WO2019154380A1 - 犬尿氨酸通路抑制剂 - Google Patents

犬尿氨酸通路抑制剂 Download PDF

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WO2019154380A1
WO2019154380A1 PCT/CN2019/074642 CN2019074642W WO2019154380A1 WO 2019154380 A1 WO2019154380 A1 WO 2019154380A1 CN 2019074642 W CN2019074642 W CN 2019074642W WO 2019154380 A1 WO2019154380 A1 WO 2019154380A1
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compound
group
mixture
pharmaceutically acceptable
added
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PCT/CN2019/074642
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English (en)
French (fr)
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周明
陆剑宇
胡国平
胡利红
丁照中
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Priority to CN201980012783.6A priority Critical patent/CN111868032B/zh
Publication of WO2019154380A1 publication Critical patent/WO2019154380A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • the present invention relates to a novel compound which is a kynurenine pathway inhibitor, and specifically discloses a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • the invention further relates to the use of a compound of formula (I) and a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.
  • Malignant tumors are one of the major diseases that endanger human life today.
  • humans have developed a variety of treatments and treatments including the most commonly used chemotherapy, surgery, radiotherapy and targeted therapy.
  • These therapies delay the development of tumors to a certain extent and prolong the life of patients.
  • the above treatments still fail to achieve the desired inhibitory effect.
  • the toxic side effects of the above therapies are also key factors limiting their application.
  • immunotherapy has been developed as an emerging therapy for the treatment of malignant tumors, characterized by mobilizing the host's natural defense mechanisms to counter the growth of tumors.
  • the main way is to activate the host's original immune system, enhance the host's collective immune response to tumor cells, and use the immune system's ability to achieve accurate and effective killing of tumors and curb their development.
  • TDO indoleamine-2,3-dioxygenase
  • Trptophan 2,3-dioxygenase tryptophan 2,3-dioxygenase
  • TDO indoleamine-2,3-dioxygenase
  • Tryptophan 2,3-dioxygenase tryptophan 2,3-dioxygenase
  • TDO TDO regulation
  • the above enzyme can rapidly consume tryptophan in the tumor microenvironment, so that T cells infiltrating into the tumor are arrested in the middle of G1 phase due to lack of tryptophan, thereby inhibiting T cell proliferation and blocking T cell signaling, and losing function.
  • an increase in the concentration of kynurenine leads to a microenvironment in which tumors form immunosuppression. Therefore, inhibiting the production of kynurenine in tumors helps to activate the collective immune system and resist tumor growth.
  • the kynurenine pathway inhibitor has a good application prospect in the pharmaceutical industry as a drug, but there is no kynurenine pathway inhibitor listed on the market.
  • the clinical kynurenine pathway inhibitors are only (D)-1-methyltrylinic acid developed by NewLink Genetics, NLG-0919 and Incyte's INCB-24360 and Bristol-Myers Squibb's BMS-985205.
  • existing clinical kynurenine pathway inhibitors have problems such as CYP inhibition (NLG 0919), large dose, short half-life, high number of administrations (INCB-24360), and poor solubility (BMS-986205). Therefore, kynurenine pathway inhibitors without the above disadvantages remain an unmet medical need.
  • NLG-0919, INCB-24360 and BMS-986205 are as follows:
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from the group consisting of phenyl, pyridyl, cyclopentyl 1H-carbazolyl, 2H-carbazolyl, 1H-indenyl and cyclohexyl;
  • Ring B is selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolinyl, 1H-carbazolyl and 2H-carbazolyl;
  • L is selected from the group consisting of a single bond, -O-, -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -;
  • X is selected from CH and N;
  • L' is selected from the group consisting of a single bond and -O-;
  • R 1 is each independently selected from the group consisting of halogen, NH 2 , CN, C 1-3 alkyl, CF 3 , CHF 2 , CH 2 F, C 1-3 heteroalkyl;
  • R 2 is independently selected from the group consisting of halogen, CN, C 1-3 alkyl, CF 3 , CHF 2 , CH 2 F, C 1-3 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic ring Alkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 3-6 membered cycloalkyl-NH-, 3-6 membered heterocycloalkyl-NH-;
  • n and n are independently selected from 0, 1, 2 and 3, respectively;
  • Heter means a hetero atom or a hetero atom group, said C 1-3 heteroalkyl group, 3-6 membered heterocycloalkyl group, 3-6 membered heterocycloalkyl-O- and 3-6 membered heterocycloalkyl group -
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 and 3.
  • R 1 above is independently selected from the group consisting of F, Cl, Br, I, NH 2 , CN, CH 3 , CF 3 , CH 3 CH 2 , CH 3 O, and CH 3 CH 2 O.
  • R 2 are independently selected from the group consisting of F, Cl, Br, I, CN, CH 3 , CF 3 , CHF 2 , CH 2 F, CH 3 CH 2 , CH 3 O-, CH 3 CH 2 O-,
  • R 1 above is independently selected from the group consisting of F, Cl, Br, I, NH 2 , CN, CH 3 , CF 3 , CH 3 CH 2 , CH 3 O, and CH 3 CH 2 O, Other variables are as defined above.
  • R 2 are independently selected from the group consisting of F, Cl, Br, I, CN, CH 3 , CF 3 , CHF 2 , CH 2 F, CH 3 CH 2 , CH 3 O-, CH 3 CH 2 O-, Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • rings A, X, m, n, L, L', R 1 and R 2 are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • L, R 1 and R 2 are as defined above.
  • R 1 above is independently selected from the group consisting of F, Cl, Br, I, NH 2 , CN, CH 3 , CF 3 , CH 3 CH 2 , CH 3 O, and CH 3 CH 2 O, Other variables are as defined by the present invention.
  • R 2 are independently selected from the group consisting of F, Cl, Br, I, CN, CH 3 , CF 3 , CHF 2 , CH 2 F, CH 3 CH 2 , CH 3 O-, CH 3 CH 2 O-, Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • rings A, m, n, X, L, L', R 1 and R 2 are as defined herein.
  • L, R 1 and R 2 are as defined in the present invention.
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for treating cancer.
  • the invention provides a novel structure of kynurenine pathway inhibitor, which has excellent in vitro cell activity; the cyclic structure of the amide ortho position in the structure can enhance the metabolic stability of the series of compounds in vivo.
  • the structure of the invention has a higher AUC than BMS-986205, while having a longer half-life.
  • the compounds of this series have better solubility than BMS-986205, and the oral bioavailability is higher.
  • the tissue distribution in mice is better and the comprehensive pharmacokinetic properties are better.
  • the novel structure provided by the present invention is likely to be a selective IDO inhibitor.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug.
  • Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • “Optional” or “optionally” means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • 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.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent.
  • X when X is vacant in A-X, the structure is actually A.
  • substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a ring and a bridge ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • the "5-7 membered ring” includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term “ring” also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • alkyl is used to mean a straight or branched saturated hydrocarbon group, and in some embodiments, the alkyl group is a C 1-12 alkyl group; in other embodiments The alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group. It may be monosubstituted (such as -CH 2 F) or polysubstituted (such as -CF 3 ), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). .
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl) And t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • alkenyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds, and the carbon-carbon double bond may be located at any position of the group.
  • the alkenyl group is a C 2-8 alkenyl group; in other embodiments, the alkenyl group is a C 2-6 alkenyl group; in other embodiments, the alkenyl group is C 2-4 alkenyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl and the like.
  • alkynyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, and the carbon-carbon triple bond may be located at any position of the group.
  • the alkynyl group is a C 2-8 alkynyl group; in other embodiments, the alkynyl group is a C 2-6 alkynyl group; in other embodiments, the alkynyl group is C 2-4 alkynyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • heteroalkyl by itself or in conjunction with another term, denotes a stable straight or branched alkyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C1-3 heteroalkyl group.
  • a heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkyl) Oxyl) is a conventional expression and refers to those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkenyl by itself or in conjunction with another term, denotes a stable straight or branched alkenyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkenyl group is a C 2-6 heteroalkenyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkenyl group.
  • the hetero atom or heteroatom group may be located at any internal position of the heteroalkenyl group, including the position at which the alkenyl group is attached to the rest of the molecule, but the terms "alkenyloxy”, “alkenylamino” and “alkenylthio” are customary. By expression, it is meant those alkenyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl by itself or in conjunction with another term, denotes a stable straight or branched alkynyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkynyl group is a C 2-6 heteroalkynyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkynyl group.
  • hetero atom or heteroatom group may be located at any internal position of the heteroalkynyl group, including the position at which the alkynyl group is attached to the rest of the molecule, but the terms "alkynyloxy", “alkynylamino” and “alkynylthio” are customary. By expression, it is meant those alkynyl groups attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl groups include, but are not limited to, Up to two heteroatoms can be continuous, for example
  • cycloalkyl includes any stable cyclic alkyl group including monocyclic, bicyclic or tricyclic systems wherein the bicyclic and tricyclic systems include spiro, co and ring.
  • the cycloalkyl group is a C 3-8 cycloalkyl group; in other embodiments, the cycloalkyl group is a C 3-6 cycloalkyl group; in other embodiments, the The cycloalkyl group is a C 5-6 cycloalkyl group. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane and the like.
  • cycloalkenyl includes any stable cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds at any position of the group, including monocyclic, bicyclic or tricyclic The system wherein the bicyclic and tricyclic systems include spiro, parallel and bridged rings, but any ring of this system is non-aromatic.
  • the cycloalkenyl group is a C 3-8 cycloalkenyl group; in other embodiments, the cycloalkenyl group is a C 3-6 cycloalkenyl group; in other embodiments, the The cycloalkenyl group is a C 5-6 cycloalkenyl group.
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • cycloalkynyl includes any stable cyclic alkynyl group containing one or more carbon-carbon triple bonds at any position of the group, including monocyclic, bicyclic or tricyclic systems, wherein Bicyclic and tricyclic systems include spiro, parallel and bridging rings. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring. Further, in the case of the "heterocycloalkyl group", a hetero atom may occupy a position where a heterocycloalkyl group is bonded to the rest of the molecule.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkyl group.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene) -2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and
  • heterocyclenyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkenyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, Rings and bridge rings, but any ring of this system is non-aromatic.
  • a heteroatom can occupy the position of attachment of the heterocyclenyl group to the rest of the molecule.
  • the heterocycloalkenyl is 4 to 6 membered heterocycloalkenyl; in other embodiments, the heterocycloalkenyl is 5 to 6 membered heterocycloalkenyl.
  • heterocycloalkenyl groups include, but are not limited to,
  • heterocycloalkynyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkynyl” group, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring.
  • a hetero atom may occupy a position where a heterocyclic alkynyl group is bonded to the rest of the molecule.
  • the heterocycloalkynyl group is a 4 to 6 membered heterocycloalkynyl group; in other embodiments, the heterocycloalkynyl group is a 5 to 6 membered heterocycloalkynyl group.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term “haloalkyl” is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • the alkoxy group is a C 1-3 alkoxy group.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and S- Pentyloxy.
  • aromatic ring and “aryl” are used interchangeably and the term “aryl ring” or “aryl” means a polyunsaturated carbocyclic ring system which may be monocyclic, bicyclic or poly A ring system in which at least one ring is aromatic, and each ring in the bicyclic and polycyclic ring system is fused together. It may be mono- or poly-substituted, may be monovalent, divalent or multivalent, in some embodiments, the aryl is a C 6-12 aryl; in other embodiments, the aryl It is a C 6-10 aryl group.
  • aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like). Substituents for any of the above aryl ring systems are selected from the group of acceptable substituents described herein.
  • heteroaryl ring and “heteroaryl” are used interchangeably and the term “heteroaryl” means 1, 2, 3 or 4 independently selected from B, N, O and An aryl (or aromatic ring) of a hetero atom of S, which may be a monocyclic, bicyclic or tricyclic ring system in which the nitrogen atom may be substituted or unsubstituted (ie, N or NR, wherein R is H or has been herein Other substituents are defined, and are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • the heteroaryl is a 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a 5-6 membered heteroaryl.
  • the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) , imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.) , triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4- Triazolyl
  • aralkyl is intended to include those groups in which an aryl group is attached to an alkyl group.
  • the aralkyl group is a C6-10 aryl- C1-4 alkyl group.
  • the aralkyl group is a C 6-10 aryl-C 1-2 alkyl group. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like.
  • Aryloxy and "arylthio” mean those groups wherein the carbon atom (e.g., methyl) in the aralkyl group has been replaced by an oxygen or sulfur atom, and in some embodiments, the aryloxy group is C. 6-10 Aryl-OC 1-2 alkyl; in other embodiments, the aryloxy group is C 6-10 aryl-C 1-2 alkyl-O-. In some embodiments, the arylthio group is a C 6-10 aryl-SC 1-2 alkyl group; in other embodiments, the arylthio group is a C 6-10 aryl-C 1-2 alkyl group. -S-. Examples of aryloxy and arylthio groups include, but are not limited to, phenoxymethyl, 3-(1-naphthyloxy)propyl, phenylthiomethyl, and the like.
  • heteroarylkyl is meant to include those heteroaryl groups attached to an alkyl group, in some embodiments, the heteroaryl group is a 5-8 membered heteroaryl -C 1 -4 alkyl; in other embodiments, the heteroarylalkyl group is a 5-6 membered heteroaryl-C 1-2 alkyl group.
  • heteroarylalkyl include, but are not limited to, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl, and the like.
  • Heteroaryloxy and “heteroarylthio” mean those groups in which the carbon atom (eg, methyl) in the heteroaralkyl group has been replaced by an oxygen or sulfur atom, respectively, and in some embodiments, the heteroaryl The oxy group is a 5-8 membered heteroaryl-OC 1-2 alkyl group; in other embodiments, the heteroaryloxy group is a 5-6 membered heteroaryl-C 1-2 alkyl-O- group. In some embodiments, the heteroarylthio group is a 5-8 membered heteroaryl-SC 1-2 alkyl group; in other embodiments, the heteroarylthio group is a 5-6 membered heteroaryl-C 1 -2 alkyl-S-.
  • heteroaryloxy and heteroarylthio groups include, but are not limited to, pyrroleoxymethyl, pyrazolyloxymethyl, 2-pyridyloxymethyl, pyrrolethiomethyl, pyrazolethiomethyl, 2-pyridinethiomethyl Wait.
  • C n-n+m or C n -C n+m includes any one of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range of n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n to n
  • the +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • a 10-membered ring, a 11-membered ring, and a 12-membered ring and includes any one of n to n+m, for example, a 3-12-membered ring including a 3-6-membered ring, a 3-9-membered ring, and a 5-6-membered ring. Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention employs the following abbreviations: DCM stands for dichloromethane; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc and EA stands for ethyl acetate; MeOH stands for methanol; BOC stands for tert-butyl Oxycarbonyl is an amine protecting group; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; Na 2 SO 4 stands for sodium sulfate; TEA stands for triethylamine; Pd(dppf)Cl 2 stands for [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride; NaOH stands for sodium hydroxide; NaHMDS stands for sodium bis(trimethylsilyl)amide; HATU stands for 2-(7-azobenzene) And triazole)-N,N,N,N-tetramethylurea
  • Figure 1 shows the results of drug efficacy in a CT26 mouse collateral xenograft model.
  • Figure 2 is a graph showing changes in body weight in mice in a CT26 mouse collateral xenograft model.
  • Methyl iodide (185.33 g) was added to a solution of the compound 1-a (98.5 g) in acetone (1500 mL) at 0 ° C, and the mixture was reacted at 25 ° C for 1 hour, filtered, and the filter cake was dried to give compound 1-b.
  • the reactant 1-h (784.29 mg, 2.34 mmol) was added to the dioxane (8 mL) and water (2 mL).
  • EtOAc EtOAc: EtOAc (EtOAc) , triethylamine (645.62 mg, 6.38 mmol, 888.07 uL)
  • the reaction solution was heated to 90 ° C under nitrogen for 12 hours, the reaction solution was filtered, and the filtrate was diluted with water and extracted three times with ethyl acetate (50 mL*3)
  • the organic phase was combined and washed three times with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product.
  • the reactant 13-b (750 mg, 2.06 mmol), wet palladium on carbon (70 mg, 10% purity) was sequentially added to ethyl acetate (10 mL), and the mixture was replaced three times with hydrogen. The mixture was heated to 50 ° C under a hydrogen atmosphere under a hydrogen atmosphere, stirred for 2 hours, and the reaction liquid was filtered, and the filtrate was concentrated to give compound 13-c.
  • reaction product 13-d (500 mg, 1.48 mmol) was added sequentially to DMF (10 mL), EtOAc EtOAc (EtOAc, EtOAc, Propylethylamine (574.51 mg, 4.45 mmol, 774.28 uL), the reaction mixture was stirred at room temperature for 12 hr, and the mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated ammonium chloride solution (30 mL*3) After washing three times with saturated brine (30 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product.
  • EtOAc EtOAc EtOAc
  • Propylethylamine 574.51 mg, 4.45 mmol, 774.28 uL
  • Potassium tert-butoxide (74.05 mg) was added to a solution of compound 26-a (50 mg) and 4-chloro-6-fluoroquinoline (39.95 mg) in DMF (5 mL), and reacted at 90 ° C for 12 hours, 30 ml was added Diluted with ethyl acetate, the solution was washed with a saturated sodium chloride solution three times, 30 ml each time, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow gums of compound 26-b (300 mg). reaction.
  • the mixture was quenched by the addition of 0.2 M HCl (10 mL), followed by extraction using MTBE (10 mL*3) and the combined organic phase using 0.2 M HCl (10 mL*3), 0.5% NaOH (10 mL*3) and saturated salt Wash with water (10 mL * 3), dry over Na2SO4, filtered andEtOAc.
  • the aqueous phase obtained was washed with EA (30 mL*2).
  • the organic phase obtained was washed with saturated brine (20mL * 2), dried using Na 2 SO 4, filtered, and concentrated to give the crude product 28-d.
  • the aqueous phase was then washed using EA (15 mL*2).
  • the obtained organic phase was washed with saturated brine (20 mL*2), dried Na 2 SO 4 , filtered and concentrated to afford 28-e.
  • reaction product 1-l 50 mg was added sequentially to DMF (5 mL), mp. 29-a (34.72 mg), HATU (86.84 mg), diisopropylethylamine (59.04 mg).
  • ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed three times with saturated aqueous ammonium chloride solution (30 mL*3), and then washed three times with saturated brine (30 mL*3) and dried over anhydrous sodium sulfate Filtration, concentration of the filtrate gave the crude product, and the crude product was purified using a conventional reversed phase column to afford compound 29.
  • reaction product 1-l 50 mg was added sequentially to DMF (5 mL), mp 30-a (28.80 mg), HATU (86.84 mg), diisopropylethylamine (59.04 mg), at room temperature
  • ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed three times with saturated aqueous ammonium chloride solution (30 mL*3), and then washed three times with saturated brine (30 mL*3) and dried over anhydrous sodium sulfate Filtration, concentration of the filtrate to give a crude product, and the crude product was purified using a conventional reversed phase chromatography column to afford compound 30.
  • the reactant 14-a (23.08 mg) was added to tetrahydrofuran (5 mL), and sodium hexamethyldisilazide (1 M, 264.24 uL) was slowly added dropwise at -78 ° C, and the reaction mixture was stirred at this temperature for half an hour. Then, the reactant 31-a (50 mg) was added, and the reaction mixture was stirred at room temperature for 1 hour, ethyl acetate (30 mL) was added to the reaction system, and then washed three times with saturated ammonium chloride solution (30 mL*3), and then saturated. The aqueous solution was washed three times (30 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product.
  • reaction product 1-l 50 mg was added sequentially to DMF (5 mL), EtOAc (EtOAc: EtOAc (EtOAc) After stirring for 12 hours, ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed three times with saturated aqueous ammonium chloride solution (30 mL*3), and then washed three times with saturated brine (30 mL*3) and dried over anhydrous sodium sulfate Filtration, concentration of the filtrate to give a crude product, and the crude product was purified using a conventional reversed phase column to afford compound 32.
  • the compound was dissolved in 3 mM with dimethyl sulfoxide, and 15 ⁇ l of the compound was added to a 96-well plate.
  • the compound (10 ⁇ l + 20 ⁇ l) was serially diluted in 3 fold.
  • the cell culture plate was taken out and the medium was discarded, 100 ⁇ l of the compound was transferred to the cell culture plate, and the cell culture plate was transferred to an incubator for further 48 hours.
  • the cell culture plate was taken out, and 50 ⁇ l of the supernatant was transferred to a new 96-well plate, 200 ⁇ l of acetonitrile was added to the above plate and thoroughly mixed, and 40 ⁇ l of the supernatant was transferred by centrifugation to another 96-well plate. Add 360 ⁇ l of deionized water containing 2 ⁇ g/ml of internal reference and mix thoroughly to test the sample.
  • the compounds of the present invention have a significant inhibitory effect on the production of kynurenine in Hela cells.
  • the healthy adult female Balb/c mice used in this study were purchased from Shanghai Lingchang Biotechnology Co., Ltd.
  • mice Twenty-four female Balb/c mice were divided into 4 groups according to 6 rats in each group. The first group was given 2 mg/kg BMS-986205 intravenously; the second group was given 50 mg/kg BMS-986205 by intragastric administration; the third group was given 2 mg/kg of compound 1 by intravenous injection; the fourth group was given 50 mg by intragastric administration. /kg Compound 1.
  • the blood of three animals was collected at each time point by means of cross-harvesting. 40 uL of whole blood was collected before administration and 0.0833 (intravenous group only), 0.25, 0.5, 1, 2, 4, 8, 24 hours before administration. Whole blood was placed in an anticoagulant tube, and centrifuged at 3000 g for 15 minutes at 4 ° C to prepare plasma and stored at -80 °C. The concentration of the drug in the plasma was determined by LC/MS-MS.
  • Example 1 of the present invention has a better tissue distribution than the clinical molecule BMS-986205, has a higher AUC at the same dose, has a longer half-life, higher oral bioavailability, and more comprehensive pharmacokinetic properties. excellent.
  • mice Female, 18-22 g, Shanghai Slack.
  • CT26 cells mouse colon cancer cells
  • Relative tumor proliferation rate T/C (%) TRTV / CRTV ⁇ 100% (TRTV: treatment group mean RTV; CRTV: negative control group mean RTV).
  • TGI (%) 1 - (average tumor volume measured in the treatment group - average tumor volume on the day of the treatment group) / (average tumor volume on the day of the vehicle group measurement - average tumor volume on the day of the vehicle component group) ⁇ 100 %
  • the compounds of the present invention exhibit excellent antitumor activity in vivo and can synergize against PD-1 monoclonal antibody. Compared with the clinical molecule BMS-986205, it has better single drug and combined efficacy at the same dose.

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Abstract

本发明公开了新的作为犬尿氨酸通路抑制剂的化合物，具体公开了式(I)所示化合物及其药学上可接受的盐。

Description

犬尿氨酸通路抑制剂
本申请主张如下优先权：
CN201810143151.0，申请日2018年2月11日。
技术领域
本发明涉及新的作为犬尿氨酸通路抑制剂的化合物，具体公开了式(I)所示化合物及其药学上可接受的盐。本发明还涉及式(I)所示化合物及其药学上可接受的盐在制备治疗肿瘤药物中的应用。
背景技术
恶性肿瘤是现如今危害人类生命安全的主要疾病之一。近百年来，人类为了对抗恶性肿瘤，发展出了多种包括最常用的化疗，手术，放疗以及靶向疗法在内的诊疗手段与治疗方法。这些疗法在一定程度上延缓的肿瘤的发展，延长了患者生命。但是由于恶性肿瘤的无限制生长，浸润与转移的特性，以上疗法依旧无法达到理想的抑制效果。同时，以上的疗法的毒副作用也是限制其应用的关键因素。
近年来，免疫疗法作为恶性肿瘤治疗的新兴疗法被发展起来，其特点是通过调动宿主的天然防御机制来抵抗肿瘤的生长。其主要途径主要通过激活宿主原有的免疫系统，增强宿主集体对肿瘤细胞的免疫反应，利用免疫系统能力达到精准有效的杀伤肿瘤，遏制其发展。
肿瘤内部的犬尿酸的产生主要受吲哚胺2,3-双加氧酶(Indoleamine-2,3-dioxygenase，IDO)及色氨酸-2,3双加氧酶(Tryptophan 2,3-dioxygenase,TDO)的调控，其功能在于催化了色氨酸向犬尿胺酸代谢的决速步骤。以上酶可以迅速消耗肿瘤微环境内色氨酸，使得浸润至肿瘤内部的T细胞由于缺乏色氨酸而停滞于G1期中期，从而抑制了T细胞增殖并使T细胞信号传导受阻，功能丧失。同时犬尿氨酸的浓度上升会导致肿瘤形成免疫抑制的微环境。因此，抑制肿瘤内犬尿氨酸的生成有助于激活集体免疫系统，抵制肿瘤生长。
犬尿氨酸通路抑制剂作为药物在医药行业具有良好的应用前景，但是目前尚无犬尿氨酸通路抑制剂上市。处于临床的犬尿氨酸通路抑制剂只有NewLink Genetics公司开发的(D)-1-甲基色胺酸，NLG-0919与Incyte公司的INCB-24360及百时美施贵宝的BMS-985205。但是，现有临床犬尿氨酸通路抑制剂存在诸如CYP抑制(NLG 0919)、给药剂量大、半衰期短、给药次数多(INCB-24360)，溶解性差(BMS-986205)等问题。因此，无上述缺点的犬尿氨酸通路抑制剂依旧是未被满足的医疗需求。
NLG-0919，INCB-24360及BMS-986205的具体结构如下：
Figure PCTCN2019074642-appb-000001
发明内容
本发明提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2019074642-appb-000002
其中，
环A选自苯基、吡啶基、环戊基1H-吲唑基、2H-吲唑基、1H-吲哚基和环己基；
环B选自苯基、吡啶基、喹啉基、异喹啉基、1H-吲唑基和2H-吲唑基；
L选自单键、-O-、-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
X选自CH和N；
L’选自单键和-O-；
R 1分别独立地选自卤素、NH 2、CN、C 1-3烷基、CF 3、CHF 2、CH 2F、C 1-3杂烷基；
R 2分别独立地选自卤素、CN、C 1-3烷基、CF 3、CHF 2、CH 2F、C 1-3杂烷基、3-6元环烷基、3-6元杂环烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、3-6元环烷基-NH-、3-6元杂环烷基-NH-；
m和n分别独立地选自0、1、2和3；
“杂”表示杂原子或杂原子团，所述C 1-3杂烷基、3-6元杂环烷基、3-6元杂环烷基-O-和3-6元杂环烷基-NH-之“杂”选自N、-NH-、-O-、-S-、-C(＝O)-、-C(＝S)-、-C(＝O)O-、-S(＝O)-和-S(＝O) 2-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2和3。
在本发明的一些方案中，上述R 1分别独立地选自F、Cl、Br、I、NH 2、CN、CH 3、CF 3、CH 3CH 2、CH 3O和CH 3CH 2O。
在本发明的一些方案中，上述R 2分别独立地选自F、Cl、Br、I、CN、CH 3、CF 3、CHF 2、CH 2F、CH 3CH 2、CH 3O-、CH 3CH 2O-、
Figure PCTCN2019074642-appb-000003
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000004
选自
Figure PCTCN2019074642-appb-000005
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000006
选自
Figure PCTCN2019074642-appb-000007
Figure PCTCN2019074642-appb-000008
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000009
选自
Figure PCTCN2019074642-appb-000010
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000011
选自
Figure PCTCN2019074642-appb-000012
Figure PCTCN2019074642-appb-000013
Figure PCTCN2019074642-appb-000014
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000015
选自
Figure PCTCN2019074642-appb-000016
Figure PCTCN2019074642-appb-000017
在本发明的一些方案中，上述R 1分别独立地选自F、Cl、Br、I、NH 2、CN、CH 3、CF 3、CH 3CH 2、CH 3O和CH 3CH 2O，其他变量如上述所定义。
在本发明的一些方案中，上述R 2分别独立地选自F、Cl、Br、I、CN、CH 3、CF 3、CHF 2、CH 2F、CH 3CH 2、CH 3O-、CH 3CH 2O-、
Figure PCTCN2019074642-appb-000018
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000019
选自
Figure PCTCN2019074642-appb-000020
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000021
选自
Figure PCTCN2019074642-appb-000022
Figure PCTCN2019074642-appb-000023
Figure PCTCN2019074642-appb-000024
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000025
选自
Figure PCTCN2019074642-appb-000026
Figure PCTCN2019074642-appb-000027
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000028
选自
Figure PCTCN2019074642-appb-000029
Figure PCTCN2019074642-appb-000030
Figure PCTCN2019074642-appb-000031
Figure PCTCN2019074642-appb-000032
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000033
选自
Figure PCTCN2019074642-appb-000034
Figure PCTCN2019074642-appb-000035
Figure PCTCN2019074642-appb-000036
其他变量如上述所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，选自
Figure PCTCN2019074642-appb-000037
其中，环A、X、m、n、L、L’、R 1和R 2如上述所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，选自
Figure PCTCN2019074642-appb-000038
其中，L、R 1和R 2如上述所定义。
在本发明的一些方案中，上述R 1分别独立地选自F、Cl、Br、I、NH 2、CN、CH 3、CF 3、CH 3CH 2、CH 3O和CH 3CH 2O，其他变量如本发明所定义。
在本发明的一些方案中，上述R 2分别独立地选自F、Cl、Br、I、CN、CH 3、CF 3、CHF 2、CH 2F、CH 3CH 2、CH 3O-、CH 3CH 2O-、
Figure PCTCN2019074642-appb-000039
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000040
选自
Figure PCTCN2019074642-appb-000041
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000042
选自
Figure PCTCN2019074642-appb-000043
Figure PCTCN2019074642-appb-000044
Figure PCTCN2019074642-appb-000045
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000046
选自
Figure PCTCN2019074642-appb-000047
Figure PCTCN2019074642-appb-000048
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000049
选自
Figure PCTCN2019074642-appb-000050
Figure PCTCN2019074642-appb-000051
Figure PCTCN2019074642-appb-000052
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019074642-appb-000053
选自
Figure PCTCN2019074642-appb-000054
Figure PCTCN2019074642-appb-000055
Figure PCTCN2019074642-appb-000056
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，选自
Figure PCTCN2019074642-appb-000057
其中，环A、m、n、X、L、L’、R 1和R 2如本发明所定义。
10.根据权利要求9所述的化合物或其药学上可接受的盐，选自
Figure PCTCN2019074642-appb-000058
其中，L、R 1和R 2如本发明所定义。
本发明还提供化合物或其药学上可接受的盐，选自
Figure PCTCN2019074642-appb-000059
Figure PCTCN2019074642-appb-000060
Figure PCTCN2019074642-appb-000061
本发明提供一种药物组合物，其含有治疗有效量的上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供上述的化合物或其药学上可接受的盐或上述的药物组合物在制备治疗癌症药物中的应用。
本发明还有一些方案是由上述各变量任意组合而来。
技术效果
本发明提供一种新型结构的犬尿氨酸通路抑制剂，具有优异的体外细胞活性；结构中酰胺邻位的环状结构可以增强该系列化合物的体内代谢稳定性。相同剂量下，该发明中的结构相比BMS-986205具有更高的AUC,同时半衰期更长。同时该系列的化合物相比BMS-986205溶解度更好，口服生物利用度更高，小鼠体内组织分布更优，综合药代动力学性质更优。本发明提供的新型结构很可能是一个选择性的IDO抑制剂。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“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“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包 括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019074642-appb-000062
和楔形虚线键
Figure PCTCN2019074642-appb-000063
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019074642-appb-000064
和直形虚线键
Figure PCTCN2019074642-appb-000065
表示立体中心的相对构型，用波浪线
Figure PCTCN2019074642-appb-000066
表示楔形实线键
Figure PCTCN2019074642-appb-000067
或楔形虚线键
Figure PCTCN2019074642-appb-000068
或用波浪线
Figure PCTCN2019074642-appb-000069
表示直形实线键
Figure PCTCN2019074642-appb-000070
和直形虚线键
Figure PCTCN2019074642-appb-000071
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之 内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，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。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
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。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2019074642-appb-000072
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2019074642-appb-000073
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2019074642-appb-000074
所述连接基团、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)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶基和哌啶基；另一方面，术语“5～7元杂环烷基”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“烷基”用于表示直链或支链的饱和的碳氢基团，在一些实施方案中，所述烷基为C 1-12烷基；在另一些实施方案中，所述烷基为C 1-6烷基；在另一些实施方案中，所述烷基为C 1-3烷基。其可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的实例包括但不限于甲基(Me)，乙基(Et)，丙基(包括n-丙基和异丙基)，丁基(包括n-丁基，异丁基，s-丁基和t-丁基)，戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，“烯基”用于表示直链或支链的包含一个或多个碳-碳双键的碳氢基团，碳-碳双键可以位于该基团的任何位置上。在一些实施方案中，所述烯基为C 2-8烯基；在另一些实施方案中，所述烯基为C 2-6烯基；在另一些实施方案中，所述烯基为C 2-4烯基。其可以是单取代或多取代的，可以是一价、二价或者多价。烯基的实例包括但不限于乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”用于表示直链或支链的包含一个或多个碳-碳三键的碳氢基团，碳-碳三键可以位于该基团的任何位置上。在一些实施方案中，所述炔基为C 2-8炔基；在另一些实施方案中，所述炔基为C 2-6炔基；在另一些实施方案中，所述炔基为C 2-4炔基。其可以是单取代或多取代的，可以是一价、二价或者多价。炔基的实例包括但不限于乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C 1-6杂烷基；在另一些实施方案中，所述杂烷基为C 1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“杂烯基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烯基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烯基为C 2-6杂烯基；在另一些实施方案中，所述杂烷基为C 2-4杂烯基。杂原子或杂原子团可以位于杂烯基的任何内部位置，包括该烯基与分子其余部分的连接位置，但术语“烯基氧基”、“烯基氨基”和“烯基硫基”属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烯基基团。杂烯基的实例包括但不限于-O-CH＝CH 2、-O-CH＝CHCH 3、-O-CH＝C(CH 3) 2、-CH＝CH-O-CH 3、-O-CH＝CHCH 2CH 3、-CH 2-CH＝CH-OCH 3、-NH-CH＝CH 2、-N(CH＝CH 2)- CH 3、-CH＝CH-NH-CH 3、-CH＝CH-N(CH 3) 2、-S-CH＝CH 2、-S-CH＝CHCH 3、-S-CH＝C(CH 3) 2、-CH 2-S-CH＝CH 2、-S(＝O)-CH＝CH 2和-CH＝CH-S(＝O) 2-CH 3。至多两个杂原子可以是连续的，例如-CH＝CH-NH-OCH 3。
除非另有规定，术语“杂炔基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的炔基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂炔基为C 2-6杂炔基；在另一些实施方案中，所述杂烷基为C 2-4杂炔基。杂原子或杂原子团可以位于杂炔基的任何内部位置，包括该炔基与分子其余部分的连接位置，但术语“炔基氧基”、“炔基氨基”和“炔基硫基”属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些炔基基团。杂炔基的实例包括但不限于
Figure PCTCN2019074642-appb-000075
Figure PCTCN2019074642-appb-000076
Figure PCTCN2019074642-appb-000077
至多两个杂原子可以是连续的，例如
Figure PCTCN2019074642-appb-000078
除非另有规定，“环烷基”包括任何稳定的环状烷基，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。在一些实施方案中，所述环烷基为C 3-8环烷基；在另一些实施方案中，所述环烷基为C 3-6环烷基；在另一些实施方案中，所述环烷基为C 5-6环烷基。其可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，“环烯基”包括任何稳定的环状烯基，在该基团的任何位点含有一个或多个不饱和的碳-碳双键，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。在一些实施方案中，所述环烯基为C 3-8环烯基；在另一些实施方案中，所述环烯基为C 3-6环烯基；在另一些实施方案中，所述环烯基为C 5-6环烯基。其可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，“环炔基”包括任何稳定的环状炔基，在该基团的任何位点含有一个或多个碳-碳三键，其包含单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。其可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷基。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶 基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
除非另有规定，术语“杂环烯基”本身或者与其他术语联合分别表示环化的“杂烯基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。此外，就该“杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。在一些实施方案中，所述杂环烯基为4～6元杂环烯基；在另一些实施方案中，所述杂环烯基为5～6元杂环烯基。杂环烯基的实例包括但不限于
Figure PCTCN2019074642-appb-000079
Figure PCTCN2019074642-appb-000080
除非另有规定，术语“杂环炔基”本身或者与其他术语联合分别表示环化的“杂炔基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环炔基”而言，杂原子可以占据杂环炔基与分子其余部分的连接位置。在一些实施方案中，所述杂环炔基为4～6元杂环炔基；在另一些实施方案中，所述杂环炔基为5～6元杂环炔基。除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。在一些实施方案中，所述烷氧基为C 1-3烷氧基。烷氧基的实例包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，本发明术语“芳环”和“芳基”可以互换使用，术语“芳环”或“芳基”表示多不饱和的碳环体系，它可以是单环、双环或多环体系，其中至少一个环是芳香性的，所述双环和多环体系中的各个环稠合在一起。其可以是单取代或多取代的，可以是一价、二价或者多价，在一些实施方案中，所述芳基为C 6-12芳基；在另一些实施方案中，所述芳基为C 6-10芳基。芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。上述任意一个芳基环系的取代基选自本发明所述的可接受的取代基。
除非另有规定，本发明术语“杂芳环”和“杂芳基”可以互换使用，术语“杂芳基”是指含有1、2、3或4个独立选自B、N、O和S的杂原子的芳基(或芳环)，其可以是单环、双环或三环体系，其中氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)，且任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。杂芳基可通过杂原子连接到分子的其余部分。在一些实施方案中，所述杂芳基为5-10元杂芳基；在另一些实施方案中，所述杂芳基为 5-6元杂芳基。所述杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)、喹啉基(包括3-喹啉基和6-喹啉基等)、吡嗪基、嘌呤基、苯基并噁唑基、吲唑基(包括1H-吲唑基和2H-吲唑基)。上述任意一个杂芳基环系的取代基选自本发明所述的可接受的取代基。
除非另有规定，术语“芳烷基”意在包括芳基附着于烷基的那些基团，在一些实施方案中，所述芳烷基为C 6-10芳基-C 1-4烷基；在另一些实施方案中，所述芳烷基为C 6-10芳基-C 1-2烷基。芳烷基的实例包括但不限于苄基、苯乙基、萘甲基等。“芳氧基”和“芳硫基”分别表示芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述芳氧基为C 6-10芳基-O-C 1-2烷基；在另一些实施方案中，芳氧基为C 6-10芳基-C 1-2烷基-O-。在一些实施方案中，所述芳硫基为C 6-10芳基-S-C 1-2烷基；在另一些实施方案中，芳硫基为C 6-10芳基-C 1-2烷基-S-。芳氧基和芳硫基的实例包括但不限于苯氧基甲基、3-(1-萘氧基)丙基，苯硫基甲基等。
除非另有规定，术语“杂芳烷基”意在包括杂芳基附着于烷基的那些基团，在一些实施方案中，所述杂芳烷基为5-8元杂芳基-C 1-4烷基；在另一些实施方案中，所述杂芳烷基为5-6元杂芳基-C 1-2烷基。杂芳烷基的实例包括但不限于吡咯基甲基、吡唑基甲基、吡啶基甲基、嘧啶基甲基等。“杂芳氧基”和“杂芳硫基”分别表示杂芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述杂芳氧基为5-8元杂芳基-O-C 1-2烷基；在另一些实施方案中，杂芳氧基为5-6元杂芳基-C 1-2烷基-O-。在一些实施方案中，所述杂芳硫基为5-8元杂芳基-S-C 1-2烷基；在另一些实施方案中，杂芳硫基为5-6元杂芳基-C 1-2烷基-S-。杂芳氧基和杂芳硫基的实例包括但不限于吡咯氧甲基、吡唑氧甲基、2-吡啶氧甲基、吡咯硫甲基、吡唑硫甲基、2-吡啶硫甲基等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指 适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明采用下述缩略词：DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc和EA代表乙酸乙酯；MeOH代表甲醇；BOC代表叔丁氧羰基是一种胺保护基团；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；Na 2SO 4代表硫酸钠；TEA代表三乙胺；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；NaOH代表氢氧化钠；NaHMDS代表双(三甲基硅基)氨基钠；HATU代表2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯；DIEA代表二异丙基乙基胺；HCl代表氯化氢；CDI代表N,N'-羰基二咪唑；MTBE代表甲基叔丁基醚；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Xanphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；PGE代表聚乙二醇。
化合物经手工或者
Figure PCTCN2019074642-appb-000081
软件命名，市售化合物采用供应商目录名称。
附图说明
图1为CT26小鼠同系移植瘤模型中的药效结果。
图2为CT26小鼠同系移植瘤模型中小鼠体重变化。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2019074642-appb-000082
Figure PCTCN2019074642-appb-000083
化合物1-b的合成：
0℃下，向化合物1-a(98.5g)的丙酮溶液(1500mL)中加入碘甲烷(185.33g)，在25℃反应1小时后，过滤，滤饼旋干得到化合物1-b。
化合物1-d的合成：
0℃下，向将二氯亚砜(96.92g,814.69mmol)慢慢滴加到无水乙醇溶液(1000mL)中，然后加入化合物1-c(95g,盐酸盐)，在80度下反应12小时后，减压浓缩得到化合物1-d。
化合物1-e的合成:
90℃下，向化合物1-d(98g,盐酸盐)和N,N-二异丙基乙胺(141.01g,1.09mol)的二氧六环(1400mL)和水(350mL)的溶液中分批加入化合物1-b(208.74g,818.28mmol)，在9008下反应12小时后，减压浓缩移除溶剂二氧六环，加入1000毫升乙酸乙酯，溶液用饱和氯化钠溶液洗涤3次，每次1000毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到化合物1-e。
化合物1-f的合成:
-70℃下，向化合物1-e(76g)和N,N-二(三氟甲烷磺酰基)苯胺(126.55g)的四氢呋喃(1500mL)溶液中滴加入NaHMDS(1M,371.09mL)，保持温度不高于-60℃，滴加完后在25℃反应12小时，加入1500mL盐酸(0.2M)溶液淬灭反应，减压浓缩移除溶剂四氢呋喃，加入1500毫升甲基叔丁基醚，溶液依次用盐酸(0.2M)溶液洗涤2次，每次1500毫升，用5％NaOH溶液洗涤3次，每次1500毫升，用饱和氯化钠溶液洗涤1次，每次1500毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到棕色胶状化合物1-f。
化合物1-h的合成:
向化合物1-f(93.5g,261.65mmol)和双频哪醇硼酯(73.09g,287.82mmol)的二氧六环(1000mL)溶液中加入溴化钠(10.77g,104.66mmol,3.37mL)、醋酸钾(77.04g)和Pd(dppf)Cl 2(9.57g)，在氮气保护和80℃反应12小时后，，加入2000毫升乙酸乙酯，过滤，滤液用饱和氯化钠溶液洗涤2次，每次1500毫升，然后加入1000毫升盐酸溶液(0.2M)，分离得水相，有机相用盐酸溶液(0.2M)萃取两次，每次1000毫升，联合的水相用乙酸乙酯洗涤2次，每次2000毫升，然后用饱和碳酸钠溶液调节pH到9，用乙酸乙酯萃取两次，每次1500毫升，两次萃取联合的有机相用饱和氯化钠溶液洗涤2次，每次2000毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到化合物1-h。
化合物1-j的合成:
向化合物1-h(29.85g)和4-氯-6-氟喹啉(14.7g)的二氧六环(240mL)和水(60mL)溶液中加入三乙胺(24.57g)和Pd(dppf)Cl2(2.96g)，在氮气保护和100℃反应12小时后，加入1000毫升乙酸乙酯，过滤，滤液用饱和氯化钠溶液洗涤2次，每次500毫升，然后用盐酸溶液(1M)调节pH到1，分离得水相，有机相用盐酸溶液(0.2M)萃取两次，每次500毫升，联合的水相用乙酸乙酯洗涤2次，每次1000毫升，然后用饱和碳酸钠溶液调节pH到9，用乙酸乙酯萃取两次，每次750毫升，两次萃取联合的有机相用饱和氯化钠溶液洗涤2次，每次1000毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到30g粗产品，粗产品加入到150毫升乙腈中，在25℃下拌1小时，过滤，滤饼旋干得到化合物1-j。
化合物1-k的合成：
向化合物1-j(21g)和吡啶(7.03g)的异丙醇溶液(400mL)中加入钯碳(4g,10％纯度)，在50℃和氢气氛围(15psi)下反应1小时后，用硅藻土过滤，浓缩得到化合物1-k。
化合物1-l的合成：
向化合物1-k(20g)的甲醇(100mL)，四氢呋喃(100mL)和水(5 0mL)溶液中加入氢氧化钠(6.73g)，在70℃下反应12小时后，减压浓缩移除溶剂甲醇和四氢呋喃，然后用盐酸(1M)将pH调到6-7，大量固体析出，过滤，滤饼减压旋干得到化合物1-l。
化合物1的合成：
向化合物1-l(5g)和对氯苯氨(2.33g)的DMF溶液(100mL)中加入N,N-二异丙基乙胺(5.90g)和HATU(8.11g)，在氮气保护和25℃下反应12小时后，加入400毫升乙酸乙酯稀释，溶液用饱和氯化钠溶液洗涤3次，每次500毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到9g粗品，粗产品加入到45毫升乙腈中，在25乙腈搅拌12小时，过滤，滤饼旋干得到纯化后的粗品，粗品通过制备级高效液相色谱(甲酸体系)制备纯化得到化合物1。
1H NMR(400MHz,DMSO-d 6)δ＝9.58(s,1H),8.82(d,J＝4.5Hz,1H),8.08(dd,J＝6.0,9.2Hz,1H),8.02(dd,J＝2.8,11.2Hz,1H),,7.82-7.75(m,2H),7.65(dt,J＝2.8,8.7Hz,1H),7.48(d,J＝4.6Hz,1H),7.41-7.34(m,2H),3.39-3.34(m,1H),2.99(d,J＝11.2Hz,2H),2.45-2.23(m,6H),1.91-1.68(m,6H).
实施例2
Figure PCTCN2019074642-appb-000084
化合物2的合成
将化合物1-l(50mg)溶于DMF(5mL)中，并在25℃下，往溶液中加入DIEA(98.39mg)和HATU(86.84mg).所得混合物在25℃下搅拌30分钟.然后向反应液中加2-a(23.59mg),所得混合物在25℃下搅拌12小时.向反应液中加入水(10mL)淬灭反应并用乙酸乙酯(30mL*3)萃取.合并有机相用Na 2SO 4干燥,过滤后减压浓缩得到粗品.粗品通过制备色谱纯化得到化合物2.
1H NMR(400MHz,CCl 3D)δppm 1.69-1.91(m,3H)2.00-2.10(m,3H)2.33-2.56(m,6H)3.00(br d,J＝11.74Hz,2H)3.18(br t,J＝11.80Hz,1H)6.77-6.88(m,2H)7.31(d,J＝4.65Hz,1H)7.39-7.48(m,1H)7.61(dd,J＝10.33,2.63Hz,1H)8.03-8.15(m,1H)8.28(td,J＝9.23,5.99Hz,1H)8.80(d,J＝4.65Hz,1H)9.42(br s,1H).
实施例3
Figure PCTCN2019074642-appb-000085
化合物3的合成
将化合物1-l(50mg)溶于DMF(3mL)中，并在25℃下，往溶液中加入DIEA(98.39mg)和HATU(86.84mg).所得混合物在25℃下搅拌30分钟.然后向反应液中加3-a(23.31mg),所得混合物在25℃下搅拌12小时.向反应液中加入水(10mL)淬灭反应并用乙酸乙酯(20mL*3)萃取.合并有机相用Na 2SO 4干燥,过滤后减压浓缩得到粗品.粗品通过制备色谱纯化得到化合物3.
1H NMR(400MHz,CCl 3D)δppm 1.68-1.92(m,3H)1.96-2.10(m,3H)2.25-2.58(m,6H)3.02(br d,J＝11.25Hz,2H)3.18(br t,J＝12.10Hz,1H)7.01(dd,J＝8.01,1.04Hz,1H)7.17(s,1H)7.21(s,1H)7.37-7.48(m,2H)7.60(dd,J＝10.33,2.63Hz,1H)7.66(s,1H)8.07-8.14(m,1H)8.80(d,J＝4.65Hz,1H)9.11(br s,1H).
实施例4
Figure PCTCN2019074642-appb-000086
化合物4的合成
将化合物1-l(100mg)溶解在DMF(3mL)中，然后再加入DIEA(118.07mg)和HATU(231.58mg,)，再将4-a(58.26mg)加入到混合物中，该反应在25℃N 2保护下反应12小时，反应液为棕色溶液。将反应液倾倒入水50mL,随后用EA 120mL(40mL*3)萃取，合并有机相用饱和食盐水洗60mL(30mL*2),Na 2SO 4干燥,过滤浓缩后得到粗品.将粗品通过制备色谱纯化后得到4。
1H NMR(400MHz,DMSO-d 6)δppm 1.73-1.94(m,6H)2.24-2.45(m,7H)3.02(br d,J＝11.2Hz,2H)4.14(s,3H)7.42(dd,J＝9.2,1.6Hz,1H)7.49-7.57(m,2H)7.66(td,J＝8.8,2.6Hz,1H)7.99-8.12(m,2H)8.26(s,1H)8.83(d,J＝4.4Hz,1H)9.40(s,1H)
实施例5
Figure PCTCN2019074642-appb-000087
化合物5的合成
将化合物1-l(100mg)溶解于DMF(5mL)中，然后加入DIEA(196.79mg),HATU(173.68mg),5-a(43.25mg).氮气置换三次，所得混合物在25℃下搅拌12小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物5。
1H NMR(400MHz,DMSO-d 6)δ＝9.67(s,1H),8.83(d,J＝4.4Hz,1H),8.20(s,1H),8.11-8.01(m,2H),7.96(br dd,J＝2.4,7.6Hz,1H),7.92(br dd,J＝2.4,7.5Hz,1H),7.66(dt,J＝2.8,8.7Hz,1H),7.58-7.48(m,1H),7.44-7.36(m,1H),3.56-3.28(m,1H),3.17(br s,2H),3.00(s,2H),2.97(br s,4H),2.54-2.53(m,4H),2.47-2.22(m,2H).
实施例6
Figure PCTCN2019074642-appb-000088
化合物6的合成
将化合物1-l(100mg)溶解于DMF(5mL)中，然后加入DIEA(196.79mg),HATU(173.68mg),6-a(33.22mg)。氮气置换三次，所得混合物在25℃下搅拌12小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物6。
1H NMR(400MHz,DMSO-d 6)δ＝8.82(br d,J＝3.8Hz,1H),8.19(s,1H),8.14-8.04(m,1H),8.01(s,1H),7.99(br s,1H),7.66(br t,J＝7.6Hz,1H),7.47(br d,J＝3.8Hz,1H),3.64(br s,1H),3.35-3.25(m,1H),2.90(br d,J＝10.4Hz,2H),2.43-2.27(m,2H),2.16(br dd,J＝8.8,19.4Hz,4H),1.92-1.80(m,2H),1.79-1.63(m,8H),1.58(br d,J＝12.6Hz,1H),1.36-1.18(m,4H),1.14(br s,1H).
实施例7
Figure PCTCN2019074642-appb-000089
化合物7的合成
将化合物1-l(50mg)溶解于DMF(5mL)中，然后加入DIEA(98.39mg)，HATU(86.84mg)，7-a(28.81mg).氮气置换三次，所得混合物在25℃下搅拌12小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物7. 1H NMR(400MHz,DMSO-d 6)δ＝9.59(s,1H),8.83(d,J＝4.4Hz,1H),8.31(br s,1H),8.12-8.07(m,2H),8.04(d,J＝10.4Hz,2H),7.76-7.64(m,1H),7.54-7.47(m,3H),3.63(br s,1H),3.35(br t,J＝11.2Hz,2H),2.99(br d,J＝11.0Hz,2H),2.47-2.24(m,4H),1.92-1.68(m,6H).
实施例8
Figure PCTCN2019074642-appb-000090
化合物8的合成
将化合物1-l(50mg)溶解于DMF(5mL)中，然后加入DIEA(98.39mg),HATU(86.84mg),8-a(18.61mg).氮气置换三次，所得混合物在25℃下搅拌12小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物8。
1H NMR(400MHz,DMSO-d 6)δ＝9.52(s,1H),8.83(d,J＝4.6Hz,1H),8.25(s,1H),8.12-8.01(m,2H),7.79-7.73(m,2H),7.67(dt,J＝2.8,8.7Hz,1H),7.50(d,J＝4.4Hz,1H),7.17(t,J＝8.2Hz,2H),3.36(br t,J＝12Hz,1H),3.26(br s,2H),3.00(br d,J＝10Hz,2H),2.46-2.22(m,4H),1.93-1.68(m,6H).
实施例9
Figure PCTCN2019074642-appb-000091
化合物9的合成
将化合物1-l(50mg)溶解于DMF(5mL)中，然后加入DIEA(98.39mg),HATU(86.84mg),9-a(18.11mg)。氮气置换三次，所得混合物在25℃下搅拌12小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物9。
1H NMR(400MHz,DMSO-d 6)δ＝9.56(s,1H),8.83(d,J＝4.4Hz,1H),8.76(d,J＝2.2Hz,1H),8.22(s,1H),8.13-7.97(m,3H),7.66(dt,J＝2.8,8.7Hz,1H),7.50(d,J＝4.4Hz,1H),7.22(d,J＝8.4Hz,1H),3.63(br s,1H),3.35(br t,J＝11.2Hz,2H),3.10(br d,J＝11.2Hz,4H),3.00(br d,J＝11.2Hz,4H),2.46-2.24(m,2H),1.93-1.68(m,4H)，1.65-1.42(m,2H)。
实施例10
Figure PCTCN2019074642-appb-000092
化合物10的合成
将化合物1-l(62.68mg)溶解于DMF(2mL)中，之后添加HATU(108.86mg)和DIEA(74.00mg)在氮气氛围.将混合液在25℃搅拌30分钟。之后添加10-a(32.43mg)。将混合液在25℃搅拌11.5小时。混合液保持淡黄色。将反应液稀释使用水(30mL)并萃取使用EA(50mL*2).将结合的有机相清洗使用饱和食盐水(30mL*4),用Na 2SO 4干燥，过滤，浓缩得到粗品。将粗品纯化使用制备色谱纯化得到化合物10。
1H NMR(400MHz,DMSO-d 6)δ＝10.13(br s,1H),8.92(d,J＝4.4Hz,1H),8.23(dd,J＝2.8,10.8Hz,1H),8.15(dd,J＝5.6,9.2Hz,1H),7.75(dt,J＝2.8,8.8Hz,1H),7.50-7.41(m,3H),7.39-7.33(m,1H),3.86-3.31(m,4H),2.79-2.65(m,4H),2.44-2.31(m,1H),2.28(s,3H),2.18-2.08(m,4H),2.04-1.84(m,2H)。
实施例11
Figure PCTCN2019074642-appb-000093
化合物11的合成
将化合物1-l(54mg)溶解于DMF(1mL)中，之后添加HATU(93.79mg)和DIEA(63.76mg,)在氮气氛围。将混合液在25℃搅拌30分钟。之后添加11-a(28.72mg)。将混合液在25℃搅拌11.5小时。将反应液稀释使用水(30mL)并萃取使用EA(50mL*2).将结合的有机相清洗使用饱和食盐水(30mL*4),用Na 2SO 4干燥，过滤，浓缩得到粗品。将粗品纯化使用制备色谱纯化得到化合物11。
1H NMR(400MHz,DMSO-d 6)δ＝10.41(br s,1H),8.94(d,J＝4.4Hz,1H),8.24-8.12(m,2H),8.07(dd,J＝2.4,6.8Hz,1H),7.79-7.70(m,2H),7.54-7.46(m,2H),3.81(br s,1H),3.62(br d,J＝11.2Hz,2H),3.28(br s,2H),2.84-2.61(m,4H),2.18-2.03(m,4H),2.00-1.77(m,2H)。
实施例12
Figure PCTCN2019074642-appb-000094
化合物12的合成
将化合物1-l(62.68mg)溶解于DMF(1mL)中，之后添加HATU(108.86mg)和DIEA(74.00mg)在氮气氛围。将混合液在25℃搅拌30分钟。之后化合物12-a(24.77mg)加入反应液中。将混合液在25℃搅拌11.5小时。将混合液稀释使用水(30mL)并萃取使用EA(50mL*2)。将结合的有机相清洗使用饱和食盐水(30mL*4),干燥使用Na2SO4,过滤并在真空中浓缩得粗品。将获得的粗品通过制备色谱纯化得到化合物12。
1H NMR(400MHz,DMSO-d 6)δ＝9.69(s,1H),8.83(d,J＝4.8Hz,1H),8.30(d,J＝5.6Hz,1H),8.08(dd,J＝6.0,9.2Hz,1H),8.03(dd,J＝2.8,11.2Hz,1H),7.69-7.61(m,2H),7.59(dd,J＝1.6,5.6Hz,1H),7.48(d,J＝4.4Hz,1H),3.43-3.21(m,1H),2.98(br d,J＝11.2Hz,2H),2.42(s,3H),2.41-2.35(m,2H),2.32(br d,J＝8.4Hz,4H),1.91-1.68(m,6H)。
实施例13
Figure PCTCN2019074642-appb-000095
化合物13-b的合成：
向二氧六环(8mL)和水(2mL)中依次加入反应物1-h(784.29mg,2.34mmol)，反应物13-a(500mg,2.13mmol)，钯催化剂(77.81mg,106.34μmol),三乙基胺(645.62mg,6.38mmol,888.07uL)，反应液在氮气保护下加热到90℃搅拌12小时，将反应液过滤，滤液加入水稀释，用乙酸乙酯萃取三次(50mL*3)，有机相合并用饱和食盐水洗涤三次(50mL*3),用无水硫酸钠干燥，过滤，将滤液浓缩得到粗产 品，柱层析纯化得到化合物13-b。
化合物13-c的合成：
向乙酸乙酯(10mL)中依次加入反应物13-b(750mg,2.06mmol)，湿钯碳(70mg,10％纯度)，所得混合物用氢气置换三次。在氢气氛围下，常压下加热到50℃，搅拌2小时，将反应液过滤，滤液浓缩得到化合物13-c。
化合物13-d的合成：
向乙醇(8mL)和水(2mL)中依次加入反应物13-c(700mg,1.92mmol)，氢氧化钠(229.81mg,5.75mmol)，加热到70℃搅拌2小时，将反应液浓缩，加入水稀释，用乙酸乙酯萃取三次(30mL*3)，水相加入稀盐酸(1M)调节pH至3，用乙酸乙酯萃取三次(30mL*3)，所得有机相合并用饱和食盐水洗涤三次(50mL*3),用无水硫酸钠干燥，过滤，将滤液浓缩得到化合物13-d。
化合物13的合成：
向DMF(10mL)中依次加入反应物13-d(500mg,1.48mmol)，反应物1-n(226.84mg,1.78mmol)，缩合剂HATU(845.12mg,2.22mmol),N，N-二异丙基乙基胺(574.51mg,4.45mmol,774.28uL)，反应液在室温下搅拌12小时，将反应液加入乙酸乙酯(30mL)稀释，用饱和氯化铵溶液洗涤三次(30mL*3)，再用饱和食盐水洗涤三次(30mL*3)，有机相用无水硫酸钠干燥，过滤，将滤液浓缩得到粗产品，反相色谱纯化得到化合物13。
1H NMR(400MHz,MeOD-d 4)δppm 1.85-2.02(m,6H)2.40-2.55(m,6H)2.73-2.82(m,1H)3.12(s,3H)3.16(br d,J＝11.49Hz,2H)7.36(d,J＝7.78Hz,2H)7.57(d,J＝8.31Hz,2H)7.65(d,J＝8.46Hz,2H)7.91(d,J＝8.44Hz,2H)8.13(s,1H)。
实施例14
Figure PCTCN2019074642-appb-000096
化合物14-a的合成
向化合物1-l(1g)的DCM(30mL)溶液中加入CDI(740.68mg)，在25℃下反应12小时后，加入100mL DCM稀释，然后用饱和食盐水洗(100mL*3),Na 2SO 4干燥,过滤浓缩后得到化合物14-a。
化合物14的合成
将化合物14-b(20.47mg)溶解于THF(5mL)中，然后在0℃下逐滴加入NaHMDS(1M,158.54uL)，氮气置换三次，然后让其在0℃下反应半小时。然后在0℃下加入化合物14-a(50mg)。所得混合物在0℃下搅拌1小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物14。
1H NMR(400MHz,DMSO-d 6)δ＝9.80(s,1H),8.83(d,J＝4.4Hz,1H),8.45(s,1H),8.09(t,J＝7.0Hz,2H),8.04(d,J＝10.4Hz,4H),7.69-7.55(m,1H),2.98(br d,J＝11.0Hz,2H),2.81-2.60(m,1H),2.57-2.53(m, 6H),2.44-2.37(m,4H),2.37-2.22(m,2H)。
实施例15
Figure PCTCN2019074642-appb-000097
化合物15的合成
将化合物15-a(30.84mg)溶解于THF(2mL)中，之后逐滴添加NaHMDS(1M,190.25uL)在-75℃在10mins内在氮气氛围。将混合液在-75℃搅拌20min。之后添加14-a(60mg,158.54μmol)。将混合液在25℃搅拌9.5小时。将反应液稀释使用水(30mL)并萃取使用EA(50mL*2)。将结合的有机相清洗使用饱和食盐水(30mL*4),用Na 2SO 4干燥，过滤，浓缩得到粗品。将粗品使用制备色谱纯纯化得到化合物15。
1H NMR(400MHz,DMSO-d 6)δ＝10.05(s,1H),9.10(d,J＝2.4Hz,1H),8.82(d,J＝4.4Hz,1H),8.48(dd,J＝2.0,8.4Hz,1H),8.08(dd,J＝6.0,9.2Hz,1H),8.02(dd,J＝2.8,11.2Hz,1H),7.89(d,J＝8.8Hz,1H),7.65(dt,J＝2.8,8.8Hz,1H),7.48(d,J＝4.4Hz,1H),3.01(br d,J＝11.2Hz,2H),2.67(s,1H),2.47-2.29(m,6H),1.92-1.67(m,6H)。
实施例16
Figure PCTCN2019074642-appb-000098
化合物16的合成
将化合物16-a(30.82mg)溶解于THF(2mL)中，之后逐滴添加NaHMDS(1M,190.25uL)在0℃在10分钟内在氮气氛围。将混合液在25℃搅拌20分钟。之后添加14-a(60mg)。将混合液在25℃搅拌2小时。将反应液稀释使用水(30mL)并萃取使用EA(50mL*2)。将结合的有机相使用饱和食盐水(30mL*4)洗涤,Na 2SO 4干燥，过滤，浓缩得到粗品。将粗品纯化使用制备色谱纯化得到化合物16。
1H NMR(400MHz,DMSO-d6)δ＝9.72(s,1H),8.83(d,J＝4.4Hz,1H),8.31(s,1H),8.15(d,J＝2.4Hz,1H),8.08(dd,J＝5.6,9.2Hz,1H),8.03(dd,J＝2.8,11.2Hz,1H),7.76(dd,J＝2.4,8.8Hz,1H),7.65(dt,J＝2.8,8.8Hz,1H),7.58(d,J＝8.8Hz,1H),7.48(d,J＝4.8Hz,1H),2.98(br d,J＝11.2Hz,2H),2.67(br d,J＝1.6Hz,1H),2.41(br t,J＝10.4Hz,2H),2.35-2.25(m,4H),1.93-1.79(m,4H),1.79-1.67(m,2H)。
实施例17
Figure PCTCN2019074642-appb-000099
化合物17的合成
将化合物17-a(20.23mg)溶解于THF(5mL)中，然后在0℃下逐滴加入NaHMDS(1M,158.54uL).氮气置换三次，然后让其在0℃下反应半小时，然后在0℃下加入化合物14-a(50mg)。所得混合物在0℃下搅拌1小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物17。
1H NMR(400MHz,DMSO-d 6)δ＝9.94(s,1H),8.85(d,J＝4.4Hz,1H),8.26(dd,J＝1.4,8.2Hz,1H),8.11(t,J＝7.0Hz,2H),8.05(d,J＝10.4Hz,1H),7.68(dt,J＝2.8,8.7Hz,1H),7.53(d,J＝7.6Hz,1H),7.47(d,J＝4.8Hz,1H),7.37(t,J＝7.8Hz,1H),2.96(br d,J＝11.4Hz,2H),2.69-2.53(m,1H),2.48-2.39(m,4H),2.39-2.31(m,2H),2.30-2.18(m,2H),2.01-1.72(m,4H)。
实施例18
Figure PCTCN2019074642-appb-000100
化合物18的合成
将化合物18-a(25.55mg)溶解于THF(5mL)中，然后在-78℃下逐滴加入NaHMDS(1M,158.54μL).氮气置换三次，然后让其在-78℃下反应半小时。然后在-78℃下加入化合物14-a(50mg)。所得混合物在25℃下搅拌11.5小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物18。
1H NMR(400MHz,DMSO-d 6)δ＝9.81(s,1H),8.83(d,J＝4.5Hz,1H),8.12-7.93(m,4H),7.72-7.63(m,3H),7.49(d,J＝4.5Hz,1H),3.62(br s,1H),3.35(br t,J＝11.2Hz,2H),3.01(br d,J＝11.1Hz,2H),2.47-2.25(m,4H),1.93-1.70(m,4H)，1.68-1.47(m,2H)。
实施例19
Figure PCTCN2019074642-appb-000101
化合物19的合成
将化合物19-a(18.73mg)溶解于THF(5mL)中，然后在-78℃下逐滴加入NaHMDS(1M,158.54μL)。氮气置换三次，然后让其在-78℃下反应半小时。然后在-78℃下加入化合物14-a(50mg)。所得混合物在25℃下搅拌11.5小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗涤(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物19。
1H NMR(400MHz,DMSO-d 6)δ＝9.79(s,1H),8.84(d,J＝4.4Hz,1H),8.28(s,2H),8.25(br s,3H),8.12-8.01(m,1H),7.66(dt,J＝2.8,8.7Hz,3H),3.48-3.21(m,1H),3.00(br d,J＝11.4Hz,2H),2.83-2.62(m,2H),2.57-2.53(m,4H),2.47-2.23(m,4H),1.93-1.69(m,2H).
实施例20
Figure PCTCN2019074642-appb-000102
化合物20的合成
将化合物20-a(20.29mg)溶解在THF(2mL)中，将NaHMDS(1M,158.54μL)在0℃滴加，混合物在0℃搅拌1小时，再将14-a(50mg)溶于THF(1mL)加入到该混合物中，反应在0℃N2保护下反应1小时。将水(15mL)加入至反应液，随后用EA 45mL(15mL*3)萃取，合并有机相用饱和食盐水洗40mL(20mL*2)，Na 2SO 4干燥，过滤浓缩后得到粗品。粗品通过制备色谱纯化得到产物20。
1H NMR(400MHz,DMSO-d 6)δppm 1.72-1.91(m,6H)2.29-2.35(m,4H)2.43(br d,J＝11.00Hz,2H)2.99(br d,J＝10.88Hz,2H)3.35(br t,J＝11.25Hz,1H)7.48(d,J＝4.52Hz,1H)7.65(td,J＝8.71,2.63Hz,1H)7.79(d,J＝8.68Hz,2H)7.96-8.11(m,4H)8.82(d,J＝4.52Hz,1H)9.87(s,1H)
实施例21
Figure PCTCN2019074642-appb-000103
化合物21-b的合成
将混合物21-a(500mg)和1-h(1.02g)溶解在二氧六环(12mL)和水(3mL)中，然后加入TEA(836.08mg)，之后Pd(dppf)Cl2(201.52mg)在N 2保护下加入至该混合物中，所得混合物用N 2置换数次，该反应在85℃下搅拌12小时得黑色溶液，将反应液过滤后，加入水50mL，随后用EA(50mL*3)萃取，合并有机相用饱和食盐水洗50mL(25mL*2)，Na 2SO 4干燥，过滤浓缩后得到粗品。粗品通过柱层析纯化得到化合物21-b。
化合物21-c的合成
将化合物21-b(590mg)溶解于EtOAc(10mL)中，然后在N2保护下加入Pd/C(60mg,10％纯度)，所得混合物不断通入H 2并置换数次，反应在25℃、H 2(15psi)下搅拌12小时得黑色悬浊液。将反应液过滤浓缩后得21-c。
化合物21-d的合成
将化合物21-c(510mg)溶于MeOH(8mL)中，并加入NaOH(228.95mg)的水(2mL)溶液，所得混合物在75℃下搅拌12小时得黄色溶液。将反应液浓缩，然后加入水6mL，该溶液用3M HCl调节pH至7左右,将溶液在0℃搅拌30min，大量白色沉淀形成，过滤、然后将滤饼浓缩得21-d。
化合物21的合成
将化合物21-d(160mg)溶解在DMF(4mL)中，然后再加入DIEA(188.95mg)和HATU(240.88mg)，将该混合物在25℃下搅拌1小时，再将1-n(80.82mg)加入到混合物中，该反应在50℃N2保护下反应11小时，反应液为黄色溶液。然后将水40mL加入至反应液，随后用EA 60mL(20mL*3)萃取，合并有机相用饱和食盐水洗40mL(20mL*2)，Na 2SO 4干燥,过滤浓缩后得到粗品。粗品通过制备色谱纯化得到化合物21。
1H NMR(400MHz,DMSO-d 6)δppm 1.83-2.01(m,1H)1.83-2.01(m,2H)2.16(br s,4H)2.77(br s,4H)2.99-3.25(m,3H)3.61(br s,2H)7.53(br d,J＝7.6Hz,2H)7.65(br s,1H)7.77-7.86(m,3H)8.79(br d, J＝3.6Hz,1H)10.36(br s,1H)
实施例22
Figure PCTCN2019074642-appb-000104
化合物22-b的合成
将混合物22-a(500mg)和1-h(980.66mg)溶解在二氧六环(12mL)和水(3mL)中，然后加入TEA(807.27mg),之后Pd(dppf)Cl2(194.58mg)在N 2保护下加入至该混合物中，所得混合物用N 2置换数次，该反应在85℃下搅拌12小时得棕色溶液，将反应液过滤后，加入水50mL，随后用EA150(50mL*3)萃取，合并有机相用饱和食盐水洗50mL(25mL*2)，Na 2SO 4干燥，过滤浓缩后得到粗品。粗品通过柱层析纯化，得到化合物22-b。
化合物22-c的合成
将化合物22-b(500mg)溶解于EtOAc(10mL)中，然后在N2保护下加入Pd/C(50mg,10％purity)，所得混合物不断通入H2并置换数次，反应在50℃、H 2(15psi)下搅拌3小时得黑色悬浊液。将反应液过滤浓缩后得22-c。
化合物22-d的合成
将化合物22-c(520mg)(粗品)溶于MeOH(10mL)中，并加入NaOH(228.62mg)的水(2mL)溶液，所得混合物在70℃下搅拌12小时得黄色溶液。反应液浓缩，然后加入水15mL，该溶液用2M HCl调节pH至6左右，然后将混合液浓缩得粗品。将MeOH 15mL加入至粗品中，搅拌30min后过滤，将滤液浓缩得22-d。
化合物22的合成
将化合物22-d(200mg)溶解在DMF(5mL)中，然后再加入DIEA(267.07mg)和HATU(340.48mg)，再将1-n(114.23mg)加入到混合物中，该反应在25℃N 2保护下反应12小时，反应液为黄色溶液。将水40mL加入至反应液，随后用EA 60(20mL*3)萃取，合并有机相用饱和食盐水洗40mL(20mL*2)，Na 2SO 4干燥,过滤浓缩后得到粗品。将粗品通过制备色谱纯化，得化合物22。
1H NMR(400MHz,DMSO-d 6)δppm 1.67-1.83(m,6H)2.13-2.35(m,7H)2.94(br d,J＝11.2Hz,2H)3.82(s,3H)6.67(s,1H)6.90(d,J＝5.2Hz,1H)7.37(d,J＝8.80Hz,2H)7.73-7.78(m,2H)8.06(d,J＝5.26Hz,1H)9.54(s,1H)。
实施例23
Figure PCTCN2019074642-appb-000105
化合物23-b的合成
将化合物23-a(3.2g)溶解于EA(30mL)中，之后添加Me 3OBF 4(4.52g)在氮气氛围。将混合液在25℃搅拌6小时。将所得悬浊液过滤并将滤饼真空干燥得粗品23-b。
合物23-c的合成
将化合物23-b(1.63g,10.86mmol)溶解于DCM(17mL)中，之后添加吡啶(1.29g)和二(三氟乙酸)碘苯(5.60g)在氮气氛围。将所得混合液在30℃搅拌30分钟，之后添加I 2(3.31g)。将所得混合液在30℃搅拌15.5小时。将所得悬浊液过滤并将滤饼真空干燥得粗品23-c。
化合物23-d的合成
将化合物1-h(2.40g,7.17mmol,1eq)和23-c(1.98g,7.17mmol,1eq)溶解于二氧六环(20mL)和水(5mL)中，之后添加Pd(dppf)Cl 2(262.41mg,358.63μmol,0.05eq)和Et 3N(2.18g,21.52mmol,3.00mL,3eq)在氮气氛围。将混合液使用氮气置换三次。将混合液在100℃搅拌8小时。将混合液过滤并清洗滤饼使用EA(80mL)，之后添加水(40mL)，分液。将水相萃取使用EA(70mL*2)。并将合并的有机相清洗使用饱和食盐水(50mL*2),Na 2SO 4干燥，过滤浓缩后得到粗品。将所得粗品使用柱层析纯化得到化合物23-d。
化合物23-e的合成
将化合物23-d(800mg,2.24mmol)溶解于MeOH(10mL)中，之后添加Pd/C(80mg,10％纯度)在H 2氛围(35psi)。将混合液置换气体三次使用H 2。将混合液在H 2(15psi)氛围在50℃搅拌20小时。将混合 液过滤并将所得溶液浓缩得到化合物23-e。
化合物23-f的合成
将化合物23-e(803mg,2.23mmol)溶解于MeOH(10mL)和水(5mL)中，之后添加NaOH(268.09mg,6.70mmol)在氮气氛围。将所得混合液在70℃搅拌12小时。使用3M HCl调节溶液pH约为pH＝8,此时有固体析出，过滤并用水(10mL)清洗滤饼，将滤饼真空干燥得粗品23-f。
化合物23的合成
将化合物23-f(100mg,301.76μmol)溶解于DMF(2mL)之后添加DIEA(117.00mg,905.29μmol,157.68uL)和HATU(172.11mg,452.65μmol)在氮气氛围。将所得混合液在25℃搅拌30min。之后添加1-n(46.20mg,362.12μmol)。将混合液在25℃搅拌11.5小时。将反应液稀释使用水(30mL)并萃取使用EA(50mL*2)。将结合的有机相使用饱和食盐水(30mL*4)洗涤,用Na 2SO 4干燥，过滤，浓缩得到粗品。粗品通过制备色谱纯化得到化合物23。
1H NMR(400MHz,DMSO-d 6)δ＝9.66(s,1H),7.79(d,J＝8.8Hz,2H),7.65-7.53(m,2H),7.38(d,J＝8.8Hz,2H),7.09(dt,J＝2.4,9.2Hz,1H),4.09(s,3H),2.99(br d,J＝11.2Hz,2H),2.67(s,1H),2.37-2.22(m,6H),2.19-2.04(m,2H),1.92-1.83(m,2H),1.79-1.69(m,2H).
实施例24
Figure PCTCN2019074642-appb-000106
化合物24的合成
将化合物14-a(23.32mg)溶于THF(3mL)中，并在-78℃下，往溶液中滴加NaHMDS(1M,158.54μL).所得混合物在-78℃下搅拌30分钟.然后在该温度下向反应液中滴加溶于THF(3mL)的24-a(50mg,132.12μmol),所得混合物在25℃下搅拌12小时。向反应液中加入水(10mL)淬灭反应并用乙酸乙酯(20mL*3)萃取.合并有机相用Na2SO4干燥,过滤后减压浓缩得到粗品.粗品通过制备色谱纯化得到化合物24.
1H NMR(400MHz,DMSO-d 6)δppm 1.67-1.97(m,6H)2.24-2.37(m,5H)2.42(br t,J＝10.45Hz,2H)2.97(br d,J＝11.37Hz,2H)7.49(d,J＝4.52Hz,1H)7.67(td,J＝8.71,2.63Hz,1H)7.78(dd,J＝10.58,6.54Hz,2H)7.98-8.14(m,2H)8.84(d,J＝4.52Hz,1H)9.80(s,1H).
实施例25
Figure PCTCN2019074642-appb-000107
化合物25的合成
将化合物25-a(22.38mg)溶于THF(3mL)中，并在-78℃下，往溶液中滴加NaHMDS(1M,158.54μL).所得混合物在-78℃下搅拌30分钟.然后在该温度下向反应液中滴加溶于THF(3mL)的14-a(50mg),所得混合物在20℃下搅拌12小时.向反应液中加入水(10mL)淬灭反应并用乙酸乙酯(20mL*3)萃取.合并有机相用Na 2SO 4干燥,过滤后减压浓缩得到粗品.粗品通过制备色谱纯化得到化合物25.
1H NMR(400MHz,DMSO-d 6)δppm 1.74-2.03(m,6H)2.21(br t,J＝8.86Hz,2H)2.31-2.36(m,1H)2.34(br s,1H)2.33-2.46(m,1H)2.38-2.46(m,1H)2.38-2.44(m,1H)2.93(br d,J＝11.00Hz,2H)3.92(s,3H)6.78(td,J＝8.74,2.69Hz,1H)7.01(dd,J＝10.76,2.69Hz,1H)7.50(d,J＝4.52Hz,1H)7.63-7.74(m,1H)8.00-8.22(m,3H)8.88(d,J＝4.52Hz,1H)9.71(s,1H)。
实施例26
Figure PCTCN2019074642-appb-000108
化合物26-a的合成
向化合物1-e(2g)的乙醇溶液(30mL)中加入硼氢化钠(503.80mg)，在25℃下反应12小时后，加入100毫升乙酸乙酯稀释，溶液用饱和氯化钠溶液洗涤三次，每次100毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到化合物26-a。
化合物26-b的合成
向化合物26-a(50mg)和4-氯-6-氟喹啉(39.95mg)的DMF溶液(5mL)中加入叔丁醇钾(74.05mg)，在90℃ 下反应12小时，加入30毫升乙酸乙酯稀释，溶液用饱和氯化钠溶液洗涤3次，每次30毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到黄色胶状化合26-b(300mg)，直接用于下一步反应。
化合物26-c的合成
向化合物26-b(300mg)的甲醇(5mL)和水(5mL)溶液中加入氢氧化钠(161.09mg)，在65℃下反应12小时后，用盐酸(1M)将pH调到6-7，减压浓缩得到粗品，粗品通过反相快速柱层系纯化得到化合物26-c。
化合物26的合成
向化合物26-c(40mg)和1-n(16.30mg)的DMF溶液(5mL)中加入N,N-二异丙基乙胺((75.06mg)和HATU(66.25mg)，在氮气保护和25℃下反应12小时后，加入30毫升乙酸乙酯稀释，溶液用饱和氯化钠溶液洗涤3次，每次30毫升，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品通过制备色谱(甲酸体系)纯化得到26。
1H NMR(400MHz,DMSO-d 6)δ＝9.56(s,1H),8.67(d,J＝5.1Hz,1H),8.00(dd,J＝5.4,9.2Hz,1H),7.77-7.60(m,4H),7.36(d,J＝8.9Hz,2H),7.14(d,J＝5.1Hz,1H),4.81(br s,1H),2.80-2.70(m,2H),2.50-2.40(m,2H),2.32-2.17(m,4H),2.15-2.05(m,2H),1.95-1.80(m,2H),1.80-1.57(m,2H).
实施例27
Figure PCTCN2019074642-appb-000109
化合物27-b的合成
将化合物26-a(50mg)，27-a(39.93mg)溶解在DMF(5mL)中，然后加入t-BuOK(74.05mg)氮气置换三次，所得混合物在氮气保护下，90℃下搅拌12小时。将反应物用EtOAc(15mL*3)萃取.合并有机相用饱和食盐水洗(15mL*3),Na 2SO 4干燥,过滤浓缩后得到27-b。
化合物27-c的合成
将化合物27-b(460mg)溶解于MeOH(5mL)和水(5mL)中，加入NaOH(148.22mg,3.71mmol)，所得混合物在60℃下氮气保护下搅拌12小时.将甲醇拉干后，在0℃下用1M HCl调节PH为7，水相直接旋干。粗品通过制备色谱纯化得到化合物27-c。
化合物27的合成
将化合物27-c(50mg)溶解于DMF(5mL)中，然后加入DIEA(93.84mg,726.05μmol,126.47uL),HATU(82.82mg),对氯苯胺(20.38mg).氮气置换三次，所得混合物在25℃下搅拌12小时.将反应液用EtOAc(10mL*3)萃取，合并有机相用饱和食盐水洗(10mL*3),Na 2SO 4干燥,过滤浓缩后得到粗品，粗品通过制备色谱纯化得到化合物27。
1H NMR(400MHz,DMSO-d 6)δ＝9.55(s,1H),8.53(d,J＝5.6Hz,1H),7.75(d,J＝8.0Hz,2H),7.44-7.34(m,1H),7.31-7.25(m,2H),7.29(dd,J＝2.4,5.7Hz,1H),4.72(td,J＝4.4,8.3Hz,1H),3.43(br s,2H),2.81-2.71 (m,4H),2.44-2.17(m,2H),2.12-1.94(m,2H),1.78-1.63(m,4H)。
实施例28
Figure PCTCN2019074642-appb-000110
化合物28-b的合成
将化合物28-a(1g,6.04mmol,HCl)溶解于二氧六环(8mL)和水(2mL)中，之后添加DIEA(1.56g)。之后添加1-b(2.31g,9.06mmol)到混合液中在90℃。将所得混合液在90℃搅拌12小时。将混合液萃取使用EtOAc(10mL*3),将结合的有机相清洗使用饱和食盐水(10mL*3),干燥使用Na 2SO 4,过滤,过滤浓缩后得到28-b。
化合物28-c的合成
将化合物28-b(670mg,3.17mmol)溶解于THF(10mL)中，之后添加N,N-二(三氟甲烷磺酰基)苯胺(1.25g,3.49mmol)。将混合液使用氮气置换三次。之后将NaHMDS(1M,4.12mL)逐滴添加到混合液中在-78℃。将所得混合液在-78℃搅拌1小时。之后将混合液在25℃搅拌11小时。将混合液淬灭通过添加0.2M HCl(10mL)，之后萃取使用MTBE(10mL*3),将结合的有机相使用0.2M HCl(10mL*3),0.5％NaOH(10mL*3)和饱和食盐水(10mL*3)洗涤,Na2SO4干燥,过滤,浓缩得化合物28-c。
化合物28-d的合成
将化合物28-c(200mg,582.55μmol),双联频哪醇硼酸酯(192.31mg,757.31μmol),KOAc(171.51mg,1.75mmol),NaBr(23.98mg,233.02μmol,7.49uL)溶解于二氧六环(2mL)中，之后在氮气氛围下添加Pd(dppf)Cl 2(21.31mg,29.13μmol)。将混合液使用氮气置换三次。将混合液在100℃搅拌12小时。将反应液过滤并且清洗使用EA(80mL)，之后加入水(40mL)。将获得有机相清洗使用饱和食盐水(30mL*2)。调节溶液pH为pH＝3使用1M HCl。将获得水相使用EA(30mL*2)洗涤。使用饱和碳酸钠溶液调节水相pH为pH＝10，使用EA(40mL*2)萃取。将获得的有机相使用饱和食盐水(20mL*2)洗涤，干燥使用Na 2SO 4，过滤并浓缩得粗产品28-d。
化合物28-e的合成
将化合物28-d(210mg,653.76μmol)和1-i(98.93mg,544.80μmol)溶解于二氧六环(4mL)和水(1mL) 中，之后添加Et 3N(165.39mg,1.63mmol,227.49μL)和Pd(dppf)Cl 2(19.93mg,27.24μmol)在氮气氛围。将混合液使用氮气置换三次。将混合液在110℃搅拌8小时。将反应液过滤使用EA(40mL)，之后清洗使用水(20mL)。将有机相清洗使用饱和食盐水(15mL*2)。调节溶液pH为pH＝3使用1M HCl。之后清洗水相使用EA(15mL*2)。调节溶液pH为pH＝10使用饱和碳酸钠溶液，萃取使用EA(20mL*2)。将获得的有机相清洗使用饱和食盐水(20mL*2)，干燥使用Na 2SO 4，过滤并浓缩得28-e。
化合物28-f的合成
将化合物28-e(156mg,458.30μmol)和吡啶(54.38mg,687.44μmol,55.49uL)溶解于IPA(2mL)中，之后添加Pd/C(32mg,10％纯度)在H 2(15psi)氛围。将混合液使用氢气置换三次。将混合液在H 2(15psi)氛围在50℃搅拌8小时。将混合液过滤，浓缩滤液得到化合物28-f。
化合物28-g的合成
将化合物28-f(152mg,443.92μmol)溶解于MeOH(2mL)和水(1mL)中，之后添加NaOH(71.03mg,1.78mmol)在氮气氛围。将混合液在70℃搅拌12小时。将混合液浓缩得粗品，通过制备色谱纯化得到28-g。
化合物28的合成
化合物28-g(26mg,82.71μmol)溶解于DMF(1mL)中，之后添加HATU(47.17mg,124.06μmol)和DIEA(32.07mg,248.13μmol,43.22uL)在氮气氛围。将混合液在25℃搅拌30min。之后加入1-n(12.66mg,99.25μmol)。将混合液在25℃搅拌11.5小时。将混合液稀释使用水(30mL)并使用EA(50mL*2)萃取。将结合的有机相使用饱和食盐水(30mL*4)洗涤,使用Na 2SO4干燥,过滤并在真空中浓缩得粗品。粗品通过制备色谱纯化得到化合物28。
1H NMR(400MHz,DMSO-d6)δ＝10.11(s,1H),8.86(d,J＝4.4Hz,1H),8.18-8.05(m,2H),7.98(dd,J＝2.8,10.8Hz,1H),7.77(d,J＝8.8Hz,2H),7.68(dt,J＝2.8,8.8Hz,1H),7.58(d,J＝4.4Hz,1H),7.39(d,J＝8.8Hz,2H),3.29-3.25(m,1H),2.88(br d,J＝11.1Hz,2H),2.54(br s,2H),2.09-2.01(m,2H),1.86(br d,J＝12.0Hz,2H),1.15(br d,J＝15.6Hz,4H).
实施例29
Figure PCTCN2019074642-appb-000111
化合物29的合成
向DMF(5mL)中依次加入反应物1-l(50mg)，反应物29-a(34.72mg)，HATU(86.84mg),二异丙基乙基胺(59.04mg)，反应液在室温下搅拌12小时，向反应体系中加入乙酸乙酯(30mL)，然后用饱和氯化铵溶液洗涤三次(30mL*3)，再用饱和食盐水洗涤三次(30mL*3),用无水硫酸钠干燥，过滤，将滤液浓缩得到粗产品，粗产品用常规反相色谱柱进行纯化得到化合物29。
1H NMR(400MHz,MeOD-d 4)δppm 1.83-1.93(m,2H)1.94-2.01(m,2H)2.04(br s,2H)2.36-2.44 (m,2H)2.45-2.52(m,2H)2.54-2.61(m,2H)3.10-3.15(m,2H)3.36-3.39(m,1H)7.21(t,J＝8.68Hz,1H)7.58(d,J＝4.65Hz,1H)7.61(d,J＝2.69Hz,1H)7.63(d,J＝2.81Hz,1H)7.94(dd,J＝10.70,2.63Hz,1H)8.07-8.08(m,1H)8.08-8.12(m,1H)8.79(d,J＝4.65Hz,1H)。
实施例30
Figure PCTCN2019074642-appb-000112
化合物30的合成
向DMF(5mL)中依次加入反应物1-l(50mg)，反应物30-a(28.80mg)，HATU(86.84mg),二异丙基乙基胺(59.04mg)，反应液在室温下搅拌12小时，向反应体系中加入乙酸乙酯(30mL)，然后用饱和氯化铵溶液洗涤三次(30mL*3)，再用饱和食盐水洗涤三次(30mL*3),用无水硫酸钠干燥，过滤，将滤液浓缩得到粗产品，粗产品用常规反相色谱柱进行纯化，得到化合物30。
1H NMR(400MHz,METHANOL-d 4)δppm 1.92-2.00(m,2H)2.01-2.09(m,2H)2.09-2.16(m,2H)2.48-2.63(m,4H)2.71-2.83(m,2H)3.23-3.29(m,2H)3.48-3.53(m,1H)3.93(s,3H)7.21(dd,J＝8.56,2.20Hz,1H)7.33(d,J＝8.56Hz,1H)7.57(d,J＝4.65Hz,1H)7.61(d,J＝2.08Hz,1H)7.64(dd,J＝8.74,2.14Hz,1H)7.96(dd,J＝10.51,2.69Hz,1H)8.12(d,J＝3.55Hz,1H)8.81(d,J＝4.65Hz,1H)。
实施例31
Figure PCTCN2019074642-appb-000113
化合物31的合成
向四氢呋喃(5mL)中加入反应物14-a(23.08mg)，在-78℃下缓慢滴加六甲基二硅基氨基钠(1M,264.24uL)，反应液在该温度下搅拌半小时，然后加入反应物31-a(50mg)，反应液在室温下搅拌1小时，向反应体系中加入乙酸乙酯(30mL)，然后用饱和氯化铵溶液洗涤三次(30mL*3)，再用饱和食盐水洗涤三次(30mL*3),用无水硫酸钠干燥，过滤，将滤液浓缩得到粗产品，粗产品用常规反相色谱柱进行纯化，得到化合物31。
1H NMR(400MHz,MeOD-d 4)δppm 1.84-1.95(m,2H)1.98(br d,J＝12.72Hz,2H)2.04(br d,J＝5.50Hz,2H)2.35-2.43(m,2H)2.46-2.60(m,4H)3.11(br d,J＝10.88Hz,2H)3.37-3.47(m,1H)7.43(br s, 2H)7.56-7.65(m,2H)7.81(br d,J＝11.86Hz,1H)7.93(br d,J＝10.76Hz,1H)8.08-8.13(m,1H)8.77-8.81(m,1H)。
实施例32
Figure PCTCN2019074642-appb-000114
化合物32的合成
向DMF(5mL)中依次加入反应物1-l(50mg)，反应物32-a(25.87mg)，HATU(86.84mg),二异丙基乙基胺(59.04mg)，反应液在室温下搅拌12小时,向反应体系中加入乙酸乙酯(30mL)，然后用饱和氯化铵溶液洗涤三次(30mL*3)，再用饱和食盐水洗涤三次(30mL*3),用无水硫酸钠干燥，过滤，将滤液浓缩得到粗产品，粗产品用常规反相色谱柱进行纯化，得到化合物32。
1H NMR(400MHz,DMSO-d 6)δppm 1.81-1.99(m,2H)2.06-2.14(m,3H)2.28-2.42(m,5H)2.57-2.84(m,5H)2.86-2.93(m,2H)3.19-3.41(m,1H)7.42-7.50(m,2H)7.63(dd,J＝8.50,2.26Hz,1H)7.69-7.77(m,2H)8.11-8.20(m,2H)8.91(d,J＝4.52Hz,1H)10.15-10.28(m,1H)。
实施例33
Figure PCTCN2019074642-appb-000115
化合物33-b的合成
将化合物33-a(2g,27.75mmol)溶于MTBE(30mL)后加入碘化锌(88.59mg,277.54μmol)和TMSCN(2.75g,27.75mmol,3.47mL).所得混合物在25℃下搅拌12小时.将反应液浓缩得到粗品化合物33-b.
化合物33-c的合成
将化合物33-b(3g,17.52mmol,1eq)和化合物33-h(3.26g,17.52mmol,1eq)溶于MTBE(50mL)后在25℃下搅拌12小时.将反应液浓缩得到粗品化合物33-c.
化合物33-d的合成
将33-c(2g,7.48mmol)溶于MeOH(20mL)和水(4mL)中后加入NaOH(897.72mg,22.44mmol).所得混合物在60℃下搅拌4小时.将反应液浓缩后用水(50mL)稀释EA(60mL*2)萃取.水相用HCl(1M,20mL)调节pH到5,EA(100mL*2)萃取.所得有机相用饱和食盐水(100mL*2)洗涤,Na 2SO 4干燥,过滤浓缩得到化合物33-d.
化合物33-f的合成
将33-d(780mg,2.73mmol),33-e(782.20mg,3.28mmol),Pd 2(dba) 3(250.32mg,273.36μmol),Xantphos(316.34mg,546.72μmol)和碳酸铯(1.78g,5.47mmol)溶于1,4二氧六环(20mL)。所得混合液用N 2置换三次后在80℃下搅拌12小时.将反应液过滤，滤液用水(50mL)稀释,EA(80mL*3)萃取.所得混合有机相用饱和食盐水(80mL*2)洗涤,Na 2SO 4干燥,过滤浓缩得到粗品产物.粗品通过制备硅胶板纯化得到化合物33-f.
化合物33-g的合成
将化合物33-f(640mg,1.62mmol)溶于MeOH(10mL)后加入HCl二氧六环溶液(4M,4.04mL).所得混合物在25℃下搅拌2小时.将反应液浓缩得到化合物33-g.
化合物33的合成
将化合物33-g(200mg,676.22μmol),1-i(61.40mg,338.11μmol),Pd 2(dba) 3(61.92mg,67.62μmol),Xantphos(78.25mg,135.24μmol)和碳酸铯(440.65mg,1.35mmol)溶于1,4二氧六环(10mL)后用N 2置换三次。所得混合液在80℃下搅拌12小时.将反应液过滤后用水(20mL)稀释,乙酸乙酯(30mL*3)萃取.所得有机相用饱和食盐水(30mL*2)洗涤,Na 2SO 4干燥,过滤浓缩后通过制备色谱纯化得到化合物33.
1H NMR(400MHz,MeOD-d 4)δppm 2.95-3.04(m,4H)3.88-4.08(m,4H)4.86(br s,4H)7.29(d,J＝6.85Hz,1H)7.34-7.38(m,2H)7.64-7.70(m,2H)7.79-7.97(m,2H)8.05(dd,J＝9.29,4.89Hz,1H)8.58(d,J＝6.85Hz,1H).
实施例34
Figure PCTCN2019074642-appb-000116
化合物34-a的合成
将化合物23-f(100mg,301.76umol)溶于DCM(5mL)中，往溶液中加入CDI(73.40mg,452.65umol).所得混合物在25℃下搅拌反应12小时.向反应液中加入水(20mL)淬灭反应并用乙酸乙酯(20mL*3)萃取.合并有机相用饱和氯化钠溶液(20mL*3)洗涤，Na 2SO 4干燥,过滤后减压浓缩得到34-a.
化合物34的合成
将化合物20-a(29.73mg,251.67umol)溶于THF(5mL)中，并在-78℃下，往溶液中滴加NaHMDS(1M,251.67uL).所得混合物在-78℃下搅拌30分钟.然后在该温度下向反应液中滴加溶于THF(2mL)中34-a(80mg,209.73umol),所得混合物在20℃下搅拌12小时.向反应液中加入水(10mL)淬灭反应并用乙酸乙酯(20mL*3)萃取,合并有机相用Na 2SO 4干燥,过滤后减压浓缩得到粗品.粗品通过制备色谱纯化得到化合物34.
1H NMR(400MHz,DMSO-d 6)δppm 1.70-1.94(m,4H)2.03-2.21(m,2H)2.22-2.39(m,6H)2.99(br d,J＝11.13Hz,2H)3.14(ddd,J＝12.10,8.68,3.67Hz,1H)4.09(s,3H)7.09(td,J＝9.26,2.38Hz,1H)7.52-7.65(m,2H)7.79(d,J＝8.68Hz,2H)8.00(d,J＝8.68Hz,2H)9.94(s,1H).
实验例1：化合物对Hela细胞犬尿氨酸通路活性抑制的评价
实验目的：
检测本发明化合物对Hela细胞犬尿氨酸通路活性的抑制效应。
实验方法：
以二甲亚砜将化合物溶解到3mM，取15μl化合物加入到96孔板。以3倍连续稀释化合物(10μl+20μl)。加入192μl检测培养基到一个96孔板中，向化合物板中加入78μl DMEM培养基(Dulbecco's modified Eagle's medium)并充分混匀，转移8μl DMEM培养基稀释过的化合物到已经加入检测培养基的96孔板。取出细胞培养板并弃去其中的培养基，转移100μl化合物到细胞培养板中，将细胞培养板转入培养箱中继续培养48小时。
取出细胞培养板，并转出50μl上清到一新的96孔板，加入200μl乙腈到上述板中并充分混匀，4度离心转移40μl上清到另一96孔板。加入360μl含有2μg/ml内参的去离子水，充分混匀对样品进行检测。
实验结果：见表1。
表1体外筛选试验结果
受试化合物 EC 50(nM)
1 11
5 82
7 17
8 36
13 65
20 16
21 11
22 14
23 3
26 22
27 24
30 30
31 26
结论：本发明的化合物对Hela细胞内犬尿氨酸的产生具有明显的抑制作用。
实验例2：化合物药代动力学的评价
试验动物
本研究使用的健康的成年雌性Balb/c小鼠，均购自上海灵畅生物科技有限公司。
药物的配制
静脉注射组给药溶液的配制
精确称量适量化合物，加入一定量的PEG400超声2分钟后得到澄清溶液，然后加入适量的纯水。得到终浓度为1mg/mL的澄清溶液，给药溶媒为60％PEG400+40％纯水。静脉注射组溶液在给药前用2um的滤膜进行过滤。
口服给组给药溶液的配制
精确称量适量化合物，加入一定量的PEG400超声2分钟后得到澄清溶液，然后加入适量的纯水。得到终浓度为10mg/mL的混悬溶液，给药溶媒为60％PEG400+40％纯水。
给药
24只雌性Balb/c小鼠，按照每组6只，分为4组。第一组，静脉注射给予2mg/kg的BMS-986205；第二组，灌胃给予50mg/kg BMS-986205；第三组，静脉注射给予2mg/kg化合物1；第四组，灌胃给予50mg/kg化合物1。
样品采集
采用交叉采血方式，每个时间点采集三只动物的血液。分别于给药前及给药后0.0833(仅静注组)、0.25、0.5、1、2、4、8、24小时采集40uL全血。将全血至于抗凝管中，在4℃条件先，3000g离心15分钟，制备血浆并保存于-80℃。应用LC/MS-MS测定血浆中的药物浓度。
表2药代动力学参数
Figure PCTCN2019074642-appb-000117
“-”表示尚未得到数据
结论：本发明的实施例1相比临床分子BMS-986205具有更好的组织分布，相同剂量下具有更高的AUC,同时半衰期更长，口服生物利用度更高，综合药代动力学性质更优。
实验例3：化合物以及与PD-1单抗组合用药在CT26小鼠同系移植瘤模型中的药效评估
试验动物：
BALB/c小鼠，雌性，18～22g，上海斯莱克。
供试药品：
实施例1及对照化合物BMS-986205，PD-1单抗。
细胞及接种：
1.细胞系：CT26细胞(小鼠结肠癌细胞)
2.接种量：3×10 5/0.1mL
3.接种途径：皮下注射
分组及给药方案：
Figure PCTCN2019074642-appb-000118
Figure PCTCN2019074642-appb-000119
实验结果：见图1、图2和表3。
表3 CT26小鼠同系移植瘤模型中小鼠肿瘤体积数据
Figure PCTCN2019074642-appb-000120
a.相对肿瘤增殖率T/C(％)＝TRTV/CRTV×100％(TRTV：治疗组平均RTV；CRTV：阴性对照组平均RTV)。
b.肿瘤生长抑制率TGI(％)＝1-(治疗组测量当天平均肿瘤体积-治疗组分组当天平均肿瘤体积)/(溶媒组测量当天平均肿瘤体积-溶媒组分组当天平均肿瘤体积)×100％
c.P值：第18天肿瘤体积指与溶媒对照相比
结论：本发明化合物表现出优异的体内抗肿瘤活性，且能对PD-1单抗起到增效作用。相比临床分子BMS-986205，在相同剂量下，具有更优的单药及联用药效。

Claims (13)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2019074642-appb-100001
    其中，
    环A选自苯基、吡啶基、环戊基、2H-吲唑基、1H-吲哚基和环己基；
    环B选自苯基、吡啶基、喹啉基、异喹啉基、1H-吲唑基和2H-吲唑基；
    L选自单键、-O-、-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
    X选自CH和N；
    L’选自单键和-O-；
    R 1分别独立地选自卤素、NH 2、CN、C 1-3烷基、CF 3、CHF 2、CH 2F、C 1-3杂烷基；
    R 2分别独立地选自卤素、CN、C 1-3烷基、CF 3、CHF 2、CH 2F、C 1-3杂烷基、3-6元环烷基、3-6元杂环烷基、3-6元环烷基-O-、3-6元杂环烷基-O-、3-6元环烷基-NH-、3-6元杂环烷基-NH-；
    m和n分别独立地选自0、1、2和3；
    “杂”表示杂原子或杂原子团，所述C 1-3杂烷基、3-6元杂环烷基、3-6元杂环烷基-O-和3-6元杂环烷基-NH-之“杂”选自N、-NH-、-O-、-S-、-C(＝O)-、-C(＝S)-、-C(＝O)O-、-S(＝O)-和-S(＝O) 2-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2和3。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 1分别独立地选自F、Cl、Br、I、NH 2、CN、CH 3、CF 3、CH 3CH 2、CH 3O和CH 3CH 2O。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 2分别独立地选自F、Cl、Br、I、CN、CH 3、CF 3、CHF 2、CH 2F、CH 3CH 2、CH 3O-、CH 3CH 2O-、
    Figure PCTCN2019074642-appb-100002
    Figure PCTCN2019074642-appb-100003
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019074642-appb-100004
    选自
    Figure PCTCN2019074642-appb-100005
    Figure PCTCN2019074642-appb-100006
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019074642-appb-100007
    选自
    Figure PCTCN2019074642-appb-100008
  6. 根据权利要求2或5所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019074642-appb-100009
    选自
    Figure PCTCN2019074642-appb-100010
  7. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019074642-appb-100011
    选自
    Figure PCTCN2019074642-appb-100012
  8. 根据权利要求3或7所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019074642-appb-100013
    选自
    Figure PCTCN2019074642-appb-100014
    Figure PCTCN2019074642-appb-100015
  9. 根据权利要求1-8任意一项所述的化合物或其药学上可接受的盐，选自
    Figure PCTCN2019074642-appb-100016
    其中，环A、m、n、X、L、L’、R 1和R 2如权利要求1-8任意一项所定义。
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，选自
    Figure PCTCN2019074642-appb-100017
    其中，L、R 1和R 2如权利要求9所定义。
  11. 化合物或其药学上可接受的盐，选自
    Figure PCTCN2019074642-appb-100018
    Figure PCTCN2019074642-appb-100019
    Figure PCTCN2019074642-appb-100020
  12. 一种药物组合物，其含有治疗有效量的根据权利要求1-11任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  13. 根据权利要求1-11任意一项所述的化合物或其药学上可接受的盐或根据权利要求12所述的药物组合物在制备治疗癌症药物中的应用。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106999450A (zh) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 免疫调节剂
CN107205970A (zh) * 2014-11-05 2017-09-26 弗莱塞斯生物科学公司 免疫调节剂
WO2017192813A1 (en) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106999450A (zh) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 免疫调节剂
CN107205970A (zh) * 2014-11-05 2017-09-26 弗莱塞斯生物科学公司 免疫调节剂
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂
WO2017192813A1 (en) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 7 August 2002 (2002-08-07), Database accession no. 442896-85-7 *

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