CN112442049A - Pyrimidine derivatives as Wee1 inhibitors - Google Patents

Pyrimidine derivatives as Wee1 inhibitors Download PDF

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Publication number
CN112442049A
CN112442049A CN201910828780.1A CN201910828780A CN112442049A CN 112442049 A CN112442049 A CN 112442049A CN 201910828780 A CN201910828780 A CN 201910828780A CN 112442049 A CN112442049 A CN 112442049A
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compound
reaction
esi
pharmaceutically acceptable
synthesis
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樊后兴
谢雨礼
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Wigen Biomedicine Technology Shanghai Co Ltd
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Priority to PCT/CN2020/112948 priority patent/WO2021043152A1/en
Priority to CN202080049357.2A priority patent/CN114072411A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Abstract

Pyrimidine derivatives as Weel inhibitors. The invention relates to a novel compound shown as a formula (1A) or a formula (1B) and/or pharmaceutically acceptable salt thereof, a composition containing the compound shown as the formula (1A) or the formula (1B) and/or pharmaceutically acceptable salt thereof, a preparation method and application of the compound serving as a Wee1 inhibitor in preparation of antitumor drugs.

Description

Pyrimidine derivatives as Wee1 inhibitors
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel compound with a Wee1 kinase inhibition effect, a preparation method thereof and application of the compound in preparation of antitumor drugs.
Background
Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints. The cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell resting phase) to S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (cell division preparatory phase) to M (cell division phase) and the spindle checkpoint for the transition from M phase metaphase to anaphase. Wee-1 protein kinase plays an important role in the checkpoint at G2. Cell entry into M phase is dependent on CDK1 kinase activity, Wee-1 inhibits CDK1 activity by phosphorylating Tyr15 of CDK1 protein, preventing cells from entering M phase (cell division phase). Polo kinase phosphorylates Wee-1, activates degradation of Wee-1 protein, and promotes cells to enter M phase. It can be seen that Wee-1 kinase activity determines the activity of the G2 checkpoint and, in turn, regulates the G2 to M phase transition in cells [ Cell Cycle,2013.12(19): p.3159-64 ].
Cell cycle checkpoints are activated primarily following DNA damage and play an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoints blocks the cell cycle promoting DNA repair. Inhibiting the function of check point, the DNA damage can not be repaired, and the cell is apoptotic. Compared with normal cells, a plurality of tumor cells repair DNA damage and avoid apoptosis mainly depending on the activation of a G2 stage checkpoint because the function of a P53 protein which is an important protein of the G1 stage checkpoint is damaged. Therefore, inhibition of the checkpoint at stage G2 selectively kills tumor cells. While the role of Wee-1 kinase activity in the checkpoint at stage G2 suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage, inhibition of Wee-1 activity promotes the entry of unrepaired tumor cells into stage M after DNA damage, inducing apoptosis [ Curr Clin Pharmacol,2010.5(3): p.186-91 ].
In addition to its role in the G2 checkpoint, Wee-1 has been implicated in DNA synthesis, DNA homology repair, post-translational modification of histones, and other functions that are closely related to tumorigenesis and development [ J Cell Biol,2011.194(4): p.567-79 ]. In a large number of tumors including liver, breast, cervical, melanoma and lung cancers [ PLoS One,2009.4(4): p.e5120 ]; hepatology,2003.37(3): p.534-43; mol Cancer,2014.13: p.72 ], Wee-1 expression was greatly elevated. While the high expression of Wee-1 is positively correlated with the poor development and prognosis of tumors, suggesting that Wee-1 kinase may be involved in the development and development of tumors. Studies in vitro cell models and in vivo animal models have shown that inhibition of Wee-1 activity while inducing DNA damage can significantly inhibit the growth of a variety of tumors [ Cancer Biol Ther,2010.9(7): p.514-22; mol Cancer Ther,2009.8(11): p.2992-3000 ].
Therefore, the development of specific, small molecule inhibitors of highly active Wee-1 kinase would be of significant clinical value for tumor therapy, especially in targeting tumors with an impaired G1 checkpoint such as a P53 deletion.
Disclosure of Invention
The invention provides a compound with a structure shown as a formula (1A) or a formula (1B), an optical isomer thereof or a pharmaceutically acceptable salt thereof,
Figure BDA0002189966480000021
wherein the content of the first and second substances,
"+" indicates a chiral center;
n is 0 or 1;
w is-CO-or-CH2-；
Y is H, F, Me or OMe;
m is-CH2-、-CF2-、-O-、-NR1-、-N(COR1)-、-N(COOR1)-、-CH(OR1) -or-CH (NR)2R3) -, wherein R1Is H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen substituted C3-C6 cycloalkyl or heterocycloalkyl, R2And R3Independently is H or C1-C3 alkyl, or R2And R3And N forms a 4-7 membered heterocycloalkyl group;
q is-O-, -S-or-NR4-, wherein R4Is H, C1-C3 alkyl or C3-C6 cycloalkyl;
x is the following group:
Figure BDA0002189966480000022
Figure BDA0002189966480000031
wherein ". x" indicates a direct connection to the pyrimidine ring, ". x" indicates a connection to W,R5and R6Independently H, F, Cl or Me, R7Is H, C1-C3 alkyl or C3-C6 cycloalkyl, R8Is H, CN, C1-C3 alkyl or halogen substituted C1-C3 alkyl, R9Is C1-C3 alkyl or halogen substituted C1-C3 alkyl.
In some embodiments of the invention, R is as defined above1Is H, Me, Et,n-Pr、i-Pr、t-Bu, cyclobutyl, cyclopentyl, cyclohexyl,
Figure BDA0002189966480000032
In some embodiments of the invention, R is as defined above2And R3Independently H, Me or Et, or R2And R3Formation of a common N atom
Figure BDA0002189966480000033
In some embodiments of the invention, R is as defined above4Is H, Me, Et,n-Pr or cyclopropyl.
In some embodiments of the invention, X is the following:
Figure BDA0002189966480000041
in some embodiments of the invention, the above compound, isomer, or pharmaceutically acceptable salt is selected from the group consisting of:
Figure BDA0002189966480000051
Figure BDA0002189966480000061
Figure BDA0002189966480000071
another object of the present invention is a pharmaceutical composition comprising a pharmacologically acceptable excipient or carrier, and the compound represented by formula (1A) or formula (1B) of the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
Still another object of the present invention is to provide the use of the above-mentioned compound of the present invention, its isomer, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of related diseases mediated by Wee 1.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined otherwise, should not be considered as indefinite or unclear, but rather construed according to a common definition, when appearing herein with a trade name, is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, compositions and/or formulations which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain particular aspects, pharmaceutically acceptable salts are obtained by reacting a compound of formula (1A) or formula (1B) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, etc., an organic acid, e.g., formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and an acidic amino acid, e.g., aspartic acid, glutamic acid, etc.
References to pharmaceutically acceptable salts are understood to include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1A) or formula (1B) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of formula (1A) or (1B) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, using an organic solvent including, but not limited to, acetonitrile, tetrahydrofuran, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for purposes of the compounds and methods provided herein.
In other embodiments, the compounds of formula (1A) or formula (1B) are prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-sized forms. In addition, the compound of formula (1A) or formula (1B) includes crystalline forms, and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
In another aspect, the compounds of formula (1A) or formula (1B) have one or more stereogenic centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
Using wedge-shaped keys, unless otherwise indicated
Figure BDA0002189966480000091
And dotted bond
Figure BDA0002189966480000092
Representing an absolute configuration of a solid centre, by wavy lines
Figure BDA0002189966480000093
Denotes a wedge bond or a dotted bond: (
Figure BDA0002189966480000094
Or
Figure BDA0002189966480000095
)。
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C3H) Iodine-125 (125I) Or carbon-14 (14C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The compound and the pharmaceutically acceptable salt thereof can be prepared into various preparations, wherein the preparation comprises the compound or the pharmaceutically acceptable salt thereof in a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment and other specific conditions of a treated subject.
"pharmaceutically acceptable excipient or carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, olive oil etc.), and the likeOil, mannitol, sorbitol, etc.), emulsifier (e.g., sorbitol, mannitol, etc.)
Figure BDA0002189966480000096
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
When the compounds of the present invention are administered, they may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Unless otherwise specified, the term "alkyl" denotes saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1to 6 carbon atoms. Lower alkyl groups having 1to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3，CH3CH2，CF3，CHF2，CF3CH2，iPr，nPr，iBu，cPr，nBu ortBu。
Unless otherwise specified, the term "cycloalkylalkyl" refers to a saturated or partially saturated non-aromatic cyclic group consisting of carbon atoms and a heteroatom selected from nitrogen, oxygen or sulfur, which cyclic group may be a monocyclic or polycyclic group, in the present invention, the number of heteroatoms in the heterocycloalkyl group is preferably 1,2, 3 or 4, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may be optionally oxidized. The nitrogen atom may optionally be further substituted with other groups to form tertiary amines or quaternary ammonium salts. Examples of heterocycloalkyl groups include, but are not limited to: aziridinyl, azetidin-1-yl, N-alkylazetidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, morpholin-4-yl, thiomorpholin-S-oxid-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl, and the like.
Unless otherwise specified, the term "halogen substituted" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Further, "haloalkyl" is intended to include monohaloalkyl or polyhaloalkyl. For example, "halogenated C1-C3 alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2, 2-trifluoroethyl 2-chloropropyl, 3-bromopropyl, and the like.
The term "membered ring" includes any cyclic structure. The term "element" is intended to mean the number of backbone atoms constituting a ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are five-membered rings.
The term "fragment" refers to a specific part or functional group of a molecule. Chemical moieties are generally considered to be chemical entities contained in or attached to a molecule.
Synthesis of Compounds
The process for producing the compound of formula (1A) or (1B) of the present invention is specifically described below, but these specific processes do not set any limit to the present invention.
The compounds of formula (1A) or (1B) described above may be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials for the synthesis of compounds of formula (1A) or formula (1B) may be synthesized or obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co, (Milwaukee, Wis.) or Sigma Chemical Co, (st. The compounds described herein and other related compounds having various substituents can be synthesized using well-known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4thEd., (Wiley 1992); carey and Sundberg, ADVANCED ORGANICCHEMISTRY 4thEd, Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS 3rdThe method in ed., (Wiley 1999). The general method of compound preparation may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, and the like, are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a process for the preparation of said compound of formula (1A) or formula (1B), which is prepared by process a or process B as follows:
method a comprises the following steps: firstly, compound A1 and compound A2 react under alkaline conditions to generate compound A3, compound A3 further reacts under the action of strong base to generate compound A4, compound A4 is reduced in the presence of a reducing agent to generate compound A5, and compound A5 and compound A6 further react to generate target compound A7.
Figure BDA0002189966480000111
In the above reaction equation, M, Q, Y, W, X and n are as defined above, and Z is CH3S，CH3SO、CH3SO2Br, Cl or I.
Method B comprises the following steps: firstly, a compound B1 and a compound B2 react under alkaline conditions to generate a compound B3, a compound B3 removes a protecting group to obtain a compound B4, then the compound B4 is subjected to intramolecular coupling reaction to obtain a compound B5, the compound B5 is reduced to obtain a compound B6, and the compound B6 and the compound A6 further react to generate a target compound B7.
Figure BDA0002189966480000121
In the above reaction equation, M, Q, Y, W, X and n are as defined above, and Z is CH3S，CH3SO、CH3SO2Br, Cl or I.
Therapeutic uses
The compounds or compositions described herein are generally useful for inhibiting Wee1 kinase and, thus, may be useful for treating one or more disorders associated with Wee1 kinase activity. Thus, in certain embodiments, the present invention provides methods for treating a Wee1 kinase-mediated disorder, comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.
Cancers that can be treated with the compounds of the invention include, but are not limited to, hematological malignancies (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic syndrome, and myeloproliferative family syndrome), and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancers and osteosarcoma, and interstitial tumors), among others.
The various specific aspects, features and advantages of the compounds, methods and pharmaceutical compositions described above are set forth in detail in the following description, which makes the present invention clear. It should be understood herein that the detailed description and examples, while indicating specific embodiments, are given by way of illustration only. After reading the description of the invention, one skilled in the art can make various changes or modifications to the invention, and such equivalents fall within the scope of the invention as defined in the application.
In all examples, melting points were measured using an X-4 melting point apparatus with the thermometer uncorrected;1H-NMR was recorded using a Varian Mercury400 NMR spectrometer with chemical shifts expressed in delta (ppm); the silica gel used for separation is not illustrated to be 200-300 meshes, and the proportions of the eluents are volume ratios.
The invention employs the following abbreviations: ACN represents acetonitrile; AcOH represents acetic acid; ar represents Ar; CDCl3Represents deuterated chloroform; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; DMF represents dimethylformamide; DMSO represents dimethyl sulfoxide; EA represents ethyl acetate; EtOH stands for ethanol; h represents hour; h2Represents hydrogen; k2CO3Represents potassium carbonate; LC-MS stands for liquid-mass spectrometry; m-CPBA represents m-chloroperoxybenzoic acid; mL represents mL; MeOH represents methanol; min represents min; MS represents mass spectrum; NaBH3CN represents cyanoborohydrideDissolving sodium; NaBH (OAc)3Represents sodium triacetoxyborohydride; na (Na)2CO3Represents sodium carbonate; NaH represents sodium hydride; NaHCO 23Represents sodium bicarbonate; na (Na)2SO3Represents sodium sulfite; na (Na)2SO4Represents sodium sulfate; NMR stands for nuclear magnetic resonance; DEG C represents centigrade degree; pd (OAc)2Represents palladium acetate; PE represents petroleum ether; r.t. represents room temperature; SOCl2Represents thionyl chloride; TFA represents trifluoroacetic acid; toluene stands for Toluene; TsCl represents p-methylbenzenesulfonyl chloride.
Detailed Description
Example 1: compound 1
Figure BDA0002189966480000131
The synthetic route is as follows:
Figure BDA0002189966480000141
step 1: synthesis of Compound 1-1
Dissolving 3-hydroxymethyl piperazine-1-carboxylic acid tert-butyl ester (1.0g,4.63mmol) and 1, 2-difluoro-4-nitrobenzene (809mg,5.1mmol) in DMF (20mL), adding DIPEA (1.8g,13.89mmol), heating to 120 ℃ for reaction overnight, monitoring the reaction by LC-MS, adding water (100mL) into the reaction system, extracting with EA (50 mL. multidot.2), combining organic phases, washing the organic phase with saturated saline (50mL), and adding anhydrous Na2SO4Drying, concentration of the filtrate and column chromatography of the residue (PE/EA: 10/1to 5/1) gave the compound as a yellow solid (600mg, 60% yield), ESI-MS M/z:356.1[ M + H ], (ESI-MS M/z)]+。
Step 2: synthesis of Compound 1-2
Dissolving compound 1-1((3.6g,10mmol) in DMF (30mL), ice-cooling, adding NaH (60% content, 440mg,11mmol), heating to 80 deg.C for reaction overnight, monitoring the reaction by LC-MS, cooling, pouring into ice water (100mL), EA (50 mL. times.2) extracting, combining organic phases, washing the organic phases with water (150 mL. times.2), saturated brine (50mL), anhydrous Na2SO4Drying, concentrating the filtrate and subjecting the residue to column chromatography (PE/EA: 20/1to 10/1) to give the compound as a yellow solid (2.1g, 62% yield), ESI-MS M/z:336.1[ M + H ]/]+。
And step 3: synthesis of Compounds 1-3
Compound 1-2(2.0g,6.0mmol) was dissolved in EA (40mL), HCl/dioxane solution (4.0M,10mL) was added, r.t. stirred for 3H, LC-MS monitored for reaction completion, concentrated directly to give crude yellow solid (2.0g, 100% yield) which was not purified and directly charged to the next reaction, ESI-MS M/z:236.1[ M + H ]: 236.1]+。
And 4, step 4: synthesis of Compounds 1-4
Dissolving compound 1-3(2.0g,6.0mmol) in ACN (20mL), adding aqueous formaldehyde solution (35% -40%, 0.5mL), AcOH (360mg,6.0mmol), stirring r.t. for 1h, adding NaBH (OAc)3(2.5g,12mmol), r.t. reaction overnight, LC-MS after completion of the reaction, concentrate, dissolve the residue with EA (50mL), saturated NaHCO3Solution (30mL) wash with anhydrous Na2SO4Drying, concentration of the filtrate and purification of the residue by column chromatography (DCM/MeOH 100/1to 20/1) gave a yellow solid (1.0g, 66% yield), ESI-MS M/z:250.1[ M + H ]/]+。
And 5: synthesis of Compounds 1-5
Dissolve compounds 1-4(1.0g,4.0mmol) in MeOH (50mL), add Pd/C (10%, 200mg), inject hydrogen, r.t. react overnight, LC-MS monitors the reaction completion, filter, concentrate the filtrate to give a pale yellow solid compound (800mg, 91% yield) which was used in the next reaction without purification, ESI-MS M/z:220.1[ M + H ]]+。
Step 6: synthesis of Compound 1
Compound 1-6 (see wo2017075629,360mg,1.0mmol for synthesis) was dissolved in toluene (10mL), m-CPBA (377mg,2.0mmol) was added under cooling on ice, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 1-5(220mg,1.0mmol) were added to the reaction solution, reacted at 80 ℃ overnight, LC-MS monitored for reaction completion, directly concentrated, and the residue was subjected to column chromatography (DCM/MeOH: 100/1to 10/1) to give compound 1 (300mg of yellow solid, 56% yield).
1H NMR(400MHz,DMSO-d6)δ:10.09(s,1H),8.79(s,1H),7.95(t,J＝7.9Hz,1H),7.72(d,J＝8.1Hz,1H),7.57(dd,J＝7.7,0.9Hz,1H),7.16(d,J＝29.3Hz,2H),6.79(d,J＝8.9Hz,1H),5.62(ddd,J＝16.5,10.7,5.3Hz,1H),5.30(s,1H),4.99-4.92(m,1H),4.78(dd,J＝17.1,1.5Hz,1H),4.66(s,2H),4.21(d,J＝10.5Hz,1H),3.87(t,J＝9.8Hz,1H),3.64(d,J＝11.6Hz,1H),2.96(t,J＝9.9Hz,1H),2.79(d,J＝10.9Hz,2H),2.61-2.51(m,1H),2.19(s,3H),2.09-2.00(m,1H),1.65(t,J＝10.6Hz,1H),1.42(s,6H)；ESI-MS m/z:529.2[M+H]+.
Two optical isomers of the compound 1 can be obtained by different chiral raw materials or chiral separation methods, and the structural formula is as follows:
Figure BDA0002189966480000161
example 2: compound 2
Figure BDA0002189966480000162
The synthetic route is as follows:
Figure BDA0002189966480000163
step 1: synthesis of Compound 2-1
Dissolve compound 1-3(706mg,3.0mmol) in 1, 2-dichloroethane (20mL), add acetone (1mL), AcOH (180mg,3.0mmol), stir r.t. for 1h, add NaBH (OAc)3(1.26g,6mmol), r.t. reaction overnight, LC-MS monitoring completion of reaction, concentration, dissolution of residue with EA (30mL), saturated NaHCO3Solution (30mL) wash with anhydrous Na2SO4Drying, concentration of the filtrate and column chromatography of the residue (DCM/MeOH. 100/1to 20/1) gave a yellow solid (400g, 48% yield), ESI-MS M/z:278.1[ M + H ])]+。
Step 2: synthesis of Compound 2-2
Compound 2-1(400mg,1.44mmol) was dissolved in MeOH (30mL), Pd/C (10%, 80mg) was added, and H was bubbled through2R.t. reaction overnight, LC-MS after reaction completion, filtration, concentration of filtrate to give pale yellow solid compound (300mg, yield 84%), which was used in the next reaction without purification, ESI-MS M/z:248.1[ M + H ], (ESI-MS M/z)]+。
And step 3: synthesis of Compound 2
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), cooled on ice, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for completion of reaction, DIPEA (520mg,4.0mmol) and compound 2-2(247mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for completion of reaction, directly concentrated, and the residue was column chromatographed (DCM/MeOH: 100/1to 10/1) to give compound 2 (320 mg, 57% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:10.12(s,1H),8.80(s,1H),7.97(t,J＝7.9Hz,1H),7.75(d,J＝8.1Hz,1H),7.60(dd,J＝7.7,0.9Hz,1H),7.19(d,J＝13.3Hz,2H),6.81(d,J＝8.9Hz,1H),5.65-5.55(m,1H),5.31(s,1H),5.05-4.95(m,1H),4.80(dd,J＝17.1,1.5Hz,1H),4.68(s,2H),4.23(d,J＝10.5Hz,1H),3.91(t,J＝9.8Hz,1H),3.65(d,J＝11.6Hz,1H),2.97(t,J＝9.9Hz,1H),2.93-2.81(m,2H),2.62-2.50(m,2H),2.09-2.00(m,1H),1.65(t,J＝10.6Hz,1H),1.42(s,6H),1.25(s,6H)；ESI-MS m/z:557.2[M+H]+.
Example 3: compound 3
Figure BDA0002189966480000171
Using oxetane and the compounds 1to 3 as raw materials, compound 3 was obtained by a synthesis method similar to that of example 2.
1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H),8.76(s,1H),7.94(t,J＝7.9Hz,1H),7.72(d,J＝8.1Hz,1H),7.58(dd,J＝7.7,0.9Hz,1H),7.15(d,J＝9.3Hz,2H),6.79(d,J＝8.9Hz,1H),5.67-5.56(m,1H),5.28(s,1H),4.81-4.73(m,3H),4.64-4.48(m,4H),4.22(d,J＝10.5Hz,1H),3.87-3.70(m,2H),3.64(d,J＝11.6Hz,1H),2.96(t,J＝9.9Hz,1H),2.79(d,J＝10.9Hz,2H),2.63-2.50(m,2H),2.09-2.00(m,1H),1.70-1.60(m,1H),1.43(s,6H)；ESI-MS m/z:571.2[M+H]+.
Example 4 Compound 4
Figure BDA0002189966480000181
Using cyclobutanone and compounds 1to 3 as starting materials, compound 4 was obtained by a synthesis method similar to that in example 2.
1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H),8.79(s,1H),7.95(t,J＝7.9Hz,1H),7.73(d,J＝8.1Hz,1H),7.56(dd,J＝7.7,0.9Hz,1H),7.15(d,J＝11.3Hz,2H),6.78(d,J＝8.9Hz,1H),5.65-5.57(m,1H),5.30(s,1H),4.99-4.92(m,1H),4.78(dd,J＝17.1,1.5Hz,1H),4.66(s,2H),4.21(d,J＝10.5Hz,1H),3.87(t,J＝9.8Hz,1H),3.64(d,J＝11.6Hz,1H),2.96(t,J＝9.9Hz,1H),2.83-2.71(m,3H),2.61-2.51(m,1H),2.05-1.92(m,3H),1.69-1.58(m,5H),1.42(s,6H)；ESI-MS m/z:569.2[M+H]+.
Example 5 Compound 5
Figure BDA0002189966480000182
The synthetic route is as follows:
Figure BDA0002189966480000191
step 1: synthesis of Compound 5-1
Dissolving the compounds 1-3(2.35g,10mmol) in DCM (50mL), adding DIPEA (2.6g,20mmol), adding acetyl chloride (940mg,12mmol) under ice bath cooling, r.t. reacting for 3h, pouring into ice water (30mL) after LC-MS monitoring reaction, separating liquid, and separating organic layer with anhydrous Na2SO4Drying, concentrating the filtrate, and column chromatography of the residue (PE/EA: 20/1to 10/1) gave the compound as a yellow solid (2.1g, 76% yield), ESI-MS M/z:278.1[ M + H ], (M + H)]+。
Step 2: synthesis of Compound 5-2
Compound 5-1(1.0g,3.6mmol) was dissolved in MeOH (50mL), Pd/C (10%, 200mg) was added, hydrogen was bubbled in, r.t. reaction overnight, LC-MS monitored reaction completion, filtered and concentrated to give a pale yellow solid compound (770mg, 86% yield) which was used in the next reaction without purification ESI-MS M/z:248.1[ M + H: 248.1]+。
And step 3: synthesis of Compound 5
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 5-2(247mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 5 (320 mg, 57% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.89(s,1H),8.78(s,1H),7.95(t,J＝7.9Hz,1H),7.72(d,J＝8.1Hz,1H),7.57(dd,J＝8.0,0.9Hz,1H),7.16(d,J＝9.5Hz,2H),6.79(d,J＝8.9Hz,1H),5.58-5.52(m,1H),5.31(s,1H),4.97-4.91(m,1H),4.78(dd,J＝13.1,1.5Hz,1H),4.66(s,2H),4.21(d,J＝10.5Hz,1H),3.86(t,J＝9.8Hz,1H),3.65(d,J＝10.6Hz,1H),2.96(t,J＝9.9Hz,1H),2.75-2.65(m,3H),2.15(s,3H),2.12-1.96(m,2H),1.42(s,6H)；ESI-MS m/z:557.2[M+H]+.
Example 6 Compound 6
Figure BDA0002189966480000201
Using methyl chloroformate and compounds 1to 3 as starting materials, compound 6 was obtained in a similar manner to that in example 5.
1H NMR(400MHz,DMSO-d6)δ:9.96(s,1H),8.76(s,1H),7.96(t,J＝7.9Hz,1H),7.69(d,J＝8.1Hz,1H),7.58(dd,J＝8.1,1.2Hz,1H),7.12(d,J＝11.3Hz,2H),6.78(d,J＝9.2Hz,1H),5.62-5.55(m,1H),5.29(s,1H),4.96-4.92(m,1H),4.76(dd,J＝12.1,1.6Hz,1H),4.61(s,2H),4.21(d,J＝10.5Hz,1H),3.86(t,J＝9.8Hz,1H),3.70(s,3H),3.62(d,J＝10.6Hz,1H),2.93(t,J＝9.6Hz,1H),2.71-2.60(m,3H),2.15(s,3H),2.05-1.91(m,2H),1.43(s,6H)；ESI-MS m/z:573.2[M+H]+.
Example 7 Compound 7
Figure BDA0002189966480000202
The synthetic route is as follows:
Figure BDA0002189966480000211
step 1: synthesis of Compound 7-1
Piperidin-2-ylmethanol (2.3g,20mmol), 1, 2-difluoro-4-nitrobenzene (3.82g,24mmol) were dissolved in EtOH (50mL) and NaHCO was added3(1.68g,20mmol) was refluxed for 5H, and after monitoring by LC-MS, the reaction was completed, filtered, the filtrate was concentrated, and the residue was subjected to column chromatography (PE/EA: 10/1to 5/1) to give a yellow solid compound (3.56g, yield 70%), ESI-MS M/z:255.1[ M + H/z ], (M + H): 5H)]+。
Step 2: synthesis of Compound 7-2
Dissolving compound 7-1(2.54g,10mmol) in THF (30mL), adding NaH (60% content, 600mg,15mmol) under cooling in ice bath, heating to 70 deg.C for reflux reaction for 5h, monitoring reaction completion by LC-MS, cooling, pouring into ice water (100mL), EA (50mL x 2) extracting, combining organic phases, washing organic phase with water (150mL), saturated saline (50mL), anhydrous Na2SO4Drying, concentrating the filtrate, and column chromatography of the residue (PE/EA: 20/1to 10/1) gave the compound as a yellow solid (1.8g, 76% yield), ESI-MS M/z:235.1[ M + H ])]+。
And step 3: synthesis of Compound 7-3
Compound 7-2(1.0g,4.3mmol) was dissolved in MeOH (50mL), Pd/C (10%, 200mg) was added, hydrogen was bubbled in, r.t. reaction overnight, LC-MS monitored completion of reaction, filtration, concentration of filtrate afforded light yellow solid compound (800mg, 91% yield) which was used in the next reaction without purification, ESI-MS M/z:205.1[ M + H ], as]+。
And 4, step 4: synthesis of Compound 7
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 7-3(204mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 7 (260mg, 51% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.97(s,1H),8.79(s,1H),7.95(t,J＝7.9Hz,1H),7.73(d,J＝8.1Hz,1H),7.56(dd,J＝7.7,0.9Hz,1H),7.15(d,J＝11.3Hz,2H),6.78(d,J＝8.9Hz,1H),5.65-5.60(m,1H),5.30(s,1H),4.99-4.92(m,1H),4.78(d,J＝10.5Hz,1H),4.66(s,2H),4.21(d,J＝10.5Hz,1H),3.78(t,J＝9.8Hz,1H),3.45-3.35(m,1H),3.05-2.95(m,2H),1.95-1.75(m,3H),1.65-1.50(m,3H),1.43(s,6H)；ESI-MS m/z:514.2[M+H]+.
Example 8 Compound 8
Figure BDA0002189966480000221
The synthetic route is as follows:
Figure BDA0002189966480000222
step 1: synthesis of Compound 8-1
4, 4-Difluoropiperidine-2-carboxylic acid ethyl ester (synthesis reference WO2008125570,1.93g,10mmol) and 1, 2-difluoro-4-nitrobenzene (1.91g,12mmol) were dissolved in DMF (30mL), NaHCO was added3(840mg,10mmol) and reaction at 90 ℃ for 5H, LC-MS monitoring completion of the reaction, filtration, concentration of the filtrate and column chromatography of the residue (PE/EA: 10/1to 5/1) to give the compound as a yellow solid (2.0g, 60% yield), ESI-MS M/z:333.1[ M + H/]]+。
Step 2: synthesis of Compound 8-2
Compound 8-1(1.66g,5.0mmol) was dissolved in EtOH (20mL), and NaBH was added under cooling in an ice bath4(380mg,10mmol), r.t. reactionAfter overnight, LC-MS monitored completion of the reaction, concentrated, the residue dissolved with EA (50mL), washed with water (50mL), and the organic layer washed with anhydrous Na2SO4Drying, concentrating the filtrate, and column chromatography of the residue (PE/EA: 10/1to2/1) gave the compound (1.0g, 69% yield) as a yellow solid, ESI-MS M/z:291.1[ M + H ]/]+。
And step 3: synthesis of Compound 8-3
Dissolving compound 8-2(1.0g,3.45mmol) in THF (30mL), adding NaH (60% content, 208mg,5.2mmol) under cooling in ice bath, heating to 70 deg.C for reflux reaction for 5h, monitoring by LC-MS after reaction completion, cooling, pouring into ice water (100mL), EA (50 mL. about.2) extracting, combining organic phases, washing organic phase with water (150mL), saturated saline (50mL), anhydrous Na2SO4Drying, concentrating the filtrate, and column chromatography of the residue (PE/EA: 20/1to 5/1) gave the compound as a yellow solid (460mg, 49% yield), ESI-MS M/z:271.1[ M + H ]/, (M + H)]+。
And 4, step 4: synthesis of Compound 8-4
Dissolve compound 8-3(400mg,1.48mmol) in MeOH (30mL), add Pd/C (10%, 100mg), inject hydrogen, r.t. react overnight, after LC-MS monitors the reaction is complete, filter, concentrate the filtrate to give the compound as a pale yellow solid (300mg, 84% yield), which is used in the next step without purification, ESI-MS M/z:241.1[ M + H ])]+。
And 5: synthesis of Compound 8
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 8-4(270mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 8 (220mg, 40% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.56(s,1H),8.77(s,1H),7.93(t,J＝7.9Hz,1H),7.72(d,J＝8.1Hz,1H),7.55(dd,J＝7.7,0.9Hz,1H),7.14(d,J＝11.3Hz,2H),6.78(d,J＝8.9Hz,1H),5.65-5.60(m,1H),5.30(s,1H),4.99-4.92(m,1H),4.67(d,J＝10.5Hz,1H),4.61(s,2H),4.20(d,J＝10.5Hz,1H),3.65(t,J＝9.8Hz,1H),3.45-3.35(m,1H),3.05-2.95(m,2H),1.95-1.75(m,4H),1.43(s,6H)；ESI-MS m/z:550.2[M+H]+.
Example 9 Compound 9
Figure BDA0002189966480000241
Using (S) -pyrrolidin-2-ylmethanol instead of piperidin-2-ylmethanol as a starting material, compound 9 was obtained by a synthesis method similar to that in example 7.
1H NMR(400MHz,DMSO-d6)δ:9.87(s,1H),8.76(s,1H),7.96(t,J＝7.8Hz,1H),7.72(d,J＝7.8Hz,1H),7.55(dd,J＝7.7,0.9Hz,1H),7.16(d,J＝10.3Hz,2H),6.78(d,J＝8.8Hz,1H),5.65-5.60(m,1H),5.30(s,1H),4.99-4.92(m,1H),4.56(d,J＝10.8Hz,1H),4.60(s,2H),4.21(d,J＝10.8Hz,1H),3.68(t,J＝9.8Hz,1H),3.35-3.25(m,1H),3.03-2.93(m,2H),1.65-1.50(m,4H),1.41(s,6H)；ESI-MS m/z:500.2[M+H]+.
Example 10 Compound 10
Figure BDA0002189966480000242
Using a synthesis method similar to that in example 7, starting from morpholin-3-ylmethanol instead of piperidin-2-ylmethanol, compound 10 was obtained.
1H NMR(400MHz,DMSO-d6)δ:10.02(s,1H),8.79(s,1H),7.96(t,J＝7.9Hz,1H),7.71(d,J＝8.1Hz,1H),7.56(d,J＝10.4Hz,1H),7.17(d,J＝10.3Hz,2H),6.79(d,J＝8.9Hz,1H),5.61(ddd,J＝15.5,10.5,5.2Hz,1H),5.31(s,1H),5.01-.93(m,1H),4.79(d,J＝10.1Hz,1H),4.65(s,2H),4.22(d,J＝10.5Hz,1H),3.87(t,J＝9.8Hz,1H),3.75-3.65(m,4H),3.60-3.45(m,3H),1.42(s,6H)；ESI-MS m/z:516.2[M+H]+.
Example 11 Compound 11
Figure BDA0002189966480000251
The synthetic route is as follows:
Figure BDA0002189966480000252
step 1: synthesis of Compound 11-1
(2S,4R) -4- (dimethylamino) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (synthetic reference WO2001000206,2.44g,10.0mmol) was dissolved in EA (40mL), HCl/dioxane (4.0M,15mL) was added, r.t. stirring was performed for 3H, LC-MS monitored reaction was completed, direct concentration was performed to obtain a yellow solid compound (2.5g, yield 100%) which was directly put into the next reaction without purification, ESI-MS M/z:145.1[ M + H ]/(M + H): 145.1]+。
Step 2: synthesis of Compound 11-2
Dissolving compound 11-1(2.5g,10mmol) and 1, 2-difluoro-4-nitrobenzene (1.91g,12mmol) in DMF (20mL), adding DIPEA (6.5g,50mmol), heating to 120 ℃, reacting overnight, monitoring by LC-MS, after the reaction is finished, adding into water (60mL), EA (30mL x 3) extracting, combining organic phases, washing the organic phase with water (60mL), washing with saturated saline (60mL), drying with anhydrous Na2SO4, concentrating the filtrate, subjecting the residue to column chromatography (DCM/MeOH 100/1to 30/1) to obtain yellow solid compound (2.0g, yield 70%), ESI-MS M/z:284.1[ M + H ], (M + H): 30/1)]+。
And step 3: synthesis of Compound 11-3
Dissolving compound 11-2(1.42g,5.0mmol) in THF (30mL), adding NaH (60% content, 300mg,7.5mmol) under cooling in ice bath, heating to 70 deg.C for reflux reaction for 5h, monitoring the reaction completion by LC-MS, cooling, pouring into ice water (100mL), extracting with EA (50 mL. multidot.2), combining organic phases, washing the organic phase with water (150mL), washing with saturated saline (50mL), and adding anhydrous Na2SO4Drying, concentration of the filtrate and column chromatography of the residue (DCM/MeOH. 100/1to 30/1) gave the compound as a yellow solid (1.0g, 75% yield), ESI-MS M/z:264.1[ M + H ])]+。
And 4, step 4: synthesis of Compound 11-4
Dissolve compound 11-3(1.0g,3.8mmol) in MeOH (50mL), add Pd/C (10%, 200mg), insert hydrogen, r.t. reverseThe reaction was monitored by LC-MS overnight, filtered, and the filtrate was concentrated to give the compound as a pale yellow solid (600mg, 67% yield) which was used in the next reaction without purification, ESI-MS M/z:234.1[ M + H ]]+。
And 5: synthesis of Compound 11
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 11-4(233mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 11 (220mg, 41% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.89(s,1H),8.77(s,1H),7.95(t,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.55(dd,J＝7.7,0.9Hz,1H),7.14(d,J＝10.3Hz,2H),6.79(d,J＝8.8Hz,1H),5.65-5.60(m,1H),5.30(s,1H),4.99-4.92(m,1H),4.56(d,J＝10.6Hz,1H),4.63(s,2H),4.21(d,J＝10.6Hz,1H),3.78(t,J＝9.8Hz,1H),3.35-3.25(m,1H),3.03-2.93(m,2H),2.85-2.72(m,1H),2.35(s,6H),1.65-1.50(m,2H),1.41(s,6H),ESI-MS m/z:543.2[M+H]+.
Example 12 Compound 12
Figure BDA0002189966480000271
Compound 12 was obtained by a synthesis method similar to that in example 7 using ((2S,4R) -4-methoxypyrrolidin-2-yl) methanol (synthesis reference WO2011088045) instead of piperidin-2-yl methanol as a starting material.
1H NMR(400MHz,DMSO-d6)δ:9.92(s,1H),8.78(s,1H),7.96(t,J＝7.9Hz,1H),7.71(d,J＝7.6Hz,1H),7.53(dd,J＝7.5,0.9Hz,1H),7.15(d,J＝10.2Hz,2H),6.76(d,J＝8.9Hz,1H),5.67-5.62(m,1H),5.31(s,1H),5.01-4.95(m,1H),4.66(d,J＝10.6Hz,1H),4.60(s,2H),4.15(d,J＝10.6Hz,1H),3.68(t,J＝9.8Hz,1H),3.56(s,3H),3.35-3.25(m,2H),3.13-3.03(m,2H),2.05-1.92(m,2H),1.42(s,6H)；ESI-MS m/z:530.2[M+H]+.
Example 13 Compound 13
Figure BDA0002189966480000272
Compound 13 was obtained by a synthesis method similar to that of example 11 using tert-butyl (2S,4S) -4- (dimethylamino) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (synthesis reference WO2016008411) as a starting material.
1H NMR(400MHz,DMSO-d6)δ:9.88(s,1H),8.77(s,1H),7.96(t,J＝7.8Hz,1H),7.73(d,J＝7.9Hz,1H),7.55(dd,J＝7.8,1.0Hz,1H),7.14(d,J＝10.3Hz,2H),6.78(d,J＝8.8Hz,1H),5.64-5.60(m,1H),5.31(s,1H),4.98-4.93(m,1H),4.57(d,J＝10.5Hz,1H),4.65(s,2H),4.21(d,J＝10.5Hz,1H),3.77(t,J＝9.9Hz,1H),3.35-3.25(m,1H),3.03-2.92(m,2H),2.86-2.73(m,1H),2.33(s,6H),1.66-1.52(m,2H),1.42(s,6H)；ESI-MS m/z:543.2[M+H]+.
Example 14 Compound 14
Figure BDA0002189966480000281
Compound 14 was obtained by a similar synthesis method to that of example 7 using ((2S,4S) -4-methoxypyrrolidin-2-yl) methanol (see Journal of Medicinal Chemistry,2017,60(4),1417-1431) instead of piperidin-2-yl methanol as a starting material.
1H NMR(400MHz,DMSO-d6)δ:9.93(s,1H),8.78(s,1H),7.96(t,J＝7.9Hz,1H),7.72(d,J＝7.6Hz,1H),7.51(dd,J＝7.6,1.0Hz,1H),7.16(d,J＝10.3Hz,2H),6.77(d,J＝8.8Hz,1H),5.68-5.62(m,1H),5.31(s,1H),5.00-4.95(m,1H),4.65(d,J＝10.5Hz,1H),4.61(s,2H),4.16(d,J＝10.6Hz,1H),3.69(t,J＝9.0Hz,1H),3.57(s,3H),3.36-3.22(m,2H),3.14-3.03(m,2H),2.06-1.91(m,2H),1.43(s,6H)；ESI-MS m/z:530.2[M+H]+.
Example 15 Compound 15
Figure BDA0002189966480000282
The synthetic route is as follows:
Figure BDA0002189966480000291
step 1: synthesis of Compound 15-1
Dissolving tert-butyl 4- (2-fluoro-4-nitrobenzene) -3- (hydroxymethyl) piperazine-1-carboxylate (3.55g,10mmol) in DCM (50mL), adding DIPEA (2.6g,20mmol), adding TsCl (2.3g,12mmol), stirring r.t. after the addition is finished, reacting overnight, monitoring by LC-MS, adding into water (50mL), separating, extracting the water layer with DCM (30mL), combining the organic phases, washing the organic phase with water (50mL), washing with saturated saline (50mL), and washing with anhydrous Na2SO4Drying, concentrating the filtrate, column chromatography (PE/EA: 20/1to 5/1) to give a pale yellow gum (4.0g, 78% yield), ESI-MS M/z:510.1[ M + H ], (ESI-MS M/z)]+。
Step 2: synthesis of Compound 15-2
Compound 15-1(1.4g,2.75mmol) was dissolved in EtOH (20mL), methylamine alcohol solution (25% -30%, 1.8g, ca.55mmol) was added and reacted in a sealed tube at 80 ℃ overnight, LC-MS monitored completion of reaction, concentrated, residue was chromatographed (PE/EA: 5/1to 1/1) to give a yellow gum (480mg, 50% yield), ESI-MS M/z:510.1[ M + H ], (ii) ESI-MS M/z: M]+。
And step 3: synthesis of Compound 15-3
Dissolve compound 15-2(3.48g,10.0mmol) in EA (50mL), add HCl/dioxane (4.0M,15mL), stir at r.t. for 3H, LC-MS monitor reaction completion, concentrate directly to give yellow solid compound (3.5g, 100% yield) which is not purified and directly charged to the next reaction, ESI-MS M/z:249.1[ M + H ]/(M + H)]+。
And 4, step 4: synthesis of Compound 15-4
Compound 15-3(3.5g,10mmol) was dissolved in DMF (20mL) and K was added2CO3(6.91g,50mmol), MeI (1.43g,10mmol), r.t. reaction overnight, LC-MS monitoring completion of reaction, filtration, concentration, and column chromatography of the residue (DCM/MeOH-100/1 to 20/1) afforded the compound as a yellow solid (1.8g, yield 68％)，ESI-MS m/z:263.1[M+H]+。
And 5: synthesis of Compound 15-5
15-5(786mg,3.0mmol) was dissolved in MeOH (30mL), Pd/C (10%, 150mg) was added, hydrogen was bubbled through, r.t. reaction overnight, LC-MS monitored reaction completion, filtration, filtrate concentration to give a pale yellow solid compound (500mg, 71% yield) which was used in the next reaction without purification, ESI-MS M/z:233.1[ M + H ]]+。
Step 6: synthesis of Compound 15
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 15-5(233mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 15 (220mg, 40% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.89(s,1H),8.76(s,1H),7.94(t,J＝7.9Hz,1H),7.70(d,J＝8.2Hz,1H),7.57(dd,J＝7.7,0.9Hz,1H),6.98(s,1H),6.76(s,1H),6.59(s,1H),5.62(ddt,J＝16.5,10.2,5.9Hz,1H),5.29(s,1H),4.98-4.91(m,1H),4.78(dq,J＝17.1,1.5Hz,1H),4.61(d,J＝5.9Hz,2H),3.64(d,J＝12.3Hz,1H),3.22-3.11(m,2H),3.02(d,J＝10.1Hz,2H),2.97-2.81(m,2H),2.69-2.61(m,4H),2.30-2.20(m,4H),1.42(s,6H)；ESI-MS m/z:542.2[M+H]+.
Example 16 Compound 16
Figure BDA0002189966480000311
The synthetic route is as follows:
Figure BDA0002189966480000312
step 1: synthesis of Compound 16-1
(4- (2-fluoro-4-nitrophenyl) morpholin-3-yl) methanol (2.56g,10mmol) was dissolvedAdding DIPEA (2.6g,20mmol) into DCM (50mL), adding TsCl (2.3g,12mmol), stirring overnight at r.t. after the addition is finished, monitoring by LC-MS, pouring into water (50mL), separating, extracting water layer with DCM (30mL), combining organic phases, washing organic phase with water (50mL), washing saturated saline (50mL), and anhydrous Na2SO4Drying, concentrating the filtrate and column chromatography (PE/EA: 20/1to 5/1) gave a pale yellow gum (3.0g, 73% yield), ESI-MS M/z:411.1[ M + H ])]+。
Step 2: synthesis of Compound 16-2
Dissolving compound 16-1(2.05g,5mmol) in EtOH (30mL), adding methylamine alcohol solution (25% -30%, 1.8g, ca.55mmol), reacting at 80 deg.C in a sealed tube overnight, monitoring by LC-MS the reaction is over, concentrating, subjecting the residue to column chromatography (PE/EA: 5/1to 2/1) to obtain light yellow gum (600mg, yield 48%), ESI-MS M/z:250.1[ M + H ])]+。
And step 3: synthesis of Compound 16-3
Dissolve compound 16-2(500mg,2mmol) in MeOH (30mL), add Pd/C (10%, 100mg), inject hydrogen, r.t. react overnight, LC-MS monitors the reaction is complete, filter, concentrate filtrate to give a pale yellow solid compound (300mg, yield 68%), which is used in the next step without purification, ESI-MS M/z:220.1[ M + H ]/(M + H)]+。
And 4, step 4: synthesis of Compound 16
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 16-3(220mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 16 (310 mg, 58% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.95(s,1H),8.77(s,1H),7.95(t,J＝7.9Hz,1H),7.71(d,J＝8.1Hz,1H),7.56(d,J＝10.4Hz,1H),6.99(s,1H),6.77(s,1H),6.61(s,1H),5.62-5.58(m,1H),5.30(s,1H),5.01-4.93(m,1H),4.79(d,J＝10.1Hz,1H),4.65(s,2H),3.90-3.80(m,3H),3.75-3.65(m,4H),3.60-3.45(m,2H),1.42(s,6H)；ESI-MS m/z:529.2[M+H]+.
Example 17 Compound 17
Figure BDA0002189966480000321
The synthetic route is as follows:
Figure BDA0002189966480000331
step 1: synthesis of Compound 17-1
A100 mL reaction flask was charged with 1-N-tert-butoxycarbonyl-2- (hydroxymethyl) piperazine (2g,9.2mmol) and paraformaldehyde (1.38g,46mmol), followed by a mixture of MeOH (20mL) and HOAc (5mL), and NaBH was added at r.t3CN (2.3g,36.8mmol), stirred at 80 ℃ under reflux for 3h, monitored by LC-MS for reaction completion, concentrated, residue dissolved with EA (50mL), saturated NaHCO3The solution (50mL) was washed, concentrated and the residue was column chromatographed (DCM/MeOH 100/1to 20/1) to give a pale yellow gum (1.7g, 80% yield), ESI-MS M/z:231.1[ M + H/z ])]+。
Step 2: synthesis of Compound 17-2
Adding THF solution (17mL) of compound 17-1(1.0g,4.3mmol) into a 100mL reaction flask under anhydrous and oxygen-free conditions, adding NaH (60% content, 0.34g,8.6mmol) at 0 ℃, reacting for 20min, adding 2-bromo-1-fluoro-4-nitrobenzene (0.86g,3.87mmol), raising the reaction flask to 85 ℃, refluxing and stirring for reaction for 5h, monitoring the reaction completion by LC-MS, adding water (50mL) for quenching, EA (50mL x 2) extracting, combining organic phases, washing with saturated saline (50mL), and anhydrous Na2SO4Drying, concentration of the filtrate and column chromatography of the residue (DCM/MeOH. 100/1to 20/1) gave a pale yellow gum (835mg, 50% yield), ESI-MS M/z:430.1[ M + H ]/]+。
And step 3: synthesis of Compound 17-3
A50 mL reaction flask was charged with a solution of compound 17-2(600mg,1.4mmol) in DCM (2mL), followed by TFA (0.6mL), stirred at r.t., LC-MS monitored completion of the reaction and saturated NaHCO was added3Neutralizing the solution (5mL), andadding water (30mL), extracting with DCM (30 mL. times.2), mixing to obtain organic phase, washing with saturated saline (30mL), and removing anhydrous Na2SO4Drying, distillation of the filtrate and column chromatography (DCM/MeOH. 100/1to 10/1) gave a yellow gum (370mg, 80% yield), ESI-MS M/z:330.0[ M + H ])]+。
And 4, step 4: synthesis of Compound 17-4
Compound 17-3(1.3g,3.9mmol), Pd (OAc) was added to a 100mL reaction flask in the absence of water and oxygen2(22mg,0.0975mmol),CsCO3(3.8g,11.7mmol), BINAP (121mg,0.195mmol) in toluene (60mL) at 100 deg.C, LC-MS monitoring the completion of the reaction, cooling and diluting the reaction with EA (30mL), washing with water (50mL), saturated brine (50mL), anhydrous Na2SO4Drying, concentration of the filtrate and column chromatography (DCM/MeOH. 100/1to 10/1) gave the compound as a yellow solid (710mg, 73% yield), ESI-MS M/z:250.1[ M + H ])]+。
And 5: synthesis of Compound 17-5
Compound 17-4(500mg,2.0mmol) was dissolved in MeOH (40mL), Pd/C (10%, 100mg) was added, hydrogen was bubbled in, r.t. reaction overnight, LC-MS monitored reaction completion, filtration, filtrate concentration to give a pale yellow solid compound (260mg, 59% yield) which was used in the next reaction without purification, ESI-MS M/z:220.1[ M + H ], ESI-MS M/z]+。
Step 6: synthesis of Compound 17
Compound 1-6(360mg,1.0mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (377mg,2.0mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (520mg,4.0mmol) and compound 17-5(220mg,1.0mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 17 (230mg, 43% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.97(s,1H),8.79(s,1H),7.93(t,J＝7.9Hz,1H),7.67(d,J＝8.1Hz,1H),7.59(d,J＝7.7Hz,1H),7.13(d,J＝2.4Hz,1H),6.98(dd,J＝8.6,2.3Hz,1H),6.63(d,J＝8.6Hz,1H),5.68-5.55(m,1H),5.32(s,1H),4.95(dd,J＝10.2,1.6Hz,1H),4.78(dd,J＝17.1,1.7Hz,1H),4.61(dd,J＝6.0,2.5Hz,2H),4.17(dd,J＝10.6,2.7Hz,1H),3.84(dd,J＝10.6,8.7Hz,1H),3.33-3.23(m,1H),3.12-3.02(m,1H),2.90-2.80(m,2H),2.65-2.55(m,1H),2.27(s,3H),2.20-2.10(m,1H),1.85-1.75(m,1H),1.42(s,6H)；ESI-MS m/z:529.2[M+H]+.
Two optical isomers of compound 17 can be obtained by different chiral raw materials or chiral separation methods, and the structural formula is as follows:
Figure BDA0002189966480000351
example 18 Compound 18
Figure BDA0002189966480000352
The synthetic route is as follows:
Figure BDA0002189966480000361
step 1: synthesis of Compound 18-1
Into a 500mL reaction flask was added 1-N-tert-butoxycarbonyl-2- (hydroxymethyl) piperazine (5g,23.9mmol), THF (80mL) and H2O (80mL), dissolved by stirring, and slowly added dropwise (Boc) at r.t2O (22mL,95.6mmol), followed by addition of anhydrous Na2CO3(20.3g,191.2mmol) the solution was cloudy, stirred at r.t. for 2h, LC-MS monitored that the reaction was complete, some of the solvent was evaporated to dryness, extracted with EA (50mL x 3), the organic phases combined and washed with saturated brine (50mL), anhydrous Na2SO4Drying, concentrating the filtrate, and column chromatography of the residue (PE/EA: 20/1to 8/1) gave the compound as a white solid (6.0g, 79% yield), ESI-MS M/z:317.2[ M + H ])]+。
Step 2: synthesis of Compound 18-2
Under anhydrous and oxygen-free conditions, compound 18-1(3g,9.48mmol) was added to a 250mL reaction flask and N was replaced2Cubic, N2Under protection addAdding anhydrous DCM (100mL), stirring to dissolve, adding Dess-Martin oxidant (8g,18.96mmol) to obtain white turbid solution, reacting for 3h at r.t., monitoring by LC-MS, and adding saturated NaHCO3The solution (50mL) was quenched and saturated Na was added2SO3The solution (50mL) was stirred until clear, the layers were separated, the aqueous layer was extracted with DCM (100mL), the organic layers were combined, washed with saturated brine (100mL), anhydrous Na2SO4Drying, concentrating the filtrate, and column chromatography of the residue (PE/EA: 20/1to 10/1) gave the compound as a white solid (2.6g, 80% yield), ESI-MS M/z:315.2[ M + H ])]+。
And step 3: synthesis of Compound 18-3
Compound 18-2(2.8g,8.9mmol), DCM (25mL) was added to a 100mL reaction flask, stirred to dissolve, and CH was added3NH2Hydrochloride (1.8g,26.6mmol), triethylamine (5mL) was added dropwise, the solution was cloudy, r.t. stirred for 4h, LC-MS monitored reaction completion, solvent was spun dry, MeOH (30mL) was added, stirring was allowed to dissolve, and NaBH was added3CN (3.6g,57.3mmol), r.t. stirring for 2H, LC-MS monitoring reaction complete, solvent spin-drying, and column chromatography of the residue (DCM/MeOH 100/1to 10/1) to give the compound as a colourless oil (2.3g, 78% yield), ESI-MS M/z:330.2[ M + H/] -]+。
And 4, step 4: synthesis of Compound 18-4
Compound 18-3(1g,3mmol) and DMF (30mL) were added to a 100mL reaction flask, stirred to dissolve, and then K was added2CO3(830mg,6mmol), 3-bromo-4-fluoronitrobenzene (1.33g,6mmol), r.t. stirring for 4H, the solution gradually changed from colorless to yellow and then orange, LC-MS monitoring of the reaction was complete, direct concentration, and the residue was chromatographed (PE/EA. 20/1to 10/1) to give a yellow solid compound (960mg, 60% yield), ESI-MS M/z:529.1[ M + H ], (M + H): 529.1)]+。
And 5: synthesis of Compound 18-5
Compound 18-4(900mg,1.7mmol), DCM (5mL) was added to a 50mL reaction flask, stirred to dissolve, TFA (10mL) was slowly added dropwise at 0 deg.C, and the solution was dark yellow, rising to r.t. and reacted overnight. Monitoring the reaction by LC-MS, and directly concentrating to obtain IIIFluoroacetate, saturated NaHCO3The solution (50mL) was neutralized, DCM (50mL x 3) was extracted, the organic phases were combined and washed with saturated brine (50mL), anhydrous Na2SO4Drying, concentration of the filtrate and column chromatography of the residue (DCM/MeOH. 100/1to 20/1) gave the compound as a yellow solid (230mg, 51% yield) and ESI-MS M/z:329.1[ M + H ]/(ESI-MS M/z)]+。
Step 6: synthesis of Compound 18-6
Adding compound 18-5(200mg,0.6mmol), Pd (OAc) into a 100mL reaction flask under anhydrous and oxygen-free conditions2(3.5mg,0.015mmol)、Cs2CO3(596mg,1.8mmol), BINAP (19mg,0.03mmol), substitution of N2Three times, anhydrous toluene (10mL) was added, the reaction was carried out at 100 ℃ for 3H, the solution gradually turned orange, the reaction was monitored by LC-MS, cooled to r.t., filtered, the filtrate was concentrated, and the residue was subjected to column chromatography (DCM/MeOH: 100/1to 20/1) to give an orange solid compound (100mg, yield 67%), ESI-MS M/z:249.1[ M + H ], ESI-MS M/z]+。
And 7: synthesis of Compounds 18-7
A100 mL reaction flask was charged with compound 18-6(200mg,0.8mmol) and paraformaldehyde (142mg,4mmol), MeOH (15mL) and HOAc (3mL) were added, stirred to dissolve, and NaBH was added r.t3CN (238mg,3.2mmol), stirred at 80 ℃ under reflux for 3H, monitored by LC-MS for completion of the reaction, cooled to r.t., concentrated, and the residue subjected to column chromatography (DCM/MeOH 100/1to 20/1) to give an orange solid compound (100mg, yield 47%), ESI-MS M/z:263.1[ M + H ], []+。
And 8: synthesis of Compounds 18-8
18-7(300mg,1.14mmol) was dissolved in MeOH (30mL), Pd/C (10%, 60mg) was added, hydrogen was bubbled in, r.t. reaction overnight, LC-MS monitored reaction completion, filtration, concentration gave compound as a pale yellow solid (150mg, 56% yield) which was used in the next reaction without purification, ESI-MS M/z:233.1[ M + H ]]+。
And 8: synthesis of Compound 18
Compound 1-6(232mg,0.64mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (241mg,1.28mmol) was added, r.t. reaction was performed for 3h, TLC monitored for reaction completion, DIPEA (332mg,2.56mmol) and compound 18-8(150mg,0.64mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for reaction completion, directly concentrated, and the residue was column chromatographed (DCM/MeOH-100/1 to 10/1) to give compound 18 (128 mg, 37% yield as a yellow solid).
1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H),8.79(s,1H),7.94(t,J＝7.8Hz,1H),7.68(d,J＝8.2Hz,1H),7.60(d,J＝7.8Hz,1H),7.14(d,J＝2.4Hz,1H),6.99(dd,J＝8.6,2.3Hz,1H),6.65(d,J＝8.6Hz,1H),5.68-5.55(m,1H),5.32(s,1H),4.95(dd,J＝10.2,1.6Hz,1H),4.78(dd,J＝17.1,1.7Hz,1H),4.61(dd,J＝6.0,2.5Hz,2H),3.65-3.55(m,1H),3.33-3.23(m,2H),3.12-3.02(m,2H),2.90-2.80(m,1H),2.65-2.55(m,1H),2.45(s,3H),2.27(s,3H),2.20-2.10(m,1H),1.85-1.75(m,1H)1.42(s,6H)；ESI-MS m/z:542.2[M+H]+.
Two optical isomers of compound 18 can be obtained by different chiral starting materials or chiral separation methods, and the structural formula is as follows:
Figure BDA0002189966480000391
example 19 Compound 19
Figure BDA0002189966480000392
The synthetic route is as follows:
Figure BDA0002189966480000393
compound 19-1 (synthetic reference wo2018001569,406mg,1.0mmol) was dissolved in toluene (20mL), compound 17-5A (220mg,1.0mmol) and DIPEA (390mg,3.0mmol) were added and reacted at 80 ℃ overnight, LC-MS monitored completion of the reaction, directly concentrated, and the residue was column chromatographed (DCM/MeOH 20/1to 5/1) to give compound 19(270mg, 48% yield) as a yellow solid.
1H NMR(400MHz,CDCl3)δ:8.79(s,1H),7.62(t,J＝7.9Hz,1H),7.40(s,1H),7.29(d,J＝7.8Hz,1H),7.06(d,J＝2.3Hz,1H),6.84-6.76(m,1H),6.72(d,J＝8.5Hz,1H),6.65(d,J＝8.0Hz,1H),5.71-5.55(m,1H),5.03-4.92(m,2H),4.85(d,J＝6.6Hz,2H),4.17(dd,J＝10.6,2.8Hz,1H),3.98(dd,J＝10.6,8.9Hz,1H),3.46(d,J＝9.4Hz,1H),3.31(d,J＝10.6Hz,6H),3.21(t,J＝10.0Hz,1H),2.87(d,J＝11.5Hz,1H),2.78(t,J＝14.4Hz,2H),2.34(s,3H),2.23-2.15(m,1H),1.85-1.80(m,1H)；ESI-MS m/z:562.2[M+H]+.
Example 20 Compound 20
Figure BDA0002189966480000401
The synthetic route is as follows:
Figure BDA0002189966480000402
compound 20 was obtained by a synthesis method similar to that of example 19 using compound 18-8A instead of compound 17-5A as a starting material.
1H NMR(400MHz,CDCl3)δ8.79(s,1H),7.62(t,J＝7.9Hz,1H),7.40(s,1H),7.29(d,J＝7.8Hz,1H),7.06(d,J＝2.3Hz,1H),6.84-6.76(m,1H),6.72(d,J＝8.5Hz,1H),6.65(d,J＝8.0Hz,1H),5.71-5.55(m,1H),5.03-4.92(m,2H),4.85(d,J＝6.6Hz,2H),3.65-3.55(m,1H),3.35(s,6H),3.33-3.23(m,2H),3.12-3.02(m,2H),2.90-2.80(m,1H),2.65-2.55(m,1H),2.45(s,3H),2.27(s,3H),2.20-2.10(m,1H),1.85-1.75(m,1H)；ESI-MS m/z:575.2[M+H]+.
Example 21 Compound 21
Figure BDA0002189966480000411
The synthetic route is as follows:
Figure BDA0002189966480000412
step 1: synthesis of Compound 21-1
2-allyl-6- (methylthio) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (synthetic reference WO2017075629,2.2g,10mmol), 2-bromo-6-methylthiopyridine (2.0g,10mmol), CuI (1.9g,10mmol), potassium carbonate (2.8g,20mmol), N, N' -dimethylethylenediamine (880mg,10mmol) was added to 1,4-dioxane (100mL), and the mixture was heated to 100 ℃ under the protection of Ar for reaction overnight. LC-MS monitoring completion of the reaction, filtration, concentration of the filtrate, column chromatography of the residue (DCM/MeOH. 100/1to 30/1) afforded the compound as a pale yellow solid (1.0g, 29% yield), ESI-MS M/z:346.1[ M + H/z ] (ESI + H + M: 30/1)]+。
Step 2: synthesis of Compound 21-2
Dissolving the compound 21-1(345mg,1mmol) in DCM (10mL), slowly adding m-CPBA (0.87g,5mmol) under cooling of an ice bath, reacting for 5h at r.t., monitoring the reaction by LC-MS, and directly using the reaction liquid for the next reaction.
And step 3: synthesis of Compound 21
To the reaction mixture of compound 21-2 obtained in the above step, DIPEA (780mg,6.0mmol) and compound 17-5A (220mg,1.0mmol) were added, reacted overnight at r.t., and LC-MS monitored completion of the reaction, directly concentrated, and the residue was subjected to column chromatography (DCM/MeOH 100/1to 10/1) to give compound 21 as a yellow solid (200mg, yield 36%).
1H NMR(400MHz,CDCl3)δ:8.78(s,1H),7.63(t,J＝7.9Hz,1H),7.51(s,1H),7.40(d,J＝7.8Hz,1H),7.12(d,J＝2.3Hz,1H),6.85-6.77(m,1H),6.73(d,J＝8.5Hz,1H),6.66(d,J＝8.0Hz,1H),5.72-5.57(m,1H),5.05-4.95(m,2H),4.81(d,J＝6.8Hz,2H),4.13(dd,J＝10.5,2.8Hz,1H),3.97(dd,J＝10.5,8.8Hz,1H),3.46(d,J＝9.5Hz,1H),3.40(s,3H),3.21(t,J＝10.0Hz,1H),2.88(d,J＝11.5Hz,1H),2.76(t,J＝14.4Hz,2H),2.34(s,3H),2.26-2.17(m,1H),1.83-1.18(m,1H)；ESI-MS m/z:549.2[M+H]+.
Example 22 Compound 22
Figure BDA0002189966480000421
The synthetic route is as follows:
Figure BDA0002189966480000422
compound 22 was obtained by a similar synthesis method to that of example 21 using compound 18-8A and compound 21-2 as starting materials.
1H NMR(400MHz,CDCl3)δ:8.76(s,1H),7.62(t,J＝7.9Hz,1H),7.50(s,1H),7.39(d,J＝7.8Hz,1H),7.11(d,J＝2.3Hz,1H),6.84-6.75(m,1H),6.73(d,J＝8.5Hz,1H),6.66(d,J＝8.0Hz,1H),5.72-5.57(m,1H),5.05-4.95(m,2H),4.81(d,J＝6.8Hz,2H),3.65-3.55(m,1H),3.39(s,3H),3.33-3.23(m,2H),3.12-3.02(m,2H),2.90-2.80(m,1H),2.65-2.55(m,1H),2.45(s,3H),2.27(s,3H),2.23-2.08(m,1H),1.83-1.73(m,1H)；ESI-MS m/z:562.2[M+H]+.
Example 23 Compound 23
Figure BDA0002189966480000431
The synthetic route is as follows:
Figure BDA0002189966480000432
step 1: synthesis of Compound 23
Compound 23-1 (see wo2018133829,375mg,1.0mmol) was dissolved in toluene (10mL), m-CPBA (377mg,2.0mmol) was added under cooling on ice, r.t. reaction was performed for 3h, DIPEA (520mg,4.0mmol) was added, 17-5A (220mg,1.0mmol) was added, reaction was performed overnight at r.t., LC-MS monitored for completion of reaction, direct concentration was performed, and the residue was subjected to column chromatography (DCM/MeOH: 100/1to 10/1) to give compound 23(300mg, yield 55%) as a yellow solid.
1H NMR(400MHz,CDCl3)δ:8.76(s,1H),7.62(s,1H),7.43(s,1H),7.22(d,J＝7.8Hz,1H),7.06(d,J＝2.3Hz,1H),6.83-6.73(m,1H),6.73(d,J＝8.5Hz,1H),6.66(d,J＝8.0Hz,1H),5.72-5.57(m,1H),5.05-4.95(m,2H),4.83(d,J＝6.8Hz,2H),4.17(dd,J＝10.6,2.8Hz,1H),3.98(dd,J＝10.6,8.9Hz,1H),3.46(d,J＝9.4Hz,1H),3.21(t,J＝10.0Hz,1H),2.87(d,J＝11.5Hz,1H),2.78(t,J＝14.4Hz,2H),2.34(s,3H),2.29(s,6H),2.23-2.15(m,1H),1.85-1.80(m,1H)；ESI-MS m/z:547.2[M+H]+.
Example 24 Compound 24
Figure BDA0002189966480000441
The synthetic route is as follows:
Figure BDA0002189966480000442
compound 24 was obtained according to a synthesis method similar to that of example 23 using compound 23-1 and compound 18-8A as starting materials.
1H NMR(400MHz,CDCl3)δ:8.76(s,1H),7.62(s,1H),7.43(s,1H),7.22(d,J＝7.8Hz,1H),7.06(d,J＝2.3Hz,1H),6.83-6.73(m,1H),6.73(d,J＝8.5Hz,1H),6.66(d,J＝8.0Hz,1H),5.72-5.57(m,1H),5.05-4.95(m,2H),4.81(d,J＝6.8Hz,2H),3.66-3.56(m,1H),,3.32-3.22(m,2H),3.11-3.02(m,2H),2.91-2.82(m,1H),2.65-2.55(m,1H),2.46(s,3H),2.29(s,3H),2.25(s,6H)2.20-2.10(m,1H),1.83-1.70(m,1H)；ESI-MS m/z:560.2[M+H]+。
Example 25 Compound 25
Figure BDA0002189966480000443
The synthetic route is as follows:
Figure BDA0002189966480000451
compound 25 was obtained by a synthesis method similar to that of example 23 using compound 25-1 (see WO2009054332 for synthesis) and 17-5A as starting materials.
1H NMR(400MHz,CDCl3)δ:8.76(s,1H),7.95(s,1H),7.82(s,1H),7.62(s,1H),7.53(s,1H),7.43(s,1H),7.22(d,J＝7.8Hz,1H),7.06(d,J＝2.3Hz,1H),6.83-6.73(m,1H),6.75-6.68(m,2H),6.66(d,J＝8.0Hz,1H),5.73-5.53(m,1H),5.05-4.95(m,2H),4.81(d,J＝6.8Hz,2H),4.17(dd,J＝10.6,2.8Hz,1H),3.98(dd,J＝10.6,8.9Hz,1H),3.46(d,J＝9.4Hz,1H),3.22(t,J＝10.0Hz,1H),2.87(d,J＝11.5Hz,1H),2.78(t,J＝10.4Hz,2H),2.35(s,3H),2.25-2.15(m,1H),1.86-1.79(m,1H)；ESI-MS m/z:564.2[M+H]+.
Example 26 Compound 26
Figure BDA0002189966480000452
The synthetic route is as follows:
Figure BDA0002189966480000453
compound 26 was obtained by a similar synthetic method to that of example 23, starting from compound 25-1 and 18-8A.
1H NMR(400MHz,CDCl3)δ:8.79(s,1H),7.94(s,1H),7.81(s,1H),7.60(s,1H),7.51(s,1H),7.41(s,1H),7.21(d,J＝7.8Hz,1H),7.04(d,J＝2.3Hz,1H),6.85-6.75(m,1H),6.75-6.65(m,3H),5.73-5.51(m,1H),5.05-4.95(m,2H),4.81(d,J＝6.8Hz,2H),3.63-3.52(m,1H),3.30-3.21(m,2H),3.13-3.01(m,2H),2.92-2.81(m,1H),2.63-2.53(m,1H),2.48(s,3H),2.28(s,3H),2.23-2.10(m,1H),1.79-1.68(m,1H)；ESI-MS m/z:577.2[M+H]+.
Example 27 Compound 27
Figure BDA0002189966480000461
The synthetic route is as follows:
Figure BDA0002189966480000462
compound 27 was obtained according to a synthesis method similar to that in example 23, using compound 27-1 (synthesis reference WO2018171633) and compound 17-5A as starting materials.
1H NMR(400MHz,CDCl3)δ:8.79(s,1H),7.65(s,1H),7.41(s,1H),7.12(d,J＝7.8Hz,1H),6.83-6.73(m,1H),6.73(d,J＝8.5Hz,1H),6.66(d,J＝8.0Hz,1H),5.72-5.57(m,2H),4.78(s,2H),4.66(d,J＝6.8Hz,2H),4.17(dd,J＝10.6,2.8Hz,1H),3.98(dd,J＝10.6,8.9Hz,1H),3.46-3.36(m,3H),3.21(t,J＝10.0Hz,1H),2.87(d,J＝11.5Hz,1H),2.78(t,J＝14.4Hz,2H),2.34(s,3H),2.23-2.15(m,1H),1.95-1.80(m,3H),1.65-1.55(m,2H)；ESI-MS m/z:582.2[M+H]+.
Example 28 Compound 28
Figure BDA0002189966480000471
The synthetic route is as follows:
Figure BDA0002189966480000472
compound 27-1 and compound 18-8A were synthesized in a similar manner to example 23 using the above-mentioned starting materials to give compound 28.
1H NMR(400MHz,CDCl3)δ:8.78(s,1H),7.63(s,1H),7.40(s,1H),7.14(s,1H),6.83-6.73(m,1H),6.75(d,J＝8.5Hz,1H),6.68(d,J＝8.0Hz,1H),5.32-5.56(m,2H),4.78(s,2H),4.65(d,J＝6.8Hz,2H),3.64-3.53(m,1H),3.34-3.22(m,4H),3.12-3.02(m,2H),2.90-2.80(m,1H),2.65-2.55(m,1H),2.45(s,3H),2.27(s,3H),2.20-2.10(m,3H),1.85-1.75(m,1H),1.66-1.50(m,2H)；ESI-MS m/z:595.2[M+H]+.
Example 29 Compound 29
Figure BDA0002189966480000473
The synthetic route is as follows:
Figure BDA0002189966480000481
compound 29-1 (see WO2019085933 for synthesis) and compound 17-5A were used as starting materials, and compound 29 was obtained according to a synthesis method similar to that of example 23.
1H NMR(400MHz,CDCl3)δ:8.79(s,1H),7.62(s,1H),7.41(s,1H),7.12(d,J＝7.8Hz,1H),7.05(d,J＝7.8Hz,1H),6.83-6.73(m,1H),6.73(d,J＝8.5Hz,1H),6.67(d,J＝8.0Hz,1H),5.72-5.57(m,2H),4.82(d,J＝17.1Hz,1H),4.66(d,J＝6.8Hz,2H),4.17(dd,J＝10.6,2.8Hz,1H),3.98(dd,J＝10.6,8.9Hz,1H),3.46-3.36(m,1H),3.21(t,J＝10.0Hz,1H),2.87-2.65(m,5H),2.34(s,3H),2.23-2.15(m,1H),1.95-1.80(m,1H),1.65-1.55(m,4H),1.42(s,3H)；ESI-MS m/z:555.2[M+H]+.
Example 30 Compound 30
Figure BDA0002189966480000482
The synthetic route is as follows:
Figure BDA0002189966480000483
compound 29-1 and compound 18-8A were synthesized in a similar manner to example 23 using the above-mentioned starting materials to give compound 30.
1H NMR(400MHz,CDCl3)δ:8.79(s,1H),7.62(s,1H),7.41(s,1H),7.12(d,J＝7.8Hz,1H),7.05(d,J＝7.8Hz,1H),6.83-6.73(m,1H),6.73(d,J＝8.5Hz,1H),6.67(d,J＝8.0Hz,1H),5.72-5.57(m,2H),4.82(d,J＝17.1Hz,1H),4.66(d,J＝6.8Hz,2H),3.65-3.55(m,1H),3.33-3.23(m,2H),3.12-3.02(m,2H),2.90-2.80(m,1H),2.65-2.55(m,1H),2.45(s,3H),2.27(s,3H),2.20-2.10(m,5H),1.85-1.75(m,3H),1.42(s,3H)；ESI-MS m/z:568.2[M+H]+.
Example 31 Compound 31
Figure BDA0002189966480000491
The synthetic route is as follows:
Figure BDA0002189966480000492
compound 31 was obtained according to a synthesis method similar to that in example 23, using compound 31-1 (synthesis see WO2018090939) and compound 17-5A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:10.23(s,1H),8.70(s,1H),7.75-7.61(m,3H),7.13(d,J＝2.4Hz,1H),6.98(dd,J＝8.6,2.3Hz,1H),6.63(d,J＝8.6Hz,1H),4.65-4.52(m,2H),4.25-4.10(m,3H),3.84(dd,J＝10.6,8.7Hz,1H),3.33-3.23(m,1H),3.12-3.02(m,1H),2.90-2.80(m,2H),2.65-2.55(m,1H),2.27(s,3H),2.21-2.10(m,1H),1.84-1.72(m,1H)；ESI-MS m/z:551.2[M+H]+。
Example 32 Compound 32
Figure BDA0002189966480000501
The synthetic route is as follows:
Figure BDA0002189966480000502
compound 32 was obtained by a synthesis method similar to that of example 23 using compound 31-1 and compound 18-8A as starting materials.
1H NMR(400MHz,DMSO-d6):δ10.25(s,1H),8.71(s,1H),7.73-7.58(m,3H),7.10(d,J＝2.4Hz,1H),6.95(dd,J＝8.6,2.3Hz,1H),6.65(d,J＝8.6Hz,1H),4.60-4.50(m,2H),4.22-4.08(m,2H),3.65-3.53(m,1H),3.34-3.23(m,2H),3.12-3.03(m,2H),2.90-2.80(m,1H),2.65-2.55(m,1H),2.45(s,3H),2.27(s,3H),2.20-2.10(m,1H),1.83-1.72(m,1H)；ESI-MS m/z:564.2[M+H]+.
Example 33 Compound 33
Figure BDA0002189966480000503
The synthetic route is as follows:
Figure BDA0002189966480000511
compound 33-1 (synthesis see US20120220572) and compound 17-5A were used as starting materials, and compound 33 was obtained according to a synthesis method similar to that of example 23.
1H NMR(400MHz,DMSO-d6)δ:10.29(s,1H),8.75(s,1H),7.75-7.61(m,3H),7.35-7.25(m,2H),7.13(d,J＝2.4Hz,1H),6.98(dd,J＝8.6,2.3Hz,1H),6.63(d,J＝8.6Hz,1H),4.25-4.10(m,1H),3.84(dd,J＝10.6,8.7Hz,1H),3.33-3.23(m,1H),3.12-3.01(m,1H),2.92-2.81(m,2H),2.67-2.56(m,1H),2.29(s,3H),2.26-2.06(m,1H),1.88-1.79(m,1H)；ESI-MS m/z:549.2[M+H]+.
Example 34 Compound 34
Figure BDA0002189966480000512
The synthetic route is as follows:
Figure BDA0002189966480000513
compound 33-1 and compound 18-8A were synthesized in a similar manner to example 23 using these compounds as starting materials to give compound 34.
1H NMR(400MHz,DMSO-d6)δ:10.28(s,1H),8.76(s,1H),7.73-7.60(m,3H),7.33-7.22(m,2H),7.11(d,J＝2.4Hz,1H),6.98(dd,J＝8.5,2.3Hz,1H),6.63(d,J＝8.5Hz,1H),3.65-3.54(m,1H),,3.32-3.23(m,2H),3.12-3.02(m,2H),2.90-2.80(m,1H),2.66-2.55(m,1H),2.43(s,3H),2.26(s,3H),2.20-2.11(m,1H),1.85-1.73(m,1H)；ESI-MS m/z:562.2[M+H]+.
Example 35 Compound 35
Figure BDA0002189966480000521
The synthetic route is as follows:
Figure BDA0002189966480000522
compound 35 was obtained according to a synthesis method similar to that of example 23, starting from compound 35-1 (see WO2010067888 for synthesis) and compound 17-5A.
1H NMR(400MHz,DMSO-d6)δ:10.01(s,1H),8.78(s,1H),7.63-7.51(m,3H),7.10(d,J＝2.3Hz,1H),6.95(dd,J＝8.0,2.3Hz,1H),6.65(d,J＝8.0Hz,1H),4.25-4.10(m,1H),3.84(dd,J＝10.6,8.7Hz,1H),3.35(s,3H),3.33-3.23(m,1H),3.12-3.02(m,1H),2.90-2.80(m,2H),2.66-2.55(m,1H),2.41(s,3H),2.21-2.11(m,1H),1.87-1.80(m,1H)；ESI-MS m/z:540.1[M+H]+.
Example 36 Compound 36
Figure BDA0002189966480000523
The synthetic route is as follows:
Figure BDA0002189966480000531
compound 36 was obtained according to a synthesis method similar to that of example 23, starting from compound 35-1 and compound 18-8A.
1H NMR(400MHz,DMSO-d6)δ:9.87(s,1H),8.79(s,1H),7.62-7.50(m,3H),7.02(d,J＝2.3Hz,1H),6.91(dd,J＝8.0,2.3Hz,1H),6.62(d,J＝8.0Hz,1H),3.64-3.55(m,1H),3.36(s,3H),3.33-3.22(m,2H),3.13-3.02(m,2H),2.91-2.80(m,1H),2.65-2.53(m,1H),2.45(s,3H),2.26(s,3H),2.23-2.10(m,1H),1.83-1.76(m,1H)；ESI-MS m/z:553.1[M+H]+.
Example 37 Compound 37
Figure BDA0002189966480000532
The synthetic route is as follows:
Figure BDA0002189966480000533
compound 37 was obtained according to a synthesis method similar to that of example 23, using compound 37-1 (see synthesis WO2013059485) and compound 17-5A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.89(s,1H),8.95(s,1H),8.05(s,1H),7.63-7.51(m,3H),7.10(d,J＝2.3Hz,1H),6.95(dd,J＝8.0,2.3Hz,1H),6.65(d,J＝8.0Hz,1H),4.25-4.10(m,1H),3.84(dd,J＝10.6,8.7Hz,1H),3.55(s,3H),3.33-3.23(m,1H),3.12-3.02(m,1H),2.90-2.80(m,2H),2.66-2.55(m,1H),2.41(s,3H),2.21-2.11(m,1H),1.87-1.80(m,1H)；ESI-MS m/z:523.1[M+H]+.
Example 38 Compound 38
Figure BDA0002189966480000541
The synthetic route is as follows:
Figure BDA0002189966480000542
compound 37-1 and compound 18-8A were synthesized in a similar manner to example 23 using these compounds as starting materials to give compound 38.
1H NMR(400MHz,DMSO-d6)δ:9.86(s,1H),8.85(s,1H),8.03(s,1H),7.61-7.51(m,3H),7.09(d,J＝2.3Hz,1H),6.93(dd,J＝8.0,2.3Hz,1H),6.63(d,J＝8.0Hz,1H),3.65-3.55(m,1H),3.51(s,3H),3.33-3.23(m,2H),3.12-3.02(m,2H),2.90-2.80(m,1H),2.65-2.54(m,1H),2.46(s,3H),2.26(s,3H),2.23-2.10(m,1H),1.85-1.74(m,1H)；ESI-MS m/z:536.1[M+H]+.
Example 39 Compound 39
Figure BDA0002189966480000551
The synthetic route is as follows:
Figure BDA0002189966480000552
compound 39 was obtained according to a synthesis method similar to that of example 23, starting from compound 39-1 (see synthesis WO2015092431) and compound 17-5A.
1H NMR(400MHz,CDCl3)δ:8.68(s,1H),7.46-7.38(m,2H),7.31-7.25(m,1H),7.17(d,J＝2.5Hz,2H),6.85(d,J＝8.6Hz,1H),6.73(d,J＝8.5Hz,1H),4.85(s,2H),4.17(dd,J＝10.5,2.7Hz,1H),3.98(dd,J＝10.5,8.8Hz,1H),3.69-3.61(m,1H),3.24(t,J＝9.7Hz,1H),3.14(s,3H),2.96-2.76(m,3H),2.34(s,3H),2.28-2.17(m,1H),1.83(t,J＝10.8Hz,1H)；ESI-MS m/z:526.1[M+H]+.
Example 40 Compound 40
Figure BDA0002189966480000553
The synthetic route is as follows:
Figure BDA0002189966480000561
compound 39-1 and compound 18-8A were used as starting materials, and Compound 40 was obtained according to a synthesis method similar to that of example 23.
1H NMR(400MHz,CDCl3)δ:8.66(s,1H),7.45-7.36(m,2H),7.30-7.23(m,1H),7.10(d,J＝2.5Hz,2H),6.84(d,J＝8.6Hz,1H),6.71(d,J＝8.5Hz,1H),4.83(s,2H),3.64-3.55(m,1H),3.33-3.21(m,2H),3.13(s,3H),3.13-3.02(m,2H),2.90-2.80(m,1H),2.65-2.52(m,1H),2.49(s,3H),2.29(s,3H),2.20-2.11(m,1H),1.83-1.76(m,1H)；ESI-MS m/z:539.1[M+H]+.
Example 41 Compound 41
Figure BDA0002189966480000562
The synthetic route is as follows:
Figure BDA0002189966480000563
compound 41 was obtained according to a synthesis method similar to that of example 23 using compound 41-1 (synthesis see WO2014167347) and compound 17-5A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.89(s,1H),8.75(s,1H),7.63-7.51(m,2H),7.25-7.15(m,2H),7.11(d,J＝2.3Hz,1H),6.94(dd,J＝8.0,2.3Hz,1H),6.66(d,J＝8.0Hz,1H),6.32(d,J＝9.0Hz,1H),4.25-4.12(m,1H),3.85(dd,J＝10.6,8.7Hz,1H),3.33-3.21(m,1H),3.13-3.02(m,1H),2.90-2.80(m,2H),2.63-2.53(m,1H),2.37(s,3H),2.22-2.11(m,1H),1.86-1.81(m,1H)；ESI-MS m/z:509.1[M+H]+.
Example 42 Compound 42
Figure BDA0002189966480000571
The synthetic route is as follows:
Figure BDA0002189966480000572
compound 42 was obtained by a similar synthesis method to that of example 23 using compound 41-1 and compound 18-8A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.86(s,1H),8.74(s,1H),7.63-7.50(m,2H),7.28-7.14(m,2H),7.10(d,J＝2.3Hz,1H),6.94(dd,J＝8.0,2.3Hz,1H),6.65(d,J＝8.0Hz,1H),6.31(d,J＝9.0Hz,1H),3.65-3.53(m,1H),3.33-3.21(m,2H),3.11-3.02(m,2H),2.90-2.81(m,1H),2.65-2.52(m,1H),2.47(s,3H),2.30(s,3H),2.26-2.12(m,1H),1.81-1.73(m,1H)；ESI-MS m/z:522.1[M+H]+.
Example 43 Compound 43
Figure BDA0002189966480000573
The synthetic route is as follows:
Figure BDA0002189966480000581
compound 43 was obtained according to a synthesis method similar to that of example 23, using compound 43-1 (synthesis reference WO2014167347) and compound 17-5A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.89(s,1H),8.75(s,1H),7.63-7.51(m,2H),7.25-7.15(m,1H),7.12-7.02(m,2H),6.94(dd,J＝8.0,2.3Hz,1H),6.66(d,J＝8.0Hz,1H),4.25-4.12(m,1H),3.85(dd,J＝10.6,8.7Hz,1H),3.33-3.21(m,1H),3.13-3.02(m,1H),2.90-2.80(m,2H),2.63-2.53(m,1H),2.37(s,3H),2.26(s,3H),2.22-2.11(m,1H),1.86-1.81(m,1H)；ESI-MS m/z:523.1[M+H]+.
Example 44 Compound 44
Figure BDA0002189966480000582
The synthetic route is as follows:
Figure BDA0002189966480000583
compound 44 was obtained according to a synthesis method similar to that of example 23, starting from compound 43-1 and compound 18-8A.
1H NMR(400MHz,DMSO-d6)δ:9.89(s,1H),8.74(s,1H),7.62-7.50(m,2H),7.23-7.12(m,1H),7.10-7.01(m,2H),6.93(dd,J＝8.0,2.3Hz,1H),6.64(d,J＝8.0Hz,1H),3.67-3.55(m,1H),,3.33-3.22(m,2H),3.13-3.01(m,2H),2.91-2.80(m,1H),2.65-2.54(m,1H),2.46(s,3H),2.28(s,3H),2.25(s,3H),2.21-2.10(m,1H),1.80-1.71(m,1H)；ESI-MS m/z:536.1[M+H]+.
Example 45 Compound 45
Figure BDA0002189966480000591
The synthetic route is as follows:
Figure BDA0002189966480000592
compound 45 was obtained according to a synthesis method similar to that of example 23, using compound 45-1 (see WO2013126656 for synthesis) and compound 17-5A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.96(s,1H),8.83(s,1H),7.63-7.51(m,3H),7.35-7.25(m,1H),7.12(d,J＝2.3Hz,1H),6.96(dd,J＝8.0,2.3Hz,1H),6.65(d,J＝8.0Hz,1H),5.75-5.60(m,1H),4.25-4.10(m,1H),3.86(dd,J＝10.6,8.7Hz,1H),3.31-3.21(m,1H),3.12-3.02(m,1H),2.92-2.80(m,2H),2.63-2.51(m,1H),2.37(s,3H),2.23-2.11(m,1H),1.85-1.80(m,1H)；ESI-MS m/z:559.1[M+H]+.
Example 46 Compound 46
Figure BDA0002189966480000593
The synthetic route is as follows:
Figure BDA0002189966480000601
compound 46 was obtained by a synthetic method similar to that of example 23 using compound 45-1 and compound 18-8A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.93(s,1H),8.81(s,1H),7.62-7.50(m,3H),7.35-7.23(m,1H),7.11(d,J＝2.3Hz,1H),6.97(dd,J＝8.0,2.3Hz,1H),6.65(d,J＝8.0Hz,1H),5.75-5.61(m,1H),3.65-3.53(m,1H),3.34-3.23(m,2H),3.11-3.02(m,2H),2.90-2.83(m,1H),2.65-2.52(m,1H),2.42(s,3H),2.30(s,3H),2.27-2.10(m,1H),1.80-1.70(m,1H)；ESI-MS m/z:572.1[M+H]+.
Example 47 Compound 47
Figure BDA0002189966480000602
The synthetic route is as follows:
Figure BDA0002189966480000603
compound 47 was obtained by a similar method to that of example 23, using compound 47-1 (see WO2018011570 for synthesis) and compound 17-5A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H),8.86(s,1H),7.78-7.68(s,1H),7.63-7.51(m,2H),7.35-7.25(m,1H),7.12(d,J＝2.3Hz,1H),6.96(dd,J＝8.0,2.3Hz,1H),6.65(d,J＝8.0Hz,1H),4.27-4.15(m,1H),3.88(dd,J＝10.6,8.7Hz,1H),3.32-3.16(m,1H),3.13-3.02(m,1H),2.95-2.83(m,2H),2.65-2.55(m,1H),2.40(s,3H),2.28-2.15(m,1H),1.94-1.87(m,1H)；ESI-MS m/z:534.1[M+H]+.
Example 48 Compound 48
Figure BDA0002189966480000611
The synthetic route is as follows:
Figure BDA0002189966480000612
compound 47-1 and compound 18-8A were used as starting materials, and Compound 48 was obtained according to a synthesis method similar to that of example 23.
1H NMR(400MHz,DMSO-d6)δ:9.86(s,1H),8.81(s,1H),7.75-7.66(s,1H),7.60-7.50(m,2H),7.33-7.21(m,1H),7.14(d,J＝2.3Hz,1H),6.97(dd,J＝8.0,2.3Hz,1H),6.67(d,J＝8.0Hz,1H),4.26-4.13(m,1H),3.87(dd,J＝10.6,8.7Hz,1H),3.33-3.18(m,1H),3.11-3.01(m,1H),2.93-2.81(m,2H),2.62-2.50(m,1H),2.38(s,3H),2.24-2.10(m,1H),1.90-1.86(m,1H)；ESI-MS m/z:547.1[M+H]+.
Example 49 Compound 49
Figure BDA0002189966480000613
The synthetic route is as follows:
Figure BDA0002189966480000621
step 1: synthesis of Compound 49-1
4-hydroxy-2- (methylthio) pyrimidine-5-carboxylic acid (3.7g,20mmol) was added to SOCl2To (100mL) was added dropwise a catalytic amount of DMF (0.25mL) and the reaction was refluxed for 2h, and after monitoring by LC-MS, the reaction was directly concentrated to give a beige solid, which was dissolved by heating in toluene (50mL) and n-hexane (50mL), respectively, filtered, and the filtrate was concentrated to give a white solid compound (4.0g, yield 78%) which was used in the next reaction without purification.
Step 2: synthesis of Compound 49-2
Dissolving 2, 6-dichloroaniline (3.24,20mmol) in DCM (50mL), adding pyridine (3.95g,50mmol), cooling in ice bath, adding a solution of compound 49-1(5.2g,20mmol) in DCM (30mL) dropwise, reacting for 2 days at r.t., monitoring the reaction by LC-MS, pouring into water (50mL), separating, washing the organic phase with dilute hydrochloric acid (30mL), saturated saline (50mL), anhydrous Na2SO4Drying, concentrating the filtrate to give a pale yellow solid as the initial product, and recrystallizing with ethanol (20mL) to give an off-white solid compound (3g, 43% yield), ESI-MS M/z:347.9[ M + H ]]+。
And step 3: synthesis of Compound 49-3
Compound 49-2(3.5g,10mmol) was dissolved in THF (20mL) in an ice bath and NH was added3MeOH (7M,5mL), r.t. reaction overnight, LC-MS monitoring completion of the reaction, concentration, washing of the residue with water (30mL), drying to give a pale yellow solid (2.5g, 76% yield), ESI-MS M/z:329.0[ M + H ], []+。
And 4, step 4: synthesis of Compound 49-4
Placing compound 49-3(3.3g,10mmol) in a three-necked flask, protecting with Ar, heating triethyl orthoacetate (14.6g,90mmol), adding HOAc (1.2g,20mmol) under stirring, reacting at 60 deg.C for 5H, monitoring by LC-MS for completion of the reaction, cooling, adding n-heptane (50mL), precipitating a solid, washing the solid with n-heptane (10mL), drying to obtain a light yellow solid compound (2.3g, yield 65%), ESI-MS M/z:353.0[ M + H M/z ] (M + H + M)]+。
And 5: synthesis of Compound 49-5
Dissolving the compound 49-4(353mg,1.0mmol) in DCM (10mL), adding m-CPBA (377mg,2.0mmol) under ice-bath cooling, reacting for 3h at r.t., monitoring the reaction by LC-MS, and directly using the reaction liquid for the next reaction. ESI-MS M/z 385.0[ M + H ]]+。
Step 6: synthesis of Compound 49
To the reaction solution of compound 49-5 (theoretical amount, 1.0mmol), DIPEA (520mg,4.0mmol) was added, compound 17-5A (220mg,1.0mmol) was added, the reaction was allowed to react overnight at 50 ℃, LC-MS monitored completion of the reaction and directly concentrated, and the residue was subjected to column chromatography (DCM/MeOH-100/1 to 10/1) to give compound 49(100mg, yield 19%) as a yellow solid.
1H NMR(400MHz,DMSO-d6)δ:9.93(s,1H),8.68(s,1H),7.58-7.40(m,3H),7.08(d,J＝2.5Hz,1H),6.92(dd,J＝8.6,2.5Hz,1H),6.63(d,J＝8.6Hz,1H),4.26-4.11(m,1H),3.83(dd,J＝10.6,8.7Hz,1H),3.33-3.23(m,1H),3.10-3.01(m,1H),2.90-2.81(m,2H),2.64-2.52(m,1H),2.43(s,3H),2.36(s,3H),2.26-2.18(m,1H),1.92-1.87(m,1H)；ESI-MS m/z:524.1[M+H]+.
Example 50 Compound 50
Figure BDA0002189966480000631
The synthetic route is as follows:
Figure BDA0002189966480000641
compound 49-4 and compound 18-8A were used as starting materials, and Compound 50 was obtained according to a synthesis method similar to that of example 23.
1H NMR(400MHz,DMSO-d6)δ:9.87(s,1H),8.79(s,1H),7.56-7.38(m,3H),7.05(d,J＝2.1Hz,1H),6.92(dd,J＝8.2,2.1Hz,1H),6.63(d,J＝8.2Hz,1H),3.63-3.53(m,1H),3.33-3.22(m,2H),3.13-3.00(m,2H),2.91-2.81(m,1H),2.65-2.51(m,1H),2.46(s,3H),2.36(s,3H),2.25(s,3H),2.25-2.16(m,1H),1.88-1.79(m,1H)；ESI-MS m/z:537.1[M+H]+.
Example 51: compound 51
Figure BDA0002189966480000642
The synthetic route is as follows:
Figure BDA0002189966480000643
compound 51 was obtained according to a synthesis method similar to that in example 23, using compound 51-1 (see synthesis WO2018133829) and compound 17-5A as starting materials.
1H NMR(400MHz,CDCl3)δ:8.75(s,1H),7.58(s,1H),7.33(s,1H),6.82-6.67(m,3H),6.72(d,J＝8.6Hz,1H),6.64(d,J＝8.5Hz,1H),5.71-5.56(m,1H),5.05-4.93(m,2H),4.68(d,J＝6.8Hz,2H),4.15(dd,J＝10.3,2.6Hz,1H),3.95(dd,J＝10.4,8.9Hz,1H),3.78(s,3H),3.42(d,J＝9.8Hz,1H),3.20(t,J＝10.0Hz,1H),2.86(d,J＝11.5Hz,1H),2.76(t,J＝14.4Hz,2H),2.35(s,3H),2.25-2.10(m,1H),1.91-1.85(m,1H)；ESI-MS m/z:501.2[M+H]+.
Example 52: compound 52
Figure BDA0002189966480000651
The synthetic route is as follows:
Figure BDA0002189966480000652
compound 51-1 and compound 18-8A were synthesized in a similar manner to example 23 using these compounds as starting materials to give compound 52.
1H NMR(400MHz,CDCl3)δ:8.73(s,1H),7.56(s,1H),7.30(s,1H),6.83-6.66(m,3H),6.70(d,J＝8.5Hz,1H),6.63(d,J＝8.5Hz,1H),5.70-5.53(m,1H),5.03-4.92(m,2H),4.66(d,J＝6.9Hz,2H),3.76(s,3H),3.63-3.54(m,1H),3.31-3.20(m,2H),3.12-3.02(m,2H),2.92-2.82(m,1H),2.65-2.53(m,1H),2.46(s,3H),2.29(s,3H),2.23-2.10(m,1H),1.80-1.71(m,1H)；ESI-MS m/z:514.2[M+H]+。
Example 53: compound 53
Figure BDA0002189966480000661
The synthetic route is as follows:
Figure BDA0002189966480000662
step 1: synthesis of Compound 53-1
2-allyl-6- (methylthio) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (synthesis reference WO2017075629,2.2g,10mmol), 2-bromo-6- (2,2, 2-trifluoroethoxy) pyridine (synthesis reference US20120225061,2.56g,10mmol), CuI (1.9g,10mmol), K2CO3(2.8g,20mmol), N, N' -dimethylethylenediamine (880mg,10mmol) was added to 1,4-dioxane (100mL) and the mixture was heated to 100 ℃ under Ar protection for reaction overnight. LC-MS monitoring completion of the reaction, filtration, concentration of the filtrate and column chromatography of the residue (DCM/MeOH. 100/1to 30/1) gave 53-1(1.2g, 30% yield) as a pale yellow solid, ESI-MS M/z:398.1[ M + H ]/(yield: 30%)]+。
Step 2: synthesis of Compound 53
Compound 53-1(255mg,0.64mmol) was dissolved in toluene (10mL), ice-cooled, m-CPBA (241mg,1.28mmol) was added, r.t. reaction was performed for 3h, TLC monitored for completion of reaction, DIPEA (332mg,2.56mmol) and compound 17-5A (150mg,0.64mmol) were added to the reaction mixture, reacted overnight at 80 ℃, LC-MS monitored for completion of reaction, directly concentrated, and the residue was column chromatographed (DCM/MeOH: 100/1to 10/1) to give compound 53 (150mg, 41% yield as a yellow solid).
1H NMR(400MHz,CDCl3)δ:8.74(s,1H),7.57(s,1H),7.33(s,1H),6.82-6.67(m,3H),6.71(d,J＝8.9Hz,1H),6.62(d,J＝8.8Hz,1H),5.71-5.57(m,1H),5.02-4.94(m,2H),4.72(s,2H),4.60(d,J＝6.2Hz,2H),4.16(dd,J＝10.1,2.6Hz,1H),3.96(dd,J＝10.2,8.8Hz,1H),3.42(d,J＝9.1Hz,1H),3.21(t,J＝10.0Hz,1H),2.87(d,J＝10.5Hz,1H),2.75(t,J＝12.4Hz,2H),2.34(s,3H),2.26-2.11(m,1H),1.92-1.86(m,1H)；ESI-MS m/z:569.2[M+H]+.
Example 54: compound 54
Figure BDA0002189966480000671
The synthetic route is as follows:
Figure BDA0002189966480000672
compound 54 was obtained by a similar synthetic method to that of example 23, starting from compound 53-1 and compound 18-8A.
1H NMR(400MHz,CDCl3)δ:8.75(s,1H),7.58(s,1H),7.31(s,1H),6.80-6.68(m,3H),6.70(d,J＝8.6Hz,1H),6.60(d,J＝8.5Hz,1H),5.70-5.55(m,1H),5.01-4.93(m,2H),4.71(s,2H),4.58(d,J＝6.5Hz,2H),3.60-3.50(m,1H),3.30-3.19(m,2H),3.08-3.00(m,2H),2.91-2.80(m,1H),2.62-2.51(m,1H),2.45(s,3H),2.30(s,3H),2.23-2.12(m,1H),1.85-1.72(m,1H)；ESI-MS m/z:582.2[M+H]+。
Example 55 Compound 55
Figure BDA0002189966480000681
The synthetic route is as follows:
Figure BDA0002189966480000682
compound 17-5A (220mg,1.0mmol) and compound 55-1 (see Journal of Medicinal Chemistry,2009,52(16), 5152-5163; 397mg,1.0mmol) were dissolved in DMF (10mL) and Pd (OAc) was added2(23mg,0.1mmol)，BINAP(75mg,0.12mmol)，K2CO3(415mg,3.0mmol) under Ar, warm to 80 ℃ overnight, LC-MS monitor the reaction to completion, filter, concentrate the filtrate directly and column chromatographe the residue (DCM/MeOH. 100/1to 10/1) to give the compound as a yellow solid (200mg, 40% yield).
1H NMR(400MHz,DMSO-d6)δ:9.45(s,1H),8.42(s,1H),8.13(d,J＝4.5Hz,1H),7.12(d,J＝2.3Hz,1H),6.96(dd,J＝8.0,2.3Hz,1H),6.65(d,J＝8.0Hz,1H),4.32(s,3H),4.17(dd,J＝10.5,2.8Hz,1H),3.98(dd,J＝10.5,8.9Hz,1H),3.46(d,J＝8.9Hz,1H),3.21(t,J＝10.0Hz,1H),2.90-2.80(m,4H),2.75-2.65(m,4H),2.34(s,3H),2.23-2.15(m,1H),1.95-1.85(m,1H),1.35(s,6H)；ESI-MS m/z:489.2[M+H]+.
Example 56 Compound 56
Figure BDA0002189966480000683
The synthetic route is as follows:
Figure BDA0002189966480000691
compound 56 was obtained by a similar synthesis method to that of example 55 using compound 55-1 and compound 18-8A as starting materials.
1H NMR(400MHz,DMSO-d6)δ:9.41(s,1H),8.40(s,1H),8.11(d,J＝4.5Hz,1H),7.10(d,J＝2.3Hz,1H),6.96(dd,J＝8.0,2.3Hz,1H),6.63(d,J＝8.0Hz,1H),4.33(s,3H),3.65-3.55(m,1H),,3.33-3.23(m,2H),3.12-3.02(m,2H),2.90-2.80(m,3H),2.65-2.55(m,4H),2.45(s,3H),2.27(s,3H),2.20-2.10(m,1H),1.85-1.75(m,1H),1.32(s,6H)；ESI-MS m/z:502.3[M+H]+.
Example 57 inhibition of Wee-1 enzyme Activity by Compounds
Compounds were tested for inhibition of Wee-1 kinase activity using the Lanthrora Screen Wee-1 kinase kit (invitrogen). After mixing well 5. mu.L of DMSO-diluted gradient compound, 5. mu.L of Wee-1 kinase (final concentration 5nM), 5. mu.L of Eu-Anti-GST Antibody (final concentration 2nM) mixture and 5. mu.L of kinase Tracer 178 (final concentration 50nM), the plates were read after incubation for one hour at room temperature. IC of compound inhibition of Wee-1 kinase activity was calculated as compared to DMSO solvent control group50。
TABLE 1 IC inhibition of Wee1 kinase Activity by Compounds of the invention50
Figure BDA0002189966480000692
Figure BDA0002189966480000701
As can be seen from the data in Table 1, the compounds of the present invention have strong inhibition effect on Wee1 kinase.
Example 58 determination of the anti-cell-proliferation Activity of HT29
Planting 3000 HT29 cells in 384-well plate (Fisher 142762), adhering overnight, adding compound diluted in gradient, adding compound for 72 hr, adding Cell Titer-Lumi (Biyunyian C0068XL), measuring ATP content in cells, evaluating Cell growth, and calculating IC of compound for inhibiting Cell growth50。
TABLE 2 IC inhibition of HT-29 cell growth by compounds of the invention50
Figure BDA0002189966480000711
Figure BDA0002189966480000721
As can be seen from the data in Table 2, the compounds of the present invention have potent antiproliferative activity against HT-29 cells.

Claims (9)

1. A compound with a structure shown as a formula (1A) or a formula (1B), an optical isomer thereof or a pharmaceutically acceptable salt thereof,
Figure FDA0002189966470000011
wherein the content of the first and second substances,
"+" indicates a chiral center;
n is 0 or 1;
w is-CO-or-CH2-；
Y is H, F, Me or OMe;
m is-CH2-、-CF2-、-O-、-NR1-、-N(COR1)-、-N(COOR1)-、-CH(OR1) -or-CH (NR)2R3) -, wherein R1Is H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen substituted C3-C6 cycloalkyl or heterocycloalkyl, R2And R3Independently is H or C1-C3 alkyl, or R2And R3And N forms a 4-7 membered heterocycloalkyl group;
q is-O-, -S-or-NR4-, wherein R4Is H, C1-C3 alkyl or C3-C6 cycloalkyl;
x is the following group:
Figure FDA0002189966470000012
Figure FDA0002189966470000021
wherein ". x" indicates a direct connection to the pyrimidine ring, ". x" indicates a connection to W, R5And R6Independently H, F, Cl or Me, R7Is H, C1-C3 alkyl or C3-C6 cycloalkyl, R8Is H, CN, C1-C3 alkyl or halogenSubstituted by an element C1-C3 alkyl group, R9Is C1-C3 alkyl or halogen substituted C1-C3 alkyl.
2. A compound according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R1Is H, Me, Et,n-Pr、i-Pr、t-Bu, cyclobutyl, cyclopentyl, cyclohexyl,
Figure FDA0002189966470000022
3. A compound according to claims 1 and 2, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R2And R3Independently H, Me or Et, or R2And R3Formation of a common N atom
Figure FDA0002189966470000023
4. A compound according to claims 1-3, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R4Is H, Me, Et,n-Pr or cyclopropyl.
5. The compound according to claims 1-4, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the formulae (1A) and (1B), X is the following group:
Figure FDA0002189966470000024
Figure FDA0002189966470000031
6. the compound of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
Figure FDA0002189966470000041
Figure FDA0002189966470000051
Figure FDA0002189966470000061
7. a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active component comprises a compound as shown in formula (1A) or formula (1B) as claimed in any one of claims 1-6, an isomer thereof or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable auxiliary materials are pharmaceutically acceptable carriers, diluents and/or excipients.
8. Use of a compound of formula (1A) or (1B), an isomer thereof, or a pharmaceutically acceptable salt thereof, as set forth in any of claims 1to 6, or a composition as set forth in claim 7, for the preparation of a Wee1 inhibitor.
9. Use of a compound of formula (1A) or formula (1B), an isomer thereof, or a pharmaceutically acceptable salt thereof, as set forth in any of claims 1-6, or a composition of claim 7, for the manufacture of a medicament for the treatment of a related disorder mediated by Wee 1.
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CN113387962A (en) * 2020-03-12 2021-09-14 上海迪诺医药科技有限公司 Pyrazolo [3,4-d ] pyrimidine-3-one derivative, pharmaceutical composition and application thereof
CN114072411A (en) * 2019-09-03 2022-02-18 微境生物医药科技(上海)有限公司 Pyrimidine derivatives as Wee1 inhibitors
WO2022174765A1 (en) * 2021-02-19 2022-08-25 微境生物医药科技(上海)有限公司 Fused ring compound as wee-1 inhibitor
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