WO2020083404A1 - 作为Wee1抑制剂的嘧啶并吡唑酮类衍生物及其应用 - Google Patents

作为Wee1抑制剂的嘧啶并吡唑酮类衍生物及其应用 Download PDF

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WO2020083404A1
WO2020083404A1 PCT/CN2019/113622 CN2019113622W WO2020083404A1 WO 2020083404 A1 WO2020083404 A1 WO 2020083404A1 CN 2019113622 W CN2019113622 W CN 2019113622W WO 2020083404 A1 WO2020083404 A1 WO 2020083404A1
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compound
independently selected
isomer
alkyl
pharmaceutically acceptable
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PCT/CN2019/113622
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English (en)
French (fr)
Inventor
钱文远
杨纯道
李正伟
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to JP2021522414A priority Critical patent/JP7481336B2/ja
Priority to CN201980070354.4A priority patent/CN112955454A/zh
Priority to EP19876246.0A priority patent/EP3875460A4/en
Priority to US17/288,707 priority patent/US20210403451A1/en
Publication of WO2020083404A1 publication Critical patent/WO2020083404A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a pyrimidopyrazolone derivative as a Wee1 inhibitor and its application in the preparation of a medicament for treating Wee1 related diseases. Specifically, it relates to a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the progress of the cell cycle is a complex process controlled by a series of cell cycle regulatory systems.
  • the core component of the cell cycle regulatory system is CDKs / Cyclins formed by the combination of cyclin-dependent kinases (CDKs) and cyclins (Cyclins) Complexes, these complexes can promote the cell to enter the proliferation cycle, and the CDK1 (human homologue also known as CDC2) / Cyclin B complex plays a key role in controlling the cell to enter the M phase.
  • the main function of the cell cycle checkpoint is to suspend the cell cycle and allow the cell to complete DNA repair before entering the M phase.
  • the G1 / S checkpoint at the end of G1 and the G2 / M checkpoint at G2 are the two main cell cycle checkpoints, and they share the functions of DNA damage identification and repair.
  • Wee1 protein kinase is a cell cycle regulator that belongs to the family of serine and threonine protein kinases in the nucleus and is a key kinase in the G2 / M checkpoint.
  • the human "Wee" protein kinase family mainly includes Wee1 and Myt1, which can phosphorylate the Tyr15 site of CDC2, inhibit the activation of CDC2 / CyclinB complex, and block the cell from entering the M phase until DNA repair is completed.
  • Myt1 can also phosphorylate the Thr14 site on CDC2, which is also a negative regulation of CDC2 activity.
  • Wee1 kinase is highly expressed in many cancerous cells. By inhibiting Wee1 kinase, tumor cells can directly skip G2 phase DNA repair, enter mitosis earlier, and cause tumor cell death, so as to achieve the purpose of treating cancer.
  • AstraZeneca's Wee1 inhibitor AZD1775 has entered clinical phase II, there are more than 30 clinical trials are being developed, and has shown good therapeutic effects.
  • AZD1775 was first developed by Merck, so it is also known as MK-1775. In September 2013, Merck transferred the compound to AstraZeneca worldwide.
  • the patents related to it are mainly US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743, etc.
  • Abbott and Abbvie have also conducted research on Wee1 inhibitors, and related patents mainly include US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031, WO2013126656 and so on.
  • Almac's patents on Wee1 inhibitors include WO2014167347, WO2015019037, and WO2015092431.
  • the present invention provides a compound represented by formula (I), its isomer or a pharmaceutically acceptable salt thereof,
  • n 1, 2 or 3;
  • Ring A is selected from C 6-10 aryl, 5-12 membered heteroaryl, C 3-8 cycloalkyl and 4-10 membered heterocycloalkyl;
  • R 1 is selected from H and C 1-3 alkyl, wherein said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b is substituted, and R 2 and R 3 are not H at the same time;
  • R 4 is selected from C 3-8 cycloalkyl and 4-10 membered heterocycloalkyl, the C 3-8 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R c Replace
  • R 5 is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 Rd substitutions;
  • R a is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R b is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the NH 2 and C 1-3 alkyl are optionally substituted by 1, 2 or 3 R replaced;
  • R d is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • the 5-12 membered heteroaryl group and 4-10 membered heterocycloalkyl group contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, O, -S- and N.
  • the aforementioned ring A is selected from C 6-8 membered aryl and 5-10 membered heteroaryl, and other variables are as defined in the present invention.
  • the above compound has the structure represented by formula (II) or (III):
  • n 1, 2 or 3;
  • R 1 each independently selected from H and C 1-3 alkyl, wherein said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b is substituted, and R 2 and R 3 are not H at the same time;
  • R 4 is independently selected from C 3-8 cycloalkyl and 4-10 membered heterocycloalkyl, and the C 3-8 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R c substitutions;
  • R 5 is independently selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, and C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted by 1 , 2 or 3 Rd substitutions;
  • R a is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R b is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c is independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the NH 2 and C 1-3 alkyl are optionally substituted by 1, 2 or 3 R replaced;
  • R d is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • the 4-10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, O, -S- and N;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the above compound has the structure represented by formula (II-A) or (III-A):
  • r is 1 or 2;
  • D is independently selected from -N (R 6 )-and -C (R 7 ) (R 8 )-;
  • R 6 is independently selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 R e ;
  • R 7 and R 8 are independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the NH 2 and C 1-3 alkyl are optionally substituted by 1, 2 Or 3 R f substitutions;
  • R e is independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R f is independently selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • R 1 , R 2 and R 3 are as defined in the present invention.
  • R c is independently selected from F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and other variables are as defined in the present invention.
  • R f is independently selected from F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and other variables are as defined in the present invention.
  • R 1 is independently selected from H, CH 3 and Et, and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and R 2 and R 3 are not H at the same time, other The variables are as defined in the present invention.
  • R 5 is independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et, and OCH 3 , and other variables are as defined in the present invention.
  • R 6 is independently selected from H, CH 3 and Et, and other variables are as defined in the present invention.
  • R 7 and R 8 are independently selected from H, F, Cl, Br, I, OH, NH 2 , -NH (CH 3 ), -N (CH 3 ) 2 , CH 3 And Et, other variables are as defined in the present invention.
  • R 7 is independently selected from H, F, Cl, Br, I, OH, NH 2 , -NH (CH 3 ), -N (CH 3 ) 2 , CH 3 and Et, Other variables are as defined in the present invention.
  • R 8 is independently selected from H, F, Cl, Br, I, OH, CH 3 and Et, and other variables are as defined in the present invention.
  • the above compound, its enantiomer, its optical isomer or a pharmaceutically acceptable salt thereof the compound has the formula (II-A1), (II-A2) or (III- AA1) Structure shown
  • R 1 , R 2 , R 3 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the above compound, its enantiomer and its pharmaceutically acceptable salt the compound has the structure represented by formula (II-1), (II-2) or (III-A1)
  • R 1 , R 2 , R 3 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention also provides a compound of the formula, its isomer or a pharmaceutically acceptable salt thereof,
  • the above compound, its isomer or a pharmaceutically acceptable salt thereof in some embodiments of the present invention, the above compound, its isomer or a pharmaceutically acceptable salt thereof,
  • the invention also provides the application of the above compound or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Wee1 related diseases.
  • the compound of the present invention has a good inhibitory effect on Wee1 kinase and has good permeability; in terms of pharmacokinetics, many pharmacokinetic indicators are good, including in vivo clearance rate, half-life, in vivo concentration integration and Bioavailability has obvious advantages.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base or
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and their racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers in a mirror image relationship with each other.
  • cis-trans isomer or “geometric isomer” is caused by the fact that double bonds or single bonds of ring-forming carbon atoms cannot rotate freely.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and there is a non-mirror relationship between the molecules.
  • wedge-shaped solid line key And wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys And straight dotted keys Represents the relative configuration of the three-dimensional center
  • wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dotted keys
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or (A-2) or as two isomers of formula (A-1) and formula (A-2) Exists in the form of a mixture;
  • the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or in both formula (B-1) and formula (B-2) There is a mixture of isomers.
  • the following formula (C) indicates that the compound exists as a single isomer of formula (C-1) or (C-2) or as two isomers of formula (C-1) and formula (C-2) In the form of a mixture.
  • tautomer or “tautomeric form” means that at room temperature, isomers of different functional groups are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton migration such as ketone-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include some recombination of bond-forming electrons for mutual conversion.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “rich in one isomer”, “isomer enriched”, “rich in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or pairs
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater or equal 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the excess of isomer or enantiomer (ee value) is 80% .
  • optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography, which uses a chiral stationary phase, and is optionally combined with chemical derivatization methods (for example, the formation of amino groups from amines) Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • the hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have lower toxicity and increase drug stability. , Strengthen the efficacy, extend the biological half-life of drugs and other advantages.
  • the conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.
  • “Optional” or “optionally” means that the subsequently described event or condition may, but need not necessarily occur, and that the description includes situations where the event or condition occurs and circumstances where the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R in each case has independent options.
  • combinations of substituents and / or variants thereof are only allowed if such combinations will produce stable compounds.
  • linking group When the number of a linking group is 0, such as-(CRR) 0- , it means that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, it means that the structure is actually A-Z. When a substituent is vacant, it means that the substituent does not exist. For example, when X is vacant in A-X, it means that the structure is actually A.
  • the number of atoms on a ring is usually defined as the number of members of the ring.
  • “5-7 membered ring” refers to a “ring” with 5-7 atoms arranged around it.
  • 4-10 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl consisting of 4 to 10 ring atoms Radical or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic system such as a spiro ring, a bicyclic ring, and a bridge ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 4-10 member ring includes 4-9 member, 4-8 member, 4-7 member, 4-6 member ring, 4-10 member, 4-9 member, 4-8 member, 4-7 member ring, etc. .
  • "4-7 membered ring” includes, for example, phenyl, pyridyl, piperidinyl and the like; on the other hand, the term “4-7 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • the term "ring” also includes ring systems containing at least one ring, where each "ring" independently conforms to the above definition.
  • 5-12 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl consisting of 5 to 12 ring atoms Radical or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic system such as a spiro ring, a bicyclic ring, and a bridge ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 5-12 member ring includes 5-10 member, 5-9 member, 5-8 member, 5-7 member, 5-6 member, 6-10 member, 6-9 member, 6-8 member and 6-member 7 yuan ring etc.
  • 5-7 membered ring includes, for example, phenyl, pyridyl, piperidinyl, and the like; on the other hand, the term “5-7 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, where each "ring" independently conforms to the above definition.
  • 6-12 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl consisting of 6 to 12 ring atoms Radical or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic system such as a spiro ring, a bicyclic ring, and a bridge ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 6-12 member ring includes 6-10 member, 6-9 member, 6-8 member, 6-7 member ring and the like.
  • 5-7 membered ring includes, for example, phenyl, pyridyl, piperidinyl, and the like; on the other hand, the term “5-7 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, where each "ring” independently conforms to the above definition.
  • 5-10 membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl group consisting of 5 to 10 ring atoms Radical or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic system such as a spiro ring, a bicyclic ring, and a bridge ring.
  • the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 5-10 member ring includes 5-9 member, 5-8 member, 5-7 member, 5-6 member ring, 6-10 member, 6-9 member, 6-8 member, 6-7 member ring, etc. .
  • 5-7 membered ring includes, for example, phenyl, pyridyl, piperidinyl and the like; on the other hand, the term “5-7 membered heterocycloalkyl” includes piperidinyl and the like but does not include phenyl.
  • ring also includes ring systems containing at least one ring, where each "ring” independently conforms to the above definition.
  • 5-8 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl consisting of 5 to 8 ring atoms Radical or heteroaryl.
  • the ring includes a single ring, and also includes a double ring system such as a spiro ring, a bicyclic ring, and a bridge ring.
  • the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 5-8 member ring includes 5-7 member, 6-8 member, 6-7 member and so on.
  • 5-7 membered ring includes, for example, phenyl, pyridyl, piperidinyl, and the like; on the other hand, the term “5-7 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, where each "ring” independently conforms to the above definition.
  • 5-6 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl consisting of 5 to 6 ring atoms Radical or heteroaryl.
  • the ring includes a single ring, and also includes a double ring system such as a spiro ring, a bicyclic ring, and a bridge ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 5-6 member ring includes 5 member, 6 member ring, and the like.
  • 5-6 membered ring includes, for example, phenyl, pyridyl, piperidinyl, and the like; on the other hand, the term “5-6 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, where each "ring” independently conforms to the above definition.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc .; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule by one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include but are not limited to -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 , -N (CH 3 ) CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 etc.
  • C 3-8 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro ring, para ring and Bridge ring.
  • the C 3-8 cycloalkyl includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl, etc .; It can be one price, two prices or multiple prices.
  • C 3-8 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, and the like.
  • the term "4-10 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 10 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes monocyclic, bicyclic and tricyclic systems, of which the bicyclic and tricyclic systems include spiro ring, parallel ring and bridge ring.
  • a hetero atom may occupy the connection position of the heterocyclic alkyl group to the rest of the molecule.
  • the 4-10 membered heterocycloalkyl group includes 4-8 membered, 4-6 membered, 4-5 membered, 5-6 membered, 4 membered, 5 membered, 6 membered heterocyclic alkyl group and the like.
  • 4-10 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thiatanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithialkyl, isoxazolidinyl, isothiazolidinyl
  • 5-12 membered heteroaryl ring and “5-12 membered heteroaryl group” of the present invention can be used interchangeably.
  • the term “5-12 membered heteroaryl group” means from 5 to 12 ring atoms
  • the cyclic group consisting of a conjugated ⁇ electron system has 1, 2, 3, or 4 ring atoms as heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. It can be a monocyclic ring, fused bicyclic ring or fused tricyclic ring system, where each ring is aromatic.
  • nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , p is 1 or 2).
  • the 5-12 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom.
  • the 5-12 membered heteroaryl group includes 5-10 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups.
  • Examples of the 5-12 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazoly
  • C 6-10 aromatic ring and “C 6-10 aryl group” of the present invention can be used interchangeably.
  • the term “C 6-10 aromatic ring” or “C 6-10 aryl group” means A cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated ⁇ -electron system. It can be a single ring, a fused bicyclic ring, or a fused tricyclic ring system, where each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).
  • C 6-8 aromatic ring and “C 6-8 aryl group” of the present invention can be used interchangeably.
  • the term “C 6-8 aromatic ring” or “C 6-8 aryl group” means A cyclic hydrocarbon group consisting of 6 to 8 carbon atoms with a conjugated ⁇ -electron system. It can be a single ring, a fused bicyclic ring or a fused tricyclic ring system, where each ring is aromatic. Examples which may be a C 6-8 aryl group is a monovalent, divalent or polyvalent, C 6-8 aryl groups include C 6 aryl groups include but are not limited to, phenyl and the like.
  • C n-n + m or C n -C n + m includes any specific case of n to n + m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also includes any range from n to n + m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc .; similarly, n yuan to n + m member means that the number of atoms in the ring is n to n + m, for example, 3-12 member ring includes 3 member ring, 4 member ring, 5 member ring, 6 member ring, 7 member ring, 8 member ring, 9 member ring , 10-membered
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc .; acyloxy, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyld
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of hydroxyl groups.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl groups (such as acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-flu
  • the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffractometry (SXRD), the cultured single crystal is collected with Bruker D8 venture diffractometer to diffract the intensity data, the light source is CuK ⁇ radiation, scanning mode: After scanning and collecting relevant data, the crystal structure can be further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.
  • SXRD single crystal X-ray diffractometry
  • the cultured single crystal is collected with Bruker D8 venture diffractometer to diffract the intensity data
  • the light source is CuK ⁇ radiation
  • scanning mode After scanning and collecting relevant data, the crystal structure can be further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • the compounds of the present invention may have various uses or indications, including but not limited to the specific uses or indications listed in this application.
  • the solvent used in the present invention is commercially available.
  • the following abbreviations are used in the present invention: aq stands for water; ACN stands for acetonitrile; Tris-HCl stands for trimethylolaminomethane hydrochloride; EDTA stands for ethylenediaminetetraacetic acid; m-CPBA stands for m-chloroperoxybenzoic acid; NH 3 H 2 O stands for ammonia; DEA stands for diethanolamine; IPA stands for isopropanol.
  • reaction system was poured into 17.5L of water to quench, liquid separation was allowed to stand, the liquid phase was extracted again with 8.8L of toluene, the organic phase was combined, washed with water (15.8L * 2), concentrated under reduced pressure to no fraction to obtain black liquid 1 -D.
  • the dichloromethane (500mL) solution (60.96g, 164.58mmol) of the starting compound 1-F was cooled to -40 ° C in a dry ice ethanol bath, and then exposed to ozone for 2.5 hours. After the reaction was completed, the open Oxygen was added for 40 minutes, and then nitrogen was vented for 20 minutes. Triphenylphosphine (47.48g, 181.04mmol) was slowly added to the system at -40 ° C. After the addition, triphenylphosphine was slowly returned to the reaction at 20 ° C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure and dried to obtain a crude product.
  • the crude product was added to ethyl acetate (80 mL), then slowly added petroleum ether (300 mL), stirred (a sticky substance precipitated), filtered, and the filtrate was decompressed Concentrate and spin to no fraction, and a solid precipitates.
  • To the crude product add petroleum ether (300 mL), stir for 10 minutes, and filter. The filtrate is concentrated under reduced pressure and rotated to a non-fraction to obtain the crude product.
  • reaction solution was concentrated under reduced pressure and rotated to no fraction, then 100 mL of water and 80 mL of ethyl acetate extraction and ammonia water (5 mL of 25%) were added, the solution was allowed to stand for separation, and the lower aqueous phase was reused with ethyl acetate ( Add 3mL of 25% aqueous ammonia) to extract (50mL * 1), combine the two organic phases, and wash the organic phase with water (80mL * 1), then with saturated brine (100mL * 1), leave the liquid to stand for separation, the organic phase Concentrate under reduced pressure and spin to obtain no crude fraction.
  • reaction solution was added with water (100 mL), concentrated under reduced pressure to remove the solvent, then added with water (100 mL), extracted with ethyl acetate (80 mL * 1), and the organic phase was washed with saturated brine (100 mL *) 1), The organic phase is concentrated under reduced pressure and rotated to no fraction to obtain crude product.
  • reaction solution was added to a saturated sodium sulfite solution (3 mL) and stirred for 10 minutes, then sodium hydroxide solution (4 mL, 3N) was added, stirred for 10 minutes, and then dichloromethane was added for extraction (10 mL * 3), and the organic phases were combined, The organic phase was washed with water (25 mL * 1), then with saturated brine (20 mL * 2), and allowed to stand for liquid separation. The organic phase was concentrated under reduced pressure and rotated to a non-fraction fraction to obtain a crude product.
  • the crude product was separated by preparative liquid phase (chiral column: Waters Xbridge BEH C18 100 * 30mm * 10 ⁇ m; mobile phase: [H 2 O (0.04% NH 3 H 2 O + 10 mM NH 4 HCO 3 ) -ACN]; ACN% : 20% -50%, 10 min) to obtain crude compound 1.
  • the crude compound continues resolved by SFC (Chiral column: DAICEL CHIRALPAK AD (250mm * 30mm , 10 ⁇ m); mobile phase: [0.1% NH 3 H 2 O MeOH]; MeOH%: 60% -60%, 15min) to give Target compound 1 (retention time: 6.02 minutes).
  • compound 2-K (4.59 g, 18.71 mmol) was added to methylene chloride (90 mL), and then formaldehyde solution (3.04 g, 37.43 mmol, 2.79 mL, 37% purity) and Triethylamine (3.79g, 37.43mmol, 5.21mL), after stirring for 5 minutes, add acetic acid (3.5mL), stir at 20 ° C for 1 hour, then add sodium cyanoborohydride (3.53g, 56.14mmol), stir 2hr.
  • reaction solution was first cooled by ice water, and slowly added sodium hydroxide solution to the reaction solution to quench (50mL, 1M), then diluted with water (150mL), left to separate, and the dichloromethane organic phase was reused It was washed once with saturated brine (100 mL), and the organic phase was concentrated under reduced pressure and rotated to no fraction to obtain a crude product.
  • Triethylsilyl triflate (4.35g, 16.46mmol, 3.72mL, 0.1eq) was added at -10 ° C to 0 ° C, and stirring was continued for 12h hours. After the reaction was completed, the reaction solution was washed with saturated citric acid solution (500 mL * 3) to obtain the target compound 1-F in methylene chloride solution and directly put into the next step.
  • the raw material was a solution of compound 1-F in dichloromethane (500 mL) (according to the theoretical yield of 164.58 mmol), and the temperature was reduced to -40 ° C through a dry ice ethanol bath, and then exposed to ozone for 2.5 hours. After the reaction was detected, it was opened. Oxygen was bubbled in for 45 minutes, and then nitrogen gas was opened for 30 minutes. Triphenylphosphine (43.17g, 164.58mmol,) was slowly added to the system at -40 ° C. After the addition was completed, the reaction was slowly resumed at 20 ° C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure and spin-dried to obtain a crude product.
  • the system was cooled to room temperature, concentrated to remove the solvent, 200 mL of water and 20 mL of ammonia water were added thereto, and then liquid separation was extracted with 200 mL of ethyl acetate, the liquid phase was again extracted and separated with 100 mL of ethyl acetate, the organic phases were combined, and 200 mL of water and 10 mL were combined It was washed with ammonia water and then with 200 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried.
  • reaction solution was added with water (50 mL), followed by extraction with dichloromethane (30 mL), the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL) again, the organic phases were combined twice, and the organic phase It was washed once with saturated common salt (120 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to no fraction to obtain compound 2-E. Invest directly in the next step.
  • compound 2-G (0.23 g, 593.65 ⁇ mol) was added to methylene chloride (3 mL), followed by m-chloroperoxybenzoic acid (192.08 mg, 890.48 ⁇ mol, 80% purity, 1.5 eq), After stirring for 2 hours, the raw material spots did not disappear completely after detecting the reaction. After adding m-chloroperoxybenzoic acid (64.03 mg, 296.83 ⁇ mol, 80% purity), stirring was continued for 1 hour. The reaction is detected, the raw material point disappears, and an intermediate state is generated.
  • N, N-diisopropylethylamine (191.81 mg, 1.48 mmol, 258.51 ⁇ L) and compound 2-H (136.14 mg, 593.65 ⁇ mol) were sequentially added, and the mixture was heated to 40 ° C and stirred for 12 hours.
  • the reaction solution was quenched with saturated sodium sulfite (7ml) and stirred for 10 minutes, then sodium hydroxide solution (6mL, 3M) was added, extracted with ethyl acetate (10mL * 3), the organic phases were combined, and the organic phase was used It was washed with saturated brine (25 mL * 2), and the organic phase was concentrated under reduced pressure and rotated to no fraction to obtain a crude product.
  • the crude product was separated by high-performance liquid phase (chiral column: Waters Xbridge Prep OBD C18 150 * 40mm * 10 ⁇ m; mobile phase: [H 2 O (10mM NH 4 HCO 3 ) -ACN]; ACN%: 30% -60%, 8min ) To obtain the target compound 2.
  • the compounds of the present invention for experiments are all self-made.
  • the experimental tests are conducted at Eurofins, and the experimental results are provided by the company.
  • mice The experimental animals selected were BALB / c nude mice (6 in each group), 6-8 weeks old, and weighed 16-21 grams.
  • the establishment of the PC-07-0049 human pancreatic cancer model was originally derived from surgically removed clinical samples and was defined as the P0 generation after implantation in nude mice.
  • the implantation of P0 tumor tissue into the next generation is called P1 generation. And so on continue to implant in nude mice.
  • the FP3 tumor was recovered through the P2 generation.
  • the next generation produced by the FP3 generation is defined as FP4, and so on, the tumor tissue of the FP5 generation will be used for this drug efficacy test.
  • PC-07-0049 FP5 tumor tissue was cut into small pieces (20-30mm 3 ) after removing necrotic tissue, and subcutaneously inoculated into the right back of each nude mouse. When the average tumor volume reached about 193mm 3 , according to the tumor volume Randomly group and start dosing.
  • TGI (%) [(1- (average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group)) / (average tumor 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

一种作为Wee1抑制剂的嘧啶并吡唑酮类衍生物，以及在制备治疗Wee1相关疾病的药物中的应用。具体涉及式(I)所示化合物、其异构体或其药学上可接受的盐。（I）

Description

作为Wee1抑制剂的嘧啶并吡唑酮类衍生物及其应用
相关申请的交叉引用
CN201811257877.3，申请日：2018年10月26日；
CN201910650345.4，申请日：2019年07月18日。
技术领域
本发明涉及一种作为Wee1抑制剂的嘧啶并吡唑酮类衍生物，以及在制备治疗Wee1相关疾病的的药物中的应用。具体涉及式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐。
背景技术
细胞周期的进程是由一系列细胞周期调控系统控制的复杂过程，细胞周期调控系统的核心成分是周期蛋白依赖性激酶(cyclin-dependent kinases,CDKs)与周期蛋白(Cyclins)结合形成的CDKs/Cyclins复合物，这些复合物能促进细胞进入增殖周期，其中CDK1(人类的同源体也称为CDC2)/Cyclin B的复合物对控制细胞进入M期起关键性的作用。
在细胞进入M期之前需要完成DNA的复制，由于受到各种内源性和外源性因素的干扰DNA经常会发生突变或损伤，这些发生异常的DNA必须完成修复，否则会引起有丝分裂灾难，造成细胞死亡。细胞周期检查点的主要功能就是暂停细胞周期，让细胞完成DNA的修复后再进入M期。位于G1末期的G1/S检查点和G2期的G2/M检查点是两个主要的细胞周期检查点，它们共同担负DNA损伤的识别和修复功能。正常细胞利用G1/S检查点在G1期就可以完成DNA的修复，而近50％的癌变细胞存在抑癌基因p53缺陷，这也同时使它们缺失了G1/S检查点功能，它们需要更多地依赖G2/M检查点完成DNA的修复。G2/M检查点很少发生突变，正是因为有了它，癌细胞可以逃过DNA损伤剂和放射的治疗。
Wee1蛋白激酶是一种细胞周期调节因子，属于核内的丝氨酸和苏氨酸蛋白激酶家族的一员，是G2/M检查点的关键激酶。人类的”Wee”蛋白激酶家族主要包括Wee1和Myt1两种，均可使CDC2上的Tyr15位点磷酸化，抑制CDC2/CyclinB复合物的激活，阻滞细胞进入M期，直到完成DNA的修复，而Myt1还可磷酸化CDC2上的Thr14位点，这也是针对CDC2活性进行的负调控。在很多种癌变细胞中Wee1激酶高表达，通过对Wee1激酶的抑制，可以使肿瘤细胞直接跳过G2期的DNA修复，提前进入有丝分裂，致肿瘤细胞死亡，达到治疗癌症的目的。
目前AstraZeneca的Wee1抑制剂AZD1775已进入临床II期，有超过30项的临床实验正在开发，并已显示出良好的治疗效果。AZD1775最早由Merck开发，因此又称为MK-1775，2013年9月Merck向AstraZeneca在全球范围内转让了该化合物，与之相关的专利主要有US20070254892、WO2007126122、EP2213673、WO2008133866、WO2011034743等。Abbott和Abbvie对Wee1抑制剂也展开过研究，相关专利主要有US2012220572、WO2013126656、WO2013012681、WO2013059485、WO2013013031、 WO2013126656等。Almac公司关于Wee1抑制剂的专利包括WO2014167347、WO2015019037、WO2015092431。
发明内容
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019113622-appb-000001
其中，
Figure PCTCN2019113622-appb-000002
为单键或双键；
n为1、2或3；
环A选自C 6-10芳基、5-12元杂芳基、C 3-8环烷基和4-10元杂环烷基；
R 1选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代，且R 2和R 3不同时为H；
R 4选自C 3-8环烷基和4-10元杂环烷基，所述C 3-8环烷基和4-10元杂环烷基任选被1、2或3个R c取代；
R 5选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基任选被1、2或3个R d取代；
R a分别独立地选自F、Cl、Br、I、OH和NH 2；
R b分别独立地选自F、Cl、Br、I、OH和NH 2；
R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述NH 2和C 1-3烷基任选被1、2或3个R取代；
R d分别独立地选自F、Cl、Br、I、OH和NH 2；
R分别独立地选自F、Cl、Br、I、OH和NH 2；
所述5-12元杂芳基和4-10元杂环烷基包含1、2、3或4个独立选自-NH-、O、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述环A选自C 6-8元芳基和5-10元杂芳基，其他变量如本发明所定义。
本发明的一些方案中，上述化合物具有式(Ⅱ)或(Ⅲ)所示结构：
Figure PCTCN2019113622-appb-000003
其中，
Figure PCTCN2019113622-appb-000004
为单键或双键；
n为1、2或3；
R 1分别独立地选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代，且R 2和R 3不同时为H；
R 4分别独立地选自C 3-8环烷基和4-10元杂环烷基，所述C 3-8环烷基和4-10元杂环烷基任选被1、2或3个R c取代；
R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基任选被1、2或3个R d取代；
R a分别独立地选自F、Cl、Br、I、OH和NH 2；
R b分别独立地选自F、Cl、Br、I、OH和NH 2；
R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述NH 2和C 1-3烷基任选被1、2或3个R取代；
R d分别独立地选自F、Cl、Br、I、OH和NH 2；
R分别独立地选自F、Cl、Br、I、OH和NH 2；
所述4-10元杂环烷基包含1、2、3或4个独立选自-NH-、O、-S-和N的杂原子或杂原子团；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述化合物具有式(Ⅱ-A)或(Ⅲ-A)所示结构：
Figure PCTCN2019113622-appb-000005
其中，
r为1或2；
D分别独立地选自-N(R 6)-和-C(R 7)(R 8)-；
R 6分别独立地选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R e取代；
R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述NH 2和C 1-3烷基任选被1、2或3个R f取代；
R e分别独立地选自F、Cl、Br、I、OH和NH 2；
R f分别独立地选自F、Cl、Br、I、OH、NH 2和C 1-3烷基；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
R 1、R 2和R 3如本发明所定义。
本发明的一些方案中，上述R c分别独立地选自F、Cl、Br、I、OH、NH 2、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R f分别独立地选自F、Cl、Br、I、OH、NH 2、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R 1分别独立地选自H、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，且R 2和R 3不同时为H，其他变量如本发明所定义。
本发明的一些方案中，上述R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 6分别独立地选自H、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2、-NH(CH 3)、-N(CH 3) 2、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、-NH(CH 3)、-N(CH 3) 2、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R 8分别独立地选自H、F、Cl、Br、I、OH、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019113622-appb-000006
选自
Figure PCTCN2019113622-appb-000007
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019113622-appb-000008
选自
Figure PCTCN2019113622-appb-000009
其他变量如本发明所定义。
本发明的一些方案中，上述构单元
Figure PCTCN2019113622-appb-000010
选自
Figure PCTCN2019113622-appb-000011
Figure PCTCN2019113622-appb-000012
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019113622-appb-000013
选自
Figure PCTCN2019113622-appb-000014
Figure PCTCN2019113622-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述化合物、其对映异构体、其旋光异构体或其药学上可接受的盐，其化合物具有式(Ⅱ-A1)、(Ⅱ-A2)或(Ⅲ-AA1)所示结构
Figure PCTCN2019113622-appb-000016
其中，R 1、R 2、R 3、R 6、R 7和R 8如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
上述
Figure PCTCN2019113622-appb-000017
表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。
本发明的一些方案中，上述化合物、其对映异构体其药学上可接受的盐，其化合物具有式(Ⅱ-1)、(Ⅱ-2)或(Ⅲ-A1)所示结构
Figure PCTCN2019113622-appb-000018
其中，R 1、R 2、R 3、R 6、R 7和R 8如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明还提供了下式化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019113622-appb-000019
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019113622-appb-000020
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗Wee1相关疾病药物中的应用。
技术效果
作为新型的Wee1抑制剂，本发明化合物对Wee1激酶具有很好的抑制作用，渗透性良好；药代动力学方面，药代动力学多项指标良好，其中体内清除率，半衰期，体内浓度积分以及生物利用度都有明显优势。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸 氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019113622-appb-000021
和楔形虚线键
Figure PCTCN2019113622-appb-000022
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019113622-appb-000023
和直形虚线键
Figure PCTCN2019113622-appb-000024
表示立体中心的相对构型，用波浪线
Figure PCTCN2019113622-appb-000025
表示楔形实线键
Figure PCTCN2019113622-appb-000026
或楔形虚线键
Figure PCTCN2019113622-appb-000027
或用波浪线
Figure PCTCN2019113622-appb-000028
表示直形实线键
Figure PCTCN2019113622-appb-000029
和直形虚线键
Figure PCTCN2019113622-appb-000030
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2019113622-appb-000031
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2019113622-appb-000032
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物 半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，“4-10元环”表示由4至10个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述4-10元环包括4-9元、4-8元、4-7元、4-6元环、4-10元、4-9元、4-8元和4-7元环等。“4-7元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“4-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，“5-12元环”表示由5至12个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-12元环包括5-10元、5-9元、5-8元、5-7元、5-6元、6-10元、6-9元、6-8元和6-7元环等。“5-7元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，“6-12元环”表示由6至12个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。 除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述6-12元环包括6-10元、6-9元、6-8元、6-7元环等。“5-7元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，“5-10元环”表示由5至10个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-10元环包括5-9元、5-8元、5-7元、5-6元环、6-10元、6-9元、6-8元和6-7元环等。“5-7元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，“5-8元环”表示由5至8个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-8元环包括5-7元、6-8元和6-7元等。“5-7元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，“5-6元环”表示由5至6个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-6元环包括5元、6元环等。“5-6元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“5-6元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，“C 3-8环烷基”表示由3至8个碳原子组成的饱和环状碳氢基团，其包括单环和双环 体系，其中双环体系包括螺环、并环和桥环。所述C 3-8环烷基包括C 3-6、C 3-5、C 4-8、C 4-6、C 4-5、C 5-8或C 5-6环烷基等；其可以是一价、二价或者多价。C 3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。
除非另有规定，术语“4-10元杂环烷基”本身或者与其他术语联合分别表示由4至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“4-10元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-10元杂环烷基包括4-8元、4-6元、4-5元、5-6元、4元、5元和6元杂环烷基等。4-10元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。
除非另有规定，本发明术语“5-12元杂芳环”和“5-12元杂芳基”可以互换使用，术语“5-12元杂芳基”表示由5至12个环原子组成的具有共轭π电子体系的环状基团，，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-12元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-12元杂芳基包括5-10元、5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-12元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。
除非另有规定，本发明术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。
除非另有规定，本发明术语“C 6-8芳环”和“C 6-8芳基”可以互换使用，术语“C 6-8芳环”或“C 6-8芳基”表示由6至8个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-8芳基包括C 6芳基等C 6-8芳基的实例包括但不限于苯基。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2019113622-appb-000033
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以有多种用途或适应症，包括但不限于本申请所列举的具体用途或适应症。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；ACN代表乙腈；Tris-HCl 代表三羟甲基氨基甲烷盐酸盐；EDTA代表乙二胺四乙酸；m-CPBA代表间氯过氧苯甲酸；NH 3H 2O代表氨水；DEA代表二乙醇胺；IPA代表异丙醇。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
中间体1
Figure PCTCN2019113622-appb-000034
参考专利WO2007126122中的合成方法制备。
实施例1：化合物1
Figure PCTCN2019113622-appb-000035
合成路线：
Figure PCTCN2019113622-appb-000036
步骤1：化合物1-A的合成。
20～30℃，向5L四口瓶中加入2.5L二氯甲烷，然后加入2,6-二溴吡啶(500g，2.11mol)，氮气置换三次，干冰乙醇冷却至-60～-70℃。控温-60～-70℃，逐滴滴加886.5mL正丁基锂(2M)，滴毕后，保温-60～-70℃反应1小时，滴加丙酮(233mL，3.17mol)，滴毕，保温反应20～30分钟，高效液相跟踪反应完全。向体系中加入250mL饱和氯化铵溶液淬灭反应。将体系回温至室温，加入1.6L水，搅拌10分钟后，静置分液，有机相用1.6L水洗涤，有机相干燥浓缩后得到黑色液体1-A，直接用于下一步。
步骤2：化合物1-B的合成。
20～30℃，将1.75L浓硫酸加入到5L三口瓶中，逐滴滴加1-A(1.75kg，8.10mol)，控温≤60℃。滴毕后，将体系保温在50～60℃反应12小时。高效液相跟踪反应完全，将反应液冷却至室温，将其倒入6Kg冰水中，用6N氢氧化钠溶液调节pH＝9～10。体系用10L正庚烷萃取分液，有机相减压浓缩得到粗品。粗品经快速硅胶垫(正庚烷淋洗)得到黄色液体1-B。
步骤3：化合物1-C的合成。
20～30℃向50L球形釜中加入10L叔丁醇和10L水，搅拌下，加入无水碳酸钾(1.74kg,12.59mol)，赤钾(4.16kg，12.59mol)，锇酸钾二水合物(3.72g，0.01mol)和氢化奎宁1,4-(2,3-二氮杂萘)二醚(19.67g，0.025mol)，加毕后，20～30℃搅拌10～20分钟。冰水浴将体系降温至0～15℃，加入化合物1-B(1kg，5.04mol)，保温反应15～20小时，高效液相跟踪反应完全。用10L饱和亚硫酸钠溶液淬灭反应，然后加入15L乙酸乙酯，萃取分液，有机相再用15L饱和食盐水溶液洗涤，有机相减压浓缩得到粘稠液体。向粗品中加入4L正庚烷，0℃下搅拌1小时，过滤，将滤饼干燥得到化合物1-C。
步骤4：化合物1-D的合成。
15～30℃，向50L夹套釜中加入21L甲苯，搅拌下加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(4.13kg,27.13mol)和化合物1-C(2.1kg，9.04mol)。将体系冷却至0～5℃，滴加全氟丁基磺酰氟(4.24kg，14.01mol)，滴毕后，保温0～5℃反应15～20小时，高效液相跟踪反应完全。将反应体系倒入17.5L水中淬灭，静置分液，水相再次用8.8L甲苯萃取分液，合并有机相，用水(15.8L*2)洗涤，减压浓缩至无馏分得到黑色液体1-D。
步骤5：化合物1-E的合成。
20～30℃，将干燥洁净的5L三口瓶氮气置换三次，加入烯丙基溴化镁(1M乙醚溶液，1.64L，1.92mol)，干冰乙醇冷却至<-60℃，滴加化合物1-D(293g，1.37mol)的1L二氯甲烷溶液，全程控温<-50℃。滴毕后，控温<-50℃反应0.5～1小时。高效液相跟踪反应完全，将体系倒入2.5L饱和氯化铵溶液中淬灭，然后用25～30％氨水调节pH≥10，加入3.5L乙酸乙酯，搅拌后静置分液，有机相用1L饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干得到粗品。粗品经快速硅胶垫(乙酸乙酯：正庚烷＝1:10)得到棕色液体1-E。 1H NMR(DMSO-d 6)：7.71(t,J＝7.6Hz,1H),7.64(d,J＝7.2Hz,1H),7.44(d,J＝6.8Hz,1H),5.69～5.78(m,1H),5.25(s,1H),4.84～4.93(m,2H),1.67～2.04(m,4H),1.42(s,3H)。
步骤6：化合物1-F的合成。
将化合物1-E(50.00g,164.58mmol)和2,6-二甲基吡啶(21.16g,197.50mmol,23.00mL)加入到二氯甲烷(500mL)，通过干冰降温至-10℃～0℃，然后向体系中缓慢加入三乙基硅基三氟甲磺酸酯(56.56g,213.95mmol,48.34mL)，在-10℃～0℃之间搅拌反应2.5小时。将反应液用饱和的柠檬酸溶液萃取(500mL*2)，有机相再用水洗涤(500mL*1)，下层得到的有机相(500mL)，即为化合物1-F的二氯甲烷溶液直接投入下一步。
步骤7：化合物1-G的合成。
将原料化合物1-F的二氯甲烷(500mL)溶液(60.96g,164.58mmol)，通过干冰乙醇浴降温至-40℃，然后敞口通入臭氧反应2.5小时，检测反应完全后，敞口通入氧气40分钟，然后敞口通氮气20min，在-40℃下向体系中缓慢加入三苯基膦(47.48g,181.04mmol)，加毕后慢慢恢复20℃反应12小时。反应 完成后，反应液直接经减压浓缩旋干得粗品，将粗品加入乙酸乙酯(80mL)，然后缓慢加入石油醚(300mL)，搅拌(有粘状物析出)，过滤，滤液经减压浓缩旋至无馏分，有固体析出，向旋好的粗品中再加入石油醚(300mL)，搅拌10分钟，过滤，滤液经减压浓缩旋至无馏分得粗品。将粗品通过快速柱层析分离(硅胶目数：100-200目，二氯甲烷：石油醚＝3:1)得到目标化合物1-G。
1H NMR(400MHz,CHCl 3-d)δppm 9.65(s,1H)7.44-7.60(m,2H)7.31(d,J＝7.58Hz,1H)2.29-2.41(m,2H)2.02-2.14(m,2H)1.68(s,3H)0.92-1.02(m,9H)0.66(q,J＝7.91Hz,6H)。MS-ESI m/z:372.0[M+H] +，MS-ESI m/z:374.0[M+H] +。
步骤8：化合物1-H的合成。
将化合物三乙基2-膦酰基丙酯(7.68g,32.23mmol,7.04mL)溶于四氢呋喃(100mL)中，用氮气置换气三次，然后通过干冰丙酮浴降温至-70℃，然后将正丁基锂(2.5M,12.89mL,1.2eq)缓慢滴加到体系中，控制温度不超过-70℃，加毕后，保温反应1小时，然后向体系中缓慢滴加化合物1-G(10g,26.85mmol)的四氢呋喃(20mL)溶液，并控制温度不超过-70℃，加毕后，保温反应1小时。反应完成后，向反应液中缓慢加入饱和氯化铵溶液(100mL)，然后静置分液，将水相再用乙酸乙酯萃取(100mL*1)，合并有机相，，用水洗涤(100mL*1)，再用饱和食盐水洗涤(120mL*1)，有机相加入无水硫酸钠干燥，过滤，滤液经减压浓缩旋至无馏分得粗品。将粗品通过快速柱层析分离(硅胶目数：200-300目，石油醚：乙酸乙酯＝70:1)得到目标化合物1-H。 1H NMR(400MHz,CHCl 3-d)δppm 7.72(d,J＝7.72Hz,1H)7.58-7.64(m,1H)7.41(d,J＝7.72Hz,1H)5.83-5.90(m,1H)4.20-4.31(m,2H)2.48-2.61(m,1H)2.17-2.35(m,2H)1.93(s,3H)1.84-1.91(m,1H)1.77(s,3H)1.34(t,J＝7.06Hz,3H)1.08-1.14(m,9H)0.79(q,J＝8.09Hz,6H)。MS-ESI m/z:457.9[M+H] +。
步骤9：化合物1-I的合成。
将化合物1-H(3.17g,6.94mmol)加入到二氯甲烷(30mL)中，用氮气置换气三次，然后通过冰盐浴降温至0℃，然后向体系中缓慢滴加二异丁基氢化铝(1M,17.36mL)，控制温度在-5℃与0℃之间，加毕后，保温及恢复室温19℃反应12小时。反应完成后，向反应液中缓慢滴加饱和的酒石酸钾钠溶液(50mL)，然后通过硅藻土过滤，滤饼用二氯甲烷淋洗(500mL*2)，滤液经减压浓缩旋至无馏分得粗品。粗品经快速柱层析分离(硅胶目数：200-300目，石油醚：乙酸乙酯＝10:1)得目标化合物1-I。 1H NMR(400MHz,CHCl 3-d)δppm 7.51(d,J＝7.72Hz,1H)7.42(t,J＝7.72Hz,1H)7.19-7.23(m,1H)5.08(br t,J＝6.84Hz,1H)3.91(br d,J＝4.85Hz,2H)1.90-2.07(m,2H)1.63(s,3H)1.55-1.61(m,2H)1.53(s,3H)0.86-0.97(m,9H)0.59(q,J＝8.01Hz,6H)。
步骤10：化合物1-J的合成。
将化合物1-N(3.9g,17.55mmol)和化合物1-I(7.27g,17.55mmol)加入到1,4-二氧六环(60mL)，然后依次加入碳酸钾(3.37g,24.39mmol,)，N,N'-二甲基乙二胺(464.03mg,5.26mmol,566.58μL)和碘化亚铜 (501.26mg,2.63mmol)，用氮气置换三次，然后在氮气条件下加热105℃搅拌12小时。反应完成后，将反应液经减压浓缩旋至无馏分，然后加入100mL水和80mL的乙酸乙酯萃取和氨水(5mL 25％)，静置分液，将下层水相再用乙酸乙酯(加入3mL 25％的氨水)萃取(50mL*1)，合并两次有机相，有机相用水洗涤(80mL*1)，再用饱和食盐水洗涤(100mL*1)，静置分液，有机相经减压浓缩旋至无馏分得粗品。粗品通过快速柱层析分离(硅胶目数：100-200目，洗脱剂：石油醚：乙酸乙酯＝2:1)得到化合物1-J淡黄色油状液体。 1H NMR(400MHz,CHCl 3-d)δppm 8.92(s,1H)7.81-7.88(m,1H)7.71(d,J＝8.07Hz,1H)7.60(d,J＝7.70Hz,1H)5.65(ddt,J＝16.87,10.36,6.19,6.19Hz,1H)5.10(br t,J＝6.91Hz,1H)5.03(d,J＝10.27Hz,1H)4.90(s,1H)4.81-4.88(m,2H)3.93(d,J＝5.26Hz,2H)2.57(s,3H)1.97-2.17(m,2H)1.68-1.84(m,2H)1.67(s,3H)1.62(s,3H)1.00(t,J＝7.89Hz,9H)0.68(q,J＝8.03Hz,6H)，MS-ESI m/z:556.2[M+H] +。
步骤11：化合物1-K的合成。
将化合物1-J(8.38g,15.08mmol)和巴比妥酸(4.71g,30.15mmol)加入到二氯甲烷(100mL)，然后加入四(三苯基膦)钯(348.45mg,301.54μμmol,0.02eq)，用氮气置换气三次，然后加热至40℃搅拌14小时。反应完成后，将反应液加入水(150mL)，静置分液，将上层水相再用二氯甲烷萃取(50mL*1)，合并两次有机相，有机相加入饱和的碳酸氢钠溶液洗涤(120mL*1)，再用饱和食盐水洗涤(200mL*1)，有机相加入无水硫酸钠干燥，过滤，滤液经减压浓缩旋至无馏分得粗品。将粗品通过快速柱层析分离(硅胶目数：200-300目，石油醚：乙酸乙酯＝2：1～二氯甲烷：甲醇＝70:1)得到目标化合物1-K。 1H NMR(400MHz,CHCl 3-d)δppm 8.95(s,1H)8.34(d,J＝8.38Hz,1H)7.86(t,J＝7.94Hz,1H)7.55(d,J＝7.72Hz,1H)5.24(br t,J＝7.06Hz,1H)3.84-4.08(m,2H)2.71(s,3H)2.27-2.39(m,1H)2.05(s,2H)1.72-1.85(m,2H)1.69(s,3H)1.65(s,3H)0.97-1.07(m,9H)0.71(q,J＝8.01Hz,6H)，MS-ESI m/z:516.1[M+H] +，MS-ESI m/z:538.2[M+Na] +。
步骤12：化合物1-L的合成。
将化合物1-K(2.63g,5.10mmol)和三苯基膦(1.74g,6.63mmol)加入到四氢呋喃(85mL)中，然后用氮气置换气三次，在氮气条件下，通过冰盐浴降温至0℃后，缓慢滴加偶氮二甲酸二异丙酯(1.34g,6.63mmol,1.29mL)，控制温度在0℃～5℃之间，滴加完毕后，恢复20℃搅拌12小时。反应完成后，将反应液加入水(100mL)，减压浓缩选走溶剂，然后再加入水(100mL)，用乙酸乙酯萃取(80mL*1)，有机相再用饱和食盐水洗涤(100mL*1)，有机相经减压浓缩旋至无馏分得粗品。将粗品通过快速柱层析分离(硅胶目数：100-200目；洗脱剂：石油醚：乙酸乙酯：二氯甲烷＝4:1:0.2)得到目标化合物1-L。 1H NMR(400MHz,CHCl 3-d)δppm 8.97(s,1H)7.75-7.84(m,1H)7.55-7.72(m,2H)4.97(td,J＝12.51,6.50Hz,1H)4.88(br s,1H)2.58(s,3H)1.92-2.03(m,2H)1.77(s,3H)1.53-1.69(m,1H)1.33-1.50(m,2H)1.26(d,J＝6.17Hz,4H)0.99(t,J＝7.94Hz,9H)0.67(q,J＝7.94Hz,6H)，MS-ESI m/z:498.0[M+H] +。
步骤13：化合物1-M的合成。
将化合物1-L(1.02g,2.05mmol)加入到四氢呋喃(6mL)中，然后向体系中加入四丁基氟化铵(1M,4.10mL)，加热至45℃搅拌2.5小时。反应完成后，将反应液加入水(30mL)，然后用乙酸乙酯萃取(10mL*1)，有机相经减压浓缩至无馏分得粗品。将粗品通过快速柱层析分离(硅胶目数：100-200目，石油醚：乙酸乙酯＝3:1～2:1)得到化合物1-M。 1H NMR(400MHz,DMSO-d 6)δppm 9.02(s,1H)7.96(t,J＝7.94Hz,1H)7.66(br s,2H)5.33-5.39(m,1H)4.83(br s,1H)4.71(br d,J＝14.33Hz,1H)2.53(s,3H)1.99(s,1H)1.89(br d,J＝16.32Hz,1H)1.61(s,3H)1.21-1.39(m,3H),MS-ESI m/z:383.9[M+H] +。
步骤14：化合物1的合成。
将化合物1-L(0.175g,456.36μmol)溶于到二氯甲烷(3.5mL)，然后加入间氯过氧苯甲酸(147.66mg,684.54μmol,80％纯度)，在20℃搅拌2小时，经检测后。向体系中缓慢加入N,N-二异丙基乙胺(147.45mg,1.14mmol,198.72μL)和化合物4-(4-甲基哌嗪)苯胺(96.02mg,502.00μmol)，加热40℃搅拌12小时。反应完成后，将反应液加入饱和亚硫酸钠溶液(3mL)搅拌10分钟，然后加入氢氧化钠溶液(4mL，3N)，搅拌10分钟，然后加入二氯甲烷萃取(10mL*3)，合并有机相，有机相用水洗涤(25mL*1)，再用饱和食盐水洗涤(20mL*2)，静置分液，有机相经减压浓缩旋至无馏分得粗品。将粗品通过制备液相分离(手性柱:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[H 2O(0.04％NH 3H 2O+10mM NH 4HCO 3)-ACN]；ACN％:20％-50％,10min)得到粗品化合物1。粗品化合物1继续经SFC拆分(手性柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O MeOH]；MeOH％:60％-60％,15min)得到目标化合物1(保留时间：6.02分)。 1H NMR(400MHz,CHCl 3-d)δppm 8.85(s,1H)7.81(br t,J＝7.61Hz,2H)7.47(br d,J＝8.82Hz,2H)7.21-7.31(m,1H)6.91(br d,J＝8.60Hz,2H)5.52(br s,1H)4.21-5.12(m,2H)3.13-3.27(m,4H)2.54-2.65(m,4H)2.37(s,3H)1.99-2.12(m,1H)1.80-1.99(m,3H)1.70(s,4H)。MS-ESI m/z:527.2[M+H] +。
实施例2：化合物2
Figure PCTCN2019113622-appb-000037
合成路线：
Figure PCTCN2019113622-appb-000038
步骤1：化合物2-I合成。
将化合物N-叔丁氧羰基-4-羟基哌啶(10g,49.69mmol)加入到二氯甲烷(200mL)，然后控制温度在0℃～5℃之间，加入三乙胺(7.54g,74.53mmol,10.37mL)和甲基磺酰氯(6.89g,60.12mmol,4.65mL)，保温搅拌3小时。反应完全后，将反应液加入柠檬酸溶液(180mL，5％)，静置分液，有机相依次用饱和碳酸氢钠溶液(150mL)，饱和食盐水洗涤(150mL)，有机相加入无水硫酸钠干燥，过滤，滤液经减压浓缩旋至无馏分得目标化合物2-I。 1H NMR(400MHz,CHCl 3-d)δppm 4.88(tt,J＝7.75,3.72Hz,1H)3.64-3.76(m,2H)3.24-3.36(m,2H)3.04(s,3H)1.90-2.02(m,2H)1.76-1.88(m,2H)1.46(s,9H)。
步骤2：化合物2-J合成。
将化合物5-硝基吲哚(6g,37.00mmol)加入到N，N-二甲基甲酰胺(60mL)中，然后在0℃下体系中加入钠氢(2.96g,74.01mmol,60％纯度)，搅拌1小时，然后加入化合物2-I(10.34g,37.00mmol)，加热至100℃搅拌12小时。反应完成后，将反应加入水淬灭(200mL)，然后用乙酸乙酯萃取(50mL*3)，有机相用稀氢氧化钠溶液洗涤一次(150mL)，在用饱和食盐水洗涤一次(150mL)，有机相经减压浓缩旋干得目标化合物2-J，直接投入下一步。(MS-ESI m/z:245.9)
步骤3：化合物2-K合成。
将化合物2-J(12.90g,37.35mmol)加入到乙酸乙酯(100mL)，然后加入盐酸/乙酸乙酯(4M,80mL)，在20℃下搅拌2小时。反应完成后，将反应液经减压浓缩旋走盐酸气，然后过滤，滤饼经乙酸乙酯淋洗一次(20mL)，滤饼经减压浓缩旋至无馏分得到目标化合物2-K，直接投入下一步。
步骤4：化合物2-L合成。
在20℃下，将化合物2-K(4.59g,18.71mmol)加入到二氯甲烷(90mL)中，然后向体系中缓慢加入甲醛溶液(3.04g,37.43mmol,2.79mL,37％纯度)和三乙胺(3.79g,37.43mmol,5.21mL)，搅拌5分钟后，加入醋酸(3.5mL)，在20℃下搅拌1小时，然后加入氰基硼氢化钠(3.53g,56.14mmol)，搅拌2hr。反应完成后，先将反应液通过冰水降温，向反应液中缓慢加入氢氧化钠溶液淬灭(50mL，1M)，然后加水稀释(150mL)，静置分液，二氯甲烷有机相再用饱和食盐水洗涤一次(100mL)，有机相经减压浓缩旋至无馏分得粗品。将粗品通过快速柱层析分离(硅胶目数：100-200目，洗脱剂：二氯甲烷：甲醇＝40:1)得到目标化合物2-L。 1H NMR(400MHz,CH 3OH-d 4)δppm 8.53(d,J＝2.20Hz,1H)8.06(dd,J＝9.15,2.09Hz,1H)7.61(d,J＝9.04Hz,1H)7.58(d,J＝3.53Hz,1H)6.73(d,J＝3.31Hz,1H)4.42-4.52(m,1H)3.06(br d,J＝12.13Hz,2H)2.38(s,3H)2.29-2.36(m,2H)2.00-2.18(m,4H)。MS-ESI m/z:260.0[M+H] +。
步骤5：化合物2-H合成。
将化合物2-L(1g,3.86mmol)加入到甲醇(35mL)和氨水(1mL)，然后加入钯/碳(0.6g,10％纯度)，用氢气换气三次，在氢气球条件下20℃搅拌12小时。反应完成后，将反应液通过硅藻土过滤，用甲醇淋洗(400mL)，滤液经减压浓缩旋至无馏分得到目标化合物2-H。 1H NMR(400MHz,CH 3OH-d 4)δppm 7.24(d,J＝8.68Hz,1H)7.20(d,J＝3.18Hz,1H)6.94(d,J＝1.83Hz,1H)6.72(dd,J＝8.62,2.02Hz,1H)6.26(d,J＝2.93Hz,1H)4.18-4.29(m,1H)3.02(br d,J＝12.10Hz,2H)2.36(s,3H)2.23-2.33(m,2H)1.94-2.13(m,4H)。
步骤6：化合物1-F的合成。
将化合物1-E(50.00g，164.58mmol)和2,6-二甲基吡啶(21.16g,197.50mmol,23.00mL)加入到二氯甲烷(500mL)，通过干冰降温至-10℃～0℃，然后向体系中缓慢加入三乙基硅基三氟甲磺酸酯(52.21g,197.50mmol,44.62mL,1.2eq)，在-10℃～0℃之间搅拌反应4小时，经检测后，在-10℃～0℃补加三 乙基硅基三氟甲磺酸酯(4.35g,16.46mmol,3.72mL,0.1eq)，继续搅拌12h小时。反应完成后，将反应液用饱和的柠檬酸溶洗涤(500mL*3)，得到目标化合物1-F的二氯甲烷溶液直接投入下一步。
步骤7：化合物1-G的合成。
将原料是化合物1-F的二氯甲烷(500mL)溶液(按照理论产量164.58mmol)，通过干冰乙醇浴降温至-40℃，然后敞口通入臭氧反应2.5小时，检测反应完全后，敞口通入氧气45分钟，然后敞口通氮气30分钟，在-40℃下向体系中缓慢加入三苯基膦(43.17g,164.58mmol,)，加毕后慢慢恢复20℃反应12小时。反应完成后，反应液直接经减压浓缩旋干得粗品。将粗品通过快速柱层析分离(硅胶目数：100-200目，二氯甲烷：石油醚＝3:1与石油醚：乙酸乙酯＝30:1～10:1)得到目标化合物1-G。 1H NMR(400MHz,CHCl 3-d)δppm 9.54-9.58(m,1H)7.40-7.51(m,2H)7.24(dd,J＝7.61,0.99Hz,1H)2.22-2.34(m,2H)1.95-2.06(m,2H)1.56-1.63(m,3H)0.85-0.94(m,9H)0.58(q,J＝8.01Hz,6H)。
步骤8：化合物2-A的合成。
将2-氟-2磷酰基乙酸三乙酯(9.73g,40.17mmol,8.18mL)溶于四氢呋喃(50mL)中，冷却至-78℃，逐滴滴加正丁基锂(2.5M,17.53mL)，滴毕后搅拌30分钟，然后逐滴滴加1-G(13.6g,36.52mmol)的四氢呋喃(50mL)溶液，滴毕后，-78℃反应1小时，TLC(二氯甲烷:石油醚＝1:1,R f＝0.3)显示反应完全。向体系中逐滴滴加60mL饱和氯化铵溶液淬灭反应，然后缓慢回温至室温，分液，水相用30mL乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，过滤，旋干得到淡黄色液体化合物2-A。未进一步纯化，直接用于下一步。
步骤9：化合物2-B的合成。
将化合物2-A(19g,41.26mmol)溶于二氯甲烷(150mL)中，0℃下，逐滴滴加二异丁基氢化铝(1M,103.16mL)。滴毕后，0℃反应2h。LCMS显示反应完全。向体系中加入60mL的10％酒石酸钾钠溶液，搅拌30分钟后，过滤，向滤液中加入150mL水和150mL乙酸乙酯萃取分液，有机相浓缩至无馏分得黄色粘稠液体化合物2-B。粗品直接用于下一步，未进一步纯化。
步骤10：化合物2-C的合成。
将1-N(6.9g,31.04mmol)，化合物2-B(14.29g,34.15mmol)，N,N'-二甲基乙二胺(820.97mg,9.31mmol,1.00mL)，碳酸钾(10.73g,77.61mmol)和CuI(886.84mg,4.66mmol)加入到二氧六环(150mL)中，氮气置换三次后，升温至105℃反应15hr。将体系降温至室温，浓缩除去溶剂，向其中加入200mL水和20mL氨水，再用200mL乙酸乙酯萃取分液，水相再次用100mL乙酸乙酯萃取分液，合并有机相，并用200mL水和10mL氨水洗涤，再用200mL水洗涤，有机相用无水硫酸钠干燥，过滤，旋干。粗品经柱层析(TLC:乙酸乙酯:石油醚＝1:1,Rf＝0.4，洗脱剂：乙酸乙酯:石油醚＝1:4)纯化得到黄色粘稠液体化合物2-C。
步骤11：化合物2-D的合成。
将化合物2-C(1g,1.79mmol)，甲酸胺(225.29mg,3.57mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(26.14mg,35.73μmol)加入到二氧六环(10mL)中，氮气置换三次后，升温至100℃反应4hr。
将化合物2-C(1g,1.79mmol,)，甲酸胺(225.29mg,3.57mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(26.14mg,35.73μmol)加入到二氧六环(10mL)中，氮气置换三次后，升温至60℃反应1h，然后升温至100℃反应4h。
将两批体系用干冰快速降温至室温。搅拌下，向体系中加入100mL水，有大量固体析出，抽滤，滤饼用20mL水淋洗，得到棕褐色固体。将固体用50mL二氯甲烷溶解后，通过快速硅胶柱(TLC:甲醇:二氯甲烷＝1:10,Rf＝0.4，洗脱剂甲醇:二氯甲烷＝1:20)得到淡黄色固体化合物2-D。
步骤12：化合物2-E的合成
将化合物2-D(2.5g,4.81mmol)和三乙胺(1.46g,14.43mmol,2.01mL)加入到二氯甲烷(25mL)，然后在0℃下加入甲基磺酰氯(1.10g,9.62mmol,744.65μL)，然后恢复20℃搅拌1.5小时。反应完成后，将反应液加入水(50mL)，然后加入二氯甲烷萃取(30mL)，静置分液，将水相再用二氯甲烷萃取(30mL)，合并两次有机相，有机相再用饱和食盐洗涤一次(120mL)，有机相加入无水硫酸钠干燥，过滤，滤液经减压浓缩至无馏分得到化合物2-E。直接投入下一步。
步骤13：化合物2-F的合成。
将化合物2-E(3.31g,5.54mmol)加入到N，N-二甲基甲酰胺中(90mL)，然后加入碳酸钾(1.99g,14.40mmol)，加热至50℃搅拌12小时，反应完成后，将反应液加入水(200mL)，然后加入乙酸乙酯萃取(250mL*1)，将下层水相再用乙酸乙酯萃取(100mL*1)，静置分液，合并两次有机相，有机相用半饱和食盐水洗涤(150mL*2)，有机相加入无水硫酸钠干燥，过滤，滤液经减压浓缩旋至无馏分得到目标化合物2-F。MS-ESI m/z:502.2[M+H] +
步骤14：化合物2-G的合成。
将化合物2-F(2.41g,4.80mmol)加入到四氢呋喃(5mL)，然后加入四丁基氟化铵(1M,9.61mL)，加热至40℃搅拌12小时。反应完成后，将反应液中加入水(20mL)，然后用乙酸乙酯萃取(30mL*2)，合并两次有机相，有机相用水洗涤一次(50mL)，再用半饱和食盐水洗涤一次(50mL)，将有机相加入无水硫酸钠干燥，过滤，滤液经减压浓缩旋至无馏分得粗品。粗品通过中压液相色谱分离(硅胶目数：100-200目，乙酸乙酯：石油醚＝1:1)得到目标化合物2-G。 1H NMR(400MHz,CHCl 3-d)δppm 8.98(s,1H)7.89-7.97(m,1H)7.84(br d,J＝7.95Hz,1H)7.36(d,J＝7.58Hz,1H)5.31(s,1H)5.17-5.34(m,1H)4.72-4.85(m,1H)4.49-4.72(m,1H)4.00(s,1H)2.61(s,3H)2.16-2.28(m,1H)2.02-2.13(m,1H)1.76-1.89(m,1H)1.71(s,3H)。MS-ESI m/z:388.0[M+H] +。
步骤15：化合物2的合成
在19℃下，将化合物2-G(0.23g,593.65μmol)加入到二氯甲烷(3mL)中，然后加入间氯过氧苯甲 酸(192.08mg,890.48μmol,80％纯度,1.5eq)，搅拌2小时，检测反应后，原料点未完全消失。补加间氯过氧苯甲酸(64.03mg,296.83μmol,80％纯度)后，继续搅拌1小时。检测反应，原料点消失，有中间态生成。然后依次加入N,N-二异丙基乙胺(191.81mg,1.48mmol,258.51μL)和化合物2-H(136.14mg,593.65μmol)，加热至40℃搅拌12小时。反应完成后，将反应液加入饱和亚硫酸钠淬灭(7ml)，搅拌10分钟，然后加入氢氧化钠溶液(6mL，3M)，用乙酸乙酯萃取(10mL*3)，合并有机相，有机相用饱和食盐水洗涤(25mL*2)，有机相经减压浓缩旋至无馏分得到粗品。粗品经过高效液相分离(手性柱:Waters Xbridge Prep OBD C18 150*40mm*10μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；ACN％:30％-60％,8min)得到目标化合物2。 1H NMR(400MHz,CHCl 3-d)δppm 8.87(br s,1H)7.96(br d,J＝7.82Hz,2H)7.80-7.88(m,1H)7.35(d,J＝8.80Hz,1H)7.20-7.30(m,1H)7.20-7.30(m,2H)6.48(d,J＝2.93Hz,1H)5.31(s,1H)4.64-4.77(m,1H)4.47(br d,J＝15.89Hz,1H)4.16-4.28(m,1H)4.07(br s,1H)3.06(br d,J＝11.13Hz,2H)2.39(s,3H)2.02-2.28(m,1H)2.02-2.28(m,7H)1.73-1.86(m,2H)1.66-1.72(m,3H)。MS-ESI m/z:569.3[M+H] +。
实施例3：化合物3和化合物4
Figure PCTCN2019113622-appb-000039
合成路线:
Figure PCTCN2019113622-appb-000040
步骤1：化合物3-A的合成。
化合物3-SM(28g,86.94mmol)和2,6-二甲基吡啶(11.18g,104.33mmol,12.15mL)溶于二氯甲烷(300mL)，在-40℃下，慢慢滴加三乙基硅基三氟甲磺酸酯(27.58g,104.33mmol,23.57mL)，之后反应液在-40℃下搅拌2小时。向反应液加入50mL水洗涤一次，经无水硫酸钠干燥，过滤旋干得粗品。粗品用100mL石油醚溶解，通过硅胶垫快速过滤，并用1.5L石油醚淋洗硅胶垫，至经TLC(石油醚/乙酸乙酯＝10:1，Rf＝0.8)确认产物点消失为止，有机相旋干得化合物3-A。MS m/z:371.8[M+H] +。
步骤2：化合物3-B的合成。
化合物3-A(1g,2.70mmol)溶于1,4-二氧六环(45mL)和水(15mL)，加入2,6-二甲基吡啶(659.56mg,6.16mmol,716.92μL)和二水合锇酸钾(19.90mg,54.00μmol)，最后加入高碘酸钠(2.31g,10.80mmol)，在18℃下搅拌2小时。反应液过滤，用50mL乙酸乙酯淋洗滤饼，滤液分液，有机相经无水硫酸钠干燥，过滤，滤液旋干得粗品。粗品经柱层析(石油醚/乙酸乙酯＝5/1，TLC(石油醚/乙酸乙酯＝5/1,Rf＝0.8))分离，得到化合物3-B。
1H NMR(400MHz,CHCl 3-d)δ＝9.67-9.63(m,1H),7.59-7.55(m,1H),7.55-7.49(t,1H),7.32(dd,J＝1.0,7.5Hz,1H),2.41-2.31(m,2H),2.16-2.03(m,2H),1.68(s,4H),1.00-0.95(t,9H),0.66(q,J＝7.9Hz,6H)。MS m/z:373.9[M+H] +。
步骤3：化合物3-C的合成。
化合物2-氟磷酰基乙酸三乙酯(8.58g,35.45mmol,7.21mL)溶于四氢呋喃(200mL)，氮气置换3次，降温至-70℃，滴加正丁基锂(2.5M,14.18mL)，滴加完毕后搅拌30分钟，再慢慢滴加化合物3-B(11g,29.54mmol)溶于四氢呋喃(50mL)的溶液。滴加完毕后在-70℃搅拌2.5小时，之后缓慢升温至15℃搅拌13小时。将反应液降温到0℃，缓慢滴加饱和氯化铵水溶液(100mL)，加完后搅拌20min。分液，水相再用乙酸乙酯(50mL*3)萃取，有机相合并后加饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥，过滤，旋干，得到化合物3-C。MS m/z:460.1[M+H] +。
步骤4：化合物3-D的合成。
化合物3-C(14.03g,30.47mmol)溶于二氯甲烷(150mL)，氮气置换3次，降温至0℃，滴加二异丁基氢化铝(1M,76.18mL)，加完后在0℃下搅拌2小时。向反应液中缓慢加入饱和酒石酸钾钠水溶液(100mL)，注意放气严重。加完后搅拌0.5小时，得到胶状浑浊液，经硅藻土过滤，滤饼用二氯甲烷(50mL*2)萃取，有机相加饱和食盐水(100mL)洗涤，加无水硫酸钠干燥，过滤，旋干，得到化合物3-D。
1H NMR(400MHz,CHCl 3-d)δ＝7.62-7.56(d,1H),7.55-7.49(t,1H),7.31(d,J＝7.6Hz,1H),5.18-5.01(m,1H),4.19-4.05(m,2H),2.18-1.97(m,2H),1.80-1.67(m,2H),1.62(s,3H),1.02-0.96(t,9H),0.67(q,J＝7.8Hz,6H)。MS m/z:420.0[M+H] +。
步骤5：化合物3-E的合成。
化合物1-N(6.84g,30.79mmol)溶于1,4-二氧六环(200mL)，加入3-D(11.71g,27.99mmol)，碳酸钾(5.34g,38.62mmol)，碘化亚铜(5.33g,27.99mmol)和N,N-二甲基乙二胺(2.76g,31.34mmol,3.37mL)，氮气置换3次，在105℃下搅拌12小时。加入50mL氨水，用乙酸乙酯(50mL*3)萃取，合并有机相并用饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥，过滤，滤液旋干得粗品。粗品经柱层析(石油醚/乙酸乙酯＝2/1，TLC(石油醚/乙酸乙酯＝2/1,Rf＝0.4))分离。得到化合物3-E。
1H NMR(400MHz,CHCl 3-d)δ＝8.93(s,1H),7.86(t,J＝7.9Hz,1H),7.73(dd,J＝0.8,8.0Hz,1H),7.60(d,J＝7.5Hz,1H),5.65(m,1H),5.08-4.97(m,2H),4.91-4.76(m,3H),4.05(d,J＝6.3Hz,1H),4.02-3.98(d,1H),2.58(s,3H),2.12-2.05(m,2H),1.79-1.70(m,2H),1.63(s,3H),1.61(s,1H),1.02-0.97(t,9H),0.68(q,J＝8.0Hz,6H)。MS m/z:560.2[M+H] +。
步骤6：化合物3-F的合成。
化合物3-E(9.94g,17.76mmol)溶于1,4-二氧六环(100mL)，加入甲酸铵(2.24g,35.51mmol)和1,1-双(二苯基膦)二茂铁氯化钯(649.66mg,887.87μmol)，氮气置换3次，在100℃下搅拌4小时。加水150mL，加二氯甲烷(100mL*2)萃取。有机相合并后加饱和食盐水洗涤(100mL*2)，加无水硫酸钠干燥，过滤，旋干，得到化合物3-F。MS m/z:520.1[M+H] +。
步骤7：化合物3-G的合成。
化合物3-F(8.5g,16.36mmol)溶于二氯甲烷(100mL)，加入三乙胺(4.97g,49.07mmol)，在0℃下慢慢加入甲黄酰氯(4.33g,37.80mmol,2.93mL)，之后在15℃搅拌2小时。缓慢加水30mL淬灭，分液，水相用二氯甲烷萃取(15mL*2)，有机相合并后加饱和食盐水30mL洗涤，加无水硫酸钠干燥，过滤，旋干，得到化合物3-G。MS m/z:676.1[M+H] +。
步骤8：化合物3-H的合成。
化合物3-G(10.4g,15.39mmol)溶于N,N-二甲基甲酰胺(250mL)，加入碳酸钾(5.53g,40.01mmol)，在50℃下搅拌5小时。加入500mL水，用乙酸乙酯(50mL*3)萃取，有机相再用500mL水洗涤一次，饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥，过滤，旋干，得到化合物3-H。MS m/z:502.0[M+H] +。
步骤9：化合物3-I的合成。
化合物3-H(8.74g,17.42mmol)溶于四氢呋喃(100mL)，加入四丁基氟化铵(1M,17.42mL)，在20℃下搅拌24小时。反应液旋干，加入二氯甲烷(50mL)溶解，用水(30mL*2)洗涤，再用饱和食盐水(30mL)洗涤一次，无水硫酸钠干燥，过滤，旋干，得粗品。粗品经柱层析(乙酸乙酯/石油醚＝1/1，3/1，4/1，TLC(乙酸乙酯/石油醚＝3/1，Rf＝0.4))分离。得到3-I。
步骤10：化合物3-J的合成。
化合物3-I(1.1g,2.84mmol)溶于二氯甲烷(30mL)，加入间氯过氧苯甲酸(734.93mg,3.41mmol,80％purity)，在30℃下搅拌1小时。加入N,N-二异丙基乙胺(917.37mg,7.1mmol)和4-(4-甲基哌嗪)苯胺(597.37mg,3.12mmol)，在50℃下搅拌12小时。向反应液中加入10mL饱和碳酸钠溶液，搅拌10分钟，用乙酸乙酯(15mL*3)萃取，合并有机相，用饱和亚硫酸钠溶液(20mL)洗涤一次，再用饱和食盐水(20mL)洗涤一次，无水硫酸钠干燥，过滤，滤液旋干得粗品。粗品经柱层析(二氯甲烷/甲醇＝10/1，TLC(二氯甲烷/甲醇＝10/1，Rf＝0.3))分离，得到固体再加入5mL甲醇溶解，有固体析出，搅拌2小时，过滤，滤饼旋干，得到化合物3-J。MS m/z:531.1[M+H] +。
步骤11：化合物3和化合物4的合成。
化合物3-J经过SFC手性拆分(色谱柱:DAICEL CHIRALPAK AD 250mm*30mm直径.,10μm；流动相:A:超临界CO 2,B:ETOH(0.1％NH 3H 2O)，A:B＝55:45at 70mL/min，得3，保留时间：9.1min。 1H NMR(400MHz,CHCl 3-d)δ＝8.90-8.83(s,1H),7.90-7.82(d,2H),7.78-7.54(m,1H),7.47(d,J＝9.0Hz,2H),7.32-7.27(m,1H),6.98-6.88(d,2H),5.31(m,1H),4.71(t,J＝15.3Hz,1H),4.47(m,1H),4.08(s,1H),3.25-3.17(m,4H),2.65-2.56(m,4H),2.40-2.34(s,4H),2.19(m,1H),2.13-2.01(m,1H),1.87-1.73(m,2H),1.70(s,3H)。MS m/z:531.0[M+H] +。和4，保留时间：11.8min。 1H NMR(400MHz,CHCl 3-d)δ＝8.87(s,1H),7.87(d,J＝4.8Hz,2H),7.47(d,J＝9.0Hz,2H),7.33-7.28(m,1H),6.94(d,J＝9.0Hz,2H),5.38-5.28(m,1H),4.78-4.65(t,2H),4.57-4.38(m,1H),4.06(s,1H),3.27-3.16(m,6H),2.65-2.56(m,4H),2.38(s,3H),2.22(m,1H),2.13-2.03(m,1H),1.85-1.72(m,2H),1.70(s,3H)MS m/z:531.0[M+H] +。
实施例4：化合物5和化合物6
Figure PCTCN2019113622-appb-000041
合成路线：
Figure PCTCN2019113622-appb-000042
步骤1：化合物5-A的合成
将化合物碳酸钾(0.36g,2.60mmol)的水(0.36mL)溶液和四丁基溴化铵(0.1g,310.21μmol)的水(0.1mL)溶液混合，加入化合物2-氟-2磷酰基乙酸三乙酯(78.05mg,322.26μmol,65.58μL)。15min后加入化合物1-G(0.1g,268.55μmol,1eq)15℃搅拌16hr。点板检测，反应完全。向反应液中加石油醚/乙酸乙酯＝10:1(50mL*2)萃取，将有机相加无水硫酸钠干燥，过滤，旋干。经制备薄层层析纯化得到化合物5-A.MS m/z:460.0[M+H] +。
步骤2：化合物5-B的合成
将化合物5-A(9.67g,21.00mmol)加入二氯甲烷(100mL)，然后用氮气置换气三次，在0℃下向体系缓慢加入二异丁基氢化铝(1M,52.50mL)，加毕后，0℃下慢慢恢复至19℃搅拌12hr。将反应液加入60mL的饱和酒石酸钾钠溶液(溶液呈糊状)，然后将体系通过硅藻土过滤，滤饼共用1L的二氯甲烷分多次淋洗，将滤液经减压浓缩旋至无馏分，然后加入100mL的水，用二氯甲烷萃取(70mL*2)，合 并两次有机相，有机相用100mL的饱和食盐水洗涤一次，有机相加入无水硫酸钠干燥，过滤，滤液经减压浓缩旋至无馏分得粗品。将粗品通过快速柱层析(石油醚/乙酸乙酯＝5/1)得到化合物5-B。
步骤3：化合物5-C的合成
将5-B(2.82g,6.75mmol)溶于二氧六环(30mL)，加入N,N'-二甲基乙二胺(178.47mg,2.03mmol,217.91μL)，碳酸钾(1.31g,9.45mmol,1.4eq)和化合物1-N(1.5g,6.75mmol)，氮气置换3次，加入CuI(192.79mg,1.01mmol)。升温到100℃搅拌15h。将反应液降温后浓缩，除掉大部分溶剂。加水50mL,氨水5mL，用乙酸乙酯(50mL*2)萃取。有机相合并后加水(50mL)，氨水1mL洗涤，加饱和食盐水50mL洗涤，加无水硫酸钠干燥，过滤，旋干。得到化合物5-C。 1H NMR(400MHz,CHCl 3-d)δppm 0.69(q,J＝8.01Hz,6H)0.92-1.07(m,9H)1.63(s,3H)1.65-1.83(m,3H)2.06-2.23(m,2H)2.59(s,3H)3.99(dd,J＝15.55,6.28Hz,2H)4.60(t,J＝7.28Hz,0.5H)4.69(t,J＝7.28Hz,0.5H)4.76-4.92(m,3H)5.02(d,J＝10.14Hz,1H)5.65(ddt,J＝16.87,10.42,6.09,6.09Hz,1H)7.63(d,J＝7.72Hz,1H)7.70(d,J＝7.94Hz,1H)7.82-7.90(m,1H)8.93(s,1H)。
步骤4：化合物5-D的合成
将5-C(3g,5.36mmol)溶于二氧六环(45mL)，加入[1,1’-双(二苯基膦基)二茂铁]二氯化钯(196.07mg,267.97μmol)和甲酸铵(675.88mg,10.72mmol)。氮气置换3次，加热到100℃搅拌4hr。反应液降温到20℃，加水50mL，搅拌10min后过滤。将滤饼旋干。加二氯甲烷(20ml)搅拌10min后过滤，将滤饼旋干，得到化合物5-D(1.87g,3.60mmol)。 1H NMR(400MHz,CHCl 3-d)δppm 0.72(q,J＝7.86Hz,6H)0.89-1.11(m,9H)1.53-1.69(m,1H)1.71-1.80(m,3H)1.85(td,J＝12.29,4.08Hz,1H)2.12-2.43(m,2H)2.70(s,3H)3.50(s,1H)3.86-4.08(m,2H)4.57-4.80(m,1H)7.56(d,J＝7.72Hz,1H)7.85(t,J＝7.94Hz,1H)8.35(d,J＝8.16Hz,1H)8.95(s,1H)。
步骤5：化合物5-E的合成
将化合物5-D(1.67g,3.21mmol)溶于二氯甲烷(50mL)，加入三乙胺(975.48mg,9.64mmol,1.34mL)，降温到0℃滴加甲基磺酰氯(736.18mg,6.43mmol,497.42μL)。加完后搅拌1h。缓慢加水30mL淬灭，分液，水相用二氯甲烷萃取(15mL).有机相合并后加饱和食盐水50mL洗涤，加无水硫酸钠干燥，过滤，旋干，得到化合物黄色油状5-E(粗品)
步骤6：化合物5-F的合成
将化合物5-E(2.17g,3.21mmol,)溶于N,N-二甲基甲酰胺(65mL),加入碳酸钾(1.15g,8.35mmol)。升温到80℃搅拌3hr。将反应液降温，减压浓缩掉大部分溶剂后加水(100mL)，水相用乙酸乙酯(50mL*2)萃取。有机相合并后加饱和食盐水(100mL)洗涤，加无水硫酸钠干燥，过滤，旋干。硅胶柱纯化洗脱剂极性为石油醚:乙酸乙酯＝3:1得到5-F(0.4g,797.30μmol,)。 1H NMR(400MHz,CHCl 3-d)δppm 0.65(q,J＝8.09Hz,6H)0.98(t,J＝7.83Hz,9H)1.68(s,3H)1.69-1.76(m,1H)1.85(br d,J＝11.91 Hz,1H)2.24(br d,J＝13.89Hz,1H)2.55(s,3H)2.62-2.77(m,1H)3.48-3.67(m,1H)3.69-3.86(m,1H)5.19(br d,J＝15.44Hz,1H)7.52(d,J＝7.72Hz,1H)7.75(d,J＝7.28Hz,1H)7.85-7.90(m,1H)8.94(s,1H)。
步骤7：化合物5-G的合成
将化合物5-E(350mg,697.64μmol)溶于四氢呋喃(2mL)，加入四丁基溴化铵(1M,2.09mL,3eq).加完后升温到40℃，搅拌1hr。将反应液加水15mL，乙酸乙酯(20mL)萃取。有机相加饱和食盐水洗涤(20mL*2)，无水硫酸钠干燥，过滤，旋干，得到化合物5-G。 1H NMR(400MHz,CHCl 3-d)δppm 1.56(td,J＝13.51,3.64Hz,2H)1.64-1.70(m,3H)1.77(br dd,J＝14.00,3.20Hz,1H)2.01-2.12(m,1H)2.56(s,3H)3.00-3.14(m,1H)3.49-3.67(m,1H)3.81-3.96(m,1H)4.59(d,J＝3.09Hz,1H)5.25(br d,J＝15.66Hz,1H)7.32(d,J＝7.72Hz,1H)7.62(d,J＝7.94Hz,1H)7.90-7.97(m,1H)8.96(s,1H)。
步骤8：化合物5和化合物6的合成
将化合物5-G(0.3g,774.33μmol)溶于二氯甲烷(10mL)，15℃加入间氯过氧苯甲酸(235.81mg,1.16mmol,85％纯度)，搅拌0.5hr。加入N,N-二异丙基乙胺(200.15mg,1.55mmol,269.74μL,2eq)和化合物4-(4-甲基哌嗪)苯胺(162.92mg,851.77μmol)，15℃搅拌15hr。加饱和亚硫酸钠溶液15mL和3N氢氧化钠水溶液，搅拌0.5h，萃取。水相用二氯甲烷(10mL)萃取。有机相合并后加饱和食盐水(20mL*2)洗涤，加无水硫酸钠干燥，过滤，旋干。加甲醇5mL搅拌0.5hr，过滤，滤饼用甲醇洗涤(2mL*2)。将滤饼减压旋干。SFC纯化(手性柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O IPA]；IPA％:50％-50％,10min)得到5(保留时间：9.61分)。 1H NMR(400MHz,CHCl 3-d)δppm 1.52-1.55(m,1H)1.67(s,3H)1.74–1.78(m,1H)2.04–2.08(m,1H)2.37(s,3H)2.58-2.60(m,4H)3.09–3.18(m,1H)3.18-3.21(m,4H)3.48–3.60(m,1H)3.93-3.95(m,1H)4.65(br d,J＝3.2Hz,2H)5.18–5.22(m,1H)6.90(d,J＝8.8Hz,2H)7.26(m,1H)7.44(br d,J＝8.8Hz,2H)7.59-7.61(m,1H)7.85-7.91(m,1H)8.84(s,1H)。
MS m/z:531.2[M+H] +。
生物测试
实验例1:本发明化合物的体外体外酶学抑制活性
供实验用的本发明化合物均为自制，其化学名称和结构式见各化合物的制备实施例，实验测试在Eurofins公司进行，实验结果由该公司提供。
在Wee1反应体系中，加入20mM Tris-HCl，pH 8.5，0.2mM EDTA，500μM多肽底物(LSNLYHQGKFLQTFCGSPLYRRR)，10mM醋酸镁和一定浓度的[8-33P]-ATP(强度大约500cpm/pmol)。加入Mg 2+和ATP混合液后，反应起始，室温孵育40min。加入3％磷酸缓冲液，终止反应。 取10μL反应液在连续过滤机P30上过滤，用75mM磷酸缓冲液清洗三次，甲醇清洗一次，每次清洗5min。干燥后闪烁计数法读值。
表1：本发明化合物体外酶学活性测定结果(IC 50)
编号 Wee1(IC 50nM)
1 130
2 37
3 28
4 110
5 43
实验结论：
通过表1可以看出，本发明化合物对Wee1激酶具有很好的抑制作用。
实验例2：受试药对人胰腺癌PC-07-0049裸小鼠皮下移植瘤模型的体内药效学研究
实验方法：选用的实验动物是BALB/c裸小鼠(每组6只)，6－8周龄，体重16-21克。
人源胰腺癌PC-07-0049模型的建立最初来源于外科手术切除的临床样本，在植入裸鼠体内后被定义为P0代。将P0代的肿瘤组织植入下一代被称为P1代。以此类推持续在裸鼠体内植入。其中FP3的肿瘤是通过P2代重新复苏得到。由FP3代产生的下一代被定义为FP4，以此类推，FP5代的肿瘤组织将会被用于此次药效试验。
将PC-07-0049 FP5肿瘤组织剔除坏死组织后切成(20-30mm 3)的小块，皮下接种于每只裸鼠的右后背，当肿瘤平均体积达到约193mm 3时，根据瘤体积随机分组，并开始给药。
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。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％。
最终实验结果如下：
表2小鼠肿瘤体内药效结果
Figure PCTCN2019113622-appb-000043
Figure PCTCN2019113622-appb-000044
结论：通过表2可以看出，本发明化合物3和和吉西他滨联用可以显著提高对小鼠身体肿瘤的抑制作用。

Claims (22)

  1. 式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019113622-appb-100001
    其中，
    Figure PCTCN2019113622-appb-100002
    为单键或双键；
    n为1、2或3；
    环A选自C 6-10芳基、5-12元杂芳基、C 3-8环烷基和4-10元杂环烷基；
    R 1选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代，且R 2和R 3不同时为H；
    R 4选自C 3-8环烷基和4-10元杂环烷基，所述C 3-8环烷基和4-10元杂环烷基任选被1、2或3个R c取代；
    R 5选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基任选被1、2或3个R d取代；
    R a分别独立地选自F、Cl、Br、I、OH和NH 2；
    R b分别独立地选自F、Cl、Br、I、OH和NH 2；
    R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述NH 2和C 1-3烷基任选被1、2或3个R取代；
    R d分别独立地选自F、Cl、Br、I、OH和NH 2；
    R分别独立地选自F、Cl、Br、I、OH和NH 2；
    所述5-12元杂芳基和4-10元杂环烷基包含1、2、3或4个独立选自-NH-、O、-S-和N的杂原子或杂原子团。
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，环A选自C 6-8芳基和5-10元杂芳基。
  3. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其化合物具有式(Ⅱ)或(Ⅲ)所示结构
    Figure PCTCN2019113622-appb-100003
    其中，
    Figure PCTCN2019113622-appb-100004
    为单键或双键；
    n为1、2或3；
    R 1分别独立地选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代，且R 2和R 3不同时为H；
    R 4分别独立地选自C 3-8环烷基和4-10元杂环烷基，所述C 3-8环烷基和4-10元杂环烷基任选被1、2或3个R c取代；
    R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基任选被1、2或3个R d取代；
    R a分别独立地选自F、Cl、Br、I、OH和NH 2；
    R b分别独立地选自F、Cl、Br、I、OH和NH 2；
    R c分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述NH 2和C 1-3烷基任选被1、2或3个R取代；
    R d分别独立地选自F、Cl、Br、I、OH和NH 2；
    R分别独立地选自F、Cl、Br、I、OH和NH 2；
    所述4-10元杂环烷基包含1、2、3或4个独立选自-NH-、O、-S-和N的杂原子或杂原子团；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  4. 根据权利要求3所述的化合物、其异构体或其药学上可接受的盐，其化合物具有式(Ⅱ-A)或(Ⅲ-A)所示结构：
    Figure PCTCN2019113622-appb-100005
    其中，
    r为1或2；
    D分别独立地选自-N(R 6)-和-C(R 7)(R 8)-；
    R 6分别独立地选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R e取代；
    R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述NH 2和C 1-3烷基任选被1、2或3个R f取代；
    R e分别独立地选自F、Cl、Br、I、OH和NH 2；
    R f分别独立地选自F、Cl、Br、I、OH、NH 2和C 1-3烷基；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
    R 1、R 2和R 3如权利要求3所定义。
  5. 根据权利要求1或3所述的化合物、其异构体或其药学上可接受的盐，其中，R c分别独立地选自F、Cl、Br、I、OH、NH 2、CH 3和Et。
  6. 根据权利要求4所述的化合物、其异构体或其药学上可接受的盐，其中，R f分别独立地选自F、Cl、Br、I、OH、NH 2、CH 3和Et。
  7. 根据权利要求1、3或4所述的化合物、其异构体或其药学上可接受的盐，其中，R 1分别独立地选自H、CH 3和Et。
  8. 根据权利要求1、3或4所述的化合物、其异构体或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，且R 2和R 3不同时为H。
  9. 根据权利要求1或3所述的化合物、其异构体或其药学上可接受的盐，其中，R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和OCH 3。
  10. 根据权利要求4所述的化合物、其异构体或其药学上可接受的盐，其中，R 6分别独立地选自H、CH 3和Et。
  11. 根据权利要求4所述的化合物、其异构体或其药学上可接受的盐，其中，R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2、-NH(CH 3)、-N(CH 3) 2、CH 3和Et。
  12. 根据权利要求11所述的化合物、其异构体或其药学上可接受的盐，其中，R 7分别独立地选自H、 F、Cl、Br、I、OH、NH 2、-NH(CH 3)、-N(CH 3) 2、CH 3和Et。
  13. 根据权利要求11所述的化合物、其异构体或其药学上可接受的盐，其中，R 8分别独立地选自H、F、Cl、Br、I、OH、CH 3和Et。
  14. 根据权利要求4所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019113622-appb-100006
    选自
    Figure PCTCN2019113622-appb-100007
  15. 根据权利要求14所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019113622-appb-100008
    选自
    Figure PCTCN2019113622-appb-100009
  16. 根据权利要求15所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019113622-appb-100010
    选自
    Figure PCTCN2019113622-appb-100011
  17. 根据权利要求1、3或4所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019113622-appb-100012
    选自
    Figure PCTCN2019113622-appb-100013
    Figure PCTCN2019113622-appb-100014
  18. 根据权利要求1～13任意一项所述的化合物、其对映异构体、其旋光异构体或其药学上可接受的 盐，其化合物具有式(Ⅱ-A1)、(Ⅱ-A2)或(Ⅲ-AA1)所示结构
    Figure PCTCN2019113622-appb-100015
    其中，R 1、R 2、R 3、R 6、R 7和R 8如权利要求1～13所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
    上述
    Figure PCTCN2019113622-appb-100016
    表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。
  19. 根据权利要求18所述的化合物、其异构体或其药学上可接受的盐，其化合物具有式(Ⅱ-1)、(Ⅱ-2)或(Ⅲ-A1)所示结构
    Figure PCTCN2019113622-appb-100017
    其中，R 1、R 2、R 3、R 6、R 7和R 8如权利要求18所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  20. 下式化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019113622-appb-100018
    Figure PCTCN2019113622-appb-100019
  21. 根据权利要求20所述的化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019113622-appb-100020
  22. 根据权利要求1～21任意一项所述化合物、其异构体或其药学上可接受的盐在制备治疗Wee1相关疾病药物中的应用。
PCT/CN2019/113622 2018-10-26 2019-10-28 作为Wee1抑制剂的嘧啶并吡唑酮类衍生物及其应用 WO2020083404A1 (zh)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023041066A1 (zh) * 2021-09-18 2023-03-23 优领医药科技(香港)有限公司 含嘧啶并二氢吡唑啉酮类衍生物、其药学上可接受的盐及其制备方法和应用
US11613545B2 (en) * 2017-11-01 2023-03-28 Wuxi Biocity Biopharmaceutics Co., Ltd. Macrocyclic compound serving as Wee1 inhibitor and applications thereof
WO2023140629A1 (ko) * 2022-01-20 2023-07-27 닥터아이앤비(주) 단백질 키나아제 저해활성을 가지는 2, 7-치환된 피롤로[2,1-f][1,2,4]트라아진 화합물

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG11202111315XA (en) * 2019-04-30 2021-11-29 Shijiazhuang Sagacity New Drug Development Co Ltd Crystal form of wee1 inhibitor compound and use thereof

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070254892A1 (en) 2006-04-27 2007-11-01 Takeshi Sagara Dihydropyrazolopyrimidinone derivatives
WO2008133866A1 (en) 2007-04-25 2008-11-06 Merck & Co., Inc. Polymorph of dihydropyrazolopyrimidinone derivative as weel kinase.inhibitor
EP2213673A1 (en) 2007-10-23 2010-08-04 Banyu Pharmaceutical Co., Ltd. Pyridone-substituted-dihydropyrazolopyrimidinone derivative
WO2011034743A1 (en) 2009-09-15 2011-03-24 Merck Sharp & Dohme Corp. Preparation of crystalline forms of dihydropyrazolopyrimidinone
US20120220572A1 (en) 2011-02-28 2012-08-30 Abbott Laboratories Tricyclic inhibitors of kinases
WO2013013031A1 (en) 2011-07-19 2013-01-24 Abbvie Inc. Pyridazino [4, 5 -d] pyrimidin- (6h) -one inhibitors of wee - 1 kinase
WO2013012681A1 (en) 2011-07-15 2013-01-24 Abbott Laboratories Tricyclic inhibitors of kinases useful for the treatment of proliferative diseases
WO2013059485A1 (en) 2011-10-20 2013-04-25 Abbvie Inc. Pyridopyrimidinone inhibitors of kinases
WO2013126656A1 (en) 2012-02-23 2013-08-29 Abbvie Inc. Pyridopyrimidinone inhibitors of kinases
WO2014167347A1 (en) 2013-04-11 2014-10-16 Almac Discovery Limited 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors
WO2015019037A1 (en) 2013-08-05 2015-02-12 Almac Discovery Limited Pharmaceutical compounds
WO2015092431A1 (en) 2013-12-19 2015-06-25 Almac Discovery Limited Pyrimidopyrimidinones useful as wee-1 kinase inhibitors
WO2018171633A1 (zh) * 2017-03-23 2018-09-27 上海迪诺医药科技有限公司 吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用
WO2019085933A1 (zh) * 2017-11-01 2019-05-09 南京明德新药研发股份有限公司 作为Wee1抑制剂的大环类化合物及其应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2376493B1 (en) 2008-12-12 2016-10-05 Msd K.K. Dihydropyrimidopyrimidine derivative
CN105452246A (zh) 2013-06-06 2016-03-30 葛兰素史密斯克莱知识产权（第2号）有限公司 Zeste增强子同源物2的抑制剂
US10947238B2 (en) 2015-11-01 2021-03-16 The Regents Of The University Of Colorado, A Body Corporate Wee1 kinase inhibitors and methods of making and using the same

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070254892A1 (en) 2006-04-27 2007-11-01 Takeshi Sagara Dihydropyrazolopyrimidinone derivatives
WO2007126122A1 (en) 2006-04-27 2007-11-08 Banyu Pharmaceutical Co., Ltd. Dihydropyrazolopyrimidinone derivatives
CN101432284A (zh) * 2006-04-27 2009-05-13 万有制药株式会社 二氢吡唑并嘧啶酮衍生物
WO2008133866A1 (en) 2007-04-25 2008-11-06 Merck & Co., Inc. Polymorph of dihydropyrazolopyrimidinone derivative as weel kinase.inhibitor
EP2213673A1 (en) 2007-10-23 2010-08-04 Banyu Pharmaceutical Co., Ltd. Pyridone-substituted-dihydropyrazolopyrimidinone derivative
WO2011034743A1 (en) 2009-09-15 2011-03-24 Merck Sharp & Dohme Corp. Preparation of crystalline forms of dihydropyrazolopyrimidinone
US20120220572A1 (en) 2011-02-28 2012-08-30 Abbott Laboratories Tricyclic inhibitors of kinases
WO2013012681A1 (en) 2011-07-15 2013-01-24 Abbott Laboratories Tricyclic inhibitors of kinases useful for the treatment of proliferative diseases
WO2013013031A1 (en) 2011-07-19 2013-01-24 Abbvie Inc. Pyridazino [4, 5 -d] pyrimidin- (6h) -one inhibitors of wee - 1 kinase
WO2013059485A1 (en) 2011-10-20 2013-04-25 Abbvie Inc. Pyridopyrimidinone inhibitors of kinases
WO2013126656A1 (en) 2012-02-23 2013-08-29 Abbvie Inc. Pyridopyrimidinone inhibitors of kinases
WO2014167347A1 (en) 2013-04-11 2014-10-16 Almac Discovery Limited 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors
WO2015019037A1 (en) 2013-08-05 2015-02-12 Almac Discovery Limited Pharmaceutical compounds
WO2015092431A1 (en) 2013-12-19 2015-06-25 Almac Discovery Limited Pyrimidopyrimidinones useful as wee-1 kinase inhibitors
WO2018171633A1 (zh) * 2017-03-23 2018-09-27 上海迪诺医药科技有限公司 吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用
WO2019085933A1 (zh) * 2017-11-01 2019-05-09 南京明德新药研发股份有限公司 作为Wee1抑制剂的大环类化合物及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3875460A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11613545B2 (en) * 2017-11-01 2023-03-28 Wuxi Biocity Biopharmaceutics Co., Ltd. Macrocyclic compound serving as Wee1 inhibitor and applications thereof
WO2023041066A1 (zh) * 2021-09-18 2023-03-23 优领医药科技(香港)有限公司 含嘧啶并二氢吡唑啉酮类衍生物、其药学上可接受的盐及其制备方法和应用
CN115838375A (zh) * 2021-09-18 2023-03-24 优领医药科技(香港)有限公司 含嘧啶并二氢吡唑啉酮类衍生物、其药学上可接受的盐及其制备方法和应用
WO2023140629A1 (ko) * 2022-01-20 2023-07-27 닥터아이앤비(주) 단백질 키나아제 저해활성을 가지는 2, 7-치환된 피롤로[2,1-f][1,2,4]트라아진 화합물

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