[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2017016523A1 - 靶向idh2突变的抗肿瘤化合物及其使用方法 - Google Patents

靶向idh2突变的抗肿瘤化合物及其使用方法 Download PDF

Info

Publication number
WO2017016523A1
WO2017016523A1 PCT/CN2016/092375 CN2016092375W WO2017016523A1 WO 2017016523 A1 WO2017016523 A1 WO 2017016523A1 CN 2016092375 W CN2016092375 W CN 2016092375W WO 2017016523 A1 WO2017016523 A1 WO 2017016523A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
alkyl
membered
heteroalicyclic
amino
Prior art date
Application number
PCT/CN2016/092375
Other languages
English (en)
French (fr)
Inventor
王树龙
赵娜
刘希杰
胡远东
张慧
罗鸿
彭勇
校登明
韩永信
张喜全
田心
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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 US15/748,488 priority Critical patent/US10155722B2/en
Priority to EP16829888.3A priority patent/EP3330263B1/en
Priority to CN201680043894.XA priority patent/CN107922375B/zh
Priority to JP2018524524A priority patent/JP6758374B2/ja
Publication of WO2017016523A1 publication Critical patent/WO2017016523A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to the field of medicine, and in particular to active compounds for treating cancers induced by IDH2 mutations and methods of use thereof.
  • IDH the full name of isocitrate dehydrogenase, is the most important key enzyme in the intracellular tricarboxylic acid cycle. It can catalyze the oxidative decarboxylation of isocitrate to form 2-oxoglutarate (ie, a-ketoglutaric acid).
  • IDH mutations in various tumors (such as glioma, sarcoma, acute myeloid leukemia, etc.), and the mutation site is the arginine residue located in the catalytic center (IDH1/R132H, IDH2/R140Q, IDH2/R172K).
  • the mutated IDH acquires a new ability to catalyze the conversion of a-ketoglutarate (a-KG) to 2-hydroxyglutaric acid (2-HG).
  • a-ketoglutaric acid is similar in structure to 2-hydroxyglutaric acid, and 2-HG competes with a-KG, thereby reducing the activity of a-KG-dependent enzymes, resulting in hypermethylation of chromatin. This hypermethylation is thought to interfere with normal cell differentiation, leading to excessive proliferation of immature cells, leading to cancer.
  • AGI-6780 (Science. 2013, 340, 622-626) and the IDH1/R132H inhibitor AGI-5198 (Science. 2013, 340, 626-630), and WO2015017821 disclose another IDH2. /R140Q inhibitor AG-221.
  • AGI-6780 and AGI-5198 are capable of inhibiting the production of 2-HG in cells carrying the most common IDH2 and IDH1 mutants, respectively. In addition to inhibiting 2-HG production, these molecules also induce differentiation of abnormally proliferating human cancer cells in culture.
  • AGI-5198 inhibited the growth rate of glioma cells whether it was treated with AGI-5198 or a tumor-transplanted mouse.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof,
  • Ring A is selected from a benzene ring or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N, O or S;
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the A ring atom to which they are attached form a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring on the 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring
  • the methylene group may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • Each R 3 is independently selected from H, halogen, halo C 1-3 alkyl, hydroxy, amino or C 1-6 alkyl;
  • Each R 4 is independently selected from H or C 1-6 alkyl
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic;
  • One of R 5 and R 6 is a carbonyl oxygen atom, and the other is absent; or R 5 and R 6 together with the carbon atom to which they are bonded constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring, said 3 a -7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring may be optionally further substituted with a C 1-6 alkyl group, a halogen, a hydroxyl group or an amino group;
  • L 1 and L 2 are each independently selected from -C(O)-, -N(R 4 )- or -S(O) 2 -, and L 1 and L 2 are not the same;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, and may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n and n are independently 1, 2 or 3;
  • o and p are each independently selected from 0 or 1, and o and p are not 0 at the same time.
  • the application provides a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof,
  • Ring A is selected from a benzene ring or a 5-6 membered heteroaryl ring containing 1-2 N atoms;
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the A ring atom to which they are attached form a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring on the 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring
  • the methylene group may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic;
  • One of R 5 and R 6 is a carbonyl oxygen atom, and the other is absent; or R 5 and R 6 together with the carbon atom to which they are bonded constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring, said 3 a -7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring may be optionally further substituted with a C 1-6 alkyl group, a halogen, a hydroxyl group or an amino group;
  • L 1 and L 2 are each independently selected from -C(O)-, -N(R 4 )- or -S(O) 2 -, and L 1 and L 2 are different and R 4 is selected from H or C 1 -6 alkyl;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, and may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n 1, 2 or 3;
  • o and p are each independently selected from 0 or 1, and o and p are not 0 at the same time.
  • the application provides a compound of Formula III, or a pharmaceutically acceptable salt or hydrate thereof:
  • X is selected from CH or N;
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the benzene ring atom or the pyridine ring atom to which they are attached constitute a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring, said 5-7 membered cycloalkane ring or 5-7 membered hetero
  • the methylene group on the alicyclic ring may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic;
  • One of R 5 and R 6 is a carbonyl oxygen atom, and the other is absent; or R 5 and R 6 together with the carbon atom to which they are bonded constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring, said 3 a -7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring may be optionally further substituted with a C 1-6 alkyl group, a halogen, a hydroxyl group or an amino group;
  • L 1 and L 2 are each independently selected from -C(O)-, -N(R 4 )- or -S(O) 2 -, and L 1 and L 2 are different and R 4 is selected from H or C 1 -6 alkyl;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, and may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n 1, 2 or 3;
  • o and p are each independently selected from 0 or 1, and o and p are not 0 at the same time.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers Or an excipient.
  • the application provides a method of treating cancer induced by an IDH2 mutation, the method comprising administering to a subject in need thereof a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof Or a pharmaceutical composition thereof.
  • the application provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a cancer induced by an IDH2 mutation Use in.
  • the application provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, for use in treating a cancer induced by an IDH2 mutation.
  • the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
  • the cancer induced by the IDH2 mutation is selected from the group consisting of: glioblastoma, myelodysplastic syndrome, myeloid proliferative neoplasm, acute myeloid leukemia, sarcoma, melanoma, non- Small cell lung cancer, chondrosarcoma, cholangiocarcinoma or angioimmunoblastic non-Hodgkin's lymphoma.
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • 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.
  • 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 isomeric forms thereof, 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 .
  • C 1-8 alkyl refers to an alkyl group having from 1 to 8 carbon atoms.
  • 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”, “C 1-4 alkyl” or “C 1-3 alkyl” may be unsubstituted or one Or a plurality of substituents selected from a hydroxyl group, a halogen or an amino group.
  • alkenyl refers to a straight or branched aliphatic hydrocarbon group containing from 2 to 12 carbon atoms and having one or more double bonds.
  • alkenyl groups include, but are not limited to, vinyl, allyl, propenyl, 2-butenyl, and 3-hexenyl.
  • One of the double bond carbons may optionally be the attachment point of an alkenyl substituent.
  • cycloalkane ring refers to a monocyclic saturated aliphatic hydrocarbon ring consisting solely of carbon atoms and hydrogen atoms.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, such as a cyclopropyl group, Cyclobutyl, 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 group, phosphoryl group, hydroxyl group and the like.
  • heteromatic ring refers to a monocyclic or fused ring having 5 to 12 ring atoms, for example 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, in which 1, 2, 3 are contained. Or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having 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 groups, and the like.
  • Non-limiting examples of non-substituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadipine Azyl, fluorenyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl , quinolyl, isoquinolyl, triazolyl, tetrazolyl, triazinyl, acridinyl and the like.
  • heteroalicyclic refers to a monocyclic or fused ring having from 3 to 12 ring atoms, for example 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
  • 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.
  • 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, includes, but is 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 pharmaceutical composition means when combined with another active substance in the composition. The amount needed to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the individual, and also on the particular active substance, and a suitable effective amount in a case can be determined by a person skilled in the art according to routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • patient or “individual” includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
  • mammals eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:
  • Ring A is selected from a benzene ring or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N, O or S;
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the A ring atom to which they are attached form a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring on the 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring
  • the methylene group may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • Each R 3 is independently selected from hydrogen, halogen, halo C 1-3 alkyl, hydroxy, amino or C 1-6 alkyl;
  • Each R 4 is independently selected from H or C 1-6 alkyl
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic;
  • One of R 5 and R 6 is a carbonyl oxygen atom, and the other is absent; or R 5 and R 6 together with the carbon atom to which they are bonded constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring,
  • the 7-membered cycloalkane ring or the 3-7 membered heteroalicyclic ring may be optionally further substituted with a C 1-6 alkyl group, a halogen, a hydroxyl group or an amino group;
  • L 1 and L 2 are each independently selected from -C(O)-, -N(R 4 )- or -S(O) 2 -, and L 1 and L 2 are not the same;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, and may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n and n are independently 1, 2 or 3;
  • o and p are each independently selected from 0 or 1, and o and p are not 0 at the same time.
  • the application provides a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof:
  • Ring A is selected from a benzene ring or a 5-6 membered heteroaryl ring containing 1-2 N atoms;
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the A ring atom to which they are attached form a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring, which is a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring.
  • the methyl group may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic;
  • One of R 5 and R 6 is a carbonyl oxygen atom, and the other is absent; or R 5 and R 6 together with the carbon atom to which they are bonded constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring,
  • the 7-membered cycloalkane ring or the 3-7 membered heteroalicyclic ring may be optionally further substituted with a C 1-6 alkyl group, a halogen, a hydroxyl group or an amino group;
  • L 1 and L 2 are each independently selected from -C(O)-, -N(R 4 )- or -S(O) 2 -, and L 1 and L 2 are different and R 4 is selected from H or C 1 -6 alkyl;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, which may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n 1, 2 or 3;
  • o and p are each independently selected from 0 or 1, and o and p are not 0 at the same time.
  • the application provides a compound of Formula III, or a pharmaceutically acceptable salt or hydrate thereof:
  • X is selected from CH or N;
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the benzene ring atom or the pyridine ring atom to which they are attached constitute a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring, the 5-7 membered cycloalkane ring or 5-7 membered heteroaliphatic ring
  • the methylene group on the ring may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic;
  • One of R 5 and R 6 is a carbonyl oxygen atom, and the other is absent; or R 5 and R 6 together with the carbon atom to which they are bonded constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring,
  • the 7-membered cycloalkane ring or the 3-7 membered heteroalicyclic ring may be optionally further substituted with a C 1-6 alkyl group, a halogen, a hydroxyl group or an amino group;
  • L 1 and L 2 are each independently selected from -C(O)-, -N(R 4 )- or -S(O) 2 -, and L 1 and L 2 are different and R 4 is selected from H or C 1 -6 alkyl;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, which may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n 1, 2 or 3;
  • o and p are each independently selected from 0 or 1, and o and p are not 0 at the same time.
  • a compound of Formula III or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the benzene ring atom or the pyridine ring atom to which they are attached constitute a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring, the 5-7 membered cycloalkane ring or 5-7 membered heteroaliphatic ring
  • the methylene group on the ring may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic;
  • One of R 5 and R 6 is a carbonyl oxygen atom, and the other is absent; or R 5 and R 6 together with the carbon atom to which they are bonded constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring,
  • the 7-membered cycloalkane ring or the 3-7 membered heteroalicyclic ring may be optionally further substituted with a C 1-6 alkyl group, a halogen, a hydroxyl group or an amino group;
  • -(L 1 ) o -(L 2 ) p - is -C(O)-N(R 4 )-, -N(R 4 )-C(O)-, -S(O) 2 -N(R 4 ) -, -N(R 4 )-S(O) 2 - or -N(R 4 )-, wherein each R 4 is selected from H or C 1-6 alkyl;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, and may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n 1, 2 or 3.
  • a compound of Formula III or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the benzene ring atom or the pyridine ring atom to which they are attached constitute a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring, the 5-7 membered cycloalkane ring or 5-7 membered heteroaliphatic ring
  • the methylene group on the ring may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; R 5 and R 6 together with the carbon atom to which they are attached constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring, optionally a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring Substituted by C 1-6 alkyl, halogen, hydroxy or amino;
  • -(L 1 ) o -(L 2 ) p - is -C(O)-N(R 4 )-, -N(R 4 )-C(O)- or -N(R 4 )-, each of which R 4 is selected from H or C 1-6 alkyl;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, and may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n 1, 2 or 3.
  • a compound of Formula III or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein
  • Each R 1 is independently selected from halo, halo C 1-3 alkyl, carboxy, amino, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; or adjacent
  • the two R 1 groups together with the benzene ring atom or the pyridine ring atom to which they are attached constitute a 5-7 membered cycloalkane ring or a 5-7 membered heteroalicyclic ring, the 5-7 membered cycloalkane ring or 5-7 membered heteroaliphatic ring
  • the methylene group on the ring may optionally further form one or two carbonyl groups;
  • R 2 is selected from phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and may be optionally substituted by one or more R 8 ;
  • R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic; R 5 and R 6 together with the carbon atom to which they are attached constitute a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring, optionally a 3-7 membered cycloalkane ring or a 3-7 membered heteroalicyclic ring Substituted by C 1-6 alkyl, halogen, hydroxy or amino;
  • -(L 1 ) o -(L 2 ) p - is -C(O)-N(R 4 )- or -N(R 4 )-C(O)-, wherein each R 4 is selected from H or C 1-6 alkyl;
  • R 7 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heteroalicyclic, and may be optionally substituted by one or more R 9 ;
  • Each R 8 and each R 9 are each independently selected from halogen, hydroxy, amino, cyano, halo C 1-3 alkyl, C 1-6 alkyl or C 3-6 heteroalicyclic;
  • n 1, 2 or 3.
  • a compound of Formula III, or a pharmaceutically acceptable salt or hydrate thereof wherein m is 1 or 2; each R 1 is independently selected from halogen, monofluoromethyl, Fluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl; Adjacent two R 1 groups together with a benzene ring atom or a pyridine ring atom to which they are attached constitute a 5-7 membered heteroalicyclic ring, and the methylene group on the 5-7 membered heteroalicyclic ring may optionally further form a carbonyl group.
  • each R 1 is independently selected from fluoro, trifluoromethyl; or two adjacent R 1 groups are combined with a benzene ring atom or a pyridine ring atom to which they are attached to form 5
  • the nitrogen-containing heteroalicyclic ring, the methylene group on the 5-membered nitrogen-containing heteroalicyclic ring, may optionally form a carbonyl group.
  • R 2 is selected from the group consisting of phenyl, thienyl, pyrazolyl, pyridyl, and may be optionally substituted by one or more R 8 ; each R 8 is independently selected from trifluoromethyl or methyl .
  • Ethyl, propyl or isopropyl; or R 5 and R 6 together with the carbon atom to which they are attached constitute cyclopropane, cyclobutane, cyclopentane, cyclohexane, piperidine, pyrrolidine.
  • R 5 and R 6 are each independently selected from H, fluorine, amino, methyl or ethyl; or R 5 and R 6 together with the carbon atom to which they are attached constitute cyclopropane, cyclobutane or piperidine.
  • a compound of Formula III, or a pharmaceutically acceptable salt or hydrate thereof, wherein -(L 1 ) o -(L 2 ) p - is -C(O)-NH-, is preferred. Or -NH-C(O)-.
  • R 7 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, cyclopropyl.
  • Each R 9 is independently selected from halogen, hydroxy, cyano or C 1-6 alkyl.
  • R 7 is selected from ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutane, oxetanyl or azetidinyl, and may optionally be 1-3
  • Each R 9 is substituted; each R 9 is independently selected from fluoro, hydroxy, cyano or methyl.
  • a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, and an organic acid may be mentioned.
  • metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like.
  • Non-salt formed with basic amino acids Restrictive examples include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • 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 a compound of the free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of Formula I, Formula II or Formula III of the present application may exist in unsolvated or 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.
  • the compounds of formula I, formula II or formula III of the present application may exist in polymorph or amorphous form.
  • the compounds of formula I, formula II or formula III 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 formula I, formula II or formula III 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 mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the application. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are also included within the scope of the present 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 groups are cleaved to provide purity. The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then known to those skilled in the art.
  • the diastereomeric resolution is carried out by fractional 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 Formula I, Formula II or Formula III of the present application may contain unnatural proportions of atomic isotopes at 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 compositions of the compounds of Formula I, Formula II or Formula III of the present application, whether radioactive or not, are included within the scope of the present application.
  • the compound of Formula I, Formula II or Formula III provided herein, or a pharmaceutically acceptable salt or hydrate thereof has very good inhibitory activity against IDH2 enzyme and has very good levels of metabolism in the body and is very long.
  • the in vivo half-life is expected to be a more suitable drug for the treatment of cancers induced by IDH2 mutations.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers Or an excipient.
  • the pharmaceutical compositions of the present application may further comprise one or more additional therapeutic agents.
  • the pharmaceutical composition of the present application can be formulated by combining a compound of Formula I, Formula II or Formula III of the present application, or a pharmaceutically acceptable salt or hydrate thereof, with a suitable pharmaceutically acceptable carrier or excipient.
  • Preparation for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels Agents, microspheres and aerosols.
  • Typical routes of administration for administering a compound of Formula I, Formula II or Formula III of the present application, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, and Intestinal administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be prepared by a method known to those skilled 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.
  • a compound of Formula I, Formula II or Formula III of the present application, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or agent well known to those skilled in the art can be used.
  • the agent is mixed to formulate the pharmaceutical composition.
  • These carriers or excipients enable the compound of Formula I, Formula II or Formula III of the present application, or a pharmaceutically acceptable salt or hydrate thereof, to be formulated into tablets, pills, lozenges, dragees, capsules Agents, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the compound of the formula I, formula II or formula III of the present application, or a pharmaceutically acceptable salt or hydrate thereof, with a solid excipient, optionally The resulting mixture is milled, and if necessary, other suitable excipients are added, and the mixture is then processed into granules to give the core of the tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber Or cross-linked polyvinylpyrrolidone.
  • the core of the dragee can optionally be coated according to methods generally known in the pharmaceutical arts, especially enteric coatings.
  • compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • parenteral administration such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • Dosage forms suitable for parenteral administration can be prepared using suitable excipients such as fillers, buffers or surfactants.
  • the application provides a method of treating cancer induced by an IDH2 mutation, the method comprising administering to a subject in need thereof a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof Or a pharmaceutical composition thereof.
  • the application provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a cancer induced by an IDH2 mutation Use in.
  • the application provides a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, for treating cancer induced by an IDH2 mutation.
  • the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
  • the cancer induced by the IDH2 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
  • NHL vascular immunoblastic non-Hodgkin's lymphoma
  • the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, Or angioimmunoblastic non-Hodgkin's lymphoma (NHL) or the like, preferably including acute myeloid leukemia (AML) or sarcoma.
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML acute myeloid leukemia
  • melanoma chondrosarcoma
  • NDL angioimmunoblastic non-Hodgkin's lymphoma
  • AML acute myeloid leukemia
  • sarcoma preferably including acute myeloid leukemia (AML) or sarcoma.
  • a compound of Formula I, Formula II or Formula III described herein, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof may be administered by any suitable route and method, for example, by oral or gastrointestinal administration. Administration (eg, intravenous).
  • Administration eg, intravenous.
  • a compound of Formula I, Formula II or Formula III described herein, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, is administered to a subject in need thereof in a therapeutically effective amount.
  • the compound of Formula I, Formula II or Formula III can be administered at a dose of 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 frequency of administration of a compound of Formula I, Formula II or Formula III of the present application, or a pharmaceutically acceptable salt or hydrate thereof is determined by the needs of the individual patient, for example, once or twice daily, or daily repeatedly. Administration can be intermittent, for example, wherein within a period of several days, the patient receives a daily dose of a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, followed by The patient does not receive a daily dose of a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof, over a period of days or more.
  • the compounds of Formula I, Formula II or Formula III 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, in combination with other chemical synthesis methods.
  • the embodiments and the equivalents well known to those skilled in the art, the preferred embodiments include, but are not limited to, the embodiments of the present application.
  • X, R 1 , R 2 , R 7 and m are as defined for the compound of formula III;
  • 4-bromoiodobenzene is substituted with ethyl difluorobromoacetate to give 1-2; 1-2 is nitylated to give 1-3; the bromine atom of 1-3 is substituted by R 2 group, and the acetate is hydrolyzed. 1-4; 1-4 amidation reaction gives 1-5; 1-5 reduction reaction gives 1-6; 1-6 is reacted with a substituted isocyanate to obtain a compound of the formula IV.
  • Nuclear magnetic resonance chromatography was measured using a Varian VNMR S-400 nuclear magnetic resonance spectrometer; LC/MS was performed using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18, Mm, 5 microns, 35 ° C), using ESI (+) ion mode.
  • the reaction mixture was poured into water, extracted with ethyl acetate (100 mL ⁇ 2), and the organic phase was evaporated.
  • the aqueous phase was adjusted to pH 5 with dilute hydrochloric acid (2M) and extracted with ethyl acetate (100 mL ⁇ 3). Drying over anhydrous sodium sulfate, the organic phase was evaporated to remove ethyl acetate to give 2,2-difluoro-2-(3-nitro-4-(thiophen-3-yl)phenyl)acetic acid (3.640 g, yield 100%).
  • Step 4 N-cyclopropyl-2,2-difluoro-2-(3-nitro-4-(thiophen-3-yl)phenyl)acetamide
  • N-cyclopropyl-2,2-difluoro-2-(3-nitro-4-(thiophen-3-yl)phenyl)acetamide (153 mg, 0.45 mmol), reduced iron powder (128.4 mg, 2.3 mmol), ammonium chloride (123.0 mg, 2.3 mmol) was added to a mixture of methanol (40 mL) and water (40 mL). The mixture was reacted at 70 ° C for 0.5 hours and then cooled to room temperature.
  • Step 6 N-cyclopropyl-2,2-difluoro-2-(4-(thiophen-3-yl)-3-(3-(3-(trifluoromethyl)phenyl)ureido)benzene Acetamide
  • N-cyclopropyl-2,2-dichloro-2-(4-(thiophen-3-yl)-3-(3-(2-(trifluoromethyl)) was obtained.
  • Pyridin-4-yl)ureido)phenyl)acetamide was obtained.
  • N-cyclopropyl-2,2-dichloro-2-(3-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido) was obtained.
  • 4-(Thien-3-yl)phenyl)acetamide was obtained.
  • 2-(4-Bromophenyl)propionic acid (2.0 g, 8.73 mmol) was dissolved in concentrated sulfuric acid (50 mL), cooled to 0 ° C, and then evaporated toluene (2.0 mL). The mixture was stirred at 0 ° C for 1 hour to mix the mixture It was slowly added to ice water, and the solid precipitate was filtered and dried to give 2-(4-bromo-3-nitrophenyl)propionic acid (2.0 g, yield: 83.6%).
  • N-cyclopropyl-2-(3-nitro-4-(thiophen-3-yl)phenyl)propanamide (0.5 g, 1.58 mmol), reduced iron powder (433.0 mg, 7.9 mmol), chlorinated Ammonium (440.0 mg, 7.9 mmol) was added to a mixture of methanol (40 mL) and water (40 mL). The mixture was reacted at 70 ° C for 0.5 hours and then cooled to room temperature.
  • Step 6 N-cyclopropyl-2-(4-(thiophen-3-yl)-3-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)propanamide
  • N-cyclopropyl-3-nitro-4-(thiophen-3-yl)benzamide 425.7 mg, 1.48 mmol
  • reduced iron powder 413.3 mg, 7.4 mmol
  • ammonium chloride 395.8 mg, 7.4 mmol
  • the mixture was reacted at 70 ° C for 0.5 hours and then cooled to room temperature. Filtration, the solid was washed with ethyl acetate, the filtrate was separated, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated to give 3-amino-N-cyclopropyl-4-(thiophen-3-yl)benzene.
  • Formamide (364 mg, yield 95.4%).
  • Step 5 N-cyclopropyl-4-(thiophen-3-yl)-3-(3-(3-(trifluoromethyl)phenyl)ureido)benzamide
  • Step 4 1-(5-(1-(Cyclopropylamino)ethyl)-2-(thiophen-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea
  • Step 7 1-(3-Amino-4-(thien-3-yl)-phenyl)-N-cyclopropylmethanesulfonamide
  • N-cyclopropyl-1-(3-nitro-4-(thiophen-3-yl)-phenyl)methanesulfonamide (150.0 mg, 0.44 mmol), reduced iron powder (124.0 mg, 2.22 mmol), Ammonium chloride (119.0 mg, 2.22 mmol) was added to a mixture of methanol (40 mL) and water (40 mL). The mixture was reacted at 70 ° C for 0.5 hours and then cooled to room temperature.
  • Step 8 N-cyclopropyl-1-(4-(thiophen-3-yl)-3-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)methanesulfonamide
  • Step 7 N-(1-(4-(Thien-3-yl)-3-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)ethyl)cyclopropyl A Amide
  • This application is determined by the following method of application of the compounds of the present IDH2 (R172K, 40-end) inhibitory activity, the inhibitory activity of IC 50 uses the indicators to represent, 50% of the active compound IC 50 is suppressed i.e. IDH2 concentration.
  • the inhibitory activity of the compound on IDH2 was determined by subtraction of the cofactor NADPH.
  • the compound was pre-incubated with the enzyme and NADPH, then the reaction was initiated by the addition of a-KG and reacted under linear conditions for 120 minutes.
  • the reaction was then terminated by the addition of Diaphorase (lipoamide dehydrogenase) and the corresponding substrate Resazurin (Resazurin).
  • Diaphorase lipoamide dehydrogenase
  • Resazurin Resazurin
  • 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 was determined by subtraction of the cofactor NADPH.
  • reaction buffer (20 mM Tris-HCl, pH 7.5; containing 80 nM IDH2 (R172K, 40-end) and 40 ⁇ M NADPH; 150 mM NaCl; 10 mM MgCl2; 10 mM MnCl2; 0.4 mg/ml BSA and 2 mM DTT).
  • the test mixture was then incubated at 23 ° C for 120 minutes, after which 2.5 ⁇ l of reaction buffer containing 4 mM a-KG was added to initiate the reaction.
  • the IDH2 inhibitory activity of the example compounds is shown in Table 1:
  • Example number IC 50 (nM) Example number IC 50 (nM) 1 14.20 16 75.82 2 45.52 17 138.2 3 62.35 18 1231
  • the present application employs the following method to determine the pharmacokinetic parameters of the compounds of the present application:
  • 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 sample was centrifuged at 4 ° C, 4000 rpm for 5 min, and the plasma was transferred to a centrifuge tube and placed in a -80 °C is saved until analysis.
  • Plasma sample analysis was performed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma concentration-time data for individual animals were analyzed using WinNonlin (Professional Edition, Version 6.3; Pharsight) software, non-room The chamber model was used for concentration analysis to calculate the pharmacokinetic parameters of the compounds as shown in Table 3:
  • Example 5 28 AGI-6780 Dose (mg/kg) 5 5 5 T 1/2 (hr) 4.37 2.34 1.49 T max (hr) 0.42 0.33 2.83 C max (ng/mL) 494.6 414.1 191.1 AUC 0-inf (hr*ng/mL) 858.2 844.5 559.3
  • Examples 5 and 28 have very good levels of in vivo metabolism and long half-lives, and plasma concentrations are higher at the same dose than the IDH2 inhibitor AGI-6780.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

本申请涉及通式（I）、通式（Ⅱ）或通式（Ⅲ）的化合物及其药学上可接受的盐或水合物、其制备方法和其药物组合物。所述通式（Ⅰ）、通式（Ⅱ）或通式（Ⅲ）的化合物具有对异柠檬酸脱氢酶2(IDH2)的抑制活性，可治疗IDH2突变诱发的癌症。

Description

靶向IDH2突变的抗肿瘤化合物及其使用方法
相关申请的引用
本申请要求于2015年07月30日向中华人民共和国国家知识产权局提交的第201510461130.X号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及医药领域，具体而言涉及用于治疗由IDH2突变诱发的癌症的活性化合物及其使用方法。
背景技术
IDH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-氧化戊二酸酯(即，a-酮戊二酸)。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)。突变后的IDH获得一种新的能力，即催化a-酮戊二酸(a-KG)转化为2-羟基戊二酸(2-HG)。研究表明，a-酮戊二酸与2-羟基戊二酸的结构相似，2-HG与a-KG竞争，由此降低了a-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。
2013年Agios Pharmaceuticals报道了IDH2/R140Q抑制剂AGI-6780(Science.2013,340,622-626)和IDH1/R132H抑制剂AGI-5198(Science.2013,340,626-630)，以及WO2015017821公开了另一种IDH2/R140Q抑制剂AG-221。AGI-6780和AGI-5198能够分别抑制携带最常见IDH2和IDH1突变体的细胞中2-HG的生成。除能抑制2-HG生成，这些分子还诱导了培养物中异常增殖的人类癌细胞的分化。用AGI-6780治疗携带IDH2突变体的白血病细胞，用AGI-5198治疗携带IDH1突变体的神经胶质瘤细胞，均导致细胞中的成熟标记物表达增高。此外，研究人员证实不论是用AGI-5198处理细胞培养物，还是口服给药肿瘤移植小鼠，AGI-5198均可抑制神经胶质瘤细胞生长速率。
发明内容
一方面，本申请提供了通式Ⅰ的化合物或其药学上可接受的盐或水合物，
Figure PCTCN2016092375-appb-000001
其中，
A环选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环；
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
每个R3独立地选自H、卤素、卤代C1-3烷基、羟基、氨基或C1-6烷基；
每个R4独立地选自H或C1-6烷基；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
m和n独立地为1，2或3；以及
o和p分别独立地选自0或1，且o和p不同时为0。
另一方面，本申请提供了通式Ⅱ的化合物或其药学上可接受的盐或水合物，
Figure PCTCN2016092375-appb-000002
其中，
A环选自苯环或含1-2个N原子的5-6元杂芳环；
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6 环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同以及R4选自H或C1-6烷基；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
m为1，2或3；以及
o和p分别独立地选自0或1，且o和p不同时为0。
另一方面，本申请提供了通式Ⅲ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092375-appb-000003
其中，
X选自CH或N；
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同以及R4选自H或C1-6烷基；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
m为1，2或3；以及
o和p分别独立地选自0或1，且o和p不同时为0。
另一方面，本申请提供了药物组合物，其包含通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物和一种或多种药学上可接受的载体或赋形剂。
另一方面，本申请提供了治疗由IDH2突变诱发的癌症的方法，所述方法包括给予有需要的个体通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物。
另一方面，本申请提供了通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
另一方面，本申请提供了用于治疗由IDH2突变诱发的癌症的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物。
在本申请的一些实施方案中，所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
在本申请的一些实施方案中，所述由IDH2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。
发明详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
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，而是应该按照普通的含义去理解。当本文中出现商品名时，意在指代其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。
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案中，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“羧基”指-COOH。
术语“氰基”指-CN。
术语“氨基”是指-NH2、-NH(烷基)和-N(烷基)2，氨基的具体实例包括但不限于-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“C1-8烷基”指具有1-8个碳原子的烷基。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”、“C1-4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“烯基”是指含有2至12个碳原子并且具有一个或多个双键的直链或支链的脂肪烃基。烯基的实例包括但不限于乙烯基、烯丙基、丙烯基、2-丁烯基以及3-己烯基。双键碳之一可任选地为烯基取代基的附接点。
术语“环烷烃环”是指仅由碳原子和氢原子组成的单环的饱和的脂肪烃环。
术语“环烷基”是指仅由碳原子和氢原子组成的单环的饱和的脂肪烃基团，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、磷酰基和羟基等。
术语“杂芳环”是指具有5-12个环原子的单环或稠合环，例如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、羰基和杂脂环基等。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、异噁唑基、噻唑基、异噻唑基、噁二唑基、噻二唑基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四唑基、三嗪基、喋啶基等。
术语“杂脂环”是指具有3-12个环原子的单环或稠合环，例如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 PCTCN2016092375-appb-000004
4元饱和杂脂环的实例包括但不限于
Figure PCTCN2016092375-appb-000005
5元饱和杂脂环的实例包括但不限于
Figure PCTCN2016092375-appb-000006
6元饱和杂脂环的实例包括但不限于
Figure PCTCN2016092375-appb-000007
Figure PCTCN2016092375-appb-000008
7元饱和杂脂环的实例包括但不限于
Figure PCTCN2016092375-appb-000009
Figure PCTCN2016092375-appb-000010
5元不饱和杂脂环的实例包括但不限于
Figure PCTCN2016092375-appb-000011
6元不饱和杂脂环的实例包括但不限于
Figure PCTCN2016092375-appb-000012
Figure PCTCN2016092375-appb-000013
术语“杂脂环基”是指“杂脂环”分子去掉1个氢原子后余下的基团，杂脂环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、卤素或羟基等。
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。
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”是指与活性成分一同给药的、有利于活性成分给药的惰性物质，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的载体、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，药物组合物中的一种活性物质的“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，取决于个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。
术语“患者”或“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。
通式化合物
一方面，本申请提供了通式Ⅰ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092375-appb-000014
其中，
A环选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环；
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
每个R3独立地选自氢、卤素、卤代C1-3烷基、羟基、氨基或C1-6烷基；
每个R4独立地选自H或C1-6烷基；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，该3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
m和n独立地为1，2或3；以及
o和p分别独立地选自0或1，且o和p不同时为0。
另一方面，本申请提供通式Ⅱ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092375-appb-000015
其中，
A环选自苯环或含1-2个N原子的5-6元杂芳环；
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，该5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，该3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同以及R4选自H或C1-6烷基；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，其可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
m为1，2或3；以及
o和p分别独立地选自0或1，且o和p不同时为0。
再一方面，本申请提供通式Ⅲ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092375-appb-000016
其中，
X选自CH或N；
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，该5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，该3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同以及R4选自H或C1-6烷基；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，其可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
m为1，2或3；以及
o和p分别独立地选自0或1，且o和p不同时为0。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或水合物，其中
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，该5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，该3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
-(L1)o-(L2)p-为-C(O)-N(R4)-、-N(R4)-C(O)-、-S(O)2-N(R4)-、-N(R4)-S(O)2-或-N(R4)-，其中每个R4选自H或C1-6烷基；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
m为1，2或3。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或水合物，其中
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，该5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，该3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
-(L1)o-(L2)p-为-C(O)-N(R4)-、-N(R4)-C(O)-或-N(R4)-，其中每个R4选自H或C1-6烷基；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
m为1，2或3。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或水合物，其中
每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，该5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，该3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
-(L1)o-(L2)p-为-C(O)-N(R4)-或-N(R4)-C(O)-，其中每个R4选自H或C1-6烷基；
R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
m为1，2或3。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或 水合物，其中m为1或2；每个R1独立地选自卤素、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、二氯甲基或三氯甲基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元杂脂环，该5-7元杂脂环上的亚甲基可任选地进一步形成一个羰基。更优选地，其中m为1或2；每个R1独立地选自氟、三氟甲基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5元含氮的杂脂环，该5元含氮的杂脂环上的亚甲基可任选地形成一个羰基。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或水合物，其中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，并可任选地被一个或多个R8取代；每个R8独立地选自卤代C1-3烷基或C1-6烷基。更优选地，R2选自苯基、噻吩基、吡唑基、吡啶基，并可任选地被一个或多个R8取代；每个R8独立地选自三氟甲基或甲基。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或水合物，其中R5和R6分别独立地选自H、氟、氯、溴、氨基、甲基、乙基、丙基或异丙基；或R5和R6与连接它们的碳原子一起组成环丙烷、环丁烷、环戊烷、环己烷、哌啶、吡咯烷。更优选地，R5和R6分别独立地选自H、氟、氨基、甲基或乙基；或R5和R6与连接它们的碳原子一起组成环丙烷、环丁烷或哌啶。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或水合物，其中-(L1)o-(L2)p-为-C(O)-NH-或-NH-C(O)-。
在本申请的一个实施方案中，优选通式Ⅲ的化合物或其药学上可接受的盐或水合物，其中R7选自甲基、乙基、丙基、丁基、戊基、环丙烷基、环丁烷基、环戊烷基、环己烷基或含有一个选自O或N的杂原子的C3-6杂脂环基，并可任选地被一个或多个R9取代；每个R9独立地选自卤素、羟基、氰基或C1-6烷基。更优选地，R7选自乙基、丙基、丁基、戊基、环丙烷基、环丁烷基、氧杂环丁基或氮杂环丁基，并可任选地被1-3个R9取代；每个R9独立地选自氟、羟基、氰基或甲基。
在本申请的一个实施方案中，优选下述化合物：
Figure PCTCN2016092375-appb-000017
Figure PCTCN2016092375-appb-000018
Figure PCTCN2016092375-appb-000019
及其药学上可接受的盐或水合物。
作为通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物的药学上可接受的盐，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。金属盐的非限制性实例包括但不限于碱金属的盐，例如钠盐、钾盐等；碱土金属的盐，例如钙盐、镁盐、钡盐等；铝盐等。与有机碱形成的盐的非限制性实例包括但不限于与三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺等形成的盐。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。与碱性氨基酸形成的盐的非 限制性实例包括但不限于与精氨酸、赖氨酸、鸟氨酸等形成的盐。与酸性氨基酸形成的盐的非限制性实例包括但不限于与天冬氨酸、谷氨酸等形成的盐。
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。
本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的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。本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物可以以多晶型物或无定形形式存在。
本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的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。
本申请中的消旋体、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。当本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物含有烯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。
本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ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，也均包括在本申请的范围之内。
可以通过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一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，然后通过本领域技术人员已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)。
本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ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)。本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ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。
本申请提供的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物具有非常好的对IDH2酶的抑制活性，并且具有非常好的体内代谢水平和非常长的体内半衰期，有望成为更适于治疗由IDH2突变诱发的癌症的药物。
药物组合物
另一方面，本申请提供了药物组合物，其包含通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐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另外的治疗剂。
本申请的药物组合物可通过将本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物与适宜的药学上可接受的载体或赋形剂组合而制备，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。
给予本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物的典型给药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。
可以采用本领域技术人员已知的方法制备本申请的药物组合物，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，可以通过将本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物与本领域技术人员熟知的药学上可接受的载体或赋形剂混合来配制该药物组合物。这些载体或赋形剂能使本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、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：将所述的本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水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料，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。可以根据药剂领域中通常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。
本申请的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来制备适于肠胃外给药的剂型。
医药用途
另一方面，本申请提供了治疗由IDH2突变诱发的癌症的方法，所述方法包括给予有需要的个体通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物。
另一方面，本申请提供了通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
另一方面，本申请提供了治疗由IDH2突变诱发的癌症的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物。
在本申请的一些实施方案中，所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
在本申请的一些实施方案中，所述的由IDH2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)。在优选的实施方案中，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)、黑色素瘤、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)或肉瘤。
本申请所述的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组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。本申请所述的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物或其药物组合物以治疗有效量给予所述有需要的个体。通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物的给药剂量可以为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物的给药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，患者接受通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物的每日剂量，接着在若干天或更多天的期间，患者不接受通式Ⅰ、通式Ⅱ或通式Ⅲ的化合物或其药学上可接受的盐或水合物的每日剂量。
制备
本申请的通式Ⅰ、通式Ⅱ或通式Ⅲ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案以及本领域技术上人员所熟知的等同替换方式，优选的实施方案均包括但不限于本申请的实施例。
本申请的具体实施方案的化学反应是在合适的溶剂中完成的，所述的溶剂必须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的通式Ⅰ、 通式Ⅱ或通式Ⅲ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。
本申请的通式Ⅳ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 PCTCN2016092375-appb-000020
其中，
X、R1、R2、R7和m的定义与通式Ⅲ的化合物相同；
Figure PCTCN2016092375-appb-000021
4-溴碘苯被二氟溴乙酸乙酯取代得到1-2；1-2发生硝基化反应得到1-3；1-3的溴原子被R2基团取代，同时乙酸酯水解得到1-4；1-4发生酰胺化反应得到1-5；1-5发生还原反应得到1-6；1-6与取代的异氰酸酯反应得到通式Ⅳ的化合物。
本申请的通式Ⅴ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 PCTCN2016092375-appb-000022
其中，
X、R1、R2、R5、R6、R7和m的定义与通式Ⅲ的化合物相同；
Figure PCTCN2016092375-appb-000023
2-1经水解反应得到2-2；2-2发生硝基化反应得到2-3；2-3发生成酰胺化反应得到2-4；2-4的溴原子被R2基团取代得到2-5；2-5发生还原反应得到2-6；2-6与取代的异氰酸酯反应得到通式Ⅴ的化合物。
本申请的式Ⅵ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 PCTCN2016092375-appb-000024
化合物3-1与3-噻吩硼酸反应得到3-2；3-2发生水解反应得到3-3；3-3与环丙胺反应得到3-4；3-4经还原反应得到3-5；3-5与3-(三氟甲基)异氰酸苯酯发生成脲反应得到式Ⅵ化合物。
本申请的通式Ⅶ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 PCTCN2016092375-appb-000025
其中，
X、R1、R2、R5、R7和m的定义与通式Ⅲ的化合物相同；
Figure PCTCN2016092375-appb-000026
化合物4-1的溴原子被R2基团取代得到4-2；4-2发生还原反应得到4-3；4-3与取代的异氰酸酯反应得到4-4；4-4与R7取代的胺反应得到通式Ⅶ的化合物。
本申请的式Ⅷ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 PCTCN2016092375-appb-000027
Figure PCTCN2016092375-appb-000028
4-溴-3-硝基苯甲酸发生还原反应得到5-2；5-2与甲磺酰氯发生酯化反应得到5-3；5-3与硫代乙酸钾发生硫代反应得到5-4；5-4与N-氯代丁二酰亚胺反应生成磺酰氯产物5-5；5-5与环丙胺反应得到5-6；5-6与3-噻吩硼酸反应得到5-7；5-7发生还原反应得到5-8；5-8与3-(三氟甲基)异氰酸苯酯发生成脲反应得到式Ⅷ化合物。
本申请的通式Ⅸ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 PCTCN2016092375-appb-000029
其中，
X、R1、R2、R5、R7、L2和m的定义与通式Ⅲ的化合物相同；
Figure PCTCN2016092375-appb-000030
化合物6-1溴原子被R2基团取代得到6-2；6-2与叔丁基亚磺酰胺反应得到6-3；6-3亚氨基被还原得到6-4；6-4磺酰胺基团被水解得到6-5；6-5发生酰胺化反应，得到6-6；6-6发生还原反应得到6-7；6-7与取代的异氰酸酯反应得到通式Ⅸ的化合物。
实施例
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发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。本领域技术人员应该理解：还有形成本申请的化合物的其它合成途径，下面提供的是非限制性的实施例。
凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本申请使用的原料都是市场上直接买到未经进一步纯化直接使用的。
柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)。薄层色谱采用E.Merck公司生产的预制板(硅胶60PF254,0.25毫米)。手性化合物分离和对映体过量值(ee)测定使用Agilent LC 1200series(柱子：CHIRALPAK AD-H,
Figure PCTCN2016092375-appb-000031
Figure PCTCN2016092375-appb-000032
毫米，5微米，30℃)。核磁共振色谱(NMR)使用Varian VNMRS-400核磁共振仪测定；液质连用(LC/MS)使用FINNIGAN Thermo LCQ Advantage MAX，Agilent LC 1200series(柱子：Waters Symmetry C18,
Figure PCTCN2016092375-appb-000033
毫米，5微米，35℃)，采用ESI(+)离子模式。
实验部分
实施例1：N-环丙基-2,2-二氟-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
通用合成方法：
Figure PCTCN2016092375-appb-000034
步骤1：2-(4-溴苯基)-2,2-二氟乙酸乙酯
搅拌下，向铜粉(8.99g,141.5mmol)和二甲亚砜(150mL)混合液中滴加二氟溴乙酸乙酯(14.35g,70.7mmol)，滴加完毕后室温继续搅拌1.5小时。向上述混合液中分批加入4-溴碘苯(10.0g,35.3mmol)，室温继续反应24小时。把反应液倒入饱和氯化铵水溶液中，用乙酸乙酯萃取(250mL×3)，合并有机相，有机相用饱和食盐水洗涤(250mL×3)并用无水硫酸钠干燥，有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得2-(4-溴苯基)-2,2-二氟乙酸乙酯(8.0g,收率81.1％)。1H-NMR(400MHz,CDCl3):δ＝7.61(d,J＝8.7Hz,2H),7.49(d,J＝8.6Hz,2H),4.25(m,2H),1.22(m,3H)。
步骤2：2-(4-溴-3-硝基苯基)-2,2-二氟乙酸乙酯
0℃下，向2-(4-溴苯基)-2,2-二氟乙酸乙酯(4.0g,14.3mmol)的硫酸(50mL)溶液中滴加发烟硝酸(4.0mL)，滴加完毕后0℃下继续反应1.0小时。把反应液倒入冰水中，用乙酸乙酯萃取(100mL×3)，合并有机相，有机相用水洗涤(150mL×3)并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯得2-(3-硝基-4-溴-3-硝基苯基)-2,2-二氟乙酸乙酯(3.9g,收率84.08％)。1H-NMR(400MHz,DMSO-d6):δ＝8.27(d,J＝2.1Hz,1H),8.10(d,J＝8.4Hz,1H),7.81(dd,J＝8.5,2.0Hz,1H),4.31(q,J＝7.1Hz,2H),1.21(m,3H)。
步骤3：2,2-二氟-2-(3-硝基-4-(噻吩-3-基)苯基)乙酸
氮气保护下，把2-(3-硝基-4-溴-3-硝基苯基)-2,2-二氟乙酸乙酯(3.9g,12.0mmol)，3-噻吩硼酸(2.3g,18.0mmol)，醋酸钾(3.5g,35.7mmol)和四三苯基膦钯(0.7g,0.6mmol)加到1,4-二氧六环(160mL)和水(40mL)的混合液中。将该混合物80℃反应8小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×2)，丢掉有机相，水相用稀盐酸(2M)调节pH为5，用乙酸乙酯萃取(100mL×3)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯得2,2-二氟-2-(3-硝基-4-(噻吩-3-基)苯基)乙酸(3.640g,收率100％)。
步骤4：N-环丙基-2,2-二氟-2-(3-硝基-4-(噻吩-3-基)苯基)乙酰胺
把环丙胺(57.0mg,1.0mmol)加到2,2-二氟-2-(3-硝基-4-(噻吩-3-基)苯基)乙酸(200.0mg,0.67mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(382mg,1.0mmol)，二异丙基乙基胺(173.2mg,1.34mmol)的N,N-二甲基甲酰胺(25mL)的溶液中。将该混合物于50℃反应3.0小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×2)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得N-环丙基-2,2-二氟-2-(3-硝基-4-(噻吩-3-基)苯基)乙酰胺(153mg,收率67.7％)。1H-NMR(400MHz,DMSO-d6):δ＝9.13(s,1H),8.12(s,1H),7.87(d,J＝8.2Hz,1H),7.83–7.72(m,2H),7.68(ddd,J＝4.9,2.9,0.7Hz,1H),7.20–7.12(m,1H),2.73(d,J＝3.7Hz,1H),0.67(q,J＝6.9Hz,2H),0.57(d,J＝2.9Hz,2H)。
步骤5：2-(3-氨基-4-(噻吩-3-基)苯基)-N-环丙基-2,2-二氟乙酰胺
把N-环丙基-2,2-二氟-2-(3-硝基-4-(噻吩-3-基)苯基)乙酰胺(153mg,0.45mmol)，还原铁粉(128.4mg,2.3mmol)，氯化铵(123.0mg,2.3mmol)加到甲醇(40mL)和水(40mL)的混合液中。将该混合物于70℃反应0.5小时后冷却到室温。过滤，滤饼用乙酸乙酯洗涤，把滤液分液，有机相用无水硫酸钠干燥，把有机相旋转蒸发去除得2-(3-氨基-4-(噻吩-3-基)苯基)-N-环丙基-2,2-二氟乙酰胺(140mg,收率100％)。
步骤6：N-环丙基-2,2-二氟-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000035
把2-(3-氨基-4-(噻吩-3-基)苯基)-N-环丙基-2,2-二氟乙酰胺(50.0mg,0.16mmol)和3-(三氟甲基)异氰酸苯酯(35.5mg,0.19mmol)的二氯甲烷(50mL)溶液室温搅拌12小时。把反应液直接用硅胶柱色谱分离得N-环丙基-2,2-二氟-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺(68.3mg,收率85.01％)。1H-NMR(400MHz,DMSO-d6):δ＝9.52(s,1H),9.01(d,J＝4.3Hz,1H),8.19(s,1H),8.00(d,J＝8.0Hz,2H),7.73(m,2H),7.46(m,3H),7.28(m,3H),2.72(m,1H),0.64(m,2H),0.57(m,2H)。
实施例2：2,2-二氟-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2016092375-appb-000036
参照实施例1的合成方法，制得2,2-二氯-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)-N-(2,2,2-三氟乙基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.70(s,1H),9.50(s,1H),8.20(d,J＝1.7Hz,1H),7.97(d,J＝6.4Hz,2H),7.71(m,2H),7.48-7.39(m,3H),7.31-7.20(m,3H),3.93(m,2H)。
实施例3：2,2-二氟-N-异丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000037
参照实施例1的合成方法，制得2,2-二氯-N-异丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.58(s,1H),8.84(d,J＝7.9Hz,1H),8.21(s,1H),8.02(d,J＝5.7Hz,2H),7.88-7.69(m,2H),7.47(m,3H),7.30(m,3H),3.93(dd,J＝13.7,6.4Hz,1H),1.11(d,J＝6.6Hz,6H)。
实施例4：N-(1-氰基环丙基)-2,2-二氟-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000038
参照实施例1的合成方法，制得N-(1-氰基环丙基)-2,2-二氯-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.93(s,1H),9.44(s,1H),8.11(d,J＝1.6Hz,1H),7.90(s,2H),7.65(m,2H),7.42-7.31(m,3H),7.25-7.12(m,3H),1.45(dd,J＝8.4,5.6Hz,2H),1.16(dd,J＝8.4,5.7Hz,2H)。
实施例5：2,2-二氟-N-(氧杂丁环-3-基)-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000039
参照实施例1的合成方法，制得2,2-二氯-N-(3-氧杂丁环)-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.73(d,J＝6.4Hz,1H),9.52(s,1H),8.24(d,J＝1.6Hz,1H),8.00(d,J＝2.8Hz,2H),7.75(m,2H),7.46(dd,J＝16.6,6.6Hz,3H),7.34-7.26(m,3H),4.84(dt,J＝13.9,7.0Hz,1H),4.69(t,J＝6.9Hz,2H),4.56(t,J＝6.5Hz,2H)。
实施例6：N-(氮杂丁环-3-基)-2,2-二氟-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000040
参照实施例1的合成方法，制得N-(3-氮杂丁环)-2,2-二氯-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.73(d,J＝7.1Hz,1H),9.55(s,1H),8.24(dd,J＝8.0,1.7Hz,1H),8.08-7.92(m,2H),7.82-7.71(m,2H),7.49(m,3H),7.35-7.17(m,3H),4.73-4.55(m,1H),3.88(m,2H),3.63(m,2H)。
实施例7：2,2-二氟-N-(1-甲基氮杂丁环-3-基)-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000041
参照实施例1的合成方法，制得2,2-二氯-N-(1-甲基氮杂丁环-3-基)-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz, DMSO-d6):δ＝9.52(s,1H),9.39(d,J＝6.9Hz,1H),8.22(d,J＝1.7Hz,1H),8.02(s,1H),7.98(s,1H),7.73(m,2H),7.56-7.39(m,3H),7.37-7.24(m,3H),4.23(m,1H),3.54-3.44(m,2H),2.99(t,J＝7.4Hz,2H),2.21(s,3H)。
实施例8：2,2-二氟-N-(2-羟基-2-甲基丙基)-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000042
参照实施例1的合成方法，制得2,2-二氯-N-(2-羟基-2-甲基丙基)-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.51(s,1H),8.72(t,J＝6.1Hz,1H),8.22(s,1H),8.00(d,J＝8.5Hz,2H),7.78-7.62(m,2H),7.45(m,3H),7.29(m,3H),4.54(s,1H),3.09(d,J＝6.1Hz,2H),1.02(s,6H)。
实施例9：N-环丙基-2,2-二氟-2-(4-(噻吩-3-基)-3-(3-(2-(三氟甲基)吡啶-4-基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000043
参照实施例1的合成方法，制得N-环丙基-2,2-二氯-2-(4-(噻吩-3-基)-3-(3-(2-(三氟甲基)吡啶-4-基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.87(s,1H),8.97(s,1H),8.37(d,J＝54.4Hz,1H),8.17(s,1H),8.05(s,1H),7.95(d,J＝11.1Hz,1H),7.67(m,2H),7.39(m,2H),7.23(m,2H),2.65(m,1H),0.54(m,4H)。
实施例10：N-环丙基-2,2-二氟-2-(3-(3-(4-氟-3-(三氟甲基)苯基)脲基)-4-(噻吩-3-基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000044
参照实施例1的合成方法，制得N-环丙基-2,2-二氯-2-(3-(3-(4-氟-3-(三氟甲基)苯基)脲基)-4-(噻吩-3-基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.47(s,1H),9.18(s,1H),8.99(d,J＝4.3Hz,1H),8.12(d,J＝5.5Hz,1H),7.93(m,3H),7.74-7.64(m,1H),7.56-7.42(m,1H),7.38(m,3H),2.67(m,1H),0.62(m,2H),0.53(m,2H)。
实施例11：N-环丙基-2,2-二氟-2-(3-(3-(3-(三氟甲基)苯基)脲基)-4-(6-(三氟甲基)吡啶-2-基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000045
参照实施例1的合成方法，制得N-环丙基-2,2-二氯-2-(3-(3-(3-(三氟甲基)苯基)脲基)-4-(6-(三氟甲基)吡啶-2-基)苯基)乙酰胺。1H-NMR(400MHz,CDCl3):δ＝12.03(s,1H),8.70(s,1H),8.10(dt,J＝15.7,8.0Hz,2H),7.87(d,J＝8.4Hz,1H),7.81(s,1H),7.75(d,J＝6.7Hz,1H),7.57(d,J＝8.1Hz,1H),7.50(d,J＝8.5Hz,1H),7.44(t,J＝7.8Hz,1H),7.33(d,J＝7.3Hz,1H),6.64(s,1H),6.47(s,1H),2.80(m,1H),0.94-0.81(m,2H),0.66(m,2H)。
实施例12：N-环丙基-2,2-二氟-2-(2-(3-(3-(三氟甲基)苯基)脲基)-[1,1’-联苯基]-4基)乙酰胺
Figure PCTCN2016092375-appb-000046
参照实施例1的合成方法，制得N-环丙基-2,2-二氯-2-(2-(3-(3-(三氟甲基)苯基)脲基)-[1,1’-联苯基]-4基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.42(s, 1H),9.01(d,J＝4.3Hz,1H),8.19(s,1H),8.00(m,3H),7.73(m,3H),7.46(m,3H),7.28(m,3H),2.72(m,1H),0.58(m,2H),0.50(m,2H)。
实施例13：N-环丙基-2-(4-(1,3-二甲基-1H-吡唑-5-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)-2,2-二氟乙酰胺
Figure PCTCN2016092375-appb-000047
参照实施例1的合成方法，制得N-环丙基-2-(4-(1,3-二甲基-1H-吡唑-5-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)-2,2-二氟乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.57(s,1H),8.09(s,1H),7.98(d,J＝8.0Hz,2H),7.73(m,2H),7.46(m,3H),7.28(m,2H),3.80(s,3H,),2.72(m,4H),0.59(m,2H),0.47(m,2H)。
实施例14：N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)丙酰胺
通用合成方法：
Figure PCTCN2016092375-appb-000048
步骤1：2-(4-溴苯基)丙酸
向2-(4-溴苯基)丙酸乙酯(3.0g,11.7mmol)的四氢呋喃(50mL)，甲醇(50mL)和水(50mL)的混合液中加固体一水合氢氧化锂(0.56g,23.4mmol)。将该混合物室温搅拌4小时，用2mol/L的稀盐酸调节pH为5，旋转蒸发去除有机溶剂，所得固体过滤，水洗，干燥得2-(4-溴苯基)丙酸(2.0g,收率74.8％)。
步骤2：2-(4-溴-3-硝基苯基)丙酸
将2-(4-溴苯基)丙酸(2.0g，8.73mmol)溶于浓硫酸(50mL)，冷却到0℃，向反应物中慢慢滴加发烟硝酸(2.0mL)。混合物在0℃下搅拌1个小时，将混合物 慢慢加入到冰水中，将固体沉淀过滤，干燥得2-(4-溴-3-硝基苯基)丙酸(2.0g，收率83.6％)。
步骤3：2-(4-溴-3-硝基苯基)-N-环丙基丙酰胺
把环丙胺(0.25g,4.38mmol)加到2-(4-溴-3-硝基苯基)丙酸(1.0g,3.65mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.8g,7.3mmol)，二异丙基乙基胺(1.88g,14.6mmol)的N,N-二甲基甲酰胺(50mL)的溶液中。将该混合物50℃反应3小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×2)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得2-(4-溴-3-硝基苯基)-N-环丙基丙酰胺(0.6g,收率52.5％)。
步骤4：N-环丙基-2-(3-硝基-4-(噻吩-3-基)苯基)丙酰胺
氮气保护下，将2-(4-溴-3-硝基苯基)-N-环丙基丙酰胺(0.6g,1.92mmol)，3-噻吩硼酸(0.37g,2.88mmol)，碳酸钠(0.61g,5.76mmol)和四三苯基膦钯(0.11g,0.1mmol)加到1,4-二氧六环(100mL)和水(25mL)的混合液中。将该混合物90℃反应8小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×3)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得N-环丙基-2-(3-硝基-4-(噻吩-3-基)苯基)丙酰胺(0.5g,收率82.5％)。
步骤5：2-(3-氨基-4-(噻吩-3-基)苯基)-N-环丙基丙酰胺
把N-环丙基-2-(3-硝基-4-(噻吩-3-基)苯基)丙酰胺(0.5g,1.58mmol)，还原铁粉(433.0mg,7.9mmol)，氯化铵(440.0mg,7.9mmol)加到甲醇(40mL)和水(40mL)的混合液中。将该混合物70℃反应0.5小时后冷却到室温。过滤，固体用乙酸乙酯洗涤，把滤液分液，有机相用无水硫酸钠干燥，把有机相旋转蒸发去除得2-(3-氨基-4-(噻吩-3-基)苯基)-N-环丙基丙酰胺(325.0mg,收率71.8％)。
步骤6：N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)丙酰胺
Figure PCTCN2016092375-appb-000049
把2-(3-氨基-4-(噻吩-3-基)苯基)-N-环丙基丙酰胺(80.0mg,0.28mmol)和3-(三氟甲基)异氰酸苯酯(78.0mg,0.42mmol)的二氯甲烷(50mL)溶液室温搅拌12小时。把反应液直接用硅胶柱色谱分离得N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)丙酰胺(60.0mg,收率45.3％)。1H-NMR(400MHz,DMSO-d6):δ＝9.35(s,1H),8.03(d,J＝4.3Hz,1H),7.97(s,1H),7.82-7.72(m,2H),7.63(dd,J＝4.9,2.9Hz,1H),7.60-7.55(m,1H),7.47-7.39(m,2H),7.28-7.15(m,3H),7.03(dd,J＝8.0,1.8Hz,1H),3.51-3.41(m,1H),2.55(qd,J＝7.9,4.0Hz,1H),1.27(d,J＝7.0Hz,3H),0.60-0.44(m,2H),0.40-0.24(m,2H)。
实施例15：N-环丙基-2-甲基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)丙酰胺
Figure PCTCN2016092375-appb-000050
参照实施例14的合成方法，制得N-环丙基-2-甲基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)丙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.34(s,1H),7.95(s,1H),7.84-7.71(m,2H),7.64(dd,J＝4.9,2.9Hz,1H),7.58(d,J＝1.7Hz,1H),7.49-7.38(m,2H),7.35(d,J＝3.8Hz,1H),7.22(m,3H),6.99(dd,J＝8.1,1.8Hz,1H),2.56(m,1H),1.45(s,6H),0.58-0.45(m,2H),0.43-0.35(m,2H)。
实施例16：N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000051
参照实施例14的合成方法，制得N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.03(s,1H),7.78(d,J＝4.1Hz,1H),7.65(s,1H),7.45(s,1H),7.39(d,J＝1.5Hz,1H),7.31(dd,J＝4.9,2.9Hz,1H),7.27-7.22(m,1H),7.12-7.05(m,2H),6.97-6.81(m,3H),6.62(dd,J＝7.9,1.7Hz,1H),3.17(s,2H),2.83-2.73(m,1H),0.59(m,2H),0.38(m,2H)。
实施例17：N-环丙基-1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)环丙甲酰胺
Figure PCTCN2016092375-appb-000052
参照实施例14的合成方法，制得N-环丙基-1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)环丙甲酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.39(s,1H),8.00(s,1H),7.89(s,1H),7.85(d,J＝1.6Hz,1H),7.71(dd,J＝5.0,2.9Hz,1H),7.67-7.64(m,1H),7.50(q,J＝8.3Hz,2H),7.28(m,3H),7.06(dd,J＝7.9,1.7Hz,1H),6.97(d,J＝3.8Hz,1H),2.60(m,1H),1.33(m,2H),0.97(m,2H),0.55(m,2H),0.42(m,2H)。
实施例18：N-环丙基-2-甲基-(3-(3-(3-氧代异吲哚-5-基)脲基)-4-(噻吩-3-基)苯基)丙酰胺
Figure PCTCN2016092375-appb-000053
参照实施例14的合成方法，制得N-环丙基-2-甲基-(3-(3-(3-氧代异吲哚-5-基)脲基)-4-(噻吩-3-基)苯基)丙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.47(s,1H),8.46(s,1H),7.93(s,1H),7.84(d,J＝1.7Hz,1H),7.75(d,J＝1.8Hz,1H),7.63(dd,J＝4.7,2.5Hz,2H),7.40(m,3H),7.28-7.17(m,2H),6.98(dd,J＝8.1,2.0Hz,1H),4.24(s,2H),2.59-2.49(m,1H),1.38(s,6H),0.54-0.44(m,2H),0.41-0.33(m,2H)。
实施例19：N-环丙基-1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)环丁甲酰胺
Figure PCTCN2016092375-appb-000054
参照实施例14的合成方法，制得N-环丙基-1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)环丁甲酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.39(s,1H),8.00(s,1H),7.88-7.76(m,2H),7.68(dd,J＝4.9,2.9Hz,1H),7.63-7.57(m,2H),7.53-7.40(m,2H),7.26(dd,J＝9.2,4.5Hz,3H),7.09(dd,J＝8.0,1.8Hz,1H),2.76-2.61(m,2H),2.58(m,1H),2.39-2.23(m,2H),1.81-1.68(m,2H),0.60-0.47(m,2H),0.47-0.35(m,2H)。
实施例20：N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)叔丁酰胺
Figure PCTCN2016092375-appb-000055
参照实施例14的合成方法，制得N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)叔丁酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.41(s,1H),8.12(d,J＝4.2Hz,1H),8.03(s,1H),7.82(s,2H),7.68(m,1H),7.63(m,1H),7.48(m,2H),7.26(m,3H),7.08(d,J＝8.0Hz,1H),3.23(m,1H),2.59(m,1H),1.61-1.94(m,2H),0.82(t,J＝7.3Hz,3H),0.57(m,2H),0.34(m,2H)。
实施例21：2-氨基-N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺
Figure PCTCN2016092375-appb-000056
参照实施例14的合成方法，制得2-氨基-N-环丙基-2-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.74(s,1H),8.70(m,2H),8.12-8.04(m,3H),7.78–7.39(m,3H),7.28(m,3H),4.79(d,J＝5.1Hz,1H),3.69(s,1H),2.69(dd,J＝7.5,3.5Hz,1H),0.63(m,2H),0.45(m,2H)。
实施例22：N-环丙基-4-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)哌啶-4-甲酰胺
Figure PCTCN2016092375-appb-000057
参照实施例14的合成方法，制得N-环丙基-4-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)哌啶-4-甲酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.57(d,J＝14.3Hz,1H),8.61(s,2H),8.04(d,J＝8.1Hz,2H),7.98(s,1H),7.89(s,1H),7.81(m,1H),7.68(m,1H),7.48(m,2H),7.35-7.23(m,2H),7.04(t,J＝5.9Hz,1H), 3.26(m,3H),2.87(m,2H),2.65(m,1H),2.53(m,2H),2.00(m,2H),0.57(m,2H),0.42(m,2H)。
实施例23：N-环丙基-4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯甲酰胺
Figure PCTCN2016092375-appb-000058
步骤1：3-硝基-4-(噻吩-3-基)苯甲酸甲酯
氮气保护下，把4-溴-3-硝基苯甲酸甲酯(1.30g,5.0mmol)，3-噻吩硼酸(0.77g,6.0mmol)，碳酸钠(1.06g,10.0mmol)和四三苯基膦钯(0.29g,0.25mmol)加到1,4-二氧六环(160mL)和水(40mL)的混合液中。将该混合物90℃反应8小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×3)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得3-硝基-4-(噻吩-3-基)苯甲酸甲酯(1.12g,收率85.1％)。1H-NMR(400MHz,DMSO-d6):δ＝8.39(d,J＝1.7Hz,1H),8.22(dd,J＝8.1,1.8Hz,1H),7.83-7.76(m,2H),7.69(dd,J＝5.0,2.9Hz,1H),7.16(dd,J＝5.0,1.4Hz,1H),3.91(s,3H)。
步骤2：3-硝基-4-(噻吩-3-基)苯甲酸
向3-硝基-4-(噻吩-3-基)苯甲酸甲酯(496.0mg,1.88mmol)的四氢呋喃(20mL)，甲醇(20mL)和水(20mL)的混合液中加固体一水合氢氧化锂(157.8mg,3.76mmol)。将该混合物室温搅拌4小时，用2M稀盐酸调节pH为5，旋转蒸发去除有机溶剂，所得固体过滤，水洗，干燥得3-硝基-4-(噻吩-3-基)苯甲酸(416.0mg,收率88.6％)。
步骤3：N-环丙基-3-硝基-4-(噻吩-3-基)苯甲酰胺
把环丙胺(190.7mg,3.34mmol)加到3-硝基-4-(噻吩-3-基)苯甲酸(416.0mg,1.67mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.27g,3.34mmol)，二异丙基乙基胺(0.86g,6.68mmol)的N,N-二甲基甲酰胺(25mL)的溶液中。将该混合物50℃反应3小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×2)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去 除乙酸乙酯，残留物用硅胶柱色谱分离得N-环丙基-3-硝基-4-(噻吩-3-基)苯甲酰胺(425.7mg,收率88.5％)。
步骤4：3-氨基-N-环丙基-4-(噻吩-3-基)苯甲酰胺
把N-环丙基-3-硝基-4-(噻吩-3-基)苯甲酰胺(425.7mg,1.48mmol)，还原铁粉(413.3mg,7.4mmol)，氯化铵(395.8mg,7.4mmol)加到甲醇(40mL)和水(40mL)的混合液中。将该混合物70℃反应0.5小时后冷却到室温。过滤，固体用乙酸乙酯洗涤，把滤液分液，有机相用无水硫酸钠干燥，把有机相旋转蒸发去除得3-氨基-N-环丙基-4-(噻吩-3-基)苯甲酰胺(364mg,收率95.4％)。
步骤5：N-环丙基-4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯甲酰胺
Figure PCTCN2016092375-appb-000059
把3-氨基-N-环丙基-4-(噻吩-3-基)苯甲酰胺(70.0mg,0.27mmol)和3-(三氟甲基)异氰酸苯酯(76.7mg,0.41mmol)的二氯甲烷(50mL)溶液室温搅拌12小时。把反应液直接用硅胶柱色谱分离得N-环丙基-4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯甲酰胺(91.0mg,收率75.4％)。1H-NMR(400MHz,DMSO-d6):δ＝9.40(s,1H),8.44(d,J＝4.2Hz,1H),8.26(d,J＝1.7Hz,1H),7.98(m,2H),7.72(m,2H),7.61-7.44(m,3H),7.40(d,J＝8.0Hz,1H),7.29(m,1H),2.85(m,1H),0.68(m,2H),0.56(m,2H)。
实施例24：1-(5-(1-(环丙基氨基)乙基)-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲
通用合成方法：
Figure PCTCN2016092375-appb-000060
步骤1：1-(3-硝基-4-(噻吩-3-基)苯基)乙酮
氮气保护下，把4-溴-3-硝基苯乙酮(500.0mg,2.05mmol)，3-噻吩硼酸(315.0mg,2.46mmol)，醋酸钾(603.0mg,6.15mmol)和四三苯基膦钯(118.0mg,0.1mmol)加到1,4-二氧六环(100mL)和水(25mL)的混合液中。将该混合物90℃反应8小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×3)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得1-(3-硝基-4-(噻吩-3-基)苯基)乙酮(400.0mg,收率79.0％)。
步骤2:1-(3-氨基-4-(噻吩-3-基)苯基)乙酮
把1-(3-硝基-4-(噻吩-3-基)苯基)乙酮(247.0mg,1.0mmol)，还原铁粉(280.0mg,5.0mmol)，氯化铵(268.0mg,5.0mmol)加到甲醇(40mL)和水(40mL)的混合液中。将该混合物于70℃反应0.5小时后冷却到室温。过滤，固体用乙酸乙酯洗涤，把滤液分液，有机相用无水硫酸钠干燥，把有机相旋转蒸发去除得1-(3-氨基-4-(噻吩-3-基)苯基)乙酮(100.0mg,收率46.1％)。
步骤3：1-(5-乙酰基-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲
把1-(3-氨基-4-(噻吩-3-基)苯基)乙酮(100.0mg,0.46mmoL)和3-(三氟甲基)异氰酸苯酯(130.0mg,0.69mmoL)的二氯甲烷(50mL)溶液室温搅拌12小时。把反应液直接用硅胶柱色谱分离得1-(5-乙酰基-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲(178.0mg,收率95.6％)。
步骤4：1-(5-(1-(环丙基氨基)乙基)-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲
Figure PCTCN2016092375-appb-000061
将1-(5-乙酰基-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲(70.0mg，0.173mmol)溶于1,2-二氯乙烷(50.0mL)中，冷却到0℃。向反应物中加入环丙胺(12.0mg，0.21mmoL)和2滴醋酸。室温搅拌10分钟，加入三乙酰基硼氢化钠(73.0mg，0.35mmol)，反应物室温搅拌过夜。反应结束后，慢慢滴加水淬灭反应，用二氯甲烷萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩。得到的残留物用硅胶色谱柱纯化，得到产品1-(5-(1-(环丙基氨基)乙基)-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲(50.0mg，收率64.8％)。1H-NMR(400MHz,DMSO-d6):δ＝9.58(s,1H),8.09-7.88(m,3H),7.75-7.65(m,2H),7.48(t,J＝6.6Hz,2H),7.36(d,J＝7.8Hz,1H),7.31-7.20(m,3H),4.11(m,1H),2.16(m,1H),1.43(s,3H),0.52(m,4H)。
实施例25：1-(5-(环丙胺基)甲基)-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲
Figure PCTCN2016092375-appb-000062
参照实施例24的合成方法，制得1-(5-(环丙胺基)甲基)-2-(噻吩-3-基)苯基)-3-(3-(三氟甲基)苯基)脲。1H-NMR(400MHz,DMSO-d6):δ＝9.37(s,1H),7.93(s,1H),7.81(s,1H),7.72(s,1H),7.59(dd,J＝4.9,2.9Hz,1H),7.54(dd,J＝7.5,5.9Hz,1H),7.48-7.37(m,2H),7.18(dd,J＝7.9,4.0Hz,3H),7.01(t,J＝8.7Hz,1H),3.65(s,2H),2.08(m,1H),0.35(m,2H),0.29(m,2H)。
实施例26：N-环丙基-1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)甲磺酰胺
Figure PCTCN2016092375-appb-000063
步骤1：(4-溴-3-硝基苯基)甲醇
氮气充分置换下，将原料4-溴-3-硝基苯甲酸(1.50g，6.10mmol)溶于四氢呋喃(150mL)中，将10M的硼烷的二甲硫醚溶液(0.65mL，6.53mmol)慢慢地加入反应物中，反应物室温搅拌48个小时。加水淬灭反应，用乙醚萃取，有机相用水，饱和食盐水洗涤，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩得到产品(4-溴-3-硝基苯基)甲醇(1.40g，收率99.0％)。
步骤2：4-溴-3-硝基苄基甲磺酸酯
将原料(4-溴-3-硝基苯基)甲醇(1.40g，6.03mmol)溶于二氯甲烷(150mL)中，冷却到0℃，加入三乙胺(0.90g,9.05mmol)，慢慢滴加甲基磺酰氯(0.76g,6.63mmol)。反应混合物室温搅拌两个小时，加水淬灭反应，慢慢滴加饱和碳酸氢钠水溶液直到pH值为碱性，用二氯甲烷萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩得到产品4-溴-3-硝基苄基甲磺酸酯(1.50g，收率80.2％)。
步骤3：4-溴-3-硝基硫代乙酸苄酯
将原料4-溴-3-硝基苄基甲磺酸酯(1.50g，4.84mmol)溶于二甲基亚砜(100mL)中，加入硫代乙酸钾(0.60g，5.32mmol)，反应混合物室温搅拌16个小时。加水淬灭反应，用二氯甲烷萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩，得到的残留物用硅胶色谱柱纯化，得到产品4-溴-3-硝基硫代乙酸苄酯(0.90g，收率64.1％)。
步骤:4：4-溴-3-硝基苯甲磺酰氯
4-溴-3-硝基硫代乙酸苄酯(0.90g，3.10mmol)溶于乙腈(100mL)中，冷却到0℃，慢慢滴加N-氯代丁二酰亚胺(1.66g，12.4mmol)的乙腈(5mL)和盐酸(1mL，1N)的混合溶液，反应混合物0℃下继续搅拌1小时。加水淬灭反应，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩，得到产品4-溴-3-硝基苯甲磺酰氯(0.90g，收率92.2％)。
步骤5：1-(4-溴-3-硝基苯基)-N-环丙基苯甲磺酰胺
在0℃下，向环丙胺(100.0mg，1.75mmol)和吡啶(377.0mg，4.77mmol)的二氯甲烷(50mL)溶液中加入原料4-溴-3-硝基苯甲磺酰氯(500.0mg，1.59mmol)，反应混合物室温搅拌过夜。加水淬灭反应，用二氯甲烷萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩得到1-(4-溴-3-硝基苯基)-N-环丙基苯甲磺酰胺(180.0mg，收率33.8％)。
步骤6：N-环丙基-1-(3-硝基-4-(噻吩-3-基)-苯基)甲磺酰胺
氮气保护下，把1-(4-溴-3-硝基苯基)-N-环丙基苯甲磺酰胺(180.0mg,0.54mmol)，3-噻吩硼酸(82.0mg,0.65mmol)，醋酸钾(160.0mg,0.65mmol)和四三苯基膦钯(30.0mg,0.03mmol)加到1,4-二氧六环(100mL)和水(25mL)的混合液中。将该混合物90℃反应8小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(100mL×3)，合并有机相并用无水硫酸钠干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得N-环丙基-1-(3-硝基-(4-(噻吩-3-基)-苯基)甲磺酰胺(150.0mg,收率82.5％)。
步骤7：1-(3-氨基-4-(噻吩-3-基)-苯基)-N-环丙基甲磺酰胺
把N-环丙基-1-(3-硝基-4-(噻吩-3-基)-苯基)甲磺酰胺(150.0mg,0.44mmol)，还原铁粉(124.0mg,2.22mmol)，氯化铵(119.0mg,2.22mmol)加到甲醇(40mL)和水(40mL)的混合液中。将该混合物70℃反应0.5小时后冷却到室温。过滤，固体用乙酸乙酯洗涤，把滤液分液，有机相用无水硫酸钠干燥，把有机相旋转蒸发去除得1-(3-氨基-4-(噻吩-3-基)-苯基)-N-环丙基甲磺酰胺(135.0mg,收率 98.7％)。
步骤8：N-环丙基-1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)甲磺酰胺
Figure PCTCN2016092375-appb-000064
把1-(3-氨基-(4-(噻吩-3-基)-苯基)-N-环丙基甲磺酰胺(60.0mg,0.20mmoL)和3-(三氟甲基)异氰酸苯酯(55.0mg,0.29mmoL)的二氯甲烷(50mL)溶液室温搅拌12小时。把反应液直接用硅胶柱色谱分离得N-环丙基-1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)甲磺酰胺(40.0mg,收率41.4％)。1H-NMR(400MHz,DMSO-d6):δ＝9.42(s,1H),8.02(s,1H),7.92(d,J＝13.8Hz,2H),7.70(m,2H),7.49(m,3H),7.33(d,J＝7.9Hz,1H),7.27(d,J＝5.0Hz,2H),7.13(d,J＝7.8Hz,1H),4.37(s,2H),2.52(m,1H),0.66-0.38(m,4H)。
实施例27：N-(1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙基)环丙基甲酰胺
通用合成方法：
Figure PCTCN2016092375-appb-000065
步骤1：1-(3-硝基-4-(噻吩-3-基)苯基)乙酮
氮气保护下，把4-溴-3-硝基苯乙酮(3.0g,12.3mmol)，3-噻吩硼酸(1.9g,14.7mmol)，醋酸钾(3.6g,36.9mmol)和四三苯基膦钯(0.7g,0.6mmol)加到1,4-二氧六环(160mL)和水(40mL)的混合液中。将该混合物90℃反应8小时后冷却到室温。把反应混合物倒入水中，用乙酸乙酯萃取(150mL×3)，合并有机相并用无水硫酸 钠干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得1-(3-硝基-4-(噻吩-3-基)苯基)乙酮(2.6g,收率85.5％)。
步骤2：2-甲基-N-(1-(3-硝基-4-(噻吩-3-基)苯基)亚乙基)丙烷-2-亚磺酰胺
向原料1-(3-硝基-4-(噻吩-3-基)苯基)乙酮(500mg，2.02mmol)，叔丁基亚磺酰胺(270mg，2.22mmol)和钛酸四乙酯(911mg，4.00mmol)的混合物中加入四氢呋喃(100mL)。混合物加热回流12个小时，将反应混合物冷却到室温，在减压下浓缩，得到的残留物用硅胶色谱柱纯化，得到2-甲基-N-(1-(3-硝基-4-(噻吩-3-基)苯基)亚乙基)丙烷-2-亚磺酰胺(300mg，收率42.3％)。
步骤3：2-甲基-N-(1-(3-硝基-4-(噻吩-3-基)苯基)乙基)丙烷-2-亚磺酰胺
将原料2-甲基-N-(1-(3-硝基-4-(噻吩-3-基)苯基)亚乙基)丙烷-2-亚磺酰胺(300mg，0.86mmol)溶于四氢呋喃(100mL)中，冷却至0℃，向反应物中分批次加入硼氢化钠(65mg，1.71mmol)，反应物升到室温搅拌2小时，加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩得到2-甲基-N-(1-(3-硝基-4-(噻吩-3-基)苯基)乙基)丙烷-2-亚磺酰胺(200mg，收率66.3％)。
步骤4：1-(3-硝基-4-(噻吩-3-基)苯基)乙胺
将2-甲基-N-(1-(3-硝基-4-(噻吩-3-基)苯基)乙基)丙烷-2-亚磺酰胺(200mg，0.57mmol)溶于甲醇(100mL)中，向反应物中加入6M盐酸水溶液(10mL)，反应物室温搅拌12个小时。反应物减压下浓缩，得到的残留物溶于水中，用氨水调节PH到7-8，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩得到1-(3-硝基-4-(噻吩-3-基)苯基)乙胺(130mg，收率92.3％)。
步骤5：N-(1-(3-硝基-4-(噻吩-3-基)苯基)乙基)环丙基甲酰胺
在0℃下，向原料1-(3-硝基-4-(噻吩-3-基)苯基)乙胺(130mg，0.52mmol)和三乙胺(212mg，2.10mmoL)的二氯甲烷(50mL)溶液中加入环丙酰氯(64mg，0.62mmoL)，反应混合物室温搅拌1个小时。加水淬灭反应，用二氯甲烷萃取，将有机相用无水硫酸钠干燥，过滤，并在减压下浓缩得到N-(1-(3-硝基-4-(噻吩-3-基)苯基)乙基)环丙基甲酰胺(150mg，收率90.6％)。
步骤6：N-(1-(3-氨基-4-(噻吩-3-基)苯基)乙基)环丙基甲酰胺
把N-(1-(3-硝基-4-(噻吩-3-基)苯基)乙基)环丙基甲酰胺(150.0mg,0.47mmol)，还原铁粉(140mg,2.27mmol)，氯化铵(128mg,2.27mmol)加到甲醇(40mL)和水(40mL)的混合液中。将该混合物70℃反应0.5小时后冷却到室温。过滤，固体用乙酸乙酯洗涤，把滤液分液，有机相用无水硫酸钠干燥，把有机相旋转蒸发去除得N-(1-(3-氨基-4-(噻吩-3-基)苯基)乙基)环丙基甲酰胺(100mg,收率73.6％)。
步骤7：：N-(1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙基)环丙基甲酰胺
Figure PCTCN2016092375-appb-000066
把N-(1-(3-氨基-(4-(噻吩-3-基)苯基)乙基)环丙基甲酰胺(100.0mg,0.35mmoL)和3-(三氟甲基)异氰酸苯酯(98.0mg,0.52mmoL)的二氯甲烷(50mL)溶液室温搅拌12小时。把反应液直接用硅胶柱色谱分离得N-(1-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苯基)乙基)环丙基甲酰胺(150.0mg,收率90.7％)。1H-NMR(400MHz,DMSO-d6):δ＝9.39(s,1H),8.54(d,J＝7.9Hz,1H),8.00(s,1H),7.86-7.75(m,2H),7.66(dd,J＝4.9,2.9Hz,1H),7.60(dd,J＝2.8,1.1Hz,1H),7.45(d,J＝5.1Hz,2H),7.28-7.18(m,3H),7.03(dd,J＝7.9,1.5Hz,1H),4.87(p,J＝7.0Hz,1H),1.63-1.49(m,1H),1.34(d,J＝7.0Hz,3H),0.73-0.45(m,4H)。
实施例28：N-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苄基)环丙基甲酰胺
Figure PCTCN2016092375-appb-000067
参照实施例27的合成方法，制得N-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苄基)环丙基甲酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.35(s,1H),8.57(t,J＝5.9Hz,1H),7.97(s,1H),7.81(s,1H),7.72(d,J＝1.4Hz,1H),7.64(dd,J＝4.9,2.9Hz,1H),7.57(dd,J＝2.9,1.3Hz,1H),7.47-7.38(m,2H),7.22(m,2H),7.19(dd,J＝4.9,1.3Hz,1H),6.97(dd,J＝7.9,1.6Hz,1H),4.22(s,2H),1.64-1.48(m,1H),0.75-0.53(m,4H)。
实施例29：N-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苄基)环丙基磺酰胺
Figure PCTCN2016092375-appb-000068
参照实施例27的合成方法，制得N-(4-(噻吩-3-基)-3-(3-(3-(三氟甲基)苯基)脲基)苄基)环丙基磺酰胺。1H-NMR(400MHz,DMSO-d6):δ＝9.40(s,1H),8.01(s,1H),7.87(d,J＝3.5Hz,2H),7.73-7.60(m,3H),7.51-7.46(m,2H),7.33-7.22(m,3H),7.16-7.08(m,1H),4.20(d,J＝6.4Hz,2H),2.61-2.49(m,1H),0.91(m,4H)。实验例1：IDH2抑制活性的测定
本申请采用以下方法来测定本申请的化合物对IDH2(R172K,40-end)的抑制活性，该抑制活性采用IC50这一指标来表示，IC50即IDH2的活性被抑制50％时的化合物的浓度。
材料和方法：
通过辅助因子NADPH的消减来测定化合物对IDH2(R172K,40-end)的抑制活性。将化合物与酶和NADPH进行预孵育，然后通过添加a-KG启动反应，线性条件下反应120分钟。之后通过添加Diaphorase(硫辛酰胺脱氢酶)和相应的底物Resazurin(刃天青)终止反应。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。
具体地说，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80nM IDH2(R172K，40-end)和40μM NADPH的反应缓冲液(20mM Tris-HCl,PH7.5；150mM NaCl；10mM MgCl2；10mM MnCl2；0.4mg/ml BSA和2mM DTT)。然后将上述测试混合物在23℃孵育120分钟，之后添加2.5μl含有4mM a-KG的反应缓冲液启动反应。室温孵育120分钟后，加入5μl用反应缓冲液配制的终止混合物(0.4U/ml Diaphorase和40μM 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。
实施例化合物的IDH2抑制活性如表1所示：
表1
实施例编号 IC50(nM) 实施例编号 IC50(nM)
1 14.20 16 75.82
2 45.52 17 138.2
3 62.35 18 1231
4 56.51 19 87.47
5 29.54 20 361.8
10 391.4 21 622.5
13 105.70 23 550.6
14 69.93 24 312.0
15 65.66 27 82.89
12 53.75 28 55.01
实施例2：药代动力学参数的测定
本申请采用以下方法来测定本申请的化合物的药代动力学参数：
研究使用7-9周龄健康雄性成年大鼠，辅剂为10％DMSO+70％PEG400+20％NS，每组动物(3只雄性大鼠)单次灌胃给药，剂量为5mg/kg，灌胃给药组的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。
在给药后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。
血浆样品分析使用已确证的液相色谱-串联质谱联用方法(LC-MS/MS)，个体动物的血浆浓度-时间数据用WinNonlin(专业版，版本6.3；Pharsight公司)软件进行分析，非房室模型被用于浓度分析，计算化合物的药代动力学参数，如表3所示：
表3
实施例 5 28 AGI-6780
剂量(mg/kg) 5 5 5
T1/2(hr) 4.37 2.34 1.49
Tmax(hr) 0.42 0.33 2.83
Cmax(ng/mL) 494.6 414.1 191.1
AUC0-inf(hr*ng/mL) 858.2 844.5 559.3
结论：实施例5和28具有非常好的体内代谢水平和长的半衰期，并且在同等剂量下血药浓度高于IDH2抑制剂AGI-6780。

Claims (26)

  1. 通式Ⅰ的化合物或其药学上可接受的盐或水合物，
    Figure PCTCN2016092375-appb-100001
    其中，
    A环选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环；
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    每个R3独立地选自H、卤素、卤代C1-3烷基、羟基、氨基或C1-6烷基；
    每个R4独立地选自H或C1-6烷基；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
    m和n独立地为1，2或3；以及
    o和p分别独立地选自0或1，且o和p不同时为0。
  2. 通式Ⅱ的化合物或其药学上可接受的盐或水合物，
    Figure PCTCN2016092375-appb-100002
    其中，
    A环选自苯环或含1-2个N原子的5-6元杂芳环；
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同以及R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
    m为1，2或3；以及
    o和p分别独立地选自0或1，且o和p不同时为0。
  3. 通式Ⅲ的化合物或其药学上可接受的盐或水合物，
    Figure PCTCN2016092375-appb-100003
    其中，
    X选自CH或N；
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    L1和L2分别独立地选自-C(O)-、-N(R4)-或-S(O)2-，且L1和L2不相同以及R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；
    m为1，2或3；以及
    o和p分别独立地选自0或1，且o和p不同时为0。
  4. 权利要求1-2中任一项所述的化合物，其中
    A环选自苯环或含1个N原子的6元杂芳环；
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    -(L1)o-(L2)p-为-C(O)-N(R4)-、-N(R4)-C(O)-、-S(O)2-N(R4)-、-N(R4)-S(O)2-或-N(R4)-，其中每个R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
    m为1，2或3。
  5. 权利要求1-2中任一项所述的化合物，其中
    A环选自苯环或含1个N原子的6元杂芳环；
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    -(L1)o-(L2)p-为-C(O)-N(R4)-、-N(R4)-C(O)-或-N(R4)-，其中每个R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
    m为1，2或3。
  6. 权利要求1-2中任一项所所述的化合物，其中
    A环选自苯环或含1个N原子的6元杂芳环；
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    -(L1)o-(L2)p-为-C(O)-N(R4)-或-N(R4)-C(O)-，其中每个R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
    m为1，2或3。
  7. 权利要求1-2和4-6中任一项所述的化合物，其中，m为1或2；每个R1独立地选自卤素、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、二氯甲基或三氯甲基；或相邻两个R1基团与连接它们的A环原子一起组成5-7元杂脂环，所述5-7元杂脂环上的亚甲基可任选地进一步形成一个羰基；优选地，m为1或2；每个R1独立地选自氟、三氟甲基；或相邻两个R1基团与连接它们的A环原子一起组成5元含氮的杂脂环，所述5元含氮的杂脂环上的亚甲基可任选地形成一个羰基。
  8. 权利要求3所述的化合物，其中
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6其中一个为羰基氧原子，另一个不存在；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    -(L1)o-(L2)p-为-C(O)-N(R4)-、-N(R4)-C(O)-、-S(O)2-N(R4)-、-N(R4)-S(O)2-或-N(R4)-，其中每个R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
    m为1，2或3。
  9. 权利要求3所述的化合物，其中
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    -(L1)o-(L2)p-为-C(O)-N(R4)-、-N(R4)-C(O)-或-N(R4)-，其中每个R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
    m为1，2或3。
  10. 权利要求3所述的化合物，其中
    每个R1独立地选自卤素、卤代C1-3烷基、羧基、氨基、C1-6烷基、C3-6环烷基或C3-6杂脂环基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元环烷烃环或5-7元杂脂环，所述5-7元环烷烃环或5-7元杂脂环上的亚甲基可任选地进一步形成一个或两个羰基；
    R2选自苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并可任选地被一个或多个R8取代；
    R5和R6分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C2-6烯基、C3-6环烷基或C3-6杂脂环基；或R5和R6与连接它们的碳原子一起组成3-7元环烷烃环或3-7元杂脂环，所述3-7元环烷烃环或3-7元杂脂环可任选地进一步被C1-6烷基、卤素、羟基或氨基取代；
    -(L1)o-(L2)p-为-C(O)-N(R4)-或-N(R4)-C(O)-，其中每个R4选自H或C1-6烷基；
    R7选自C1-6烷基、C3-6环烷基或C3-6杂脂环基，并可任选地被一个或多个R9取代；
    每个R8和每个R9分别独立地选自卤素、羟基、氨基、氰基、卤代C1-3烷基、C1-6烷基或C3-6杂脂环基；以及
    m为1，2或3。
  11. 权利要求3和8-10中任一项所述的化合物，其中，m为1或2；每个R1独立地选自卤素、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、二氯甲基或三氯甲基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5-7元杂脂环，所述5-7元杂脂环上的亚甲基可任选地进一步形成一个羰基；优选地，m为1或2；每个R1独立地选自氟、三氟甲基；或相邻两个R1基团与连接它们的苯环原子或吡啶环原子一起组成5元含氮的杂脂环，所述5元含氮的杂脂环上的亚甲基可任选地形成一个羰基。
  12. 权利要求1-11中任一项所述的化合物，其中，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，并可任选地被一个或多个R8取代；以及每个R8独立地选自卤代C1-3烷基或C1-6烷基；优选地，R2选自苯基、噻吩基、吡唑基、吡啶基，并可任选地被一个或多个R8取代；以及每个R8独立地选自三氟甲基或甲基。
  13. 权利要求1-12中任一项所述的化合物，其中，R5和R6分别独立地选自H、氟、氯、溴、氨基、甲基、乙基、丙基或异丙基，或R5和R6与连接它们的碳原子一起组成环丙烷、环丁烷、环戊烷、环己烷、哌啶、或吡咯烷；优选地，R5和R6分别独立地选自H、氟、氨基、甲基或乙基，或R5和R6与连接它们的碳 原子一起组成环丙烷、环丁烷或哌啶。
  14. 权利要求1-13中任一项所述的化合物，其中，-(L1)o-(L2)p-为-C(O)-NH-或-NH-C(O)-。
  15. 权利要求1-14中任一项所述的化合物，其中，R7选自甲基、乙基、丙基、丁基、戊基、环丙烷基、环丁烷基、环戊烷基、环己烷基或含有一个选自O、N的杂原子的C3-6杂脂环基，并可任选地被一个或多个R9取代；以及每个R9独立地选自卤素、羟基、氰基或C1-6烷基；优选地，R7选自乙基、丙基、丁基、戊基、环丙烷基、环丁烷基、氧杂环丁基或氮杂环丁基，并可任选地被1-3个R9取代；以及每个R9独立地选自氟、羟基、氰基或甲基。
  16. 权利要求1-3中任一项所述的化合物，其选自
    Figure PCTCN2016092375-appb-100004
    Figure PCTCN2016092375-appb-100005
    Figure PCTCN2016092375-appb-100006
    及其药学上可接受的盐或水合物。
  17. 药物组合物，其包含权利要求1-16中任一项所述的化合物及其药学上可接受的盐或水合物和一种或多种药学上可接受的载体或赋形剂。
  18. 治疗由IDH2突变诱发的癌症的方法，所述方法包括给予有需要的个体权利要求1-16中任一项所述的化合物或其药学上可接受的盐或水合物或权利要求17所述的药物组合物。
  19. 权利要求18所述的方法，其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
  20. 权利要求18或19所述的方法，其中所述由IDH2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。
  21. 权利要求1-16中任一项所述的化合物或其药学上可接受的盐或水合物或权利要求17所述的药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
  22. 权利要求21所述的用途，其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
  23. 权利要求21或22所述的用途，其中所述由IDH2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。
  24. 用于治疗由IDH2突变诱发的癌症的权利要求1-16中任一项所述的化合物或其药学上可接受的盐或水合物或权利要求17所述的药物组合物。
  25. 权利要求24所述的化合物或其药学上可接受的盐或水合物或药物组合物，其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变
  26. 权利要求24或25所述的化合物或其药学上可接受的盐或水合物或药物组合物，其中所述由IDH2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。
PCT/CN2016/092375 2015-07-30 2016-07-29 靶向idh2突变的抗肿瘤化合物及其使用方法 WO2017016523A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/748,488 US10155722B2 (en) 2015-07-30 2016-07-29 Antitumor compound targeting IDH2 mutation and method of use thereof
EP16829888.3A EP3330263B1 (en) 2015-07-30 2016-07-29 Phenylurea derivatives as isocitrate dehydrogenase 2 inhibitors for treating cancer
CN201680043894.XA CN107922375B (zh) 2015-07-30 2016-07-29 靶向idh2突变的抗肿瘤化合物及其使用方法
JP2018524524A JP6758374B2 (ja) 2015-07-30 2016-07-29 Ｉｄｈ２突然変異を標的とする抗腫瘍化合物及びその使用方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510461130.X 2015-07-30
CN201510461130 2015-07-30

Publications (1)

Publication Number Publication Date
WO2017016523A1 true WO2017016523A1 (zh) 2017-02-02

Family

ID=57883994

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/092375 WO2017016523A1 (zh) 2015-07-30 2016-07-29 靶向idh2突变的抗肿瘤化合物及其使用方法

Country Status (6)

Country Link
US (1) US10155722B2 (zh)
EP (1) EP3330263B1 (zh)
JP (1) JP6758374B2 (zh)
CN (1) CN107922375B (zh)
TW (1) TW201704203A (zh)
WO (1) WO2017016523A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019008441A1 (en) 2017-07-04 2019-01-10 Intocell, Inc. COMPOUNDS COMPRISING A CLIABABLE BIT AND USES THEREOF
CN113453726A (zh) * 2019-01-03 2021-09-28 尹图赛利有限公司 包含可裂解接头的化合物及其用途
CN111662275B (zh) * 2019-03-08 2023-08-22 中国药科大学 苯磺酰胺类idh突变体抑制剂、其制备方法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014062511A1 (en) * 2012-10-15 2014-04-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2315646C (en) * 1997-12-22 2010-02-09 Bayer Corporation Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
BRPI0512891A (pt) * 2004-07-02 2008-04-15 Icos Corp composto e um sal ou pró-droga ou solvato farmaceuticamente aceitável do mesmo, composição, métodos de inibir a quinase 1 do ponto de verificação em uma célula, de sensibilizar células em um indivìduo que passa por um tratamento quimioterapêutico ou radioterapêutico para uma condição médica e de inibir a proliferação de célula aberrante, uso de um composto, e artigo de fabricação para o uso farmacêutico em humano

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014062511A1 (en) * 2012-10-15 2014-04-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions

Also Published As

Publication number Publication date
JP6758374B2 (ja) 2020-09-23
TW201704203A (zh) 2017-02-01
EP3330263B1 (en) 2020-11-18
EP3330263A4 (en) 2019-01-02
CN107922375B (zh) 2020-05-22
US10155722B2 (en) 2018-12-18
JP2018522068A (ja) 2018-08-09
CN107922375A (zh) 2018-04-17
US20180222853A1 (en) 2018-08-09
EP3330263A1 (en) 2018-06-06

Similar Documents

Publication Publication Date Title
TWI409247B (zh) ４-取代之苯氧基苯基乙酸衍生物
WO2017016513A1 (zh) 1,3,5-三嗪衍生物及其使用方法
JP4944286B1 (ja) シクロプロパン化合物
WO2018006795A1 (zh) 芳香乙炔或芳香乙烯类化合物、其中间体、制备方法、药物组合物及应用
JP3397320B2 (ja) 縮合イミダゾリウム誘導体
US6703379B2 (en) Benzene derivatives and pharmaceutical use thereof
US5952509A (en) Production of benzaldehyde compounds
WO2000075113A1 (fr) Nouveaux derives carboxamide heterocycliques
WO2011145669A1 (ja) アミド誘導体
JP7273723B2 (ja) タウオリゴマーの形成を阻害する新規キナゾリノン及びその使用方法
WO2019196714A1 (zh) 作为dhodh抑制剂的n-取代丙烯酰胺衍生物及其制备和用途
WO2017162157A1 (zh) 内磺酰胺化合物及其使用方法
JPWO2009041559A1 (ja) インダゾールアクリル酸アミド化合物
WO2017016523A1 (zh) 靶向idh2突变的抗肿瘤化合物及其使用方法
US20200255380A1 (en) Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide
TWI817191B (zh) 新穎聯芳基衍生物及其作為針對二醯基甘油醯基轉移酶２之抑制劑之用途
JP6953538B2 (ja) ビアリール化合物、その製造方法及び用途
JP2007015952A (ja) ナフタレン誘導体
WO2005085201A1 (ja) 置換又は無置換アミノ基を導入した４－ピリジルアルキルチオ基を有する新規環式化合物
JP2007500750A (ja) テトラヒドロカルバゾール誘導体およびそれらの薬学的使用
JPWO2002057216A1 (ja) 置換アミノ基を有するテルフェニル化合物
WO2017008681A1 (zh) 酰胺类衍生物、其制备方法及其在医药上的用途
US11739082B2 (en) Thiophene compounds, process for synthesis and use thereof
WO2024183807A1 (zh) 芳基并咪唑类化合物及其医药用途
WO2024140671A1 (zh) 一种稠三环类衍生物、包含其的药物组合物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16829888

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15748488

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2018524524

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016829888

Country of ref document: EP