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(110mg,0.192mmol)的DMF溶液中，加入碳酸钾(80mg,0.576mmol)，反应混合物室温搅拌过夜。反应完毕，加水，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(2S)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(46mg，收率44.7％)。
1H-NMR(400MHz,CDCl3):δ＝7.80-7.52(m,1H),7.39(d,J＝7.9Hz,1H),7.25-7.12(m,1H),6.99-6.88(m,4H),6.56-6.36(m,1H),6.32(s,1H),5.54(d,J＝7.8Hz,1H),5.39(d,J＝10.0Hz,1H),4.15-4.05(m,1H),3.86-3.70(m,1H),2.50-2.24(m,4H),1.98(d,J＝10.9Hz,1H),1.84(d,J＝12.4Hz,1H),1.74(d,J＝13.4Hz,1H),1.61(d,J＝16.0Hz,2H),1.42-1.34(m,2H),1.28(d,J＝7.0Hz,3H),1.22-0.97(m,3H)。
m/z＝537[M+H]+。
实施例3：(R)-2-(氮丙啶-1-磺酰氨基)-N-((R)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
实施例4：(R)-2-(氮丙啶-1-磺酰氨基)-N-((S)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000058
步骤A：(2R)-1-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-1-氧代丙烷-2-基-氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000059
室温下将2-氯-苯甲醛(400mg,2.846mmol)和3-氟苯胺(317mg,2.846mmol)于MeOH(12mL)中混合搅拌30分钟。然后加入Boc-D-丙氨酸(540mg,2.846mmol)并搅拌反应混合物10分钟。然后添加环己基异腈(311mg,2.846mmol)并且在室温下搅拌反应混合物过夜。真空除去溶剂，柱层析硅胶柱分离得到(2R)-1-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-1-氧代丙烷-2-基-氨基甲酸叔丁酯(1.272g，收率84％)。
m/z＝532[M+H]+。
步骤B：(2R)-2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000060
冰浴搅拌下，向盛有(2R)-1-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-1-氧代丙烷-2-基-氨基甲酸叔丁酯(1.27g,2.387mmol)的THF溶液中，慢慢滴加6N浓盐酸(4.0mL,23.87mmol)。反应物室温搅拌过夜。反应完毕，饱和碳酸氢钠水溶液淬灭中和，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(2R)-2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(798mg，收率77.5％)。
m/z＝432[M+H]+。
步骤C：(2R)-2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000061
冰浴搅拌下，将2-氯乙基氨基磺酰氯(136mg,0.832mmol)加入(2R)-2-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(180mg,0.416mmol)和吡啶(177mg,2.08mmol)的DCM(10mL)混合物中。反应物升温到室温搅拌过夜。加水淬灭，用DCM萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(2R)-2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(102mg,收率43％)。
m/z＝573[M+H]+。
步骤D：(R)-2-(氮丙啶-1-磺酰氨基)-N-((R)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(实施例3)
(R)-2-(氮丙啶-1-磺酰氨基)-N-((S)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(实施例4)
Figure PCTCN2017077611-appb-000062
室温搅拌下，向盛有(2R)-2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(102mg,0.178mmol)的DMF溶液中，加入碳酸钾(74mg,0.534mmol)。反应混合物室温搅拌过夜。反应完毕，加水，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(R)-2-(氮丙啶-1-磺酰氨基)-N-((R)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(46mg,收率48％)和(R)-2-(氮丙啶-1-磺酰氨基)-N-((S)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(46mg，收率48％)。
实施例3：1H-NMR(400MHz,CDCl3):δ＝7.80-7.53(m,1H),7.39(d,J＝7.9Hz,1H),7.23-7.14(m,2H),7.03-6.88(m,3H),6.60-6.35(m,1H),6.32(s,1H),5.57(d,J＝8.0Hz,1H),5.43(d,J＝9.9Hz,1H),4.19-4.05(m,1H),3.87-3.67(m,1H),2.45-2.24(m,4H),2.08-1.92(m,1H),1.85(d,J＝12.6Hz,1H),1.79-1.67(m,1H),1.63-1.45(m,2H),1.40-1.00(m,8H)。
m/z＝537[M+H]+。
实施例4：1H-NMR(400MHz,CDCl3):δ＝7.79-7.63(m,1H),7.33-7.18(m,1H),7.16-6.72(m,6H),6.44(s,1H),5.70(d,J＝9.5Hz,1H),5.56(d,J＝8.1Hz,1H),4.25-4.16(m,1H),3.93-3.80(m,1H),2.58-2.20(m,4H),2.00(d,J＝12.3Hz,1H),1.91(d,J＝10.7Hz,1H),1.79-1.49(m,3H),1.41-0.98(m,8H)。
m/z＝537[M+H]+。
实施例5：3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000063
步骤A：3-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-3-氧代丙基)氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000064
参照实施例1中的步骤B,得到3-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-3-氧代丙基)氨基甲酸叔丁酯(1.02g,收率68％)。
1H-NMR(400MHz,CDCl3):δ＝7.35(d,J＝8.0Hz,1H),7.23-6.94(m,6H),6.90-6.86(m,1H),6.43(s,1H),5.52(d,J＝7.6Hz,1H),5.32(m,1H),3.95-3.82(m,1H),3.45-3.35(m,2H),2.43-2.18(m,2H),2.04(d,J＝11.2Hz,1H),1.90(d,J＝11.2Hz,1H),1.85-1.55(m,4H),1.53-0.96(m,13H)。
m/z＝532[M+H]+。
步骤B：3-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000065
室温搅拌下，向3-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-3-氧代丙基)氨基甲酸叔丁酯(912mg,1.7mmol)的四氢呋喃溶液中加入浓盐酸(3mL,12M,34mmol)，反应过夜。加入饱和碳酸氢钠溶液，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到经减压蒸馏浓缩，柱层析硅胶柱分离得到3-氨基-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(547mg,收率74％)。
1H-NMR(400MHz,CDCl3):δ＝7.31(d,J＝8.0Hz,1H),7.17-6.91(m,5H),6.86(t,J＝7.4Hz,2H),6.46(s,1H),5.69(d,J＝7.8Hz,1H),3.90-3.80(m,1H),2.94(t,J＝6.2Hz,2H),2.25(t,J＝6.0Hz,2H),1.99(d,J＝11.6Hz,1H),1.88(d,J＝11.6Hz,1H),1.75-1.55(m,6H),1.45-0.97(m,4H)。
m/z＝432[M+H]+。
步骤C：3-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000066
参照实施例1中的步骤D，得到3-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(101mg,收率62％)。
1H-NMR(400MHz,CDCl3):δ＝7.35-7.32(m,1H),7.21-7.07(m,3H),7.03-6.96(m,4H),6.47(s,1H),5.94(s,1H),5.70(s,1H),5.44(s,1H),3.90-3.80(m,1H),3.76-3.67(m,2H),3.63(t,J＝5.9Hz,2H),3.45-3.41(m,2H),2.64-2.27(m,2H),2.05-1.85(m,2H),1.79-1.51(m,4H),1.42-0.97(m,4H)。
m/z＝572[M+H]+。
步骤D：3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000067
参照实施例1中的步骤E，得到3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(60mg,收率40％)。
1H-NMR(400MHz,CDCl3):δ＝7.35(d,J＝7.8Hz,1H),7.23-7.07(m,3H),7.02-6.98(m,3H),6.89-6.87(m,1H),6.44(s,1H),5.63(s,1H),5.41-5.35(d,J＝8.0Hz,1H),3.87-3.82(s,1H),3.47(m,2H),2.46(t,J＝5.2Hz,2H),2.32(s,4H),1.97(m,2H),1.58(m,4H),1.46-0.77(m,4H)。
m/z＝537[M+H]+。
实施例6：3-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000068
步骤A：3-(氯磺酰基)丙酸甲酯
Figure PCTCN2017077611-appb-000069
冰浴搅拌下，向盛有3-巯基丙酸甲酯(6.5g,54mmol)和冰的二氯甲烷溶液中，通入氯气至到反应液变 为淡绿色，继续通入氯气0.5小时，通入氮气将反应体系中的氯气赶走。反应液用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩得到3-(氯磺酰基)丙酸甲酯(9.7g,收率96％)。
1H-NMR(400MHz,CDCl3):δ＝4.05(t,J＝7.2Hz,2H),3.82(s,3H),3.10(t,J＝7.6Hz,2H)。
步骤B：3-(N-(2-氯乙基)氨基磺酰基)丙酸甲酯
Figure PCTCN2017077611-appb-000070
冰浴搅拌下，向盛有2-氯乙胺盐酸盐(5.0g,26.8mmol)的二氯甲烷溶液中，加入三乙胺(18.7mL,134mmol)，然后滴加3-(氯磺酰基)丙酸甲酯(3.42g,29.5mmol)，滴加完毕，将反应液升至室温搅拌过夜，向反应液中加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到3-(N-(2-氯乙基)氨基磺酰基)丙酸甲酯(4.7g,收率76％)。
1H-NMR(400MHz,CDCl3):δ＝4.77(s,1H),3.74(s,3H),3.68(t,J＝5.6Hz,2H),3.47(dt,J＝11.6,5.7Hz,2H),3.40(t,J＝7.3Hz,2H),2.86(t,J＝7.2Hz,2H)。
步骤C：3-(氮丙啶-1-基磺酰基)丙酸
Figure PCTCN2017077611-appb-000071
将氢氧化锂(260mg,10.9mmol)加入到3-(N-(2-氯乙基)氨基磺酰基)丙酸甲酯(500mg,2.2mmol)的甲醇和水的混合溶液(甲醇/水＝5/1)中。室温搅拌反应过夜，减压蒸馏除去甲醇溶液，使用PH为1的盐酸溶液将反应液调pH至4，然后乙酸乙酯萃取，经硫酸钠干燥，过滤并真空浓缩得到3-(氮丙啶-1-基磺酰基)丙酸(190mg,收率49％)。
1H-NMR(400MHz,CDCl3):δ＝9.26(s,1H),3.48(t,J＝7.4Hz,2H),2.98(t,J＝7.4Hz,2H),2.39(s,4H)。
步骤D：3-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000072
参照实施例1中的步骤B,得到3-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(62mg,收率31％)。
1H-NMR(400MHz,CDCl3):δ＝7.33(d,J＝7.9Hz,1H),7.18-7.06(m,3H),7.01-6.80(m,4H),6.42(s,1H),5.53(d,J＝8.3Hz,1H),3.95-3.76(m,1H),3.53(t,J＝7.4Hz,2H),2.77-2.60(m,2H),2.32(s,4H),1.99(d,J＝10.6Hz,1H),1.88(d,J＝12.5Hz,1H),1.81-1.58(m,4H),1.43-0.95(m,4H)。
m/z＝522[M+H]+。
实施例7：2-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)(((R)-2-异丙基氮丙啶-1-基)磺酰基)氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000073
步骤A：(R)-N-(1-羟基-3-甲基丁-2-基)氨磺酰氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000074
0℃下，在D-缬氨醇(500mg,4.85mmol)和三乙胺(1.35mL,9.69mmol)的二氯甲烷(15mL)溶液中滴加Boc-氨基磺酰氯(1.15g,5.33mmol)的二氯甲烷溶液，随后升至室温反应1小时。反应结束后，用1N HCl中和反应，分离有机层，静置析出固体产物(R)-N-(1-羟基-3-甲基丁-2-基)氨磺酰氨基甲酸叔丁酯(750mg,收率55％)。
1H-NMR(400MHz,CDCl3):δ＝7.36(br s,1H),5.32(d,J＝8.4Hz,1H),3.76-3.72(m,1H),3.69-3.66(m,1H),3.27-3.23(m,1H),2.20-2.19(m,1H),1.49(d,J＝5.2Hz,9H),0.99(m,6H)。
步骤B：(R)-2-异丙基氮丙啶-1-基磺酰基氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000075
0℃下，在(R)-N-(1-羟基-3-甲基丁-2-基)氨磺酰氨基甲酸叔丁酯(750mg,2.65mmol)和三苯基膦(1.39g,5.32mmol)的四氢呋喃(30mL)溶液中滴加DIAD(1.05mL,5.32mmol)，随后升至室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝3:1)分离得到产物(R)-2-异丙基氮丙啶-1-基磺酰基氨基甲酸叔丁酯(362mg,收率52％)。
1H-NMR(400MHz,CDCl3):δ＝7.71(br s,1H),2.74(d,J＝6.8Hz,1H),2.69-2.66(m,1H),2.27(d,J＝4.8Hz,1H),1.55(d,J＝6.8Hz,1H),1.51-1.49(m,9H),1.08-1.04(m,3H),1.01-0.98(m,3H)。
步骤C：2-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)(((R)-2-异丙基氮丙啶-1-基)磺酰基)氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000076
氮气保护下，在15mL四氢呋喃溶液中加入N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)-2-羟基乙酰胺(79mg,0.19mmol)、(R)-N-(1-羟基-3-甲基丁-2-基)氨磺酰氨基甲酸叔丁酯(50mg,0.19mmol)和三苯基膦(99mg,0.38mmol)，然后冷却至0℃，在反应液中滴加DIAD(75μL,0.38mmol)，随后升至室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到2-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)(((R)-2-异丙基氮丙啶-1-基)磺酰基)氨基甲酸叔丁酯(80mg,收率64％)。
1H-NMR(400MHz,CDCl3):δ＝7.33(d,J＝8.4Hz,1H),7.15-6.91(m,7H),6.51(s,1H),4.52-4.16(m,1H),4.13-4.10(m,1H),3.83-3.82(m,2H),2.77-2.72(m,2H),2.30-2.27(m,1H),2.05-1.99(m,2H),1.88-1.85(m,1H),1.72-1.22(m,17H),1.06-1.03(m,3H),1.00-0.97(m,3H)。
m/z＝665[M+H]+。
实施例8：3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000077
步骤A：3-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-3-氧代丙基]氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000078
参照实施例1中的步骤B,由1,1-二氟-3-异氰基环丁烷(参照专利CN201180043254.6所述方法制备)(1.0g,8.54mmol)得到3-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-3-氧代丙基]氨基甲酸叔丁酯(2.33g,收率62％)。
m/z＝540[M+H]+。
步骤B：3-氨基-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000079
参照实施例5中的步骤B，由3-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-3-氧代丙基]氨基甲酸叔丁酯(2.33g,4.32mmol)得到3-氨基-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(900mg,收率47％)。
步骤C：3-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000080
冰浴搅拌下，向盛有3-氨基-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(50mg,0.114mmol)的二氯甲烷溶液中，加入DIEA(74μL,0.445mmol)，然后滴加(2-氯乙基)磺酰氯(37mg,0.227mmol)，滴加完毕，将反应液升至室温搅拌过夜，向反应液中加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到3-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(63mg,收率95％)。
1H-NMR(400MHz,CDCl3):δ＝7.34(d,J＝7.9Hz,1H),7.21-7.06(m,3H),7.01-6.88(m,4H),6.46(s,1H),6.25(d,J＝6.5Hz,1H),5.47(t,J＝6.3Hz,1H),4.83(t,J＝6.3Hz,1H),4.36-4.29(m,1H),3.69(t,J＝5.7Hz,2H),3.42-3.38(m,2H),3.34-3.25(m,2H),3.14-2.90(m,2H),2.66-2.30(m,4H)。
m/z＝581[M+H]+。
步骤D：3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000081
参考实施例1中的步骤E，由3-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(55mg,0.0946mmol)得到3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(38mg,收率74％)。
1H-NMR(400MHz,CDCl3):δ＝7.36(d,J＝7.9Hz,1H),7.17(m,3H),6.95(m,4H),6.44(s,1H),5.99(d,J＝6.6Hz,1H),5.62(t,J＝6.4Hz,1H),4.37-4.30(m,1H),3.48-3.43(m,2H),3.09-2.96(m,2H),2.66-2.37(m,4H),2.30(s,4H)。
m/z＝545[M+H]+。
实施例9：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-((R)-2-异丙基氮丙啶-1-磺酰氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000082
在2-((1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)(((R)-2-异丙基氮丙啶-1-基)磺酰基)氨基甲酸叔丁酯(由实施例7制备得到，80mg,0.12mmol)的二氯甲烷溶液中加入1mL TFA，室温搅拌1小时，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到产物(41mg,收率60％)。
1H-NMR(400MHz,CDCl3):δ＝7.78-7.59(brs,1H),7.34(d,J＝8.4Hz,1H),7.16-7.14(m,3H),7.01-6.90(m,4H),6.42(d,J＝8.0Hz,1H),5.53(d,J＝4.0Hz,2H),3.87-3.63(m,3H),2.47-2.40(m,2H),2.08-2.05(m,1H),2.01-1.98(m,1H),1.88-1.85(m,1H),1.72-1.22(m,8H),1.06-1.03(m,3H),1.00-0.97(m,3H)。
m/z＝565[M+H]+。
实施例10：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基}-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000083
步骤A：2-((N-(2-氯乙基)磺酰氨基)氨基)乙酸叔丁酯
Figure PCTCN2017077611-appb-000084
参照实施例1中的步骤D，由2-氨基乙酸叔丁酯盐酸盐(3g,17.9mmol)得到2-((N-(2-氯乙基)磺酰氨基)氨基)乙酸叔丁酯(4.67g,收率96％)。
1H-NMR(400MHz,CDCl3):δ＝4.86(s,1H),4.76(s,1H),3.75(d,J＝5.6Hz,2H),3.69(t,J＝5.6Hz,2H),3.48-3.38(m,2H),1.49(s,9H)。
步骤B：2-((N-(2-氯乙基)氨基磺酰基)氨基)乙酸
Figure PCTCN2017077611-appb-000085
冰浴搅拌下，向盛有2-((N-(2-氯乙基)磺酰氨基)氨基)乙酸叔丁酯(2.2g,8.0mmol,1.0eq.)的二氯甲烷溶液中，滴加三氟乙酸(12mL)。室温反应过夜，减压蒸馏充分除去三氟乙酸和二氯甲烷溶液，再利用二氯甲烷打浆，抽滤得到白色固体为2-((N-(2-氯乙基)氨基磺酰基)氨基)乙酸(1.65g,94％收率)。
1H-NMR(400MHz,CDCl3):δ＝12.62(s,1H),7.33(t,J＝6.1Hz,1H),7.21(t,J＝5.8Hz,1H),3.66-3.52(m,4H),3.17-3.12(m,2H)。
步骤C：2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000086
参照实施例13中的步骤C，由2-((N-(2-氯乙基)氨基磺酰基)氨基)乙酸(90mg,0.415mmol)得到2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(61mg,收率26％)。
步骤D：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基}-N-(3-氟苯基) 乙酰胺
Figure PCTCN2017077611-appb-000087
参照实施例1中的步骤E，由2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(61mg,0.108mmol)得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基}-N-(3-氟苯基)乙酰胺(34mg,收率60％)。
1H-NMR(400MHz,CDCl3):δ＝7.55-7.45(m,1H),7.38-7.36(m,2H),7.22-7.12(m,2H),7.02-6.92(m,3H),6.43(s,1H),5.97(d,J＝6.5Hz,1H),5.51(s,1H),4.32-4.13(m,1H),3.80-3.69(m,2H),3.07-2.95(m,2H),2.59-2.33(m,2H),2.30(s,4H)。
m/z＝531[M+H]+。
实施例11：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺
Figure PCTCN2017077611-appb-000088
步骤A：2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁烷)氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺
Figure PCTCN2017077611-appb-000089
参照实施例13中的步骤C，由3-氨基-5-氟吡啶(46.5mg,0.415mmol)和2-((N-(2-氯乙基)磺酰氨基)氨基)乙酸(90mg,0.415mmol)得到2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁烷)氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺(46mg,收率19％)。
m/z＝568[M+H]+。
步骤B：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺
Figure PCTCN2017077611-appb-000090
合成步骤同实施例1中的步骤E，由2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁烷)氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺(46mg,0.081mmol)得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺(4mg,9.3％收率)。
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.68-7.42(m,2H),7.39(d,J＝8.0Hz,1H),7.23-7.20(m,1H),7.05-7.01(m,1H),6.94(d,J＝7.1Hz,1H),6.49(s,1H),6.24(s,1H),5.70(s,1H),4.34-4.27(m,1H),3.83-3.58(m,2H),3.04-2.96(m,2H),2.69-2.38(m,4H),2.31(s,4H)。
m/z＝532[M+1]+。
实施例12：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(N-甲基氮丙啶-1-磺酰胺基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000091
步骤A：2-噁唑烷酮-3-磺酰氯
Figure PCTCN2017077611-appb-000092
0℃下，在氯磺酰异氰酸酯(5g,35.33mmol)的二氯甲烷(200mL)溶液中滴加溴乙醇(4.41g,35.33mmol)搅拌30分钟，浓缩得到白色固体2-噁唑烷酮-3-磺酰氯(9.5g,收率100％)。
1H-NMR(400MHz,CDCl3):δ＝4.64-4.59(m,2H),3.61-3.56(m,2H)。
步骤B：2-(2-噁唑烷酮-3-磺酰氨基)乙酸叔丁酯
Figure PCTCN2017077611-appb-000093
0℃下，在200mL二氯甲烷中加入2-噁唑烷酮-3-磺酰氯(3.68g,19.83mmol)、甘氨酸叔丁酯(2.60g,19.82mmol)和三乙胺(2.00g,39.64mmol)，升至室温搅拌过夜。反应结束后加入1N HCl中和反应，水洗，盐洗，分离有机相，无水硫酸钠干燥，减压浓缩，硅胶柱色谱(PE:EA＝1:1)分离得到固体产物2-(2-噁唑烷酮-3-磺酰氨基)乙酸叔丁酯(1.11g,收率20％)。
1H-NMR(400MHz,CDCl3):δ＝5.73(br s,1H),4.44-4.36(m,2H),4.07-4.04(m,2H),3.95(d,J＝5.6Hz,2H),1.48(s,9H)。
步骤C：2-(N-甲基-2-噁唑烷酮-3-磺酰氨基)乙酸叔丁酯
Figure PCTCN2017077611-appb-000094
0℃下，在2-(2-噁唑烷酮-3-磺酰基)氨基乙酸叔丁酯(500mg,1.78mmol)的DMF溶液中加入钠氢(51.41mg,2.14mmol)，搅拌30分钟后加入碘甲烷(167μL,2.68mmol)，升至室温搅拌过夜。反应结束后加入50mL水淬灭反应，乙酸乙酯(20mL×3)萃取，无水硫酸钠干燥，减压浓缩，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物2-(N-甲基-2-噁唑烷酮-3-磺酰氨基)乙酸叔丁酯(339mg,收率65％)。
1H-NMR(400MHz,CDCl3):δ＝4.43-4.39(m,2H),4.09-4.05(m,4H),3.13(s,3H),1.48(s,9H)。
步骤D：2-(N-甲基-2-噁唑烷酮-3-磺酰氨基)乙酸
Figure PCTCN2017077611-appb-000095
0℃下，在2-(N-甲基-2-噁唑烷酮-3-磺酰氨基)乙酸叔丁酯(180mg,0.61mmol)的二氯甲烷溶液中加入1mL TFA，室温搅拌1小时。反应结束后减压旋蒸除去TFA和溶剂得到固体产物2-(N-甲基-2-噁唑烷酮-3-磺酰氨基)乙酸(149mg,收率100％)。
1H-NMR(400MHz,CDCl3):δ＝4.46-4.42(m,2H),4.28(s,2H),4.11-4.05(m,2H),3.13(s,3H)。
步骤E：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(N-甲基-2-噁唑烷酮-3-磺酰胺基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000096
室温下，10mL甲醇中加入邻氯苯甲醛(69μL,0.61mmol)和间氟苯胺(59μL,0.61mmol)，搅拌十分钟后加入2-(N-甲基-2-噁唑烷酮-3-磺酰氨基)乙酸(145mg,0.61mmol)继续搅拌十分钟，然后加入环己基异氰(67mg,0.61mmol)，室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(N-甲基-2-噁唑烷酮-3-磺酰胺基)乙酰氨基)乙酰胺(240mg,收率68％)。
1H-NMR(400MHz,CDCl3):δ＝7.35(d,J＝8.0Hz,1H),7.15(t,J＝7.2Hz,3H),6.99-6.90(m,4H),6.51(s,1H),5.71(d,J＝7.6Hz,1H),4.42-4.38(m,2H),4.14-4.07(m,2H),4.01-3.82(m,3H),3.19(s,3H),1.99-1.89(m,2H),1.76-1.68(m,2H),1.39-1.09(m,6H)。
m/z＝581[M+H]+。
步骤F：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨磺酰胺)(甲基)氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000097
室温下，在2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(N-甲基-2-噁唑烷酮-3-磺酰胺基)乙酰氨基)乙酰胺(120mg,0.206mmol)的甲醇溶液中加入3N的氢氧化钠溶液，搅拌15分钟。反应完全后减压除去溶剂，乙酸乙酯(20mL×3)萃取，无水硫酸钠干燥，浓缩得到固体产物2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨磺酰胺)(甲基)氨基)乙酰氨基)乙酰胺(113mg,收率99％)。
1H-NMR(400MHz,CDCl3):δ＝7.35(d,J＝8.0Hz,1H),7.16(t,J＝7.2Hz,2H),6.99-6.91(m,4H),6.43(s,1H),5.48(s,1H),5.46(s,1H),3.86-3.75(m,5H),3.37-3.33(m,2H),2.97(s,3H),2.94(s,1H),2.01-1.84(m,2H),1.79-1.70(m,2H),1.40-1.06(m,6H)。
m/z＝555[M+H]+。
步骤G：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(N-甲基氮丙啶-1-磺酰胺基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000098
氮气保护下，在10mL四氢呋喃溶液中加入2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨磺酰胺)(甲基)氨基)乙酰氨基)乙酰胺(112mg,0.20mmol)和三苯基膦(169mg,0.60mmol)，然后冷却至0℃，在反应中滴加DIAD(119μL,0.60mmol)，随后升至室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(N-甲基氮丙啶-1-磺酰胺基)乙酰氨基)乙酰胺(18mg,收率17％)。
1H-NMR(400MHz,CDCl3):δ＝7.34(d,J＝8.0Hz,1H),7.12(t,J＝7.2Hz,2H),7.01-6.96(m,3H),6.89-6.86(m,1H),6.46(s,1H),5.49(d,J＝8.0Hz,1H),3.93-3.83(m,2H),3.72(d,J＝17.2Hz,1H),3.09(s,3H),2.26(s,4H),2.01-1.98(m,2H),1.91-1.88(m,1H),1.75-1.58(m,3H),1.41-0.94(m,5H)。
m/z＝537[M+H]+。
实施例13：4-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丁酰胺
Figure PCTCN2017077611-appb-000099
步骤A：4-((N-(2-氯乙基)氨基磺酰基)氨基)丁酸甲酯
Figure PCTCN2017077611-appb-000100
参照实施例1中的步骤D，由4-氨基丁酸甲酯盐酸盐(1g,6.51mmol)得到4-((N-(2-氯乙基)氨基磺酰基)氨基)丁酸甲酯(787mg,收率47％)。
1H-NMR(400MHz,CDCl3):δ＝4.69(s,1H),4.49(s,1H),3.76-3.68(m,5H),3.44-3.40(m,2H),3.18-3.14(m,2H),2.45(t,J＝7.0Hz,2H),1.96-1.89(m,2H)。
步骤B：4-(氮丙啶-1-磺酰氨基)丁酸
Figure PCTCN2017077611-appb-000101
参照实施例6中的步骤C，由4-((N-(2-氯乙基)氨基磺酰基)氨基)丁酸甲酯(787mg,3.04mmol)得到4-(氮丙啶-1-磺酰氨基)丁酸(590mg,收率93％)。
步骤C：4-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丁酰胺
Figure PCTCN2017077611-appb-000102
室温搅拌下，向3-氟苯胺(39μL,0.405mmol)的甲醇溶液中加入邻氯苯甲醛(46μL,0.405mmol)，反应15分钟后，加入4-(氮丙啶-1-磺酰氨基)丁酸(90mg,0.432mmol)，继续反应30分钟后，加入1,1-二氟-3-异氰基环丁烷(47mg,0.405mmol)，室温反应过夜，经减压蒸馏浓缩，柱层析硅胶柱分离得到4-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丁酰胺(50mg,收率21％)。
1H-NMR(400MHz,CDCl3):δ＝7.33(d,J＝8.1Hz,1H),7.19-7.06(m,3H),7.05-6.94(m,2H),6.91-6.87(m,1H),6.62(d,J＝6.4Hz,1H),6.44(s,1H),5.74(t,J＝5.8Hz,1H),4.34-4.21(m,1H),3.30-3.19(m,2H),3.08-2.86(m,2H),2.68-2.39(m,2H),2.27(s,4H),2.23-2.19(m,2H),1.97-1.87(m,2H).
m/z＝559[M+H]+。
实施例14：3-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺
Figure PCTCN2017077611-appb-000103
参考实施例1中的步骤B，由3-(氮丙啶-1-基磺酰基)丙酸(60mg,0.335mmol)和1,1-二氟-3-异氰基环丁烷(39mg,0.335mmol)得到3-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)丙酰胺(46mg,收率26％)。
1H-NMR(400MHz,CDCl3):δ＝7.34(d,J＝8.0Hz,1H),7.23-7.05(m,3H),7.03-6.87(m,4H),6.52(s,1H),6.40(d,J＝5.2Hz,1H),4.33(m,1H),3.68-3.61(m,1H),3.53-3.41(m,1H),3.05-2.96(m,2H),2.78-2.44(m,4H),2.34(s,4H)。
m/z＝530[M+H]+。
实施例15：2-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000104
步骤A：2-(氯磺酰基)乙酸甲酯
Figure PCTCN2017077611-appb-000105
参考实施例6中的步骤A,由2-巯基乙酸甲酯(9.6mL,108mmol)得到2-(氯磺酰基)乙酸甲酯(14.7g,收率79％)。
1H-NMR(400MHz,CDCl3):δ＝4.61(s,2H),3.91(s,3H)。
步骤B：2-(N-(2-氯乙基)氨基磺酰基)乙酸甲酯
Figure PCTCN2017077611-appb-000106
参考实施例6中的步骤B,由2-(氯磺酰基)乙酸甲酯(14.7g,85.2mmol)得到2-(N-(2-氯乙基)氨基磺酰基)乙酸甲酯(3.22g,收率18％)。
1H-NMR(400MHz,CDCl3):δ＝5.37(s,1H),4.07(s,2H),3.82(s,3H),3.68(t,J＝5.7Hz,2H),3.55-3.50(m,2H)。
步骤C：2-(氮丙啶-1-基磺酰基)乙酸
Figure PCTCN2017077611-appb-000107
参考实施例6中的步骤C，由2-(N-(2-氯乙基)氨基磺酰基)乙酸甲酯(500mg,2.32mmol)得到2-(氮丙啶-1-基磺酰基)乙酸(268mg,收率70％)。
1H-NMR(400MHz,CDCl3):δ＝9.11(s,1H),4.24(s,2H),2.51(s,4H)。
步骤D：2-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000108
参照实施例1中的步骤B，由2-(氮丙啶-1-基磺酰基)乙酸(70mg,0.424mmol)得到2-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(20mg,收率9％)。
1H-NMR(400MHz,CDCl3):δ＝7.62(s,1H),7.34(s,1H),7.16(s,1H),7.08-6.80(m,4H),6.67-6.58(m,1H),6.52(s,1H),5.84(s,1H),4.10(d,J＝1.4Hz,2H),3.99-3.78(m,1H),2.49(d,J＝2.5Hz,4H),2.05-1.90(m,2H),1.78-1.63(m,4H),1.50-1.03(m,4H)。
m/z＝508[M+H]+。
实施例16：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3,5-二氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000109
步骤A：2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3,5-二氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000110
参照实施例1中的步骤B,由2-(氮丙啶-1-基磺酰基)乙酸(105mg,0.485mmol)和3,5-二氟苯氨(63mg,0.485mmol)得到2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3,5-二氟苯基)乙酰胺(147mg,收率52％)。
m/z＝577[M+H]+。
步骤B：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3,5-二氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000111
参照实施例1中的步骤E，由2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3,5-二氟苯基)乙酰胺(147mg,0.254mmol)得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3,5-二氟苯基)乙酰胺(2.95mg,收率2.1％)。
1H-NMR(400MHz,CDCl3):δ＝7.58-7.46(brs,1H),7.40-7.36(m,1H),7.26-7.18(m,1H),7.03-7.02(m,2H),6.69-6.60(m,1H),6.40(s,1H),6.38-6.23(brs,1H),5.45-5.40(m,2H),3.90-3.75(m,3H),2.31(s,4H),2.05-1.96(m,1H),1.92-1.84(m,1H),1.78-1.60(m,2H),1.42-1.02(m,6H)。
m/z＝541[M+H]+。
实施例17：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺
Figure PCTCN2017077611-appb-000112
步骤A：2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺
Figure PCTCN2017077611-appb-000113
参照实施例1中的步骤B，由2-(氮丙啶-1-基磺酰基)乙酸(105mg,0.485mmol)和3-氨基-5-氟吡啶(63mg,0.484mmol)得到2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺(71mg,收率26％)。
m/z＝560[M+H]+。
步骤B：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺
Figure PCTCN2017077611-appb-000114
参照实施例1中的步骤E，由2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺(71mg,0.127mmol)得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(5-氟吡啶-3-基)乙酰胺(15mg,收率22％)。
1H-NMR(400MHz,CDCl3):δ＝8.33(d,J＝2.4,1H),7.39-7.37(m,1H),7.24-7.17(m,2H),7.03-6.93(m,3H),6.46(s,1H),5.45-5.44(m,2H),3.85-3.68(m,3H),2.31(s,4H),2.02-1.98(m,1H),1.89-1.87(m,1H),1.73-0.96(m,8H)。
m/z＝524[M+H]+。
实施例18：(S)-1-(氮丙啶-1-基磺酰基)-N-((R)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺
实施例19：(S)-1-(氮丙啶-1-基磺酰基)-N-((S)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺
Figure PCTCN2017077611-appb-000115
Figure PCTCN2017077611-appb-000116
步骤A：(S)-1-(N-(2-氯乙基)氨基磺酰基)吡咯烷-2-甲酸叔丁酯
Figure PCTCN2017077611-appb-000117
0℃下，在L-脯氨酸叔丁酯盐酸盐(200mg,0.96mmol)和DIEA(622μL,4.81mmol)的二氯甲烷溶液中加入2-(氯乙基)氨基磺酰氯(471mg,2.89mmol)，升至室温搅拌过夜。反应结束后加入1N HCl调pH至中性，分离有机相，无水硫酸钠干燥，减压浓缩，硅胶柱色谱(PE:EA＝4:1)分离得到固体产物(S)-1-(N-(2-氯乙基)氨基磺酰基)吡咯烷-2-甲酸叔丁酯(263mg,收率87％)。
1H-NMR(400MHz,CDCl3):δ＝5.08(q,J＝6.0Hz,1H),4.32-4.26(m,1H),3.73-3.65(m,2H),3.56-3.42(m,4H),2.32-2.22(m,1H),2.03-1.94(m,3H),1.47(d,J＝4.0Hz,9H)。
步骤B：(S)-1-(N-(2-氯乙基)氨基磺酰基)吡咯烷-2-甲酸
Figure PCTCN2017077611-appb-000118
0℃下，在(S)-1-(N-(2-氯乙基)氨基磺酰基)吡咯烷-2-甲酸叔丁酯(150mg,0.48mmol)的二氯甲烷溶液中加入1mL TFA，室温搅拌过夜。反应结束后减压旋蒸除去TFA和溶剂得到固体产物(S)-1-(N-(2-氯乙基)氨基磺酰基)吡咯烷-2-甲酸(123mg,收率100％)。
1H-NMR(400MHz,DMSO-d6):δ＝12.57(br s,1H),7.53(t,J＝5.6Hz,1H),4.13-4.10(m,1H),3.67-3.62(m,2H),3.33-3.23(m,4H),2.25-2.14(m,1H),1.90-1.84(m,3H)。
步骤C：(S)-1-(N-(2-氯乙基)氨基磺酰基)-N-((R)-1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(C1)
(S)-1-(N-(2-氯乙基)氨基磺酰基)-N-((S)-1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(C2)
Figure PCTCN2017077611-appb-000119
Figure PCTCN2017077611-appb-000120
室温下，10mL甲醇中加入邻氯苯甲醛(66μL,0.58mmol)和间氟苯胺(56μL,0.58mmol)，搅拌十分钟后加入(S)-1-(N-(2-氯乙基)氨基磺酰基)吡咯烷-2-甲酸(149mg,0.58mmol)，继续搅拌十分钟加入环己基异氰(68mg,0.58mmol)，室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物(S)-1-(N-(2-氯乙基)氨基磺酰基)-N-((R)-1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(46mg,收率13.2％)和(S)-1-(N-(2-氯乙基)氨基磺酰基)-N-((S)-1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(46mg,收率13.2％)。
C1：1H-NMR(400MHz,CDCl3):δ＝7.34-7.31(m,2H),7.13(t,J＝7.2Hz,2H),6.93-6.90(m,3H),6.61(m,1H),6.36(d,J＝7.6Hz,2H),5.49(t,J＝4.0Hz,1H),4.13(t,J＝6.8Hz,1H),3.95-3.86(m,1H),3.71-3.68(m,2H),3.55-3.46(m,4H),2.07-1.63(m,6H),1.39-1.18(m,8H)。
m/z＝599[M+H]+。
C2：1H-NMR(400MHz,CDCl3):δ＝7.58(br s,1H),7.32(d,J＝8.0Hz,1H),7.13(t,J＝6.4Hz,2H),6.98-6.93(m,4H),6.86(t,J＝8.4Hz,1H),6.51(s,1H),5.37(d,J＝7.6Hz,1H),5.23(t,J＝4.0Hz,1H),4.30-4.27(m,1H),3.87-3.82(m,1H),3.76-3.72(m,2H),3.55-3.46(m,4H),2.10-1.61(m,9H),1.38-1.02(m,5H)。
m/z＝599[M+H]+。
步骤D：(S)-1-(氮丙啶-1-基磺酰基)-N-((R)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(实施例18)
(S)-1-(氮丙啶-1-基磺酰基)-N-((S)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(实施例19)
Figure PCTCN2017077611-appb-000121
室温下，在5mL DMF中加入(S)-1-(N-(2-氯乙基)氨基磺酰基)-N-((R)-1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(C1)(62mg,0.10mmol)和碳酸钾(29mg,0.21mmol)，室温搅拌过夜。反应结束后，混合物中加入20mL二氯甲烷，然后水洗(30mL×3)，有机相无水硫酸钠干燥，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物(S)-1-(氮丙啶-1-基磺酰基)-N-((R)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺(45mg,收率77％)。
(S)-1-(氮丙啶-1-基磺酰基)-N-((S)-1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-2-甲酰胺可通过同样的方法由C2制备得到。
实施例18：1H-NMR(400MHz,CDCl3):δ＝7.31(d,J＝8.0Hz,2H),7.12(t,J＝7.6Hz,2H),7.02-6.92(m,3H),6.56(s,1H),6.45(d,J＝7.2Hz,2H),4.23-4.20(m,1H),3.91-3.83(m,1H),3.73-3.67(m,1H),3.56-3.52(m,1H),2.24(s,4H),1.98-1.86(m,5H),1.75-1.62(m,3H),1.41-1.14(m,6H)。
m/z＝563[M+H]+。
实施例19：1H-NMR(400MHz,CDCl3):δ＝7.64(br s,1H),7.31(br s,1H),7.11(br s,1H),7.02-6.92(m,3H),6.86-6.79(m,2H),6.51(s,1H),5.44(br s,1H),4.36-4.31(m,1H),3.88-3.81(m,1H),3.70-3.65(m,1H),3.56-3.52(m,1H),2.27(s,4H),2.19-2.10(m,2H),2.00-1.79(m,4H),1.74-1.68(m,2H),1.40-1.01(m,6H)。
m/z＝563[M+H]+。
实施例20：5-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)戊酰胺
Figure PCTCN2017077611-appb-000122
步骤A：5-(氯磺酰基)戊酸甲酯
Figure PCTCN2017077611-appb-000123
向剧烈搅拌的五水硫代硫酸钠(3.3g,13.3mmol)的50％的饱和甲醇溶液中，加入5-氯戊酸甲酯(2g,13.3mmol)，然后将反应液加热至回流反应大约3小时，至到反应混合液变为同相。减压蒸馏后得到浓缩物，加入乙酸和冰作为反应溶剂，冰浴搅拌下，通入氯气至到反应液变为淡绿色，继续通入氯气0.5小时，通入氮气将反应体系中的氯气赶走。反应液用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩得到5-(氯磺酰基)戊酸甲酯(2.23g,收率78％)。
步骤B：5-(N-(2-氯乙基)氨基磺酰基)戊酸甲酯
Figure PCTCN2017077611-appb-000124
参照实施例6中的步骤B，由5-(氯磺酰基)戊酸甲酯(700mg,3.26mmol)得到5-(N-(2-氯乙基)氨基磺酰基)戊酸甲酯(335mg,收率40％)。
1H-NMR(400MHz,CDCl3):δ＝4.71(t,J＝6.1Hz,1H),3.76-3.62(m,5H),3.57-3.44(m,2H),3.17-3.04(m,2H),2.40(t,J＝7.1Hz,2H),1.95-1.73(m,4H)。
步骤C：5-(氮丙啶-1-基磺酰基)戊酸
Figure PCTCN2017077611-appb-000125
参照实施例6中的步骤C，由5-(N-(2-氯乙基)氨基磺酰基)戊酸甲酯(175mg,0.68mmol)甲酯得到5-(氮丙啶-1-基磺酰基)戊酸(130mg,收率92％)。
步骤D：5-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)戊酰胺
Figure PCTCN2017077611-appb-000126
合成步骤同实施例1中的步骤B,由5-(氮丙啶-1-基磺酰基)戊酸(120mg,0.579mmol,1eq)得到(RS)-5-(氮丙啶-1-基磺酰基)-N-[1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基]-N-(3-氟苯基)戊酰胺(43mg,14％收率)。
1H-NMR(400MHz,CDCl3):δ＝7.32(d,J＝7.8Hz,1H),7.17-7.04(m,3H),7.05-6.92(m,3H),6.91-6.82(m,1H),6.40(s,1H),5.47(d,J＝8.1Hz,1H),3.83(m,1H),3.08(t,J＝7.6Hz,2H),2.33(s,4H),2.12(t,J＝6.9Hz,2H),1.99(d,J＝9.4Hz,1H),1.93-1.54(m,9H),1.42-0.94(m,4H)。
m/z＝550[M+H]+。
实施例21：4-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丁酰胺
Figure PCTCN2017077611-appb-000127
步骤A：4-(氯磺酰基)丁酸乙酯和4-(溴磺酰基)丁酸乙酯的混合物
Figure PCTCN2017077611-appb-000128
参照实施例19中的步骤A，由4-溴丁酸乙酯(5g,26mmol)得到4-(氯磺酰基)丁酸乙酯和4-(溴磺酰基)丁酸乙酯的混合物(6.07g,收率98％)。
步骤B：4-(N-(2-氯乙基)氨基磺酰基)丁酸乙酯
Figure PCTCN2017077611-appb-000129
合成步骤同实施例6中的步骤B，由4-(氯磺酰基)丁酸乙酯和4-(溴磺酰基)丁酸乙酯(1g,4.22mmol)得到4-(N-(2-氯乙基)氨基磺酰基)丁酸乙酯(387mg,收率36％)。
1H-NMR(400MHz,CDCl3):δ＝4.75(t,J＝6.0Hz,1H),4.15(q,J＝7.1Hz,2H),3.68(t,J＝5.6Hz,2H),3.50-3.46(m,2H),3.20-3.11(m,2H),2.51(t,J＝7.0Hz,2H),2.21-2.09(m,2H),1.27(t,J＝7.1Hz,3H)。
步骤C：4-(氮丙啶-1-基磺酰基)丁酸
Figure PCTCN2017077611-appb-000130
参照实施例6中的步骤C，由4-(N-(2-氯乙基)氨基磺酰基)丁酸乙酯(210mg,0.815mmol)甲酯得到4-(氮丙啶-1-基磺酰基)丁酸(104mg,收率66％)。
步骤D：4-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丁酰胺
Figure PCTCN2017077611-appb-000131
参照实施例1中的步骤B，由4-(氮丙啶-1-基磺酰基)丁酸(104mg,0.538mmol)得到4-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-(环己基氨基)-2-氧代乙基)-N-(3-氟苯基)丁酰胺(26mg,收率9％)。
1H-NMR(400MHz,CDCl3):δ＝7.33(d,J＝7.4Hz,1H),7.17-7.03(m,3H),7.03-6.91(m,3H),6.91-6.82(m,1H),6.44(s,1H),5.51(d,J＝7.9Hz,1H),3.85(m,1H),3.24(t,J＝7.6Hz,,2H),2.40-2.28(m,4H),2.27-2.16(m,4H),2.02-1.88(m,2H),1.79-1.55(m,4H),1.44-0.99(m,4H)。
m/z＝536[M+H]+。
实施例22：3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)环丁基甲酰胺
Figure PCTCN2017077611-appb-000132
步骤A：3-邻苯二甲酰亚氨基环丁基甲酸苄酯
Figure PCTCN2017077611-appb-000133
氮气保护下，在50mL四氢呋喃溶液中加入3-羟基环丁基甲酸苄酯(500mg,2.43mmol)、邻苯二甲酰亚胺(357mg,2.43mmol)和三苯基膦(1.91g,7.28mmol)，然后冷却至0℃，在反应中滴加DIAD(1.43mL,7.28mmol)，随后升至室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物3-邻苯二甲酰亚氨基环丁基甲酸苄酯(293mg,收率36％)。
1H-NMR(400MHz,CDCl3):δ＝7.84-7.82(m,2H),7.72-7.70(m,2H),7.39-7.34(m,5H),5.19(s,2H),5.07-5.04(m,1H),3.40-3.34(m,1H),3.19-3.14(m,2H),2.68-2.62(m,2H)。
步骤B：3-邻苯二甲酰亚氨基环丁基甲酸
Figure PCTCN2017077611-appb-000134
室温下，在10mL乙醇中加入3-邻苯二甲酰亚氨基环丁基甲酸苄酯(293mg,0.87mmol)和10％的钯碳(93mg,0.09mmol)，抽干空气通入氢气，搅拌过夜。反应结束后过滤除去钯碳，浓缩得到固体产物3-邻苯二甲酰亚氨基环丁基甲酸(214mg,收率100％)。
1H-NMR(400MHz,CDCl3):δ＝7.85-7.83(m,2H),7.73-7.71(m,2H),5.12-5.06(m,2H),3.37-3.34(m,1H),3.25-3.16(m,2H),2.72-2.66(m,2H)。
步骤C：N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-3-(1,3-二氧代异吲哚啉-2-基)-N-(3-氟苯基)环丁基甲酰胺
Figure PCTCN2017077611-appb-000135
室温下，10mL甲醇中加入邻氯苯甲醛(104μL,0.92mmol)和间氟苯胺(89μL,0.92mmol)，搅拌十分钟后加入3-邻苯二甲酰亚氨基环丁基甲酸(214mg,0.87mmol)，继续搅拌十分钟加入环己基异氰(67mg,0.61mmol)，室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-3-(1,3-二氧代异吲哚啉-2-基)-N-(3-氟苯基)环丁基甲酰胺(217mg,收率42％)。
1H-NMR(400MHz,CDCl3):δ＝7.79-7.76(m,2H),7.68-7.65(m,2H),7.32(d,J＝8.0Hz,1H),7.14-7.04(m,4H),6.98-6.94(m,2H),6.87-6.82(m,1H),6.47(s,1H),5.54(d,J＝8.0Hz,1H),5.10-5.06(m,1H),3.90-3.85(m,1H),3.19-3.15(m,1H),2.83-2.68(m,4H),2.06-2.02(m,1H),1.93-1.90(m,1H),1.76-1.63(m,2H),1.43-1.00(m,6H)。
m/z＝588[M+H]+。
步骤D：3-氨基-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)环丁基甲酰胺
Figure PCTCN2017077611-appb-000136
在N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-3-(1,3-二氧代异吲哚啉-2-基)-N-(3-氟苯基)环丁基甲酰胺(217mg,0.37mmol)的乙醇溶液中加入水合肼(94μL,1.93mmol)，80℃搅拌4小时。反应结束后过滤，浓缩母液，硅胶柱色谱(PE:EA＝5:1)分离得到固体产物3-氨基-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)环丁基甲酰胺(118mg,收率71％)。
1H-NMR(400MHz,CDCl3):δ＝7.31(d,J＝8.0Hz,1H),7.11(t,J＝7.2Hz,1H),7.05-7.03(m,2H),6.97-6.93(m,1H),6.85-6.81(m,2H),6.43(s,1H),5.61(d,J＝8.0Hz,1H),3.88-3.83(m,1H),3.70-3.67(m,1H),2.96-2.92(m,1H),2.66-2.60(m,2H),2.02-1.97(m,1H),1.92-1.87(m,4H),1.77-1.58(m,4H),1.38-1.01(m,6H)。
m/z＝458[M+H]+。
步骤E：3-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)-环丁基甲酰胺
Figure PCTCN2017077611-appb-000137
0℃下，在3-氨基-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)环丁基甲酰胺(118mg,0.26mmol)和DIEA(170μL,1.03mmol)的二氯甲烷溶液中加入2-(氯乙基)氨基磺酰氯(84mg,0.52mmol)，升至室温搅拌过夜。反应结束后加入1N HCl调pH至中性，分离有机相，无水硫酸钠干燥，减压浓缩，硅胶柱色谱(PE:EA＝4:1)分离得到固体产物(140mg,收率90％)。
1H-NMR(400MHz,CDCl3):δ＝7.32(d,J＝8.0Hz,1H),7.12(t,J＝6.8Hz,1H),6.99-6.92(m,3H),6.86-6.82(m,1H),6.42(s,1H),5.52(d,J＝8.0Hz,1H),4.77(t,J＝6.4Hz,1H),4.42(d,J＝8.4Hz,1H),4.15-4.09(m,1H),3.86-3.83(m,1H),3.67-3.64(m,2H),3.34-3.31(m,2H),2.94-2.88(m,1H),2.77-2.73(m,2H),2.05-1.88(m,4H),1.77-1.58(m,4H),1.39-1.01(m,6H)。
m/z＝599[M+H]+。
步骤F：3-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)环丁基甲酰胺
Figure PCTCN2017077611-appb-000138
室温下，在5mL DMF中加入(RS)-3-[N-(2-氯乙基)氨磺酰]氨-N-[1-(2-氯苯基)-2-环己基氨基-2-氧代乙基]-N-(3-氟苯基)-环丁基甲酰胺(140mg,0.23mmol)和碳酸钾(65mg,0.47mmol)，室温搅拌过夜。反应结束后，混合物中加入20mL二氯甲烷，然后水洗(30mL×3)，有机相无水硫酸钠干燥，硅胶柱色谱(PE:EA＝1:1)分离得到标题化合物(73mg,56％)。
1H-NMR(400MHz,CDCl3):δ＝7.32(d,J＝6.8Hz,1H),7.12(t,J＝7.2Hz,1H),7.06(br s,1H),7.01-6.93(m,2H),6.85(t,J＝6.8Hz,1H),6.42(s,1H),5.47(d,J＝8.0Hz,1H),4.42(d,J＝8.0Hz,1H),3.87-3.84(m,1H),2.96-2.89(m,1H),2.79-2.75(m,2H),2.26(s,4H),2.05-1.88(m,4H),1.75-1.59(m,4H),1.39-1.01(m,6H)。
m/z＝563[M+H]+。
实施例23：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-三氟甲基苯基)乙酰胺
Figure PCTCN2017077611-appb-000139
步骤A：2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-三氟甲基苯基)乙酰胺
Figure PCTCN2017077611-appb-000140
参照实施例13中的步骤C，由3-(三氟甲基)苯胺(45.7μL,0.37mmol)和2-((N-(2-氯乙基)氨基磺酰基)氨基)乙酸(3g,17.9mmol)得到2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-三氟甲基苯基)乙酰胺(98mg,收率43％)。
1H-NMR(400MHz,CDCl3):δ＝8.17-7.86(m,1H),7.49(d,J＝6.9Hz,1H),7.36-7.34(m,1H),7.19-7.15(m,2H),6.97-6.81(m,3H),6.49(s,1H),6.18(d,J＝6.4Hz,1H),5.59(t,J＝5.1Hz,1H),4.77(t,J＝4.0Hz,1H),4.31(s,1H),3.67(t,J＝5.7Hz,2H),3.57(s,2H),3.45-3.35(m,2H),3.10-2.72(m,2H),2.60-2.55(m,1H),2.49-2.37(m,1H)。
m/z＝617[M+H]+。
步骤B：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-三氟甲基苯基)乙酰胺
Figure PCTCN2017077611-appb-000141
参照实施例1中的步骤E，由2-((N-(2-氯乙基)磺酰氨基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-三氟甲基苯基)乙酰胺(95mg,0.154mmol)得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-三氟甲基苯基)乙酰胺(33mg,收率37％)。
1H-NMR(400MHz,CDCl3):δ＝8.24-7.86(m,1H),7.48(d,J＝7.3Hz,1H),7.37-7.34(m,2H),7.17(m,1H),6.96-6.84(m,3H),6.46(s,1H),6.04(d,J＝6.6Hz,1H),5.61(s,1H),4.31(s,1H),3.72(s,2H),3.11-2.95(m,2H),2.64-2.48(m,1H),2.46-2.41(m,1H),2.31(s,4H)。
m/z＝581[M+H]+。
实施例24：1-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017077611-appb-000142
步骤A：3-((1-(2-氯苯基l)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基甲酰基)氮杂环丁烷-1-甲酸叔丁酯
Figure PCTCN2017077611-appb-000143
室温下，10mL甲醇中加入邻氯苯甲醛(113μL,1.00mmol)和间氟苯胺(96μL,1.00mmol)，搅拌十分钟后加入1-N-Boc-3-氮杂环丁烷羧酸(201mg,1.00mmol)，继续搅拌十分钟加入环己基异氰(110mg,1.00mmol)，室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物3-((1-(2-氯苯基l)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基甲酰基)氮杂环丁烷-1-甲酸叔丁酯(330mg,收率61％)。
1H-NMR(400MHz,CDCl3):δ＝7.33(d,J＝8.4Hz,1H),7.14(t,J＝8.8Hz,3H),7.00-6.94(m,3H),6.88-6.84(m,1H),6.44(s,1H),5.47-5.45(m,1H),4.18-4.14(m,2H),3.87-3.82(m,1H),3.69-3.59(m,2H),3.22-3.18(m,1H),2.05-2.00(m,1H),1.91-1.89(m,1H),1.75-1.59(m,3H),1.40(s,9H),1.36-0.99(m,5H)。
m/z＝544[M+H]+。
步骤B：N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017077611-appb-000144
0℃下，在3-((1-(2-氯苯基l)-2-(环己基氨基)-2-氧代乙基)(3-氟苯基)氨基甲酰基)氮杂环丁烷-1-甲酸叔丁酯(330mg,0.61mmol)的二氯甲烷溶液中加入1mL TFA，室温搅拌过夜。反应结束后减压旋蒸除去TFA和溶剂得到固体产物N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)氮杂环丁烷-3-甲酰胺(200mg,收率74％)。
1H-NMR(400MHz,CDCl3):δ＝7.32(d,J＝8.0Hz,1H),7.16-7.10(m,3H),6.98-6.97(m,3H),6.94-6.88(m,1H),6.44(s,1H),5.91(d,J＝8.0Hz,1H),4.19(t,J＝9.2Hz,2H),3.82-3.79(m,1H),3.72(t,J＝8.8Hz,1H),3.62(t,J＝8.8Hz,1H),3.53-3.49(m,1H),1.97-1.94(m,1H),1.89-1.85(m,1H),1.73-1.58(m,3H),1.52-1.47(s,1H),1.36-1.02(m,5H)。
m/z＝444[M+H]+。
步骤C：1-(N-(2-氯乙基)氨基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)-氮杂环丁烷-3-甲酰胺
Figure PCTCN2017077611-appb-000145
0℃下，在N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)氮杂环丁烷-3-甲酰胺(200mg,0.45mmol)和DIEA(320μL,1.81mmol)的二氯甲烷溶液中加入2-(氯乙基)氨基磺酰氯(147mg,0.90mmol)，升至 室温搅拌过夜。反应结束后加入1N HCl调pH至中性，分离有机相，无水硫酸钠干燥，减压浓缩，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物1-(N-(2-氯乙基)氨基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)-氮杂环丁烷-3-甲酰胺(100mg,收率38％)。
1H-NMR(400MHz,CDCl3):δ＝7.34(d,J＝8.0Hz,1H),7.15-7.13(m,3H),6.98-6.97(m,3H),6.89(t,J＝8.0Hz,1H),6.43(s,1H),5.47(d,J＝8.4Hz,1H),4.69(t,J＝6.4Hz,1H),4.17-4.10(m,2H),3.87-3.83(m,1H),3.68-3.63(m,3H),3.59(t,J＝8.8Hz,1H),3.46-3.43(m,2H),3.26(t,J＝8.8Hz,1H),2.02-2.00(m,1H),1.91-1.89(m,1H),1.76-1.64(m,2H),1.40-1.02(m,6H)。
m/z＝585[M+H]+。
步骤D：1-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017077611-appb-000146
室温下，在5mL DMF中加入1-(N-(2-氯乙基)氨基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)-氮杂环丁烷-3-甲酰胺(100mg,0.17mmol)和碳酸钾(48mg,0.34mmol)，室温搅拌过夜。反应结束后，混合物中加入20mL二氯甲烷，然后水洗(30mL×3)，有机相无水硫酸钠干燥，硅胶柱色谱(PE:EA＝1:1)分离得到固体产物1-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)氮杂环丁烷-3-甲酰胺(56mg,收率60％)。
1H-NMR(400MHz,CDCl3):δ＝7.34(d,J＝7.6Hz,1H),7.16-7.12(m,3H),6.98-6.94(m,3H),6.91-6.88(m,1H),6.44(s,1H),5.48(d,J＝7.6Hz,1H),4.39-4.34(m,2H),3.87-3.82(m,1H),3.72(t,J＝8.0Hz,1H),3.65(d,J＝7.6Hz,1H),3.38-3.30(m,1H),2.33(s,4H),2.02-1.99(m,1H),1.91-1.88(m,1H),1.75-1.59(m,3H),1.42-0.99(m,5H)。
m/z＝549[M+H]+。
实施例25：(S)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000147
步骤A：2-噁唑烷酮-3-磺酰氯
Figure PCTCN2017077611-appb-000148
冰浴搅拌下，向盛有氯磺酰异氰酸酯(30.0g,212.0mmol)的干燥二氯甲烷溶液中，缓慢滴加2-溴乙醇(15.0mL,212mmol)的二氯甲烷溶液。0℃下反应4小时，减压蒸馏浓缩得到2-噁唑烷酮-3-磺酰氯(39.4g,收率100％)。
1H-NMR(400MHz,CDCl3):δ＝4.63(t,J＝5.9Hz,2H),3.59(t,J＝5.9Hz,2H)。
步骤B：(S)-2-[(1-(4-甲氧苯基)乙基)氨基]乙酸苄酯
Figure PCTCN2017077611-appb-000149
向(S)-1-(4-甲氧苯基)乙基胺(1.95mL,12.0mmol)和三乙胺(5mL,36.1mmol)的二氯甲烷溶液中加入溴乙酸苄酯(1.95mL,13.2mmol)。室温搅拌反应过夜，加水淬灭，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(S)-2-[(1-(4-甲氧苯基)乙基)氨基]乙酸苄酯(2.2g,收率62％)。
1H-NMR(400MHz,CDCl3):δ＝7.40-7.29(m,5H),7.23-7.18(m,2H),6.88-6.82(m,2H),5.13(d,J＝1.0Hz,2H),3.79(s,3H),3.75(q,J＝6.5Hz,1H),3.30(q,J＝17.5Hz,2H),1.35(d,J＝6.6Hz,3H)。
m/z＝300[M+H]+。
步骤C：(S)-2-(N-(1-(4-甲氧苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酸苄酯
Figure PCTCN2017077611-appb-000150
冰浴搅拌下，向盛有(S)-2-[(1-(4-甲氧苯基)乙基)氨基]乙酸苄酯(2.2g,7.4mmol)的二氯甲烷溶液中，加入三乙胺(2.1mL,14.8mmol)，然后缓慢加2-噁唑烷酮-3-磺酰氯(2.1g,11.1mmol)，滴加完毕，将反应液升至室温搅拌过夜，向反应液中加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(S)-2-(N-(1-(4-甲氧苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酸苄酯(2.1g,收率64％)。
1H-NMR(400MHz,CDCl3):δ＝7.43-7.23(m,6H),6.90-6.80(m,2H),5.40(q,J＝7.0Hz,1H),5.02(d,J＝12.4Hz,2H),4.33-4.14(m,3H),4.05-3.80(m,3H),3.78(s,3H),1.55(d,J＝7.1Hz,3H)。
m/z＝449[M+H]+。
步骤D：(S)-2-(N-(1-(4-甲氧苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酸
Figure PCTCN2017077611-appb-000151
室温搅拌下，将钯碳(1.5g)加入到(S)-2-(N-(1-(4-甲氧苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酸苄酯(1.5g,3.3mmol)的甲醇溶液中。氢气置换三次，室温反应过夜，过滤除去钯碳并真空浓缩得到(S)-2-(N-(1-(4-甲氧苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酸(1.2g,收率100％)。
1H-NMR(400MHz,CDCl3):δ＝7.31(d,J＝8.6Hz,2H),6.89-6.86(m,2H),5.36-5.26(m,1H),4.39-4.21(m,3H),4.06-3.82(m,3H),3.80(s,3H),1.60(d,J＝7.1Hz,3H)。
步骤E：(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-(N-((S)-1-(4-甲氧基苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000152
室温搅拌下，向3-氟苯胺(105.7μL,1.1mmol)的甲醇溶液中加入邻氯苯甲醛(123.8μL,1.1mmol)，反应15分钟后，加入(S)-2-(N-(1-(4-甲氧苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酸(394mg,1.1mmol)，继续反应30分钟后，加入1,1-二氟-3-环丁基异氰(128.8mg,1.1mmol)，室温反应过夜，经减压蒸馏浓缩，柱层析硅胶柱分离得到(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-(N-((S)-1-(4-甲氧基苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酰氨基)乙酰胺(70mg,收率9％)。
1H-NMR(400MHz,CDCl3):δ＝7.59-7.35(m,1H),7.36-7.23(m,3H),7.13(m,2H),7.02-6.79(m,6H),6.36(s,1H),6.13(s,1H),5.37(q,J＝6.9Hz,1H),4.31-4.29(t,J＝8.2Hz,3H),4.00-3.91(m,3H),3.80(s,3H),3.69(s,1H),3.04-2.94(m,2H),2.69-2.39(m,2H),1.54(d,J＝7.0Hz,3H)。
m/z＝709[M+H]+。
步骤F：(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)((S)-1-(4-甲氧苯基)乙基)氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000153
冰浴搅拌下，向盛有(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-(N-((S)-1-(4-甲氧基苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酰氨基)乙酰胺(59mg,0.08mmol)的甲醇溶液中，滴加氢氧化钠溶液(0.24mL,1M,0.24mmol)。滴加完毕升至室温搅拌0.5小时，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)((S)-1-(4-甲氧苯基)乙基)氨基)乙酰氨基)乙酰胺(41mg,收率72％)。
1H-NMR(400MHz,CDCl3):δ＝7.52(s,1H),7.33-7.26(m,2H),7.17-7.11(m,2H),7.02-6.88(m,4H),6.82(m,3H),6.37(s,1H),6.16-5.96(m,2H),5.12(q,J＝6.8Hz,1H),4.31(s,1H),3.85-3.82(m,2H),3.78(s,3H),3.75-3.65(m,1H),3.46-3.17(m,3H),3.16-2.91(m,2H),2.70-2.36(m,3H),1.53(d,J＝7.1Hz,3H)。
m/z＝683[M+H]+。
步骤G：(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000154
冰浴搅拌下，向盛有(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰 基)((S)-1-(4-甲氧苯基)乙基)氨基)乙酰氨基)乙酰胺(41mg,0.06mmol)的二氯甲烷溶液中，滴加三氟乙酸(0.6mL)。滴加完毕升至搅拌0.5小时，减压蒸馏后，加入二氯甲烷，用饱和碳酸氢钠溶液洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)氨基)乙酰氨基)乙酰胺(32mg,收率97％)。
1H-NMR(400MHz,CDCl3):δ＝7.36(d,J＝7.9Hz,1H),7.23-7.10(m,3H),7.06-6.89(m,4H),6.41(s,1H),6.14(d,J＝6.4Hz,1H),5.51(t,J＝5.3Hz,1H),4.88(t,J＝5.8Hz,1H),4.29(s,1H),3.79-3.71(m,2H),3.62(d,J＝5.1Hz,2H),3.26-3.22(m,2H),3.18-2.91(m,3H),2.60-2.43(m,2H)。
m/z＝549[M+H]+。
步骤H：(S)-2-((N-(2-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)氨磺酰基)氨基)乙基4-甲基苯磺酸酯
Figure PCTCN2017077611-appb-000155
冰浴搅拌下，向盛有(S)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)氨基)乙酰氨基)乙酰胺(32mg,0.06mmol)的二氯甲烷溶液中，加入三乙胺(25μL,0.18mmol)，然后加入对甲苯磺酰氯(20mg,0.1mmol)，滴加完毕，将反应液升至室温搅拌过夜，向反应液中加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(S)-2-((N-(2-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)氨磺酰基)氨基)乙基4-甲基苯磺酸酯(32mg,收率50％)。
m/z＝703[M+H]+。
步骤I：(S)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000156
将碳酸钾(8mg,0.06mmol)加入到(S)-2-((N-(2-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)氨磺酰基)氨基)乙基4-甲基苯磺酸酯(21mg,0.03mmol)的DMF溶液中。室温搅拌反应过夜，加水淬灭，用乙酸乙酯萃取，合并的有机相用盐水洗涤3次，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(S)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(14mg,收率88％)。
1H-NMR(400MHz,CDCl3):δ＝7.52(s,1H),7.36(d,J＝7.9Hz,1H),7.22-7.08(m,2H),7.04-6.90(m,3H),6.79-6.47(m,1H),6.44(s,1H),6.12(d,J＝6.4Hz,1H),5.71(s,1H),4.29(s,1H),3.75(d,J＝16.7Hz,2H),3.07-2.93(m,2H),2.63-2.37(m,2H),2.30(s,4H)。
m/z＝531[M+H]+。
实施例26：(R)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000157
步骤A：(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-(N-((S)-1-(4-甲氧基苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000158
(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-(N-((S)-1-(4-甲氧基苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酰氨基)乙酰胺由实施例25步骤E分离得到，(65mg,收率8％)。
1H-NMR(400MHz,CDCl3):δ＝7.37(d,J＝8.0Hz,1H),7.25(m,2H),7.17(m,2H),7.00-6.80(m,6H),6.75(s,1H),6.58(s,1H),6.50-6.10(brs,1H),5.37(q,J＝7.0Hz,1H),4.44-4.20(m,3H),4.09(d,J＝18.6Hz,1H),3.98-3.82(m,2H),3.77(s,3H),3.46(d,J＝18.5Hz,1H),3.08-2.89(m,2H),2.79-2.56(m,2H),1.62(d,J＝7.1Hz,3H)。
m/z＝709[M+H]+。
步骤B：(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)((S)-1-(4-甲氧苯基)乙基)氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000159
冰浴搅拌下，向盛有(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-(N-((S)-1-(4-甲氧基苯基)乙基)-2-噁唑烷酮-3-磺酰氨基)乙酰氨基)乙酰胺(44mg,0.06mmol)的甲醇溶液中，滴加氢氧化钠溶液(0.18mL,1M,0.18mmol)。滴加完毕升至室温搅拌0.5小时，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)((S)-1-(4-甲氧苯基)乙基)氨基)乙酰氨基)乙酰胺(32mg,收率76％)。
1H-NMR(400MHz,CDCl3):δ＝7.35(d,J＝8.0Hz,1H),7.28-7.23(m,2H),7.18-7.13(m,2H),7.02-6.76(m,7H),6.39(s,1H),6.20(d,J＝6.3Hz,1H),5.84(t,J＝6.2Hz,1H),5.12(q,J＝6.8Hz,1H),4.30(s,1H),3.82(s,2H),3.77(s,3H),3.68(d,J＝17.8Hz,1H),3.43-3.36(m,2H),3.27(d,J＝17.7Hz,1H),3.13-2.93(m,2H),2.61-2.49(m,3H),1.58(d,J＝7.0Hz,2H)。
m/z＝684[M+H]+。
步骤C：(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)氨基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000160
冰浴搅拌下，向盛有(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-{[N-(2-羟基乙基)氨基磺酰基][(S)-1-(4-甲氧苯基)乙基]氨基}乙酰氨基)乙酰胺(32mg,0.047mmol)的二氯甲烷溶液中，滴加三氟乙酸(0.4mL)。滴加完毕升至搅拌0.5小时，减压蒸馏后，加入二氯甲烷，用饱和碳酸氢钠溶液洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-((N-(2-羟基乙基)氨基磺酰基)氨基)乙酰氨基)乙酰胺(25mg,收率97％)。
1H-NMR(400MHz,CDCl3):δ＝7.36(d,J＝8.1Hz,1H),7.24-7.07(m,3H),7.07-6.90(m,4H),6.42(s,1H),6.14(d,J＝6.5Hz,1H),5.52(t,J＝5.1Hz,1H),4.89(t,J＝5.9Hz,1H),4.29(s,1H),3.79-3.72(m,2H),3.62(d,J＝5.1Hz,2H),3.27-3.23(m,2H),3.07-2.97(m,3H),2.70-2.35(m,2H)。
m/z＝549[M+H]+。
步骤D：(R)-2-((N-(2-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)氨基磺酰基)氨基)乙基4-甲基苯磺酸酯
Figure PCTCN2017077611-appb-000161
冰浴搅拌下，向盛有(R)-2-(2-氯苯基)-N-(3,3-二氟环丁基)-2-(N-(3-氟苯基)-2-{[N-(2-羟基乙基)氨基磺酰基]氨基}乙酰氨基)乙酰胺(25mg,0.045mmol)的二氯甲烷溶液中，加入三乙胺(12.6μL,0.091mmol)，然后加入对甲苯磺酰氯(10mg,0.055mmol)，滴加完毕，将反应液升至室温搅拌过夜，向反应液中加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(R)-2-((N-(2-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基)-2-氧代乙基)氨基磺酰基)氨基)乙基4-甲基苯磺酸酯(10mg,收率32％)。
1H-NMR(400MHz,CDCl3):δ＝7.80(d,J＝8.3Hz,2H),7.41-7.31(m,3H),7.22-7.11(m,3H),7.04-6.91(m,4H),6.47(s,1H),6.36(d,J＝6.5Hz,1H),5.50(t,J＝5.3Hz,1H),5.02(t,J＝6.3Hz,1H),4.30(s,1H),4.14(t,J＝5.3Hz,2H),3.66-3.52(m,2H),3.41-3.26(m,2H),3.09-2.89(m,2H),2.66-2.37(m,5H)。
m/z＝703[M+H]+。
步骤E：(R)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000162
将碳酸钾(4mg,0.024mmol)加入到(R)-2-[(N-{2-[{1-(2-氯苯基)-2-[(3,3-二氟环丁基)氨基]-2-氧代乙基}(3-氟苯基)氨基]-2-氧代乙基}氨基磺酰基)氨基]乙基4-甲基苯磺酸酯(10mg,0.014mmol)的DMF溶液中。室温搅拌反应过夜，加水淬灭，用乙酸乙酯萃取，合并的有机相用盐水洗涤3次，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(R)-2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(5mg,收率66％)。
1H-NMR(400MHz,CDCl3):δ＝7.78-7.44(m,1H),7.36(d,J＝8.0Hz,1H),7.18-7.14(m,2H),7.05-6.91(m,3H),6.77-6.49(m,1H),6.44(s,1H),6.10(d,J＝6.2Hz,1H),5.67(t,J＝4.8Hz,1H),4.30(s,1H),3.82-3.68(m,2H),3.07-2.92(m,2H),2.60-2.44(m,2H),2.30(s,4H)。
m/z＝531[M+H]+。
实施例27：1-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
Figure PCTCN2017077611-appb-000163
步骤A：3-((1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)(3-氟苯基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯
Figure PCTCN2017077611-appb-000164
室温下，10mL甲醇中加入邻氯苯甲醛(226μL,2.00mmol)和间氟苯胺(192μL,2.00mmol)，搅拌十分钟后加入1-Boc-吡咯烷-3-甲酸(430mg,2.00mmol)，继续搅拌十分钟加入环己基异氰(220mg,2.00mmol)，室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物3-((1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)(3-氟苯基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯(678mg,收率61％)。
1H-NMR(400MHz,CDCl3):δ＝7.35-7.31(m,1H),7.16-7.11(m,3H),7.02-6.87(m,4H),6.45-6.42(m,1H),5.58-5.47(m,1H),3.85-3.83(m,1H),3.52-3.45(m,3H),3.14-3.12(m,1H),2.85-2.81(m,1H),2.23-2.16(m,1H),2.01-1.98(m,1H),1.90-1.88(m,2H),1.74-1.56(m,2H),1.42(s,9H),1.38-0.98(m,6H)。
m/z＝558[M+H]+。
步骤B：1-(N-(2-氯乙基)氨磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
Figure PCTCN2017077611-appb-000165
在3-((1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)(3-氟苯基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯(678mg, 1.21mmol)的二氯甲烷溶液中加入3mL TFA，室温搅拌1小时。反应结束后减压旋蒸除去TFA和溶剂得到固体产物(620mg)。0℃下，在该固体化合物(620mg,1.35mmol)和DIEA(895μL,5.41mmol)的二氯甲烷溶液中加入2-(氯乙基)氨基磺酰氯(441mg,2.71mmol)，升至室温搅拌过夜。反应结束后加入1N HCl调pH至中性，分离有机相，无水硫酸钠干燥，减压浓缩，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物1-(N-(2-氯乙基)氨磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(481mg,收率66％)。
1H-NMR(400MHz,CDCl3):δ＝7.63(br s,1H),7.35-7.32(m,1H),7.16-7.12(m,2H),6.98-6.97(m,2H),6.91-6.87(m,1H),6.42(d,J＝5.6Hz,1H),5.52-5.46(m,1H),5.02-4.98(m,1H),3.87-3.80(m,1H),3.68-3.56(m,3H),3.52-3.22(m,5H),2.99-2.95(m,1H),2.26-2.21(m,1H),1.96-1.89(m,3H),1.74-1.59(m,3H),1.42-1.30(m,3H),1.21-1.01(m,3H)。
m/z＝599[M+H]+。
步骤C：1-(氮丙啶-1-基磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
Figure PCTCN2017077611-appb-000166
室温下，在15mL DMF中加入1-(N-(2-氯乙基)氨磺酰基)-N-(1-(2-氯苯基)-2-环己基氨基-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(481mg,0.80mmol)和碳酸钾(22mg,1.60mmol)，室温搅拌过夜。反应结束后，混合物中加入20mL二氯甲烷，然后水洗(30mL×3)，有机相无水硫酸钠干燥，硅胶柱色谱(PE:EA＝2:1)分离得到标题化合物(397mg,收率88％)。
1H-NMR(400MHz,CDCl3):δ＝7.68(br s,1H),7.35-7.32(m,1H),7.15-7.11(m,1H),7.01-6.97(m,2H),6.92-6.87(m,1H),6.44-6.40(m,1H),5.45(d,J＝8.0Hz,1H),3.84-3.82(m,1H),3.67-3.47(m,3H),3.39-3.32(m,1H),2.97-2.93(m,1H),2.31-2.25(m,1H),2.23(s,4H),1.98-1.90(m,3H),1.79-1.58(m,3H),1.38-1.24(m,3H),1.172-1.01(m,3H).
m/z＝563[M+H]+。
实施例28：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氨基磺酰基苯基)乙酰胺
Figure PCTCN2017077611-appb-000167
步骤A：2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氨基磺酰基苯基)乙酰胺
Figure PCTCN2017077611-appb-000168
参照实施例13中的步骤C，由3-氨基苯磺酰胺(45.7μL,0.37mmol)和2-((N-(2-氯乙基)氨基磺酰基)氨基)乙酸(3g,17.9mmol)得到2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氨基磺酰基苯基)乙酰胺(80mg,收率34％)。
1H-NMR(400MHz,CDCl3):δ＝8.50-8.36(m,1H),8.11-7.93(m,1H),7.81(d,J＝7.6Hz,1H),7.55-7.45(m,1H),7.38(d,J＝8.0Hz,1H),7.20(t,J＝8.5Hz,1H),7.07-6.92(m,2H),6.53(s,2H),5.85(t,J＝4.4Hz,1H),5.66-5.21(m,3H),4.27(s,1H),3.67(t,J＝5.9Hz,2H),3.51(s,2H),3.44-3.38(m,2H),3.04-2.91(m,2H),2.60-2.39(m,2H)。
m/z＝628[M+H]+。
步骤B：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氨基磺酰基苯基)乙酰胺
Figure PCTCN2017077611-appb-000169
参照实施例1中的步骤E，由2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氨基磺酰基苯基)乙酰胺(80mg,0.127mmol)得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氨基磺酰基苯基)乙酰胺(20mg,收率27％)。
1H-NMR(400MHz,CDCl3):δ＝8.50和8.00(brs,1H),7.80(d,J＝6.3Hz,1H),7.57和7.52(brs,1H),7.36(d,J＝8.0Hz,1H),7.21-7.15(m,2H),7.00(s,2H),6.71-6,65(m,1H),6.50(s,1H),6.24(s,1H),5.68(s,1H),5.34-5.21(m,1H),4.22(s,1H),3.84(s,2H),3.04-2.81(m,2H),2.60-2.26(m,6H)。
m/z＝592[M+H]+。
实施例29：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3,4-二氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000170
步骤A：2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3,4-二氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000171
参照实施例13中的步骤C，由3,4-二氟苯胺(63mg,0.49mmol)和2-((N-(2-氯乙基)氨基磺酰基)氨基)乙酸(106mg,0.49mmol)得到2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3,4-二氟苯基)乙酰胺(4.67g,收率90％)。
1H-NMR(400MHz,CDCl3):δ＝7.83-7.54(m,1H),7.38(d,J＝7.7Hz,1H),7.21(t,J＝7.4Hz,1H),7.04(t,J＝7.2Hz,1H),6.95(d,J＝7.9Hz,1H),6.90-6.78(m,1H),6.57(s,1H),6.44(s,1H),6.12(d,J＝6.6Hz,1H),5.57(t,J＝5.0Hz,1H),4.77(t,J＝6.4Hz,1H),4.30(s,1H),3.67(t,J＝5.7Hz,2H),3.60-2.56(m,2H),3.44-3.33(m,2H),3.11-2.91(m,2H),2.64-2.39(m,2H)。
m/z＝585[M+H]+。
步骤B：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3,4-二氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000172
参照实施例1中的步骤E，由2-((N-(2-氯乙基)氨基磺酰基)氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3,4-二氟苯基)乙酰胺(95mg,0.162mmol)得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3,4-二氟苯基)乙酰胺(62mg,收率70％)。
1H-NMR(400MHz,CDCl3):δ＝7.81-7.63(m,1H),7.39(d,J＝7.9Hz,1H),7.23(t,J＝7.6Hz,1H),7.05(t,J＝7.2Hz,1H),7.01-6.94(m,1H),6.88(s,1H),6.57(s,1H),6.44(s,1H),6.17(d,J＝6.5Hz,1H),5.79(t,J＝4.8Hz,1H),4.30(s,1H),3.82-3.69(m,2H),3.17-2.90(m,2H),2.61-2.56(m,1H),2.47-2.42(m,1H),2.32(s,4H)。
m/z＝549[M+H]+。
实施例30：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(4,4-二氟环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000173
步骤A：4-氧代环己基氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000174
冰浴搅拌下，将戴斯-马丁氧化剂(29.0g,68.3mmol)滴加到盛有N-4-Boc-氨基环己醇(9.8g,45.52mmol)的二氯甲烷(200mL)溶液中，升至室温并搅拌反应混合物过夜。在冰浴下用饱和硫代硫酸钠水溶液小心淬灭，二氯甲烷萃取三次，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到4-氧代环己基氨基甲酸叔丁酯(7.96g，收率82.1％)。
步骤B：(4,4-二氟环己基)氨基甲酸叔丁酯
Figure PCTCN2017077611-appb-000175
冰盐浴搅拌下，将二乙胺基三氟化硫(8.54g,52.981mmol)逐滴加入到盛有4-氧代环己基氨基甲酸叔丁酯(7.96g,37.323mmol)的二氯甲烷(200mL)溶液中，缓慢升至室温并搅拌反应混合物过夜。在冰浴下用饱和氯化铵水溶液小心淬灭，二氯甲烷萃取三次，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(4,4-二氟环己基)氨基甲酸叔丁酯(约70％)和4-氟环己基-3烯基甲酸叔丁酯(约30％)。
冰浴搅拌下，将m-CPBA(6.9g,40.0mmol)缓慢滴加到上述混合物的二氯甲烷溶液中并保持体系内温度在5℃以下，滴加完毕后升至室温搅拌过夜。在冰浴下用饱和硫代硫酸钠水溶液小心淬灭并在室温下搅拌半小时，二氯甲烷萃取三次，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，无须纯化直接用于下一步。
将上述浓缩残留物溶于甲醇中，冰浴下，少量分批次加入硼氢化钠(630mg,16.662mmol)。反应混合物升至室温搅拌过夜，溶剂甲醇真空浓缩，冰浴下加水淬灭，室温下搅拌半小时充分淬灭，乙酸乙酯萃取三次，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩得(4,4-二氟环己基)氨基甲酸叔丁酯(4.8g,收率54.7％)。
1H-NMR(400MHz,CDCl3):δ＝4.46(s,1H),3.59(s,1H),2.25-1.69(m,6H),1.61-1.20(m,11H)。
步骤C：4,4-二氟环己胺盐酸盐
Figure PCTCN2017077611-appb-000176
(4,4-二氟环己基)氨基甲酸叔丁酯(1.4g,5.950mmol)和6N HCl/MeOH(14mL)的混合物在室温下搅拌2小时，真空下浓缩得到4,4-二氟环己胺盐酸盐(1.02g,收率100％)，无须纯化直接投下一步。
1H-NMR(400MHz,CDCl3):δ＝4.89(s,2H),3.32-3.26(m,1H),2.14-2.01(m,4H),2.02-1.85(m,2H),1.74-1.65(m,2H)。
步骤D：N-(4,4-二氟环己基)甲酰胺
Figure PCTCN2017077611-appb-000177
4,4-二氟环己胺盐酸盐(1.02g,5.943mmol)，TEA(1.82g,17.830mmol)和甲酸乙酯(14mL)的混合物在80℃下封管密封搅拌过夜，真空浓缩，柱层析硅胶柱分离得到N-(4,4-二氟环己基)甲酰胺(854mg,收率88.0％)。
1H-NMR(400MHz,CDCl3):δ＝8.14(s,1H),5.98(s,1H),3.96-3.90(m,1H),2.54-2.19(m,1H),2.15-1.39(m,7H)。
步骤E：1,1-二氟-4-异氰环已烷
Figure PCTCN2017077611-appb-000178
冰盐浴搅拌下，将三光气(129mg,0.434mmol)的二氯甲烷溶液滴加到N-(4,4-二氟环己基)甲酰胺(202 mg,1.24mmol)和TEA(437mg,3.72mmol)的二氯甲烷的混合物中，室温下搅拌2小时，冰浴旋转蒸发除去二氯甲烷，向残留物加入乙醚，柱层析硅胶柱(洗脱剂为乙醚)分离，冰浴旋转蒸发得到(180mg,收率100％)，直接投下一步。
步骤F：2-(N-(2-氯乙基)氨基磺酰氨基)-N-(1-(2-氯苯基)-2-(4,4-二氟环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000179
室温搅拌下2-氯-苯甲醛(64mg,0.462mmol)和3-氟苯胺(52mg,0.462mmol)于MeOH(6.0mL)中的混合物30分钟。添加2-(N-(2-氯乙基)氨基磺酰氨基)乙酸(100mg,0.462mmol)并搅拌反应混合物10分钟。然后添加1,1-二氟-4-异氰环已烷(67mg,0.462mmol)并且在室温下搅拌反应混合物过夜。真空除去溶剂，柱层析硅胶柱分离得到2-(N-(2-氯乙基)氨基磺酰氨基)-N-(1-(2-氯苯基)-2-(4,4-二氟环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(190mg，收率69.1％)，直接投入下一步。
m/z＝595[M+H]+。
步骤G：2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(4,4-二氟环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺
Figure PCTCN2017077611-appb-000180
室温搅拌下，向盛有2-(N-(2-氯乙基)氨基磺酰氨基)-N-(1-(2-氯苯基)-2-(4,4-二氟环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(190mg,0.319mmol)的DMF溶液中，加入碳酸钾(132mg,0.576mmol)。反应混合物室温搅拌过夜。反应完毕，加水，用乙酸乙酯萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到2-(氮丙啶-1-磺酰氨基)-N-(1-(2-氯苯基)-2-(4,4-二氟环己基氨基)-2-氧代乙基)-N-(3-氟苯基)乙酰胺(140mg，收率78.7％)。
1H-NMR(400MHz,CDCl3):δ＝7.37-7.33(m,2H),7.23-7.10(m,2H),7.07-6.87(m,4H),6.41(s,1H),5.53(dd,J＝11.7,6.5Hz,2H),3.96(s,1H),3.77-3.69(m,2H),2.30-2.23(m,4H),2.14-1.75(m,6H),1.59(d,J＝10.0Hz,2H)。
m/z＝559[M+H]+。
实施例31：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(((R)-2-甲基氮丙啶)-1-磺酰胺基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000181
步骤A：2-[(氯磺酰基)氨基]乙酸甲酯
Figure PCTCN2017077611-appb-000182
向盛有甘氨酸甲酯盐酸盐(5.0g,39.8mmol)的乙腈溶液中，加入氯磺酸(18.7mL,230.7mmol)。然后将反应液加热至80℃反应18小时，减压蒸馏得2-[(氯磺酰基)氨基]乙酸甲酯(6.5g,收率87％)。
步骤B：(R)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸甲酯
Figure PCTCN2017077611-appb-000183
冰浴搅拌下，向盛有D-氨基丙醇(500mg,6.66mmol)的二氯甲烷溶液中，加入三乙胺(1.8mL,13.3mmol)，然后滴加2-[(氯磺酰基)氨基]乙酸甲酯(1.37g,7.30mmol)，滴加完毕，将反应液升至室温搅拌过夜，向反应液中加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取，合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并真空浓缩，柱层析硅胶柱分离得到(R)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸甲酯(99mg,收率7％)。
1H-NMR(400MHz,CDCl3):δ＝4.92(s,1H),4.02(d,J＝5.5Hz,2H),3.80(s,3H),2.78-2.66(m,1H),2.52(d,J＝6.9Hz,1H),2.02(d,J＝4.5Hz,1H),1.29(d,J＝5.6Hz,3H)。
步骤C：(R)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸
Figure PCTCN2017077611-appb-000184
氢氧化锂(44mg,1.8mmol)加入到(R)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸甲酯(95mg,0.456mmol)的甲醇和水的混合溶液(甲醇/水＝5/1)中。室温搅拌反应过夜，减压蒸馏除去甲醇溶液，使用pH为1的盐酸溶液将反应液调到pH为4，然后乙酸乙酯萃取，经硫酸钠干燥，过滤并真空浓缩得到(R)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸(26mg,收率29％)。
1H-NMR(400MHz,CDCl3):δ＝8.88(s,1H),5.48(s,1H),4.05(s,2H),2.73(d,J＝4.9Hz,1H),2.52(d,J＝6.6Hz,1H),2.06(d,J＝4.2Hz,1H),1.30(d,J＝5.3Hz,3H)。
步骤D：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(((R)-2-甲基氮丙啶)-1-磺酰胺基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000185
参照实施例1中的步骤B，由(R)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸(20mg,0.103mmol)得到2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(((R)-2-甲基氮丙啶)-1-磺酰胺基)乙酰氨基)乙酰胺(45mg,收率81％)。
1H-NMR(400MHz,CDCl3):δ＝7.80-7.56(m,1H),7.36(d,J＝8.0Hz,1H),7.18-7.17(m,2H),7.01-6.89(m,4H),6.42(d,J＝5.1Hz,1H),5.53-5.30(m,2H),3.88-3.60(m,3H),2.69-2.68(m,1H),2.50-2.48(m,1H),2.02-1.88(m,2H),1.89-1.86(m,1H),1.75-1.58(m,4H),1.43-1.28(m,5H),1.27-0.96(m,2H)。
m/z＝537[M+H]+。
实施例32：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(((S)-2-甲基氮丙啶)-1-磺酰胺基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000186
步骤A：(S)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸甲酯
Figure PCTCN2017077611-appb-000187
参照实施例31中的步骤B，由L-氨基丙醇(1g,13.3mmol)得到(S)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸甲酯(160mg,收率6％)。
1H-NMR(400MHz,CDCl3):δ＝4.93(s,1H),4.06-4.00(m,2H),3.86-3.76(m,3H),2.77-2.65(m,1H),2.52(d,J＝6.9Hz,1H),2.02(d,J＝4.5Hz,1H),1.36-1.26(m,3H)。
步骤B：(S)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸
Figure PCTCN2017077611-appb-000188
参照实施例31中的步骤B，由(S)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸甲酯(95mg,0.457mmol)得到(S)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸(80mg,收率90％)。
1H-NMR(400MHz,CDCl3):δ＝12.73(s,1H),7.79(t,J＝5.2Hz,1H),3.72(d,J＝5.4Hz,2H),2.50-2.45(m,1H),2.25(d,J＝7.2Hz,1H),1.99(d,J＝4.4Hz,1H),1.17(d,J＝5.6Hz,3H)。
步骤C：2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(((S)-2-甲基氮丙啶)-1-磺酰胺基)乙酰氨基)乙酰胺
Figure PCTCN2017077611-appb-000189
参照实施例1中的步骤B，由(S)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸(39mg,0.20mmol)得到2-(2-氯苯基)-N-环己基-2-(N-(3-氟苯基)-2-(((S)-2-甲基氮丙啶)-1-磺酰胺基)乙酰氨基)乙酰胺(60mg,收率56％)。
1H-NMR(400MHz,CDCl3):δ＝7.70-7.66(m,1H),7.34(d,J＝8.0Hz,1H),7.16-7.14(m,2H),7.24-6.68(m,4H),6.42(d,J＝4.9Hz,1H),5.52-5.47(m,2H),3.89-3.60(m,3H),2.70-2.66(m,1H),2.49-2.45(m,1H),2.20-1.97(m,2H),1.88-1.85(m,1H),1.79-1.51(m,4H),1.51-0.94(m,7H)。
m/z＝537[M+H]+。
实施例33：2-(2-氯苯基)-2-(N-(3-氰基-5-氟苯基)-2-(((S)-2-甲基氮丙啶)-1-磺酰氨基)乙酰氨基)-N-(3,3-二氟环丁基)乙酰胺
Figure PCTCN2017077611-appb-000190
参照实施例13中的步骤C，由3-氨基-5-氟苯腈(27mg，0.2mmol)和(S)-2-(2-甲基氮丙啶-1-磺酰氨基)乙酸(20mg,0.103mmol)得到2-(2-氯苯基)-2-(N-(3-氰基-5-氟苯基)-2-(((S)-2-甲基氮丙啶)-1-磺酰氨基)乙酰氨基)-N-(3,3-二氟环丁基)乙酰胺(3.9mg,收率3.4％)。
1H-NMR(400MHz,CDCl3):δ＝8.02-7.97(m,1H),7.41(d,J＝8.0Hz,1H),7.29-7.19(m,1H),7.07-7.03(m,2H),6.97-6.93(m,1H),6.93-6.80(m,1H),6.45(d,J＝7.7Hz,1H),6.25-6.22(m,1H),5.77(d,J＝21.2Hz,1H),4.29(s,1H),3.80-3.67(m,3H),3.17-2.74(m,2H),2.75-2.69(m,1H),2.56-2.43(m,2H),2.03(t,J＝4.8Hz,1H),1.30(d,J＝8.0Hz,3H)。
m/z＝570[M+H]+。
实施例34：(S)-1-(氮丙啶-1-基磺酰基)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
实施例35：(S)-1-(氮丙啶-1-基磺酰基)-N-((R)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
Figure PCTCN2017077611-appb-000191
步骤A：(S)-3-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯
Figure PCTCN2017077611-appb-000192
室温下，10mL甲醇中加入邻氯苯甲醛(210μL,1.85mmol)和间氟苯胺(179μL,1.85mmol)，搅拌十分 钟后加入(S)-1-Boc-吡咯烷-3-甲酸(400mg,1.85mmol)，继续搅拌十分钟加入1,1-二氟-3-异氰基环丁烷(217mg,1.85mmol)，室温搅拌过夜。反应结束后，减压除去溶剂，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物(S)-3-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯(346mg,收率32％)。
1H-NMR(400MHz,CDCl3):δ＝7.53-7.48(m,1H),7.37-7.33(m,2H),7.18-7.16(m,2H),7.00-6.89(m,3H),6.45-6.42(m,1H),6.29-6.22(m,1H),4.32-4.30(m,1H),3.65-3.37(m,4H),3.12-2.98(m,2H),2.85-2.81(m,1H),2.55-2.52(m,1H),2.41-2.36(m,1H),2.23-2.21(m,1H),2.05(s,1H),1.46(s,9H)。
m/z＝566[M+H]+。
步骤B：(3S)-1-(N-(2-氯乙基)氨基磺酰基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
Figure PCTCN2017077611-appb-000193
在(S)-3-((1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)(3-氟苯基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯(173mg,0.31mmol)的二氯甲烷溶液中加入0.5mL TFA，室温搅拌1小时。反应结束后减压旋蒸除去TFA和溶剂得到固体产物(140mg)。0℃下，在该固体化合物(140mg,0.30mmol)和DIEA(198μL,1.20mmol)的二氯甲烷溶液中加入2-(氯乙基)氨基磺酰氯(98mg,0.60mmol)，升至室温搅拌过夜。反应结束后加入1N HCl调pH至中性，分离有机相，无水硫酸钠干燥，减压浓缩，硅胶柱色谱(PE:EA＝2:1)分离得到固体产物(3S)-1-(N-(2-氯乙基)氨基磺酰基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(60mg,收率32％)。
1H-NMR(400MHz,CDCl3):δ＝7.53(br s,1H),7.36-7.34(m,1H),7.20-7.17(m,1H),7.10(brs,1H),7.00-6.91(m,3H),6.60(brs,1H),6.44-6.42(m,1H),6.14-6.06(m,1H),4.94-4.87(m,1H),4.32-4.30(m,1H),3.69-3.65(m,2H),3.57-3.50(m,1H),3.46-3.25(m,5H),3.06-2.95(m,3H),2.59-2.36(m,2H),2.27-2.18(m,1H),1.94-1.90(m,1H)。
m/z＝607[M+H]+。
步骤C：(S)-1-(氮丙啶-1-基磺酰基)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(实施例34)
(S)-1-(氮丙啶-1-基磺酰基)-N-((R)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(实施例35)
Figure PCTCN2017077611-appb-000194
Figure PCTCN2017077611-appb-000195
室温下，在1mL DMF中加入(3S)-1-(N-(2-氯乙基)氨基磺酰基)-N-(1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(30mg,0.049mmol)和碳酸钾(14mg,0.098mmol)，室温搅拌过夜。反应结束后，混合物中加入20mL二氯甲烷，然后水洗(30mL×3)，有机相无水硫酸钠干燥，硅胶柱色谱(PE:EA＝1:1)分离得到固体产物(S)-1-(氮丙啶-1-基磺酰基)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(6mg,收率21％)和(S)-1-(氮丙啶-1-基磺酰基)-N-((R)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺(6mg,收率21％)。
实施例34：1H-NMR(400MHz,CDCl3):δ＝7.57(br s,1H),7.36-7.34(m,1H),7.19-7.16(m,2H),7.02-6.97(m,2H),6.94-6.90(m,2H),6.44(s,1H),6.33(d,J＝6.4Hz,1H),4.29-4.27(m,1H),3.56-3.44(m,3H),3.37-3.31(m,1H),3.04-2.93(m,3H),2.56-2.51(m,1H),2.41-2.36(m,1H),2.27-2.22(m,1H),2.04(s,4H),2.00-1.95(m,1H)。
m/z＝571[M+H]+。
实施例35：1H-NMR(400MHz,CDCl3):δ＝7.61(br s,1H),7.36-7.34(m,1H),7.17-7.15(m,2H),7.01-6.91(m,4H),6.48(s,1H),6.31(d,J＝6.4Hz,1H),4.33-4.30(m,1H),3.59-3.47(m,3H),3.35-3.29(m,1H),3.06-2.90(m,3H),2.57-2.50(m,1H),2.41-2.35(m,1H),2.29-2.21(m,1H),2.19(s,4H),2.02-1.93(m,1H)。
m/z＝571[M+H]+。
实施例36：(R)-1-(氮丙啶-1-基磺酰基)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
实施例37：(R)-1-(氮丙啶-1-基磺酰基)-N-((R)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-N-(3-氟苯基)吡咯烷-3-甲酰胺
Figure PCTCN2017077611-appb-000196
参照实施例34和35的制备，用(R)-1-Boc-吡咯烷-3-甲酸代替(S)-1-Boc-吡咯烷-3-甲酸，制备得到实施例36和37的产物。
实施例36：1H-NMR(400MHz,CDCl3):δ＝7.61(br s,1H),7.36-7.34(m,1H),7.17-7.15(m,2H), 7.01-6.91(m,4H),6.48(s,1H),6.31(d,J＝6.4Hz,1H),4.33-4.30(m,1H),3.59-3.47(m,3H),3.35-3.29(m,1H),3.05-2.90(m,3H),2.58-2.51(m,1H),2.41-2.35(m,1H),2.29-2.21(m,1H),2.19(s,4H),2.02-1.92(m,1H)。
m/z＝571[M+H]+。
实施例37：1H-NMR(400MHz,CDCl3):δ＝7.57(br s,1H),7.36-7.34(m,1H),7.19-7.16(m,2H),7.02-6.96(m,2H),6.94-6.91(m,2H),6.44(s,1H),6.33(d,J＝6.4Hz,1H),4.29-4.27(m,1H),3.55-3.44(m,3H),3.37-3.31(m,1H),3.04-2.94(m,3H),2.56-2.51(m,1H),2.41-2.36(m,1H),2.27-2.21(m,1H),2.04(s,4H),2.00-1.95(m,1H)。
m/z＝571[M+H]+。
生物活性实验
酶测定：
刃天青是一种传统的氧化还原染料，经过氧化还原作用，能够从没有荧光的蓝色刃天青还原成粉红色的荧光物质试卤灵，试卤灵可以用荧光光度计(Ex＝530-570nm，Em＝590-620nm)的相对荧光单位(RFU)来测量并量化。目前刃天青被广泛用于细菌、细胞等的活力测定以及氧化还原酶的酶活检测。我们通过检测辅助因子NADPH的消减来测定化合物针对IDHm的抑制活性，通过检测辅助因子NADPH的生成来测定化合物针对IDH WT的抑制活性。
将化合物与IDHm和NADPH进行预孵育，然后通过添加α-KG启动反应，线性条件下反应一定时间后，添加Diaphorase(硫辛酰胺脱氢酶)和相应的底物Resazurin(刃天青)进行检测。硫辛酰胺脱氢酶通过消减可供使用的辅助因子NADPH而终止IDH2m反应，它将NADPH氧化成NADP，并且将刃天青还原成高荧光的试卤灵，通过易于检测的荧光基团来量化在特定反应时间之后剩余的辅助因子NADPH的量。
将化合物与IDH-WT和NADP进行预孵育，然后通过添加异柠檬酸、Diaphorase(硫辛酰胺脱氢酶)和相应的底物Resazurin(刃天青)启动反应，线性条件下反应一定时间后，检测荧光物质的量。本实验将NADP还原成NADPH，后者在硫辛酰胺脱氢酶的作用下将刃天青还原成高荧光的试卤灵，通过检测的荧光基团来量化在特定反应时间之后生成的辅助因子NADPH的量，从而来计算化合物对IDH-WT的抑制作用。
具体操作方式为：将2.5μL 3×梯度稀释的化合物加到384孔板中，接着添加5μL含有40nM IDH1(R132H/R132C)和20μM NADPH的反应缓冲液(20mM Tris-HCl,pH7.5；150mM NaCl；10mM MgCl2；0.4mg/mL BSA(牛血清白蛋白)和2mM DTT(二硫代苏糖醇))。然后将上述测试混合物在23℃孵育16小时，之后添加2.5μL含有4mMα-KG的反应缓冲液起始反应。室温孵育60分钟后，加入5μL反应缓冲液配制的终止混合物(0.4U/ml Diaphorase和20μM Resazurin)，使刃天青转化成试卤灵来测量剩余的NADPH。23℃孵育10分钟后，通过Flexstation 3在Ex535/Em595下进行荧光值测定。每个化合物分别在12个浓度下测定酶的活性，使用GraFit6.0软件(Erithacus Software)计算数据，得到该化合物的IC50值。
化合物结合模式的测定：
将化合物同IDH1(R132H)进行孵育，将其分成N份，分别在不同的时间点加入乙腈终止反应，离心分离出有机相，并将样品于-80℃下保存直到分析，通过LC-MS/MS分析游离化合物的浓度，流动相A：水(0.1％甲酸)，B：乙腈(0.1％甲酸)，强洗针液为乙腈﹕水＝9﹕1，弱洗针液为乙腈﹕水＝1﹕9。
根据本文所述的生物学方法对上述制备的所选化合物进行分析，其结果如下：
1.化合物对IDH1突变型(R132H/R132C)的抑制活性(IC50)，如表1所示：
表1
实施例编号 IDH1(R132H)IC50(nM) IDH1(R132C)IC50(nM)
1 <20 --
2 <500 --
3 <10000 --
4 <100 --
5 <20 --
6 <20 --
7 <10000 --
8 <20 --
9 <100 --
10 <20 --
11 <100 --
12 <20 --
13 <20 --
14 <20 --
15 <20 --
16 <20 --
17 <20 --
18 <10000 --
19 <100 --
20 <20 --
21 <20 --
22 <20 --
23 <100 --
24 <20 --
25 <20 <20
26 <100 --
27 <20 --
28 <100 --
29 <20 --
30 <20 --
31 <20 --
32 <20 --
33 <100 --
34 <20 --
35 <20 --
36 <20 --
37 <1000 --
2.化合物与IDH1(R132H)结合模式的试验
如图1可知，实施例10中的化合物与酶的结合随着时间的增长而增多。
药代药动实验
雄性SD大鼠来源于北京维通利华实验动物技术有限公司，将大鼠分组，每组3只，分别口服单次灌胃给予待测样品混悬液(5mg/kg)。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8、和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC-MS/MS分析，流动相A：水(0.1％甲酸)，B：乙腈(0.1％甲酸)，强洗针液为乙腈﹕水＝9﹕1，弱洗针液为乙腈﹕水＝1﹕9。
表2
Figure PCTCN2017077611-appb-000197
Figure PCTCN2017077611-appb-000198
如图2(图2中的#7、#8、#9为试验大鼠的编号)所示PK曲线及表2所示数据可知，实施例10的化合物具有独特的药代动力学性能，其体内药物浓度随着时间延长呈下降趋势，这一趋势与药物和IDH1m的缓慢结合模式十分吻合，说明随着时间延长，该类药物逐渐结合到IDH1m上，从而药物在血浆中的浓度逐渐下降。

Claims (20)

  1. 式I化合物或其药学上可接受的盐、溶剂化物或水合物：
    Figure PCTCN2017077611-appb-100001
    其中，
    W为-(X1)p-(X2)q-(X3)r-；
    X1选自C1-6亚烷基，其可任选地被一个或多个独立地选自R5的基团取代；
    X2选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R6的基团取代；
    X3选自-NR7-；
    p为0或1；
    q为0或1；
    r为0或1；
    且p、q、r不同时为0；
    R1选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R8的基团取代；
    R2选自苯基或含有1-2个选自N、O或S原子的5-6元杂芳基，其可任选地被一个或多个独立地选自R9的基团取代；
    每个R3和R4分别独立地选自卤素、氨基、羟基、卤代C1-3烷基或C1-6烷基；
    R5、R6和R8分别独立地选自卤素、氨基、羟基、氰基、卤代C1-3烷基、C1-6烷基或C3-6环烷基；
    R7选自氢、C1-3烷基或氨基保护基；
    R9选自卤素、氨基、羟基、氰基、卤代C1-3烷基或氨基磺酰基；
    m为0或1；
    n为0或1。
  2. 式II化合物或其药学上可接受的盐、溶剂化物或水合物：
    Figure PCTCN2017077611-appb-100002
    其中，
    W为-(X1)p-(X2)q-(X3)r-；
    X1选自C1-6亚烷基，其可任选地被一个或多个独立地选自R5的基团取代；
    X2选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R6的基团取代；
    X3选自-NR7-；
    p为0或1；
    q为0或1；
    r为0或1；
    且p、q、r不同时为0；
    R1选自C3-6环烷基或C3-6杂环烷基，其可任选地被一个或多个独立地选自R8的基团取代；
    R2选自苯基或含有1-2个选自N、O或S原子的5-6元杂芳基，其可任选地被一个或多个独立地选自R9的基团取代；
    每个R3独立地选自卤素、氨基、羟基、卤代C1-3烷基或C1-6烷基；
    R5、R6和R8分别独立地选自卤素、氨基、羟基、氰基、卤代C1-3烷基、C1-6烷基或C3-6环烷基；
    R7选自氢、C1-3烷基或氨基保护基；
    R9选自卤素、氨基、羟基、氰基、卤代C1-3烷基或氨基磺酰基；
    n为0或1。
  3. 权利要求1或2所述的化合物：X1选自C1-6亚烷基；优选，X1选自-CH2-、-CH2CH2-、-CH(CH3)-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH2CH2CH2-、-CH(CH3)CH2CH2CH2-、-CH2CH(CH3)CH2CH2-、-CH2CH2CH2CH2CH2CH2-、-CH(CH3)CH2CH2CH2CH2-、-CH2CH(CH3)CH2CH2CH2-或-CH2CH2CH(CH3)CH2CH2-；进一步优选，X1选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-或-CH(CH3)-。
  4. 权利要求1-3任一项所述的化合物：X2选自环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2017077611-appb-100003
    Figure PCTCN2017077611-appb-100004
    Figure PCTCN2017077611-appb-100005
    优选，X2选自吡咯烷基、环丁基、或氮杂环丁基；进一步优选，X2选自
    Figure PCTCN2017077611-appb-100006
  5. 权利要求1-4任一项所述的化合物：X3选自-NH-、-N(CH3)-或-N(Boc)-。
  6. 权利要求1-5任一项所述的化合物：R7选自氢、甲基、乙基、叔丁氧羰基、苄氧羰基、对甲苯磺酰基、三苯甲基、甲酰基、2-联苯基-2-丙氧羰基或三氟乙酰基；优选，R7选自氢、甲基、叔丁氧羰基或苄氧羰基。
  7. 权利要求1-6任一项所述的化合物：W为-CH2NR7-、CH(CH3)NR7-、-CH2CH2NR7-、-CH2CH2CH2NR7、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、
    Figure PCTCN2017077611-appb-100007
    Figure PCTCN2017077611-appb-100008
    优选，W为-CH2-、-CH2NH-、-CH2N(CH3)-、-CH2N(Boc)-、-CH(CH3)NH-、-CH2CH2-、-CH2CH2NH-、-CH2CH2CH2-、-CH2CH2CH2NH-、-CH2CH2CH2CH2-、
    Figure PCTCN2017077611-appb-100009
    Figure PCTCN2017077611-appb-100010
  8. 权利要求1-7任一项所述的化合物：R1选自环丙基、环丁基、环戊基、环己基、吡咯烷基或哌啶基，其可任选地被一个或多个独立地选自R8的基团取代；优选R1选自环丁基或环己基，其可任选地被1个或2个独立的氟基团取代；进一步优选，R1选自
    Figure PCTCN2017077611-appb-100011
    更进一步优选，R1选自
    Figure PCTCN2017077611-appb-100012
  9. 权利要求1-8任一项所述的化合物：R8选自卤素。
  10. 权利要求1-9任一项所述的化合物：R2选自苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基，其可任选地被一个或多个独立地选自R9的基团取代；优选，R2选自苯基或吡啶基，其可任选地被一个或多个独立地选自R9的基团取代；进一步优选，R2选自
    Figure PCTCN2017077611-appb-100013
    Figure PCTCN2017077611-appb-100014
  11. 权利要求1-10任一项所述的化合物：R9选自卤素、氰基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、一氯甲基、二氯甲基、三氯甲基或氨基磺酰基；优选，R9选自卤素、氰基、三氟甲基或-SO2NH2。
  12. 权利要求1-11任一项所述的化合物：每个R3独立地选自甲基、乙基、丙基、异丙基或叔丁基；优选，每个R3独立地选自甲基或异丙基。
  13. 权利要求1-12任一项所述的化合物，所述化合物为如下化合物及其药学上可接受的盐、溶剂化物或水合物：
    Figure PCTCN2017077611-appb-100015
    Figure PCTCN2017077611-appb-100016
    Figure PCTCN2017077611-appb-100017
    Figure PCTCN2017077611-appb-100018
    Figure PCTCN2017077611-appb-100019
    Figure PCTCN2017077611-appb-100020
    Figure PCTCN2017077611-appb-100021
    Figure PCTCN2017077611-appb-100022
  14. 权利要求1-13任一项所述的化合物，所述化合物为如下化合物及其药学上可接受的盐、溶剂化物或水合物：
    Figure PCTCN2017077611-appb-100023
    Figure PCTCN2017077611-appb-100024
    Figure PCTCN2017077611-appb-100025
    Figure PCTCN2017077611-appb-100026
  15. 药物组合物，其包含治疗有效量的权利要求1-14任一项所述的式I或式II化合物或其药学上可接受的盐、溶剂化物或水合物和一种或多种药学上可接受的载体或赋形剂。
  16. 一种治疗由IDH1突变诱发的癌症的方法，所述方法包括将治疗有效量的权利要求1-14任一项所述的化合物、其药学上可接受的盐、溶剂化物或水合物或权利要求15所述的药物组合物给予有需要的患者。
  17. 如权利要求16所述的方法，其中，所述IDH1突变具有R132X突变、优选具有R132H突变。
  18. 权利要求1-14任一项所述的化合物或其药学上可接受的盐、溶剂化物或水合物或权利要求15所述的药物组合物在制备用于治疗由IDH1突变诱发的癌症的药物中的用途。
  19. 权利要求18所述的用途，其中，所述IDH1突变具有R132X突变、优选具有R132H突变。
  20. 权利要求18或19所述的用途，其中，由IDH1突变诱发的癌症选自：成胶质细胞瘤、骨髓增生异常综合征、骨髓组织增殖性赘生物、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤。
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