CN116848117B - Fused-ring compounds as Wee-1 inhibitors - Google Patents

Abstract

This invention discloses fused-ring compounds as Wee-1 inhibitors. Specifically, this invention relates to a compound of general formula (1) and its preparation method, and the use of the compound of general formula (1) and its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as Wee-1 inhibitors in the preparation of antitumor drugs.

Description

Fused ring compounds as Wee-1 inhibitors

The present application claims priority from chinese application CN202110179656.4 at 2021, 2, 9 and chinese application CN202110757479.3 at 2021, 7, 5. The present application is incorporated by reference in its entirety into the above-mentioned chinese application.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a compound with a Wee-1 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. Cell cycle checkpoints include the G1 phase checkpoint of the G1 (cell resting phase) to S phase (DNA synthesis phase) transition, the G2 phase checkpoint of the G2 (cell division preparation phase) to M (cell division phase) phase transition, and the spindle checkpoints of the M phase metaphase (cell division phase mid phase) to anaphase (cell division phase post phase) transition. Wee-1 protein kinase plays an important role in the G2 phase checkpoint. The entry of cells into the M phase depends on CDK1 kinase activity, and Wee-1 inhibits CDK1 activity by phosphorylating Tyr 15 of CDK1 protein, preventing cells from entering the M phase (cell division phase). While the Polo kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein and promotes cells to enter M phase. As can be seen, wee-1 kinase activity determines the activity of the G2 checkpoint, which in turn regulates the G2 to M phase transition of cells.

Cell cycle checkpoints are activated mainly after DNA damage, playing an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoints blocks the cell cycle to promote DNA repair. Inhibiting the function of check point, DNA damage can not be repaired, and cells undergo apoptosis. Compared with normal cells, the functions of p53 protein, which is an important protein of a G1 phase checkpoint, of various tumor cells are damaged, and DNA damage is repaired mainly by activating the G2 phase checkpoint, so that apoptosis is avoided. Thus, inhibition of the G2 phase checkpoint can selectively kill tumor cells. While the important role of the activity of the Wee-1 kinase in the G2 phase check point suggests that the Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibiting the activity of the Wee-1 can promote unrepaired tumor cells after DNA damage to enter the M phase and induce apoptosis.

Research shows that Wee-1 is involved in DNA synthesis, DNA homologous repair, post-translational modification of chromosomal histones, and other functions closely related to tumorigenesis and development, in addition to its role in the G2 checkpoint. Wee-1 expression is greatly elevated in a number of tumors including liver cancer, breast cancer, cervical cancer, melanoma, lung cancer, and the like. 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 tumor development and progression. Studies in vitro cell models and in vivo animal models have shown that inhibiting Wee-1 activity while inducing DNA damage can significantly inhibit the growth of a variety of tumors.

Thus, the development of specific, high activity small molecule inhibitors of Wee-1 kinase would be of great clinical value for tumor therapy, especially in targeting tumors such as P53 deleted G1 checkpoints that are impaired.

Currently, the Wee-1 inhibitor AZD1775 (MK-1775, adavosertib) of AstraZeneca has entered the clinical phase 2 study, with more than 30 clinical trials being developed. Patents related to AZD1775 are US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743, etc. Abbott and Abbvie have also developed Wee-1 inhibitors and related patents are mainly US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031, etc. Patents by Almac corporation for Wee-1 inhibitors include WO2014167347, WO2015019037, WO2015092431, WO2018011570, WO2018062932, WO2019138227, and the like. Wee-1 patents from GIRAFPHARMA include WO2019074979 and WO2019074981. Patents studied by Zeno company on Wee-1 include WO2018028008 and WO2019173082.

The Wee-1 inhibitor still has some problems in research, the treatment effect of single drug is poor, and the cell activity of the combination with other chemotherapeutics is not strong enough, so that the clinical combination effect is not ideal. Drug resistance usually occurs in the late stage of targeted treatment, chemotherapy is a common means for treating advanced tumors, and single-use chemotherapy drugs often produce larger side effects and poor patient tolerance, so that the Wee-1 inhibitor with good combined effect of the invention and the chemotherapy drugs has very important significance.

Disclosure of Invention

The invention provides a compound shown in a general formula (1), an optical isomer or a pharmaceutically acceptable salt thereof:

In the general formula (1):

m is 0 or 1;

x ¹ and X ² are independently CH or N;

R ¹ is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH ₂ (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;

R ² is H, C-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen-substituted C1-C6 alkyl, CN-substituted C1-C6 alkyl, OH-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl;

R ³ is H or C1-C3 alkyl;

A is aryl or heteroaryl, which may be optionally substituted with 1-3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF ₃ substituted C3-C6 cycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b or pyridonyl, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, or R ^7a and R ^7b together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl, R ⁸ is H or C1-C3 alkyl, or R5384 and R ^7a together with the atoms to which they are attached form a (3-10 membered) heterocycle;

B is a partially unsaturated C5-C7 cycloalkyl or a partially unsaturated (5-7 membered) heterocycloalkyl.

The invention provides a compound shown as a general formula (2), an optical isomer or a pharmaceutically acceptable salt thereof:

in the general formula (2):

m is 0 or 1;

x ¹ and X ² are independently CH or N;

R ¹ is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH ₂ (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;

R ² is H, C-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen-substituted C1-C6 alkyl, CN-substituted C1-C6 alkyl, OH-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl;

R ³ is H or C1-C3 alkyl;

A is aryl or heteroaryl, which may optionally be substituted with 1-3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, (3-10 membered) heterocycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, OH-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, CF ₃ -substituted C3-C6 cycloalkyl, C1-C6 alkyl-substituted (3-10 membered) heterocycloalkyl, halogen-substituted (3-10 membered) heterocycloalkyl, hydroxy-substituted (3-10 membered) heterocycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b or pyridonyl, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, or R ^7a and R ^7b together with the atom to which they are attached form a (3-to 10-membered) heterocycloalkyl, R ⁸ is H or C1-C3-alkyl, or R ⁸ and R ^7a together with the atom to which they are attached form a (3-10 membered) heterocycloalkyl; b is a partially unsaturated C5-C7 cycloalkyl, partially unsaturated (5-7 membered) heterocycloalkyl or C1-C6 alkyl substituted partially unsaturated (5-7 membered) heterocycloalkyl.

The invention provides a compound shown as a general formula (1A), an optical isomer or a pharmaceutically acceptable salt thereof:

in the general formula (1A):

m is 0 or 1;

n is 1,2 or 3;

X is CH ₂, O or S;

x ¹ and X ² are independently CH or N;

R ¹ is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH ₂ (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;

R ² is H, C-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen-substituted C1-C6 alkyl, CN-substituted C1-C6 alkyl, OH-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl;

A is aryl or heteroaryl, which may be optionally substituted with 1-3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF ₃ substituted C3-C6 cycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b or pyridonyl, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, or R ^7a and R ^7b together with the atom to which they are attached form a (3-10 membered) heterocycloalkyl, R ⁸ is H or C1-C3 alkyl, or R ⁸ and R ^7a together with the atom to which they are attached form a (3-10 membered) heterocycle.

In some embodiments of the present invention, the compound of formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, R ¹ is Me, et, R ¹ is preferablyR ¹ is more preferably

In some embodiments of the invention, a compound of formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, a is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, which phenyl, pyridinyl, pyrimidinyl, and pyrazinyl may optionally be substituted with 1-3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF ₃ substituted C3-C6 cycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b, or pyridonyl, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, or R35 is a heterocyclic ring formed by joining R25 to R35 and R10 together with the R10 and R10 (R25 or R35) is a heterocyclic ring attached thereto or a C25 membered ring.

In some embodiments of the present invention, wherein in the general formula (1), A is Wherein v is 1, 2 or 3, each R ⁶ is independently H, halogen, me, et, OMe, R ⁶ is preferably H, F, cl, br, I, me, et, OMe, R ⁶ is more preferably H, F, cl, R ⁶ is more preferably F,

In some embodiments of the present invention, wherein in the general formula (1), A is Preferably is More preferably More preferably

In some embodiments of the present invention, wherein in the general formula (1),Is that Wherein R ² is H, me, et, CD ₃,

In some embodiments of the present invention, wherein in the general formula (1),Is that Preferably is More preferably More preferably

In some embodiments of the invention, the compound, isomer or pharmaceutically acceptable salt is selected from the group consisting of:

another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound represented by the general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient.

Still another object of the present invention is to provide the use of the compound represented by the general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for treating, modulating or preventing a disease associated with Wee-1.

Still another object of the present invention is to provide a method for treating, modulating or preventing a disease associated with Wee-1 mediation, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof of the present invention or a pharmaceutical composition as described above.

Through intensive researches, the inventor discovers that the fused ring compound with the structure shown as the general formula (1) has strong Wee-1 inhibitory activity and combined administration activity with a chemotherapeutic drug Gemcitabine (GMC), and the results show that the compound provided by the invention can have better effect in clinic and combined use with the chemotherapeutic drug.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

Synthesis of Compounds

The preparation method of the compound represented by the general formula (1) of the present invention is specifically described below, but these specific methods do not impose any limitation on the present invention.

The compounds of formula (1) described above may be synthesized using standard synthetic techniques or well 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 the compounds of formula (1) may be obtained synthetically or from commercial sources such as, but not limited to, ALDRICH CHEMICAL co (Milwaukee, wis.) or SIGMA CHEMICAL co (st.louis, mo.). The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including the methods found in March, ADVANCED ORGANIC CHEMISTRY, 4 ^th Ed., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, ^th Ed., vols.A and B (Plenum 2000, 2001), green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, ^rd Ed., (Wiley 1999). The general method of preparation of the compounds 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 the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compound of formula (1), which is prepared by the following method a:

The method A comprises the following steps of firstly carrying out a coupling reaction on the compounds A1 and A2 to generate a compound A3, carrying out an oxidation reaction on the compound A3 to obtain a compound A4, and further carrying out a reaction on the compound A4 and the compound B8 to generate a target compound A5.

In the above reaction equation, A, B, X ¹、X²、R¹、R²、R³ and m are as defined above, Y is Br, I or-B (OH) ₂, W is

Further forms of the compounds

By "pharmaceutically acceptable" is meant herein a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and which is relatively non-toxic, e.g., administration of a material to an individual does not cause an undesired biological effect or interact in a deleterious manner with any of the components thereof in which it is contained.

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 specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, 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, and other organic acids, and an acidic amino acid, e.g., aspartic acid, glutamic acid.

References to pharmaceutically acceptable salts are understood to include solvent-added forms or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount 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 (1) are conveniently prepared or formed in accordance with the methods described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallisation from a mixed solvent of water/organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, solvated forms are considered to correspond to unsolvated forms.

In other specific embodiments, the compounds of formula (1) are prepared in different forms including, but not limited to, amorphous, crushed and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, 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 crystalline form to dominate.

In another aspect, the compounds of formula (1) may have chiral centers and/or axial chiralities and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axial chiral will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures, as well as 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.

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds such as tritium (³ H), iodine-125 (¹²⁵ I), and C-14 (¹⁴ C) can be labeled with radioisotopes. For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. 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.

Terminology

The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In the present application, the use of "or" and "means" and/or "unless otherwise indicated.

For convenience of compound naming, the definition of ring B in this application assumes that ring B is named as a separate group (without merging with other rings) unless otherwise specified. In the general formula (1), the B ring is condensed with an adjacent group.

Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 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, particularly alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH₃、CH₃CH₂、CF₃、CHF₂、CF₃CH₂、CF₃(CH₃)CH、ⁱPr、ⁿPr、ⁱBu、ⁿBu or ^t Bu.

Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, and includes straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl are preferred.

Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, for example ethynyl, 1-propynyl or 1-butynyl.

Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0,1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.

Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH₃、OCF₃、CHF₂O、CF₃CH₂O、^i-PrO、^n-PrO、^i-BuO、^n-BuO or ^t- BuO.

Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, an aryl group being monocyclic or polycyclic, e.g., a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.

Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), heteroaryl being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrolo [3,2-b ] pyridinyl, 1H-pyrrolo [2,3-c ] pyridinyl, 1H-pyrrolo [3,2-c ] pyridinyl, 1H-pyrrolo [2,3-b ] pyridinyl,

Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1,2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are benzo derivatives having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5] undecyl, 1-oxa-8-azaspiro [4.5] decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, tropanyl, 4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridinyl, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridinyl, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butanamide, pentalactam, imidazolone, hydantoin, dioxolanyl, phthalimide, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxo, thiomorpholinyl, S-thiomorpholinyl, 3-thiomorpholinyl, pyrrolyl, thiomorpholinyl, 3-thiomorpholinyl, pyrrolyl, and thiomorpholinyl,

Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted with F, cl, br or I, preferably F or Cl, in any combination.

"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The substituent "-O-CH ₂ -O-" means that two oxygen atoms in the substituent are attached to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:

When the number of one linking group is 0, for example- (CH ₂)₀) -means that the linking group is a single bond.

When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.

The term "membered ring" includes any cyclic structure. The term "meta" is meant to indicate the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings and cyclopentyl, pyrrolyl, furanyl and thiophenyl are five-membered rings.

The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.

Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key

Unless otherwise indicated, use ofRepresents a single bond or a double bond.

Specific pharmaceutical and medical terminology

The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.

The terms "treat," "treatment process," or "therapy" as used herein include alleviation, inhibition, or amelioration of a symptom or condition of a disease, inhibition of the production of complications, amelioration or prevention of underlying metabolic syndrome, inhibition of the production of a disease or condition, such as controlling the progression of a disease or condition, alleviation of a disease or condition, diminishment of a complication caused by a disease or condition, or prevention or treatment of a sign caused by a disease or condition. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.

"Active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the invention may contain one or more asymmetric centers (chiral centers or axial chiralities) and thus appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single 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, as well as 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.

The terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition that is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).

The term "administration (ADMINISTERED, ADMINISTERING or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a precursor (prodrug), derivative (derivative), or analog (analog) of the active compound, and the like.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.

Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. In addition, as used herein, the singular form of a noun is intended to cover the plural form of that noun, and as used herein, the plural form of that noun is intended to cover the singular form of that noun, without conflict with the context.

Therapeutic use

The compounds or compositions described herein are generally useful for inhibiting Wee-1 kinase and thus are useful for treating one or more conditions associated with Wee-1 kinase activity. Thus, in certain embodiments, the present invention provides methods for treating a Wee-1 kinase mediated condition 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 may be treated with the compounds of the present invention include, but are not limited to, hematological malignancies (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic syndrome, and myeloproliferative last name syndrome) and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue carcinomas and osteosarcomas, as well as stromal tumors), among others.

Route of administration

The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" is meant an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.

By "pharmaceutically acceptable excipient or carrier" is meant one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. 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 oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), and emulsifying agent (such as) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.

The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, such as, for example, glycerol, (d) disintegrants, such as, for example, agar-agar, calcium carbonate, potato starch, or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) slow solvents, such as, for example, paraffin, (f) absorption accelerators, such as, for example, quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, such as, for example, kaolin, and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective administration dose, and the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.

Detailed Description

The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present application. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present application will become apparent to those skilled in the art upon reading the description of the application, and such equivalents are intended to fall within the scope of the application.

In all examples, the melting point was measured by an X-4 melting point apparatus, the thermometer was uncorrected, ¹ H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, the chemical shift was expressed as delta (ppm), silica gel for separation was not shown, the proportions of the eluents were all 200-300 mesh, and the volume ratio was the same.

The invention uses the abbreviations CDCl ₃ for deuterated chloroform, cuI for cuprous iodide, DCM for methylene chloride, DIPEA for diisopropylethylamine, dioxane for 1, 4-dioxane, DMF for N, N-dimethylformamide, EA for ethyl acetate, etOH for ethanol, H for hours, H ₂ for hydrogen, H ₂SO₄ for sulfuric acid, K ₂CO₃ for potassium carbonate, KNO ₃ for potassium nitrate, LC-MS for liquid phase-mass spectrometry, liAlH ₄ for lithium aluminum hydride, m-CPBA for m-chloroperoxybenzoic acid, mL for milliliters, meOH for methanol, min for minutes, MS for mass spectrometry, naBH (OAc) ₃ for sodium triacetoxyborohydride, ⁿ BuLi for N-butyllithium, NMR for nuclear magnetic resonance, C for Centigrade, PE for petroleum ether, r.t. for room temperature, TEA for triethylamine, trifluoroacetic acid, THF for tetrahydrofuran, T ₃ P for propyl anhydride.

Preparation of 1 2-allyl-1- (6- ((dimethyl (oxo) - λ ⁶ -sulfinimide) amino) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (intermediate A3-1)

Step 1 Synthesis of Compound A0-1

Ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (13.5 g,58.06 mmol), tert-butyl 1-allylhydrazine-1-carboxylate (10 g,58.06 mmol), DIPEA (18.72 g,145.16 mmol) were dissolved in THF (300 mL), the reaction was heated to reflux overnight, LC-MS was monitored, the reaction was concentrated, the residue was dissolved with EA (200 mL), the organic phase was washed with water (150 mL), saturated brine (100 mL), dried, and concentrated to give yellow oil A0-1 (21 g, yield 98%), ESI-MS m/z 369.1[ M+H ] ⁺.

Step 2 Synthesis of Compound A1-1

A0-1 (21 g,57 mmol) was dissolved in DCM (70 mL), TFA (70 mL) was added, the reaction was allowed to proceed overnight at room temperature, and LC-Ms monitored. Directly concentrating, dissolving the residue with EtOH (120 mL), dropwise adding aqueous sodium hydroxide solution (6M, 66 mL) in ice bath, stirring at room temperature for 1h after the completion of the dropwise addition, monitoring by LC-MS, directly concentrating the reaction solution after the completion of the reaction, and subjecting the residue to column chromatography (DCM/MeOH=100/1 to 10.1) to obtain yellow solid A1-1 (10 g, yield 79%) and ESI-MS m/z:223.1[ M+H ] ⁺.

Step 3 Synthesis of Compound A3-1

A2-1 (2.5 g,10 mmol), A1-1 (2.22 g,10 mmol), cuI (1.9 g,10 mmol), K ₂CO₃ (2.07 g,15 mmol), N, N' -dimethylethylenediamine (970 mg,11 mmol) were dissolved in dioxane (100 mL), argon was used to protect, the reaction was allowed to warm up to 80℃overnight, LC-MS was monitored, the reaction was completed, the filtrate was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (DCM/MeOH=100/1 to 20/1) to give a pale yellow solid A3-1 (1.95 g, yield 50%), ESI-MS m/z:391.1[ M+H ] ⁺.

Intermediates A3-2 to A3-47 can be obtained by synthesis of intermediate A3-1 using different starting materials.

TABLE 1 structural formulas of intermediates A3-2 to A3-47

Preparation of 2 2-methyl-2, 3,7,8,9 a-hexahydro-1H-phenylpropan [ de ] isoquinolin-5-amine (intermediate B7-1)

Step 1, synthesis of a compound B2-1:

B1-1 (50 g,284 mmol), methylamine hydrochloride (57.5 g,851 mmol) and TEA (144 g,1.42mol, 197mL) were dissolved in acetonitrile (600 mL), and T ₃ P (217 g, 450 mmol,203mL,50% purity) was added dropwise at room temperature and heated to 50℃for 16 hours. The reaction was diluted with 1500mL of ethyl acetate and washed with aqueous NaHCO ₃ (400 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give the crude product as a white solid (50 g,264mmol, yield: 93.1%). The crude product was used directly in the next reaction.

¹H NMR:(400MHz,CDCl₃)δ:7.12-7.01(m,3H),6.10-5.71(m,1H),2.93(d,J＝4.9Hz,3H),2.83(br s,2H),2.79-2.71(m,2H),1.84-1.65(m,4H),MS(ESI):190.1[M+H]⁺.

Step2, synthesis of a compound B3-1:

b2-1 (50 g,264 mmol) was dissolved in THF (500 mL) and n-BuLi (2.5M, 275 mL) was slowly added dropwise at-23℃under nitrogen. DMF (48.3 g,660mmol,50.8 mL) was then slowly added dropwise at-23 ℃. HCl solution (6M, 300 mL) was then slowly added dropwise at 20 ℃. The reaction was diluted with water (100 mL), extracted with ethyl acetate (500 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55 g, crude). The crude product was used directly in the next reaction.

¹H NMR:(400MHz,CDCl₃)δ:8.36-8.20(m,1H),7.46-7.32(m,2H),6.84(s,1H),3.63-3.52(m,3H),2.99-2.92(m,3H),2.75-2.69(m,2H),2.01-1.90(m,2H),MS(ESI):200.1[M+H]⁺. Step 3, synthesis of a compound B4-1:

B3-1 (55 g,276 mmol) and 20g palladium on carbon were suspended in methanol (800 mL) and stirred overnight at 30℃under hydrogen pressure (50 psi). Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure, and column chromatography (SiO ₂, PE/etoac=1/0 to 3/1) was performed to give a yellow solid (38.5 g, yield: 69.3%).

¹H NMR:(400MHz,DMSO-d₆)δ:7.71-7.62(m,1H),7.28-7.20(m,2H),3.42(dd,J＝5.6,11.9Hz,1H),3.25(t,J＝12.5Hz,1H),3.13-2.99(m,4H),2.87-2.69(m,2H),2.06-1.90(m,2H),1.75-1.61(m,1H),1.41-1.22(m,1H),MS(ESI):202.1[M+H]⁺.

Step 4, synthesis of a compound B5-1:

B4-1 (3.1 g,19.2 mmol) was dissolved in H ₂SO₄ (300 mL) and KNO ₃ (17.9 g,177 mmol) was slowly added over 3 hours at 0deg.C and stirred for 2 hours at room temperature. TLC detection showed the reaction was complete. The reaction solution was diluted with 500mL of water, a large amount of solids was precipitated, and a precipitate was obtained by filtration, followed by drying to obtain a yellow solid (79 g, crude product). The crude product was used directly in the next reaction, MS (ESI): 247.1[ M+H ] ⁺.

Step 5, synthesis of a compound B6-1:

B5-1 (4.9, 19.9 mmol) and palladium on carbon (2 g,19.9mmol,10% purity) were suspended in methanol (100 mL) and reacted under hydrogen pressure (50 psi) at 25℃for 16 hours. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure, and column chromatography (SiO ₂, PE/ea=1/0 to 1/2) was performed to give B6-1 (1.44 g, yield: 33.5%) as a yellow solid.

¹H NMR:(400MHz,CDCl₃))δ:7.24(d,J＝2.3Hz,1H),6.56(d,J＝2.0Hz,1H),3.67(br s,2H),3.32-3.25(m,2H),3.19-3.13(m,3H),3.09-2.97(m,1H),2.81-2.65(m,2H),2.07-1.90(m,2H),1.78-1.62(m,1H),1.37-1.23(m,1H),MS(ESI):217.2[M+H]⁺.

Step 6, synthesis of a compound B7-1:

B6-1 (7 g,32.4 mmol) was dissolved in anhydrous tetrahydrofuran (300 ml) and LiAlH ₄ (6.14 g,162 mmol) was added at 0 ℃. The mixture was warmed to 25 ℃ under nitrogen protection and reacted for 2 hours. Slowly adding water to the reaction solution for quenching reaction, keeping the temperature of the reaction solution at 0-10 ℃, diluting the reaction solution with 800mL of ethyl acetate, washing with water (100 mL of 3), and drying the organic phase with anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give a crude product, which was subjected to column chromatography (SiO ₂,DCM/(MeOH+1％NH₄ OH) =10/0 to 10/1) to give a yellow oil (6.25 g, yield: 95.5%).

¹H NMR:(400MHz,CDCl₃)δ:6.31(s,1H),6.21(s,1H),3.88(d,J＝15.1Hz,1H),3.62-3.34(br s,2H),3.26(d,J＝15.1Hz,1H),2.98-2.69(m,4H),2.42(s,3H),2.03(t,J＝10.7Hz,1H),1.92(tdd,J＝3.4,6.5,13.1Hz,1H),1.88-1.75(m,2H),1.34-1.17(m,1H),MS(ESI):203.2[M+H]⁺.

Step7, preparation of compound B7-2 and compound B7-3:

b7-1 (1.5 g,7.41 mmol) was chiral resolved by preparative supercritical fluid chromatography (prep SFC) (SFC chiral resolution conditions: instrument: WATERS SFC, column: DAICEL CHIRALPAK AD (250 mm. Times.50 mm,10 um), mobile phase: A: CO ₂,B:IPA(0.1％NH₃H₂ O), gradient: B%:50% -50%, flow rate: 200ml/min, column temperature: 40 ℃ C.), and the fraction was concentrated under reduced pressure and lyophilized to give yellow oil B7-2 (peak 1,438mg, yield: 29.20%) and yellow oil B7-3 (peak 2,450mg, yield: 30.00%).

B7-2：¹H NMR:(400MHz,CDCl₃)δ:6.32(s,1H),6.22(s,1H),3.88(d,J＝15.1Hz,1H),3.48(br s,2H),3.26(br d,J＝15.1Hz,1H),2.93(dd,J＝4.6,10.5Hz,1H),2.90-2.80(m,1H),2.79-2.64(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.92(dtd,J＝3.6,6.5,9.8Hz,1H),1.87-1.79(m,2H),1.36-1.15(m,1H)

MS(ESI):203.2[M+H]⁺.

B7-3：¹H NMR:(400MHz,CDCl₃)δ:6.32(s,1H),6.22(s,1H),3.87(d,J＝15.3Hz,1H),3.47(br s,2H),3.26(d,J＝15.1Hz,1H),2.93(dd,J＝4.8,10.6Hz,1H),2.89-2.80(m,1H),2.80-2.65(m,2H),2.42(s,3H),2.02(t,J＝10.7Hz,1H),1.97-1.88(m,1H),1.87-1.75(m,2H),1.35-1.17(m,1H),MS(ESI):203.2[M+H]⁺.

Intermediates B7-4 to B7-49 can be obtained by synthesis of intermediate B7-1 using different starting materials.

TABLE 2 structural formulas of intermediates B7-4 to B7-49

Example 12 Synthesis of allyl-1- (6- ((dimethyl (oxo) - λ ⁶ -sulfa-dienyl) amino) pyridin-2-yl) -6- ((2-methyl-2, 3,7,8,9 a-hexahydro-1H-benzo [ de ] isoquinolin-5-yl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound 1)

A3-1 (390 mg,1.0 mmol) was dissolved in DCM (20 mL), and m-CPBA (319 mg,1.5 mmol) was added and reacted at room temperature for 1h. LC-MS monitoring, after the reaction is finished, the system sodium bicarbonate saturated solution is washed, the organic phase is dried, spin-dried, and the ESI-MS m/z is 405.5[ M+H ] ⁺.

The intermediate obtained in the above step was dissolved in DMF (20 mL), trifluoroacetic acid (0.3 mL,4.0 mmol), B7-1 (242 mg,1.2 mmol) was added, the reaction was carried out at 80℃overnight, and the reaction was monitored by LC-MS. DCM (50 mL) was added for dilution, water (20 mL. Times.2) was added for washing, the organic phase was dried, and the residue was spin-dried and chromatographed on silica gel (DCM/MeOH=100/1 to 10/1) to give compound 1 (72 mg, yield 13.2%) as a pale yellow solid

¹H NMR(400MHz,CDCl₃)δ:8.79(s,1H),7.65(t,J＝7.9Hz,1H),7.51(d,J＝9.8Hz,1H),7.35(d,J＝7.8Hz,1H),7.17(d,J＝17.4Hz,2H),6.66(dd,J＝8.0,0.7Hz,1H),5.63(ddt,J＝16.6,10.3,6.3Hz,1H),5.04-4.97(m,1H),4.89(dt,J＝6.2,1.3Hz,2H),3.94(d,J＝15.2Hz,1H),3.31(s,6H),3.02-2.71(m,5H),2.45(s,3H),2.01-1.76(m,5H),LC-MS:545.3[M+H]⁺.

EXAMPLE 86 Synthesis of (R) -2-allyl-1- (6- ((dimethyl (oxo) -lambda ⁶ -sulfanilide) amino) pyridin-2-yl) -6- ((2-methyl-2, 3,7,8,9 a-hexahydro-1H-benzo [ de ] isoquinolin-5-yl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound 86)

A3-1 (390 mg,1.0 mmol) was dissolved in DCM (20 mL), and m-CPBA (319 mg,1.5 mmol) was added and reacted at room temperature for 1h. LC-MS monitoring, after the reaction is finished, the system sodium bicarbonate saturated solution is washed, the organic phase is dried, spin-dried, and the ESI-MS m/z is 405.5[ M+H ] ⁺.

The intermediate obtained in the above step was dissolved in DMF (20 mL), trifluoroacetic acid (0.3 mL,4.0 mmol), B7-3 (242 mg,1.2 mmol) and reacted at 80℃overnight, monitored by LC-MS and the reaction was completed. DCM (50 mL) was added for dilution, water (20 mL. Times.2) was added for washing, the organic phase was dried, and the residue was spin-dried and chromatographed on silica gel (DCM/MeOH=100/1 to 10/1) to give compound 86 (85 mg, yield 15.6%) as a pale yellow solid

¹H NMR(400MHz,CDCl₃)δ:8.79(s,1H),7.65(t,J＝7.9Hz,1H),7.51(d,J＝9.8Hz,1H),7.35(d,J＝7.8Hz,1H),7.17(d,J＝17.4Hz,2H),6.66(dd,J＝8.0,0.7Hz,1H),5.63(ddt,J＝16.6,10.3,6.3Hz,1H),5.04-4.97(m,1H),4.89(dt,J＝6.2,1.3Hz,2H),3.94(d,J＝15.2Hz,1H),3.31(s,6H),3.02-2.71(m,5H),2.45(s,3H),2.01-1.76(m,5H),LC-MS:545.2[M+H]⁺.

EXAMPLE 89 Synthesis of (S) -2-allyl-1- (6- ((dimethyl (oxo) -lambda ⁶ -sulfanilide) amino) pyridin-2-yl) -6- ((2-methyl-2, 3,7,8,9 a-hexahydro-1H-benzo [ de ] isoquinolin-5-yl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound 89)

A3-1 (390 mg,1.0 mmol) was dissolved in DCM (20 mL), and m-CPBA (319 mg,1.5 mmol) was added and reacted at room temperature for 1h. LC-MS monitoring, after the reaction is finished, the system sodium bicarbonate saturated solution is washed, the organic phase is dried, spin-dried, and the ESI-MS m/z is 405.5[ M+H ] ⁺.

The intermediate obtained in the above step was dissolved in DMF (20 mL), trifluoroacetic acid (0.3 mL,4.0 mmol), B7-2 (242 mg,1.2 mmol) was added, the reaction was carried out at 80℃overnight, and the reaction was monitored by LC-MS. DCM (50 mL) was added for dilution, water (20 mL. Times.2) was added for washing, the organic phase was dried, and the residue was spin-dried and chromatographed on silica gel (DCM/MeOH=100/1 to 10/1) to give compound 89 (82 mg, yield 15.0%) as a pale yellow solid

¹H NMR(400MHz,CDCl₃)δ:8.79(s,1H),7.65(t,J＝7.9Hz,1H),7.51(d,J＝9.8Hz,1H),7.35(d,J＝7.8Hz,1H),7.17(d,J＝17.4Hz,2H),6.66(dd,J＝8.0,0.7Hz,1H),5.63(ddt,J＝16.6,10.3,6.3Hz,1H),5.04-4.97(m,1H),4.89(dt,J＝6.2,1.3Hz,2H),3.94(d,J＝15.2Hz,1H),3.31(s,6H),3.02-2.71(m,5H),2.45(s,3H),2.01-1.76(m,5H),LC-MS:545.2[M+H]⁺.

Examples 2-85, 87-88, and 90-93 Synthesis of Compounds 2-85, 87-88, and 90-111

Similar to the synthesis of Compound 1, the target compounds 2-85, 87-88 and 90-111 in Table 3 can be obtained using the intermediates A3-1 to A3-47 and B7-1 to B7-49 as reaction raw materials.

TABLE 3 Structure of Compounds 2-85, 87-88 and 90-93

EXAMPLE 112 Compound inhibition of Wee-1 enzymatic Activity assay

After incubation at room temperature (25 ℃) for 15 minutes, the gradient diluted compound and enzyme were mixed, and centrifuged at 1000rpm for 1 minute to mix, and 5. Mu.L of substrate was added to initiate the reaction. After 60 minutes of reaction at room temperature, 5. Mu.L of ADP-GLO reagent was added, and after 1 minute of mixing by centrifugation at 1000rpm, incubation was continued at room temperature for 60 minutes, and then 10. Mu.L of kinase detection reagent was added for 60 minutes to detect chemiluminescence. The percent inhibition of enzyme activity by the compounds was calculated compared to DMSO group, and IC ₅₀ was calculated.

TABLE 4 IC ₅₀ (nM) of the compounds of the invention to inhibit Wee-1 kinase activity

As can be seen from the data in Table 4, the compounds of the present invention have strong inhibitory effects on Wee-1 kinase, for example, the IC ₅₀ values of compounds 1, 31, 87, 88, 89, 91, etc. on Wee-1 kinase are all less than 1.5nM, and are improved by about 2 times compared with the control drug MK-1775.

Example 113 in vitro antiproliferative Activity of Compounds on MIA PaCa-2 cells

3000/Well MIA PaCa-2 cells were plated in 384 well plates and after overnight adherence, DMSO or a compound with a maximum concentration of 5. Mu.M, 1:5 gradient dilution was added. Cell survival was assessed 72 hours after dosing by measuring intracellular ATP content. The percent inhibition of cell survival by the compounds was calculated compared to DMSO group, IC ₅₀ values were calculated, and the results are listed in table 5 below.

Example 114 in vitro antiproliferative Activity of Compounds in combination with Gemcitabine (GMC) on MIA PaCa-2 cells

3000 MIA PaCa-2 cells per well were plated in 384 well plates and 20nM Gemcitabine was added, after overnight adherence, DMSO or a 1:5 gradient of the diluted compound at a maximum concentration of 100nM was added. Cell survival was assessed 72 hours after dosing by measuring intracellular ATP content. The percent inhibition of cell survival by the compounds compared to DMSO group was calculated, and IC ₅₀ values were calculated, with the results shown in table 5 below.

TABLE 5 antiproliferative activity of the compounds of the invention on MIA PaCa-2 cells alone or in combination with GMC

As can be seen from the data in Table 5, the compounds of the present invention have a stronger antiproliferative activity on MIA PaCa-2 cells than the control drug MK-1775, while the compounds of the present invention have a stronger combined activity with GMC, e.g., compound 34 has an IC ₅₀ of less than 1nM. The compound of the invention has stronger combined activity with GMC, which indicates that the compound can have better effect when being combined with chemotherapeutics clinically.

While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims (12)

1. A compound represented by general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

In the general formula (1):

m is 0 or 1;

x ¹ and X ² are independently CH or N;

R ¹ is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH ₂ (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;

R ² is H, C-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen-substituted C1-C6 alkyl, CN-substituted C1-C6 alkyl, OH-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl;

R ³ is H or C1-C3 alkyl;

A is aryl or heteroaryl which is phenyl or naphthyl, which heteroaryl is pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl or pyrrolyl, which aryl and heteroaryl may optionally be substituted with 1 to 3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF ₃ substituted C3-C6 cycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b or pyridonyl, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, R35 is taken together with R35 and R35 is a heterocyclic ring attached to form a member of R35 or a heterocyclic ring which is attached to R35, or a member of R35 is a heterocyclic ring which is attached;

B is a partially unsaturated C5-C7 cycloalkyl or a partially unsaturated (5-7 membered) heterocycloalkyl.

2. A compound represented by the general formula (2), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

in the general formula (2):

m is 0 or 1;

x ¹ and X ² are independently CH or N;

R ¹ is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH ₂ (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;

R ² is H, C-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen-substituted C1-C6 alkyl, CN-substituted C1-C6 alkyl, OH-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl;

R ³ is H or C1-C3 alkyl;

a is aryl or heteroaryl, said aryl being phenyl or naphthyl; the heteroaryl is pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl or pyrrolyl; the aryl and heteroaryl groups may optionally be substituted with 1-3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, (3-10 membered) heterocycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF ₃ substituted C3-C6 cycloalkyl, C1-C6 alkyl substituted (3-10 membered) heterocycloalkyl, halogen substituted (3-10 membered) heterocycloalkyl, hydroxy substituted (3-10 membered) heterocycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b or pyridone, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 cycloalkyl or C24 alkynyl, or R62 taken together with R62 is H or R62 is attached to R52, or R ⁸ and R ^7a together with the atom to which they are attached form a (3-10 membered) heterocycloalkyl;

B is a partially unsaturated C5-C7 cycloalkyl, partially unsaturated (5-7 membered) heterocycloalkyl or C1-C6 alkyl substituted partially unsaturated (5-7 membered) heterocycloalkyl.

3. The compound of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by general formula (1A):

in the general formula (1A):

m is 0 or 1;

n is 1,2 or 3;

X is CH ₂, O or S;

x ¹ and X ² are independently CH or N;

R ¹ is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH ₂ (C3-C6) cycloalkyl, C3-C5 alkenyl or C3-C5 alkynyl;

R ² is H, C-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogen-substituted C1-C6 alkyl, CN-substituted C1-C6 alkyl, OH-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or (4-7 membered) heterocycloalkyl;

A is aryl or heteroaryl which is phenyl or naphthyl, which heteroaryl is pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl or pyrrolyl, which aryl and heteroaryl may optionally be substituted with 1 to 3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, OH substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, hydroxy substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF ₃ substituted C3-C6 cycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b or pyridonyl, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 cycloalkyl or R35 is optionally substituted with R35 and R35 is a heterocyclic ring forming a ring, or a ring of which R35 is attached, or a ring of R35 is a member of which is attached to R35 and R35 is a heteroatom or a ring of which is attached.

4. The compound according to claim 1 or 2, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1) or the general formula (2), R ¹ is Me, et,

5. The compound of claim 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1) or (2), a is phenyl, pyridyl, pyrimidinyl, or pyrazinyl, which phenyl, pyridyl, pyrimidinyl, and pyrazinyl may be optionally substituted with 1-3R ⁶, each R ⁶ is independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, hydroxy substituted C1-C6 alkyl, cyano substituted C1-C6 alkyl, halogen substituted C3-C6 cycloalkyl, OH substituted C3-C6 cycloalkyl, cyano substituted C3-C6 cycloalkyl, CF ₃ substituted C3-C6 cycloalkyl 、-NR^7aR^7b、-N＝S(O)R^7aR^7b、-P(O)R^7aR^7b、-S(O)₂R^7a、-S(O)₂NR^7aR^7b、-NR⁸P(O)R^7aR^7b、-NR⁸S(O)₂R^7a、-NR⁸C(O)R^7a、-N＝S(＝NR⁸)R^7aR^7b, or pyridonyl, wherein R ^7a and R ^7b are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 cycloalkyl, or C3 alkynyl, or R35 is attached together with R35 to form a heterocyclic ring (R35 and R35 is attached together with R10 or a C10 membered heterocyclic ring, which is attached to form a ring, or a C10-membered ring, which is attached to R35, or a C10-membered ring.

6. The compound according to claim 5, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1) or the general formula (2), A is Wherein v is 1, 2 or 3, each R ⁶ is independently H, halogen, me, et, OMe,

7. The compound according to claim 6, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1) or the general formula (2), A is

8. The compound according to claim 1 or 2, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1) or the general formula (2),Is that Wherein R ² is H, me, et, CD ₃,

9. The compound according to claim 8, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1) or the general formula (2),Is that

10. The compound of claim 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound according to any one of claims 1 to 10, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

12. Use of a compound according to any one of claims 1-10, an optical isomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 for the preparation of a Wee-1 inhibitor.