Fused ring compounds as wee-1 inhibitors

Abstract

The present application discloses a fused ring compound as a Wee-1 inhibitor. Specifically, the present application relates to a compound shown in general formula (1) and a preparation method thereof, and the use of the compound shown in general formula (1) and each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as a Wee-1 inhibitor in the preparation of an antitumor drug.

Description

[0001] This application claims priority to Chinese application CN202110179656.4 filed on February 9, 2021 and CN202110757479.3 filed on July 5, 2021. This application incorporates the entire text of the above-mentioned Chinese applications. TECHNICAL FIELD

[0002] The present application relates to the field of medicinal chemistry, more particularly, to compounds having Wee-1 kinase inhibitory effect, and the preparation method thereof and the use of the compounds in the preparation of anti-tumor drugs. BACKGROUND

[0003] Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoint. Cell cycle checkpoint includes G1 phase checkpoint for the transition from G1 (cell resting phase) to S phase (DNA synthesis phase), G2 phase checkpoint for the transition from G2 (cell division preparation phase) to M (cell division phase), and spindle checkpoint for the transition from metaphase (cell division phase metaphase) to anaphase (cell division phase late phase). Wee-1 protein kinase plays an important role in G2 checkpoint. The entry of cells into M phase depends on the activity of CDK1 kinase, and Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr 15 of CDK1 protein, preventing cells from entering M phase (cell division phase). Polo kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein, and promotes the entry of cells into M phase. Therefore, the activity of Wee-1 kinase determines the activity of G2 checkpoint, and further regulates the transition from G2 to M phase.

[0004] Cell cycle checkpoint is mainly activated after DNA damage, and plays an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoint blocks cell cycle to promote DNA repair. Inhibition of checkpoint function, DNA damage cannot be repaired, and cells undergo apoptosis. Compared with normal cells, various tumor cells mainly rely on the activation of G2 checkpoint to repair DNA damage and evade apoptosis due to the impairment of the function of p53 protein, an important protein in G1 checkpoint. Therefore, inhibition of G2 checkpoint can selectively kill tumor cells. The important role of Wee-1 kinase activity in G2 checkpoint suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibition of Wee-1 activity can promote the entry of un-repaired tumor cells into M phase after DNA damage, inducing apoptosis.

[0005] Studies have shown that in addition to the role in G2 checkpoint, Wee-1 is also involved in DNA synthesis, DNA homologous repair, chromatin histone post-translational modification and other functions closely related to tumor occurrence and development. In a large number of tumors including liver cancer, breast cancer, cervical cancer, melanoma and lung cancer, the expression of Wee-1 is greatly increased. High expression of Wee-1 is positively correlated with tumor development and poor prognosis, suggesting that Wee-1 kinase may be involved in tumor occurrence and development. Studies in vitro cell models and in vivo animal models have shown that inhibition of Wee-1 activity can significantly inhibit the growth of various tumors while inducing DNA damage.

[0006] Therefore, the development of specific small molecule inhibitors of high-activity Wee-1 kinase has important clinical value for tumor treatment, especially for targeting tumors with impaired G1 checkpoint such as P53 deletion.

[0007] Currently, AstraZeneca's Wee-1 inhibitor AZD1775 (MK-1775, Adavosertib) has entered the clinical phase 2 research stage, and more than 30 clinical trials are being developed. Patents related to AZD1775 include US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743, etc. Abbott and Abbvie have also conducted research on Wee-1 inhibitors, and the related patents mainly include US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031, etc. Almac's patents on Wee-1 inhibitors include WO2014167347, WO2015019037, WO2015092431, WO2018011570, WO2018062932, WO2019138227, etc. Girafpharma's Wee-1 patents include WO2019074979 and WO2019074981. Zeno's patents on Wee-1 research include WO2018028008 and WO2019173082.

[0008] There are still some problems in the Wee-1 inhibitors under research. The therapeutic effect of single drug is poor, and the cell activity of combination with other chemotherapeutic drugs is not strong enough, so the clinical combination effect is not ideal. Targeted therapy usually produces drug resistance in the later stage, and chemotherapy becomes a common means of treatment for advanced tumors. The use of chemotherapeutic drugs alone often produces greater side effects, and patients have poor tolerance, so the invention of Wee-1 inhibitors with good combination effect with chemotherapeutic drugs has very important significance. SUMMARY

[0009] The present application provides a compound represented by general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] In general formula (1):

[0012] m is 0 or 1;

[0013] X 1 and X 2 are independently CH or N;

[0014] R 1 is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH2(C3-C6)cycloalkyl, C3-C5 alkenyl, or C3-C5 alkynyl;

[0015] R 2 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halo-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;

[0016] R 3 is H or C1-C3 alkyl;

[0017] A is aryl or heteroaryl, which aryl and heteroaryl can be optionally substituted with 1-3 R 6 each R 6 is independently H, halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halo-substituted C1-C6 alkyl, halo-substituted C1-C6 alkoxy, OH-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halo-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, CF3-substituted C3-C6 cycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8C(O)R 7a -N=S(=NR 8 )R 7a R 7b or pyridinone, 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 group, R 8 is H or C1-C3 alkyl, or R 8 and R 7a together with the atoms to which they are attached form a (3-10 membered)heterocycloalkyl group;

[0018] B is partially unsaturated C5-C7 cycloalkyl or partially unsaturated (5-7 membered)heterocycloalkyl.

[0019] The present application provides a compound as shown in general formula (2), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0020]

[0021] In general formula (2):

[0022] m is 0 or 1;

[0023] X 1 and X 2 are independently CH or N;

[0024] R 1 is C1-C6 alkyl, halogen-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH2(C3-C6)cycloalkyl, C3-C5 alkenyl, or C3-C5 alkynyl;

[0025] R 2 is H, C1-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;

[0026] R 3 is H or C1-C3 alkyl;

[0027] A is aryl or heteroaryl, which aryl and heteroaryl can be optionally substituted with 1-3 R 6 , each R 6independently H, halogen, CN, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, (3-10 membered)heterocycloalkyl, halogen substituted C1-C6alkyl, halogen substituted C1-C6alkoxy, OH substituted C1-C6alkyl, cyano substituted C1-C6alkyl, halogen substituted C3-C6cycloalkyl, hydroxyl substituted C3-C6cycloalkyl, cyano substituted C3-C6cycloalkyl, CF3substituted C3-C6cycloalkyl, C1-C6alkyl substituted C3-C6cycloalkyl, C1-C6alkyl substituted (3-10 membered)heterocycloalkyl, halogen substituted (3-10 membered)heterocycloalkyl, hydroxyl substituted (3-10 membered)heterocycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8 C(O)R 7a , -N=S(=NR 8 )R 7a R 7b or pyridonyl, wherein R 7a and R 7b are independently C1-C3alkyl, deuterated C1-C3alkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C6cycloalkyl, or R 7a and R 7b together with the atom to which they are attached form a (3-10 membered)heterocycloalkyl group, R 8 is H or C1-C3alkyl, or R 8 and R 7a together with the atom to which they are attached form a (3-10 membered)heterocycloalkyl group; B is partially unsaturated C5-C7cycloalkyl, partially unsaturated (5-7 membered)heterocycloalkyl or C1-C6alkyl substituted partially unsaturated (5-7 membered)heterocycloalkyl.

[0028] The present application provides a compound of Formula (1A), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0029]

[0030] In Formula (1A):

[0031] m is 0 or 1;

[0032] n is 1, 2, or 3;

[0033] X is CH2, O, or S;

[0034] X 1 and X 2 are independently CH or N;

[0035] R 1 is C1-C6 alkyl, halo-substituted C1-C3 alkyl, C3-C6 cycloalkyl, -CH2(C3-C6)cycloalkyl, C3-C5 alkenyl, or C3-C5 alkynyl;

[0036] R 2 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halo-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;

[0037] A is aryl or heteroaryl, which aryl and heteroaryl can be optionally substituted with 1-3 R 6 , each R 6 is independently H, halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halo-substituted C1-C6 alkyl, halo-substituted C1-C6 alkoxy, OH-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halo-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, CF3-substituted C3-C6 cycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8 C(O)R 7a , -N=S(=NR 8 )R 7a R 7b , or pyridonyl, wherein R 7a and R 7bindependently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, or R 7a and R 7b form, together with the atom to which they are attached, a (3-10 membered) heterocycloalkyl group, R 8 is H or C1-C3 alkyl, or R 8 and R 7a form, together with the atom to which they are attached, a (3-10 membered) heterocycloalkyl group.

[0038] In some embodiments of the application, the compound of Formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, R 1 is Me, Et, R 1 is preferably R 1 is more preferably

[0039] In some embodiments of the application, the compound of Formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A is phenyl, pyridyl, pyrimidinyl, or pyrazinyl, which phenyl, pyridyl, pyrimidinyl, and pyrazinyl is optionally substituted with 1-3 R 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, hydroxyl-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, CF3-substituted C3-C6 cycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8 C(O)R 7a , -N=S(=NR 8 )R 7a R 7b or pyridinonyl, wherein R 7a and R 7bindependently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, or R 7a and R 7b form a (3-10 membered)heterocycloalkyl group, together with the atom to which they are attached, R 8 is H or C1-C3 alkyl, or R 8 and R 7a form a (3-10 membered)heterocycloalkyl group, together with the atom to which they are attached.

[0040] In some embodiments of the application, wherein said general formula (1), A is wherein v is 1, 2, or 3, and 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,

[0041] In some embodiments of the application, wherein said general formula (1), A is is preferably is more preferably is more preferably

[0042] In some embodiments of the application, wherein said general formula (1), is wherein R 2 is H, Me, Et, CD3,

[0043] In some embodiments of the application, wherein said general formula (1), is Preferably More preferably More preferably

[0044] In some embodiments of the present application, the above-mentioned compound, isomer or pharmaceutically acceptable salt is selected from the group consisting of:

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] Another object of the present application is to provide a pharmaceutical composition containing a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of the general formula (1) of the present application, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0051] Still another object of the present application is to provide use of a compound of the general formula (1) of the present application, an optical isomer thereof or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition for the manufacture of a medicament for treating, regulating or preventing a disease associated with Wee-1.

[0052] Still another object of the present application is to provide a method for treating, regulating or preventing a disease associated with Wee-1 mediation, comprising administering to a subject a therapeutically effective amount of a compound of the general formula (1) of the present application, an optical isomer thereof or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.

[0053] The present inventors have found, through intensive research, that a fused ring compound having a structure as shown in the general formula (1) has strong Wee-1 inhibitory activity, and combined administration activity with a chemotherapeutic drug gemcitabine (GMC), and the above results indicate that the compound of the present application can have a better effect in combination with a chemotherapeutic drug in a clinical setting.

[0054] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the application as claimed.

[0055] Synthesis of compounds

[0056] The preparation of the compounds of the present application of general formula (1) is described in detail below, but these specific methods do not limit the present application.

[0057] The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques and methods incorporated herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein can be varied. The starting materials used for the synthesis of the compounds of general formula (1) can be obtained by synthesis 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 different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce the different groups in the formula provided herein.

[0058] In one aspect, the compounds described herein are prepared according to known methods in the art. However, the conditions of the methods, such as the reactants, solvents, bases, amounts of compounds used, reaction temperatures, times required for the reaction, etc. are not limited to the explanations below. The compounds of the present application can also be prepared conveniently by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily made by those skilled in the art. In one aspect, the present application also provides a method for preparing the compounds of general formula (1) described herein, which is prepared using the following Method A:

[0059] Method A comprises the following steps: first, compounds A1 and A2 are coupled to form compound A3, compound A3 is oxidized to obtain compound A4, and compound A4 and compound B8 are further reacted to form the target compound A5.

[0060]

[0061] In the above reaction scheme, A, B, X 1 , X 2 , R 1 , R 2 , R 3 and m are as defined above, Y is Br, I or -B(OH)2, and W is

[0062] Further forms of the compounds

[0063] "Pharmaceutically acceptable" means, in relation to a substance such as a carrier or diluent, that the substance is not biologically or otherwise undesirable, i.e., the substance can be administered to an individual without causing any undesirable biological effects or interacting in an adversely deleterious manner with any of the components of the composition in which it is contained.

[0064] The term "pharmaceutically acceptable salt" means a form of a compound which does not cause important stimulation of the organism to which it is administered and which does not cause the biological activity and properties of the compound to be lost. In certain specific aspects, the pharmaceutically acceptable salt is obtained by reaction of a compound of formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, etc. inorganic acids, 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. organic acids and acidic amino acids such as aspartic acid, glutamic acid.

[0065] It is understood that reference to a pharmaceutically acceptable salt includes solvate or crystalline forms, especially solvate or polymorph. Solvates contain either stoichiometric or non-stoichiometric amounts of the solvent, and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol and the like. When the solvent is water, a hydrate is formed, or when the solvent is ethanol, an alcoholate is formed. Solvates of the compounds of formula (1) are readily prepared and formed according to the methods described herein. For example, hydrates of the compounds of formula (1) are readily prepared by recrystallization from a water / organic solvent mixture, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds referred to herein can exist in unsolvated and solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0066] In other embodiments, the compounds of Formula (1) are prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms. In addition, the compounds of Formula (1) include crystalline forms, which can also be referred to as polymorphs. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvent, rate of crystallization, and storage temperature can cause a single crystal form to dominate.

[0067] In another aspect, the compounds of Formula (1) can possess chiral centers and / or axes, and therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and as individual diastereomers, as well as as cis-trans isomers. Each chiral center or axis will independently produce two optical isomers and all possible optical isomers and stereoisomeric mixtures are intended to be encompassed by the present application. The present application is meant to include all such isomeric forms of these compounds.

[0068] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) and carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen present in the compounds of the present application. Deuterium is a non-radioactive isotope of hydrogen that has been found to enhance the therapeutic potential of drugs, for example, by reducing the rate of metabolism, and thus increasing the half-life of the drug in vivo. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.

[0069] The terms

[0070] If not otherwise specified, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that, as used in the specification and the appended claims, the singular form "a" includes plural referents unless the context clearly dictates otherwise. If not otherwise specified, conventional methods of mass spectroscopy, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In the present application, "or" or "and" is used to mean "and / or" unless otherwise indicated.

[0071] Unless otherwise specified, for the convenience of naming the compounds, the definition of B ring in the present application is assumed that the B ring is named as an independent group (not annelated with other rings). In Formula (1), the B ring is fused with the adjacent groups.

[0072] Unless otherwise indicated, "alkyl" means a saturated aliphatic hydrocarbon group, including straight- chain and branched groups having from 1 to 6 carbon atoms. Preferred is lower alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-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 the group consisting of CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0073] Unless otherwise indicated, "alkylene" means a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0074] Unless otherwise indicated, "alkenyl" means an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight- chain and branched groups having from 1 to 14 carbon atoms. Preferred is lower alkenyl containing 1 to 4 carbon atoms, such as ethenyl, 1- propenyl, 1-butenyl, or 2-methylpropenyl.

[0075] Unless otherwise indicated, "alkynyl" means an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight- chain and branched groups having from 1 to 14 carbon atoms. Preferred is lower alkynyl containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl.

[0076] Unless otherwise specified, "cycloalkyl" refers to non-aromatic hydrocarbon ring systems (single ring, bi- or polycyclic), which can be referred to as "cycloalkenyl" if the carbon ring contains at least one double bond, or "cycloalkynyl" if the carbon ring contains at least one triple bond, if the carbon ring contains at least one double bond. Cycloalkyl groups can include single or multiple ring (e.g., with 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form an oxo or thio group. Cycloalkyl also includes cycloalkylidene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, the cycloalkyl group can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl group can be fused to aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl group can be fused to aryl and heterocycloalkyl. In some embodiments, the cycloalkyl group can be fused to aryl and cycloalkyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[l. l. l]pentanyl, bicyclo[2. l. l]hexanyl, and the like.

[0077] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxyl groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propyloxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and t-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxyl groups, especially alkoxyl 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.

[0078] Unless otherwise specified, "aryl" refers to a carbon-hydrogen aromatic group, which is monocyclic or polycyclic, e.g., a single ring aryl ring is fused to one or more carbon ring aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0079] Unless otherwise specified, "heteroaryl" means an aromatic group containing one or more heteroatoms (O, S, or N), which is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, 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,

[0080] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system which can optionally contain one or more alkenylene groups as part of the ring structure, which has at least one ring member that is independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, the partially unsaturated heterocycloalkyl group can be referred to as a "heterocycloalkenyl," or if the heterocycloalkyl group contains at least one triple bond, the partially unsaturated heterocycloalkyl group can be referred to as a "heterocycloalkynyl." Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., with 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 an oxo or thiono group or other oxidized linkage (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or a nitrogen atom can be quaternized. The heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as benzoderivatives of piperidine, morpholine, azepine, or thienyl, etc. Heterocycloalkyl groups containing fused aromatic rings can be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic rings. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, 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]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactamyl, valerolactamyl, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dionyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S,S-oxide, piperazinyl, pyranyl, pyridinonyl, 3-pyrrolinyl, thiopyranyl, pyryonyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,

[0081] Unless otherwise indicated, "halogen" (or halogeno) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before a group denotes that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I, in any combination, preferably F or Cl.

[0082] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0083] The substituent "-O-CH2-O-" means that the two oxygen atoms of the substituent are attached to two adjacent carbon atoms of the heterocycloalkyl, aryl or heteroaryl group, such as:

[0084] When the number of linking groups is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0085] When one of the variables is selected from a bond, it means that the two groups to which it is attached are directly connected, such as L represents a bond in X-L-Y means that the structure is actually X-Y.

[0086] The term "membered ring" includes any cyclic structure. The term "member" means the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl and thienyl are five-membered rings.

[0087] The term "moiety" refers to a specific part or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity that is included in or attached to a molecule.

[0088] Unless otherwise indicated, a wedged line and a dashed wedged line represents the absolute configuration of a stereocenter, a straight line and a dashed straight line represents the relative configuration of a stereocenter, a wavy line represents a wedged line or a dashed wedged line or a wavy line represents a straight line or a dashed straight line

[0089] Unless otherwise indicated, a represents a single or double bond.

[0090] Specific Pharmaceutical and Medical Terms

[0091] The term "acceptable," as used herein, means that a prescribed component or active ingredient has no excessively deleterious effect on the health of the general treatment population.

[0092] The terms "treatment," "treatment regime," or "therapy," as used herein, include alleviating, inhibiting or ameliorating a disease symptom or condition; inhibiting the development of complications; ameliorating or preventing a latent metabolic syndrome; inhibiting the disease or symptom, such as controlling the disease or condition development; relieving the disease or symptom; causing regression of the disease or symptom; relieving a complication caused by the disease or symptom, or preventing or treating a sign caused by the disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can cause an improvement of a disease, symptom or condition, particularly an improvement in its severity, a delay in onset, a slowing of progression, or a decrease in the duration of the condition, whether fixed or temporal, continuous or intermittent.

[0093] "Active ingredient" refers to the compounds of general formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compounds of general formula (1). The compounds of the present application can contain one or more asymmetric centers (chiral centers or axes of chirality) and therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and as individual diastereomers. The asymmetric centers that can exist, 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 are intended, as well as their pure or partially purified individual isomers. The present application is meant to include all such isomeric forms of these compounds.

[0094] The terms "compound," "composition," "agent," or "medicine" or the like are used interchangeably herein and refer to a compound or composition that, when administered to an individual (human or animal), is capable of eliciting the desired pharmacological and / or physiologic effect through local and / or systemic action.

[0095] The term "administered," "administering" or "administration" refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound, etc.

[0096] Notwithstanding that the numerical ranges and parameters setting forth the broadest scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to be

[0097] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the application belongs. Further, all citations are incorporated herein by reference, unless otherwise indicated.

[0098] Therapeutic uses

[0099] 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. Accordingly, in certain embodiments, the present application 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 application, or a pharmaceutically acceptable composition thereof.

[0100] Cancers that can be treated with the compounds of the present application include, but are not limited to, hematological malignancies (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic syndromes, and myeloproliferative syndromes) and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreatic, renal, ovarian, and soft tissue carcinomas and osteosarcomas, as well as stromal tumors).

[0101] Routes of administration

[0102] The compounds of the present application and their pharmaceutically acceptable salts can be prepared into various formulations comprising a safe and effective amount of the compound of the present application or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient or carrier. By "safe and effective amount" is meant an amount of the compound sufficient to significantly induce a desired effect, without causing serious side effects. The safe and effective amount of the compound is determined by the age, condition, treatment period, and the like of the subject.

[0103] "Pharmacologically acceptable excipient or carrier" means one or more compatible solid or liquid filler or gel materials, which are suitable for human use, and which must have sufficient purity and low toxicity. By "compatible" is meant that the components of the composition are capable of being commingled with the compounds of the present application, and with each other, in a manner such that no interaction occurs which would substantially reduce the pharmaceutical efficacy of the compounds. Examples of pharmacologically acceptable excipients or carriers include celluloses and their 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.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., lecithin), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0104] The compounds of the present application can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0105] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can also comprise buffering agents.

[0106] ​Solid dosage forms such as tablets, sugar coated tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other well-known materials. They can contain opacifying agents and can also be of a composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0107] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0108] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0109] Suspensions, in addition to the active compounds, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, as well as mixtures thereof.

[0110] The compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol glycols, and suitable mixtures thereof.

[0111] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required. The ointments can contain additives such as

[0112] The compounds of the present application can be administered alone, or in combination with other pharmaceutically acceptable compounds. When administered as a pharmaceutical composition, a safe and effective amount of the compound of the present application is administered to a mammal (e.g., human) in need of treatment, wherein the amount is a pharmaceutically effective amount, and the amount is typically 1-2000 mg, preferably 50-1000 mg, per day for a 60 kg body weight human. The specific dose level, however, will depend on the route of administration, the health condition of the patient, and the like, and is within the skill of the skilled practitioner.

[0113] The features of the above summary, or of the features of the embodiments, can be combined in any combination. All features disclosed in the specification and / or the claims can be combined in any combination. Any feature described in the specification and / or the claims can be replaced by an equivalent feature that serves the same, equivalent or similar purpose. DETAILED DESCRIPTION

[0114] The various specific aspects, features and advantages of the compounds, methods, and pharmaceutical compositions described above will become apparent to those of ordinary skill in the art upon reading the following description and examples. It is understood that the detailed description and examples described herein are given by way of example only. Various changes and modifications of the preferred embodiments described herein will become apparent to those of ordinary skill in the art upon reading the description and examples. All such modifications and changes are intended to fall within the scope of the application.

[0115] In all examples, melting points were determined using a X-4 melting point apparatus, and the thermometer was not calibrated. 1 H-NMR was recorded on a Varian Mercury 400 NMR spectrometer, and chemical shifts are reported in δ (ppm); silica gel used for separation was 200-300 mesh unless otherwise stated, and the ratio of eluent was volume ratio.

[0116] The following abbreviations are used in the present application: CDCl3 represents deuterated chloroform; Cul represents copper iodide; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide, EA represents ethyl acetate; EtOH represents ethanol; h represents hour; H2 represents hydrogen; H2SO4 represents sulfuric acid; K2CO3 represents potassium carbonate; KNO3 represents potassium nitrate; LC-MS represents liquid chromatography-mass spectrometry; LiAlH4 represents lithium aluminum hydride; m-CPBA represents meta-chloroperoxybenzoic acid; mL represents milliliter; MeOH represents methanol; min represents minute; MS represents mass spectrometry; NaBH(OAc)3 represents sodium triacetoxyborohydride; n BuLi represents n-butyllithium; NMR represents nuclear magnetic resonance; °C represents degree Celsius; PE represents petroleum ether; r.t. represents room temperature; TEA represents triethylamine; TFA represents trifluoroacetic acid; THF represents tetrahydrofuran, T3P represents propylphosphonic anhydride.

[0117] Preparation Example 1 2-allyl-1-(6-((dimethyl(oxo)-λ 6 Preparation of 2-allyl-1-(6-((dimethyl(oxo)-λ

[0118]

[0119] Step 1: Synthesis of compound A0-1

[0120] 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), heated to reflux overnight, LC-MS monitoring, reaction was completed, the reaction liquid was concentrated, the residue was dissolved with EA (200 mL), the organic phase was washed with water (150 mL), saturated brine (100 mL), dried, concentrated to get yellow oil A0-1 (21 g, yield 98%), ESI-MS m / z: 369.1 [M+H] + .

[0121] Step 2: Synthesis of compound A1-1

[0122] A0-1 (21 g, 57 mmol) was dissolved in DCM (70 mL), TFA (70 mL) was added, and the reaction was stirred at room temperature overnight. LC-MS monitoring showed that the reaction was completed. The reaction liquid was directly concentrated, the residue was dissolved in EtOH (120 mL), and sodium hydroxide aqueous solution (6 M, 66 mL) was added dropwise in an ice bath. After the addition was completed, the reaction was stirred at room temperature for 1 h. LC-MS monitoring showed that the reaction was completed. The reaction liquid was directly concentrated, and the residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 10.1) to obtain yellow solid A1-1 (10 g, yield 79%), ESI-MS m / z: 223.1 [M+H] + .

[0123] Step 3: Synthesis of compound A3-1

[0124] A2-1 (2.5 g, 10 mmol), A1-1 (2.22 g, 10 mmol), CuI (1.9 g, 10 mmol), K2CO3 (2.07 g, 15 mmol), N,N'-dimethylethylenediamine (970 mg, 11 mmol) were dissolved in dioxane (100 mL), and the reaction was stirred at 80°C overnight under argon protection. LC-MS monitoring showed that the reaction was completed. Filtration and concentration of the filtrate gave a light yellow solid A3-1 (1.95 g, yield 50%), ESI-MS m / z: 391.1 [M+H] + .

[0125] Using different raw materials, the synthesis of intermediate A3-1 can obtain intermediates A3-2 to A3-47.

[0126] Table 1. Structural formula of intermediates A3-2 to A3-47

[0127]

[0128]

[0129]

[0130]

[0131] Preparation of 2-methyl-2,3,7,8,9,9a-hexahydro-lH-benzo[de]isoquinolin-5-amine (intermediate B7-1)

[0132]

[0133] Step 1: Synthesis of compound B2-1:

[0134] B1-1 (50 g, 284 mmol), methylamine hydrochloride (57.5 g, 851 mmol) and TEA (144 g, 1.42 mol, 197 mL) were dissolved in acetonitrile (600 mL), T3P (217 g, 341 mmol, 203 mL, 50% purity) was added dropwise at room temperature, after the addition was completed, it was heated to 50°C for 16 hours. The reaction liquid was diluted with 1500 mL of ethyl acetate, and washed with NaHCO3 aqueous solution (400 mL*3), the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product as a white solid (50 g, 264 mmol, yield: 93.1%). The crude product can be directly used for the next step reaction.

[0135] 1 H NMR: (400 MHz, CDCl3) δ: 7.12-7.01 (m, 3H), 6.10-5.71 (m, 1H), 2.93 (d, J = 4.9 Hz, 3H), 2.83 (br s, 2H), 2.79-2.71 (m, 2H), 1.84-1.65 (m, 4H), MS (ESI): 190.1 [M+H] + .

[0136] Step 2: Synthesis of compound B3-1:

[0137] B2-1 (50 g, 264 mmol) was dissolved in THF (500 mL) and n-BuLi (2.5 M, 275 mL) was added slowly at -23 °C under nitrogen protection. Then DMF (48.3 g, 660 mmol, 50.8 mL) was added slowly at -23 °C. HCl solution (6 M, 300 mL) was added slowly at 20 °C. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (500 mL*3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain a yellow solid (55 g, crude product). The crude product can be directly used in the next step reaction.

[0138] 1 H NMR: (400 MHz, 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 compound B4-1:

[0139] B3-1 (55 g, 276 mmol) and 20 g of palladium on carbon were suspended in methanol (800 mL) and stirred at 30 °C under hydrogen pressure (50 psi) overnight. The palladium on carbon was removed by filtration and the filtrate was concentrated under reduced pressure. Column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) gave a yellow solid (38.5 g, yield: 69.3%).

[0140] 1 H NMR: (400 MHz, DMSO-d6) δ: 7.71-7.62 (m, 1H), 7.28-7.20 (m, 2H), 3.42 (dd, J = 5.6, 11.9 Hz, 1H), 3.25 (t, J = 12.5 Hz, 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] + .

[0141] Step 4: Synthesis of compound B5-1:

[0142] B4-1 (3.1 g, 19.2 mmol) was dissolved in H2SO4(300 mL), KNO3(17.9 g, 177 mmol) was added slowly at 0 °C in 3 hours, then the temperature was raised to room temperature and stirred for 2 hours. TLC detection showed that the reaction was complete. The reaction solution was diluted with 500 mL of water, a large amount of solid precipitated, and the precipitate was filtered and dried to obtain a yellow solid (79 g, crude product). The crude product can be directly used in the next step reaction, MS (ESI): 247.1 [M+H] + .

[0143] Step 5: Synthesis of compound B6-1:

[0144] B5-1 (4.9, 19.9 mmol) and palladium on carbon (2 g, 19.9 mmol, 10% purity) were suspended in methanol (100 mL), and hydrogen was pressurized (50 psi) at 25 °C for 16 hours. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure, and column chromatography (SiO2, PE / EA = 1 / 0 to 1 / 2) to obtain yellow solid B6-1 (1.44 g, yield: 33.5%).

[0145] 1 H NMR: (400 MHz, CDCl3)) δ: 7.24 (d, J = 2.3 Hz, 1H), 6.56 (d, J = 2.0 Hz, 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] + .

[0146] Step 6: Synthesis of compound B7-1:

[0147] B6-1 (7 g, 32.4 mmol) was dissolved in anhydrous tetrahydrofuran (300 ml), and LiAlH4(6.14 g, 162 mmol) was added at 0 °C. The mixture was warmed to 25 °C under nitrogen protection for 2 hours. Water was slowly added to the reaction solution to quench the reaction, and the temperature of the reaction solution was maintained at 0-10 °C during the process. The reaction solution was diluted with 800 mL of ethyl acetate and washed with water (100 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product, which was column chromatographed (SiO2, DCM / (MeOH+1% NH4OH) = 10 / 0 to 10 / 1) to obtain a yellow oil (6.25 g, yield: 95.5%).

[0148] 1H NMR: (400 MHz, CDC13) δ: 6.32 (s, 1H), 6.22 (s, 1H), 3.88 (d, J = 15.1 Hz, 1H), 3.48 (br s, 2H), 3.26 (br d, J = 15.1 Hz, 1H), 2.93 (dd, J = 4.6, 10.5 Hz, 1H), 2.90-2.80 (m, 1H), 2.79-2.64 (m, 2H), 2.42 (s, 3H), 2.02 (t, J = 10.7 Hz, 1H), 1.92 (dtd, J = 3.6, 6.5, 9.8 Hz, 1H), 1.87-1.79 (m, 2H), 1.36-1.15 (m, 1H) + .

[0149] Step 7: Preparation of compound B7-2 and compound B7-3:

[0150]

[0151] B7-1 (1.5 g, 7.41 mmol) was chiral split by prep SFC (SFC chiral split conditions: instrument: Waters SFC350; column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: A: CO2, B: IPA (0.1% NH3H2O); gradient: B%: 50%-50%; flow rate: 200 ml / min; column temperature: 40 °C), the fraction was concentrated under reduced pressure, freeze-dried to obtain yellow oil B7-2 (peak 1, 438 mg, yield: 29.20%) and yellow oil B7-3 (peak 2, 450 mg, yield: 30.00%).

[0152] B7-2: 1 H NMR: (400 MHz, CDC13) δ: 6.32 (s, 1H), 6.22 (s, 1H), 3.88 (d, J = 15.1 Hz, 1H), 3.48 (br s, 2H), 3.26 (br d, J = 15.1 Hz, 1H), 2.93 (dd, J = 4.6, 10.5 Hz, 1H), 2.90-2.80 (m, 1H), 2.79-2.64 (m, 2H), 2.42 (s, 3H), 2.02 (t, J = 10.7 Hz, 1H), 1.92 (dtd, J = 3.6, 6.5, 9.8 Hz, 1H), 1.87-1.79 (m, 2H), 1.36-1.15 (m, 1H)

[0153] MS (ESI): 203.2 [M+H] + .

[0154] B7-3: 1 H 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] + .

[0155] Using different starting materials, the synthesis of similar intermediate B7-1 can obtain intermediates B7-4 to B7-49.

[0156] Table 2. Structural formula of intermediates B7-4 to B7-49

[0157]

[0158]

[0159]

[0160]

[0161] Example 1 2-allyl-1-(6-((dimethyl(oxo)-λ 6 Synthesis of 2-allyl-1-(6-((dimethyl(oxo)-λ

[0162]

[0163] A3-1 (390 mg, 1.0 mmol) was dissolved in DCM (20 mL), m-CPBA (259 mg, 1.5 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that the reaction was complete. The system was washed with saturated sodium bicarbonate solution, the organic phase was dried, and rotary evaporation was carried out. The next step was directly carried out, and ESI-MS m / z: 405.5 [M+H] + .

[0164] The intermediate obtained in the previous step was dissolved in DMF (20 mL) and trifluoroacetic acid (0.3 mL, 4.0 mmol) and B7-1 (242 mg, 1.2 mmol) were added. The reaction was carried out at 80 °C overnight, monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with DCM (50 mL) and washed with water (20 mL*2). The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH = 100 / 1 to 10 / 1) to give compound 1 (72 mg, yield 13.2%) as a light yellow solid.

[0165] 1 H NMR (400 MHz, CDCl3) δ: 8.79 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 9.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 17.4 Hz, 2H), 6.66 (dd, J = 8.0, 0.7 Hz, 1H), 5.63 (ddt, J = 16.6, 10.3, 6.3 Hz, 1H), 5.04-4.97 (m, 1H), 4.89 (dt, J = 6.2, 1.3 Hz, 2H), 3.94 (d, J = 15.2 Hz, 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] + .

[0166] Example 86 (R)-2-allyl-1-(6-((dimethyl(oxo)-λ 6 - sulfone enyl)amino)pyridin-2-yl)-6-((2-methyl-2,3,7,8,9,9a-hexahydro-1H- benzo[de]isoquinolin-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Compound 86)

[0167]

[0168] A3-1 (390 mg, 1.0 mmol) was dissolved in DCM (20 mL) and m-CPBA (259 mg, 1.5 mmol) was added. The reaction was carried out at room temperature for 1 h. After completion of the reaction, the reaction mixture was washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated to dryness. The residue was directly used for the next step. ESI-MS m / z: 405.5 [M+H] + .

[0169] The intermediate obtained in the previous step was dissolved in DMF (20 mL) and trifluoroacetic acid (0.3 ml, 4.0 mmol) and B7-3 (242 mg, 1.2 mmol) were added. The reaction was carried out at 80 °C overnight, monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with DCM (50 mL) and washed with water (20 mL*2). The organic phase was dried and concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH = 100 / 1 to 10 / 1) to give compound 86 (85 mg, yield 15.6%) as a light yellow solid.

[0170] 1 H NMR (400 MHz, CDCl3) δ: 8.79 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 9.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 17.4 Hz, 2H), 6.66 (dd, J = 8.0, 0.7 Hz, 1H), 5.63 (ddt, J = 16.6, 10.3, 6.3 Hz, 1H), 5.04-4.97 (m, 1H), 4.89 (dt, J = 6.2, 1.3 Hz, 2H), 3.94 (d, J = 15.2 Hz, 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] + .

[0171] Example 89 (S)-2-allyl-1-(6-((dimethyl(oxo)-lambda 6 - sulfone enyl)amino)pyridin-2-yl)-6-((2-methyl-2,3,7,8,9,9a-hexahydro-1H- benzo[de]isoquinolin-5-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Compound 89)

[0172]

[0173] A3-1 (390 mg, 1.0 mmol) was dissolved in DCM (20 mL) and m-CPBA (259 mg, 1.5 mmol) was added. The reaction was carried out at room temperature for 1 h. After completion of the reaction, the reaction mixture was washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated to dryness. The residue was directly used for the next step. ESI-MS m / z: 405.5 [M+H] + .

[0174] The intermediate obtained in the previous step was dissolved in DMF (20 mL) and trifluoroacetic acid (0.3 ml, 4.0 mmol) and B7-2 (242 mg, 1.2 mmol) were added. The reaction was carried out at 80 °C overnight, monitored by LC-MS. After the reaction was completed, the reaction mixture was diluted with DCM (50 mL) and washed with water (20 mL*2). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give compound 89 (82 mg, yield 15.0%) as a light yellow solid.

[0175] 1 H NMR (400 MHz, CDCl3) δ: 8.79 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 9.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 17.4 Hz, 2H), 6.66 (dd, J = 8.0, 0.7 Hz, 1H), 5.63 (ddt, J = 16.6, 10.3, 6.3 Hz, 1H), 5.04-4.97 (m, 1H), 4.89 (dt, J = 6.2, 1.3 Hz, 2H), 3.94 (d, J = 15.2 Hz, 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] + .

[0176] Synthesis of compounds 2-85, 87-88, and 90-93

[0177] The target compounds 2-85, 87-88, and 90-111 in Table 3 can be obtained in analogy to the synthesis of compound 1, using intermediates A3-1 to A3-47 and B7-1 to B7-49 as starting materials.

[0178] Structure of compounds 2-85, 87-88, and 90-93 in Table 3

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187] Example 112: Assay of Compound's Inhibition of Wee-1 Enzyme Activity

[0188] After serially diluted compounds and enzymes were mixed, incubated at room temperature (25°C) for 15 minutes, centrifuged at 1000 rpm for 1 minute to mix, and then 5 μL of substrate was added to initiate the reaction. After reacting at room temperature for 60 minutes, 5 μL of ADP-GLO reagent was added, centrifuged at 1000 rpm for 1 minute to mix, and then incubated at room temperature for another 60 minutes. Then, 10 μL of kinase detection reagent was added and incubated for another 60 minutes, followed by chemiluminescence detection. The percentage of enzyme activity inhibited by the compounds was calculated compared to the DMSO group, and the IC50 was then calculated. 50 .

[0189] Table 4. IC50 of the compounds of this invention inhibiting Wee-1 kinase activity 50 (nM)

[0190]

[0191]

[0192] As can be seen from the data in Table 4, the compounds of this invention have a strong inhibitory effect on Wee-1 kinase, such as compounds 1, 31, 87, 88, 89, and 91, which have IC50 values ​​for Wee-1 kinase. 50 The values ​​were all less than 1.5 nM, which was about twice that of the control drug MK-1775.

[0193] Example 113: In vitro antiproliferative activity of the compound against MIA PaCa-2 cells

[0194] 3000 MIA PaCa-2 cells / well were seeded into 384-well plates and allowed to adhere overnight. Then, DMSO or a compound at a maximum concentration of 5 μM, serially diluted 1:5, was added. Cell viability was evaluated by measuring intracellular ATP levels 72 hours after drug addition. The percentage of cell viability inhibition by the compound was calculated compared to the DMSO group, and the IC50 was calculated. 50 The values ​​are shown in Table 5 below.

[0195] Example 114: In vitro antiproliferative activity of the compound in combination with gemcitabine (GMC) against MIA PaCa-2 cells.

[0196] 3000 cells / well MIA PaCa-2 cells were plated in 384-well plates and treated with 20 nM Gemcitabine. After overnight attachment, DMSO or compounds were added at a maximum concentration of 100 nM in 1:5 serial dilutions. Cell survival was assessed by measuring intracellular ATP content 72 hours after drug addition. The percentage of cell survival inhibition by the compounds was calculated compared to the DMSO group and the IC50values were calculated. 50 The results are shown in Table 5 below.

[0197] Table 5 Anti-proliferative activity of the compounds of the present application alone or in combination with GMC on MIA PaCa-2 cells

[0198]

[0199]

[0200] From the data in Table 5, it can be seen that the compounds of the present application have stronger anti-proliferative activity on MIA PaCa-2 cells compared to the control drug MK-1775, and at the same time, the compounds of the present application have stronger combination activity with GMC, for example, the IC50of compound 34 is less than 1 nM. The compounds of the present application have stronger combination activity with GMC, which indicates that they can have better effects in clinical combination with chemotherapeutic drugs. 50

[0201] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the scope of protection of the present application is defined by the appended claims.​

Claims

1. A compound of the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof: ###0001### (1) wherein: m is 0 or 1; B is a partially unsaturated C5-C7 cycloalkyl or a partially unsaturated (5-7 membered) heterocycloalkyl.

2. A compound of the formula (2), an optical isomer thereof, or a pharmaceutically acceptable salt thereof: ###0002### (2) wherein: m is 0 or 1; B is a partially unsaturated C5-C7 cycloalkyl, a partially unsaturated (5-7 membered) heterocycloalkyl, or a 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 of the formula (1A): ###0003### (1A) wherein: m is 0 or 1; n is 1, 2, or 3; X is CH2, O, or S. X 1 and X 2 is independently CH or N; R 1 Ci-C6-alkyl, halogen-substituted Ci-C3-alkyl, C3-C6-cycloalkyl, -CH2(C3-C6)- cycloalkyl, C3-C5-alkenyl or C3-C5-alkynyl; R 2 H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halo-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 R is H or C1-C3 alkyl; A is aryl or heteroaryl, said aryl is phenyl or naphthyl; said heteroaryl is pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, or pyrrolyl; said aryl and heteroaryl can be optionally substituted with 1-3 R 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, CF3-substituted C3-C6 cycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8 C(O)R 7a , -N=S(=NR 8 )R 7a R 7b or pyridinonyl, 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 group, R 8 is H or C1-C3 alkyl, or R 8 and R 7a together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl group; 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: ###0006### ###0007### 11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and a compound of any one of claims 1-10, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient.

12. Use of a compound of any one of claims 1-10, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 11, in the manufacture of a Wee-1 inhibitor. ​ X 1 and X 2 is independently CH or N; R 1 Ci-C6-alkyl, halogen-substituted Ci-C3-alkyl, C3-C6-cycloalkyl, -CH2(C3-C6)- cycloalkyl, C3-C5-alkenyl or C3-C5-alkynyl; R 2 is H, C1-C6alkyl, C3-C6cycloalkyl, deuterated C1-C6alkyl, halogen-substituted C1-C6alkyl, CN-substituted C1-C6alkyl, OH-substituted C1-C6alkyl, C1-C3alkoxy-substituted C1-C6alkyl, C3-C6cycloalkyl-substituted C1-C6alkyl, or (4-7 membered)heterocycloalkyl; R 3 is H or C1-C3alkyl; A is aryl or heteroaryl, said aryl is phenyl or naphthyl; said heteroaryl is pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, or pyrrolyl; said aryl and heteroaryl can be optionally substituted with 1-3 R 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, hydroxyl-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, CF3-substituted C3-C6 cycloalkyl, C1-C6 alkyl-substituted C3-C6 cycloalkyl, C1-C6 alkyl-substituted (3-10 membered)heterocycloalkyl, halogen-substituted (3-10 membered)heterocycloalkyl, hydroxyl-substituted (3-10 membered)heterocycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8 C(O)R 7a , -N=S(=NR 8 )R 7a R 7b , or pyridinonyl, 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 group, R 8 is H or C1-C3 alkyl, or R 8 and R 7a together with the atoms to which they are attached form a (3-10 membered)heterocycloalkyl group; ​ ​ ​ ​ ​ ​ X 1 and X 2 is independently CH or N; R 1 Ci-C6-alkyl, halogen-substituted Ci-C3-alkyl, C3-C6-cycloalkyl, -CH2(C3-C6)- cycloalkyl, C3-C5-alkenyl or C3-C5-alkynyl; R 2 is H, C1-C6alkyl, C3-C6cycloalkyl, deuterated C1-C6alkyl, halogen-substituted C1-C6alkyl, CN-substituted C1-C6alkyl, OH-substituted C1-C6alkyl, C1-C3alkoxy-substituted C1-C6alkyl, C3-C6cycloalkyl-substituted C1-C6alkyl, or (4-7 membered)heterocycloalkyl; A is aryl or heteroaryl, said aryl is phenyl or naphthyl; said heteroaryl is pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, or pyrrolyl; said aryl and heteroaryl can be optionally substituted with 1-3 R 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, CF3-substituted C3-C6 cycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8 C(O)R 7a , -N=S(=NR 8 )R 7a R 7b or pyridinonyl, 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 group, R 8 is H or C1-C3 alkyl, or R 8 and R 7a together with the atoms to which they are attached form a (3-10 membered) heterocycloalkyl group.

4. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R in General Formula (1) or General Formula (2) is Me, Et, 1 ​ 5. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, in the general formula (1) or general formula (2), A is phenyl, pyridyl, pyrimidinyl, or pyrazinyl, which is optionally substituted by 1 to 3 R 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, CF3-substituted C3-C6 cycloalkyl, -NR 7a R 7b , -N=S(O)R 7a R 7b , -P(O)R 7a R 7b , -S(O)2R 7a , -S(O)2NR 7a R 7b , -NR 8 P(O)R 7a R 7b , -NR 8 S(O)2R 7a , -NR 8 C(O)R 7a , -N=S(=NR 8 )R 7a R 7b , or pyridinonyl, 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 group, 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 group.

6. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 5, wherein A is in General Formula (1) or General Formula (2) wherein v is 1, 2, or 3, and each R 6 is independently H, halogen, Me, Et, OMe, 7. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 6, wherein A is in General Formula (1) or General Formula (2).

8. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein in the general formula (1) or general formula (2), is wherein R 2 is H, Me, Et, CD3, 9. The compound, optical isomer thereof, or pharmaceutically acceptable salt thereof according to claim 8, wherein in the general formula (1) or general formula (2), is ​ 11. A pharmaceutical composition, characterized by, ​ ​

Images