WO2023045942A1 - 1,2-dihydro-3h-pyrazole[3,4-d]pyrimidin-3-one compound serving as wee-1 inhibitor - Google Patents

Abstract

Disclosed is a 1,2-dihydro-3H-pyrazole[3,4-d]pyrimidin-3-one compound serving as a Wee-1 inhibitor. Specifically, the present invention relates to a compound as shown in general formula (1) and a preparation method therefor, as well as a use of the compound of general formula (I) and an isomer, crystal forms, a pharmaceutically acceptable salt, a hydrate or a solvent complex in serving as a Wee-1 inhibitor. The compound and the isomer, the crystal forms, the pharmaceutically acceptable salts, the hydrate or the solvent complex can be used for prepare drugs for preparing a drug for treating or preventing diseases associated with a Wee-1 protein kinase.

Description

1,2-Dihydro-3H-pyrazol[3,4-d]pyrimidin-3-one compounds as Wee-1 inhibitors

This application claims the priority of Chinese patent application 202111108819.6 with a filing date of September 22, 2021. This application cites the full text of the above-mentioned Chinese patent application.

technical field

The present invention relates to the field of medicinal chemistry, and more specifically relates to a class of fused ring compounds with Wee1 kinase inhibitory effect, a preparation method thereof, and the use of such compounds in the preparation of drugs for treating or preventing related diseases mediated by Wee1 the use of.

Background technique

Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell resting phase) to the S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (cell division preparation phase) to the M (cell division phase) phase, and the M The spindle checkpoint for the metaphase (middle phase of cell division) to anaphase (late phase of cell division) transition. Wee-1 protein kinase plays an important role in the G2 phase checkpoint. The entry of cells into the M phase depends on the activity of CDK1 kinase. Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr 15 of the CDK1 protein, preventing cells from entering the M phase (cell division phase). Polo kinase kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein, and promotes cells to enter the M phase. It can be seen that the activity of Wee-1 kinase determines the activity of G2 checkpoint, and then regulates the transition from G2 to M phase of cells [Cell Cycle, 2013.12(19): p.3159-64.].

Cell cycle checkpoints are mainly activated after DNA damage and play an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoints arrests the cell cycle and promotes DNA repair. Inhibit the function of the checkpoint, the DNA damage cannot be repaired, and the cell undergoes apoptosis. Compared with normal cells, a variety of tumor cells mainly rely on the activation of G2 checkpoints to repair DNA damage and avoid apoptosis due to the impaired function of the important protein p53 in the G1 phase checkpoint. Therefore, inhibiting the G2 phase checkpoint can selectively kill tumor cells. The important role of Wee-1 kinase activity in the G2 phase 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 unrepaired tumor cells into M2 after DNA damage. period, induce apoptosis [Curr Clin Pharmacol, 2010.5(3):p.186-91.].

Studies have shown that, in addition to its role in the G2 checkpoint, Wee-1 is also involved in DNA synthesis, DNA homology repair, post-translational modification of chromosomal histones and other functions closely related to tumorigenesis and development [J Cell Biol, 2011.194( 4): p.567-79.]. In a large number of tumors including liver cancer, breast cancer, cervical cancer, melanoma and lung cancer [PLoS One, 2009.4(4): p.e5120.; Hepatology, 2003.37(3): p.534-43.; Mol Cancer, 2014.13 :p.72.], Wee-1 expression was greatly increased. The high expression of Wee-1 is positively correlated with the development of tumor and poor prognosis, suggesting that Wee-1 kinase may be involved in the occurrence and development of tumor. Studies on 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 various tumors [Cancer Biol Ther, 2010.9(7): p.514-22.; Mol Cancer Ther, 2009.8(11): p.2992-3000.].

Therefore, the development of specific small-molecule inhibitors of highly active Wee-1 kinase is of great clinical value for tumor therapy, especially targeting tumors with impaired G1 checkpoints such as p53 deletion.

Contents of the invention

The present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (1):

X is CH or N;

R ¹ is -OH or -CN;

R ^1a and R ^1b are each independently -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein (C1 -C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups:- H, -D, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O )NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ; or R ^1a and the carbon atom to which R ^1b is attached together form a (3-7 membered) cycloalkyl group, wherein the (3-7 membered) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R ⁶ , -OR ⁶ , -NR ⁶ R ⁷ and -CN;

R ² is (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C5) alkenyl, (C2-C5) alkynyl or (C3-C6) cycloalkyl, wherein said (C1- C5) alkyl, (C1-C5) haloalkyl, (C2-C5) alkenyl, (C2-C5) alkynyl or (C3-C6) cycloalkyl can each be independently optionally replaced by 1, 2, 3 or 4 The following groups are substituted: -H, -D, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ;

R ³ is (C3-C6) cycloalkyl or (4-6 membered) heterocycloalkyl, wherein said (C3-C6) cycloalkyl or (4-6 membered) heterocycloalkyl can each independently optionally Substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , - NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S (O) ₂ NR ⁶ R ⁷ ;

Each R ⁴ is independently -H, -D, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ , -S(O) ₂ NR ⁶ R ⁷ , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl, wherein ( C1-C6) Alkyl, (C1-C6) Haloalkyl, (C2-C6) Alkenyl, (C2-C6) Alkynyl or (C3-C6) Cycloalkyl can be independently optionally replaced by 1,2,3 Or substituted by 4 of the following groups: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , - CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ; or when 2 R ⁴ are connected on the same atom, 2 R ⁴ form an oxo group; or 2 adjacent R ⁴ and the atom they are connected form together (5-7 yuan) hetero Cycloalkyl or (C3-C6) cycloalkyl, wherein said (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl can be optionally replaced by 1, 2, 3 or 4 of the following groups Substitution: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O )NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ; or the same 2 ^R4 on carbon atoms and the carbon atoms they are connected together form (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (4-7 membered) heterocycloalkyl Or (C3-C6)cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ;

R ⁵ is -H, -(CH ₂ ) _m OR ⁶ , -(CH ₂ ) _m NR ⁶ R ⁷ , (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C6) cycloalkyl , wherein the (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C6) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D , halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ;

R ⁶ and R ⁷ are each independently -H, (C1-C6) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, or R ⁶ and R ⁷ on the same nitrogen atom and The N atoms they are connected together form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group can be optionally substituted by 1, 2, 3 or 4 of the following groups:- H, halogen, ^R8 and ^-OR8 ;

^R is -H, (C1-C6) alkyl or (C3-C6) cycloalkyl; and

p is an integer of 0, 1 or 2, s is an integer of 0, 1, 2, 3 or 4, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.

In another preferred example, in the general formula (1), R ^1a and R ^1b are each independently -H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) Alkenyl or (C3-C5) cycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl can be independently Optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH ₃ , -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -N(CH ₃ ) ₂ and -CN; or R ^1a and R ^1b together form a (3-6 membered) cycloalkyl group with the carbon atoms they are connected to, wherein ( 3-6 membered) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, _-CH3 , -OH, _-OCH3 , -N(CH ₃ ) ₂ and -CN.

In another preferred example, in the general formula (1), the structural unit

for:

preferably

more preferably

In another preferred example, in the general formula (1), R ^is (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkyne group or (C3-C5) cycloalkyl, wherein said (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C5 ) cycloalkyl groups may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, -F, -CN,

In another preference, wherein in the general formula (1), R ² is:

preferably

more preferably

In another preference, wherein in the general formula (1), R ³ is (C3-C6) cycloalkyl or (4-6 membered) heterocycloalkyl, wherein the (C3-C6) cycloalkane or (4-6 membered) heterocycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -OH, -CH ₂ OCH ₃ , -CH ₂ N (CH ₃ ) ₂ , -OCH ₃ , -OCF ₃ , -N(CH ₃ ) ₂ , -CN, -C(O)NH ₂ , -C(O)NH(CH ₃ ), -C(O)N (CH ₃ ) ₂ , -NHC(O)CH ₃ , -N(CH ₃ )-C(O)CH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )-S(O) ₂ CH _3. -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ NH ₂ , -S(O) ₂ NH(CH ₃ ), -S(O) ₂ N(CH ₃ ) ₂ ,

In another preference, wherein in the general formula (1), R ³ is:

preferably

more preferably

In another preferred example, in the general formula (1), each R ⁴ is independently -H, -D, -F, -Cl, -Br, -I, R ⁶ , -OH, -( CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -SR ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ NR ⁶ R ⁷ , (C1-C3) alkyl, (C1-C3) haloalkane (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4 )alkenyl, (C2-C4)alkynyl or (C3-C6)cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br , -I, -CH ₃ , -OH, -OCH ₃ , -N(CH ₃ ) ₂ and -CN; or when two R ⁴ are connected to the same atom, two R ⁴ can form an oxo group ; or 2 adjacent R ⁴ and their connected atoms can jointly form (5-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (5-6 membered) heterocycloalkane or (C3-C6)cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH ₃ , -OH, - CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -N(CH ₃ ) ₂ and -CN; or two R ⁴ on the same carbon atom together with the carbon atom they are connected to (4-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (4-6 member) heterocycloalkyl or (C3-C6) cycloalkyl can be optionally replaced by 1,2, Substituted by 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH ₃ , -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -N(CH ₃ ) ₂ and -CN.

In another preferred example, in the general formula (1), each R ⁴ is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH ₂ OCH _3. -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -OCF ₃ , -N(CH ₃ ) ₂ , -CN, -C(O)NH ₂ , -C(O)NH(CH ₃ ), -C(O)N(CH ₃ ) ₂ , -NHC(O)CH ₃ , -N(CH ₃ )-C(O)CH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )- S(O) ₂ CH ₃ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ NH ₂ , -S(O) ₂ NH(CH ₃ ), -S(O) ₂ N( CH ₃ ) ₂ 、

Or 2 R ⁴ on the same carbon atom together with the carbon atom they are connected to form

Each ^R4 is preferably -H, -D or -F; more preferably -H.

In another preferred example, in the general formula (1), R ⁵ is -H, -(CH ₂ ) ₂ OR ⁶ , -(CH ₂ ) ₂ NR ⁶ R ⁷ , (C1-C3)alkyl , (C1-C3) haloalkyl or (C3-C6) cycloalkyl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl can be independently optionally Substitution by 1, 2, 3 or 4 of the following groups: -H, -D, -F, -OH, -CH ₃ , -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ ,

-OCF ₃ , -CH ₂ N(CH ₃ ) ₂ , -(CH ₂ ) ₂ N(CH ₃ ) ₂ , -N(CH ₃ ) ₂ and -CN.

In another preferred example, in the general formula (1), R ⁵ is: -H, -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₂ OH, -(CH ₂ ) ₂ N(CH ₃ ) ₂ ,

preferably

more preferably

more preferably

In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:

Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.

Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Use for preparing medicines for treating, regulating or preventing diseases related to Wee-1 protein. Wherein, said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.

Another object of the present invention is also to provide a method for treating, regulating or preventing diseases related to Wee-1 protein, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of them Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.

By synthesizing and carefully studying a variety of new compounds related to Wee-1 inhibitory effect, the inventors found that among the compounds of general formula (1), the compound unexpectedly has strong Wee-1 inhibitory activity.

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.

compound synthesis

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

The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.

In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared using the following general reaction scheme 1:

General reaction scheme 1

Compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R ¹ , R ^1a , R ^1b , R ² , R ³ , R ⁴ , R ⁵ , X and s are as defined above, H represents hydrogen, N represents Nitrogen, Z represents chlorine, bromine or iodine, S represents sulfur, and O represents oxygen. As shown in general reaction scheme 1, compounds 1-1 and 1-2 undergo a substitution reaction under basic conditions to generate compound 1-3, compound 1-3 generates compound 1-4 under acidic conditions, and compound 1-4 generates compound 1-4 under alkaline conditions. Reaction under neutral conditions generates 1-5, compound 1-5 reacts with compound 1-6 to generate compound 1-7 under alkaline condition, compound 1-7 reacts with m-CPBA to generate compound 1-8, compound 1-8 and 1-9 undergoes a substitution reaction to generate the target compound 1-10.

Further forms of compounds

"Pharmaceutically acceptable" here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.

The term "pharmaceutically acceptable salt" refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound. In some specific aspects, the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other 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 and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.

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

In other embodiments, compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually 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 crystal form to predominate.

In another aspect, the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur. Each chiral center or axial chirality will independently give rise to 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 unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

the term

Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.

Unless otherwise specified, "alkyl" means a saturated aliphatic hydrocarbon group, 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, especially 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 ^tBu .

Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including 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 an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. A lower alkynyl group having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, is preferred.

Unless otherwise specified, "cycloalkyl" means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl". Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.

Unless otherwise specified, "heterocycloalkyl" means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl 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 be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included in 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 piperidine, morpholine, azepine or Benzo derivatives such as thienyl. A heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring. Examples of heterocycloalkyl 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, pyrrole Alkyl, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butane Amide group, valerolactam group, imidazolinone group, hydantoin group, dioxolan group, phthalimide group, pyrimidine-2,4(1H,3H)-dione group, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , pyridonyl, 3-pyrrolinyl, thiopyranyl, pyroneyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,

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

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

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a single bond.

When one of the variables is selected from a chemical bond, it means that the two groups connected are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.

The term "membered ring" includes any ring structure. The term "member" is meant to indicate the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl 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 molecules.

Unless otherwise noted, keys with wedge-shaped solid lines

and dotted wedge keys

Indicates the absolute configuration of a stereocenter, with a straight solid line bond

and straight dashed keys

Indicates the relative configuration of the stereocenter, with a wavy line

Indicates wedge-shaped solid-line bond

or dotted wedge key

or with tilde

Indicates a straight solid line key

or straight dotted key

Unless otherwise specified, use

Indicates a single or double bond.

Certain pharmaceutical and medical terms

The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.

The term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom. As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.

"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers. The asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to 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 "medicine or medicament" are used interchangeably herein and refer to In animals), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

The term "administered, administering, or administration" as used herein means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. 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 mean, as considered by those skilled in the art. Except for experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein should be understood to be Those) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood as the number of significant digits indicated plus the usual rounding method.

Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.

therapeutic use

The compound or pharmaceutical composition of the general formula (1) of the present invention can generally be used to inhibit Wee-1 kinase, and thus can be used to treat one or more diseases related to Wee-1 kinase activity. Therefore, in certain embodiments, the present invention provides a method for treating a Wee-1 kinase-mediated disorder, the method comprising administering a compound of general formula (1) of the present invention, or a pharmaceutical agent thereof, to a patient in need thereof. steps on an acceptable composition.

In some embodiments, there is provided a method for treating cancer, the method comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof. In some embodiments, the compound of general formula (1) can be used in combination with other cancer treatment drugs. In some embodiments, the compound of general formula (1) can be used in combination with Gemcitabine. In some embodiments, wherein the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative syndrome) and solid tumors (cancer such as prostate , breast, lung, colon, pancreas, kidney, ovary, soft tissue cancer and osteosarcoma, and stromal tumors) etc.

Route of administration

The compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts . Wherein, "safe and effective amount" means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. The safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.

"Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity . "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

When the compounds of the present invention are administered, they can 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 extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain 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, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and 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 non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention 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 present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

Detailed ways

In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions will be described in detail, so that the content of the present invention will become very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined in the present application.

In all the examples, ¹ H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.

The present invention adopts the following abbreviations: Ac ₂ O represents acetic anhydride; (Boc) ₂ O represents di-tert-butyl dicarbonate; CDCl ₃ represents deuterated chloroform; Cs ₂ CO ₃ represents cesium carbonate; EtOAc represents ethyl acetate; Hexane stands for n-hexane; HPLC stands for high performance liquid chromatography; MeCN stands for acetonitrile; DCM stands for dichloromethane; DIPEA stands for diisopropylethylamine; Dioxane stands for 1,4-dioxane; DMF stands for N,N-di Methylformamide; DMP stands for Dess-Martin oxidant; DMAP stands for 4-(dimethylamino)pyridine; DMSO stands for dimethylsulfoxide; EtOH stands for ethanol; EtMgBr stands for ethylmagnesium bromide; Alcohol; _min stands for minute; _K2CO3 stands for potassium carbonate; KOAc stands for potassium acetate; KOH stands for potassium _hydroxide ; _K3PO4 stands for potassium phosphate; min stands for minute; MeOH stands for methanol; MeMgBr stands for methylmagnesium bromide; MS MsOH stands for methanesulfonic acid; m-CPBA stands for m-chloroperoxybenzoic acid; n-BuLi stands for n-butyllithium; NMR stands for nuclear magnetic resonance; NIS stands for iodosuccinimide; Pd/C stands for palladium on carbon ; Pd(PPh ₃ ) ₄ represents tetrakistriphenylphosphine palladium; Pd ₂ (dba) ₃ represents tris(dibenzylideneacetone) dipalladium (0); Pd(dppf)Cl ₂ represents [1,1'-bis (Diphenylphosphine)ferrocene]palladium(II) dichloride; PE represents petroleum ether; POBr ₃ represents phosphorus oxybromide; POCl ₃ represents phosphorus oxychloride; TEA represents triethylamine; TFA represents trifluoroacetic acid ; T ₃ P represents 1-propyl phosphoric anhydride; XantPhos represents 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; TfOH represents trifluoromethanesulfonic acid; TLC represents thin-layer chromatography; XPhos Represents 2-dicyclohexylphosphorus-2′,4′,6′-triisopropylbiphenyl.

Synthesis of Preparation Example 1 Intermediate A-1

Step 1: the synthesis of compound int_A-1-2:

Int_A-1-1 hydrochloride (10.0 g, 46.10 mmol) was dissolved in TfOH (50.0 mL), and NIS (15.7 g, 69.88 mmol) was added under nitrogen protection at 0°C. The reaction was stirred at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Cool the reaction solution to room temperature, pour the reaction solution into ice water, adjust the pH value to 8-9 with dilute NaOH solution, filter to obtain a black solid int_A-1-2 (14g, 46.0mmol, crude product), the crude product can be used directly react in the next step.

ESI-MS m/z: 305 [M+H] ⁺ .

Step 2: the synthesis of compound int_A-1-3:

Int_A-1-2 (14.0 g, 46.0 mmol), (Boc) ₂ O (25.1 g, 115 mmol, 26.4 mL) was dissolved in DCM (200 mL), and TEA (14.0 g, 138 mmol, 19.2 mL) was added at room temperature. The reaction was stirred at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Water (100 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (150 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product (1.1 mg, crude product). The crude product was preparatively purified by column chromatography (SiO ₂ , EtOAc/PE=0/1-1/9) to obtain a white solid (10 g, yield: 53.7%).

ESI-MS m/z: 349 [M+H] ⁺ .

Step 3: Synthesis of compound int_A-1-5:

Int_A-1-3 (3.00g, 7.42mmol), int_A-1-4 (3.19g, 37.1mmol), cesium carbonate (4.84g, 14.8mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (606mg , 742umol) was dissolved in 1,4-dioxane (40mL) and water (4mL), under argon protection, heated to 100°C and stirred for 5 hours. LC-MS monitoring showed the reaction was complete. The reaction solution was spin-dried, and the crude product was prepared and purified by column chromatography (SiO ₂ , EtOAc/PE=0/1-1/9) to obtain a white solid (1.4 g, yield: 59.3%). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.95(d, J=2.0Hz, 1H), 7.62(d, J=2.3Hz, 1H), 4.62(br s, 2H), 3.63(br t, J＝5.9Hz, 2H), 2.98(t, J＝5.9Hz, 2H), 2.04-1.94(m, 1H), 1.47-1.35(m, 9H), 1.05-0.93(m, 2H), 0.74-0.62 (m,2H).

Step 4: Synthesis of compound int_A-1-6:

Dissolve int_A-1-5 (1 g, 3.14 mmol) in dichloromethane (100 mL), add trifluoroacetic acid (20 mL), and react at room temperature for 2 hours. LC-MS monitoring shows that the reaction is complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid (680 mg, crude product). The crude product can be directly used in the next reaction.

ESI-MS m/z: 219 [M+H] ⁺ .

Step 5: Synthesis of compound int_A-1-7:

Dissolve int_A-1-6 (680mg, 3.12mmol) and DIPEA (805mg, 6.23mmol) in dichloromethane (2mL) and methanol (20mL), add aqueous formaldehyde (37-40%, 1mL) and sodium acetate borohydride (1.32g, 6.23mmol), reacted at room temperature for 1 hour, monitored by LC-MS, and the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid product (575 mg, yield: 79.3%).

ESI-MS m/z: 233 [M+H] ⁺ .

Step 6: Synthesis of compound int_A-1:

int_A-1-7 (500mg, 2.15mmol) and palladium on carbon (50mg, 10% purity) were suspended in methanol (25mL), and reacted at 25°C for 5 hours under hydrogen pressure (25psi). Palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, and column chromatography gave a solid (418 mg, yield: 96%).

1H NMR(400MHz,DMSO)δ6.06(s,2H),4.67(s,2H),3.29(s,2H),2.71(t,J＝6.0Hz,2H),2.55(t,J＝6.0Hz , 2H), 2.28(s, 3H), 1.72(tt, J=8.4, 5.3Hz, 1H), 0.88–0.75(m, 2H), 0.53–0.37(m, 2H).

MS (ESI): 203 [M+H] ⁺ .

Preparation 2-13 Synthesis of intermediates A-2 to A-13

Using the above synthesis method and using different raw materials, the target intermediates A-2 to A-13 in Table 1 can be obtained.

Table 1

Synthesis of Preparation Example 14 Intermediate B-1

Step 1: Synthesis of Compound B-1:

Dissolve int_B-1-1 (10g, 42.2mmol) in tetrahydrofuran (10mL), and add n-butyl lithium (1.6M, 26.3mL, 42.2mmol) at -78°C under nitrogen protection. The mixture was reacted at -78°C for 30 minutes, and acetone (3.67 g, 63.3 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was reacted at -78°C for 1 hour, and then raised to room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate (150 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (0.44 g, yield: 38.9%). The crude product can be directly used in the next reaction.

¹ H NMR (CHLOROFORM-d) δ: 7.52-7.59 (m, 1H), 7.33-7.40 (m, 2H), 4.05 (br.s., 1H), 1.55 (s, 6H).

MS (ESI): 216 [M+H] ⁺ .

Synthesis of Preparation Example 15-18 Intermediate B-2 to B-5

Using the above synthesis method and using different raw materials, the target intermediates B-2 to B-5 in Table 2 can be obtained.

Table 2

The synthesis of embodiment 1 compound 1

Step 1: Synthesis of compound int_1-3

Dissolve int_1-1 (13.5g, 58.06mmol), int_1-2 (10g, 58.06mmol), DIPEA (18.72g, 145.16mmol) in THF (300mL), heat and reflux overnight, monitor by LC-MS, the reaction is complete , the reaction solution was concentrated, the residue was dissolved in ethyl acetate (200 mL), the organic phase was washed with water (150 mL), saturated brine (100 mL), dried, and concentrated to obtain a yellow oil (21 g, yield 98%).

MS (ESI): 369 [M+H] ⁺ .

Step 2: Synthesis of compound int_1-4

Dissolve int_1-3 (21 g, 57 mmol) in DCM (70 mL), add TFA (70 mL), react overnight at room temperature, and monitor by LC-MS, the reaction is complete. Concentrate directly, dissolve the residue with EtOH (120mL), add aqueous sodium hydroxide solution (6M, 66mL) dropwise under ice bath, after the dropwise addition is completed, stir at room temperature for 1 hour, monitor by LC-MS, after the reaction is completed, the reaction solution is directly concentrated, The residue was subjected to column chromatography (DCM/MeOH=100/1 to 10/1) to obtain a yellow solid (10 g, yield 79%). MS (ESI): 223 [M+H] ⁺ .

Step 3: Synthesis of compound int_1-5

Int_1-4 (2.5g, 10mmol), B-1 (2.16g, 10mmol), CuI (1.9g, 10mmol), K ₂ CO ₃ (2.07g, 15mmol), N,N'-dimethylethylene di Amine (970mg, 11mmol) was dissolved in dioxane (100mL), under argon protection, the temperature was raised to 80°C and reacted overnight, monitored by LC-MS, after the reaction was completed, filtered, the filtrate was concentrated, and the residue was subjected to column chromatography (DCM/MeOH=100/ 1 to 20/1) gave a pale yellow solid (2 g, 57% yield).

MS (ESI): 358 [M+H] ⁺ .

Step 4: Synthesis of compound int_1-6:

Dissolve int_1-5 (357 mg, 1.0 mmol) in DCM (20 mL), add m-CPBA (305 mg, 1.5 mmol, 85%), and react at room temperature for 1 hour. LC-MS monitoring showed that the reaction was complete, the system was washed with saturated sodium bicarbonate solution, the organic phase was dried, and spin-dried to obtain a crude product (360 mg, yield 96%), which could be directly used in the next reaction.

MS (ESI): 374 [M+H] ⁺ .

Step 5: Synthesis of compound 1:

Dissolve int_1-6 (360mg, 0.96mmol) in DMF (20mL), add trifluoroacetic acid (0.3mL, 4.0mmol), A-1 (242mg, 1.2mmol), react overnight at 80°C, monitor by LC-MS, The reaction is complete. Add DCM (50mL) to dilute, wash with water (20mL*2), dry the organic phase, and spin dry under reduced pressure. The residue is subjected to silica gel column chromatography (DCM/MeOH=100/1 to 10/1) to obtain a light yellow solid compound (80 mg, yield 16.2%).

MS (ESI): 512 [M+H] ⁺ .

The synthesis of embodiment 2-28 compound 2-28

Using the above synthesis method and using different raw materials (different intermediates A, different intermediates B and other different intermediates), the target compounds 2-28 in Table 3 can be obtained.

table 3

Example 29 Compound of the present invention inhibits recombinant protein Wee-1 enzyme activity test in vitro

The inhibitory effect of compounds on the enzyme activity of recombinant protein Wee-1 was determined by HTRF method.

DMSO or serially diluted compound (up to 200nM, 1:5 serial dilution) and recombinant protein were incubated in kinase buffer at 37°C for 30 minutes, after adding Fluorescein-PolyGAT and ATP, the substrate was added to start the reaction. After reacting at room temperature for 90 minutes, add the antibody and detection solution, continue to incubate at room temperature for 60 minutes, and read the fluorescence value (excitation wavelength: 340nm, emission wavelength: 495nm and 520nm. Calculate the ratio of fluorescence intensity at 520nm/495nm, compare with the DMSO group, and then Compound inhibition percentages and _IC50 were calculated. Results are shown in Table 4 below.

Table 4. The inhibitory activity of the compounds of the present invention on recombinant protein Wee-1 (IC ₅₀ , nM)

compound	IC50	compound	IC50	compound	IC50	compound	IC50
1	+++	2	+++	3	+++	4	+++
5	+++	6	+++	7	+++	8	+++
9	+++	10	+++	11	+++	12	+++
13	+++	14	+++	15	+++	16	+++
17	+++	18	+++	19	+++	20	+++

twenty one	+++	twenty two	+++	twenty three	+++	twenty four	+++
25	+++	26	+++	27	+++	28	+++

+++ means IC ₅₀ less than or equal to 10nM

++ indicates an _IC50 of 10nM to 50nM

+ means _IC50 greater than 50nM

It can be seen from the data in Table 4 that the compounds of the present invention have better inhibitory activity on the enzyme activity of the recombinant protein Wee-1.

Embodiment 30 Compounds of the present invention combined with gemcitabine (Gemcitabine) to MIA PaCa-2 cells in vitro anti-proliferative activity

3000/well MIA PaCa-2 cells were plated in 384-well plates and 20nM Gemcitabine was added. After overnight attachment, DMSO or the compound with the highest concentration of 100nM was added in a 1:5 gradient dilution. 72 hours after adding the drug, the cell survival was evaluated by measuring the ATP content in the cells. Compared with the DMSO group, the percentage of inhibition of cell survival by the compound was calculated, and then the _IC50 value was calculated. The results are shown in Table 5 below.

Table 5 Compounds of the present invention combined with gemcitabine (Gemcitabine) to the in vitro antiproliferative activity of MIA PaCa-2 cells

From the data in Table 5, it can be seen that the compound of the present invention combined with gemcitabine (Gemcitabine) has strong in vitro anti-proliferation activity on MIA PaCa-2 cells.

Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (15)

1. A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

   

   In general formula (1):

   X is CH or N;

   R ¹ is -OH or -CN;

   R ^1a and R ^1b are each independently -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein (C1 -C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C3-C6)cycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups:- H, -D, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O )NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ; or R ^1a and the carbon atom to which R ^1b is attached together form a (3-7 membered) cycloalkyl group, wherein the (3-7 membered) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R ⁶ , -OR ⁶ , -NR ⁶ R ⁷ and -CN;

   R ² is (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C5) alkenyl, (C2-C5) alkynyl or (C3-C6) cycloalkyl, wherein said (C1- C5) alkyl, (C1-C5) haloalkyl, (C2-C5) alkenyl, (C2-C5) alkynyl or (C3-C6) cycloalkyl can each be independently optionally replaced by 1, 2, 3 or 4 The following groups are substituted: -H, -D, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ;

   R ³ is (C3-C6) cycloalkyl or (4-6 membered) heterocycloalkyl, wherein said (C3-C6) cycloalkyl or (4-6 membered) heterocycloalkyl can each independently optionally Substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , - NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S (O) ₂ NR ⁶ R ⁷ ;

   Each R ⁴ is independently -H, -D, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ , -S(O) ₂ NR ⁶ R ⁷ , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl, wherein ( C1-C6) Alkyl, (C1-C6) Haloalkyl, (C2-C6) Alkenyl, (C2-C6) Alkynyl or (C3-C6) Cycloalkyl can be independently optionally replaced by 1,2,3 Or substituted by 4 of the following groups: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , - CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ; or when 2 R ⁴ are connected on the same atom, 2 R ⁴ form an oxo group; or 2 adjacent R ⁴ and the atom they are connected form together (5-7 yuan) hetero Cycloalkyl or (C3-C6) cycloalkyl, wherein said (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl can be optionally replaced by 1, 2, 3 or 4 of the following groups Substitution: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O )NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ; or the same 2 ^R4 on carbon atoms and the carbon atoms they are connected together form (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (4-7 membered) heterocycloalkyl Or (C3-C6)cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ;

   R ⁵ is -H, -(CH ₂ ) _m OR ⁶ , -(CH ₂ ) _m NR ⁶ R ⁷ , (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C6) cycloalkyl , wherein the (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C6) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D , halogen, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -S(O) _p R ⁶ and -S(O) ₂ NR ⁶ R ⁷ ;

   R ⁶ and R ⁷ are each independently -H, (C1-C6) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, or R ⁶ and R ⁷ on the same nitrogen atom and The N atoms they are connected together form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group can be optionally substituted by 1, 2, 3 or 4 of the following groups:- H, halogen, ^R8 and ^-OR8 ;

   R ^is -H, (C1-C6) alkyl or (C3-C6) cycloalkyl; and

   p is an integer of 0, 1 or 2, s is an integer of 0, 1, 2, 3 or 4, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.
2. The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ^1a and R ^1b are independently is -H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl or (C3-C5) cycloalkyl, wherein said (C1-C3) alkyl, ( C1-C3)haloalkyl, (C2-C4)alkenyl or (C3-C5)cycloalkyl can each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, -F , -Cl, -Br, -I, -CH ₃ , -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -N(CH ₃ ) ₂ and -CN; or R ^1a and R ^1b together form a (3-6 membered) cycloalkyl group with the carbon atom to which they are attached, wherein the (3-6 membered) cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups : -H, -F, -Cl, -Br, -I, -CH ₃ , -OH, -OCH ₃ , -N(CH ₃ ) ₂ and -CN.
3. The compound according to any one of claims 1-2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structure unit

   

   for:

   

   

   preferably

   

   

   

   more preferably

   
4. The compound according to any one of claims 1-3 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ² is (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C5) cycloalkyl, wherein said (C1-C4 ) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C5) cycloalkyl can be independently optionally replaced by 1, 2, 3 or 4 The following groups are substituted: -H, -D, -F, -CN,

   

   
5. The compound as claimed in claim 4 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ² is:

   

   

   

   preferably

   

   more preferably

   
6. The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ³ is (C3-C6) cycloalkyl or (4-6 member) heterocycloalkyl, wherein said (C3-C6) cycloalkyl or (4-6 member) heterocycloalkyl can be independently optionally Substitution by 1, 2, 3 or 4 of the following groups: -H, -F, -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH 3 , -OCF _{3 ,} -N(CH ₃ ) ₂ , -CN, -C(O)NH ₂ , -C(O)NH(CH ₃ ), -C(O)N(CH ₃ ) ₂ , -NHC(O)CH ₃ , -N(CH ₃ ) -C(O)CH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )-S(O) ₂ CH ₃ , -SCH ₃ , -S(O) ₂ CH ₃ , -S( O) ₂ NH ₂ , -S(O) ₂ NH(CH ₃ ), -S(O) ₂ N(CH ₃ ) ₂ ,

   

   
7. The compound as claimed in claim 6 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ³ is:

   

   

   

   preferably

   

   

   more preferably

   

   
8. The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each Each R ⁴ is independently -H, -D, -F, -Cl, -Br, -I, R ⁶ , -OH, -(CH ₂ ) _n OR ⁶ , -(CH ₂ ) _n NR ⁶ R ⁷ , -OR ⁶ , -NR ⁶ R ⁷ , -CN, -C(O)NR ⁶ R ⁷ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -SR ⁶ , -S (O) ₂ R ⁶ , -S(O) ₂ NR ⁶ R ⁷ , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) ring The alkyl groups can each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, _-CH3 , -OH, _-OCH3 , -N( CH ₃ ) ₂ and -CN; or when 2 R ⁴ are connected to the same atom, 2 R ⁴ form an oxo group; or 2 adjacent R ⁴ form together with the atoms they are connected to (5 -6 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein said (5-6 member) heterocycloalkyl or (C3-C6) cycloalkyl can be optionally replaced by 1, 2, 3 or Substituted by 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH ₃ , -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , - N(CH ₃ ) ₂ and -CN; or two R ⁴ on the same carbon atom and the carbon atoms they are connected together form a (4-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl, Wherein the (4-6 membered) heterocycloalkyl or (C3-C6) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br , -I, -CH ₃ , -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -N(CH ₃ ) ₂ and -CN.
9. The compound as claimed in claim 8 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R ⁴ is independently : -H, -D, -F, -Cl, -Br, -I, -OH, -CH ₂ OCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OCH ₃ , -OCF ₃ , -N(CH ₃ ) ₂ , -CN, -C(O)NH ₂ , -C(O)NH(CH ₃ ), -C(O)N(CH ₃ ) ₂ , -NHC(O)CH ₃ , -N(CH ₃ ) -C(O)CH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )-S(O) ₂ CH ₃ , -SCH ₃ , -S(O) ₂ CH ₃ , -S( O) ₂ NH ₂ , -S(O) ₂ NH(CH ₃ ), -S(O) ₂ N(CH ₃ ) ₂ ,

   

   

   Or 2 R ⁴ on the same carbon atom together with the carbon atom they are connected to form

   

   Each ^R4 is preferably -H, -D or -F; more preferably -H.
10. The compound according to any one of claims 1-9 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ⁵ is -H, -(CH ₂ ) ₂ OR ⁶ , -(CH ₂ ) ₂ NR ⁶ R ⁷ , (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, Wherein said (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D , -F, -OH, -CH ₃ , -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ ,

    

    -OCF ₃ , -CH ₂ N(CH ₃ ) ₂ , -(CH ₂ ) ₂ N(CH ₃ ) ₂ , -N(CH ₃ ) ₂ and -CN.
11. The compound as claimed in claim 10 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ⁵ is: -H, -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₂ OH, -(CH ₂ ) ₂ N(CH ₃ ) ₂ ,

    

    

    preferably

    

    more preferably

    

    more preferably

    
12. The compound according to any one of claims 1-11 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), wherein The compound has one of the following structures:

    

    
13. A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-12, or its isomers, crystal forms, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
14. A compound as described in any one of claims 1-12, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the drug as claimed in claim 13 Use of the composition in preparing medicines for treating or preventing related diseases mediated by Wee-1.
15. The use according to claim 14, wherein said disease is cancer, and said cancer is hematological cancer and solid tumor.