WO2022194248A1 - Ctla-4小分子降解剂及其应用 - Google Patents

Ctla-4小分子降解剂及其应用 Download PDF

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WO2022194248A1
WO2022194248A1 PCT/CN2022/081458 CN2022081458W WO2022194248A1 WO 2022194248 A1 WO2022194248 A1 WO 2022194248A1 CN 2022081458 W CN2022081458 W CN 2022081458W WO 2022194248 A1 WO2022194248 A1 WO 2022194248A1
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cancer
compound
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PCT/CN2022/081458
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French (fr)
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梅德盛
何宝坤
吕仕铭
孙高睿
汪奎
肖程
梁敏
凌欣
刘帅帅
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苏州国匡医药科技有限公司
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Priority to CN202280021932.7A priority Critical patent/CN117157284A/zh
Priority to KR1020237035441A priority patent/KR20230158659A/ko
Priority to EP22770601.7A priority patent/EP4310081A1/en
Priority to JP2023557330A priority patent/JP2024510306A/ja
Publication of WO2022194248A1 publication Critical patent/WO2022194248A1/zh

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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a class of small molecule degraders that can degrade CTLA-4 proteins by inhibiting the interaction between LRBA proteins and CTLA-4 proteins, their preparation methods, pharmaceutical compositions and their uses in medicine.
  • PD-1/PD-L1 inhibitor is one of the most important tumor immune drugs at present, but the clinical response rate is relatively low (10-30%), and it is ineffective for most tumor patients, and new clinical solutions are needed. Combination administration of PD-1/PD-L1 inhibitors with other oncology drugs may be a better strategy.
  • CTLA-4 cytotoxic T lymphocyte-associated protein-4
  • CTLA-4 inhibitors can activate anti-tumor immune responses for tumor immunotherapy.
  • the CTLA-4 inhibitor ipilimumab (Yervoy, "Y" drug) has been used in the treatment of various tumors including melanoma.
  • CTLA-4 and PD-1/PD-L1 coordinately regulate immune response in different stages of tumor immune response: CTLA-4, early and middle stage of tumor immune response; PD-1, late stage of tumor immune response. Therefore, the combined administration of CTLA-4 and PD-1/PD-L1 inhibitors is feasible, and this combined administration strategy has been fully validated in the clinic: for example, the FDA has approved hepatocellular carcinoma, non-small cell lung cancer, etc. 6 a clinical indication.
  • ORR objective response rate of ipilimumab (Yervoy, "Y” drug) and the PD-1 inhibitor nivolumab (OPDIVO, "O" drug) when administered in combination with the "O" drug alone ratio was significantly improved.
  • ORR objective response rate
  • OPDIVO nivolumab
  • the dual immunotherapy combination of drug Y and drug O is the first and currently the only dual immunotherapy approved by the FDA.
  • CTLA-4 inhibitors such as "Y” drugs are antibody drugs, and there are some inherent limitations of this antibody and this type of antibody drugs: 1) The side effects are large, and about 54% of patients with combined use will produce grade 3-4 in clinical practice. The serious side effects (irAEs) associated with immunotherapy greatly limit the clinical use of such drugs, and the side effects are related to the ADCC effect and immunogenicity of antibodies; 2) Difficulty in intratumoral proliferation: CTLA-4 antibody drugs are a major Molecular drugs, it is difficult to infiltrate into solid tumors, which limits the therapeutic effect of single or combined drugs; 3) Poor compliance: CTLA-4 antibody drugs are mainly administered intravenously, subcutaneously or intramuscularly, and cannot be administered orally medication, and poor patient compliance.
  • CTLA-4 small molecule degraders Compared with CTLA-4 monoclonal antibody drugs, CTLA-4 small molecule degraders have their unique advantages: 1) Significantly reduce toxic and side effects: CTLA-4 small molecule degraders achieve the purpose of releasing immunosuppression by degrading CTLA-4 protein, It has no effect on other activities of T cells, and small molecules do not have the ADCC effect and immunogenicity of antibodies, so the side effects will be greatly reduced; 2) It is easy to spread in the tumor: small molecule drugs are more likely to infiltrate into solid tumors, greatly improving single use Or the therapeutic effect of the combination drug; 3) Good compliance: small molecule drugs can be taken orally; 4) Price advantage: the production cost of small molecule drugs is low.
  • CTLA-4 small molecule degraders or small molecule inhibitors there is no development or report of CTLA-4 small molecule degraders or small molecule inhibitors in the world.
  • the present invention provides a new class of small molecule compounds with high degradation activity and high in vivo activity on CTLA-4 for the first time in the world.
  • the present invention provides the following technical solutions:
  • R 1 , R 2 , R 3 , R 6 , R 7 and R 14 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkyne radical, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloheteroalkyl, halogen, -OH, unsubstituted or substituted alkoxy, unsubstituted or substituted arylalkyl, unsubstituted or substituted Arheteroalkyl, unsubstituted or substituted aryl ether, unsubstituted or substituted aryl ether, -CN, -N(R 4 R 5 ), -NO 2 , -N 3 , boronic acid group, Unsubstituted or substituted boronic ester group, carboxyl group, ester group, unsubstitute
  • W is selected from direct bond, unsubstituted or substituted aryl, unsubstituted or substituted aryl hetero, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloheteroalkyl, unsubstituted or substituted bridged ring Alkyl, unsubstituted or substituted bridged cycloheteroalkyl, unsubstituted or substituted spirocycloalkyl, unsubstituted or substituted spirocycloheteroalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkane group, unsubstituted or substituted alkenyl, unsubstituted or substituted heteroalkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted heteroalkynyl, unsubstituted or substituted -N(R 12 R 13
  • W and Q may be linked or fused to form a substituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl or arylheteroyl.
  • At least one of the C, G and I is an N atom.
  • At least one of J, K and M is an N atom.
  • said I, J and K are all N atoms, or I, M and K are all N atoms.
  • each of R 1 , R 2 , R 3 , R 6 , R 7 and R 14 is independently selected from hydrogen, deuterium, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 2 -6 alkenyl, unsubstituted or substituted C 2-6 alkynyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted 3-7 membered cycloheteroalkyl, halogen, -OH, unsubstituted Substituted or substituted C 1-6 alkoxy, unsubstituted or substituted C 6-10 arylethyl, unsubstituted or substituted 5-10-membered arylheteroethyl, unsubstituted or substituted C 6-10 Aryl ether group, unsubstituted or substituted 5-10-membered aryl heteroyl ether group, -CN, -
  • the W is selected from direct bond, substituted or unsubstituted aryl, aryl hetero, cycloalkyl, cycloheteroalkyl, bridged alkyl, bridged heterocycloalkyl, spirocycloalkyl, spiro Cycloheteroalkyl, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, -N(R 12 R 13 ), aminoalkyl, aminoalkylamino, unsubstituted or replaced unsubstituted or substituted
  • the substitution is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkenyl, C 1-6 haloalkynyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, halogen,
  • the W is selected from substituted or unsubstituted 5-7-membered cycloheteroalkyl, substituted or unsubstituted-amino-C 1-6 alkyl, and the substitution is selected from hydrogen, deuterium, halogen , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkenyl, C 1-6 haloalkynyl, C 3- 7 -cycloalkyl, 3-7 membered heterocycloalkyl, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkoxy, -CN, -NH 2 , -NO 2 , -N 3 , Substituents of boronic acid group, carboxyl group, ester group, carboxamide group, C 1-6 alkyl amide group, C 6-10 aryl group, 5-10-membered aromatic hetero group, and
  • the atom connected to the ring containing J and K in the W is N.
  • W is selected from substituted or unsubstituted 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl contains at least one nitrogen atom, more preferably, the 5-7 membered heterocycloalkyl For piperidinyl or piperazinyl.
  • the W and Q can be connected or fused to form a ring, and the ring is a substituted or unsubstituted 5-7 membered cycloalkyl, substituted or unsubstituted 5-7 membered cycloheteroalkyl, substituted or unsubstituted cycloheteroalkyl Substituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl.
  • the substitution is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 halo Alkenyl, C 1-6 haloalkynyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkoxy , -CN, -NH 2 , -NO 2 , -N 3 , boronic acid group, carboxyl group, ester group, carboxamide group, C 1-6 alkyl amido group, C 6-10 aryl group, 5-10-membered aromatic hetero group substituted with the substituents of the alkylamine group and the alkylamine group.
  • the compound of the formula I structure is:
  • C, G, I, J, and K are each independently selected from CR 6 and N, and at least one of C, G, and I is N, and at least one of J and K is N;
  • R 1 , R 2 , R 3 , R 6 , o, m, n, W, Q have the same definitions as above.
  • the compound of the formula I structure is:
  • C, G, I, K, M are each independently selected from CR 6 and N, and at least one of C, G, I is N, and at least one of K and M is N;
  • R 1 , R 2 , R 3 , R 6 , o, m, n, W, Q have the same definitions as above.
  • the present invention reports for the first time in the world a new type of small molecule compound with strong degradation activity to CTLA-4;
  • the compounds of the present invention show good activity on CTLA-4 at the nanomolar (nM) level;
  • the compounds of the present invention have excellent tumor-inhibiting effects in the study of in vivo xenograft tumor models, such as the commonly used MC-38 model for tumor immunity.
  • direct bond means that two atoms or groups connected to a direct bond are directly connected by a chemical bond, preferably, the chemical bond includes a single bond and a double bond.
  • substituted is substituted with the following substituents: alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, boronic acid, boronic ester, phosphine Ester, ester, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkanoyl ylthio, arylthio, arylalkylthio, arylthiocarbonyl, aryo, alkanoyl ylthio, ary
  • alkyl or “alkylene” are both intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms.
  • C 1-6 alkyl means an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl) and Pentyl (eg n-pentyl, isopentyl, neopentyl).
  • heteroalkyl or “alkheteroyl” means that 1-4 carbon atoms on the alkyl group are substituted by heteroatoms, preferably, 1-3 carbon atoms on the alkyl group are substituted by heteroatoms, more Preferably, 1-2 carbon atoms on the alkyl group are substituted by heteroatoms; preferably, the alkyl group before being substituted by a heteroatom is a C 2-10 alkyl group, more preferably, the alkyl group before being substituted by a heteroatom is a C 2-6 alkyl group; the substitution position of the heteroatom can be the terminal position of the alkyl group or the middle position of the alkyl group, and the heteroatom is independently selected from N, O, S, P and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length.
  • C 2-6 alkenyl contains two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, hexenyl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and usually 2 to 20 carbon atoms in length.
  • C2-6alkynyl contains two to six carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, pentynyl, hexynyl, and the like.
  • heteroalkenyl means that one or more carbon atoms in “alkenyl” as defined above are replaced by a heteroatom selected from N, O, S, or by a group containing a heteroatom selected from N, O, S replaced.
  • heteroalkynyl means that one or more carbon atoms in “alkynyl” as defined above are replaced by a heteroatom selected from N, O, S, or by a group containing a heteroatom selected from N, O, S replaced.
  • alkoxy refers to -O-alkyl.
  • C 1-10 alkoxy (or alkyloxy) is intended to include C 1 -C 10 alkoxy.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (such as n-propoxy and isopropoxy), and tert-butoxy, while the alkoxy may have multiple oxygen atoms in it Such as 1-10 oxygen atoms.
  • alkylthio or “thioalkoxy” represents an alkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, methyl-S- and ethyl-S-.
  • ester group is intended to include carboxylate, phosphate, phosphite, silicate, borate, and the like, eg -COOR,B(OR) 2 , where R is an alkyl group.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • the monocyclic cyclic alkyl group refers to a C 3-8 cyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • Bicyclic cyclic alkyl groups include bridged, spiro or fused ring cycloalkyl groups.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group.
  • Monocyclic cyclic alkenyl refers to C 3-8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl”.
  • Bicyclic cyclic alkenyl groups include bridged, spiro or fused ring cyclic alkenyl groups.
  • Halo or halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups” which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms and substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group, as defined above, having the indicated number of carbon atoms attached through an oxygen bridge.
  • C1-6 haloalkoxy is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy.
  • Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” represents a haloalkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, trifluoromethyl-S- and pentafluoroethyl -S-.
  • aryl refers to groups having a total of 6 to 10
  • aryl refers to an aromatic ring system including, but not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl.
  • a fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. For example, an arrowed line drawn from a ring system indicates that a bond may be attached to any suitable ring atom.
  • heteroaryl /"heteroarylene, “heteroaryl ring”, “arheterylene”, “heteroaryl”, “heteroaryl” or “heteroaryl” means stable 3-membered, 4-membered, 5-membered, or 7-membered aromatic monocyclic or aromatic bicyclic ring or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14-membered aromatic polycyclic heterocycle, It is fully unsaturated, partially unsaturated, and it contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups , where any of the heterocycles defined above are fused to a benzene ring.
  • Nitrogen and sulfur heteroatoms can optionally be oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or, if defined, another substituent). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogens in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one.
  • aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxanyl azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] tetrahydrofuranyl, furanyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-
  • heterocycloalkyl and “cycloheteroalkyl” as used herein refer to a monocyclic heterocycloalkyl system, or to a bicyclic heterocycloalkyl system.
  • Monocyclic heterocycloalkyl refers to 3-12 members (preferably 3-8 members, more preferably 5-7 members), and contains at least one saturated or unsaturated selected from O, N, S, P, but not Aromatic cyclic alkyl system.
  • Bicyclic heteroalkyl systems refer to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a cycloheteroalkyl group, or a heteroaryl group.
  • heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl , thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, 1,4-diazaalkyl, etc.
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group of any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocycloalkyl refers to polycyclic compounds that share two or more carbon atoms or heteroatoms
  • the " Bridged heterocycloalkyl”, “heterobridged cycloalkyl” and “bridged cycloheteroalkyl” contain at least one heteroatom selected from O, N, S, P and the like.
  • bicyclic heterobridged cycloalkyl and polycyclic heterobridged cycloalkyl, the former is composed of two alicyclic rings sharing more than two carbon atoms or heteroatoms; the latter is a heterobridge composed of three or more rings Cycloalkyl.
  • spirohydrocarbon and "spirocycloalkyl” as used herein refer to polycyclic hydrocarbons and polycyclic alkyl groups in which a single carbon atom (called a spiro atom) is shared between single rings.
  • spirocyclic heteroalkyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen , oxygen, and heteroatoms of sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl.
  • tautomers refer to those having different energies that can be interconverted through a low energy barrier structural isomers. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
  • proton tautomers include, but are not limited to, interconversion by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, Amide-imino alcohol isomerization, etc.
  • Stepoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like. Unless otherwise indicated, all tautomeric, stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and the substitution results in a stable compound.
  • nitrogen atoms eg, amines
  • these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (eg, mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention .
  • oxidizing agents eg, mCPBA and/or hydrogen peroxide
  • both shown and claimed nitrogen atoms are considered to encompass the shown nitrogen and its N-oxide (N ⁇ O) derivatives.
  • any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at each other occurrence.
  • the group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R.
  • substituents and/or variables are only permissible if such combinations result in stable compounds.
  • amino /"amine group
  • C 1-6 alkylamino alone or in combination denotes an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one C 1-6 alkyl , wherein "alkyl " means as defined above, correspondingly, "C 1-6 alkylamino” includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutyl amino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3 -Methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamine group, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino,
  • (C 1-6 alkyl) 2 amine group alone or in combination denotes an amine group as defined above, wherein the hydrogen atom of the amino group is replaced by two C 1-6 alkyl groups, wherein ""Alkyl” means as defined above, and accordingly, “(C 1-6 alkyl) 2amino " includes dimethylamino, diethylamino, methylethylamino, and the like.
  • amino acid residue refers to that the carbon-terminal carboxyl or amine group of an amino acid participates in the formation of a bond and loses a molecule of water, and this amino acid unit is called an amino acid residue.
  • [Cu] refers herein to a copper (Cu + ) or copper - divalent (Cu2 + ) containing reagent such as CuI, CuBr, CuCl, CuI2 , CuBr2 , CuCl2, and the like.
  • isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Therefore, the single stereochemical isomers of the compounds contemplated in the present invention or their enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) Mixtures are within the scope of the present invention.
  • pharmaceutically acceptable salts refer to derivatives of compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali metal or organic salts of acidic groups such as carboxylic acids.
  • Pharmaceutically acceptable salts include conventional nontoxic or quaternary ammonium salts of the parent compound formed from, for example, nontoxic inorganic or organic acids.
  • the conventional non-toxic salts described above include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; and salts prepared from organic acids such as acetic, propionic, succinic , glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2 -Acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid, etc.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids
  • organic acids such as acetic
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods.
  • the above salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two; usually, such as diethyl ether, ethyl acetate, ethanol, Non-aqueous media such as isopropanol or acetonitrile.
  • a suitable salts can be found in Remington: The Science and Practice of Pharmacy, 22nd Edition, 25 Allen, L.V.Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosures of which are incorporated herein by reference .
  • solvate means a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. Solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate” encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • esters are used to refer to organic esters, including monoesters, diesters, triesters, and more generally polyesters.
  • isotopic derivatives refers to isotopic derivatives obtained by replacing the hydrogen atom in the general formula (I) with 1-6 deuterium atoms (D), and the carbon atom in the general formula (I) by 1-3 carbon atoms. Isotopic derivatives obtained by substitution of atom (14C).
  • treating includes any effect that results in amelioration of a condition, disease, disorder, etc., eg, alleviation, reduction, modulation, amelioration or elimination, or amelioration of symptoms thereof.
  • composition refers to the combination of an active agent with an inert or active carrier, making the composition particularly suitable for use in in vivo or ex vivo diagnosis or therapy.
  • bases include, but are not limited to, alkali metal (eg, sodium) hydroxides, alkaline earth metal (eg, magnesium) hydroxides, ammonia, and the like.
  • salts of compounds of the present invention For therapeutic use, salts of compounds of the present invention are intended to be pharmaceutically acceptable.
  • non-pharmaceutically acceptable salts of acids and bases can also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.
  • cancer refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, is capable of metastasizing (spreading).
  • This type of cancer includes, but is not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).
  • the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (I) formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally One or more of the other therapeutic agents described above.
  • the compounds of the present invention may be administered for any of the above-mentioned uses by any suitable means, eg orally, such as tablets, capsules (each including sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques ( For example, in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to nasal membranes, such as by inhalation spray; topical, such as in creams or ointments; or rectally, such as in suppositories form. They can be administered alone, but are usually administered using a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.
  • Such carriers may include many different ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binders, and the like.
  • suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources such as Allen, L.V.Jr.et.al.Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.
  • dosage regimens for the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient. nature and extent of symptoms; type of concomitant treatment; frequency of treatment; route of administration, renal and hepatic function of the patient, and desired effect.
  • the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably, when used for the indicated effect Typically from about 0.1 mg/day to about 600 mg/day.
  • the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are usually in the form of suitable pharmaceutical diluents, excipients or carriers (herein) appropriately selected according to the intended form of administration (eg, oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practice. are administered in the form of a mixture of drug carriers).
  • Dosage forms suitable for administration may contain from about 0.1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.
  • a typical injectable formulation can be prepared by aseptically placing at least one compound of the invention (250 mg) in a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.
  • compositions comprising, either alone or in combination with a pharmaceutical carrier, a therapeutically effective amount of at least one compound of the present invention as an active ingredient.
  • the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).
  • the compounds of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient, without being toxic to the patient.
  • the dose level selected will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors well known in the medical arts such as age, sex, weight, condition, general health and previous medical history of the patient being treated.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition.
  • a physician or veterinarian may initiate a dose of a compound of the present invention used in a pharmaceutical composition at a level below that required and gradually increase the dose until the desired effect is achieved.
  • a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend on the factors discussed above.
  • oral, intravenous, intramuscular, intracerebroventricular and subcutaneous doses of the compounds of the invention for patients will range from about 0.01 to about 1000 mg/kg body weight/day.
  • an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form.
  • the dosing is once a day.
  • composition may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical formulation (composition).
  • the present invention provides a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, deuterated compound, isomer, solvate, prodrug or isotopic label thereof:
  • R 1 , R 2 , R 3 , R 6 , R 7 and R 14 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkyne radical, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloheteroalkyl, halogen, -OH, unsubstituted or substituted alkoxy, unsubstituted or substituted arylalkyl, unsubstituted or substituted Arheteroalkyl, unsubstituted or substituted aryl ether, unsubstituted or substituted aryl ether, -CN, -N(R 4 R 5 ), -NO 2 , -N 3 , boronic acid group, Unsubstituted or substituted boronic ester group, carboxyl group, ester group, unsubstitute
  • the adjacent two R 1 and/or the adjacent two R 3 can also be connected to form a cycloalkyl, cycloheteroalkyl, aryl or heteroaryl;
  • n, and o are each independently selected from an integer from 0 to 4.
  • W is selected from direct bond, unsubstituted or substituted aryl, unsubstituted or substituted aryl hetero, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloheteroalkyl, unsubstituted or substituted bridged ring Alkyl, unsubstituted or substituted bridged cycloheteroalkyl, unsubstituted or substituted spirocycloalkyl, unsubstituted or substituted spirocycloheteroalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkane group, unsubstituted or substituted alkenyl, unsubstituted or substituted heteroalkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted heteroalkynyl, unsubstituted or substituted -N(R 12 R 13
  • W and Q may be linked or fused to form a substituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl or arylheteroyl.
  • At least one of C, G, and I is an N atom, for example, any one of C, G, and I is an N atom, or any two of C, G, and I are N atoms (ie, C and G is an N atom, or C and I are N atoms, or G and I are N atoms), or C, G, and I are all N atoms.
  • At least one of J, K and M is an N atom, for example, J is an N atom or K is an N atom, or both J and K are N atoms.
  • the I, J, and K are all N atoms, or, or I, M, and K are all N atoms.
  • each of R 1 , R 2 , R 3 , R 6 , R 7 and R 14 is independently selected from hydrogen, deuterium, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 2 -6 alkenyl, unsubstituted or substituted C 2-6 alkynyl, unsubstituted or substituted C 3-7 cycloalkyl, unsubstituted or substituted 3-7 membered cycloheteroalkyl, halogen, -OH, unsubstituted Substituted or substituted C 1-6 alkoxy, unsubstituted or substituted C 6-10 arylethyl, unsubstituted or substituted 5-10-membered arylheteroethyl, unsubstituted or substituted C 6-10 Aryl ether group, unsubstituted or substituted 5-10-membered aryl heteroyl ether group, -CN, -
  • the W is selected from the group consisting of direct bond, substituted or unsubstituted aryl, aryl hetero, cycloalkyl, cycloheteroalkyl, bridged cycloalkyl, bridged cycloheteroalkyl, spirocycloalkyl, spiro Cycloheteroalkyl, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, -N(R 12 R 13 ), aminoalkyl, aminoalkylamino, unsubstituted or replaced unsubstituted or substituted
  • the substitution is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkenyl, C 1-6 haloalkynyl, C 3-7 cycloalkyl, 3-7 membered
  • the W is selected from substituted or unsubstituted 5-7-membered cycloheteroalkyl, substituted or unsubstituted-amino-C 1-6 alkyl, and the substitution is selected from hydrogen, deuterium, halogen , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkenyl, C 1-6 haloalkynyl, C 3- 7 -cycloalkyl, 3-7 membered heterocycloalkyl, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkoxy, -CN, -NH 2 , -NO 2 , -N 3 , Substituents of boronic acid group, carboxyl group, ester group, carboxamide group, C 1-6 alkyl amide group, C 6-10 aryl group, 5-10-membered aromatic hetero group, and
  • the atom connected to the ring containing J and K in the W is N.
  • W is selected from substituted or unsubstituted 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl contains at least one nitrogen atom, more preferably, the 5-7 membered heterocycloalkyl For piperidinyl or piperazinyl.
  • the W and Q can be connected or fused to form a ring, and the ring is a substituted or unsubstituted 5-7 membered cycloalkyl, substituted or unsubstituted 5-7 membered cycloheteroalkyl, substituted or unsubstituted cycloheteroalkyl Substituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl.
  • the substitution is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 halo Alkenyl, C 1-6 haloalkynyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, halogen, -OH, C 1-6 alkoxy, C 1-6 haloalkoxy , -CN, -NH 2 , -NO 2 , N 3 , boronic acid group, carboxyl group, ester group, carboxamide group, C 1-6 alkyl amido group, C 6-10 aryl group, 5-10-membered aromatic hetero group , substituted by the substituents of alkylamine groups.
  • the compound of the formula I structure is:
  • C, G, I, J, and K are each independently selected from CR 6 and N, and at least one of C, G, and I is N, and at least one of J and K is N;
  • R 1 , R 2 , R 3 , R 6 , o, m, n, W, Q have the same definitions as above.
  • the compound of the formula I structure is:
  • C, G, I, K, M are each independently selected from CR 6 and N, and at least one of C, G, I is N, and at least one of K and M is N;
  • R 1 , R 2 , R 3 , R 6 , o, m, n, W, Q have the same definitions as above.
  • the present invention also provides the following compounds or their pharmaceutically acceptable salts, esters, deuterated compounds, isomers, solvates, prodrugs or isotopic labels, the compounds are selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above-mentioned compounds or pharmaceutically acceptable salts, esters, deuterated compounds, isomers, solvates, prodrugs or isotopic labels thereof, and Pharmaceutically acceptable excipients.
  • the pharmaceutical composition is in the form of aqueous dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release agents, fast solvents, foams Any of bolus, lyophilized, tablet, powder, pill, sugar-coated finish, capsule, delayed release, prolonged release, pulsatile controlled release, multiparticulate or immediate release.
  • the present invention also provides any of the above-mentioned compounds or pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotopic labels thereof, or any of the above-mentioned pharmaceutical compositions in the preparation of treatment Medications for CTLA-4-related diseases.
  • the CTLA-4 related disease includes cancer, autoimmune disease, immunodeficiency disease, viral infection, organ transplant rejection.
  • the cancer is selected from the group consisting of skin cancer, bladder cancer, breast cancer, pancreatic cancer, bone cancer, brain cancer, neurocytoma, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, Tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, choriocarcinoma, pancreatic cancer, urinary cancer, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma Tumors and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), gallbladder cancer, bronchial cancer , multiple myeloma, basal cell tumor, teratoma, retino
  • the unit in the weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of the solute in 100 ml of the solution.
  • the organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by flash column chromatography.
  • Example 1 In addition to replacing piperidin-4-ylmethanamine in Example 1 with tert-butyl piperazine-1-carboxylate, and replacing it with 3-(2-chloro-6-methoxypyrimidin-4-yl)quinoline
  • Example 1 in addition to 3-(2-chloropyrimidin-4-yl)quinoline, 4-(4-methoxy-6-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxyl
  • the synthesis of acid tert-butyl ester is the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine in Example 1. Yield 55%.
  • 3-(2-Chloro-5-methoxypyrimidin-4-yl)quinoline was used in place of Example 1, except that piperazine-1-carboxylate tert-butyl ester was used in place of piperidin-4-ylmethanamine in Example 1.
  • the synthesis of butyl ester is the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine in Example 1. The yield was 68%.
  • 3-(2-Chloro-5-cyclopropylpyrimidin-4-yl)quinoline was used in place of Example 1, except that piperazine-1-carboxylate tert-butyl ester was used in place of piperidin-4-ylmethanamine in Example 1.
  • 4-(5-cyclopropyl-4-(quinolin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tertiary The synthesis of butyl ester is the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine in Example 1. The yield was 79%.
  • 3-(2-chloropyrimidine was replaced by 3-(6-chloro-5-methylpyrimidin-4-yl)quinoline, except piperazine-1-carboxylate tert-butyl ester was used instead of piperidin-4-ylmethanamine -4-yl)quinoline, and replacing DIPEA with TEA, 4-(5-methyl-6-(quinolin-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester
  • the synthesis was the same as that of (1-(4-(quinolin-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine in Example 1. The yield was 89%.
  • HEK293 cells were plated on 96-well plates, and LRBA and CTLA-4 reporter system were co-transfected into HEK293 cells after 24 h, and the final concentrations were 0.01, 0.033, 0.10, 0.33, 1.00, 3.33, 10.00, 33.33, and 100.00 after 24 h, respectively. ⁇ M of different compounds. 24 hours after dosing, the cell culture medium was removed and the cells were washed with cold PBS, and then the activity of the compound was detected by a dual-luciferase detection kit, and IC 50 was calculated according to the detection result.
  • IC50 The concentration of compound that inhibits 50% of the activity of the reporter system
  • IC 50 sizes are divided into four levels:
  • the IC 50 of the compounds of the present invention is shown in Table 1 below.
  • Cell culture Mouse colon cancer MC-38 cells were adherently cultured in vitro, and the culture conditions were RPMI-1640 medium with 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, 5% at 37°C CO 2 incubator culture. Passages are routinely processed two to three times a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cell count is collected, and the cell concentration is adjusted for experimental inoculation.
  • mice C57BL/6 mice, female, 7 weeks old, weighing 18-20 grams, 8 mice in each group.
  • Tumor inoculation 0.02 mL (0.2 ⁇ 10 6 cells) of MC-38 cells were subcutaneously inoculated on the right back of each mouse. On the 7th day after inoculation, the tumor volume of the animals was measured, and then the groups were randomized according to tumor volume and dosing started.
  • TGI (%) [(1-(average tumor volume at the end of administration of a certain treatment group - average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment in the solvent control group Volume - the average tumor volume of the solvent control group at the beginning of treatment)] ⁇ 100%.

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Abstract

一种CTLA-4小分子降解剂及其应用，所述CTLA-4小分子降解剂具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物：一类对CTLA-4具有高降解活性的新型小分子化合物，所述化合物在体外研究中，对CTLA-4在纳摩尔(nM)水平即显示出良好的降解活性。

Description

CTLA-4小分子降解剂及其应用 技术领域
本发明属于医药化学领域，具体地涉及一类通过抑制LRBA蛋白和CTLA-4蛋白相互作用从而导致CTLA-4蛋白降解的小分子降解剂、其制备方法、药物组合物以及在医药方面的用途。
背景技术
PD-1/PD-L1抑制剂是目前最重要的肿瘤免疫类药物之一，但是临床反应率比较低(10-30％)，对于大部分肿瘤患者无效，临床需新的解决方案。PD-1/PD-L1抑制剂与其它肿瘤治疗药物进行联合给药，可能是较好策略。
CTLA-4(细胞毒性T淋巴细胞相关蛋白-4)是一种蛋白受体，其作为免疫检查点起作用并下调免疫应答。它在T细胞，尤其调节性T细胞中组成型高表达，当与抗原呈递细胞表面上的CD80或CD86结合时，起到“关闭”开关的作用。CTLA-4抑制剂可以激活抗肿瘤免疫反应，用于肿瘤的免疫治疗。CTLA-4抑制剂伊匹木单抗(Yervoy，“Y”药)已经用于黑色素瘤等多种肿瘤的治疗。
考虑到CTLA-4和PD-1/PD-L1于肿瘤免疫反应不同阶段协同调控免疫反应：CTLA-4，肿瘤免疫反应早中期阶段；PD-1，肿瘤免疫反应后期阶段。所以CTLA-4与PD-1/PD-L1抑制剂联合给药是可行的，并且此联合给药策略已在临床中获得充分验证：如FDA已经批准了肝细胞癌、非小细胞肺癌等6个临床适应症。如伊匹木单抗(Yervoy，“Y”药)与PD-1抑制剂纳武单抗(OPDIVO，“O”药)联合给药时客观缓解率(ORR)与“O”药单药相比，得到显著提高。Y药与O药的双免疫治疗组合，是首个也是目前唯一获得FDA批准的双免疫疗法。
Figure PCTCN2022081458-appb-000001
但目前的CTLA-4抑制剂如“Y”药等是抗体药物，该抗体及该类抗体药物存在一些固有局限性：1)副作用大，临床上54％左右联用患者会产生3-4级免疫治疗相关的严重副作用(irAEs)，极大限制了此类药物的临床使用，同时该副作用作用与抗体的ADCC作用和免疫原性有关；2)瘤内扩散难：CTLA-4抗体药物作为大分子药物，实体瘤内浸润比较困难，限制了单用或者联合用药的治疗效果；3)依从性差：CTLA-4 抗体药物的给药方式以静脉、皮下或者肌肉注射给药为主，无法口服给药，患者依从性差。
与CTLA-4单抗类药物而言，CTLA-4小分子降解剂具有其独特优势：1)显著减少毒副作用：CTLA-4小分子降解剂通过降解CTLA-4蛋白达到解除免疫抑制的目的，本身对T细胞其它活性没有影响，并且小分子没有抗体的ADCC作用和免疫原性，因此副作用会大大降低；2)瘤内易扩散：小分子药物较容易浸润到实体瘤内，大大提高单用或者联合用药的治疗效果；3)依从性好：小分子药物可以口服用药；4)价格优势：小分子药物生产成本低。
但是目前在全球范围内，尚未有CTLA-4小分子降解剂或小分子抑制剂的开发或报道。
发明内容
发明要解决的问题
为了解决上述技术问题，本发明在全球范围内首次提供了一类对CTLA-4具有高降解活性和高体内活性的新型小分子化合物。
用于解决问题的方案
为了解决上述技术问题，本发明提供了以下技术方案：
一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物：
Figure PCTCN2022081458-appb-000002
其中，
A、B、C、D、E、F、G、H、I、J、K、L和M各自独立地选自直连键、CR 6、CR 6R 14、N、NR 7、O、S和C＝O；
每一个R 1、R 2、R 3、R 6、R 7和R 14各自独立地选自氢、氘、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的炔基、未取代或取代的环烷基、未取代或取代的环杂烷基、卤素、-OH、未取代或取代的烷氧基、未取代或取代的芳基烷基、未取代或取代的芳杂基烷基、未取代或取代的芳基醚基、未取代或取代的芳杂基醚基、-CN、-N(R 4R 5)、-NO 2、-N 3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲酰基、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的硫醚基、未取代或取代的亚砜基、未取代或取代的砜基、未取代或取代的磺酰胺基、
Figure PCTCN2022081458-appb-000003
未取代或取代的膦酸酯基，其中R 4、R 5、R 8、R 9、R 10和R 11各自独立地选自氢、氘、未取代或取代的C 1-6烷基、C 3-7环烷基、未取代或取代的芳基、未取代或取代的芳杂基，且R 4和R 5、R 8和R 9可与相邻的氮原子或碳原子连接成环；或相邻的两个R 1和/或相邻的两个R 3也可连接成环烷基、环杂烷基、芳基或芳杂基；m、n、o各自独立地选自0～4的整数；
W选自直连键、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的环烷基、未取代或取代的环杂烷基、未取代或取代的桥环烷基、未取代或取代的桥环杂烷基、未取代或取代的螺环烷基、未取代或取代的螺环杂烷基、未取代或取代的烷基、未取代或取代的杂烷基、未取代或取代的烯基、未取代或取代的杂烯基、未取代或取代的炔基、未取代或取代的杂炔基、未取代或取代的-N(R 12R 13)、未取代或取代的胺基烷基、未取代或取代的胺基烷基胺基、未取代或取代的
Figure PCTCN2022081458-appb-000004
未取代或取代的
Figure PCTCN2022081458-appb-000005
其中R 12和R 13各自独立地选自氢、氘、C 1-6烷基、C 3-7环烷基、未取代或取代的烷基胺基、未取代或取代的芳基、取代或未取代的芳杂基，或R 12和R 13可连接成环；
Q为-H、-NH 2、-OH、-烷基-NHC(＝O)H、环烷基、未取代或取代的烷基酰基、未取代或取代的烷基羟基、未取代或取代的烯基羟基、未取代或取代的炔基羟基、未取代或取代的烷基胺基、未取代或取代的磺酰胺基、未取代或取代的烷基磺酰胺基、氨基酸残基、
Figure PCTCN2022081458-appb-000006
磺酰胺基、磺酰肼基、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的
Figure PCTCN2022081458-appb-000007
未取代或取代的
Figure PCTCN2022081458-appb-000008
取代或未取代的-(CH 2) n1-(M) n2-(CH 2) n3-(M) n4-(CH 2) n5-(M) n6，其中每个M各自独立地选自O、OH、S、SO、SO 2和未取代或取代的胺基，每个n1、n2、n3、n4、n5和n6各自独立地选自0-6的整数；
或W和Q可以连接或融合成取代或非取代的环烷基、环杂烷基、芳基或芳杂基。
优选的，所述C、G、I中至少一个为N原子。
优选的，所述J、K、M中至少一个为N原子。
优选的，所述I、J、K均为N原子，或I、M、K均为N原子。
优选的，每一个R 1、R 2、R 3、R 6、R 7和R 14各自独立地选自氢、氘、未取代或取代的C 1-6烷基、未取代或取代的C 2-6烯基、未取代或取代的C 2-6炔基、未取代或取代的C 3-7环烷基、未取代或取代的3-7元环杂烷基、卤素、-OH、未取代或取代的C 1-6烷氧基、未取代或取代的C 6-10芳基乙基、未取代或取代的5-10元芳杂基乙基、未取代或取代的C 6-10芳基醚基、未取代或取代的5-10元芳杂基醚基、-CN、-NH 2、-NO 2、-N 3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲酰基、未取代或取代的C 6-10芳基、未取代或取代的5-10元芳杂基、未取代或取代的硫醚基、未取代或取代的亚砜基、未取代或取代的 砜基、未取代或取代的磺酰胺基、
Figure PCTCN2022081458-appb-000009
未取代或取代的膦酸酯基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W选自直连键、取代或非取代的芳基、芳杂基、环烷基、环杂烷基、桥烷基、桥环杂环烷基、螺环烷基、螺环杂烷基、烷基、杂烷基、烯基、杂烯基、炔基、杂炔基、-N(R 12R 13)、胺基烷基、胺基烷基胺基、未取代或取代的
Figure PCTCN2022081458-appb-000010
未取代或取代的
Figure PCTCN2022081458-appb-000011
所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W选自取代或非取代的5-7元环杂烷基、取代或非取代的-胺基-C 1-6烷基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W中与含J、K的环相连的原子为N。
优选的，W选自取代或非取代的5-7元环杂烷基，所述5-7元杂环烷基至少包含一个氮原子，更优选的，所述5-7元杂环烷基为哌啶基或哌嗪基。
优选的，所述Q为-H、-NH 2、-OH、-C 1-6烷基-HNC(＝O)H、未取代或取代的C 1-6烷基羟基、未取代或取代的C 2-6烯基羟基、未取代或取代的C 2-6炔基羟基、未取代或取代的烷基胺基、磺酰胺基和磺酰肼基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W和Q可以连接或融合成环，所述环为取代或非取代的5-7元环烷基、取代或非取代的5-7元的环杂烷基、取代或非取代的C 6-10芳基、取代或非取代的5-10元芳杂基。
更优选的，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述式Ⅰ结构的化合物为：
Figure PCTCN2022081458-appb-000012
其中，C、G、I、J、K各自独立地选自CR 6和N，且C、G、I中至少一个为N，J和K中至少一个为N；R 1、R 2、R 3、R 6、o、m、n、W、Q的定义和上述定义相同。
优选的，所述式Ⅰ结构的化合物为：
Figure PCTCN2022081458-appb-000013
其中，C、G、I、K、M各自独立地选自CR 6和N，且C、G、I中至少一个为N，K和M中至少一个为N；R 1、R 2、R 3、R 6、o、m、n、W、Q的定义和上述定义相同。
发明的效果
1、本发明在全球范围内首次报道了一类对CTLA-4具有强降解活性的新型小分子化合物；
2、本发明所述化合物在体外研究中，对CTLA-4在纳摩尔(nM)水平即显示出良好活性；
3、本发明所述化合物如化合物18等在体内移植瘤模型如肿瘤免疫常用MC-38模型研究中，具有优秀的抑瘤效果。
具体实施方式
为了更为清晰地描述本发明的内容，现将所涉及的全部术语定义如下：
本文中使用的术语“直连键”指的是与直连键相连的两个原子或基团直接通过化学键相连，优选的，所述化学键包括单键和双键。
除非另有定义，本文使用的术语“取代”是被下列取代基所取代：烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、硼酸基、硼酸酯、膦酸酯、酯基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基(其中2个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO 2NH 2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH 2、取代 的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”均意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如，“C 1-6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。
术语“杂烷基”或“烷杂基”是指烷基上的1-4个碳原子被杂原子所取代，优选的，烷基上的1-3个碳原子被杂原子所取代，更优选的，烷基上的1-2个碳原子被杂原子所取代；优选的，被杂原子取代前的烷基为C 2-10烷基，更优选的，被杂原子取代前的烷基为C 2-6烷基；杂原子取代的位置可以为烷基的端位，也可以为烷基的中间位置，所述杂原子分别独立地选自N、O、S、P等。
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C 2-6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、己烯基等。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C 2-6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基、戊炔基、己炔基等。
术语“杂烯基”表示上述定义的“烯基”中的一个或多个碳原子被选自N、O、S的杂原子替换，或者被含有选自N、O、S的杂原子基团所取代。
术语“杂炔基”表示上述定义的“炔基”中的一个或多个碳原子被选自N、O、S的杂原子替换，或者被含有选自N、O、S的杂原子基团所取代。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C 1-10烷氧基”(或烷基氧基)意欲包括C 1-C 10的烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基，同时烷氧基中可以带有多个氧原子如1-10个氧原子。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。
术语“羰基”和“酰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“酯基”是包括羧酸酯基、磷酸酯基、亚磷酸酯基、硅酸酯基、硼酸酯基等，例如-COOR，B(OR) 2,其中R为烷基。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指C 3-8的环状烷基，包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基等。支化环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或融合环的环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指C 3-8的环状烯基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或融合环的环状烯基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。 例如，“C 1-6卤代烷氧基”意欲包括C1、C2、C3、C4、C5和C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。
术语“芳基”/“亚芳基”，单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有总计6至10个环成员的单环、二环或三环的环系统，其中所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。在本发明的某些实施方案中，“芳基”是指芳族环系统，其包括但不限于苯基、茚满基、1-萘基、2-萘基和四氢萘基。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例如从环系统中画出的箭头线表明键可连接至任意合适的环原子。
术语“杂芳基”/“亚杂芳基”、“杂芳环”、“亚芳杂基”、“芳杂基”、“杂芳环基”或“杂芳环基团”意指稳定的3元、4元、5元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元、13元或14元芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。芳杂环的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲25哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”和“环杂烷基”指的是一个单环杂环烷基体系，或为一个二环杂环烷基体系。单环的杂环烷基指的是3-12元(优选3-8元，更优选5-7元)、且至少含一个选自O、N、S、P的饱和或 不饱和但不为芳香性的环状烷基体系。二环杂烷基体系指的是一个杂环烷基融合到一个苯基、或一个环烷基、或一个环烯基、或一个环杂烷基、或一个杂芳基。所述杂环烷基包括但不限于氮丙啶基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、四氢吡喃基、1,1-二氧硫代吗啉基、1,4-二氮烷基等。
本文使用的术语“桥环烷基”指的是5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。
本文使用的术语“桥杂环烷基”、“杂桥环烷基”和“桥环杂烷基”指的是共用两个或两个以上碳原子或杂原子的多环化合物，所述“桥杂环烷基”、“杂桥环烷基”和“桥环杂烷基”至少含一个选自O、N、S、P等的杂原子。可分为二环杂桥环烷基及多环杂桥环烷基，前者由两个脂环共用两个以上碳原子或杂原子所构成；后者是由三个以上的环组成的杂桥环烷基。
本文使用的术语“螺环烃”、“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃、多环烷基。
本文使用的术语“螺环杂烷基”指的是5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
本文中使用的术语“异构体”中包括了“互变异构体”、“立体异构体”等，“互变异构体”指的是具有不同能量的，可通过低能垒互相转化的结构异构体。若互变异构是可能的(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(或称质子转移互变异构体)包括但不限于通过质子迁移来进行的互相转化，如酮-烯醇异构化、亚胺-烯胺异构化、酰胺-亚胺醇异构化等。“立体异构体”指的是具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何(顺/反)异构体、阻转异构体，等等。除非另外指出，本发明的化合物的所有互变异构体、立体异构体形式都在本发明的范围之内。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C＝C、C＝N或N＝N)。
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物(N→O)衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
当键合至取代基的键显示为与连接环中的两个原子的键交叉时，则上述取代基可键合至该环上的任一 原子。当列举取代基但未指明该取代基中键合至具有给定式的化合物的其余部分上的原子时，则上述取代基可经由该取代基中的任一原子来键合。取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
术语“氨基”/“胺基”单独或者以组合方式表示伯胺基(-NH 2)，仲胺基(-NH-)或叔胺基(
Figure PCTCN2022081458-appb-000014
Figure PCTCN2022081458-appb-000015
等)等。
术语“C 1-6烷基胺基”单独或者以组合方式表示如上所定义的胺基基团，其中胺基基团的氢原子被至少一个C 1- 6烷基所取代，其中“烷基”表示如以上所定义，相应地，“C 1-6烷基胺基”包括甲基胺基、乙基胺基、丙基胺基、异丙基胺基、正丁基胺基、异丁基胺基、2-丁基胺基、叔丁基胺基、正戊基胺基、2-戊基胺基、3-戊基胺基、2-甲基-2-丁基胺基、3-甲基-2-丁基胺基、3-甲基-1-丁基胺基、2-甲基-1-丁基胺基、正己基胺基、2-己基胺基、3-己基胺基、2-甲基-2-戊基胺基、3-甲基-2-戊基胺基、4-甲基-2-戊基胺基、3-甲基-3-戊基胺基、2-甲基-3-戊基胺基、2,3-二甲基-2-丁基胺基、3,3-二甲基-2-丁基胺基等。特别的“C 1-6烷基胺基”是甲基胺基、乙基胺基、异丙基胺基、叔丁基胺基等。
术语“(C 1-6烷基) 2胺基”单独或者以组合方式表示如上所定义的胺基基团，其中氨基基团的氢原子被两个C 1- 6烷基所取代，其中“烷基”表示如以上所定义，相应地，“(C 1-6烷基) 2胺基”包括二甲胺基、二乙胺基、甲基乙基胺基等。
本文使用的术语“氨基酸残基”指的是一个氨基酸的碳端羧基或胺基参与了键的形成而失去一分子水，此氨基酸单位称为氨基酸残基。
本文使用的术语“[Cu]”在本文中指的是含一价铜(Cu +)或二价铜(Cu 2+)试剂，如CuI、CuBr、CuCl、CuI 2、CuBr 2、CuCl 2等。
术语“异构体”包含所有的同分异构形式包括对映异构体、非对映异构体、互变异构体和几何异构体(包括顺反异构体)。因此，本发明中所设计的化合物的单个立体化学异构体或其对映异构体、非对映异构体、互变异构体或几何异构体(或顺反异构体)的混合物都属于本发明的范围。
本文使用的“药学上可接受的盐”是指本发明化合物的衍生物，其中母体化合物通过制备其酸或碱盐来修饰。药用盐的实例包括但不限于碱性基团(诸如胺)的无机或有机酸盐；及酸性基团(诸如羧酸)的碱金属盐或有机盐。药用盐包括由(例如)无毒的无机或有机酸形成的母体化合物的常规无毒盐或季铵盐。例如，上述常规无毒盐包括衍生自例如以下无机酸的那些：盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸；及由例如以下有机酸制备的盐：乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、苯磺酸、甲磺酸、乙二磺酸、草酸和羟乙磺酸等。
本发明的药学上可接受的盐可通过常规化学方法自含有碱性或酸性部分的母体化合物合成。通常，可通过在水或有机溶剂或二者的混合物中使这些化合物的游离酸或碱形式与化学计量的适合碱或酸反应来制备上述盐；通常，优选如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水性介质。合适盐的列表可参见Remington:The Science and Practice of Pharmacy,22nd Edition,25 Allen,L.V.Jr.,Ed.；Pharmaceutical Press,London,UK(2012)，通过引用的方式将其披露内容并入本文中。
术语“溶剂化物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂化物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂化物。示例性溶剂化物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
术语“酯”用于表示有机酯，包括单酯、二酯、三酯、和更通常地多酯。
术语“同位素衍生物”表示通式(I)中的氢原子被1-6个氘原子(D)所取代得到的同位素衍生物、通式(I)中的碳原子被1-3个碳14原子(14C)所取代得到的同位素衍生物。
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。
本文使用的术语“药物组合物”是指活性剂与惰性或活性的载体的组合，使得所述组合物尤其适用于体内或离体诊断或治疗。碱的实例包括但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨等。对于治疗用途，本发明化合物的盐对于治疗用途，本发明化合物的盐预期为是药用的。然而，非药用的酸和碱的盐也可用于例如药用化合物的制备或纯化中。
特定药学及医学术语
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于，固体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
药物组合物和剂量
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种式(I)化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、胶囊剂(各包括持续释放或定时释放制剂)、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen,L.V.Jr.et.al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成 分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约1000mg/天，且最优选地为约0.1mg/天至约600mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约0.1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发明的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的排泄速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、肌肉注射、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约1000mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
首先，本发明提供了一种一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物：
Figure PCTCN2022081458-appb-000016
其中，
A、B、C、D、E、F、G、H、I、J、K、L和M各自独立地选自直连键、CR 6、CR 6R 14、N、NR 7、O、S和C＝O；
每一个R 1、R 2、R 3、R 6、R 7和R 14各自独立地选自氢、氘、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的炔基、未取代或取代的环烷基、未取代或取代的环杂烷基、卤素、-OH、未取代或取代的烷氧基、未取代或取代的芳基烷基、未取代或取代的芳杂基烷基、未取代或取代的芳基醚基、未取代或取代的芳杂基醚基、-CN、-N(R 4R 5)、-NO 2、-N 3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲酰基、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的硫醚基、未取代或取代的亚砜基、未取代或取代的砜基、未取代或取代的磺酰胺基、
Figure PCTCN2022081458-appb-000017
未取代或取代的膦酸酯基，其中R 4、R 5、R 8、R 9、R 10和R 11各自独立地选自氢、氘、未取代或取代的C 1-6烷基、C 3-7环烷基、未取代或取代的芳基、未取代或取代的芳杂基，且R 4和R 5、R 8和R 9可与相邻的氮原子或碳原子连接成环；
或相邻的两个R 1和/或相邻的两个R 3也可连接成环烷基、环杂烷基、芳基或芳杂基；
m、n、o各自独立地选自0～4的整数；
W选自直连键、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的环烷基、未取代或取代的环杂烷基、未取代或取代的桥环烷基、未取代或取代的桥环杂烷基、未取代或取代的螺环烷基、未取代或取代的螺环杂烷基、未取代或取代的烷基、未取代或取代的杂烷基、未取代或取代的烯基、未取代或取代的杂烯基、未取代或取代的炔基、未取代或取代的杂炔基、未取代或取代的-N(R 12R 13)、未取代或取代的胺基烷基、未取代或取代的胺基烷基胺基、未取代或取代的
Figure PCTCN2022081458-appb-000018
未取代或取代的
Figure PCTCN2022081458-appb-000019
其中R 12和R 13各自独立地选自氢、氘、C 1-6烷基、C 3-7环烷基、未取代或取代的烷基胺基、未取代或取代的芳基、取代或未取代的芳杂基，或R 12和R 13可连接成环；
Q为-H、-NH 2、-OH、-烷基-NHC(＝O)H、环烷基、未取代或取代的烷基酰基、未取代或取代的烷基羟基、未取代或取代的烯基羟基、未取代或取代的炔基羟基、未取代或取代的烷基胺基、未取代或取代的磺酰胺 基、未取代或取代的烷基磺酰胺基、氨基酸残基、
Figure PCTCN2022081458-appb-000020
磺酰胺基、磺酰肼基、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的
Figure PCTCN2022081458-appb-000021
未取代或取代的
Figure PCTCN2022081458-appb-000022
取代或未取代的-(CH 2) n1-(M) n2-(CH 2) n3-(M) n4-(CH 2) n5-(M) n6，其中每个M各自独立地选自O、OH、S、SO、SO 2和未取代或取代的胺基，每个n1、n2、n3、n4、n5和n6各自独立地选自0-6的整数；
或W和Q可以连接或融合成取代或非取代的环烷基、环杂烷基、芳基或芳杂基。
优选的，所述C、G、I中至少一个为N原子，例如C、G、I中的任一个为N原子，或C、G、I中的任意两个为N原子(即，C和G为N原子，或C和I为N原子，或G和I为N原子)，或C、G、I均为N原子。
优选的，所述J、K、M中至少一个为N原子，例如，J为N原子或K为N原子，或J、K均为N原子。
优选的，所述I、J、K均为N原子，或，或I、M、K均为N原子。
优选的，每一个R 1、R 2、R 3、R 6、R 7和R 14各自独立地选自氢、氘、未取代或取代的C 1-6烷基、未取代或取代的C 2-6烯基、未取代或取代的C 2-6炔基、未取代或取代的C 3-7环烷基、未取代或取代的3-7元环杂烷基、卤素、-OH、未取代或取代的C 1-6烷氧基、未取代或取代的C 6-10芳基乙基、未取代或取代的5-10元芳杂基乙基、未取代或取代的C 6-10芳基醚基、未取代或取代的5-10元芳杂基醚基、-CN、-NH 2、-NO 2、-N 3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲酰基、未取代或取代的C 6-10芳基、未取代或取代的5-10元芳杂基、未取代或取代的硫醚基、未取代或取代的亚砜基、未取代或取代的砜基、未取代或取代的磺酰胺基、
Figure PCTCN2022081458-appb-000023
未取代或取代的膦酸酯基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W选自直连键、取代或非取代的芳基、芳杂基、环烷基、环杂烷基、桥环烷基、桥环杂烷基、螺环烷基、螺环杂烷基、烷基、杂烷基、烯基、杂烯基、炔基、杂炔基、-N(R 12R 13)、胺基烷基、胺基烷基胺基、未取代或取代的
Figure PCTCN2022081458-appb-000024
未取代或取代的
Figure PCTCN2022081458-appb-000025
所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W选自取代或非取代的5-7元环杂烷基、取代或非取代的-胺基-C 1-6烷基，所述取代是 被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W中与含J、K的环相连的原子为N。
优选的，W选自取代或非取代的5-7元环杂烷基，所述5-7元杂环烷基至少包含一个氮原子，更优选的，所述5-7元杂环烷基为哌啶基或哌嗪基。
优选的，所述Q为-H、-NH 2、-OH、-C 1-6烷基-HNC(＝O)H、未取代或取代的C 1-6烷基羟基、未取代或取代的C 2-6烯基羟基、未取代或取代的C 2-6炔基羟基、未取代或取代的烷基胺基、磺酰胺基和磺酰肼基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述W和Q可以连接或融合成环，所述环为取代或非取代的5-7元环烷基、取代或非取代的5-7元的环杂烷基、取代或非取代的C 6-10芳基、取代或非取代的5-10元芳杂基。
更优选的，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
优选的，所述式Ⅰ结构的化合物为：
Figure PCTCN2022081458-appb-000026
其中，C、G、I、J、K各自独立地选自CR 6和N，且C、G、I中至少一个为N，J和K中至少一个为N；R 1、R 2、R 3、R 6、o、m、n、W、Q的定义和上述定义相同。
优选的，所述式Ⅰ结构的化合物为：
Figure PCTCN2022081458-appb-000027
其中，C、G、I、K、M各自独立地选自CR 6和N，且C、G、I中至少一个为N，K和M中至少一个为N；R 1、R 2、R 3、R 6、o、m、n、W、Q的定义和上述定义相同。
在一项优选的实施方案中，本发明还提供了如下化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，所述化合物选自：
Figure PCTCN2022081458-appb-000028
Figure PCTCN2022081458-appb-000029
Figure PCTCN2022081458-appb-000030
Figure PCTCN2022081458-appb-000031
Figure PCTCN2022081458-appb-000032
本发明还提供了一种药物组合物，该组合物包含上述任一所述的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物和药学上可接受的赋形剂。
在一项优选的实施方案中，所述药物组合物的形式为水性分散剂、液体、啫哩、糖浆、西也剂、药浆、悬浮液、气雾剂、控释剂、速溶剂、泡腾剂、冻干剂、片剂、粉末、药丸、糖衣完、胶囊、延迟释放剂、延长释放剂、脉冲控释剂、多微粒剂或立即释放剂中的任一种。
本发明还提供了上述任一所述的化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者上述任一所述的药物组合物在制备治疗CTLA-4相关疾病的药物中的应用。
在一项优选的实施方案中，所述CTLA-4相关疾病包括癌症、自身免疫疾病、免疫缺陷疾病、病毒感 染、器官移植排斥。
在一项更优选的实施方案中，所述癌症选自皮肤癌、膀胱癌、乳腺癌、胰腺癌、骨癌、脑癌、神经细胞瘤、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、绒毛膜癌、胰腺癌、泌尿癌、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、胆囊癌、支气管癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤、乳头状瘤、芽状神经胶质瘤、肉瘤(包括但不限于软骨肉瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤)、黑素瘤、血管瘤、瘢痕瘤、鳞状细胞癌、星细胞瘤、淋巴瘤(包括但不限于非霍奇金淋巴瘤、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病以及中枢神经系统淋巴瘤)、呼吸道癌(包括但不限于肺癌，例如小细胞及非小细胞肺癌，以及支气管腺瘤和胸膜肺母细胞瘤)、头颈癌(包括但不限于头癌、颈癌、喉癌、下咽癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌)、膀胱癌、乳癌(包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌)、消化道癌(包括但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、直肠癌、胃癌、小肠癌以及唾液腺癌)、甲状腺癌、副甲状腺癌及其远距离转移灶、胰腺癌、肝癌(包括但不限于肝细胞癌、具有或不具有纤维板层形式的肝细胞癌、胆管细胞癌以及混合型肝细胞胆管细胞癌)、白血病(包括但不限于急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓性白血病、慢性骨髓性白血病以及绒毛细胞白血病)、脑癌(包括但不限于脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤)、生殖器官癌(包括但不限于前列腺癌、睾丸癌、卵巢癌、子宫内膜癌、宫颈癌、子宫内膜癌、阴道癌和外阴癌以及子宫肉瘤)、尿道癌、眼癌(包括但不限于眼内黑素瘤和成视网膜细胞瘤)、皮肤癌(包括但不限于卡波西肉瘤、鳞状细胞瘤、恶性黑素瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌)、肾实质癌、肾癌(也称为肾细胞癌和肾腺癌)等相关癌症。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
这些实施例仅供例证说明的目的，并不限定在此提供的权利要求的范围。
1H-NMR谱Bruker-400或OXFORD-AS500核磁共振仪，化学位移的单位是百万分之一，内标是四甲基硅烷。耦合常数(J)接近0.1Hz。使用的缩略语如下说明：s,单重峰；d，双重峰；t,三重峰；q,四重峰；qu，五重峰；m，多重峰；brs，宽峰。质谱使用Quattro MicroTM API三重四极杆质谱仪。
实施例1 (1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺(化合物1)的制备
Figure PCTCN2022081458-appb-000033
3-(2-氯嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000034
将喹啉-3-基硼酸(5.0g,33.58mmoL)和2,4-二氯嘧啶(5.8g,33.58mmoL)加入到乙腈(100mL)中，再加入2M碳酸钠水溶液(50mL)，最后加入Pd(dppf)Cl 2(492mg,0.67mmol)。加料完毕后置换三次氮气，升温至80℃反应。TLC检测反应完全后，将反应体系用硅藻土过滤，滤液浓缩。加入乙酸乙酯，分液。有机相经减压蒸去溶剂，残留物用快速柱层析法分离，洗脱体系为石油醚/乙酸乙酯＝2/1。得目标产物6.2g，收率为77％。
1H NMR(400MHz,CDCl 3)δ9.51(d,J＝4.0Hz,1H),8.95(d,J＝4.0Hz,1H),8.73(d,J＝4.0Hz,1H),8.17(d,J＝8.0Hz,1H),7.97(d,J＝8.0Hz,1H),7.86–7.79(m,2H),7.68–7.60(m,1H)。
化合物1
Figure PCTCN2022081458-appb-000035
将3-(2-氯嘧啶-4-基)喹啉(1.1g,4.56mmoL)和哌啶-4-基甲胺(0.52g,4.56mmoL)加入到DMSO(10mL)中，再加入DIPEA(1.2g,9.12mmoL)。加料完毕后升温至80℃反应。2h后TLC检测反应完全，加入到水(30mL)中，乙酸乙酯萃取分液，有机相用饱和食盐水洗，水洗后浓缩，残留物用快速柱层析分离，洗脱体系为二氯甲烷/甲醇＝10/1。得到目标产物600mg，收率为40％。
1H NMR(400MHz,DMSO-d6)δ9.59(d,J＝4.0Hz,1H),9.07(d,J＝4.0Hz,1H),8.50(d,J＝4.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.08(d,J＝8.0Hz,1H),7.87–7.81(m,1H),7.74–7.65(m,1H),7.38(d,J＝4.0Hz,1H),4.86(d,J＝12.0Hz,2H),3.16(s,2H),3.02–2.88(m,2H),1.87–1.76(m,2H),1.68–1.52(m,1H),1.19–1.02(m,2H)。
MS-ESI:320.5[M+H] +。
实施例2 N-((1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲基)甲酰胺(化合物2)的制备
Figure PCTCN2022081458-appb-000036
除了反应时间用24小时替代2小时外，化合物2的制备同化合物1。收率为26％。
1H NMR(400MHz,DMSO-d6)δ9.58(d,J＝4.0Hz,1H),9.06(d,J＝2.0Hz,1H),8.49(d,J＝4.0Hz,1H),8.13(d,J＝8.0Hz,1H),8.06(dd,J＝12.0,8.0Hz,3H),7.87–7.79(m,1H),7.67(t,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),4.83(d,J＝12.0Hz,2H),3.06–3.00(m,2H),2.94(t,J＝12.0Hz,2H),1.75(d,J＝12.0Hz,2H),1.20–1.07(m,2H)。
MS-ESI:348.6[M+H] +。
实施例3 (1-(4-(喹啉-6-基)嘧啶-2-基)哌啶-4-基)甲胺(化合物3)的制备
Figure PCTCN2022081458-appb-000037
6-(2-氯嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000038
除了用喹啉-6-硼酸化合物替代实施例1中喹啉-3-硼酸外，化合物3-(2-氯嘧啶-4-基)-6-氟喹啉的合成同实施列1中的3-(2-氯嘧啶-4-基)喹啉。收率为81％。
1H NMR(400MHz,CDCl 3)δ9.01(dd,J＝4.0,2.0Hz,1H),8.72(d,J＝8.0Hz,1H),8.68(d,J＝2.0Hz,1H),8.36(dd,J＝8.0,4.0Hz,1H),8.32(d,J＝8.0Hz,1H),8.24(d,J＝8.0Hz,1H),7.80(d,J＝4.0Hz,1H),7.50(dd,J＝8.0,4.0Hz,1H)。
MS-ESI:242.4[M+H] +。
化合物3
Figure PCTCN2022081458-appb-000039
除了用6-(2-氯嘧啶-4-基)喹啉替代3-(2-氯嘧啶-4-基)喹啉外，化合物3的合成同化合物1。收率为46％。
1H NMR(400MHz,DMSO-d6)δ8.95(dd,J＝4.0,2.0Hz,1H),8.77(d,J＝4.0Hz,1H),8.55–8.44(m,3H),8.12(d,J＝8.0Hz,1H),7.59(dd,J＝8.0,4.0Hz,1H),7.32(d,J＝4.0Hz,1H),4.85(d,J＝12.0Hz,2H),2.93(td,J＝12.0,4.0Hz,2H),2.53(d,J＝4.0Hz,2H),1.89–1.76(m,2H),1.70–1.57(m,1H),1.20–1.06(m,2H)。
MS-ESI:320.5[M+H] +。
实施例4 N-((1-(4-(喹啉-6-基)嘧啶-2-基)哌啶-4-基)甲基)甲酰胺(化合物4)的制备
Figure PCTCN2022081458-appb-000040
除了用6-(2-氯嘧啶-4-基)喹啉替代3-(2-氯嘧啶-4-基)喹啉外，化合物4的合成同实施例2中的化合物2。收率为56％。
1H NMR(400MHz,DMSO-d6)δ8.95(dd,J＝4.0,2.0Hz,1H),8.76(d,J＝4.0Hz,1H),8.54–8.44(m,3H),8.11(d,J＝8.0Hz,1H),8.03(s,1H),7.59(dd,J＝8.0,4.0Hz,1H),7.32(d,J＝4.0Hz,1H),4.83(d,J＝12.0Hz,2H),3.03(t,J＝8.0Hz,2H),2.93(t,J＝12.0Hz,2H),178–1.70(m,3H),1.20–1.05(m,2H)。
MS-ESI:348.6[M+H] +。
实施例5 (1-(4-(喹啉-2-基)嘧啶-2-基)哌啶-4-基)甲胺(化合物5)的制备
Figure PCTCN2022081458-appb-000041
1-(2-(4-(氨基甲基)哌啶-1-基)嘧啶-4-基)乙-1-酮
Figure PCTCN2022081458-appb-000042
除了用1-(2-氯嘧啶-4-基)乙-1-酮替代实施例(4-1)中3-(2-氯嘧啶-4-基)喹啉外，1-(2-(4-(氨基甲基)哌啶-1-基)嘧啶-4-基)乙-1-酮的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为98％。
MS-ESI:235.4[M+H] +。
(1-(4-(喹啉-2-基)嘧啶-2-基)哌啶-4-基)甲胺
Figure PCTCN2022081458-appb-000043
将邻氨基苯甲醛(197mg,1.63mmol)和1-(2-(4-(氨基甲基)哌啶-1-基)嘧啶-4-基)乙-1-酮(380mg,1.63mmol)溶于EtOH(10mL)中，再加入氢氧化钾(182mg,3.25mmol)。加料完毕，80℃反应过夜。次日TLC检测反应完全。减压蒸去溶剂，残留物中加入乙酸乙酯和水，分液，有机相用水洗。减压蒸去溶剂，残留物用快速柱层析分离，得产物450mg，收率为86％。
1H NMR(400MHz,CDCl 3)δ8.50(t,J＝6.8Hz,2H),8.25(d,J＝8.6Hz,1H),8.17(d,J＝8.6Hz,1H),7.84(d,J＝8.0Hz,1H),7.73(t,J＝7.2Hz,2H),7.56(t,J＝7.4Hz,1H),4.97(d,J＝13.2Hz,2H),3.01-2.94(m,2H),2.67(d,J＝6.6Hz,2H),2.32(brs,2H),1.89(d,J＝13.2Hz,2H),1.75-1.65(m,1H),1.32-1.19(m,2H)。
MS-ESI:320.5[M+H] +。
实施例6 (1-(4-(喹喔啉-2-基)嘧啶-2-基)哌啶-4-基)甲胺(化合物6)的制备
Figure PCTCN2022081458-appb-000044
2-(2-氯嘧啶-4-基)喹喔啉
Figure PCTCN2022081458-appb-000045
除了用2-(4,4,5,5-四甲基-1,3,2-二氧杂环芳烃-2-基)喹喔啉化合物替代实施例1中喹啉-3-基硼酸外，化合物2-(2-氯嘧啶-4-基)喹喔啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为57％。
MS-ESI:243.2[M+H] +。
化合物6
Figure PCTCN2022081458-appb-000046
除了用2-(2-氯嘧啶-4-基)喹喔啉替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，化合物6的合成同实施例1中的化合物1。收率为63％。
MS-ESI:321.2[M+H] +。
实施例7 (1-(4-(6-氟喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺(化合物7)的制备
Figure PCTCN2022081458-appb-000047
3-(2-氯嘧啶-4-基)-6-氟喹啉
Figure PCTCN2022081458-appb-000048
除了用6-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环芳烃-2-基)喹啉化合物替代实施例1中喹啉-3-基硼酸外，化合物3-(2-氯嘧啶-4-基)-6-氟喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为56％。
1H NMR(400MHz,CD 3OD)δ9.54(d,J＝4.0Hz,1H),9.13(d,J＝4.0Hz,1H),8.80(d,J＝8.0Hz,1H),8.17(d,J＝8.0Hz,1H),8.16–8.12(m,1H),7.79(dd,J＝8.0,4.0Hz,1H),7.73–7.66(m,1H)。
MS-ESI:260.3[M+H] +。
化合物7
Figure PCTCN2022081458-appb-000049
除了用3-(2-氯嘧啶-4-基)-6-氟喹啉替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，化合物7的合成同实施例1中的化合物1。收率为73％。
1H NMR(400MHz,CD 3OD)δ9.51(d,J＝4.0Hz,1H),8.97(d,J＝4.0Hz,1H),8.44(d,J＝8.0Hz,1H),8.15–8.10(m,1H),7.76(dd,J＝12.0,4.0Hz,1H),7.66(td,J＝8.0,4.0Hz,1H),7.25(d,J＝4.0Hz,1H),4.96(d,J＝12.0Hz,2H),3.00(td,J＝12.0,4.0Hz,2H),2.66(d,J＝8.0Hz,2H),1.89(d,J＝12.0Hz,2H),1.86–1.72(m,1H),1.30–1.18(m,2H)。
MS-ESI:338.4[M+H] +。
实施例8 (1-(3-(2-(4-(氨基甲基)哌啶-1-基)嘧啶-4-基)喹啉-2-基)哌啶-4-基)甲胺(化合物8)
Figure PCTCN2022081458-appb-000050
3-(2-氯嘧啶-4-基)-2-氟喹啉
Figure PCTCN2022081458-appb-000051
除了用(2-氟喹啉-3-基)硼酸化合物替代实施例1中喹啉-3-基硼酸外，化合物3-(2-氯嘧啶-4-基)-6-氟喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为42％。
1H NMR(400MHz,CD 3OD)δ9.28(d,J＝8.0Hz,1H),8.82(d,J＝8.0Hz,1H),8.16(d,J＝8.0Hz,1H),8.05(dd,J＝8.0,4.0Hz,1H),7.97–7.85(m,2H),7.69(t,J＝8.0Hz,1H)。
MS-ESI:260.3[M+H] +。
化合物8
Figure PCTCN2022081458-appb-000052
除了用3-(2-氯嘧啶-4-基)-2-氟喹啉替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，化合物8的合成同实施例1中的化合物1。收率为73％。
1H NMR(400MHz,CD 3OD)δ8.40–8.32(m,2H),7.81(dd,J＝8.0,4.0Hz,2H),7.65(t,J＝8.0Hz,1H),7.39(t,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),4.96(d,J＝16.0Hz,2H),3.79(d,J＝16.0Hz,2H),3.01(t,J＝12.0Hz,2H),2.93–2.85(m,6H),2.08–1.96(m,1H),1.94–1.74(m,5H),1.46–1.26(m,4H)。
MS-ESI:432.5[M+H] +。
实施例9 (1-(4-(2-甲氧基喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺(化合物9)的制备
Figure PCTCN2022081458-appb-000053
3-(2-氯嘧啶-4-基)-2-甲氧基喹啉
Figure PCTCN2022081458-appb-000054
除了用化合物(2-甲氧基喹啉-3-基)硼酸替代实施例1中喹啉-3-基硼酸外，化合物3-(2-氯嘧啶-4-基)-2-甲氧基喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为52％。
1H NMR(400MHz,CDCl 3):δ9.00(s,1H),8.67(d,J＝4.0Hz,1H),8.17(d,J＝8.0Hz,1H),7.94-7.85(m,2H),7.72(t,J＝8.0Hz,1H),7.46(t,J＝4.0Hz,1H),4.21(s,3H)。
MS-ESI:272.3[M+H] +。
化合物9
Figure PCTCN2022081458-appb-000055
除了用3-(2-氯嘧啶-4-基)-2-甲氧基喹啉替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，化合物9的合成同实施例1中的化合物1。收率为76％。
1H NMR(400MHz,CDCl 3):δ8.75(s,1H),8.37(d,J＝4.0Hz,1H),7.85(t,J＝7.0Hz,2H),7.65(t,J＝7.6Hz,1H),7.40(t,J＝8.0Hz,1H),7.27(s,1H),4.93(d,J＝16.0Hz,2H),4.15(s,3H),3.71(q,J＝7.0Hz,2H),2.94(t,J＝12.8Hz,2H),2.65(d,J＝4.0Hz,2H),1.86(d,J＝16.0Hz,2H),1.78-1.60(m,1H),1.31-1.17(m,2H)。
MS-ESI:350.4[M+H] +。
实施例10 3-(2-(4-(氨基甲基)哌啶-1-基)嘧啶-4-基)喹啉-2-醇(化合物10)的制备
Figure PCTCN2022081458-appb-000056
将化合物9(300mg，0.86mmoL)和DCM(6mL)加入至封管中，随后加入三溴化硼(539mg，2.16mmoL)，50℃加热反应。TLC监测反应完全后，加水分液，有机相依次用饱和碳酸氢钠和水。减压蒸去溶剂，残留物用用快速柱层析分离。得化合物10为155mg，收率为54％。
1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.39(d,J＝4.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.74(d,J＝4.0Hz,1H),7.60–7.54(m,1H),7.36(d,J＝8.0Hz,1H),7.25–7.9(m,1H),4.78(d,J＝12.0Hz,2H),3.47–3.42(m,2H),2.97–2.76(m,4H),1.75(d,J＝16.0Hz,2H),1.70–1.60(m,1H)。
MS-ESI:336.4[M+H] +。
实施例11 (1-(4-(喹啉-3-基-2-d)嘧啶-2-基)哌啶-4-基)甲胺(化合物11)的制备
Figure PCTCN2022081458-appb-000057
3-(2-氯嘧啶-4-基)喹啉-2-d
Figure PCTCN2022081458-appb-000058
除了用(喹啉-3-基-2-d)硼酸替代实施例1中喹啉-3-基硼酸外，3-(2-氯嘧啶-4-基)喹啉-2-d的合成同实施列1中的3-(2-氯嘧啶-4-基)喹啉。收率为32％。
1H NMR(400MHz,CD 3OD)δ9.01(s,1H),8.43(d,J＝4.0Hz,1H),8.09(d,J＝4.0Hz,2H),7.90–7.78(m,1H),7.73–7.64(m,1H),7.27(d,J＝4.0Hz,1H)。
MS-ESI:243.2[M+H] +。
化合物11
Figure PCTCN2022081458-appb-000059
除了用3-(2-氯嘧啶-4-基)喹啉-2-d替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，化合物11的合成同实施例1中的化合物1。收率为67％。
1H NMR(400MHz,CD 3OD)δ9.01(s,1H),8.43(d,J＝4.0Hz,1H),8.13–8.03(m,2H),7.89–7.81(m,1H),7.72–7.63(m,1H),7.27(d,J＝4.0Hz,1H),4.96(d,J＝16.0Hz,2H),2.99(td,J＝12.0,4.0Hz,2H),2.59(d,J＝8.0Hz,2H),1.94–1.84(m,2H),1.80–1.66(m,1H),1.27–1.19(m,2H)。
MS-ESI:321.3[M+H] +。
实施例12 (1-(4-(喹啉-3-基)吡啶-2-基)哌啶-4-基)甲胺(化合物12)的制备
Figure PCTCN2022081458-appb-000060
3-(2-氯吡啶-4-基)喹啉
Figure PCTCN2022081458-appb-000061
除了用化合物3-溴喹啉替代实施例1中喹啉-3-基硼酸，用(2-氯吡啶-4-基)硼酸替代实施例(4-1)中的2，4-二氯嘧啶外，化合物12的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为65％。
1H NMR(400MHz,DMSO-d6)δ9.37(d,J＝4.0Hz,1H),8.94(d,J＝4.0Hz,1H),8.57(d,J＝4.0Hz,1H),8.13(s,1H),8.10(d,J＝12.0Hz,2H),8.00(dd,J＝8.0,4.0Hz,1H),7.89–7.83(m,1H),7.71(t,J＝8.0Hz,1H)。
MS-ESI:241.2[M+H] +。
化合物12
Figure PCTCN2022081458-appb-000062
除了用3-(2-氯吡啶-4-基)喹啉替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，化合物12的合成同实施例1中的(化合物1。收率为64％。
1H NMR(400MHz,DMSO-d6)δ9.29(d,J＝4.0Hz,1H),8.77(d,J＝4.0Hz,1H),8.22(d,J＝8.0Hz,1H),8.06(d,J＝12.0Hz,2H),7.80(t,J＝8.0Hz,1H),7.66(t,J＝8.0Hz,1H),7.28(s,1H),7.10(d,J＝4.0Hz,1H),4.49(d,J＝12.0Hz,2H),2.84(t,J＝12.0Hz,2H),2.63(d,J＝4.0Hz,2H),1.78(d,J＝12.0Hz,2H),1.75–1.65(m,1H),1.26–1.14(m,2H)。
MS-ESI:319.3[M+H] +。
实施例13 2-(2-(4-(氨基甲基)哌啶-1-基)嘧啶-4-基)-4氢-苯并吡喃-4-酮(化合物13)的制备
Figure PCTCN2022081458-appb-000063
2-(4-((叔丁氧羰基)氨基)甲基)哌啶-1-基)嘧啶-4-羧酸甲酯
Figure PCTCN2022081458-appb-000064
除了用2-氯嘧啶-4-羧酸甲酯替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，2-(4-((叔丁氧羰基)氨基)甲基)哌啶-1-基)嘧啶-4-羧酸甲酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为88％。
MS-ESI:351.2[M+H] +。
((1-(4-(羟甲基)嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯
Figure PCTCN2022081458-appb-000065
将2-(4-((叔丁氧羰基)氨基)甲基)哌啶-1-基)嘧啶-4-羧酸甲酯(1.56g,4.5mmoL)溶于DCM(30mL)搅拌，在-70℃条件下缓慢加入DIBAL-H(4.5mL，6.7mmoL)。次日TLC监测还有原料剩余，补加DIBAL-H(3mL)，3h后反应完全，加入MeOH(5mL)淬灭反应。加饱和NaHCO 3分液，减压蒸馏，残留物用快速柱层析分离。得目标产物760mg，收率为55％。
1H NMR(400MHz,CDCl 3):δ8.21(dd,J＝8.0,0.6Hz,1H),6.35(d,J＝4.0Hz,1H),4.79(d,J＝16.0Hz,2H),4.65(s,1H),4.54(d,J＝4.0Hz,2H),3.73-3.71(m,1H),3.05-3.02(m,2H),2.86(t,J＝12.0,7.6Hz,2H),1.79-1.75(m,2H),1.45(s,9H),1.18(dd,J＝12.2,3.8Hz,2H)。
MS-ESI:323.4[M+H] +。
((1-(4-甲酰嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯
Figure PCTCN2022081458-appb-000066
将((1-(4-(羟甲基)嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯(760mg,0.24mmoL)溶于DCM(30mL)中，再将PCC(1.5g,7.0mmoL)和硅胶(1.5g)混合均匀加入反应体系，3h后TLC监测反应完全。过滤，滤液进行分液，有机相用盐水洗，减压蒸去溶剂，残留物用快速柱层析分离。得目标产物360mg，收率为46％。
1H NMR(400MHz,CDCl 3):δ9.81(s,1H),8.50(d,J＝4.0Hz,1H),6.92(d,J＝4.0Hz,1H),4.87(d,J＝12.0Hz,2H),3.07-3.04(m,2H),2.86(t,J＝12.0,7.6Hz,2H),1.87-1.74(m,3H),1.45(s,9H),1.29-1.11(m,2H)。
MS-ESI:321.6[M+H] +。
((1-(4-(1-羟基-3-(2-羟基苯基)-3-氧丙基)嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯
Figure PCTCN2022081458-appb-000067
将((1-(4-甲酰嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯(360mg,0.1mmoL)和1-(2-羟基苯基)乙烷-1-酮(184mg,0.1mmoL)溶于MeOH(20mL)中，再加入KOH(126mg,0.2mmoL)，3h后TLC监测反应完全。用2M的HCl溶液将pH调至6～7。减压蒸去溶剂，残留物经高真空干燥得粗品。不做纯化，直接进行下步反应。
MS-ESI:457.5[M+H] +。
((1-(4-(4-氧代-4H-铬烯-2-基)嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯
Figure PCTCN2022081458-appb-000068
将((1-(4-(1-羟基-3-(2-羟基苯基)-3-氧丙基)嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯溶于DMSO(6mL)中，加入I 2(5mg)。加料完毕后，体系温度升至100℃，次日TLC监测反应基本完全，加入水，用DCM提取。有机相用饱和碳酸氢钠洗，减压蒸去溶剂。残留物用快速柱层析分离。得到目标产物40mg，收率为38％。
1H NMR(400MHz,CDCl 3):δ8.41(d,J＝4.0Hz,1H),7.82-7.79(m,1H),7.71-7.67(m,1H),7.32(d,J＝8.0Hz,1H),7.29-7.27(m,1H),7.24-7.21(m,1H),6.77-6.72(m,1H),4.89-4.79(m,2H),3.78-3.66(m,1H),3.08-3.02(m,2H),2.92-2.86(m,2H),1.80(d,J＝12.0Hz,2H),1.44(s,9H),1.33-1.15(m,2H)。
MS-ESI:437.4[M+H] +。
化合物13
Figure PCTCN2022081458-appb-000069
将((1-(4-(4-氧代-4H-铬烯-2-基)嘧啶-2-基)哌啶-4-基)甲基)氨基甲酸叔丁酯(40mg,0.09mmoL)溶于HCl-Dioxane(6mL)中，1h后TLC监测反应完全。减压旋干溶剂，加入饱和碳酸氢钠将PH调至6～7，残留物用快速柱层析分离。得化合物13为20mg，收率为65％。
1H NMR(400MHz,CD 3OD):δ8.44(d,J＝4.0Hz,1H),7.81(t,J＝7.4Hz,2H),7.45(d,J＝8.0Hz,1H),7.36(dd,J＝16.0,6.4Hz,2H),6.61(s,1H),4.59(s,2H),2.95(t,J＝12.0,7.4Hz,2H),2.87(d,J＝8.0Hz,2H),2.0-1.90(m,1H),1.86(d,J＝12.8Hz,2H),1.35-1.22(m,2H)。
MS-ESI:337.3[M+H] +。
实施例14 (1-(6-(喹啉-3-基)吡啶-2-基)哌啶-4-基)甲胺(化合物14)的制备
Figure PCTCN2022081458-appb-000070
(1-(6-溴吡啶-2-基)哌啶-4-基)甲胺
Figure PCTCN2022081458-appb-000071
将2,6-二溴吡啶(1.7g,7.17mmoL)和哌啶-4-基甲胺(0.9g,7.88mmoL)溶于1,4-二氧六环(15mL)中，并加入磷酸钾(1.52g,7.17mmoL)。随后置换三次氮气，加热至105℃反应。8h后基本反应完毕，将体系浓缩，加入乙酸乙酯和水。分液，有机相经减压蒸去溶剂残留物用快速柱层析分离。得产物1.36g，收率为70％。
1H NMR(400MHz,DMSO-d6)δ7.41–7.33(m,1H),6.77(d,J＝12.0Hz,1H),6.70(d,J＝8.0Hz,1H),4.21(d,J＝16.0Hz,2H),2.76(td,J＝12.0,4.0Hz,2H),2.42(d,J＝8.0Hz,2H),1.73(d,J＝12.0Hz,2H),1.55–1.40(m,1H),1.03(qd,J＝12.0,4.0Hz,2H)。
化合物14
Figure PCTCN2022081458-appb-000072
除了用化合物(1-(6-溴吡啶-2-基)哌啶-4-基)甲胺替代实施例1中2，4-二氯嘧啶外，化合物14的合成同实施例1中的化合物1。收率为42％
1H NMR(400MHz,DMSO-d6)δ9.57(d,J＝4.0Hz,1H),8.93(d,J＝4.0Hz,1H),8.11(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.82–7.74(m,1H),7.73–7.60(m,2H),7.42(d,J＝4.0Hz,1H),6.92(d,J＝8.0Hz,1H),4.50(d,J＝12.0Hz,2H),2.88(t,J＝12.0Hz,3H),2.69(d,J＝4.0Hz,3H),1.95–1.85(d,J＝11.3Hz,3H),1.33–1.14(m,2H)。
MS-ESI:319.3[M+H] +。
实施例15 (1-(3-(喹啉-3-基)苯基)哌啶-4-基)甲胺(化合物15)的制备
Figure PCTCN2022081458-appb-000073
3-(3-溴苯基)喹啉
Figure PCTCN2022081458-appb-000074
除了用化合物1-溴-3-碘苯替代实施例1中2，4-二氯嘧啶外，化合物15的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为82％。
1H NMR(400MHz,DMSO-d6)δ9.26(d,J＝4.0Hz,1H),8.71(d,J＝4.0Hz,1H),8.11(t,J＝4.0Hz,1H),8.06(d,J＝8.0Hz,2H),7.91(d,J＝8.0Hz,1H),7.82–7.76(m,1H),7.69–7.63(m,2H),7.51(t,J＝8.0Hz,1H)。
化合物15
Figure PCTCN2022081458-appb-000075
将化合物3-(3-溴苯基)喹啉(630mg,2.22mmoL)、哌啶-4-基甲胺(380mg,3.33mmoL)和XPhos(21mg,0.044mmoL)加入至THF(10mL)中，随后向体系缓慢加入2.0M NaHMDS(1.42g,7.77mmoL)，最后再加入Pd(dba) 3(41mg,0.044mmoL)置换三次氮气，70℃反应7h，TLC监测基本反应完全。加入盐酸将调节pH调至中性。将反应体系浓缩，加入DCM和水分液。有机相经减压蒸去溶剂，残留物用快速柱层析分离。得产物150mg，收率为21％。
1H NMR(400MHz,DMSO-d6)δ9.23(d,J＝4.0Hz,1H),8.64(d,J＝4.0Hz,1H),8.05(t,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,2H),7.67–7.61(m,1H),7.38(d,J＝4.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.10(d,J＝12.0Hz,1H),7.06–6.98(m,1H),3.87(d,J＝12.0Hz,2H),2.80–2.64(m,4H),1.90–1.80(m,3H),1.38–1.26(m,2H)。
实施例16 3-(2-(4-(氨基甲基)哌啶-1-基)嘧啶-4-基)喹啉-2-胺(化合物16)的制备
Figure PCTCN2022081458-appb-000076
3-(2-氯嘧啶-4-基)喹啉-2-胺
Figure PCTCN2022081458-appb-000077
除了用化合物3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)喹啉-2-胺替代实施例1中喹啉-3-基硼酸外，化合物3-(2-氯嘧啶-4-基)喹啉-2-胺的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为64％。
1H NMR(400MHz,CDCl 3)δ8.92(d,J＝8.0Hz,1H),8.51(d,J＝4.0Hz,1H),8.14(s,1H),8.08(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,2H),7.57(t,J＝8.0Hz,1H),7.39(s,1H)。
MS-ESI:257.3[M+H] +。
化合物16
Figure PCTCN2022081458-appb-000078
除了用3-(2-氯嘧啶-4-基)喹啉-2-胺替代实施例1中3-(2-氯嘧啶-4-基)喹啉外，化合物16的合成同实施例1中的化合物1。收率为82％。
1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),8.12(s,1H),7.85(d,J＝8.0Hz,2H),7.79–7.68(m,1H),7.66–7.58(m,1H),7.54–7.46(m,1H),4.73(d,J＝12.0Hz,2H),3.11(t,J＝12.0Hz,2H),2.90(d,J＝8.0Hz,2H),2.09–1.99(m,1H),1.92(d,J＝16.0Hz,2H),1.38(dd,J＝12.0,4.0Hz,2H)。
MS-ESI:335.4[M+H] +。
实施例17 1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-胺(化合物17)的制备
Figure PCTCN2022081458-appb-000079
除了用哌啶-4-胺替代实施例1中哌啶-4-基甲胺外，化合物17的合成同实施例1中的化合物1。收率为65％。
1H NMR(400MHz,DMSO-d6)δ9.63(d,J＝4.0Hz,1H),9.11(d,J＝4.0Hz,1H),8.54(d,J＝4.0Hz,1H),8.18(d,J＝8.0Hz,1H),8.11(d,J＝8.0Hz,1H),7.91–7.84(m,1H),7.71(t,J＝8.0Hz,1H),7.42(d,J＝4.0Hz,1H),4.75(d,J＝8.0Hz,2H),3.11(t,J＝12.0Hz,2H),3.04–2.94(m,1H),1.89(d,J＝8.0Hz,2H),1.40–1.20(m,2H)。
MS-ESI:306.3[M+H] +。
实施例18 3-(2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物18)的制备
Figure PCTCN2022081458-appb-000080
4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000081
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺外，4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为95％。
MS-ESI:392.2[M+H] +。
化合物18
Figure PCTCN2022081458-appb-000082
向4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯(6.1g,15.56mmoL)中加入4M盐酸/1，4-二氧六环溶液(50mL)，室温搅拌30分钟。TLC监测反应完全，将反应体系浓缩，加入甲醇钠的甲醇溶液将产物游离出来。减压蒸去溶剂，残留物用快速柱层析分离得到产物4.55g，收率为98％。
1H NMR(400MHz,DMSO-d6)δ9.65(d,J＝4.0Hz,1H),9.15(d,J＝4.0Hz,1H),8.60(d,J＝8.0Hz,1H),8.17–8.12(m,1H),8.09(d,J＝8.0Hz,1H),7.86(t,J＝8.0Hz,1H),7.70(t,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),4.15–4.08(m,4H),3.25–3.12(m,4H)。
MS-ESI:292.2[M+H] +。
实施例19 2-(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)乙胺(化合物19)的制备
Figure PCTCN2022081458-appb-000083
除了用哌啶-4-基乙胺替代实施例1中哌啶-4-基甲胺外，化合物19的合成同实施例1中的化合物1。收率为36％。
1H NMR(400MHz,DMSO-d6)δ9.60(d,J＝4.0Hz,1H),9.09(d,J＝4.0Hz,1H),8.51(d,J＝4.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.09(d,J＝8.0Hz,1H),7.88–7.83(m,1H),7.69(t,J＝8.0Hz,1H),4.86(d,J＝12.0Hz,2H),2.98–2.92(m,2H),2.90–2.83(m,2H),2.54(s,2H),1.79(d,J＝8.0Hz,2H),1.54–1.48(m,1H),1.20–1.12(m,2H)。
MS-ESI:334.2[M+H] +。
实施例20 (1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲醇(化合物20)的制备
Figure PCTCN2022081458-appb-000084
除了用哌啶-4-基甲醇替代实施例1中的哌啶-4-基甲胺外，化合物20的合成同实施例1中的化合物1。收率为83％。
1H NMR(400MHz,DMSO-d6)δ9.58(d,J＝4.0Hz,1H),9.07(d,J＝4.0Hz,1H),8.49(d,J＝4.0Hz,1H),8.14(d,J＝8.0Hz,1H),8.07(d,J＝8.0Hz,1H),7.88–7.79(m,1H),7.73–7.63(m,1H),7.36(d,J＝4.0Hz,1H),4.85(d,J＝12.0Hz,2H),4.51(t,J＝8.0Hz,1H),3.31–3.24(m,2H),2.98–2.86(m,2H),1.76(d,J＝12.0 Hz,2H),1.72–1.63(m,1H),1.11(qd,J＝12.0,4.0Hz,2H)。
MS-ESI:321.2[M+H] +。
实施例21 (1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)乙醇(化合物21)的制备
Figure PCTCN2022081458-appb-000085
除了用哌啶-4-基乙醇替代实施例1中哌啶-4-基甲胺外，化合物21的合成同实施例1中的化合物1。收率为49％。
1H NMR(400MHz,DMSO-d6)δ9.57(d,J＝4.0Hz,1H),9.05(d,J＝1.9Hz,1H),8.48(d,J＝4.0Hz,1H),8.13(d,J＝8.0Hz,1H),8.07(d,J＝8.0Hz,1H),7.88–7.77(m,1H),7.67(t,J＝8.0Hz,1H),7.35(d,J＝8.0Hz,1H),4.81(d,J＝12.0Hz,2H),4.40(s,1H),3.47(d,J＝4.0Hz,1H),2.91(t,J＝12.0Hz,1H),1.82–1.63(m,3H),1.38(q,J＝8.0Hz,2H),1.17–0.99(m,2H)。
MS-ESI:335.3[M+H] +。
实施例22 3-(2-((3S，5R)-3,5-二甲基哌嗪-1-基)嘧啶-4-基)喹啉(化合物22)的制备
Figure PCTCN2022081458-appb-000086
除了用(2S，6R)-2,6-二甲基哌嗪替代实施例1中哌啶-4-基甲胺外，化合物22的合成同实施例1中的化合物1。收率为83％。
1H NMR(400MHz,DMSO-d6):δ9.61(d,J＝2.2Hz,1H),9.08(d,J＝2.2Hz,1H),8.51(d,J＝5.2Hz,1H),8.15(d,J＝8.2Hz,1H),8.09(d,J＝8.4Hz,1H),7.89-7.81(m,1H),7.69(t,J＝7.4Hz,1H),7.40(d,J＝5.2Hz,1H),4.72(d,J＝12.4Hz,2H),2.81-2.74(m,2H),2.45(t,J＝12.0Hz,2H),1.09(s,3H),1.07(s,3H)。
MS-ESI:320.2[M+H] +。
实施例23 3-(2-(4-甲基哌嗪-1-基)嘧啶-4-基)喹啉(化合物23)的制备
Figure PCTCN2022081458-appb-000087
除了用1-甲基哌嗪替代实施例1中哌啶-4-基甲胺外，化合物23的合成同实施例1中的化合物1。收率为78％。
1H NMR(400MHz,CD 3OD):δ9.56(d,J＝4.0Hz,1H),9.05(d,J＝2.4Hz,1H),8.48(d,J＝8.0Hz,1H),8.10(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.80(t,J＝7.2Hz,1H),7.64(t,J＝7.2Hz,1H),7.39(d,J＝8.0Hz,1H),3.86-3.79(m,4H),2.41-2.34(m,4H),2.20(s,3H)。
MS-ESI:306.4[M+H] +。
实施例24 3-(2-(1,4-二氮杂-1-基)嘧啶-4-基)喹啉(化合物24)的制备
Figure PCTCN2022081458-appb-000088
4-(4-(喹啉-3-基)嘧啶-2-基)-1,4-二氮烷-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000089
除了用1,4-二氮烷-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺外，4-(4-(喹啉-3-基)嘧啶-2-基)-1,4-二氮烷-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为71％。
MS-ESI:406.3[M+H] +。
化合物24
Figure PCTCN2022081458-appb-000090
除了用4-(4-(喹啉-3-基)嘧啶-2-基)-1,4-二氮烷-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物24的合成同实施例18中的化合物18。收率为84％。
1H NMR(400MHz,CDCl 3)δ9.59(d,J＝4.0Hz,1H),8.75(d,J＝4.0Hz,1H),8.45(d,J＝4.0Hz,1H),8.15(d,J＝8.0Hz,1H),7.94(d,J＝8.0Hz,1H),7.82–7.74(m,1H),7.60(t,J＝8.0Hz,1H),7.07(d,J＝8.0Hz,1H),4.12–3.84(m,4H),3.13(s,2H),3.03–2.86(m,2H),2.38–2.20(m,1H),2.00(s,2H)。
MS-ESI:306.2[M+H] +。
实施例25 3-(2-(3,8-二氮杂二环[3.2.1]辛烷-3-基)嘧啶-4-基)喹啉(化合物25)的制备
Figure PCTCN2022081458-appb-000091
8-(4-(喹啉-3-基)嘧啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯
Figure PCTCN2022081458-appb-000092
除了用3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺外，8-(4-(喹啉-3-基)嘧啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为41％。
MS-ESI:418.2[M+H] +。
化合物25
Figure PCTCN2022081458-appb-000093
除了用8-(4-(喹啉-3-基)嘧啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物25的合成同实施例18中的化合物18。收率为63％。
1H NMR(400MHz,CDCl 3)δ9.56(d,J＝4.0Hz,1H),8.76(d,J＝4.0Hz,1H),8.46(d,J＝8.0Hz,1H),8.16(d,J＝8.0Hz,1H),7.95(d,J＝8.0Hz,1H),7.78(t,J＝8.0Hz,1H),7.61(t,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),3.22(d,J＝12.0Hz,2H),2.84(d,J＝12.0Hz,2H),2.20–1.99(m,6H)。
MS-ESI:318.2[M+H] +。
实施例26 N-(4-(喹啉-3-基)嘧啶-2-基)乙烷-1,2-二胺(化合物26)的制备
Figure PCTCN2022081458-appb-000094
(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)乙基)氨基甲酸叔丁酯
Figure PCTCN2022081458-appb-000095
除了用(2-氨基乙基)氨基甲酸叔丁酯替代实施例1中哌啶-4-基甲胺外，(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)乙基)氨基甲酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为64％。
MS-ESI:366.2[M+H] +。
化合物26
Figure PCTCN2022081458-appb-000096
除了用(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)乙基)氨基甲酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物26的合成同实施例18中的化合物18。收率为79％。
1H NMR(400MHz,CDCl 3)δ9.54(s,1H),8.78(s,1H),8.42(d,J＝8.0Hz,1H),8.15(d,J＝12.0Hz,1H),7.94(d,J＝8.0Hz,1H),7.78(t,J＝8.0Hz,1H),7.61(t,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),3.68–3.56(m,2H),3.02(t,J＝8.0Hz,2H)。
MS-ESI:266.2[M+H] +。
实施例27 N-(4-(喹啉-3-基)嘧啶-2-基)丙烷-1,3-二胺(化合物27)的制备
Figure PCTCN2022081458-appb-000097
(3-((4-(喹啉-3-基)嘧啶-2-基)氨基)丙基)氨基甲酸叔丁酯
Figure PCTCN2022081458-appb-000098
除了用(2-氨基丙基)氨基甲酸叔丁酯替代实施例1中哌啶-4-基甲胺外，(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)丙基)氨基甲酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为50％。
MS-ESI:380.2[M+H] +。
化合物27
Figure PCTCN2022081458-appb-000099
除了用(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)丙基)氨基甲酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物27的合成同实施例18中的化合物18。收率为98％。
1H NMR(400MHz,CDCl 3)δ9.54(s,1H),8.78(d,J＝4.0Hz,1H),8.41(d,J＝8.0Hz,1H),8.15(d,J＝8.0Hz,1H),7.94(d,J＝8.0Hz,1H),7.81–7.75(m,1H),7.60(t,J＝8.0Hz,1H),7.11(d,J＝4.0Hz,1H),5.68(s,1H),3.67–3.62(m,2H),2.88(t,J＝8.0Hz,2H),1.82(p,J＝8.0Hz,2H),1.41(s,2H)。
MS-ESI:280.3[M+H] +。
实施例28 7-(2-(哌嗪-1-基)嘧啶-4-基)-2,3-二氢-[1,4]二氧基[2,3-b]吡啶(化合物28)的制备
Figure PCTCN2022081458-appb-000100
4-(4-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000101
将化合物2,4-二氯嘧啶(3.72g,21.5mmoL)、4-甲基哌嗪-1-羧酸叔丁酯(4.3g,21.5mmoL)溶于甲苯(50mL)中，回流反应过夜，次日TLC检测反应完全。减压蒸去溶剂，将正丙醇/水(55mL/83mL)加入至残留物中，升温至90℃，体系溶清。降温至室温析出固体，过滤，正丙醇/水(1v/1.5v，30mL×3)洗涤，高真空干燥。得到产物4.0g，收率为62％。
1H NMR(400MHz,CDCl 3)δ8.16(d,J＝5.2Hz,1H),6.52(d,J＝5.2Hz,1H),3.85-3.72(m,4H),3.52-3.41(m,4H),1.48(s,9H)。
7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氢-[1,4]二恶英[2,3b]吡啶
Figure PCTCN2022081458-appb-000102
将化合物7-溴-2,3-二氢-[1,4]二恶英[2,3-b]吡啶(180mg,0.84mmoL)、连频哪醇硼酸酯(318mg,1.26mmoL)、醋酸钾(329mg,3.36mmoL)和Pd(dppf)Cl 2(61mg,0.084mmoL)加入到1,4-二氧六环(5mL)中，在氮气保护下于90℃反应过夜。次日TLC检测反应。将反应体系用硅藻土过滤，减压蒸发去溶剂，残留物中加入乙酸乙酯。分液，减压蒸去溶剂。残留物用用快速柱层析分离。得目标产物186mg，收率为84％。
1H NMR(400MHz,CDCl 3)δ8.19(d,J＝1.6Hz,1H),7.53(d,J＝1.6Hz,1H),7.26(s,1H),4.48-4.41(m,2H),4.27-4.20(m,2H),1.33(s,12H)。
MS-ESI:264.4[M+H] +。
4-(4-(2,3-二氢-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000103
除了用7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氢-[1,4]二恶英[2,3b]吡啶替代喹啉-3-基硼酸，以及用4-(4-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代2,4-二氯嘧啶外，4-(4-(2,3-二氢-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为46％。
1H NMR(400MHz,CDCl 3)δ8.47(d,J＝2.2Hz,1H),8.36(d,J＝5.2Hz,1H),7.88(d,J＝2.2Hz,1H),6.89(d,J＝5.2Hz,1H),4.54-4.44(m,2H),4.37-4.26(m,2H),3.94-3.84(m,4H),3.56-3.46(m,4H),1.49(s,9H)。
MS-ESI:400.5[M+H] +。
化合物28
Figure PCTCN2022081458-appb-000104
除了用4-(4-(2,3-二氢-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物28的合成同实施例18中的化合物18。收率为92％。
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝2.2Hz,1H),8.39(d,J＝5.2Hz,1H),7.95(d,J＝2.2Hz,1H),7.18(d,J＝5.2Hz,1H),4.52-4.42(m,2H),4.33-4.27(m,2H),3.77-3.69(m,4H),2.83-2.72(m,4H)。
实施例29 4-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-(哌嗪-1-基)嘧啶(化合物29)的制备
Figure PCTCN2022081458-appb-000105
4-(4-(2,3-二氢苯并[b][1,4]二恶英-6-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000106
除了用(2,3-二氢苯并[b][1,4]二恶英-6-基)硼酸替代替代实施例1中喹啉-3-硼酸外，化合物4-(4-(2,3-二氢苯并[b][1,4]二恶英-6-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施列1中的3-(2-氯嘧啶-4-基)喹啉。收率为57％。
1H NMR(400MHz,CDCl 3)δ8.32(d,J＝5.2Hz,1H),7.63(d,J＝2.2Hz,1H),7.55(dd,J＝8.4,2.2Hz,1H),6.94(d,J＝8.4Hz,1H),6.88(d,J＝5.2Hz,1H),4.36-4.20(m,4H),3.89(t,J＝5.2Hz,4H),3.52(t,J＝5.2Hz,4H),1.50(s,9H)。
MS-ESI:399.5[M+H] +。
化合物29
Figure PCTCN2022081458-appb-000107
除了用4-(4-(2,3-二氢苯并[b][1,4]二恶英-6-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物29的合成同实施例18中的化合物18。收率为53％。
1H NMR(400MHz,CDCl 3)δ8.32(d,J＝5.2Hz,1H),7.63(d,J＝2.2Hz,1H),7.54(dd,J＝8.4,2.2Hz,1H),6.93(d,J＝8.4Hz,1H),6.86(d,J＝5.2Hz,1H),4.36-4.26(m,4H),3.95-3.88(m,4H),3.00-2.98(m,4H)。
MS-ESI:299.5[M+H] +。
实施例30 4-(5,6-二甲氧基-吡啶-3-基)-2-哌嗪-1-基-嘧啶(化合物30)的制备
Figure PCTCN2022081458-appb-000108
2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶
Figure PCTCN2022081458-appb-000109
除了用5-溴-2,3-二甲氧基吡啶替代7-溴-2,3-二氢-[1,4]二恶英[2,3-b]吡啶外，2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶的合成同实施例28中的7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氢-[1,4]二恶英[2,3b]吡啶。收率为93％。
1H NMR(400MHz,CDCl 3)δ8.12(s,1H),7.34(s,1H),4.04(s,3H),3.89(s,3H),1.34(s,12H)。
MS-ESI:266.4[M+H] +。
4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000110
除了用2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶替换7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氢-[1,4]二恶英[2,3b]吡啶外，4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-哌嗪-1-羧酸叔丁酯的合成实施与实施例28中的4-(4-(2,3-二氢-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯。收率为54％。
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝1.8Hz,1H),8.36(d,J＝5.2Hz,1H),7.74(d,J＝1.8Hz,1H),6.91(d,J＝5.2Hz,1H),4.08(s,3H),3.97(s,3H),3.93–3.85(m,4H),3.59–3.49(m,4H),1.50(s,9H)。
MS-ESI:402.5[M+H] +。
化合物30
Figure PCTCN2022081458-appb-000111
除了用4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物30的合成同实施例18中的化合物18。收率为40％。
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝1.8Hz,1H),8.41(d,J＝5.2Hz,1H),7.87(d,J＝1.8Hz,1H),7.23(d,J＝5.2Hz,1H),3.93(s,3H),3.87(s,3H),3.82–3.76(m,4H),2.90–2.80(m,4H)。
MS-ESI:302.4[M+H] +。
实施例31 4-(3,4-二甲氧基-苯基)-2-哌嗪-1-基-嘧啶(化合物31)的制备
Figure PCTCN2022081458-appb-000112
4-[4-(3,4-二甲氧基-苯基)-嘧啶-2-基]-哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000113
除了用2-(3,4-二甲氧基-苯基)-4,4,5,5-四甲基-[1,3,2]二氧硼烷替代2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶外，4-[4-(3,4-二甲氧基-苯基)-嘧啶-2-基]-哌嗪-1-羧酸叔丁酯的合成实施同实施例30的4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-哌嗪-1-羧酸叔丁。收率为60％。
1H NMR(400MHz,CDCl 3)δ8.33(d,J＝5.2Hz,1H),7.67–7.60(m,2H),6.94(d,J＝8.4Hz,1H),6.92(d,J＝5.2Hz,1H),3.98(s,3H),3.94(s,3H),3.92–3.86(m,4H),3.57–3.50(m,4H),1.49(s,9H)。
MS-ESI:401.5[M+H] +。
化合物31
Figure PCTCN2022081458-appb-000114
除了用4-[4-(3,4-二甲氧基-苯基)-嘧啶-2-基]-哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物31的合成同实施例18中的化合物18。收率为51％。
1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝5.2Hz,1H),7.72(dd,J＝8.4,1.8Hz,1H),7.68(d,J＝1.8Hz,1H),7.16(d,J＝5.2Hz,1H),7.06(d,J＝8.4Hz,1H),3.84(s,3H),3.82(s,3H),3.79–3.72(m,4H),2.83–2.76(m,4H)。
MS-ESI:301.5[M+H] +。
实施例32 3-(2-(哌嗪-1-基)嘧啶-4-基)-1H吲哚(化合物32)的制备
Figure PCTCN2022081458-appb-000115
3-(2-(4-(叔丁氧羰基)哌嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000116
除了用3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-1H-吲哚-1-羧酸叔丁酯替代实施例1中喹啉-3-硼酸外，化合物3-(2-(4-(叔丁氧羰基)哌嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为69％。
1H NMR(400MHz,CDCl 3):δ8.40–8.36(m,1H),8.34(d,J＝8.0Hz,1H),8.19(s,2H),7.39-7.5(m,2H),6.93(d,J＝8.0Hz,1H),3.93(t,J＝8.0Hz,4H),3.57(t,J＝8.0Hz,4H),1.71(s,9H),1.51(s,9H)。
MS-ESI:480.6[M+H] +。
3-(2-(哌嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000117
将化合物3-(2-(4-(叔丁氧羰基)哌嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯(284mg,0.59mmoL)溶于DCM(8mL)中，加入HCl/1,4-二氧六环(4M,5mL)，室温反应30min，TLC检测反应完全。减压蒸去溶剂，残留物中加入水(5mL)，用NaOH(3M)调节pH至14。减压蒸去溶剂，残留物用快速柱层析法分离。得目标产物210mg，收率为93％。
1H NMR(400MHz,CDCl 3):δ8.39–8.36(m,1H),8.33(d,J＝4.0Hz,1H),8.19(d,J＝8.0Hz,2H),7.39-7.34(m,2H),6.92(d,J＝4.0Hz,1H),3.98(t,J＝12.0Hz,4H),3.05(t,J＝12.0Hz,4H),1.71(s,9H)。
MS-ESI:380.5[M+H] +。
化合物32
Figure PCTCN2022081458-appb-000118
将化合物3-(2-(哌嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯(210mg,0.551mmoL)溶于正丁醇(2.1mL)和水(1.2mL)的混合体系中，加入浓盐酸(0.23mL)，加热反应过夜，TLC检测反应完全。减压蒸去溶剂。残留物中加入水(5mL)，用NaOH(3M)调节pH至14。.减压蒸去旋干溶剂，残留物用快速柱层析法得到目标产物124mg，收率为80％。
1H NMR(400MHz,CDCl 3)δ8.53(s,1H),8.44–8.38(m,1H),8.29(d,J＝4.0Hz,1H),7.88(d,J＝2.0Hz,1H),7.45–7.39(m,1H),7.29(s,1H),6.88(d,J＝5.2Hz,1H),3.96–3.90(m,4H),3.03-3.00(m,4H)。
MS-ESI:280.5[M+H] +。
实施例33 4-(苯并呋喃-3-基)-2-(哌嗪-1-基)嘧啶(化合物33)的制备
Figure PCTCN2022081458-appb-000119
4-(4-(苯并呋喃-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000120
除了用苯并呋喃-3-基硼酸替代喹啉-3-基硼酸，以及用4-(4-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代2,4-二氯嘧啶外，4-(4-(苯并呋喃-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为84％。
1H NMR(400MHz,CDCl 3)δ8.36(d,J＝5.1Hz,1H),8.23(q,J＝4.3,3.4Hz,2H),7.67–7.50(m,1H),7.43–7.30(m,2H),6.89(d,J＝5.1Hz,1H),4.01–3.85(m,4H),3.57(dd,J＝6.5,4.0Hz,4H),1.50(s,9H)。
MS-ESI:381.5[M+H] +。
化合物33
Figure PCTCN2022081458-appb-000121
除了用4-(4-(苯并呋喃-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物33的合成同实施例18中的化合物18。收率为86％。
1H NMR(400MHz,CDCl 3)δ8.35(d,J＝5.1Hz,1H),8.24(d,J＝10.3Hz,2H),7.65–7.50(m,1H),7.43 –7.31(m,2H),6.86(d,J＝5.1Hz,1H),3.98–3.89(m,4H),3.01(dd,J＝6.0,4.2Hz,4H)。
MS-ESI:281.4[M+H] +。
实施例34 3-甲氧基-5-(2-哌嗪-1-基-嘧啶-4-基)-吡啶-2-醇(化合物34)的制备
Figure PCTCN2022081458-appb-000122
化合物34
Figure PCTCN2022081458-appb-000123
除了将盐酸脱Boc的反应时间延长至过夜，化合物34的合成实施同实施例30的4-(5,6-二甲氧基-吡啶-3-基)-2-哌嗪-1-基-嘧啶。产率为50％。
1H NMR(400MHz,DMSO)δ8.31(d,J＝5.2Hz,1H),7.87(d,J＝2.2Hz,1H),7.44(d,J＝2.2Hz,1H),7.07(d,J＝5.4Hz,1H),3.79(s,3H),3.76–3.64(m,4H),2.83–2.68(m,4H)。
MS-ESI:288.4[M+H] +。
实施例35 3-(4-(哌嗪-1-基)-1,3,5-三嗪-2-基)喹啉(化合物35)的制备
Figure PCTCN2022081458-appb-000124
4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000125
除了用2,4-二氯-1,3,5-三嗪替代实施例1中3-(2-氯嘧啶-4-基)喹啉，以及用哌嗪-1-羧酸叔丁酯代替哌啶-4-基甲胺外，4-(4-氯-1,3,5-三嗪-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为46％。
MS-ESI:300.3[M+H] +。
4-(4-(喹啉-3-基)-1,3,5-三嗪-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000126
除了用4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯代替实施例1中喹啉-3-硼酸外，化合物4-(4-(喹啉-3-基)-1,3,5-三嗪-2-基)哌嗪-1-羧酸叔丁酯的合成同实施列1中的3-(2-氯嘧啶-4-基)喹啉。 收率为42％。
1H NMR(400MHz,CDCl 3)δ:9.92(d,J＝4.0Hz,1H),9.25(d,J＝4.0Hz,1H),8.78(s,1H),8.25(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.87(t,J＝8.0Hz,1H),7.68(t,J＝8.0Hz,1H),4.07(d,J＝44.0Hz,4H),3.65(d,J＝8.0Hz,4H),1.58(s,9H)。
MS-ESI:393.4[M+H] +。
化合物35
Figure PCTCN2022081458-appb-000127
除了用4-(4-(喹啉-3-基)-1,3,5-三嗪-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物35的合成同实施例18中的化合物18。收率为72％。
1H NMR(400MHz,DMSO-d6)δ:9.75(d,J＝4.0Hz,1H),9.30(s,1H),8.74(s,1H),8.22(d,J＝8.0Hz,1H),8.11(d,J＝8.0Hz,1H),7.88(t,J＝8.0Hz,1H),7.70(t,J＝8.0Hz,1H),3.89(d,J＝28.0Hz,4H),2.81(d,J＝16.0Hz,4H),1.23(s,1H)。
MS-ESI:293.4[M+H] +。
实施例36 2-(哌嗪-1-基)-4-(喹啉-3-基)喹唑啉(化合物36)的制备
Figure PCTCN2022081458-appb-000128
2-氯-4-(喹啉-3-基)喹唑啉
Figure PCTCN2022081458-appb-000129
除了用2,4-二氯喹唑啉替代实施例(4-1)中2,4-二氯嘧啶，以及用1,4二氧六环替代乙腈外，2-氯-4-(喹啉-3-基)喹唑啉的合成同实施例1中的中的3-(2-氯嘧啶-4-基)喹啉。收率为73％。
1H NMR(400MHz,CDCl 3)δ9.32(d,J＝4.0Hz,1H),8.67(d,J＝2.0Hz,1H),8.25(d,J＝8.0Hz,1H),8.19–8.10(m,2H),8.05–7.97(m,2H),7.88(t,J＝8.0Hz,1H),7.69(t,J＝8.0Hz,2H)。
MS-ESI:292.4[M+H] +。
4-(4-(喹啉-3-基)喹唑啉-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000130
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺外，4-(4-(喹啉-3-基)喹唑啉-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为84％。
1H NMR(400MHz,CDCl 3)δ9.30(d,J＝2.0Hz,1H),8.54(d,J＝2.0Hz,1H),8.22(d,J＝8.0Hz,1H),7.96(d,J＝8.0Hz,1H),7.91–7.80(m,2H),7.73–7.62(m,3H),7.25–7.20(m,1H),4.10–3.97(m,4H),3.64–3.52(m,4H),1.50(s,9H)。
MS-ESI:442.5[M+H] +。
化合物36
Figure PCTCN2022081458-appb-000131
除了用化合物4-(4-(喹啉-3-基)喹唑啉-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物36的合成同实施例18中的化合物18。收率为82％。
1H NMR(400MHz,DMSO-d6)δ9.23(d,J＝4.0Hz,1H),8.80(d,J＝2.0Hz,1H),8.20–8.13(m,2H),7.95–7.85(m,2H),7.80–7.70(m,2H),7.62(d,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,1H),3.96–3.84(m,4H),2.92–2.81(m,4H)。
MS-ESI:342.3[M+H] +。
实施例37 2-(哌嗪-1-基)-4-(喹啉-3-基)-5,6,7,8-四氢喹唑(化合物37)的制备
Figure PCTCN2022081458-appb-000132
2-氯-4-(喹啉-3-基)-5,6,7,8-四氢喹唑
Figure PCTCN2022081458-appb-000133
除了用2,4-二氯-5,6,7,8-四氢喹唑啉替代2,4-二氯嘧啶外，2-氯-4-(喹啉-3-基)-5,6,7,8-四氢喹唑的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为92％。
1H NMR(400MHz,CDCl 3)δ:9.09(d,J＝2.4Hz,1H),8.39(d,J＝2.4Hz,1H),8.14(d,J＝8.0Hz,1H),7.87(d,J＝8.0Hz,1H),7.78(t,J＝7.5Hz,1H),7.59(t,J＝7.5Hz,1H),2.98(t,J＝8.0Hz,2H),2.81(t,J＝8.0Hz,2H),2.00-1.87(m,2H),1.82-1.69(m,2H)。
MS-ESI:296.4[M+H] +。
4-(4-(喹啉-3-基)-5,6,7,8-四氢喹唑啉-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000134
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，以及用2-氯-4-(喹啉-3-基)-5,6,7,8-四氢喹唑代替实施例1中3-(2-氯嘧啶-4-基)喹啉外，4-(4-(喹啉-3-基)-5,6,7,8-四氢喹唑啉-2-基)哌嗪-1-羧酸叔丁酯的合成实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为78％。
1H NMR(400MHz,CDCl 3)δ:9.14(d,J＝4.0Hz,1H),8.33(d,J＝4.0Hz,1H),8.15(d,J＝8.0Hz,1H),7.88(d,J＝8.0Hz,1H),7.76(t,J＝8.0Hz,1H),7.59(t,J＝8.0Hz,1H),3.88-3.77(m,4H),3.57-3.42(m,4H),2.81(t,J＝8.0Hz,2H),2.70(t,J＝8.0Hz,2H),1.95-1.83(m,2H),1.79-1.67(m,2H),1.48(s,9H)。
MS-ESI:446.6[M+H] +。
化合物37
Figure PCTCN2022081458-appb-000135
除了用4-(4-(喹啉-3-基)-5,6,7,8-四氢喹唑啉-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物37的合成同实施例18中的化合物18。收率为73％。
1H NMR(400MHz,DMSO-d6)δ:9.07(d,J＝4.0Hz,1H),8.58(d,J＝2.4Hz,1H),8.08(t,J＝8.0Hz,2H),7.83(t,J＝8.0Hz,1H),7.67(t,J＝8.0Hz,1H),3.71-3.63(m,4H),2.80-2.69(m,6H),2.66(t,J＝8.0Hz,2H),1.86-1.77(m,2H),1.71-1.62(m,2H),1.23(s,1H)。
MS-ESI:346.5[M+H] +。
实施例38 3-(5-氨基-2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物38)的制备
Figure PCTCN2022081458-appb-000136
3-(2-氯-6-甲氧基嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000137
除了用2,4-二氯-5-氨基嘧啶替代实施例1中2,4-二氯嘧啶外，3-(2-氯-5-氨基嘧啶-4-基)喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为86％。
1H NMR(400MHz,CDCl 3)δ:9.19(d,J＝2.2Hz,1H),8.76(d,J＝2.2Hz,1H),8.29(s,1H),8.14-8.05(m,2H),7.90-7.80(m,1H),7.69(t,J＝8.0Hz,1H),5.95(s,2H)。
MS-ESI:257.3[M+H] +。
4-(5-氨基基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000138
除了用哌嗪-1-羧酸叔丁酯替代哌啶-4-基甲胺，以及用3-(2-氯-5-氨基基嘧啶-4-基)喹啉代替3-(2-氯嘧啶-4-基)喹啉外，4-(5-氨基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为42％。
1H NMR(400MHz,DMSO-d 6)δ:9.36(d,J＝2.2Hz,1H),8.85(d,J＝2.2Hz,1H),8.22(s,1H),8.16-8.06(m,2H),7.86-7.82(m,1H),7.71-7.66(m,1H),4.88(s,2H),3.68-3.61(m,4H),3.48-3.42(m,4H),1.45(s,9H)。
MS-ESI:407.4[M+H] +。
化合物38
Figure PCTCN2022081458-appb-000139
除了用4-(5-氨基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物38的合成同实施例18中的化合物18。收率63％。
1H NMR(400MHz,DMSO)δ:9.32(d,J＝2.2Hz,1H),8.82(d,J＝2.2Hz,1H),8.18(s,1H),8.09-8.03(m,2H),7.81(t,J＝7.6Hz,1H),7.66(t,J＝7.6Hz,1H),4.80(s,2H),3.59(t,J＝5.0Hz,4H),2.82(t,J＝5.0Hz,4H)。
MS-ESI:307.4[M+H] +。
实施例39 3-(6-甲氧基-2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物39)的制备
Figure PCTCN2022081458-appb-000140
3-(2-氯-6-甲氧基嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000141
除了用2,4-二氯-6-甲氧基嘧啶替代实施例1中2,4-二氯嘧啶外，3-(2-氯-6-甲氧基嘧啶-4-基)喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为57％。
1H NMR(400MHz,CDCl 3)δ:9.44(d,J＝2.4Hz,1H),8.90(d,J＝2.4Hz,1H),8.17(d,J＝8.6Hz,1H),8.00-7.93(m,1H),7.81(t,J＝8.6Hz,1H),7.67-7.58(m,1H),7.21(s,1H),4.10(s,3H)。
MS-ESI:272.3[M+H] +。
4-(4-甲氧基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000142
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，以及用3-(2-氯-6-甲氧基嘧啶-4-基)喹啉代替实施例1中3-(2-氯嘧啶-4-基)喹啉外，4-(4-甲氧基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率55％。
1H NMR(400MHz,DMSO-d 6)δ:9.58(d,J＝2.2Hz,1H),9.07(d,J＝2.2Hz,1H),8.12(d,J＝8.0Hz,1H),8.07(d,J＝8.0Hz,1H),7.90-7.78(m,1H),7.68(t,J＝7.4Hz,1H),6.93(s,1H),3.94(s,3H),3.91-3.81(m,4H),3.54-3.43(m,4H),1.44(s,9H)。
MS-ESI:422.5[M+H] +。
化合物39
Figure PCTCN2022081458-appb-000143
除了用4-(4-甲氧基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物39的合成同实施例18中的化合物18。收率为60％。
1H NMR(400MHz,DMSO)δ:9.56(d,J＝2.2Hz,1H),9.04(d,J＝2.2Hz,1H),8.12(d,J＝8.4Hz,1H),8.07(d,J＝8.4Hz,1H),7.82(t,J＝8.4Hz,1H),7.67(t,J＝8.4Hz,1H),6.87(s,1H),3.92(s,3H),3.82(t,J＝5.0Hz,4H),2.81(t,J＝5.0Hz,4H)。
MS-ESI:322.5[M+H] +。
实施例40 3-(2-(哌嗪-1-基)-6-(三氟甲基)嘧啶-4-基)喹啉(化合物40)的制备
Figure PCTCN2022081458-appb-000144
4-(4-氯-6-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000145
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，以及用2,4-二氯-6-(三氟甲基)嘧啶代替3-(2-氯嘧啶-4-基)喹啉外，4-(4-氯-6-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率40％。
1H NMR(400MHz,CDCl 3):δ6.79(s,1H),3.86-3.83(m,4H),3.52-3.50(m,4H),1.49(s,9H)。
4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000146
除了用4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代2,4-二氯嘧啶，以及用1,4-二氧六环替代乙醇外，4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为85％。
1H NMR(400MHz,CDCl 3):δ9.58(d,J＝2.0Hz,1H),8.79(m,d,J＝2.0Hz,1H),8.19(d,J＝8.0Hz,1H),7.96-7.95(m,1H),7.84-7.80(m,1H),7.66-7.64(m,1H),7.37(s,1H),4.00-3.99(m,4H),3.60-3.57(m,4H),1.51(s,9H)。
化合物40
Figure PCTCN2022081458-appb-000147
除了用4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物40的合成同实施例18中的化合物18。收率为83％。
1H NMR(400MHz,DMSO-d6):δ9.67(d,J＝4.0Hz,1H),9.25(d,J＝2.0Hz,1H),8.17-8.15(m,1H),8.10(d,J＝8.0Hz,1H),7.90-7.86(m,1H),7.82(s,1H),7.73-7.71(m,1H),3.90-3.84(m,4H),2.85-2.83(m,4H)。
MS-ESI:360.3[M+H] +。
实施例41 3-(5-(哌嗪-1-基)咪唑并[1,2-c]嘧啶-7-基)喹啉(化合物41)的制备
Figure PCTCN2022081458-appb-000148
4-(7-氯咪唑并[1,2-c]嘧啶-5-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000149
除了用5,7-二氯咪唑并[1,2-c]嘧啶代替实施例1中3-(2-氯嘧啶-4-基)喹啉，用哌嗪-1-羧酸叔丁酯代替哌啶-4-基甲胺，以及用TEA代替DIPEA外，4-(7-氯咪唑并[1,2-c]嘧啶-5-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为90％。
1H NMR(400MHz,CDCl 3)δ:7.60(s,1H),7.40(s,1H),7.21(s,1H),3.68–3.62(m,4H),3.51–3.44(m,4H),1.49(s,9H)。
3-(7-(喹啉-3-基)咪唑并[1，2-c]嘧啶-5-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000150
除了用4-(7-氯咪唑并[1,2-c]嘧啶-5-基)哌嗪-1-羧酸叔丁酯代替2,4-二氯嘧啶，以及用1，4-二氧六环代替乙醇外，4-(7-(喹啉-3-基)咪唑并[1，2-c]嘧啶-5-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为31％。
1H NMR(400MHz,CDCl 3)δ:9.59(s,1H),8.77(s,1H),8.15(d,J＝8.0Hz,1H),7.95(d,J＝8.0Hz,1H),7.84(s,1H),7.75(t,J＝8.0Hz,1H),7.70(s,1H),7.60(t,J＝8.0Hz,1H),7.49(s,1H),3.74(m,4H),3.62–3.55(m,4H),1.52(s,9H)。
化合物41
Figure PCTCN2022081458-appb-000151
除了用4-(7-(喹啉-3-基)咪唑并[1，2-c]嘧啶-5-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物41的合成同实施例18中的化合物18。收率为53％。
1H NMR(400MHz,DMSO)δ：9.68(d,J＝2.0Hz,1H),9.07(d,J＝2.0Hz,1H),8.12–8.04(m,3H),7.89(s,1H),7.83–7.76(m,1H),7.71–7.63(m,2H),3.60–3.54(m,4H),3.12–3.06(m,4H)。
MS-ESI:331.5[M+H] +。
实施例42 3-(6-氰基-2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物42)的制备
Figure PCTCN2022081458-appb-000152
4-(4-氯-6-氰基嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000153
将化合物2,6-二氯嘧啶-4-腈(125mg,0.72mmoL)、4-甲基哌嗪-1-羧酸叔丁酯(144mg,0.72mmoL)溶于甲苯(5mL)中，回流反应1.5h，TLC检测反应完全。减压蒸去溶剂，残留物用快速柱层析分离。得目标产物156mg，收率为67％。
1H NMR(400MHz,CDCl 3)δ6.79(s,1H),3.93-3.72(m,4H),3.58-3.43(m,4H),1.49(s,9H)。
MS-ESI:224.3[M-100] +。
4-(4-氰基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000154
除了用4-(4-氯-6-氰基嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例1中2,4-二氯嘧啶外，4-(4-氰基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为94％。
1H NMR(400MHz,CDCl 3)δ9.53(d,J＝2.2Hz,1H),8.75(d,J＝1.8Hz,1H),8.18(d,J＝8.6Hz,1H),7.97(d,J＝8.2Hz,1H),7.86-7.80(m,1H),7.64(t,J＝7.6Hz,1H),7.37(s,1H),4.03-3.91(m,4H),3.65-3.51(m,4H),1.51(s,9H)。
MS-ESI:417.5[M+H] +。
化合物42
Figure PCTCN2022081458-appb-000155
除了用4-(4-氰基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物42的合成同实施例18中的化合物18。收率为60％。
1H NMR(400MHz,DMSO-d6)δ9.62(d,J＝2.0Hz,1H),9.19(s,1H),8.13(d,J＝8.2Hz,1H),8.10(d,J＝8.4Hz,1H),7.99(s,1H),7.88(t,J＝7.4Hz,1H),7.71(t,J＝7.4Hz,1H),3.87-3.75(m,4H),2.88-2.76(m,4H)。
MS-ESI:317.4[M+H] +。
实施例43 3-(5-甲氧基-2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物43)的制备
Figure PCTCN2022081458-appb-000156
3-(2-氯-5-甲氧基嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000157
除了用2,4-二氯-5-甲氧基嘧啶替代实施例1中2,4-二氯嘧啶外，3-(2-氯-5-甲氧基嘧啶-4-基)喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为76％。
1H NMR(400MHz,CDCl 3)δ9.62(d,J＝2.2Hz,1H),8.95(d,J＝1.8Hz,1H),8.39(s,1H),8.15(d,J＝8.4Hz,1H),7.94(d,J＝8.0Hz,1H),7.85-7.75(m,1H),7.65-7.58(m,1H),4.07(s,3H)。
MS-ESI:272.3[M+H] +。
4-(5-甲氧基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000158
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，3-(2-氯-5-甲氧基嘧啶-4-基)喹啉代替实施例1中3-(2-氯嘧啶-4-基)喹啉外，4-(5-甲氧基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为68％。
1H NMR(400MHz,CDCl3)δ9.63(s,1H),8.91(s,1H),8.26(s,1H),8.14(d,J＝8.8Hz,1H),7.93(d,J＝8.2Hz,1H),7.79-7.73(m,1H),7.62-7.56(m,1H),3.90(s,3H),3.86-3.80(m,4H),3.58-3.51(m,4H),1.50(s,9H)。
MS-ESI:422.5[M+H] +。
化合物43
Figure PCTCN2022081458-appb-000159
除了用4-(5-甲氧基-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物43的合成同实施例18中的化合物18。收率为79％。
1H NMR(400MHz,DMSO-d 6)δ9.48(d,J＝2.2Hz,1H),8.96(d,J＝1.8Hz,1H),8.44(s,1H),8.11(d,J＝7.8Hz,1H),8.06(d,J＝8.4Hz,1H),7.86-7.79(m,1H),7.70-7.62(m,1H),3.88(s,3H),3.72-3.63(m,4H),2.85-2.75(m,4H)。
MS-ESI:322.5[M+H] +。
实施例44 3-(6-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物44)的制备
Figure PCTCN2022081458-appb-000160
3-(6-氯嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000161
除了用4，6-二氯嘧啶替代实施例1中2,4-二氯嘧啶外，3-(6-氯嘧啶-4-基)喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率60％。
1H NMR(400MHz,DMSO-d6)δ：9.68(d,J＝4.0Hz,1H),9.27(d,J＝4.0Hz,1H),9.20(d,J＝4.0Hz,1H),8.58(d,J＝2.0Hz,1H),8.13(dd,J＝20.0,8.0Hz,2H),7.94–7.86(m,1H),7.77–7.69(m,1H)。
MS-ESI:242.4[M+H] +。
4-(6-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000162
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，用3-(6-氯嘧啶-4-基)喹啉代替实施例1中3-(2-氯嘧啶-4-基)喹啉，以及用TEA替代DIPEA外，4-(6-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为95％。
1H NMR(400MHz,DMSO-d6)δ：9.64(d,J＝2.0Hz,1H),9.12(d,J＝2.0Hz,1H),8.68(s,1H),8.10(t,J＝8.0Hz,2H),7.84(t,J＝8.0Hz,1H),7.69(t,J＝8.0Hz,1H),7.60(s,1H),3.82–3.75(m,4H),3.50–3.44(m,4H),1.44(s,9H)。
MS-ESI:392.4[M+H] +。
化合物44
Figure PCTCN2022081458-appb-000163
除了用4-(6-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物44的合成同实施例18中的化合物18。收率为85％。
1H NMR(400MHz,DMSO-d6)δ:9.62(d,J＝2.0Hz,1H),9.11(d,J＝2.0Hz,1H),8.63(s,1H),8.09(t,J＝8.0Hz,2H),7.87–7.78(m,1H),7.72–7.64(m,1H),7.54(s,1H),3.74–3.66(m,4H),2.84–2.76(m,4H)。
MS-ESI:292.5[M+H] +。
实施例45 3-(9-甲基-2-(哌嗪-1-基)-9H-嘌呤-6-基)喹啉(化合物45)的制备
Figure PCTCN2022081458-appb-000164
3-(2-氯-9-甲基-9H-嘌呤-6-基)喹啉
Figure PCTCN2022081458-appb-000165
除了用2,6-二氯-9-甲基-9H-嘌呤替代实施例1中2,4-二氯嘧啶外，3-(2-氯-9-甲基-9H-嘌呤-6-基)喹啉的合成同实施例1中的6-(2-氯嘧啶-4-基)喹啉。收率为58％。
1H NMR(400MH z,DMSO-d 6)δ:10.11(d,J＝2.2Hz,1H),9.63(d,J＝2.2Hz,1H),8.74(s,1H),8.23(d,J＝8.4Hz,1H),8.12(d,J＝8.4Hz,1H),7.91(t,J＝8.2,Hz,1H),7.72(t,J＝8.2Hz,1H),3.87(s,3H)。
MS-ESI:296.3[M+H] +。
4-(9-甲基-6-(喹啉-3-基)-9H-嘌呤-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000166
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，3-(2-氯-9-甲基-9H-嘌呤-6-基)喹啉代替实施例1中3-(2-氯嘧啶-4-基)喹啉外，4-(9-甲基-6-(喹啉-3-基)-9H-嘌呤-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为84％。
1H NMR(400MHz,DMSO-d 6)δ:10.14(d,J＝2.1Hz,1H),9.67(d,J＝2.2Hz,1H),8.29(s,1H),8.18(d,J＝8.0Hz,1H),8.10(d,J＝8.8Hz,1H),7.86(t,J＝8.6Hz,1H),7.70(t,J＝8.0Hz,1H),3.96-3.89(m,4H),3.73(s,3H),3.55-3.47(m,4H)。
MS-ESI:446.5[M+H] +。
化合物45
Figure PCTCN2022081458-appb-000167
除了用4-(9-甲基-6-(喹啉-3-基)-9H-嘌呤-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物45的合成同实施例18中的化合物18。收率为92％。
1H NMR(400MHz,DMSO-d 6)δ:10.12(d,J＝2.0Hz,1H),9.64(d,J＝2.0Hz,1H),8.26(s,1H),8.17(d,J＝8.2Hz,1H),8.10(d,J＝8.4Hz,1H),7.86(t,J＝8.2Hz,1H),7.69(t,J＝8.2Hz,1H),3.86(t,J＝5.0Hz,4H),3.72(s,3H),2.86(t,J＝5.0Hz,4H)。
MS-ESI:346.4[M+H] +。
实施例46 3-(5-氟-2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物46)的制备
Figure PCTCN2022081458-appb-000168
3-(2-氯-5-氟嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000169
除了用2，4-二氯-5-氟嘧啶替代实施例1中2,4-二氯嘧啶外，3-(6-氯嘧啶-4-基)喹啉的合成同实施例1的3-(2-氯嘧啶-4-基)喹啉。收率84％。
MS-ESI:260.7[M+H] +。
4-(5-氟-4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000170
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，用3-(2-氯-5-氟嘧啶-4-基)喹啉代替实施例1 中3-(2-氯嘧啶-4-基)喹啉，以及用TEA替代DIPEA外4-(5-氟-4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为95％。
1H NMR(400MHz,DMSO-d6)δ:9.48(d,J＝2.0Hz,1H),9.00(s,1H),8.63(d,J＝4.0Hz,1H),8.18(d,J＝8.0Hz,1H),8.10(d,J＝8.0Hz,1H),7.93–7.85(m,1H),7.71(m,1H),3.84–3.77(m,4H),3.49–3.44(m,4H),1.43(s,9H)。
MS-ESI:410.5[M+H] +。
化合物46
Figure PCTCN2022081458-appb-000171
除了用4-(5-氟-4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物46的合成同实施例18中的化合物18。收率为75％。
1H NMR(400MHz,DMSO-d6)δ:9.46(s,1H),8.97(s,1H),8.59(d,J＝4.0Hz,1H),8.18(d,J＝8.0Hz,1H),8.10(d,J＝8.0Hz,1H),7.92–7.84(m,1H),7.70(m,1H),3.77–3.70(m,4H),2.84–2.76(m,4H)。
MS-ESI:310.4[M+H] +。
实施例47 2-(哌嗪-1-基)-6-(喹啉-3-基)嘧啶-4-胺(化合物47)的制备
Figure PCTCN2022081458-appb-000172
4-(4-((叔丁氧基羰基)氨基)-6-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000173
将化合物4-(4-氨基-6-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯(395mg，1.26mmoL)溶于二氯甲烷(5mL)中，再加入三乙胺(254mg,2.52mmoL)。在冰浴下缓慢滴加二碳酸二叔丁酯(412mg,1.89mmoL)，滴加完毕后逐渐升温至室温反应。反应1h后，TLC监测反应基本未反应，加入DMAP(40mg，0.33mmoL),室温继续反应。TLC监测反应基本完全。减压蒸去溶剂，残留物用快速柱层析分离。得目标产物487mg，收率为93％。
1H NMR(400MHz,CDCl 3)：δ6.89(s,1H),3.76-3.73(m,4H),3.47-3.44(m,4H),1.49(s,9H),1.46(s,9H)。
4-(4-((叔丁氧羰基)氨基)-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000174
除了用4-(4-((叔丁氧基羰基)氨基)-6-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例1中2,4-二氯嘧啶，用1,4-二氧六环替代乙醇外，4-(4-((叔丁氧羰基)氨基)-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为92％。
1H NMR(400MHz,CDCl 3):δ9.62-9.57(m,1H),8.77-8.75(m,1H),8.17-8.14(m,1H),7.96-7.93(m,1H),7.83-7.75(m,1H),7.61-7.58(m,1H),7.07-7.06(m,1H),3.90-3.87(m,4H),3.54-3.51(m,4H),1.58(s,9H),1.50(s,9H)。
化合物47
Figure PCTCN2022081458-appb-000175
除了用4-(4-((叔丁氧羰基)氨基)-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物47的合成同实施例18中的化合物18。收率为43％。
1H NMR(400MHz,DMSO-d6):δ9.42(d,J＝2.0Hz,1H),8.86(d,J＝2.0Hz,1H),8.12(d,J＝8.0Hz,1H),8.06(d,J＝8.0Hz,1H),7.82-7.79(m,1H),7.67-7.64(m,1H),6.61(s,2H),6.46(s,1H),3.78-3.75(m,4H),2.82-2.80(m,4H)。
MS-ESI:307.4[M+H] +。
实施例48 6-(哌嗪-1-基)-2-(喹啉-3-基)嘧啶-4-胺(化合物48)的制备
Figure PCTCN2022081458-appb-000176
4-(4-氨基-6-氯嘧啶-2-基)哌嗪-1-羧酸叔丁酯和4-(6-氨基-2-氯嘧啶-4-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000177
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，用2,6-二氯嘧啶-4-胺代替实施例1中3-(2-氯嘧啶-4-基)喹啉，4-(6-氨基-2-氯嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为13％。
1H NMR(400MHz,CDCl 3):δ5.41(s,1H),3.56-3.48(m,8H),1.48(s,9H)。
4-(6-氨基-2-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000178
除了用4-(6-氨基-2-氯嘧啶-4-基)哌嗪-1-羧酸叔丁酯替代实施例1中2,4-二氯嘧啶，以及用1,4-二氧六环替代乙醇外，4-(6-氨基-2-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为46％。
1H NMR(400MHz,CDCl 3):δ9.84(d,J＝2.0Hz,1H),9.06(d,J＝2.0Hz,1H),8.15(d,J＝12.0Hz,1H),7.95-7.93(m,1H),7.76-7.72(m,1H),7.58-7.54(m,1H),5.59(s,1H),4.70(s,2H),3.72-3.69(m,4H),3.59-3.56(m,4H),1.50(s,9H)。
化合物48
Figure PCTCN2022081458-appb-000179
除了用4-(6-氨基-2-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物48的合成同实施例18中的化合物18。收率为53％。
MS-ESI:307.3[M+H] +。
实施例49 4-(2-(哌嗪-1-基)-6-(喹啉-3-基)嘧啶-4-基)吗啉(化合物49)的制备
Figure PCTCN2022081458-appb-000180
4-(4-氯-6-吗啉嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000181
除了用哌嗪-1-羧酸叔丁酯替代哌啶-4-基甲胺，以及用4-(2,6-二氯嘧啶-4-基)吗啉替代3-(2-氯嘧啶-4-基)喹啉外，4-(4-氯-6-吗啉嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为89％。
1H NMR(400MHz,CDCl 3)δ5.85(s,1H),3.78-3.70(m,8H),3.58-3.51(m,4H),3.49-3.42(m,4H)。
MS-ESI:384.4[M+H] +。
4-(4-吗啉-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000182
除了用4-(4-氯-6-吗啉嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例1中2,4-二氯嘧啶，以及用1,4-二氧六环替代乙醇外，4-(4-吗啉-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为74％。
1H NMR(400MHz,CDCl 3)δ9.47(d,J＝2.2Hz,1H),8.73(d,J＝1.6Hz,1H),8.15(d,J＝8.6Hz,1H),7.93(d,J＝8.2Hz,1H),7.79-7.71(m,1H),7.59(t,J＝7.6Hz,1H),6.44(s,1H),3.94-3.86(m,4H),3.86-3.80(m,4H),3.72-3.66(m,4H),3.57-3.51(m,4H),1.50(s,9H)。
MS-ESI:477.5[M+H] +。
化合物49
Figure PCTCN2022081458-appb-000183
除了用4-(4-吗啉-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物49的合成同实施例18中的化合物18。收率为81％。
1H NMR(400MHz,DMSO-d 6)δ9.58(d,J＝2.1Hz,1H),9.03(d,J＝1.8Hz,1H),8.08(t,J＝9.1Hz,2H),7.86-7.76(m,1H),7.66(t,J＝7.1Hz,1H),6.89(s,1H),3.81-3.72(m,4H),3.71-3.63(m,8H),2.84-2.78(m,4H)。
MS-ESI:377.5[M+H] +。
实施例50 3-(5-环丙基-2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物50)的制备
Figure PCTCN2022081458-appb-000184
3-(2-氯-5-环丙基嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000185
除了用2,4-二氯-5-环丙基嘧啶替代实施例1中2,4-二氯嘧啶，以及用1,4-二氧六环替代乙醇，3-(2-氯-5-环丙基嘧啶-4-基)喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为67％。
1H NMR(400MHz,CDCl 3)δ9.36(d,J＝2.2Hz,1H),8.66(d,J＝1.7Hz,1H),8.40(s,1H),8.18(d,J＝ 8.4Hz,1H),7.94(d,J＝8.1Hz,1H),7.86–7.76(m,1H),7.66–7.61(m,1H),2.05(tt,J＝8.5,5.5Hz,1H),1.15–1.08(m,2H),0.80(q,J＝5.2Hz,2H)。
MS-ESI:282.4[M+H] +。
4-(5-环丙基-4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000186
除了用哌嗪-1-羧酸叔丁酯替代实施例1中哌啶-4-基甲胺，3-(2-氯-5-环丙基嘧啶-4-基)喹啉代替实施例1中3-(2-氯嘧啶-4-基)喹啉外，4-(5-环丙基-4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为79％。
1H NMR(400MHz,CDCl 3)δ9.37(d,J＝2.0Hz,1H),8.62(d,J＝1.8Hz,1H),8.24(s,1H),8.17(d,J＝8.5Hz,1H),7.92(d,J＝8.1Hz,1H),7.79(t,J＝7.7Hz,1H),7.59(dd,J＝20.7,13.5Hz,1H),3.90–3.80(m,4H),3.58–3.46(m,4H),1.93(dq,J＝8.4,5.4Hz,1H),1.49(s,10H),0.90(s,2H),0.57(d,J＝5.4Hz,2H)。
化合物50
Figure PCTCN2022081458-appb-000187
除了用4-(5-环丙基-4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物50的合成同实施例18中的化合物18。收率为81％。
1H NMR(400MHz,DMSO-d6)δ9.27(d,J＝2.2Hz,1H),8.79(d,J＝1.9Hz,1H),8.29(s,1H),8.13–8.01(m,2H),7.86–7.79(m,1H),7.68(t,J＝7.5Hz,1H),3.79–3.66(m,4H),2.84–2.70(m,4H),2.06–1.94(m,2H),0.87–0.71(m,3H),0.53(q,J＝5.9Hz,2H)。
MS-ESI:331.4[M+H] +。
实施例51 3-(6-(4-甲氧基苯基)-2-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物51)的制备
Figure PCTCN2022081458-appb-000188
3-(2-氯-6-(4-甲氧基苯基)嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000189
除了用2,4-二氯-6-(4-甲氧基苯基)嘧啶替代实施例1中2,4-二氯嘧啶外，3-(2-氯-6-(4-甲氧基苯基)嘧啶-4-基)喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为88％。
1H NMR(400MHz,CDCl 3)δ:9.57(d,J＝4.0Hz,1H),8.99(d,J＝4.0Hz,1H),8.26-8.13(m,3H),8.11(s,1H),8.00(d,J＝8.0Hz,1H),7.83(t,J＝8.0Hz,1H),7.65(t,J＝8.0Hz,1H),7.06(d,J＝8.0Hz,2H),3.92(s,3H)。
MS-ESI:348.4[M+H] +。
4-(4-(4-甲氧基苯基)-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000190
除了用哌嗪-1-羧酸叔丁酯替代哌啶-4-基甲胺，以及用3-(2-氯-6-(4-甲氧基苯基)嘧啶-4-基)喹啉代替3-(2-氯嘧啶-4-基)喹啉外，4-(4-(4-甲氧基苯基)-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为70％。
1H NMR(400MHz,CDCl 3)δ:9.61(d,J＝4.0Hz,1H),8.84(d,J＝4.0Hz,1H),8.19-8.13(m,3H),7.97(d,J＝8.0Hz,1H),7.78(t,J＝8.0Hz,1H),7.62(t,J＝8.0Hz,1H),7.51(s,1H),7.03(d,J＝8.0Hz,2H),4.15-3.99(m,4H),3.90(s,3H),3.66-3.55(m,4H),1.52(s,9H)。
MS-ESI:498.4[M+H] +。
化合物51
Figure PCTCN2022081458-appb-000191
除了用4-(4-(4-甲氧基苯基)-6-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物51的合成同实施例18中的化合物18。收率为74％。
1H NMR(400MHz,DMSO-d6)δ:9.73(d,J＝4.0Hz,1H),9.23(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.13(dd,J＝19.3,8.1Hz,2H),7.95(s,1H),7.85(t,J＝8.0Hz,1H),7.70(t,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,2H),3.96-3.87(m,4H),3.86(s,3H),2.89-2.82(m,4H),1.23(s,1H)。
MS-ESI:398.4[M+H] +。
实施例52 3-(1-甲基-6-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶-4-基)喹啉(化合物52)的 制备
Figure PCTCN2022081458-appb-000192
3-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000193
除了用4,6-二氯-1-甲基-1H-吡唑[3,4-d]嘧啶替代2,4-二氯嘧啶，以及用1,4-二氧六环替代乙腈外，3-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)喹啉的合成同实施例1中的中的3-(2-氯嘧啶-4-基)喹啉。未作纯化直接进行下步反应。
MS-ESI:296.2[M+H] +。
4-(1-甲基-4-(喹啉-3-基)-1H-吡唑[3,4-d]嘧啶-6-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000194
除了用哌嗪-1-羧酸叔丁酯替代哌啶-4-基甲胺外，3-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)喹啉的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为91％。
MS-ESI:296.2[M+H] +。
化合物52
Figure PCTCN2022081458-appb-000195
除了用化合物4-(1-甲基-4-(喹啉-3-基)-1H-吡唑[3,4-d]嘧啶-6-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物52的合成同实施例18中的化合物18。收率为82％。
1H NMR(400MHz,DMSO-d6)δ9.66(d,J＝2.0Hz,1H),9.18(d,J＝2.0Hz,1H),8.55(s,1H),8.27(d,J＝8.0Hz,1H),8.11(d,J＝8.0Hz,1H),7.92–7.84(m,1H),7.74–7.69(m,1H),3.93–23.89(m,4H),3.88(s,3H),2.90–2.79(m,4H)。
MS-ESI:346.4[M+H] +。
实施例53 3-(5-甲基-6-(哌嗪-1-基)嘧啶-4-基)喹啉(化合物53)的制备
Figure PCTCN2022081458-appb-000196
3-(6-氯-5-甲基嘧啶-4-基)喹啉
Figure PCTCN2022081458-appb-000197
除了用4,6-二氯-5-甲基嘧啶替代2,4-二氯嘧啶外，3-(6-氯-5-甲基嘧啶-4-基)喹啉的合成同实施例1中的3-(2-氯嘧啶-4-基)喹啉。收率为49％。
1H NMR(400MHz,CDCl 3):δ9.12(d,J＝4.0Hz,1H),8.95(s,1H),8.41(d,J＝2.0Hz,1H),8.19(dd,J＝16.0,4.0Hz,1H),7.92(dd,J＝8.0,2.0Hz,1H),7.85-7.80(m,1H),7.66-7.62(m,1H),2.53(s,3H)。
MS-ESI:256.3[M+H] +。
4-(5-甲基-6-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022081458-appb-000198
除了用哌嗪-1-羧酸叔丁酯替代哌啶-4-基甲胺，用3-(6-氯-5-甲基嘧啶-4-基)喹啉代替3-(2-氯嘧啶-4-基)喹啉，以及用TEA替代DIPEA外，4-(5-甲基-6-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成同实施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)哌啶-4-基)甲胺。收率为89％。
1H NMR(400MHz,CDCl 3)：δ9.15(d,J＝8.0Hz,1H),8.76(s,1H),8.44-8.43(m,1H),8.16(d,J＝2.0Hz,1H),7.91(dd,J＝8.0,4.0Hz,1H),7.81-7.77(m,1H),7.63-7.59(m,1H),3.62-3.59(m,4H),3.48-3.45(m,4H),2.31(s,3H),1.50(s,9H)。
化合物53
Figure PCTCN2022081458-appb-000199
除了用4-(5-甲基-6-(喹啉-3-基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯替代实施例18中4-(4-(喹啉-3-基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯外，化合物53的合成同实施例18中的化合物18。收率为82％。
1H NMR(400MHz,DMSO-d 6):δ9.17(d,J＝4.0Hz,1H),8.69-8.66(m,2H),8.09(d,J＝8.0Hz,2H),7.87-7.83(m,1H),7.69(t,J＝8.0Hz,1H),3.42-3.35(m,4H),2.85(t,J＝8.0Hz,4H),2.27(s,3H)。
MS-ESI:306.3[M+H] +。
实施例54 CTLA-4小分子降解剂活性检测(蛋白-蛋白相互作用报告系统检测法，CTLA-4蛋白表达水平初筛)
将HEK293细胞铺于96孔板，24h后将LRBA和CTLA-4报告系统共转入HEK293细胞，24h后再加入终浓度分别为0.01、0.033、0.10、0.33、1.00、3.33、10.00、33.33、100.00μM的不同化合物。加药24h后，去除细胞培养基并用冷PBS清洗细胞，再用双荧光素酶检测试剂盒检测化合物的活性，根据检测结果计算IC 50。
对于活性强的化合物(IC 50<200nM)待用蛋白质免疫印迹方法(Western Blot)进一步检测对CTLA-4蛋白降解作用。
IC 50:抑制50％报告系统活性的化合物浓度
IC 50大小分成四个层次：
++++，IC 50<200nM；+++，IC 50为200-1000nM；++，IC 50为1000-2000nM；+，IC 50>2000nM。
本发明化合物IC 50，如下表1所示。
表1化合物对CTLA-4蛋白表达水平的影响(蛋白-蛋白相互作用报告系统)
Figure PCTCN2022081458-appb-000200
Figure PCTCN2022081458-appb-000201
Figure PCTCN2022081458-appb-000202
Figure PCTCN2022081458-appb-000203
Figure PCTCN2022081458-appb-000204
实施例55 移植瘤模型(MC-38)体内活性研究
1.细胞培养：小鼠结肠癌MC-38细胞体外贴壁培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃5％CO 2孵箱培养。一周两到三次常规处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞计数，调整细胞浓度后用于实验接种。
2.动物：C57BL/6小鼠，雌性，7周龄，体重18-20克，每组8只。
3.肿瘤接种：0.02mL(0.2×10 6个)MC-38细胞皮下接种于每只小鼠的右后背。接种后第7天，测量动物肿瘤体积，然后根据肿瘤体积大小随机化分组并开始给药。
4.实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两到三次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
5.动物实验分组、给药方案及实验结果：
Figure PCTCN2022081458-appb-000205
应当理解，以上实施例均为示例性的，不用于包含权利要求所包含的所有可能的实施方式。在不脱离本公开的范围的情况下，还可以在以上实施例的基础上做出各种变形和改变。同样的，也可以对以上实施例的各个技术特征进行任意组合，以形成可能没有被明确描述的本发明的另外的实施例。因此，上述实施例仅表达了本发明的几种实施方式，不对本发明专利的保护范围进行限制。

Claims (20)

  1. 一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物：
    Figure PCTCN2022081458-appb-100001
    其中，
    A、B、C、D、E、F、G、H、I、J、K、L和M各自独立地选自直连键、CR 6、CR 6R 14、N、NR 7、O、S和C＝O；
    每一个R 1、R 2、R 3、R 6、R 7和R 14各自独立地选自氢、氘、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的炔基、未取代或取代的环烷基、未取代或取代的环杂烷基、卤素、-OH、未取代或取代的烷氧基、未取代或取代的芳基烷基、未取代或取代的芳杂基烷基、未取代或取代的芳基醚基、未取代或取代的芳杂基醚基、-CN、-N(R 4R 5)、-NO 2、-N 3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲酰基、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的硫醚基、未取代或取代的亚砜基、未取代或取代的砜基、未取代或取代的磺酰胺基、
    Figure PCTCN2022081458-appb-100002
    未取代或取代的膦酸酯基，其中R 4、R 5、R 8、R 9、R 10和R 11各自独立地选自氢、氘、C 1-6烷基、C 3-7环烷基、未取代或取代的芳基、未取代或取代的芳杂基，且R 4和R 5、R 8和R 9可与相邻的氮原子或碳原子连接成环；
    或相邻的两个R 1和/或相邻的两个R 3也可连接成未取代或取代的环烷基、未取代或取代的环杂烷基、未取代或取代的芳基或未取代或取代的芳杂基；
    m、n、o各自独立地选自0～4的整数；
    W选自直连键、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的环烷基、未取代或取代的环杂烷基、未取代或取代的桥环烷基、未取代或取代的桥环杂烷基、未取代或取代的螺环烷基、未取代或取代的螺环杂烷基、未取代或取代的烷基、未取代或取代的杂烷基、未取代或取代的烯基、未取代或取代的杂烯基、未取代或取代的炔基、未取代或取代的杂炔基、未取代或取代的-N(R 12R 13)、未取代或取代的胺基烷基、未取代或取代的胺基烷基胺基、未取代或取代的
    Figure PCTCN2022081458-appb-100003
    未取代或取代的
    Figure PCTCN2022081458-appb-100004
    其中R 12和R 13各自独立地选自氢、氘、未取代或取代的C 1-6烷基、C 3-7环烷基、未 取代或取代的烷基胺基、未取代或取代的芳基、取代或未取代的芳杂基，或R 12和R 13可连接成环；
    Q为-H、-NH 2、-OH、-烷基-NHC(＝O)H、环烷基、未取代或取代的烷基酰基、未取代或取代的烷基羟基、未取代或取代的烯基羟基、未取代或取代的炔基羟基、未取代或取代的烷基胺基、未取代或取代的磺酰胺基、未取代或取代的烷基磺酰胺基、氨基酸残基、
    Figure PCTCN2022081458-appb-100005
    磺酰胺基、磺酰肼基、未取代或取代的芳基、未取代或取代的芳杂基、未取代或取代的
    Figure PCTCN2022081458-appb-100006
    未取代或取代的
    Figure PCTCN2022081458-appb-100007
    取代或未取代的-(CH 2) n1-(M) n2-(CH 2) n3-(M) n4-(CH 2) n5-(M) n6，其中每个M各自独立地选自O、OH、S、SO、SO 2和未取代或取代的胺基，每个n1、n2、n3、n4、n5和n6各自独立地选自0～6的整数；
    或W和Q可以连接或融合成取代或非取代的环烷基、环杂烷基、芳基或芳杂基。
  2. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：C、G、I中至少一个为N原子。
  3. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：所述J、K、M至少一个为N原子。
  4. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：I、J、K均为N原子，或I、M、K均为N原子。
  5. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：每一个R 1、R 2、R 3、R 6、R 7和R 14各自独立地选自氢、氘、未取代或取代的C 1-6烷基、未取代或取代的C 2-6烯基、未取代或取代的C 2-6炔基、未取代或取代的C 3-7环烷基、未取代或取代的3-7元环杂烷基、卤素、-OH、未取代或取代的C 1-6烷氧基、未取代或取代的C 6-10芳基乙基、未取代或取代的5-10元芳杂基乙基、未取代或取代的C 6-10芳基醚基、未取代或取代的5-10元芳杂基醚基、-CN、-NH 2、-NO 2、-N 3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲酰基、未取代或取代的C 6-10芳基、未取代或取代的5-10元芳杂基、未取代或取代的硫醚基、未取代或取代的亚砜基、未取代或取代的砜基、未取代或取代的磺酰胺基、
    Figure PCTCN2022081458-appb-100008
    未取代或取代的膦酸酯基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
  6. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：W选自直连键、取代或非取代的芳基、芳杂基、环烷基、环杂烷基、桥环烷基、桥环杂烷基、螺环烷基、螺环杂烷基、烷基、杂烷基、烯基、杂烯基、炔基、杂炔基、-N(R 12R 13)、 胺基烷基、胺基烷基胺基、未取代或取代的
    Figure PCTCN2022081458-appb-100009
    未取代或取代的
    Figure PCTCN2022081458-appb-100010
    所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
  7. 如权利要求6所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：W选自取代或非取代的5-7元环杂烷基、取代或非取代的-胺基-C 1-6烷基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
  8. 如权利要求7所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：W中与含J、K的环相连的原子为N。
  9. 如权利要求7所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：W选自取代或非取代的5-7元环杂烷基，所述5-7元杂环烷基至少包含一个氮原子，优选的，所述5-7元杂环烷基为哌啶基或哌嗪基。
  10. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：Q为-H、-NH 2、-OH、-C 1-6烷基-HNC(＝O)H、未取代或取代的C 1-6烷基羟基、未取代或取代的C 2-6烯基羟基、未取代或取代的C 2-6炔基羟基、未取代或取代的烷基胺基、磺酰胺基和磺酰肼基，所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
  11. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：W和Q可以连接或融合成环，所述环为取代或非取代的5-7元环烷基、取代或非取代的5-7元的环杂烷基、取代或非取代的C 6-10芳基、取代或非取代的5-10元芳杂基。
  12. 如权利要求11所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：所述取代是被选自氢、氘、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6卤代烯基、C 1-6卤代炔基、C 3-7环烷基、3-7元杂环烷基、卤素、-OH、C 1-6烷氧基、C 1-6卤代烷氧基、-CN、-NH 2、-NO 2、-N 3、硼酸基、羧基、酯基、甲酰胺基、C 1-6烷基酰胺基、C 6-10芳基、5-10元芳杂基、烷基胺基的取代基所取代。
  13. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：所述式Ⅰ结构的化合物为：
    Figure PCTCN2022081458-appb-100011
    其中，C、G、I、J、K各自独立地选自CR 6和N，且C、G、I中至少一个为N，J和K中至少一个为N；R 1、R 2、R 3、R 6、o、m、n、W、Q的定义和权利要求1相同。
  14. 如权利要求1所述的一种具备式Ⅰ结构的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物，其特征在于：所述式Ⅰ结构的化合物为：
    Figure PCTCN2022081458-appb-100012
    其中，C、G、I、K、M各自独立地选自CR 6和N，且C、G、I中至少一个为N，K和M中至少一个为N；R 1、R 2、R 3、R 6、o、m、n、W、Q的定义和权利要求1相同。
  15. 化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，所述化合物选自：
    Figure PCTCN2022081458-appb-100013
    Figure PCTCN2022081458-appb-100014
    Figure PCTCN2022081458-appb-100015
    Figure PCTCN2022081458-appb-100016
    Figure PCTCN2022081458-appb-100017
    Figure PCTCN2022081458-appb-100018
  16. 一种药物组合物，该组合物包含如权利要求1-15任一项所述的化合物或其药学上可接受的盐、酯、氘代物、异构体、溶剂化物、前药或同位素标记物和药学上可接受的赋形剂。
  17. 根据权利要求16所述的一种药物组合物，所述药物组合物的形式为水性分散剂、液体、啫哩、糖浆、西也剂、药浆、悬浮液、气雾剂、控释剂、速溶剂、泡腾剂、冻干剂、片剂、粉末、药丸、糖衣完、胶囊、延迟释放剂、延长释放剂、脉冲控释剂、多微粒剂或立即释放剂中的任一种。
  18. 权利要求1-15任一项所述的化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者权利要求16-17任一项所述的药物组合物在制备治疗CTLA-4相关疾病的药物中的应用。
  19. 根据权利要求18所述的应用，其特征在于，所述CTLA-4相关疾病包括癌症、自身免疫疾病、免疫缺陷疾病、病毒感染、器官移植排斥。
  20. 根据权利要求19所述的应用，其特征在于，所述癌症选自皮肤癌、膀胱癌、乳腺癌、胰腺癌、骨癌、脑癌、神经细胞瘤、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、绒毛膜癌、胰腺癌、泌尿癌、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、胆囊癌、支气管癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤、乳头状瘤、芽状神经胶质瘤、肉瘤(包括但不限于软骨肉瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤)、黑素瘤、血管瘤、瘢痕瘤、鳞状细胞癌、星细胞瘤、淋巴瘤(包括但不限于非霍奇金淋巴瘤、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病以及中枢神经系统淋巴瘤)、呼吸道癌(包括但不限于肺癌，例如小细胞及非小细胞肺癌，以及支气管腺瘤和胸膜肺母细胞瘤)、头颈癌(包括但不限于头癌、颈癌、喉癌、下咽癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌)、膀胱癌、乳癌(包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌)、消化道癌(包括但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、直肠癌、胃癌、小肠癌以及唾液腺癌)、甲状腺癌、副甲状腺癌及其远距离转移灶、胰腺癌、肝癌(包括但不限于肝细胞癌、具有或不具有纤维板层形式的肝细胞癌、胆管细胞癌以及混合型肝细胞胆管细胞癌)、白血病(包括但不限于急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓性白血病、慢性骨髓性白血病以及绒毛细胞白血病)、脑癌(包括但不限于脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤)、生殖器官癌(包括但不限 于前列腺癌、睾丸癌、卵巢癌、子宫内膜癌、宫颈癌、子宫内膜癌、阴道癌和外阴癌以及子宫肉瘤)、尿道癌、眼癌(包括但不限于眼内黑素瘤和成视网膜细胞瘤)、皮肤癌(包括但不限于卡波西肉瘤、鳞状细胞瘤、恶性黑素瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌)、肾实质癌、肾癌(也称为肾细胞癌和肾腺癌)等相关癌症。
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