Heteroaryl derivative compound and use thereof

Abstract

The present invention relates to a heteroaryl derivative compound and a use thereof. The heteroaryl derivative of the present invention exhibits excellent inhibitory activity against AKT and / or AKT1 E17K, and thus can be effectively used for the treatment or prevention of diseases associated with AKT and / or AKT1 E17K overactivation, amplification or overexpression, and, in particular, can be effectively used as a therapeutic agent for cancer.

Description

Heteroaryl derivative compounds and their uses

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to heteroaryl derivative compounds having AKT inhibitory activity and their pharmaceutical uses.

[0002] The AKT enzyme is a type of serine / threonine protein kinase, also known as protein kinase B (PKB). AKT exists in three subtypes with very similar structures: AKT1, AKT2, and AKT3. AKT is part of the PI3K / AKT / mTOR signaling pathway and regulates fundamental cellular activities such as growth, division, metabolism, transcription, and apoptosis. Dysregulation of AKT signaling is known to be a cause of cancer and metabolic disorders. AKT hyperactivation has been identified in breast, ovarian, pancreatic, and prostate cancers, and this is known to promote cancer cell survival and proliferation. For this reason, research is underway to develop AKT inhibitors as potential therapeutic agents that disrupt abnormal AKT signaling.

[0003] AKT inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric AKT inhibitors (CAAI). ATP-competitive inhibitors compete with ATP to bind to AKT, allosteric inhibitors interact with the Pleckstrin homology (PH) domain to maintain the AKT protein in an inactive form, and covalent-allosteric AKT inhibitors form covalent bonds to exhibit stronger inhibitory activity and can also act selectively.

[0004] The most common mutation in AKT is AKT1 E17K (E17K: mutation of glutamic acid at position 17 to lysine), and it has been reported in 6–8% of breast cancers, 2–6% of colorectal cancers, and 6% of meningiomas.

[0005] This patent proposes a compound that is a covalent-allosteric AKT inhibitor that exhibits potent and selective inhibitory activity by forming a covalent bond with lysine of AKT, specifically AKT1 E17K.

[0006] The object of the present invention is to provide a heteroaryl derivative of a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] Another objective of the present invention is to provide a method for preparing the above heteroaryl derivative compound.

[0008] Another objective of the present invention is to provide a pharmaceutical use for the heteroaryl derivative compound, specifically to provide a pharmaceutical composition for the treatment or prevention of AKT-related diseases comprising the heteroaryl derivative compound as an active ingredient.

[0009] Another objective of the present invention is to provide a method for treating or preventing AKT-related diseases using the said compound, or a method for treating or preventing AKT-related diseases comprising the step of administering the said compound.

[0010] In order to achieve the above objective, the inventors completed the present invention by confirming, through their research efforts, that heteroaryl derivative compounds represented by Chemical Formula 1 mentioned below inhibit the proliferation of cells in which AKT and / or AKT1 E17K are overactivated, amplified, or overexpressed.

[0011] The following describes this in detail. All combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention should not be considered limited by the following detailed description.

[0012] heteroaryl derivative compounds

[0013] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] W is CH or N;

[0018] Either one of the X1 and X2 pair or the X2 and X3 pair is connected to form a 5-6 member ring, wherein if X1 and X2 are connected to form a 5-6 member ring, X3 is -H, and if X2 and X3 are connected to form a 5-6 member ring, X1 is -H, the 5-6 member ring may contain one or more N, O, or S atoms within the ring, the 5-6 member ring may be an aromatic ring or a non-aromatic ring, and one or more H atoms of the 5-6 member ring are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo;

[0019] Y1 to Y5 are each independently CR Y or N and;

[0020] R Y is -H, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -NH2, -NH-C 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), -OH, -OC 1-3 Alkyl, or -halo, and;

[0021] Z1 to Z5 are each independently CR Z or N and;

[0022] R Z is -H, -C 1-3 Alkyl, -CN, -C(=O)H, -OH, -OC 1-3 Alkyl, or -halo, and;

[0023] Ring A is -phenyl, -(9-10-membered aryl), -(9-10-membered hydroaryl), -(5-6-membered heteroaryl), -(9-10-membered heterohydroaryl), -(6-9-membered bicycloalkyl), -cubanyl, -(14-15-membered tricycloalkyl), or -(14-15-membered heterotricycloalkyl), where one or more H of ring A are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo;

[0024] Ring B is -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), -(9-10-membered heterohydroaryl), or nothing (null), wherein the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) comprises one or more N atoms within the ring, and one or more H of the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) ring is -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo;

[0025] m is 0, 1, or 2, and;

[0026] L is -NH-, -NH-C(=O)-(CH2)n-, or -C(=O)-NH-(CH2)n- and;

[0027] n is 0, 1, or 2.

[0028] According to one embodiment of the present invention,

[0029] W is CH or N;

[0030] Either one of the X1 and X2 pair or the X2 and X3 pair is connected to form a 5-6 member ring, wherein if X1 and X2 are connected to form a 5-6 member ring, X3 is -H, and if X2 and X3 are connected to form a 5-6 member ring, X1 is -H, the 5-6 member ring may contain one or more N, O, or S atoms within the ring, the 5-6 member ring may be an aromatic ring or a non-aromatic ring, and one or more H atoms of the 5-6 member ring are -C 1-3 It can be substituted with an alkyl or -halo group;

[0031] Y1 to Y5 are each independently CR Y or N and;

[0032] R Y is -H, -NH2, or -halo;

[0033] Z1 to Z5 are each independently CR Z or N and;

[0034] R Z is -H, -CN, -C(=O)H, or -OH;

[0035] Ring A is -phenyl, -(9-10-membered hydroaryl), -(5-6-membered heteroaryl), -(9-10-membered heterohydroaryl), -(6-9-membered bicycloalkyl), -cubanyl, -(14-15-membered tricycloalkyl), or -(14-15-membered heterotricycloalkyl), where one or more H of ring A are -C 1-3 It can be substituted with an alkyl group;

[0036] Ring B is -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), -(9-10-membered heterohydroaryl), or nothing (null), wherein the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) comprises one or more N atoms within the ring, and one or more H of the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) ring may be substituted with -halo;

[0037] L is -NH-, -NH-C(=O)-(CH2)n-, or -C(=O)-NH-(CH2)n- and;

[0038] m is 0 or 1 and;

[0039] n can be 0 or 1.

[0040] According to one embodiment of the present invention,

[0041] go In the case of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or and, here, the above One or more Hs of the ring are -C 1-3 Alkyl, -C 1-3 It can be substituted with haloalkyl or -halo.

[0042] In addition, according to one embodiment of the present invention,

[0043] go In the case of , , , , , , , , , , , , , or and, here, the above One or more Hs of the ring are -C 1-3 It can be substituted with alkyl or -halo groups.

[0044] According to one embodiment of the present invention,

[0045] Is , , , , , , , , , , , , , , , , , , , , , or and, here, the above One or more Hs of the ring are -C 1-3Alkyl, -C 1-3 It can be substituted with haloalkyl or -halo.

[0046] In addition, according to one embodiment of the present invention,

[0047] Is or and, here, the above One or more Hs of the ring are -C 1-3 It can be substituted with alkyl or -halo groups.

[0048] According to one embodiment of the present invention,

[0049] Is , , , , , , , , , or and, here One or more Hs of the ring are -C 1-3 Alkyl, -C 1-3 Haloalkyl, -NH2, -NH-C 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), -OH, -OC 1-3 It can be substituted with alkyl or -halo groups.

[0050] In addition, according to one embodiment of the present invention,

[0051] Is , , or and, here One or more H groups of the ring can be substituted with -NH2 or -halo groups.

[0052] According to one embodiment of the present invention,

[0053] Is , , , , , , , , , or and, here One or more Hs of the ring are -C 1-3 Alkyl, -CN, -C(=O)H, -OH, -OC 1-3 It can be substituted with alkyl or -halo groups.

[0054] In addition, according to one embodiment of the present invention,

[0055] Is or and, here One or more H atoms in the ring are -CN, -C(=O)H, -OH, -OC 1-3 It can be substituted with alkyl or -halo groups.

[0056] According to one embodiment of the present invention,

[0057] Ring A is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And;

[0058] #Is It is connected to, where one or more Hs of ring A are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo;

[0059] ## may be connected to (CH2)m.

[0060] In addition, according to one embodiment of the present invention,

[0061] Ring A is , , , , , , , , or And;

[0062] #Is It is connected to, where one or more Hs of ring A are -C 1-3 It can be substituted with an alkyl group;

[0063] ## may be connected to (CH2)m.

[0064] According to one embodiment of the present invention,

[0065] Ring B is , , , , , , , , , , , , , , , , , or nothing (null), where one or more Hs of ring B are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo;

[0066] * is connected to L;

[0067] ** could be connected to (CH2)m.

[0068] In addition, according to one embodiment of the present invention,

[0069] Ring B is , , , , , or nothing (null), where one or more Hs of ring B can be substituted with -halos;

[0070] * is connected to L;

[0071] ** could be connected to (CH2)m.

[0072] According to one embodiment of the present invention,

[0073] L can be -NH-, -NH-C(=O)-, -NH-C(=O)-(CH2)-, -C(=O)-NH-, or -C(=O)-NH-(CH2)-.

[0074] According to a specific embodiment of the present invention, the compound represented by Chemical Formula 1 may be selected from the group consisting of compounds listed in Table 1 below.

[0075] In the present invention, "alkyl" may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon combined with such acyclic hydrocarbon, unless otherwise specified. For example, "C 1-6"alkyl" may mean an alkyl containing 1 to 6 carbon atoms. Acyclic alkyls may include, as examples, methyl, ethyl,n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylpentyl, but are not limited thereto. In this specification, a residue obtained by removing one hydrogen atom from the "alkyl" is referred to as "alkylene." Cyclic alkyls may be used interchangeably with "cycloalkyl" in this specification and may include, as examples, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, but are not limited thereto.

[0076] In the present invention, "alkenyl" and "alkynyl" may refer to straight-chain or branched-chain acyclic, cyclic, or combined unsaturated hydrocarbons. For example, "C 2-6 "Alkenyl" may refer to an unsaturated hydrocarbon having 2 to 6 carbon atoms having one or more double bonds, and "C 2-6 "Alkynyl" may mean an unsaturated hydrocarbon with 2 to 6 carbon atoms having one or more triple bonds.

[0077] In the present invention, "alkoxy" may mean an alkyl ether group -(R'-OR"), where R' is a single bond and C 1-6 It can be selected from the group consisting of alkyls, and R" is C 1-6 It may be an alkyl. Here, the alkyl is as defined above. For example, "C 1-6 "of alkoxy" is C 1-6 Alkoxy containing an alkyl group, i.e., -(OC 1-6 alkyl) or -(C 1-6 Alkyl-OC 1-6It may mean alkyl, and examples of alkoxy may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, but are not limited thereto.

[0078] In the present invention, "halo" may be F, Cl, Br, or I.

[0079] In the present invention, "haloalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with one or more halos as defined herein. Examples of said haloalkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl independently substituted with one or more halogens, e.g., F, Cl, Br, or I.

[0080] In the present invention, "hydroxyalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with a hydroxy (OH). Examples of the hydroxyalkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl independently substituted with -OH.

[0081] In the present invention, "alkylamino" or "aminoalkyl" may mean -(NR'R"), where R' and R' are each independently hydrogen, C 1-6 It may be selected from the group consisting of alkyl groups and N protecting groups (e.g., Boc), and the selected R' and R" may each be independently substituted or unsubstituted. Additionally, "C 0-6 "Alkylamino" refers to an amino (-NH2) or C that does not contain an alkyl group. 1-6Amino containing an alkyl group, i.e., -NH(C 1-6 alkyl) or -N(C 1-6 It may mean alkyl)2 and may include dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino, but is not limited thereto.

[0082] In the present invention, "cyanoalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with cyano(CN).

[0083] In the present invention, "alkylsulfonyl" may mean -(R'-S(=O)2-R"), where R' is a single bond and C 1-6 It can be selected from the group consisting of alkyl groups, and R" is hydroxyl and C 1-6 It can be selected from the group consisting of alkyl groups. The selected R' and R" may each be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylsulfonyl" refers to a sulfonic acid group (-S(=O)2OH) or C that does not contain an alkyl group. 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 It may mean alkyl, and may include methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, ethylsulfonyl, (ethylsulfonyl)methyl, and (ethylsulfonyl)ethyl, but is not limited thereto.

[0084] In the present invention, "alkyl carbonyl" may mean -(R'-C(=O)-R"), where R' is a single bond and C 1-6 It can be selected from the group consisting of alkyls, and R" is hydrogen and C 1-6 It can be selected from the group consisting of alkyl groups. The selected R' and R" may each be independently substituted or unsubstituted. In addition, "C 0-6"Alkyl carbonyl" refers to an aldehyde group (-C(=O)H) or C that does not contain an alkyl group. 1-6 A ketone group containing an alkyl group, i.e., -C(=O)-(C 1-6 alkyl) or -(C 1-6 Alkyl)-C(=O)-(C 1-6 It can mean alkyl.

[0085] In the present invention, "cycloalkyl" may mean a hydrocarbon ring that does not contain heteroatoms (N, O, P, P(=O), or S, etc.) within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as a cycloalkene. Unless otherwise noted, a cycloalkyl may be a single ring or a polycyclic ring such as a spiro ring, a bridged ring, or a fused ring.

[0086] 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, if unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise noted, heterocycloalkyl may be a single ring or a multiple ring such as a spiro ring, a bridged ring, or a fused ring. Additionally, "3 to 12 atoms of heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 ring-forming atoms, and as an example, the heterocycloalkyl may include, but is not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolein, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomopoline, thiomopoline-S-oxide, thiomopoline-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, tetrahydrofuran, tetrahydrothiophene, etc.

[0087] In the present invention, "bicycloalkyl" may refer to a double ring, such as a spiro ring, a bridged ring, or a fused ring, within an aromatic hydrocarbon ring, and may be saturated or partially unsaturated. If unsaturated, it may be referred to as a bicycloalkene. Examples of bicycloalkyl may include, but are not limited to, bicyclo[2.2.2]octane or (1r,5s)-3-bicyclo[3.2.1]octane.

[0088] In the present invention, "heterobicycloalkyl" may mean a double ring such as a spiro ring, a bridged ring, or a fused 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, if unsaturated, it may be referred to as a heterobicycloalkene. Examples of heterobicycloalkyl may include, but are not limited to, quinuclidein, 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.

[0089] In the present invention, "tricycloalkyl" may refer to a triple ring in which a spiro ring, a bridged ring, or a fused ring is connected to an aromatic hydrocarbon ring, and may be saturated or partially unsaturated. If unsaturated, it may be referred to as a tricycloalkene. Examples of tricycloalkyls may include, but are not limited to, spiro[cyclohexane-1.1']indene.

[0090] In the present invention, "heterotricycloalkyl" may refer to a triple ring in which a spiro ring, a bridged ring, or a fused ring is connected and contains one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as a heterotricycloalkene. Examples of heterotricycloalkyl may include, but are not limited to, spiro[cyclohexane-1.3']indoline or spiro[cyclohexane-1.1']indoline.

[0091] In the present invention, "arene" may refer to 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 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaternbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluorantene, chrysene, etc. In this specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl".

[0092] In the present invention, "heteroarene" may be a ring comprising one or more of O, N, P, Si, and S as heteroelements. The number of ring-forming atoms of the heteroarene may be 3 or more and 30 or less, 3 or more and 20 or less, or 3 or more and 15 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 heteroalenes include thiophene, purine, pyrrole, pyrazol, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, pyridin-2-one, pyridin-3-one, pyridin-4-one, bipyridine, triazine, acryl, pyridazine, pyrazine, quinoline, quinazolin, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, Examples include, but are not limited to, benzoxazole, benzimidazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isooxazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilol, and dibenzofuran. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocycloarene comprising an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In this specification, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".

[0093] In the present invention, "hydroalene" or "hydroaryl" is a saturated form of one or more double bonds in an aromatic hydrocarbon ring.

[0094] In the present invention, "heterohydroarene" may mean a polycyclic ring (2 to 4 rings) containing 1 to 5 heteroatoms selected from N, O, and S as ring-forming atoms, at least one of the polycyclic rings may be a saturated or partially unsaturated ring, and at least one other may have an aromatic ring. In this specification, a residue obtained by removing one hydrogen atom from the "heterohydroarene" is referred to as "heterohydroaryl".

[0095] In the present invention, the "ring" may be a single ring or multiple rings. The multiple rings may be a spiro ring, a bridged ring, or a fused ring.

[0096] In the present invention, "stereoisomer" refers to a compound having the same chemical formula or molecular formula but differing stereochemically. In this specification, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemies, and mixtures thereof are also included within the scope of the present invention. For example, the compound represented by Formula 1 of the present invention may include the stereoisomers of Formula 1 because its stereochemical structure is not specified. Unless otherwise noted, solid line bonds connected to an asymmetric carbon atom It is a wedge-shaped solid line connection representing an absolute arrangement of three-dimensional centers. or wedge-shaped dotted joint It may include.

[0097] The compound represented by Formula 1 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 compound represented by Formula 1. The term "pharmaceutically acceptable salt" of the present invention refers to any organic acid or inorganic acid addition salt of said compound, wherein the side effects caused by said salt do not impair the beneficial efficacy of the compound represented by Formula 1, at a concentration that has a relatively non-toxic and harmless active effect on the patient.

[0098] In particular, the above pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, phosphoric acid, etc., non-toxic organic acids such as aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and 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.

[0099] These types of pharmaceutically acceptable salts may include sulfates, sulfites, nitrates, phosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maliates, benzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, glycolates, malates, tartrates, mandelates, etc.

[0100] The above acid addition salt can be prepared by conventional methods, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid, and filtering and drying the resulting precipitate, or by vacuum distilling the solvent and excess acid, drying, and crystallizing under an organic solvent.

[0101] In addition, the above pharmaceutically acceptable salt may be a salt obtained using a base or a metal salt. As an example of a metal salt, an alkali metal or alkaline earth metal salt may be obtained by dissolving a compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. Sodium, potassium, or calcium salts may be pharmaceutically suitable as alkali metal salts. In addition, the corresponding salt may be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate) and may be prepared through a method of salt preparation known in the art.

[0102] Uses of heteroaryl derivative compounds

[0103] The present invention provides the use of a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0104] [Chemical Formula 1]

[0105]

[0106] The above chemical formula 1 is as defined above.

[0107] The present invention provides the use of compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0108] The compounds of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof exhibit inhibitory activity against AKT.

[0109] According to one embodiment of the present invention, since the compound of the present invention exhibits excellent inhibitory activity against AKT, it can be usefully used for the treatment or prevention of AKT-related diseases, particularly cancer. In particular, since the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against AKT mutations (e.g., AKT1-E17K, etc.), it can be usefully used for the treatment or prevention of carcinomas induced by AKT.

[0110] In the present invention, the cancer includes all cancers capable of exhibiting therapeutic or preventive efficacy due to the inhibition of AKT activity, may be solid tumors or blood cancers, and includes not only primary cancers but also metastatic cancers.

[0111] As specific examples, solid tumors may be one or more from the group consisting of uterine cancer, ovarian cancer, breast cancer, gastrointestinal tract cancer, lung and thoracic cancer, genitourinary cancer, head and neck cancer, brain and nervous system tumors, endocrine tumors, bone and soft tissue tumors, and skin cancer, but are not limited thereto.

[0112] The above uterine cancer may be cervical cancer, endometrial cancer, papillary serous endometrial carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, or uterine corpus endometrial carcinoma.

[0113] The above ovarian cancer may be serous ovarian cancer or high-grade serous ovarian cancer (HGSOC).

[0114] The above breast cancer may be Luminal A breast cancer, Luminal B breast cancer, or triple-negative breast cancer (TNBC).

[0115] The above gastrointestinal tract cancer may be pancreatic cancer such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), rectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), esophageal cancer, bile duct cancer, biliary tract cancer, or liver cancer such as hepatocellular carcinoma (HCC).

[0116] The above lung and thoracic cancer may be small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), thymic cancer, mesothelioma, or squamous cell carcinoma of the lung.

[0117] The above thymic cancer may be a thymoma.

[0118] 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).

[0119] The above head and neck cancer may be head and neck squamous cell carcinoma (HNSCC) or adenoid cystic carcinoma (ACC).

[0120] The above brain and central nervous system tumor may be brain cancer, glioblastoma, glioma, or brain lower-grade glioma (LGG).

[0121] The above endocrine tumors may be thyroid cancer, parathyroid cancer, or adrenal cancer.

[0122] The above bone and soft tissue tumor may be bone cancer or soft tissue cancer, such as osteosarcoma, Ewing sarcoma, or chondrosarcoma.

[0123] The above skin cancer may be melanoma.

[0124] As a specific example, blood cancers may include leukemia such as chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL); multiple myeloma; anaplastic large cell lymphoma (ALCL); lymphoma; or non-Hodgkin lymphoma.

[0125] According to one embodiment of the present invention, the present invention provides a pharmaceutical composition for the treatment or prevention of an AKT-related disease comprising, as an active ingredient, a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Specifically, the AKT-related disease may be cancer. The types of cancer are as described above.

[0126] The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicinal effects in addition to the compound represented by Formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof.

[0127] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared to be administered in various oral and parenteral formulations.

[0128] In addition, according to one embodiment of the present invention, the present invention provides a use of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of AKT-related diseases. The compound of the present invention for the manufacture of the medicament may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be manufactured as a complex formulation with other active agents to have a synergistic effect of the active ingredients.

[0129] In addition, according to one embodiment of the present invention, the present invention provides a use of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the prevention or treatment of cancer. The types of cancer are as described above.

[0130] In addition, according to one embodiment of the present invention, the present invention provides a method for treating or preventing an AKT-related disease, comprising the step of administering a therapeutically effective amount of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal, including humans. Specifically, the AKT-related disease may be cancer. The types of cancer are as described above.

[0131] In addition, according to one embodiment of the present invention, the present invention provides a method for preventing or treating cancer, comprising the step of administering a therapeutically effective amount of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The types of cancer are as described above.

[0132] In addition, according to one embodiment of the present invention, the present invention provides a method for inhibiting AKT, comprising the step of administering a therapeutically effective amount of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0133] The term "therapeutically effective amount" as used in the present invention refers to an amount of the compound represented by Formula 1 that is effective for the treatment or prevention of AKT-related diseases. Specifically, "therapeutically effective amount" means an amount sufficient to treat the disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including individual type and severity, age, gender, type of disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. It may also be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by considering all of the above factors, and this can be easily determined by a person skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert based on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used even at doses greater than the determined dosage.

[0134] As used in the present invention, "prevention" refers to any act of suppressing or delaying the occurrence, spread, and recurrence of the said disease through the administration of the said compound, and "treatment" refers to any act of improving or beneficially altering the symptoms of the said disease through the administration of the said compound.

[0135] Additionally, according to one embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, a diluent, or an excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0136] Examples of additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizing aids, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, etc. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0137] The above pharmaceutical composition may be formulated into various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups, or emulsions) or parenteral administration (e.g., intramuscular, intravenous, or subcutaneous injection).

[0138] For example, the above pharmaceutical composition may be formulated as an oral administration preparation, and the additives used therein 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 dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms may be formulated by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., with the above composition. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used. In addition, liquid formulations for oral administration may include suspensions, emulsions, syrups, etc., and may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.

[0139] In addition, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, Witepsol, Macrogol, Tween 61, cacao oil, laurin oil, glycerogelatin, etc. may be used. Meanwhile, injectable preparations may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0140] In addition, it can be manufactured as a complex formulation with other active agents to have a synergistic effect of the active ingredients.

[0141] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they contradict one another.

[0142] The heteroaryl derivative compounds of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof exhibit excellent inhibitory activity against kinases, particularly AKT and / or AKT1 E17K, and thus can be usefully used for the treatment or prevention of diseases associated with the overactivation, amplification, or overexpression of AKT and / or AKT1 E17K, and particularly usefully used as therapeutic agents for cancer.

[0143] The present invention will be explained in detail below through examples and experimental examples. However, the following manufacturing examples, examples, and experimental examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

[0144] <Analysis and Purification Conditions>

[0145] The compounds synthesized in the manufacturing examples and embodiments of the present invention were purified or structurally analyzed under the following conditions.

[0146] 1. LC-MS, Prep-HPLC, MPLC

[0147] Analytical LC-MS (Liquid Chromatography-Mass Spectrometry)

[0148] Equipment equipped with a Waters mass QDa detector on a Waters UPLC system (ACQUITY UPLC PDA Detector) was used. Waters' ACQUITY UPLC ® A BEH C18 (1.7 μm, 2.1 x 50 mm) column was used, and the column temperature was set to 30 ℃.

[0149] Mobile phase A was water containing 0.1% formic acid, and mobile phase B was acetonitrile containing 0.1% formic acid.

[0150] Gradient condition (10-100% B for 3 min, flow rate = 0.6 mL / min)

[0151] Preparative Preparative-Liquid chromatography UV spectrometry (Prep-HPLC)

[0152] The Teledyne ACCQPrep HP150 equipment was used. Waters' XTERRA ® Prep RP18 OBD TM A (10 µm, 30 x 300 mm) column was used, and the column temperature was set to room temperature.

[0153] Gradient condition (10-100% B for 120 min, flow rate = 42 mL / min)

[0154] Medium pressure liquid chromatography (MPLC) for purification

[0155] Medium pressure liquid chromatography was performed using Teledyne ISCO's CombiFlash RF + UV.

[0156] 2. NMR Interpretation

[0157] NMR analysis was performed using a Bruker NMR AVANCE NEO 400 MHz, and data were expressed in ppm (parts per million(δ)).

[0158] The commercially available reagents used were used without additional purification. In the present invention, room temperature or ambient temperature refers to a temperature of approximately 5°C to 40°C, for example, 10°C to 30°C, or for another example, 20°C to 27°C, but is not strictly limited to the above range. A rotary evaporator was used for concentration under reduced pressure or solvent distillation removal.

[0159] Preparation Example: Preparation of the intermediate compound of the present invention

[0160] Preparation Example 1. Preparation of 2-chloro-3-nitro-quinoline

[0161] [Reaction Equation 1]

[0162]

[0163] 3-Nitroquinoline-2-ol (450.00 mg, 2.37 mmol) phosphoryl chloride (POCl3, It was added to 4.50 mL and stirred at 95 °C for 12 hours. After confirming the target compound using LC-MS, the reaction mixture was added to 10 mL of water at 0 °C. Water ammonia was added to adjust the pH of the solution to 8, and the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated to remove the remaining water using sodium sulfate, thereby obtaining the target compound as a yellow solid (400 mg, 80% yield).

[0164] 1 H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.14 (d,J= 8.4 Hz, 1H), 8.04 - 7.90 (m, 2H), 7.82 - 7.69 (m, 1H); MS (ESI): m / z = 208.9 [M+H] +

[0165] Example: Preparation of the compound of the present invention

[0166] Example 1. Preparation of 4-((1-(4-(2-(2-aminopyridine-3-yl)-3H-imidazo[4,5-b]quinoline-3-yl)benzyl)piperidine-4-yl)amino)pyrimidine-2-carbonitrile

[0167] [Reaction Equation 2]

[0168]

[0169] [Step 1] Preparation of tert-butyl 4-((2-cyanopyrimidine-4-yl)amino)piperidine-1-carboxylate

[0170] 4-chloropyrimidine-2-carbonitrile (2.00 g, 14.33 mmol) and tert-butyl 4-aminopiperidin-1-carboxylate (2.87 g, 14.33 mmol) were dissolved in acetonitrile (80 mL), then N,N-diisopropylethylamine (DIPEA, 5.56 g, 43.00 mmol) was added and stirred at room temperature for 12 hours. After identifying the target compound using LC-MS, the organic matter was extracted with water and ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain the target compound as a white solid (3.40 g, 77% yield). MS (ESI): m / z = 304.2 [M+H] +

[0171] [Step 2] Preparation of 4-(piperidine-4-ylamino)pyrimidine-2-carbonitrile

[0172] The tert-butyl 4-((2-cyanopyrimidine-4-yl)amino)piperidine-1-carboxylate (3.40 g, 11.21 mmol) obtained in Step 1 was dissolved in dichloromethane (175 mL), and then trifluoroacetic acid (TFA, 26.09 g, 228.86 mmol) was added and stirred at room temperature for 30 minutes. After confirming the target compound using LC-MS, the reaction mixture was concentrated to obtain a white solid target compound (2.34 g, TFA salt). MS (ESI): m / z = 204.2 [M+H] +

[0173] [Step 3] Preparation of 4-((1-(4-nitrobenzyl)piperidine-4-yl)amino)pyrimidine-2-carbonitrile

[0174] The 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile (1.00 g, 4.92 mmol, TFA) obtained in Step 2 was dissolved in N,N-dimethylformamide (DMF, 10 mL), and then potassium carbonate (2.04 g, 14.76 mmol) and 1-(bromomethyl)-4-nitro-benzene (1.06 g, 4.92 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. After identifying the target compound using LC-MS, the organic material was extracted with water and ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (petroleum ether / ethyl acetate = 3 / 1 to 0 / 1), and a white solid target compound (1.00 g, 54% yield) was obtained. MS (ESI): m / z = 339.0 [M+H] +

[0175] [Step 4] Preparation of 4-((1-(4-aminobenzyl)piperidine-4-yl)amino)pyrimidine-2-carbonitrile

[0176] The 4-((1-(4-nitrobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (1.00 g, 2.96 mmol) obtained in Step 3 was dissolved in tetrahydrofuran (THF, 25 mL), and then an aqueous ammonium chloride solution (3 M, 5 mL) was added. Zn-Cu (1.91 g, 14.78 mmol) was slowly added to the reaction mixture at 0 °C, followed by stirring at room temperature for 12 hours. After identifying the target compound using LC-MS, the organic matter was extracted with water and ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by prep-HPLC, yielding the target compound as a red solid (360.00 mg, 36% yield). MS (ESI): m / z = 309.0 [M+H] +

[0177] [Step 5] Preparation of 4-((1-(4-((3-nitroquinoline-2-yl)amino)benzyl)piperidine-4-yl)amino)pyrimidine-2-carbonitrile

[0178] 4-((1-(4-aminobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (360.00 mg, 1.17 mmol) obtained in Step 4 and 2-chloro-3-nitro-quinoline (365.28 mg, 1.75 mmol) obtained in Preparation Example 1 were dissolved in dioxane (6 mL), and then cesium carbonate (1.14 g, 3.50 mmol) and Xantphos Pd G4 (112.35 mg, 0.117 mmol) were added under nitrogen gas. The reaction mixture was stirred at 100 °C for 12 hours. After confirming the target compound using LC-MS, the reaction mixture was filtered through Celite and concentrated. The concentrated mixture was purified by MPLC (petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) and the target compound as a red solid (310.00 mg, 55% yield) was obtained.

[0179] 1 H NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.26 (s, 1H), 8.10 - 8.00 (m, 3H), 7.89 - 7.77 (m, 3H), 7.70 (d,J= 8.4 Hz, 1H), 7.48 - 7.39 (m, 1H), 7.31 (d,J= 8.4 Hz, 2H), 6.66 (d,J= 6.0 Hz, 1H), 3.79 (dd,J= 1.2, 4.0 Hz, 1H), 3.47 (s, 2H), 2.81 (d,J= 11.2 Hz, 2H), 2.11 (t,J=10.8 Hz, 2H), 1.87 (d,J= 10.0 Hz, 2H), 1.57 - 1.37 (m, 2H); MS (ESI): m / z = 481.2 [M+H] +

[0180] [Step 6] Preparation of 4-((1-(4-((3-aminoquinoline-2-yl)amino)benzyl)piperidine-4-yl)amino)pyrimidine-2-carbonitrile

[0181] The 4-((1-(4-((3-nitroquinoline-2-yl)amino)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (310.00 mg, 645.13 μmol) obtained in Step 5 was dissolved in THF (6 mL), and then an aqueous ammonium chloride solution (3 M, 1 mL) was added. Zn-Cu (415.91 mg, 3.23 mmol) was slowly added to the reaction mixture at 0 °C, followed by stirring at room temperature for 12 hours. After confirming the target compound using LC-MS, the organic material was extracted with water and ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate to obtain the target compound as a yellow solid (340.00 mg, crude). MS (ESI): m / z = 451.2 [M+H] +

[0182] [Step 7] Preparation of 4-((1-(4-(2-(2-aminopyridine-3-yl)-3H-imidazo[4,5-b]quinoline-3-yl)benzyl)piperidine-4-yl)amino)pyrimidine-2-carbonitrile

[0183] The 4-((1-(4-((3-aminoquinoline-2-yl)amino)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (150.00 mg, 332.94 μmol) obtained in Step 6 was dissolved in acetic acid (5 mL) and methanol (0.5 mL), after which sodium perborate (NaBO3, 49.85 mg, 499.40 μmol) and 2-aminopyridine-3-carbaldehyde (60.99 mg, 499.40 μmol) were added. The reaction mixture was stirred at 60 °C for 5 hours. After confirming the target compound using LC-MS, water (50 mL) was added to the reaction mixture. Saturated potassium carbonate aqueous solution was added to adjust the pH of the solution to 8, and the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by prep-HPLC, and the target compound as a yellow solid (26.41 mg, 14% yield) was obtained. MS (ESI): m / z = 553.2 [M+H] +

[0184] <Examples 1> to <Examples 48>

[0185] All other example compounds of the present invention (Examples 2 to 48) were prepared in a manner similar to Example 1 above, and the chemical structural formula, compound name, NMR, and LC-MS analysis results of each example compound are summarized in [Table 1] below.

[0186] [Table 1]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] Experimental Example 1. Evaluation of Inhibition of Growth and Proliferation in AKT1-E17K Mutated Ba / F3 Cells

[0201] To evaluate the inhibition of cell proliferation by the compound of the example of the present invention, the following experiment was performed. Ba / F3-AKT1-E17K cells expressing AKT1-E17K protein were seeded into White-96-well flat-bottom plates (Corning #3903) at a concentration of 3,000 cells / well and cultured for 16 hours under conditions of 37°C and 5% CO2. The cells were cultured in RPMI1640 medium (Gibco #11875093) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin / streptomycin. The compound was treated by serially diluting it threefold in 11 concentrations in dimethyl sulfoxide (DMSO) to a final concentration of 1.5 nM - 10 μM. As a control group, DMSO was applied at a concentration of 0.5% (v / v), identical to that used for compound treatment. Cells treated with the compounds were cultured at 37°C in 5% CO2 for 72 hours. To verify cell viability, 100 μL of Cell Titer-Glo (Promega #G7573) was added to the culture medium of the cells and incubated at room temperature for 10 minutes; subsequently, luminescence values ​​were measured using a microplate reader (SynergyNeo2, Biotek). The degree of cell proliferation inhibitory activity according to the treatment concentration of each compound was calculated based on the luminescence values ​​of the control cells that were not treated with the compounds. The concentration GI at which cell proliferation inhibitory activity reached 50% was used as the reference. 50 (μM) values ​​were calculated using GraphPad Prism 9.3.1 (GraphPad software Inc., San Diego). The results are shown in Table 2 below.

[0202] [Table 2]

[0203]

[0204] As shown in Table 2 above, it can be confirmed that the compounds of the embodiments of the present invention exhibit excellent proliferation inhibitory activity against AKT gene mutant cells.

[0205] Although the present invention has been described in detail through preferred embodiments and experimental examples, the scope of the invention is not limited to the compounds of specific embodiments and should be interpreted according to the appended claims. Furthermore, those skilled in the art will understand that many modifications and variations are possible without departing from the scope of the 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, W is CH or N; Either one of the X1 and X2 pair or the X2 and X3 pair is connected to form a 5-6 member ring, wherein if X1 and X2 are connected to form a 5-6 member ring, X3 is -H, and if X2 and X3 are connected to form a 5-6 member ring, X1 is -H, the 5-6 member ring may contain one or more N, O, or S atoms within the ring, the 5-6 member ring may be an aromatic ring or a non-aromatic ring, and one or more H atoms of the 5-6 member ring are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo; Y1 to Y5 are each independently CR Y or N and; R Y is -H, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -NH2, -NH-C 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), -OH, -OC 1-3 Alkyl, or -halo, and; Z1 to Z5 are each independently CR Z or N and; R Z is -H, -C 1-3 Alkyl, -CN, -C(=O)H, -OH, -OC 1-3 Alkyl, or -halo, and; Ring A is -phenyl, -(9-10-membered aryl), -(9-10-membered hydroaryl), -(5-6-membered heteroaryl), -(9-10-membered heterohydroaryl), -(6-9-membered bicycloalkyl), -cubanyl, -(14-15-membered tricycloalkyl), or -(14-15-membered heterotricycloalkyl), where one or more H of ring A are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo; Ring B is -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), -(9-10-membered heterohydroaryl), or nothing (null), wherein the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) comprises one or more N atoms within the ring, and one or more H of the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) ring is -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo; m is 0, 1, or 2, and; L is -NH-, -NH-C(=O)-(CH2)n-, or -C(=O)-NH-(CH2)n- and; n is 0, 1, or 2.

2. In Paragraph 1, W is CH or N; Either one of the X1 and X2 pair or the X2 and X3 pair is connected to form a 5-6 member ring, wherein if X1 and X2 are connected to form a 5-6 member ring, X3 is -H, and if X2 and X3 are connected to form a 5-6 member ring, X1 is -H, the 5-6 member ring may contain one or more N, O, or S atoms within the ring, the 5-6 member ring may be an aromatic ring or a non-aromatic ring, and one or more H atoms of the 5-6 member ring are -C 1-3 It can be substituted with an alkyl or -halo group; Y1 to Y5 are each independently CR Y or N and; R Y is -H, -NH2, or -halo; Z1 to Z5 are each independently CR Z or N and; R Z is -H, -CN, -C(=O)H, or -OH; Ring A is -phenyl, -(9-10-membered hydroaryl), -(5-6-membered heteroaryl), -(9-10-membered heterohydroaryl), -(6-9-membered bicycloalkyl), -cubanyl, -(14-15-membered tricycloalkyl), or -(14-15-membered heterotricycloalkyl), where one or more H of ring A are -C 1-3 It can be substituted with an alkyl group; Ring B is -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), -(9-10-membered heterohydroaryl), or nothing (null), wherein the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) comprises one or more N atoms within the ring, and one or more H of the -(4-7-membered heterocycloalkyl), -(6-10-membered heterobicycloalkyl), or -(9-10-membered heterohydroaryl) ring may be substituted with -halo; L is -NH-, -NH-C(=O)-(CH2)n-, or -C(=O)-NH-(CH2)n- and; m is 0 or 1 and; n is 0 or 1; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. In Paragraph 1, go In the case of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or and, here, the above One or more Hs of the ring are -C 1-3 Alkyl, -C 1-3 That which can be substituted with a haloalkyl or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. In Paragraph 1, Is , , , , , , , , , , , , , , , , , , , , , or and, here, the above One or more Hs of the ring are -C 1-3 Alkyl, -C 1-3 That which can be substituted with a haloalkyl or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. In Paragraph 1, Is , , , . , , , , , or, and, here One or more Hs of the ring are -C 1-3 Alkyl, -C 1-3 Haloalkyl, -NH2, -NH-C 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), -OH, -OC 1-3 That which can be substituted with an alkyl or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. In Paragraph 1, Is , , , , , , , , , or and, here One or more Hs of the ring are -C 1-3 Alkyl, -CN, -C(=O)H, -OH, -OC 1-3 That which can be substituted with an alkyl or -halo; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. In Paragraph 1, Ring A is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And; #Is It is connected to, where one or more Hs of ring A are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo; ## is connected to (CH2)m; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. In Paragraph 1, Ring B is , , , , , , , , , , , , , , , , , or nothing (null), where one or more Hs of ring B are -C 1-3 Alkyl, -C 1-3 It can be substituted with a haloalkyl or -halo; * is connected to L; ** is connected to (CH2)m; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. In Paragraph 1, L is -NH-, -NH-C(=O)-, -NH-C(=O)-(CH2)-, -C(=O)-NH-, or -C(=O)-NH-(CH2)-; A compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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

11. A pharmaceutical composition comprising a compound according to claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

12. A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient a compound according to claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. In Paragraph 12, A pharmaceutical composition that inhibits AKT and / or AKT1 E17K.

14. In Paragraph 12, A pharmaceutical composition in which the above cancer is a disease associated with AKT and / or AKT1 E17K overactivation, amplification, or overexpression.

15. In Paragraph 14, The above cancers include uterine cancer, endometrial cancer, cervical cancer, ovarian cancer, serous ovarian cancer, breast cancer, Luminal A breast cancer, Luminal B breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, colorectal cancer (CRC), rectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), cholangioduct cancer, liver cancer, liver hepatocellular carcinoma (LIHC), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the lung, leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, lymphoma, non-Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL), prostate cancer, and bladder cancer. A pharmaceutical composition comprising one or more selected from the group consisting of testicular cancer, kidney cancer, bone cancer, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue cancer, brain cancer, glioblastoma, glioma, thyroid cancer, skin cancer, melanoma, mesothelioma, and thymoma.

16. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for use in the treatment or prevention of diseases related to AKT and / or AKT1 E17K.

17. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the treatment or prevention of cancer.

18. A method for treating or preventing AKT and / or AKT1 E17K-related diseases, comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

19. Uterine cancer, endometrial cancer, cervical cancer, ovarian cancer, serous ovarian cancer, breast cancer, Luminal A breast cancer, Luminal B breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, colorectal cancer (CRC), rectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), cholangioduct cancer, liver cancer, liver hepatocellular carcinoma (LIHC), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), pulmonary squamous cell carcinoma, leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma. A method for treating or preventing one or more diseases selected from the group consisting of myeloma, lymphoma, non-Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL), prostate cancer, bladder cancer, testicular cancer, kidney cancer, bone cancer, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue cancer, brain cancer, glioblastoma, glioma, thyroid cancer, skin cancer, melanoma, mesothelioma, and thymoma.

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