Fused ring compounds as Wee-1 inhibitors, methods for their preparation and their use

Abstract

The present invention discloses fused cyclic compounds as Wee-1 inhibitors, their preparation method and their use. Specifically, the present invention relates to a compound of general formula (1), its preparation method and the use of the compound of general formula (1) or its isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate as Wee-1 inhibitors in the preparation of antitumor drugs. [Formula 1] TIFF2024515318000066.tif39168

Description

[Technical field]

[0001] This application claims priority to Chinese Application No. 202110485597.3, filed on April 30, 2021, which is incorporated by reference in its entirety herein.

[0002] The present invention relates to the field of pharmaceutical chemistry, in particular to compounds having Wee-1 kinase inhibitory activity, a process for their preparation and the use of such compounds in the preparation of antitumor drugs. [Background technology]

[0003] Wee-1 protein kinase is an important negative control protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 checkpoint, which transitions from the G1 phase (gap 1 phase) to the S phase (DNA synthesis phase), the G2 checkpoint, which transitions from the G2 phase (gap 2 phase) to the M phase (mitosis phase), and the spindle checkpoint, which transitions from mid-phase to late phase of the M phase. Wee-1 protein kinase plays an important role in the G2 checkpoint. The start of the M phase depends on CDK1 kinase activity, and Wee-1 phosphorylates Tyr15 of the CDK1 protein to inhibit CDK1 activity and prevent cells from transitioning to the M phase. On the other hand, polo kinase phosphorylates Wee-1 to activate the degradation of the Wee-1 protein, promoting the transition of cells to the M phase. Thus, the kinase activity of Wee-1 determines the activity of the G2 checkpoint, thereby regulating the transition of cells from the G2 phase to the M phase.

[0004] Cell cycle checkpoints are mainly activated after DNA damage and play an important role in repairing DNA in cells. When cell cycle checkpoints are activated normally, the cell cycle is inhibited and DNA repair is promoted. When the checkpoint function is inhibited, DNA damage cannot be repaired and cells undergo apoptosis. Compared with normal cells, various tumor cells mainly rely on activation of the G2 checkpoint to repair DNA damage and avoid apoptosis due to the decreased function of p53 protein, an important protein at the G1 checkpoint. Therefore, tumor cells can be selectively killed by inhibiting the G2 checkpoint. The important role of Wee-1 kinase activity in the G2 checkpoint suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibiting Wee-1 activity induces tumor cells that cannot be repaired after DNA damage to transition to the M phase and induce apoptosis.

[0005] In addition to its role in the G2 checkpoint, studies have shown that Wee-1 is involved in functions closely related to tumor initiation and progression, such as DNA synthesis, DNA homologous repair, and post-translational modification of chromosomal histones. Wee-1 expression is highly increased in many tumors, including liver cancer, breast cancer, cervical cancer, melanoma, and lung cancer. High expression of Wee-1 is positively correlated with tumor progression or poor prognosis, suggesting that Wee-1 kinase may be involved in tumor initiation and progression. Studies using in vitro cell models and in vivo animal models have shown that inhibition of Wee-1 activity while inducing DNA damage can significantly inhibit the growth of various tumors.

[0006] Therefore, the development of specific and highly active small molecule inhibitors of Wee-1 kinase would be of significant clinical value for tumor therapy, especially those targeting tumors with compromised G1 checkpoints, such as p53 deletions.

[0007] Currently, AstraZeneca's Wee-1 inhibitor AZD-1775 (MK-1775, Adavosertib) has entered the clinical phase II stage, and more than 30 clinical trials are underway. Patents related to AZD-1775 include U.S. Patent Application Publication No. 20070254892, International Publication No. 2007126122, European Patent Application Publication No. 2213673, International Publication No. 2008133866, and International Publication No. 2011034743. Abbott and Abbvie are also conducting research on Wee-1 inhibitors. Related patents include mainly U.S. Patent Application Publication No. 2012220572, International Publication No. 2013126656, International Publication No. 2013012681, International Publication No. 2013059485, International Publication No. 2013013031, etc. Almac's patents related to Wee-1 inhibitors include International Publication No. 2014167347, International Publication No. 2015019037, International Publication No. 2015092431, International Publication No. 2018011570, International Publication No. 2018062932, International Publication No. 2019138227, etc. Girafpharma's patents related to Wee-1 include International Publication No. 2019074979 and International Publication No. 2019074981, etc. Zeno's patents relevant to his Wee-1 work include WO 2018028008 and WO 2019173082. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US Patent Application Publication No. 20070254892 [Patent Document 2] International Publication No. 2007126122 [Patent Document 3] European Patent Application Publication No. 2213673 [Patent Document 4] International Publication No. 2008133866 [Patent Document 5] International Publication No. 2011034743 [Patent Document 6] US Patent Application Publication No. 2012220572 [Patent Document 7] International Publication No. 2013126656 [Patent Document 8] International Publication No. 2013012681 [Patent Document 9] International Publication No. 2013059485 [Patent Document 10] International Publication No. 2013013031 [Patent Document 11] International Publication No. 2014167347 [Patent Document 12] International Publication No. 2015019037 [Patent Document 13] International Publication No. 2015092431 [Patent Document 14] International Publication No. 2018011570 [Patent Document 15] International Publication No. 2018062932 [Patent Document 16] International Publication No. 2019138227 [Patent Document 17] International Publication No. 2019074979 [Patent Document 18] International Publication No. 2019074981 [Patent Document 19] International Publication No. 2018028008 [Patent Document 20] International Publication No. 2019173082 Summary of the Invention [Problem to be solved by the invention]

[0009] The Wee-1 inhibitors under investigation have the problem that they have poor therapeutic effects when used alone, and the cell activity is not strong enough when combined with other chemotherapy drugs, so the combined effect in clinical practice is not ideal. Drug resistance usually occurs in the later stages of targeted therapy, and chemotherapy has become a common method of treating advanced tumors. Chemotherapy drugs alone often cause significant side effects and patients have low drug tolerance, so it is of great significance to invent a Wee-1 inhibitor that has excellent combined effect with chemotherapy drugs. [Means for solving the problem]

[0010] (overview) The present invention provides a compound of general formula (1), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In general formula (1), m is 0 or 1; R 1 is H or a halogen, R 2 is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogenated 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- to 7-membered heterocycloalkyl; R 3 is H or C1-C3 alkyl, A is aryl or heteroaryl, wherein the aryl and the heteroaryl are each selected from 1 to 3 R 6 , each R 6are independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, OH-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halogenated 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)NR 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, where 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 nitrogen, sulfur, or phosphorus atom to which they are attached form a 3- to 10-membered heterocycloalkyl; R 8 is H or C1-C3 alkyl, or R 8 and R 7a together with the nitrogen and sulfur atoms or the nitrogen and carbon atoms bound thereto form a 3- to 10-membered heterocycloalkyl; B is a partially unsaturated C5-C7 cycloalkyl or a partially unsaturated 5-7 membered heterocycloalkyl.

[0011] In some embodiments of the present invention, in general formula (1), [ka] teeth, [ka] where R 2 H, Me, Et, CD3, [ka] It is.

[0012] In some embodiments of the present invention, in general formula (1), [ka] teeth, [ka] TIFF2024515318000008.tif29168, Preferably, [ka] It is.

[0013] In some embodiments of the present invention, general formula (1) has the structure of general formula (1A): [ka] wherein in general formula (1A): n is 1, 2 or 3; X is CH, O or S; m, A, R 1 and R 2 is as defined above.

[0014] In some embodiments of the present invention, in the general formula (1) or the general formula (1A), A is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl, and the phenyl, the pyridinyl, the pyrimidinyl, and the pyrazinyl are each independently selected from 1 to 3 R 6 and each R 6 are independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halogenated 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)NR 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, where 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 nitrogen, sulfur or phosphorus atom to which they are attached, form a 3- to 10-membered heterocycloalkyl; R 8 is H or C1-C3 alkyl, or R 8 and R 7atogether with the nitrogen and sulfur atom or together with the nitrogen and carbon atoms attached thereto form a 3- to 10-membered heterocycloalkyl.

[0015] In some embodiments of the present invention, in general formula (1) or general formula (1A), A is [ka] where v is 1, 2, or 3, and each R 6 are independently H, F, Cl, Br, I, Me, Et, [ka] It is.

[0016] In some embodiments of the present invention, in general formula (1) or general formula (1A), A is [ka] TIFF2024515318000014.tif135168, and A is preferably [ka] and A is more preferably [ka] It is.

[0017] In another particular embodiment of the invention, the compound of the invention has the following structure: [ka] It has one of the following: TIFF2024515318000018.tif230168TIFF2024515318000019.tif232168TIFF2024515318000020.tif167168.

[0018] Another object of the present invention is to provide a pharmaceutical composition containing a pharma- ceutically acceptable carrier, diluent and / or excipient and, as an active ingredient, a compound of general formula (1) or general formula (1A) of the present invention or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0019] Yet another object of the present invention is to provide the use of a compound of general formula (1) of the present invention, or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or said pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease mediated by Wee-1.

[0020] Yet another object of the present invention is to provide a method for treating, regulating or preventing related diseases mediated by Wee-1, comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) of the present invention, or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or said pharmaceutical composition.

[0021] As a result of extensive research, the present inventors have found that the fused cyclic compound having the structure of formula (1) has strong inhibitory activity against Wee-1 and has activity when administered in combination with gemcitabine (GMC), a chemotherapeutic agent, and as a result, the compound of the present invention can exert a more excellent effect when administered in combination with a chemotherapeutic agent in clinical practice.

[0022] It is to be understood that both the foregoing general description and the following detailed description of the invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] (Synthesis of Compounds)

[0024] Methods for preparing the compound of the general formula (1) of the present invention are specifically described below, but these specific methods do not limit the present invention in any way.

[0025] The compounds of general formula (1) above can be synthesized using standard synthetic techniques in combination with the methods described herein, or well-known techniques. Furthermore, the solvents, temperatures and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds can be obtained synthetically or commercially. The compounds described herein and other related compounds with different substituents are described 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), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rd Ed., (Wiley 1999). General methods for preparing compounds may be modified by using appropriate reagents and conditions to introduce various groups into the molecular formulas provided herein.

[0026] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the following description. In addition, the compounds of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains. In one embodiment, the present invention further provides a method for preparing a compound of general formula (1), where the compound of general formula (1) can be prepared using the following method A.

[0027] Method A includes the following steps: first, compound A1 is subjected to a coupling reaction with compound A2 to produce compound A3, and compound A3 is further subjected to a reaction with compound B7 to produce target compound A5. [ka]

[0028] In the above reaction scheme, A, B, and R 1 , R 2 , R 3 and m is as defined above, and Y is Br, I, or -B(OH)2.

[0029] Further forms of the compound

[0030] As used herein, "pharmaceutical acceptable" refers to a relatively non-toxic substance, such as a carrier or diluent, that does not cause a loss of biological activity or properties of a compound, e.g., when administered to an individual, the substance does not cause undesirable biological effects or deleterious interactions with any of its components.

[0031] The term "pharmaceutical acceptable salt" refers to an existing form of a compound that does not cause significant irritation to the receiving organism or eliminate the biological activity and properties of the compound. In certain embodiments, the pharmaceutical acceptable salt is obtained by reacting the compound of general formula (1) with an acid, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, organic acids such as 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, and p-toluenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

[0032] It is to be understood that pharma- ceutically acceptable salts include solvent addition forms or crystal forms, particularly solvates or polymorphs. Solvates include stoichiometric or non-stoichiometric amounts of solvent and are preferentially formed during crystallization in pharma- ceutical acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of the compounds of the general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of the compounds of the general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds described herein may exist in either unsolvated or solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0033] In other specific examples, the compound of general formula (1) is prepared in different forms, including but not limited to amorphous, milled, and nanoparticle forms. Furthermore, the compound of general formula (1) may be a polymorph, including crystalline forms. A polymorph includes different lattice arrangements of the same elements of a compound. The polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal morphology, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in a single predominant crystal system.

[0034] In another embodiment, the compounds of general formula (1) may have chiral centers and / or axial asymmetry and may therefore exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers and cis-trans isomers. Each chiral center or axial asymmetry independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomers of these compounds.

[0035] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) and C-14( 14 The deuterated pharmaceuticals may be labeled with radioisotopes such as 1,2-dihydrogen (C). As another example, deuterium may be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by general hydrogen and carbon. Compared to non-deuterated pharmaceuticals, deuterated pharmaceuticals generally have the advantages of reduced side effects, improved drug stability, enhanced efficacy, and extended in vivo half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0036] Explanation of terms

[0037] Unless otherwise specified, the terms used in the present invention, including those used in the specification and claims, are defined as follows. Please note that in this specification and the appended claims, the singular forms "a" and "an" include the plural meaning unless otherwise specified in the context. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. As used herein, "or" or "and" means "and / or" unless otherwise specified.

[0038] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched groups, containing 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, or tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyls, particularly alkyls substituted with one or more halogens. Preferred alkyls are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t is selected from Bu.

[0039] Unless otherwise specified, "alkylene" refers to a divalent alkyl as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0040] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups containing 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl, are preferred.

[0041] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, and includes straight-chain and branched groups containing 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl, are preferred.

[0042] Unless otherwise stated, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic); partially unsaturated cycloalkyls may be referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond, or "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. The cycloalkyls may include monocyclic or polycyclic groups, as well as spirocycles (e.g., having 2, 3, or 4 fused rings). In some embodiments, the cycloalkyls are monocyclic. In some embodiments, the cycloalkyls are monocyclic or bicyclic. The ring carbon atoms of the cycloalkyls may be optionally oxidized to form oxo or sulfido groups. The cycloalkyls further include cycloalkylene. In some embodiments, the cycloalkyls include 0, 1, or 2 double bonds. In some embodiments, the cycloalkyls include 1 or 2 double bonds (partially unsaturated cycloalkyls). In some embodiments, the cycloalkyl may be fused with an aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl and a heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl and a cycloalkyl. Examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0043] Unless otherwise indicated, "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy are OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0044] Unless otherwise stated, "heterocycloalkyl" refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus, which may optionally include one or more alkenylenes as part of the ring structure. Partially unsaturated heterocycloalkyls may be referred to as "heterocycloalkenyls" when the heterocycloalkyl contains at least one double bond, and "heterocycloalkynyls" when the heterocycloalkyl contains at least one triple bond. Heterocycloalkyls may include monocyclic, bicyclic, spirocyclic, or polycyclic systems (e.g., having two fused or bridged rings). In some embodiments, heterocycloalkyls are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring carbon atoms and heteroatoms of a heterocycloalkyl may be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl may be bonded through a ring carbon atom or a ring heteroatom. In some embodiments, a heterocycloalkyl contains 0-3 double bonds. In some embodiments, a heterocycloalkyl contains 0-2 double bonds. Further included within the definition of a heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., sharing a bond) to the heterocycloalkyl ring, e.g., benzo derivatives such as piperidine, morpholine, azepine, thienyl, etc. Heterocycloalkyls that contain fused aromatic rings may be bonded through any ring atom, including the ring atoms of the fused aromatic rings.Examples of heterocycloalkyl include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-isopropyl ether, and the like. midazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl, [ka] These include, but are not limited to:

[0045] Unless otherwise specified, "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group, for example, a monocyclic aryl ring may be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0046] Unless otherwise noted, "aryloxy" refers to an aryl group attached to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0047] Unless otherwise noted, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, and phenanthrylene.

[0048] Unless otherwise specified, "heteroaryl" refers to an aromatic group that contains one or more heteroatoms (O, S, or N), and the "heteroaryl" 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 include pyridinyl, 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, [ka] These include, but are not limited to:

[0049] Unless otherwise stated, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a radical name indicates that the radical is partially or fully halogenated, i.e., substituted by F, Cl, Br or I, preferably F or Cl, in any combination.

[0050] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0051] The substituent "-O-CH2-O-" means that the two oxygen atoms in the substituent are attached to two adjacent carbon atoms in a heterocycloalkyl, aryl, or heteroaryl, for example: [ka]

[0052] When the number of a linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0053] When one of the variables is selected from a chemical bond, it means that the two groups connected by this variable are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0054] The term "membered ring" includes any cyclic structure. The term "membered" is intended to refer to the number of main chain atoms that form the ring. For example, cyclohexyl, pyridinyl, pyranyl, and thiopyranyl are 6-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[0055] The term "moiety" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to refer to a chemical substance contained in or attached to a molecule.

[0056] Solid wedge connections unless otherwise noted [ka] and wedge-shaped dashed bond [ka] represents the absolute configuration of a stereocenter, and a straight solid bond [ka] and straight dashed bond [ka] represents the relative configuration of stereocenters. [ka] is a solid wedge connection [ka] or wedge-shaped dashed bond [ka] or a wavy line [ka] is a straight solid line connection [ka] or straight dashed bond [ka] Represents.

[0057] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0058] Specific pharmaceutical and medical terms

[0059] The term "acceptable" as used herein means that a formulation component or active ingredient does not have an excessive and deleterious effect on the general health of the treated subject.

[0060] The terms "treatment", "course of treatment" and "treatment" as used herein include alleviating, inhibiting or ameliorating a disease symptom or condition, inhibiting the occurrence of a complication, improving or preventing the underlying metabolic syndrome, inhibiting the occurrence of a disease or condition (e.g., controlling the progression of a disease or condition), relieving a disease or condition, regressing a disease or condition, and alleviating complications caused by a disease or condition, or preventing or treating symptoms caused by a disease or condition. As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom or condition, and in particular can improve the severity, delay the onset, delay the progression, or shorten the duration of a disease. Fixed or episodic administration, or continuous or intermittent administration, can result from or relate to administration.

[0061] "Active ingredient" refers to compounds of general formula (1) and pharma- ceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial asymmetry) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0062] As used herein, terms such as "compound," "composition," "agent," or "medicine or pharmaceutical agent" are used interchangeably and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of eliciting a desired pharmacological and / or physiological response through local and / or systemic action.

[0063] The terms "administered, administering, or administration" as used herein refer to direct administration of a compound or composition, or administration of a prodrug, derivative, analog, etc. of an active compound.

[0064] Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the relevant values ​​set forth in certain embodiments are set forth herein as precisely as possible. However, any numerical value inherently contains a standard deviation that necessarily results from certain testing methods. Here, "about" generally means that the actual value is within a particular value or range ±10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual numerical value is within an acceptable standard error of the mean value, as would be understood by one of ordinary skill in the art. Except in experimental examples or unless otherwise indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, proportions of amounts, etc.) are understood to be modified by the term "about". Thus, unless otherwise indicated, all numerical parameters set forth in this specification and the appended claims are approximations that may be varied as desired. At the very least, these numerical parameters should be interpreted as numerical values ​​obtained using the significant digits given or conventional rounding rules.

[0065] Scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein include their plurals, unless otherwise contradicted by context, and plural nouns used herein also include their singulars.

[0066] therapeutic use

[0067] The compounds or compositions provided by the present invention are generally useful for inhibiting Wee-1 kinase and may therefore be useful for treating one or more disorders associated with Wee-1 kinase activity. Thus, in certain embodiments, the present invention provides a method for treating a disorder mediated by Wee-1 kinase, comprising administering a compound of the present invention or a pharma- ceutical acceptable composition thereof to a patient in need thereof.

[0068] Cancers that may be treated with the compounds of the invention include, but are not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndromes and myeloproliferative disorders), solid tumors (carcinomas such as prostate, breast, lung, colon, pancreatic, renal, ovarian and soft tissue cancers, osteosarcoma and stromal tumors).

[0069] Route of administration

[0070] The compound of the present invention and its pharmaceutical acceptable salts can be prepared into various formulations containing a safe and effective amount of the compound of the present invention or its pharmaceutical acceptable salts and a pharmaceutical acceptable excipient or carrier, where "safe and effective amount" means the amount of compound that is sufficient to significantly improve the condition without causing serious adverse effects.The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject to be treated.

[0071] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use, have sufficient purity, and have sufficiently low toxicity. As used herein, "compatibility" means that the components of the composition can be mixed with the compound of the present invention without significantly reducing the pharmaceutical effectiveness of the compound. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0072] The compounds of the present invention may be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0073] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, 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 the following ingredients: (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, 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 retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) lubricants such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, said dosage forms may further comprise buffering agents.

[0074] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art.These may contain opacifying agents, and the active compound or compounds in such compositions can be released in a certain part of the digestive tract in a delayed manner.The examples of embedding components that can be used include polymeric materials and wax-based materials.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0075] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0076] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0077] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar-agar, or mixtures of these substances.

[0078] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous 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 excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0079] Dosage forms for topical administration of the compounds of the present 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 that may be required as required.

[0080] The compound of the present invention may be administered alone or in combination with other pharma- ceutical acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) to be treated, where the dosage is a pharma- ceutical effective dose. For a 60 kg human, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage also takes into account factors such as the route of administration and the patient's health condition, but these are well known to those skilled in the art.

[0081] The features described in the present invention or the features described above in the embodiments can be combined in any combination. All features disclosed herein can be used in any composition, and the various features disclosed herein can be replaced with any alternative features that provide the same, equivalent or similar purpose. Thus, unless otherwise specified, the features disclosed herein are merely generic examples of equivalent or similar features.

[0082] (Detailed Description)

[0083] Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions are described in detail as follows, which will make the contents of the present invention very clear. It should be understood that the following detailed description and examples are for reference purposes only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present application as defined herein.

[0084] In all examples, melting points were measured using an X-4 melting point apparatus with an uncalibrated thermometer; 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm). Unless otherwise specified, 200–300 mesh silica gel was used for separation, and the ratio of eluents was by volume.

[0085] In the present invention, the following abbreviations are used: CDCl3 is deuterated chloroform; CuI is cuprous iodide; DCM is dichloromethane; dioxane is 1,4-dioxane; DMF is N,N-dimethylformamide; EA is ethyl acetate; EtOH is ethanol; h is hour; H2 is hydrogen; H2SO4 is sulfuric acid; K2CO3 is potassium carbonate; KNO3 is potassium nitrate; LC-MS is liquid chromatography mass spectrometry; LiAlH4 is lithium aluminum hydride; mL is milliliter; MeOH is methanol; min is minute; MS is mass spectrometry; n BuLi is n-butylitidene; NMR is nuclear magnetic resonance; °C is degrees Celsius; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium; PE is petroleum ether; rt is room temperature; Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; T3P is propylphosphonic anhydride. EXAMPLES

[0086] Preparation Example 1: Preparation of N-(6-(2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)methanesulfonamide [ka]

[0087] 2-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.17 mmol), N-(6-bromopyridin-2-yl)methanesulfonamide (310 mg, 1.17 mmol), CuI (230 mg, 1.17 mmol), K2CO3 (240 mg, 1.75 mmol), 1,4-dioxane (12 mL), N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (190 mg, 1.29 mmol) was added sequentially to a 100 mL round bottom flask under Ar atmosphere. The mixture was reacted at 100° C. for 2 h. LC-MS monitoring showed that the reaction was complete. The reaction mixture was purified by reverse phase column to give a solid product (308 mg, 77% yield). LC-MS: 342.0 [M+H] + .

[0088] Intermediates A3-2 to A3-27 can be obtained by using different starting materials according to the synthesis method of intermediate A3-1.

[0089] [Table 1] TIFF2024515318000038.tif188168

[0090] Preparation Example 2: Preparation of 2-methyl-2,3,7,8,9,9a-hexahydro-1H-phenylpropyl[de]isoquinolin-5-amine (Intermediate B7-1) [ka]

[0091] Step 1: Synthesis of compound B2-1 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) and T3P (217 g, 341 mmol, 203 mL, 50% purity) was added dropwise at room temperature. After the addition, the reaction was heated at 50 °C for 16 h. The reaction solution was diluted with ethyl acetate (1500 mL) and washed with aqueous NaHCO3 (400 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give a white solid (50 g, 264 mmol, 93.1% yield, crude). This crude product was used directly in the next step. 1H NMR:(400MHz,CDCl3) δ:7.12-7.01(m,3H),6.10-5.71(m,1H),2.93(d,J=4.9Hz,3H),2.83(br s,2H),2.79-2.71(m,2H),1.84-1.65(m,4H),MS(ESI):190.1[M+H] + .

[0092] Step 2: Synthesis of compound B3-1 B2-1 (50 g, 264 mmol) was dissolved in THF (500 mL) and incubated at −23° C. under a nitrogen atmosphere. n -BuLi (2.5M, 275mL) was slowly added dropwise. Then, DMF (48.3g, 660mmol, 50.8mL) was slowly added dropwise at -23°C. Then, a solution of HCl (6M, 300mL) was slowly added dropwise at 20°C. The reaction solution was diluted with water (100mL) and extracted with ethyl acetate (500mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55g, crude). This crude product was used directly in the next step. 1 H NMR:(400MHz,CDCl3) δ:8.36-8.20(m,1H),7.46-7.32(m,2H),6.84(s,1H),3.63-3.52(m,3H),2. 99-2.92(m,3H),2.75-2.69(m,2H),2.01-1.90(m,2H),MS(ESI):200.1[M+H] + .

[0093] Step 3: Synthesis of compound B4-1 B3-1 (55 g, 276 mmol) and 20 g of palladium on carbon were suspended in methanol (800 mL), and the suspension was stirred under a hydrogen atmosphere (50 psi) at 30° C. overnight. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) to give a yellow solid (38.5 g, yield 69.3%). 1H NMR:(400MHz,DMSO-d6) δ:7.71-7.62(m,1H),7.28-7.20(m,2H),3.42(dd,J=5.6,11.9Hz,1H),3.25(t,J=12.5Hz,1H),3.13-2.99 (m,4H),2.87-2.69(m,2H),2.06-1.90(m,2H),1.75-1.61(m,1H),1.41-1.22(m,1H),MS(ESI):202.1[M+H] + .

[0094] Step 4: Synthesis of compound B5-1: B4-1 (3.1 g, 19.2 mmol) was dissolved in H2SO4 (300 mL) and KNO3 (17.9 g, 177 mmol) was added slowly at 0 °C over 3 h. After the addition, the mixture was warmed to room temperature and stirred for 2 h. LC-MS monitoring showed the reaction was complete. The reaction solution was diluted with 500 mL of water, which precipitated a large amount of solid. The precipitate was collected by filtration and dried to give a yellow solid (79 g, crude). This crude product was used directly in the next step. MS (ESI): 247.1 [M+H] + .

[0095] Step 5: Synthesis of compound B6-1: 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 the suspension was reacted under hydrogen (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 purified by column chromatography (SiO2, PE / EA=1 / 0-1 / 2) to give yellow solid B6-1 (1.44 g, 33.5% yield). 1H NMR:(400MHz,CDCl3)) δ:7.24(d,J=2.3Hz,1H),6.56(d,J=2.0Hz,1H),3.67(br s,2H),3.32-3.25(m,2H),3.19-3.13(m,3H),3.09-2.97(m,1H),2.81-2.65(m,2H) ),2.07-1.90(m,2H),1.78-1.62(m,1H),1.37-1.23(m,1H),MS(ESI):217.2[M+H] + .

[0096] Step 6: Synthesis of compound B7-1 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. Under nitrogen atmosphere, the mixture was warmed to 25°C and reacted for 2 h. Water was slowly added to the reaction solution to quench the reaction, and the temperature of the reaction solution was kept at 0-10°C during the addition. The reaction solution was diluted with ethyl acetate (800 mL) and washed with water (100 mL x 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. The crude product was purified by column chromatography (SiO2, DCM / (MeOH+1% NH4OH)=10 / 0-10 / 1) to obtain a yellow oil (6.25 g, yield 95.5%). 1 H NMR:(400MHz,CDCl3) δ:6.31(s,1H),6.21(s,1H),3.88(d,J=15.1Hz,1H),3.62-3.34(br s,2H),3.26(d,J=15.1Hz,1H),2.98-2.69(m,4H),2.42(s,3H),2.03(t,J=10.7Hz,1H),1.9 2(tdd,J=3.4,6.5,13.1Hz,1H),1.88-1.75(m,2H),1.34-1.17(m,1H),MS(ESI):203.2[M+H] + .

[0097] Step 7: Preparation of Compound B7-2 and Compound B7-3 [ka]

[0098] B7-1 (1.5 g, 7.41 mmol) was subjected to chiral separation by preparative supercritical fluid chromatography (preparative SFC) (SFC chiral separation conditions: apparatus: Waters SFC350; column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); mobile phase: A: CO2, B: IPA (0.1% NH3H2O); gradient: B%: 50% - 50%; flow rate: 200 mL / min; column temperature: 40 °C). The stepwise eluate was concentrated under reduced pressure and 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%). B7-2: 1 1H NMR: (400 MHz, CDCl3) 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), MS (ESI): 203.2 [M + H] + 。 B7-3: 1 1H NMR: (400 MHz, CDCl3) δ: 6.32 (s, 1H), 6.22 (s, 1H), 3.87 (d, J = 15.3 Hz, 1H), 3.47 (br s, 2H), 3.26 (d, J = 15.1 Hz, 1H), 2.93 (dd, J = 4.8, 10.6 Hz, 1H), 2.89 - 2.80 (m, 1H), 2.80 - 2.65 (m, 2H), 2.42 (s, 3H), 2.02 (t, J = 10.7 Hz, 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] + 。

[0099] Intermediate B7-4 to intermediate B7-39 can be obtained by using different starting materials according to the synthesis method of intermediate B7-1.

[0100] [Table 2] TIFF2024515318000042.tif192168

[0101] Example 1: (6-(5-fluoro-2-((2-methyl-2,3,7,8,9,9,9a-hexahydro-1H-benzo[de]isoquinolin-5-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imido)dimethyl-λ 6 -Synthesis of sulfanone (compound 1) [ka]

[0102] 2-Methyl-2,3,7,8,9,9a-hexahydro-1H-benzo[de]isoquinolin-5-amine (119 mg, 0.59 mmol), ((6-(2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imino)dimethyl-λ 6 -Sulfanone (200 mg, 0.59 mmol), and cesium carbonate (289 mg, 0.89 mmol) were weighed into a 100 mL single-neck flask and 1,4-dioxane (15 mL) was added. After purging the reaction solution with argon three times, Pd2(dba)3 (27 mg, 0.03 mmol) and Xantphos (41 mg, 0.07 mmol) were added and the mixture was heated to 100 °C and stirred under argon atmosphere for 5 h. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated to dryness by rotary evaporation and purified by reverse phase column to give a pale yellow solid ((6-(5-fluoro-2-((2-methyl-2,3,7,8,9,9a-hexahydro-1H-benzo[de]isoquinolin-5-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)imido)dimethyl-λ6 -sulfanone (50 mg, 17%) was obtained. 1 H NMR(400MHz, CDCl3) δ:8.63(s,1H),8.17(s,1H),7.63(d,J=27.8Hz,2H),7.13(s,2H),6.60(s,1H),3.96-3.92(m,1H),3. 34(s,7H),2.88-2.84(m,4H),2.41(s,3H),2.03-1.82(m,3H),1.23-1.21(m,2H),LC-MS:506.3[M+H] + .

[0103] Examples 2 to 70: Synthesis of Compounds 2 to 70 By the same procedure as in the synthesis of compound 1, target compounds 2 to 70 in Table 3 could be obtained using intermediates A3-1 to A3-27 and B7-1 to B7-39 as starting materials.

[0104] [Table 3] TIFF2024515318000045.tif240168TIFF2024515318000046.tif234168TIFF2024515318000047.tif244168TIFF2024515318000048.tif29168

[0105] Example 71: Assay of inhibitory activity of compounds of the present invention against Wee-1 kinase After mixing the serially diluted compounds and enzyme, the mixture was incubated at room temperature (25°C) for 15 minutes, centrifuged at 1000 rpm for 1 minute and mixed. 5 μL of substrate was added to start the reaction. The mixture was reacted at room temperature for 60 minutes, after which 5 μL of ADP-GLO reagent was added, centrifuged at 1000 rpm for 1 minute and mixed. The mixture was then incubated at room temperature for 60 minutes, after which 10 μL of kinase detection reagent was added. The mixture was incubated for 60 minutes, and chemiluminescence was measured. The inhibition rate of enzyme activity by the compounds was calculated compared with the DMSO group, and IC 50 values ​​were also calculated.

[0106] [Table 4]

[0107] As can be seen from the data in Table 4, the compounds of the present invention have a strong inhibitory effect on Wee-1 kinase. For example, the IC values ​​of compounds 1, 2, 21, 65, 66, 67, 68, 69 and 70 against Wee-1 kinase are 50 All values ​​were less than 2.0 nM, approximately two-fold higher than the control drug MK-1775.

[0108] Example 72: In vitro antiproliferative activity of compounds of the invention against MIA PaCa-2 cells MIA PaCa-2 cells were seeded in 384-well plates at 3000 cells / well. After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting from 5 μM were added. Viability was assessed 72 hours after administration by measuring intracellular ATP content. The inhibition rate of viable cells by compounds was calculated compared to the DMSO group and was expressed as IC 50 The values ​​were calculated and the results are shown in Table 5 below.

[0109] Example 73: In vitro antiproliferative activity of compounds of the invention in combination with gemcitabine (GMC) against MIA PaCa-2 cells MIA PaCa-2 cells were seeded in 384-well plates at 3000 cells / well and treated with 20 nM gemcitabine. After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting at 100 nM were added. Viability was assessed 72 hours after treatment by measuring intracellular ATP content. The inhibition rate of viable cells by compounds was calculated compared to the DMSO group and IC 50 The values ​​were calculated and the results are shown in Table 5 below.

[0110] [Table 5]

[0111] As can be seen from the data in Table 5, the compounds of the present invention have stronger antiproliferative activity against MIA PaCa-2 cells compared to the control drug MK-1775. At the same time, the compounds of the present invention have stronger activity when combined with GMC, for example, compounds 66, 67 and 68 have IC 50 is less than 1 nM. The compounds of the present invention show stronger activity in combination with GMC, which indicates that the compounds of the present invention may have better efficacy when clinically combined with chemotherapy drugs.

[0112] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1), or an isomer, crystal, pharma- ceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 1】 (In general formula (1), m is 0 or 1; R １ is H or a halogen, R ２ is H, C1-C6 alkyl, C3-C6 cycloalkyl, deuterated C1-C6 alkyl, halogenated 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- to 7-membered heterocycloalkyl; R ３ is H or C1-C3 alkyl, A is aryl or heteroaryl, wherein said aryl and said heteroaryl are each selected from 1 to 3 R ６ and each R ６ are independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, OH-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halogenated C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, CF ３ Substituted C3-C6 cycloalkyl, -NR ７ａ R ７ｂ , -N=S(O)R ７ａ R ７ｂ , -P(O)R ７ａ R ７ｂ , -S(O) ２ R ７ａ , -S(O) ２ N.R. ７ａ R ７ｂ , -NR ８ P(O)R ７ａ R ７ｂ , -NR ８ S (O) ２ R ７ａ , -NR ８ C(O)R ７ａ , -N=S (=NR ８ ) R ７ａ R ７ｂ or pyridonyl, 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 nitrogen, sulfur, or phosphorus atom to which they are attached form a 3- to 10-membered heterocycloalkyl; R ８ is H or C1-C3 alkyl, or R ８ and R ７ａ together with the nitrogen and sulfur or carbon atoms attached thereto form a 3- to 10-membered heterocycloalkyl; B is a partially unsaturated C5-C7 cycloalkyl or a partially unsaturated 5-7 membered heterocycloalkyl.

2. In general formula (1), 【Chemistry 2】 but, 【Chemistry 3】 where R ２ H, Me, Et, CD ３ , 【Chemistry 4】 2. The compound of claim 1, wherein:

3. In general formula (1), 【Chemistry 5】 but, 【Chemistry 6】 3. The compound of claim 2, wherein:

4. The compound has the structure of general formula (1A): 【Chemistry 7】 In the general formula (1A), n is 1, 2 or 3; X is CH ２ , O or S; m, A, R １ and R ２ 2. The compound of claim 1, wherein:

5. In the general formula (1) or (1A), A is phenyl, pyridinyl, pyrimidinyl or pyrazinyl, and the phenyl, pyridinyl, pyrimidinyl and pyrazinyl are each independently selected from 1 to 3 R ６ and each R ６ are independently H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halogenated C3-C6 cycloalkyl, OH-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, CF ３ Substituted C3-C6 cycloalkyl, -NR ７ａ R ７ｂ , -N=S(O)R ７ａ R ７ｂ , -P(O)R ７ａ R ７ｂ , -S(O) ２ R ７ａ , -S(O) ２ N.R. ７ａ R ７ｂ , -NR ８ P(O)R ７ａ R ７ｂ , -NR ８ S (O) ２ R ７ａ , -NR ８ C(O)R ７ａ , -N=S (=NR ８ ) R ７ａ R ７ｂ or pyridonyl, where 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 nitrogen, sulfur or phosphorus atom to which they are attached form a 3- to 10-membered heterocycloalkyl; R ８ is H or C1-C3 alkyl, or R ８ and R ７ａ together with the nitrogen and sulfur atoms or together with the nitrogen and carbon atoms bound thereto, form a 3- to 10-membered heterocycloalkyl, or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

6. In the general formula (1) or (1A), A is 【Chemistry 8】 where v is 1, 2, or 3, and each R ６ are independently H, halogen, Me, Et, 【Chemistry 9】 2. The compound of claim 1, wherein:

7. In the general formula (1) or (1A), A is 【Chemistry 10】 【change】 7. The compound of claim 6, wherein:

8. The compound has the following structure: 【Chemistry 11】 【change】 【change】 【change】 or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

9. A pharmaceutical composition comprising a pharma- ceutical acceptable excipient or carrier and, as an active ingredient, a compound according to any one of claims 1 to 8 or an isomer, crystalline form, pharma- ceutical acceptable salt, hydrate or solvate thereof.

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