Heteroaryl-derivative compound and use thereof

Abstract

The present invention relates to a heteroaryl-derivative compound and a medicinal use thereof. The heteroaryl derivative according to the present invention exhibits excellent inhibitory activity against WEE1 and / or PKMYT1, and thus can be effectively used as a therapeutic agent for diseases associated with over-activation, amplification, or overexpression of WEE1 and / or PKMYT1.

Description

Heteroaryl derivative compounds and uses thereof

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to heteroaryl derivatives having WEE1 and / or PKMYT1 inhibitory activity.

[0002] Protein kinases act as molecular switches in signal transduction pathways, requiring smooth cellular regulation of the transition between active and inactive states of target proteins. If this transition is abnormally regulated, it can lead to excessive activation or inactivation of intracellular signaling, leading to uncontrolled cell division and proliferation. In particular, abnormal activation of protein kinase genes, resulting from mutations, amplification, and / or overexpression, plays a crucial role in the development and progression of various tumors and in the pathogenesis of various diseases, including inflammatory diseases, neurodegenerative diseases, and autoimmune diseases.

[0003] The cell cycle is a tightly regulated process in which cells reproduce through DNA replication and division. During this process, cells pass through several checkpoints, consisting of the G1, S, G2, and M phases. These checkpoints detect and repair DNA damage and regulate division to ensure proper cell proliferation.

[0004] The WEE1 tyrosine kinase is a key regulator of the cell cycle. In particular, it plays a crucial role in the G2 phase checkpoint. This checkpoint maintains cellular stability by detecting DNA damage before cells enter the mitotic phase. WEE1 regulates this process by inhibiting the activity of CDK1 (or CDC2). Before cell division, CDK1 is inactive, and tyrosine is phosphorylated by WEE1, and threonine is phosphorylated by PKMYT1 (MYT1).

[0005] WEE1 is a negative regulator of the cell cycle and prevents the entry of the cyclin B-activated CDK1 complex into the nucleus. WEE1 expression and activity are both enhanced in S and G2 phases, and are then highly phosphorylated and then reduced in M ​​phase. When cells enter G2 phase and in the absence of DNA damage, polo-like protein kinase 1 (PLK1) phosphorylates WEE1 and degrades it through a ubiquitin ligase complex. PLK1 also activates the protein phosphatase cell division cycle 25 homolog (CDC25), which phosphorylates and dephosphorylates CDK1. Activated CDK1 can bind to cyclin B, promoting cell entry into the mitotic phase (Beck H et al., Molecular & Cellular Biology, 2012, 32 (20), 4226-4236).

[0006] WEE1 is overexpressed in various types of cancer, including liver cancer, breast cancer, malignant glioma, melanoma, adult brain tumors, and pediatric brain tumors. In some cancer cells, the G1 checkpoint is abnormal, or inhibition of WEE1 activity disrupts the G2 checkpoint, leading to cell division and eventual death, with unrepaired damaged DNA (Van Linden AA et al., Molecular Cancer Therapeutics, 2013, 12 (12), 2675-2684).

[0007] Meanwhile, PKMYT1 (MYT1; membrane-associated tyrosine and threonine specific cdc2 inhibitory kinase) belongs to the WEE1 kinase family and, together with WEE1, acts as a key regulator of the gateway to mitosis at the G2 checkpoint in the cell cycle. When DNA damage occurs in cancer cells, PKMYT1 plays a role in DNA damage repair (DDR) at the G2 checkpoint (Molecules, 2017, 22(12), 2045). Therefore, inhibition of PKMYT1 can suppress the activity of cancer cells by suppressing the G2 / M checkpoint function of cancer cells and inducing mitotic catastrophe (Journal of Hematology & Oncology, 2020, 13, 126).

[0008] Many patients with solid tumors do not respond to chemotherapy, which is attributed to cell cycle regulation and DDR in cancer cells. Furthermore, PKMYT1 is overexpressed in solid tumors such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), gastric cancer, hepatocellular carcinoma, glioblastoma, and breast cancer (Cell Proliferation, 2020, 53, e12741), and its overexpression in NSCLC patients is known to promote cancer progression and metastasis, leading to a poor prognosis (Eur Rev Med Pharmacol Sci., 2019, 23(10), 4210-4219).

[0009] Therefore, there is a growing need for novel compounds that may be useful in the treatment of diseases associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression.

[0010] An object of the present invention is to provide a novel structural heteroaryl derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0011] Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.

[0012] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound, and specifically, to provide a pharmaceutical composition for preventing or treating a disease related to WEE1 and / or PKMYT1 kinase activity, comprising the heteroaryl derivative compound as an active ingredient, a use for preventing or treating a disease related to WEE1 and / or PKMYT1 overactivation, amplification, or overexpression using the compound, or a method for preventing or treating a disease related to WEE1 and / or PKMYT1 overactivation, amplification, or overexpression, comprising a step of administering the compound.

[0013] In order to achieve the above purpose, the inventors of the present invention completed the present invention by confirming that the heteroaryl derivative compounds represented by the chemical formulas 1 and 2 mentioned below exhibit high inhibitory activity against WEE1 and / or PKMYT1, thereby inducing cell division and inhibiting proliferation.

[0014] Heteroaryl derivative compounds

[0015] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0016] [Chemical Formula 1]

[0017]

[0018] In the above chemical formula 1,

[0019] X1 and X2 are each independently CH or N;

[0020] R X is -C1-6 Haloalkyl, -C(=O)-OR X1 , or -C(=O)-NR X2 R X3 and;

[0021] R X1 -H or -C 1-6 It is alkyl;

[0022] R X2 and R X3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 alkylamide, or -(3-6 membered cycloalkyl), or R X2 and R X3 are connected to each other to form a -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring together with the N atom, wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkylsulfonyl, -OH, -halo, -C 1-6 Aminoalkyl, or R X4 can be replaced with;

[0023] R X4 is -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl), wherein at least one H of the -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, or -halo;

[0024] Ring Y is phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene), wherein at least one H of the phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -OC 1-6 may be substituted with alkyl, -halo, -C(=O)-Y1, or -Y1;

[0025] Y1 is -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 may be substituted with alkyl, -halo, -(3-6 membered cycloalkyl), or -Y2;

[0026] Y2 is -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 may be substituted with alkyl or halo; and

[0027] Ring Z is phenyl or -(5-10 membered heteroaryl), wherein one or more H of the phenyl or -(5-10 membered heteroaryl) ring are each independently -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OH, or -halo.

[0028] According to one specific example of the present invention, X1 is N and X2 is N.

[0029] According to another specific embodiment of the present invention, X1 is CH and X2 is N.

[0030] According to one specific example of the present invention, ring Y is , , , , , , , , , , , , , , , or It can be. More specifically, the ring Y is , , , or It may be, but is not limited to this.

[0031] According to one specific example of the present invention, Y1 is , , , , , , , , , or It may be, but is not limited to this.

[0032] According to one specific example of the present invention, Y2 is , , , , or It may be, but is not limited to this.

[0033] According to one specific example of the present invention, ring Z , , , , , , or It can be. More specifically, the ring Z is or It may be, but is not limited to this.

[0034] In addition, the present invention provides a compound represented by the following chemical formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0035] [Chemical Formula 2]

[0036]

[0037] In the above chemical formula 2,

[0038] X1 and X2 are each independently CH or N;

[0039] R X2 and R X3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 alkylamide, or -(3-6 membered cycloalkyl), or R X2 and R X3 are connected to each other to form a -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring together with the N atom, wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkylsulfonyl, -OH, -halo, -C1-6 Aminoalkyl, or R X4 can be replaced with;

[0040] R X4 is -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl), wherein at least one H of the -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, or -halo;

[0041] Ring Y is phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene), wherein at least one H of the phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -OC 1-6 may be substituted with alkyl, -halo, -C(=O)-Y1, or -Y1;

[0042] Y1 is -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6may be substituted with alkyl, -halo, -(3-6 membered cycloalkyl), or -Y2;

[0043] Y2 is -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 may be substituted with alkyl or halo; and

[0044] R Z1 Inland R Z3 are each independently -H, -methyl, -OH, or -halo.

[0045] According to one specific example of the present invention, X1 is N and X2 is N.

[0046] According to another specific embodiment of the present invention, X1 is CH and X2 is N.

[0047] According to one specific example of the present invention, ring Y is , , , , , , , , , , , , , , , or It can be. More specifically, the ring Y is , , , or It may be, but is not limited to this.

[0048] According to one specific example of the present invention, Y1 is , , , , , , , , , or It may be, but is not limited to this.

[0049] According to one specific example of the present invention, Y2 is , , , , or It may be, but is not limited to this.

[0050] According to one specific example of the present invention, R Z1 and R Z2 are each independently -methyl or -halo, and R Z3 may be hydrogen or -OH, but is not limited thereto.

[0051] According to one specific example of the present invention, the compounds represented by the chemical formulae 1 and 2 may be selected from the group consisting of compounds listed in Tables 1 and 2 described below.

[0052] In the present invention, "alkyl" may mean a straight or branched chain acyclic, cyclic or saturated hydrocarbon with a combination thereof, unless otherwise specified. For example, "C 1-6"Alkyl" may mean alkyl having 1 to 6 carbon atoms. Acyclic alkyl may include, but is not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylpentyl, for example. As used herein, a residue obtained by removing one hydrogen atom from the "alkyl" is referred to as "alkylene." Cyclic alkyl may be used interchangeably with "cycloalkyl" as used herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, for example.

[0053] In the present invention, "alkenyl" and "alkynyl" may mean a straight or branched chain acyclic, cyclic or unsaturated hydrocarbon group combined therewith. For example, "C 1-6 "Alkenyl" may mean an unsaturated hydrocarbon having 1 to 6 carbon atoms with one or more double bonds, and "C 1-6 "Alkynyl" may mean an unsaturated hydrocarbon of 1 to 6 carbon atoms having one or more triple bonds.

[0054] In the present invention, "alkoxy" may mean an alkyl ether group -(R'-OR"), where R' is a single bond and C 1-6 may be selected from the group consisting of alkyl, and R" is C 1-6 It may be alkyl. Here, alkyl is as defined above. For example, "C 1-6 "Alkoxy" is C 1-6 Alkoxy containing alkyl, i.e., -(OC 1-6 alkyl) or -(C 1-6 Alkyl-OC 1-6Alkoxy may mean, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0055] In the present invention, “halo” may be F, Cl, Br, or I.

[0056] In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo groups as defined herein. Examples of such haloalkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, each independently substituted with one or more halogens, such as F, Cl, Br, or I.

[0057] As used herein, "hydroxyalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with hydroxy (OH). Examples of such hydroxyalkyl include, but are not limited to, methyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, each independently substituted with one or more -OH.

[0058] In the present invention, "alkylamino" or "aminoalkyl" may mean -(NR'R"), wherein R' and R" are each independently hydrogen, C 1-6 alkyl, and N protecting groups (e.g., Boc), wherein the selected R' and R" may each be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylamino" is amino (-NH2) or C that does not contain alkyl. 1-6Amino containing alkyl, i.e., -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, and may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.

[0059] In the present invention, "alkylamide" may mean -(R'-CONR-R") or -(R'-NRCO-R"), wherein R' is each independently a single bond and C 1-6 may be selected from the group consisting of alkyl, and R and R" are each independently hydrogen and C 1-6 It can be selected from the group consisting of alkyl, and the selected R, R' and R" can each be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylamide" is an amide that does not contain an alkyl (-CONH2 or -NHCOH) or C 1-6 Amides containing alkyl, i.e., -(C 1-6 alkyl)-CONH-(C 1-6 alkyl), -(C 1-6 alkyl)-CON(C 1-6 alkyl)-(C 1-6 alkyl), -(C 1-6 alkyl)-NHCO-(C 1-6 alkyl), or -(C 1-6 alkyl)-N(C 1-6 alkyl)CO-(C 1-6 alkyl), where C 1-6 Alkyl may be, but is not limited to, a straight-chain or branched-chain saturated hydrocarbon.

[0060] In the present invention, “cyanoalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0061] In the present invention, "alkylsulfonyl" may mean -(R'-S(=O)2-R"), where R' is a single bond and C1-6 may be selected from the group consisting of alkyl, and R" is hydroxy and C 1-6 It can be selected from the group consisting of alkyl. The selected R' and R" can be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylsulfonyl" is a sulfonic acid group (-S(=O)2OH) or C that does not contain alkyl. 1-6 A sulfonyl group containing an alkyl group, i.e., -S(=O)2-(C 1-6 alkyl) or -(C 1-6 alkyl)-S(=O)2-(C 1-6 alkyl) and may include, but is not limited to, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, ethylsulfonyl, (ethylsulfonyl)methyl, and (ethylsulfonyl)ethyl.

[0062] In the present invention, "alkylcarbonyl" may mean -(R'-C(=O)-R"), where R' is a single bond and C 1-6 may be selected from the group consisting of alkyl, and R" is hydrogen and C 1-6 It can be selected from the group consisting of alkyl. The selected R' and R" can be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylcarbonyl" is an aldehyde group (-C(=O)H) or C that does not contain alkyl. 1-6 A ketone group containing alkyl, i.e., -C(=O)-(C 1-6 alkyl) or -(C 1-6 alkyl)-C(=O)-(C 1-6 It can mean alkyl.

[0063] In the present invention, "cycloalkyl" may mean a hydrocarbon ring that does not contain a heteroatom (such as N, O, P, P(=O), or S) within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as a cycloalkene. Unless otherwise stated, a cycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring.

[0064] In the present invention, "heterocycloalkyl" may mean a ring containing one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as heterocycloalkene. Unless otherwise stated, a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring. Additionally, “heterocycloalkyl having 3 to 12 ring atoms” may mean a heterocycloalkyl having 3 to 12 ring-forming atoms, and as examples, the heterocycloalkyl may include, but is not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, 3,9-diazaspiro[5.5]undecane, tetrahydrofuran, or tetrahydrothiophene.

[0065] In the present invention, "heterobicycloalkyl" may mean multiple rings such as a spiro ring, a bridged ring or a fused ring containing at least one selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as heterobicycloalkene. Examples of heterobicycloalkyl may include, but are not limited to, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane.

[0066] In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaternary benzene, quincbenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. In the present specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl."

[0067] In the present invention, "heteroarene" may be a ring containing at least one of O, N, P, Si, and S as a heteroatom. The number of ring-forming carbon atoms of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two-ring or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, pyridin-2-one, pyridin-3-one, pyridin-4-one, bipyridine, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or Pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, thiadiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran, but are not limited thereto. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene comprising an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. As used herein, a residue obtained by removing one hydrogen atom from the above "heteroarene" is referred to as a "heteroaryl".

[0068] In the present invention, “hydroarene” or “hydroaryl” is an aromatic hydrocarbon ring in which at least one double bond is saturated.

[0069] In the present invention, "heterohydroarene" may mean a multi-ring (bi- to tetra-ring) containing 1 to 5 heteroatoms selected from N, O, and S as ring-forming atoms, and at least one of the multi-rings may be a saturated or partially unsaturated ring, and at least another may have an aromatic ring. In the present specification, a residue obtained by removing one hydrogen atom from the "heterohydroarene" is referred to as a "heterohydroaryl."

[0070] In the present invention, the "ring" may be a single ring or a multi-ring. The multi-ring may be a spiro ring, a bridged ring, or a fused ring.

[0071] In the present invention, "stereoisomer" means a compound having the same chemical formula or molecular formula but being sterically different. In the present specification, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemates, and mixtures thereof are also included in the scope of the present invention. For example, since the chemical formulae 1 and 2 of the present invention do not specify the stereochemical structure, they may include the stereoisomers of chemical formulae 1 and 2. Unless otherwise stated, a solid bond ( ) is a wedge-shaped solid line combination representing the absolute arrangement of the stereocenter. ) or wedge-shaped dotted line joint ( ) may be included.

[0072] The compounds represented by Chemical Formulas 1 and 2 of the present invention may exist in the form of a "pharmaceutically acceptable salt." Accordingly, the category of compounds of the present invention includes pharmaceutically acceptable salts of the compounds represented by Chemical Formulas 1 and 2. The term "pharmaceutically acceptable salt" of the present invention means any organic or inorganic acid addition salt of the compound represented by Chemical Formulas 1 and 2 at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects caused by the salt do not reduce the beneficial effects of the compounds represented by Chemical Formulas 1 and 2.

[0073] In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0074] Such pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.

[0075] The above acid addition salt can be prepared by a conventional method, for example, by dissolving the derivatives of chemical formulae 1 and 2 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess of acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0076] In addition, the pharmaceutically acceptable salt may be a salt or metal salt obtained using a base. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. As an alkali metal salt, sodium, potassium, or calcium salts may be pharmaceutically suitable. In addition, a corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate), and can be prepared through a salt preparation method known in the art.

[0077] Uses of heteroaryl derivative compounds

[0078] The present invention provides a use of a compound represented by the following chemical formulae 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0079] [Chemical Formula 1]

[0080]

[0081] [Chemical Formula 2]

[0082]

[0083] The above chemical formulas 1 and 2 are as defined above.

[0084] The compounds represented by chemical formulae 1 and 2 of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof can inhibit the activity of WEE1 and / or PKMYT1. Accordingly, the present invention provides a WEE1 and / or PKMYT1 inhibitor comprising a compound represented by chemical formulae 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0085] According to one specific example of the present invention, the heteroaryl derivatives represented by the chemical formulae 1 and 2 exhibit excellent inhibitory activity against WEE1 and / or PKMYT1, and thus can be usefully used for the prevention or treatment of diseases associated with overactivation, amplification, or overexpression of WEE1 and / or PKMYT1.

[0086] The disease associated with the above WEE1 and / or PKMYT1 overactivation, amplification, or overexpression may be, for example, cancer. The cancer may be a malignant tumor that includes an abnormality that activates WEE1 and / or PKMYT1, and is associated with the overactivation, amplification, or overexpression of WEE1 and / or PKMYT1. The cancer may be a solid tumor or a hematological cancer, and includes not only primary cancer but also metastatic cancer.

[0087] As a specific example, the solid cancer may be one or more selected from the group consisting of, but is not limited to, Uterine Cancer, Cervical Cancer, Ovarian Cancer, Breast Cancer, Gastrointestinal Tract Cancer, Biliary Tract Cancer, Lung and Thoracic Cancer, Thymic Cancer, Genitourinary Cancer, Head and Neck Cancer, Brain and Nervous System Tumor, Neuroendocrine Tumor, Bone and Soft Tissue Tumor, and Skin Cancer.

[0088] The above uterine cancer may be endometrial cancer, papillary serous carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, or uterine corpus endometrial carcinoma.

[0089] The above ovarian cancer may be serous ovarian cancer or high grade serous ovarian cancer (HGSOC).

[0090] The above breast cancer may be triple-negative breast cancer (TNBC).

[0091] The above gastrointestinal tract cancer may be pancreatic cancer such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), rectal cancer, gastric cancer, esophageal cancer, or liver cancer such as liver hepatocellular carcinoma (LIHC).

[0092] The above lung cancer may be small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), or squamous cell carcinoma of the lung.

[0093] The above thymic cancer may be thymoma.

[0094] The above genitourinary cancer may be prostate cancer, bladder cancer, testicular cancer, or kidney cancer such as kidney renal papillary cell carcinoma (KIRP) or kidney renal clear cell carcinoma (KIRC).

[0095] The above head and neck cancer may be head and neck squamous cell carcinoma (HNSCC) or adenoid cystic carcinoma (ACC).

[0096] The above brain and central nervous system tumor may be brain cancer, glioblastoma, glioma, or brain lower grade glioma (LGG).

[0097] The above bone and soft tissue tumor may be bone cancer or soft tissue cancer such as osteosarcoma, Ewing sarcoma, or chondrosarcoma.

[0098] The above skin cancer may be melanoma.

[0099] As a specific example, the blood cancer may be leukemia, such as chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma, or lymphoma.

[0100] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression, which comprises a compound represented by the above chemical formulae 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the disease associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression may be cancer. The type of cancer is as mentioned above.

[0101] The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compounds represented by the chemical formulae 1 and 2, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0102] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared so that it can be administered in various oral and parenteral dosage forms.

[0103] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above chemical formulas 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a disease associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression. Specifically, the disease associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression may be cancer. The type of cancer is as mentioned above.

[0104] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above chemical formulas 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing cancer. The type of cancer is as mentioned above.

[0105] In addition, according to one specific example of the present invention, a method for preventing or treating a disease associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression is provided, comprising administering a therapeutically effective amount of a compound represented by the above chemical formulae 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal including a human. Specifically, the disease associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression may be cancer. The type of cancer is as mentioned above.

[0106] In addition, according to one specific example of the present invention, the present invention provides a method for preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Chemical Formulas 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The type of cancer is as mentioned above.

[0107] In addition, according to one specific example of the present invention, the present invention provides a method for inhibiting WEE1 and / or PKMYT1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the above chemical formulae 1 and 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0108] The term "therapeutically effective amount" as used herein refers to the amount of the compound represented by the above formulae 1 and 2 that is effective in treating or preventing a disease associated with WEE1 and / or PKMYT1 overactivation, amplification, or overexpression. Specifically, the "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and it can be easily determined by a person skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by a specialist based on various factors, such as the patient's condition, age, gender, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used in doses exceeding the determined dosage.

[0109] As used herein, “prevention” means any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering the compound, and “treatment” means any action that improves or beneficially changes the symptoms of the disease by administering the compound.

[0110] In addition, according to one specific embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formulas 1 and 2, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0111] Examples of additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, and the like. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavoring, and the like.

[0112] The above pharmaceutical composition may be formulated in various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).

[0113] For example, the pharmaceutical composition may be formulated as a preparation for oral administration, and the additives used in this case may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. In addition, liquid preparations for oral administration may include suspensions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.

[0114] Additionally, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include withepsol, macrogol, Tween 61, cacao butter, laurin, and glycerogelatin. Meanwhile, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0115] Additionally, it can be manufactured as a compound preparation with other active ingredients to have a synergistic effect of the active ingredients.

[0116] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they are contradictory.

[0117] Since the heteroaryl derivative of the present invention exhibits excellent inhibitory activity against WEE1 and / or PKMYT1, it can be usefully used for the prevention or treatment of diseases associated with overactivation, amplification, or overexpression of WEE1 and / or PKMYT1.

[0118] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0119] <Analysis and purification conditions>

[0120] The compounds synthesized in the manufacturing examples and examples of the present invention were purified or subjected to structural analysis under the following conditions.

[0121] 1. LC-MS, Prep-HPLC, MPLC

[0122] Analytical LC-MS (Liquid Chromatography-Mass Spectrometry)

[0123] A Waters-manufactured UPLC system (ACQUITY UPLC PDA Detector) equipped with a Waters-manufactured mass QDa Detector was used. Waters-manufactured ACQUITY UPLC ® A BEH C18 (1.7 μm, 2.1 Х 50 mm) column was used, and the column temperature was 30 °C.

[0124] Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.

[0125] Gradient condition (10-100% B for 3 minutes, moving speed = 0.6 mL / min)

[0126] Preparative Preparative-Liquid chromatography UV spectrometry (Preparative-Liquid chromatography UV spectrometry)

[0127] The ACCQPrep HP150 equipment manufactured by Teledyne was used. The XTERRA from Waters ® Prep RP18 OBD TM (10 ㎛, 30 Х 300 mm) column was used, and the column temperature was set to room temperature.

[0128] Gradient condition (10-100% B for 120 min, flow rate = 42 mL / min)

[0129] Medium pressure liquid chromatography (MPLC) for purification

[0130] Medium-pressure liquid chromatography was performed using a CombiFlash Rf +UV from Teledyne ISCO.

[0131] 2. NMR interpretation

[0132] NMR analysis was performed using an NMR AVANCE NEO 400 MHz manufactured by Bruker, and data are expressed in ppm (parts per million(δ)).

[0133] The commercially available reagents used were used without further purification. In the present invention, room temperature or ambient temperature refers to a temperature of about 5 to 40°C, for example, 10 to 30°C, or in another example, 20 to 27°C, but is not strictly limited to the above range. Concentration under reduced pressure or solvent distillation was performed using a rotary evaporator.

[0134] Manufacturing example: Manufacturing of intermediate compound of the present invention

[0135] Manufacturing Example 1. Preparation of 2-chloro-6-(2,6-dichlorophenyl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0136] [Reaction Formula 1]

[0137]

[0138] [Step 1] Preparation of 1,3-dichloro-2-isocyanatobenzene

[0139] 2,6-Dichloroaniline (10.0 g, 61.7 mmol) was dissolved in dichloromethane (40.0 mL), and triphosgene (9.16 g, 30.9 mmol) diluted in dichloromethane (30.0 mL) was added at 0 °C. TEA (17.21 mL, 123 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and hexane was added to the resulting solid, which was stirred for 10 min and filtered. The filtrate was concentrated to obtain a white solid compound (12.0 g, 61.7 mmol, 100% yield), which was used in the next reaction without further purification.

[0140] [Step 2] Preparation of 3-(2,6-dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione

[0141] Ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (10.0 g, 46.9 mmol) was dissolved in dimethylformamide (156 mL), and 60% NaH (3.75 g, 94 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 min, and 1,3-dichloro-2-isocyanatobenzene (10.58 g, 56.30 mmol) obtained in Step 1 was added at 0 °C, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and 1 N hydrochloric acid aqueous solution were added to the reaction mixture to extract the organic matter. The organic layer was washed with a saturated sodium chloride aqueous solution, and the combined organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (12.0 g, 33.8 mmol, 72% yield) obtained as a white solid was used in the following reaction without further purification. MS (ESI): m / z 355 [M+H] +

[0142] [Step 3] Preparation of 2-chloro-3-(2,6-dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one

[0143] 3-(2,6-Dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (15.0 g, 42.2 mmol) obtained in Step 2 was dissolved in POCl3 (39.4 mL, 422.0 mmol), and then DIPEA (40.6 mL, 232.0 mmol) was added. The reaction mixture was stirred at 90 °C for 1.5 h. After confirming the completion of the reaction using LC-MS, it was concentrated. Ethyl acetate and cold saturated aqueous sodium bicarbonate solution were added to the concentrated mixture, and the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound as a white solid (12.0 g, 32.1 mmol, 76% yield). MS (ESI): m / z 375 [M+H] +

[0144] [Step 4] Preparation of 2-amino-3-(2,6-dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one

[0145] 2-Chloro-3-(2,6-dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one (12.0 g, 32.1 mmol) obtained in the above step 3 was dissolved in 7 M ammonia solution (45.9 mL, 321.0 mmol) dissolved in ethanol and stirred at 65 °C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated and the resulting solid was washed with ether. The target compound (11.0 g, 31.1 mmol, 97% yield) obtained by filtration as a white solid was used in the next reaction without further purification. MS (ESI): m / z 354 [M+H] +

[0146] [Step 5] Preparation of 6-(2,6-dichlorophenyl)-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxylic acid

[0147] 2-Amino-3-(2,6-dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one (11.0 g, 31.1 mmol) and 3-bromo-2-oxopropionic acid (18.2 g, 109.0 mmol) obtained in the above step 4 were dissolved in dimethylformamide (155.0 mL) and stirred at 110°C for 5 hours. After confirming the completion of the reaction using LC-MS, the temperature of the reaction mixture was lowered to room temperature, distilled water was added, and the resulting brown solid compound was filtered. The target compound (13.0 g, 30.1 mmol, 99% yield) as a brown solid was used in the next reaction without further purification. MS (ESI): m / z 422 [M+H] +

[0148] [Step 6] Preparation of 6-(2,6-dichlorophenyl)-N,N-dimethyl-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0149] 6-(2,6-Dichlorophenyl)-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxylic acid (2.00 g, 4.74 mmol) obtained in Step 5 above was dissolved in tetrahydrofuran (23.7 mL), dimethylamine bichloride (1.16 g, 14.21 mmol), TEA (3.96 mL, 28.40 mmol), and HATU (3.60 g, 9.47 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction using LC-MS, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to extract organic substances. The extracted organic substances were washed with distilled water and a saturated aqueous sodium chloride solution. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (hexane / ethyl acetate), and the target compound (0.40 g, 0.89 mmol, 19% yield) was obtained as a brown solid. MS (ESI): m / z 449 [M+H] +

[0150] [Step 7] Preparation of 6-(2,6-dichlorophenyl)-2-hydroxy-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0151] 6-(2,6-Dichlorophenyl)-N,N-dimethyl-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (1.0 g, 2.23 mmol) obtained in the above step 6 was dissolved in dichloromethane (4.5 mL), and mCPBA (1.10 g, 4.45 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and a saturated aqueous sodium bisulfite solution were added to extract the organic matter. A 1 M aqueous sodium hydroxide solution was added to the combined organic layer, and then a 2 M aqueous hydrogen chloride solution was added to adjust the pH to 7, and the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (0.43 g, 1.03 mmol, 46% yield) as a concentrated brown solid was used in the next reaction without further purification. MS (ESI): m / z 419 [M+H] +

[0152] [Step 8] Preparation of 2-chloro-6-(2,6-dichlorophenyl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0153] 6-(2,6-Dichlorophenyl)-2-hydroxy-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (0.43 g, 1.03 mmol) obtained in the above step 7 was dissolved in acetonitrile (3.4 mL), and POCl3 (0.96 mL, 10.26 mmol) was added. The reaction mixture was stirred at 80 °C for 5 h. After confirming the completion of the reaction using LC-MS, it was concentrated. The concentrated mixture was dissolved in ethyl acetate, and cold saturated aqueous sodium bicarbonate solution was added, and the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and the target compound (0.38 g, 0.87 mmol, 85% yield) as a brown solid was used in the next reaction without further purification. MS (ESI): m / z 439 [M+H] +

[0154] Manufacturing Example 2. Preparation of 2-chloro-6-(6-chloro-3-hydroxy-2-methylphenyl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0155] [Reaction Formula 2]

[0156]

[0157] [Step 1] Preparation of 1-chloro-2-isocyanate-4-methoxy-3-methylbenzene

[0158] 6-Chloro-3-methoxy-2-methylaniline (3.00 g, 17.48 mmol) was dissolved in dichloromethane (40.0 mL), and triphosgene (5.19 g, 17.48 mmol) and TEA (4.87 mL, 35.00 mmol) diluted in dichloromethane (30.0 mL) were added at 0 °C. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting solid was filtered and washed several times with hexane. The filtrate was concentrated to obtain a yellow solid product (3.40 g, 17.20 mmol, 98% yield), which was used in the next reaction without further purification.

[0159] [Step 2] Preparation of 3-(6-chloro-3-methoxy-2-methylphenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione

[0160] Ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (3.50 g, 16.41 mmol) was dissolved in dimethylformamide (54.7 mL), and 60% NaH (1.31 g, 32.80 mmol) was added at 0 °C. The reaction mixture was stirred at the same temperature for 5 min, and then 1-chloro-2-isocyanate-4-methoxy-3-methylbenzene (3.24 g, 16.41 mmol) obtained in Step 1 was added at 0 °C, and the mixture was stirred at 0 °C for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and 1 N aqueous hydrogen chloride solution were added to the reaction mixture to extract organic matter, and the extracted organic matter was washed with a saturated aqueous sodium chloride solution. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (hexane / ethyl acetate), and the target compound (5.30 g, 14.53 mmol, 89% yield) was obtained as a white solid. MS (ESI): m / z 365 [M+H] +

[0161] [Step 3] Preparation of 2-chloro-3-(6-chloro-3-methoxy-2-methylphenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one

[0162] 3-(6-Chloro-3-methoxy-2-methylphenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (5.3 g, 14.5 mmol) obtained in Step 2 above was dissolved in POCl3 (13.5 mL, 145.0 mmol), and then DIPEA (14.0 mL, 80.0 mmol) was added. The reaction mixture was stirred at 90 °C for 1.5 h. After confirming the completion of the reaction using LC-MS, the mixture was concentrated. The organic matter was extracted by adding ethyl acetate and cold saturated aqueous sodium bicarbonate solution to the reaction mixture. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (hexane / ethyl acetate), obtaining the target compound (5.2 g, 13.6 mmol, 93% yield) as a white solid. MS (ESI): m / z 383 [M+H] +

[0163] [Step 4] Preparation of 2-amino-3-(6-chloro-3-methoxy-2-methylphenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one

[0164] 2-Chloro-3-(6-chloro-3-methoxy-2-methylphenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one (5.2 g, 13.6 mmol) obtained in the above step 3 was dissolved in 2 M ammonia ethanol solution (67.8 mL, 136.0 mmol) and stirred at 65 °C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated and the resulting solid was washed with ether. The brown solid product (3.8 g, 10.4 mmol, 77% yield) obtained by filtration was used in the next reaction without further purification. MS (ESI): m / z 364 [M+H] +

[0165] [Step 5] Preparation of 6-(6-chloro-3-methoxy-2-methylphenyl)-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxylic acid

[0166] 2-Amino-3-(6-chloro-3-methoxy-2-methylphenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-4(3H)-one (3.8 g, 10.4 mmol) and 3-bromo-2-oxopropionic acid (5.2 g, 31.3 mmol) obtained in the above step 4 were dissolved in dimethylformamide (52.2 mL) and stirred at 110°C for 5 h. After confirming the completion of the reaction using LC-MS, the temperature of the reaction mixture was lowered to room temperature, distilled water was added, and the resulting brown solid compound was filtered. The obtained solid mixture (4.5 g, 10.4 mmol, 100% yield) was used in the next reaction without further purification. MS (ESI): m / z 432 [M+H] +

[0167] [Step 6] Preparation of 6-(6-chloro-3-methoxy-2-methylphenyl)-N,N-dimethyl-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0168] 6-(6-Chloro-3-methoxy-2-methylphenyl)-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxylic acid (4.5 g, 10.4 mmol) obtained in Step 5 above was dissolved in tetrahydrofuran (20.8 mL), dimethylamine bichloride (4.3 g, 52.1 mmol), TEA (14.5 mL, 104.0 mmol), and HATU (11.9 g, 31.3 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction using LC-MS, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the organic matter was extracted, and the organic layer was washed with distilled water and a saturated aqueous sodium chloride solution. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (hexane / ethyl acetate), and the target compound (0.88 g, 1.92 mmol, 18% yield) was obtained as a yellow liquid. MS (ESI): m / z 459 [M+H] +

[0169] [Step 7] Preparation of 6-(6-chloro-3-methoxy-2-methylphenyl)-N,N-dimethyl-2-(methylsulfinyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0170] 6-(6-chloro-3-methoxy-2-methylphenyl)-N,N-dimethyl-2-(methylthio)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (0.85 g, 1.85 mmol) obtained in the above step 6 was dissolved in dichloromethane (3.7 mL), mCPBA (0.55 g, 2.22 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and a saturated aqueous sodium bisulfite solution were added to the reaction mixture, and the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (0.80 g, 1.68 mmol, 91% yield) obtained as a yellow solid was used in the following reaction without further purification. MS (ESI): m / z 475 [M+H] +

[0171] [Step 8] Preparation of 6-(6-chloro-3-methoxy-2-methylphenyl)-2-hydroxy-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0172] 6-(6-chloro-3-methoxy-2-methylphenyl)-N,N-dimethyl-2-(methylsulfinyl)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (0.80 g, 1.68 mmol) obtained in the above step 7 was dissolved in tetrahydrofuran (1.7 mL) and distilled water (1.7 mL), potassium hydroxide (0.095 g, 1.70 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. After confirming the completion of the reaction using LC-MS, 2 M aqueous hydrochloric acid solution was added to adjust the pH to 7, and the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (dichloromethane / methanol), and the target compound (0.39 g, 0.91 mmol, 54% yield) was obtained as a yellow solid. MS (ESI): m / z 429 [M+H] +

[0173] [Step 9] Preparation of 2-chloro-6-(6-chloro-3-methoxy-2-methylphenyl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0174] 6-(6-chloro-3-methoxy-2-methylphenyl)-2-hydroxy-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (0.39 g, 0.91 mmol) and POCl3 (0.85 mL, 9.09 mmol) obtained in Step 8 above were dissolved in acetonitrile (3.0 mL) and stirred at 80 °C for 5 h. After confirming the completion of the reaction using LC-MS, the mixture was concentrated. Ethyl acetate and cold saturated aqueous sodium bicarbonate solution were added to the concentrated mixture, and the organic matter was extracted. The combined organic layer was washed with sodium sulfate to remove the remaining water, concentrated, and the target compound (0.37 g, 0.83 mmol, 91% yield) was used in the next reaction without further purification. MS (ESI): m / z 447 [M+H] +

[0175] [Step 10] Preparation of 2-chloro-6-(6-chloro-3-hydroxy-2-methylphenyl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0176] 2-Chloro-6-(6-chloro-3-methoxy-2-methylphenyl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (0.32 g, 0.72 mmol) obtained in step 9 above was dissolved in dichloromethane (2.4 mL) and stirred at 0 °C for 1 h. BBr3 (0.21 mL, 2.15 mmol) was added at 0 °C and stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and cold saturated ammonium chloride aqueous solution were added to the reaction mixture to extract organic substances. The collected organic layer was concentrated to remove the remaining water using sodium sulfate, and the target compound (0.27 g, 0.62 mmol, 87% yield) was used in the next reaction without further purification. MS (ESI): m / z 433 [M+H] +

[0177] Example: Preparation of the compound of the present invention

[0178] Example 20. Preparation of 6-(2,6-dichlorophenyl)-N,N-dimethyl-2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0179] [Reaction Formula 3]

[0180]

[0181] 2-Chloro-6-(2,6-dichlorophenyl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (0.11 g, 0.25 mmol), tert-butyl 4-(4-amino-2-methylphenyl)piperidine-1-carboxylate (0.15 g, 0.50 mmol), and p-toluenesulfonic acid hydrate (0.096 g, 0.50 mmol) prepared in Manufacturing Example 1 were dissolved in 1,4-dioxane (2.5 mL), and the mixture was stirred at 90°C for 2 hours. Trifluoroacetic acid (0.58 mL, 7.54 mmol) and methanol (1 mL) were slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 min. After confirming the completion of the reaction using LC-MS, the mixture was concentrated. The concentrated mixture was purified using prep-HPLC (water (0.1% formic acid) / methanol (0.1% formic acid)) to obtain the target compound (0.080 g, 0.13 mmol, 50% yield) as a yellow solid. MS (ESI): m / z 591 [M+H] +

[0182] <Example 1> to <Example 120>

[0183] The example compounds of the present invention (Examples 1 to 120) were prepared in a similar manner to the above Example 20, and the compound name, chemical structural formula, NMR, and LC-MS analysis results of each example compound are summarized and shown in [Table 1] below.

[0184] [Table 1]

[0185]

[0186] Example 121. Preparation of 6-(1H-indazol-4-yl)-N,N-dimethyl-2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide

[0187] [Reaction Formula 4]

[0188]

[0189] 2-Chloro-6-(1-(4-methoxybenzyl)-1H-indazol-4-yl)-N,N-dimethyl-5-oxo-5,6-dihydroimidazo[1,2-a]pyrimido[5,4-e]pyrimidine-8-carboxamide (0.10 g, 0.19 mmol), 3-methyl-4-(1-methylpiperidin-4-yl)aniline (0.077 g, 0.38 mmol) and trifluoroacetic acid (0.073 mL, 0.95 mmol) were dissolved in acetonitrile (2.0 mL), stirred at 80 °C for 2 h, and then concentrated. The concentrated mixture was diluted with trifluoroacetic acid (1.40 mL, 18.30 mmol), stirred at 80 °C for 4 h, and then concentrated. The concentrated mixture was purified using prep-HPLC (water (0.1% formic acid) / methanol (0.1% formic acid)) to obtain the target compound as a yellow solid (0.055 g, 0.095 mmol, 50% yield). MS (ESI): m / z 577 [M+H] +

[0190] <Example 121> to <Example 122>

[0191] The example compound of the present invention (Example 122) was prepared in a similar manner to the above Example 121, and the compound name, chemical structural formula, NMR, and LCMS analysis results of each example compound are summarized and shown in [Table 2] below.

[0192] [Table 2]

[0193]

[0194] <Experimental Example 1> Evaluation of inhibitory activity against WEE1 and PLK1 kinases

[0195] In order to evaluate the inhibitory activity of the compound synthesized according to the above example against WEE1 and PLK1 kinase, the example compound was reacted with purified human WEE1 / PLK1 enzyme and evaluated by the following method.

[0196] The reaction buffer consisted of 200 mM Tris-HCl pH 7.4, 100 mM MgCl2, 0.5 mg / mL BSA, and 0.25 mM DTT, and all test reactions were performed in the reaction buffer. The compounds were diluted from a 10 mM DMSO stock in 12-step serial dilutions, and the enzyme activity was measured at a final compound concentration of 10 to 0.000169 μM. After reacting with the appropriate concentration of WEE1 / PLK1 enzyme, purified ATP, and enzyme substrate (MBP / CDC25C) at 25 °C for 1 hour, the enzyme activity was measured in vitro using ADP-Glo TM It was confirmed using kinase assay (Promega). The enzyme activity reaction solution, ADP-Glo ​​reaction solution, and enzyme activity detection solution were reacted in a 2:2:1 ratio, and the degree of enzyme activity inhibition was measured by luminescence. The degree of enzyme activity inhibition according to the treatment concentration of each compound was calculated based on the fluorescence of enzyme activity for the solvent control group that was not treated with the compound. At this time, the concentration of each compound that inhibits enzyme activity by 50% was IC. 50(nM) value and was obtained using GraphPad Prism 9.5.1 (GraphPad software Inc., San Diego) software. The results are shown in Table 3 below.

[0197] [Table 3]

[0198]

[0199] (A: IC 50 ≤ 100 nM; B: 100 nM < IC 50 ≤ 500 nM; C: 500 nM < IC 50 )

[0200] <Experimental Example 2> Evaluation of inhibitory activity against PKMYT1 kinase

[0201] In order to evaluate the inhibitory activity of the compound synthesized according to the above example against PKMYT1 kinase, the example compound was reacted with purified human PKMYT1 enzyme and evaluated by the following method.

[0202] The reaction buffer consisted of 200 mM Tris-HCl pH 7.4, 100 mM MgCl2, 0.5 mg / mL BSA, and 0.25 mM DTT, and all test reactions were performed in the reaction buffer. The compounds were diluted from a 10 mM DMSO stock in 12-step serial dilutions, and the enzyme activity was measured at a final compound concentration of 10 to 0.000169 μM. After reacting with the appropriate concentration of PKMYT1 enzyme, purified ATP, and enzyme substrate (MBP / CDC25C) at 25 °C for 1 hour, the enzyme activity was measured in vitro using ADP-Glo TMIt was confirmed using kinase assay (Promega). The enzyme activity reaction solution, ADP-Glo ​​reaction solution, and enzyme activity detection solution were reacted in a 2:2:1 ratio, and the degree of enzyme activity inhibition was measured by luminescence. The degree of enzyme activity inhibition according to the treatment concentration of each compound was calculated based on the fluorescence of enzyme activity for the solvent control group that was not treated with the compound. At this time, the concentration of each compound that inhibits enzyme activity by 50% was IC. 50 (nM) value and was obtained using GraphPad Prism 9.5.1 (GraphPad software Inc., San Diego) software. The results are shown in Table 4 below.

[0203] [Table 4]

[0204]

[0205] (A: IC 50 ≤ 100 nM; B: 100 nM < IC 50 ≤ 500 nM; C: 500 nM < IC 50 )

[0206] As shown in Tables 3 and 4 above, it can be seen that the example compounds of the present invention exhibit high inhibitory activity against WEE1 and PKMYT1 kinases.

[0207] While the present invention has been described in detail through preferred manufacturing examples, examples, and experimental examples, the scope of the present invention is not limited to the specific examples and should be interpreted in accordance with the appended claims. Furthermore, those skilled in the art will appreciate that numerous modifications and variations are possible without departing from the scope of the present invention.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X1 and X2 are each independently CH or N; R X is -C 1-6 Haloalkyl, -C(=O)-OR X1 , or -C(=O)-NR X2 R X3 and; R X1 -H or -C 1-6 It is alkyl; R X2 and R X3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 alkylamide, or -(3-6 membered cycloalkyl), or R X2 and R X3 are connected to each other to form a -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring together with the N atom, wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkylsulfonyl, -OH, -halo, -C 1-6 Aminoalkyl, or R X4 can be replaced with; R X4 is -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl), wherein at least one H of the -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, or -halo; Ring Y is phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene), wherein at least one H of the phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -OC 1-6 may be substituted with alkyl, -halo, -C(=O)-Y1, or -Y1; Y1 is -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 may be substituted with alkyl, -halo, -(3-6 membered cycloalkyl), or -Y2; Y2 is -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 may be substituted with alkyl or halo; and Ring Z is phenyl or -(5-10 membered heteroaryl), wherein one or more H of the phenyl or -(5-10 membered heteroaryl) ring are each independently -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OH, or -halo.

2. In paragraph 1, Ring Y is , , , , , , , , , , , , , , , or person, A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, Y1 is , , , , , , , , , or person, A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, Y2 is , , , , or person, A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, Ring Z is , , , , , , or person, A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. A compound represented by the following chemical formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above chemical formula 2, X1 and X2 are each independently CH or N; R X2 and R X3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 alkylamide, or -(3-6 membered cycloalkyl), or R X2 and R X3 are connected to each other to form a -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring together with the N atom, wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Alkylsulfonyl, -OH, -halo, -C 1-6 Aminoalkyl, or R X4 can be replaced with; R X4 is -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl), wherein at least one H of the -(4-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), or -(5-6 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, or -halo; Ring Y is phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene), wherein at least one H of the phenyl, -(5-6 membered heteroaryl), or -(9-14 membered heterohydroarene) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -OC 1-6 may be substituted with alkyl, -halo, -C(=O)-Y1, or -Y1; Y1 is -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) or -(7-12 membered heterobicycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 may be substituted with alkyl, -halo, -(3-6 membered cycloalkyl), or -Y2; Y2 is -(4-6 membered heterocycloalkyl), wherein at least one H of the -(4-6 membered heterocycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 may be substituted with alkyl or halo; and R Z1 Inland R Z3 are each independently -H, -methyl, -OH, or -halo.

7. A compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

9. A pharmaceutical composition for preventing or treating cancer, containing a compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

10. In paragraph 9, A pharmaceutical composition that inhibits WEE1 and / or PKMYT1.

11. In paragraph 9, A pharmaceutical composition, wherein the cancer is a disease associated with overactivation, amplification, or overexpression of WEE1 and / or PKMYT1.

12. In paragraph 9, The cancers above are uterine cancer, endometrial cancer, papillary serous carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, uterine corpus endometrial carcinoma, cervical cancer, ovarian cancer, serous ovarian cancer, high-grade serous ovarian cancer (HGSOC), breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), rectal cancer, gastric cancer, esophageal cancer, liver cancer, hepatocellular carcinoma (LIHC), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung squamous cell carcinoma, A pharmaceutical composition comprising at least one selected from the group consisting of leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphoma, prostate cancer, bladder cancer, testicular cancer, kidney cancer, kidney renal papillary cell carcinoma (KIRP), kidney renal clear cell carcinoma (KIRC), bone cancer, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue cancer, brain cancer, glioblastoma, glioma, brain lower grade glioma (LGG), head and neck cancer, adenoid cystic carcinoma (ACC), skin cancer, melanoma, and thymoma.

13. Use of a compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of diseases associated with overactivation, amplification, or overexpression of WEE1 and / or PKMYT1.

14. A method for treating or preventing a disease associated with WEE1 and / or PKMYT1 hyperactivation, amplification, or overexpression, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

15. A method for treating uterine cancer, endometrial cancer, papillary serous carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, uterine corpus endometrial carcinoma, cervical cancer, ovarian cancer, serous ovarian cancer, high grade serous ovarian cancer (HGSOC), breast cancer, triple negative breast cancer (TNBC), pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), rectal cancer, gastric cancer, esophageal cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. A method for treating or preventing at least one disease selected from the group consisting of liver cancer, liver hepatocellular carcinoma (LIHC), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung squamous cell carcinoma, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphoma, prostate cancer, bladder cancer, testicular cancer, kidney cancer, kidney renal papillary cell carcinoma (KIRP), kidney renal clear cell carcinoma (KIRC), bone cancer, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue cancer, brain cancer, glioblastoma, glioma, brain lower grade glioma (LGG), head and neck cancer, adenoid cystic carcinoma (ACC), skin cancer, melanoma, and thymoma.