Heteroaryl derivative compound and use thereof

Abstract

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

Description

Heteroaryl derivative compounds and uses thereof

[0001] The present invention relates to heteroaryl derivative compounds and pharmaceutical uses thereof, and more particularly, to heteroaryl derivative compounds having AKT inhibitory activity and pharmaceutical uses thereof.

[0002] AKT is a serine / threonine protein kinase, also known as protein kinase B (PKB). AKT has three isoforms with very similar structures: AKT1, AKT2, and AKT3. AKT is involved in 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 cause cancer and metabolic disorders. AKT overactivation has been observed in breast, ovarian, pancreatic, and prostate cancers, and is known to promote cancer cell survival and proliferation. For this reason, research is underway to develop AKT inhibitors as potential therapeutic agents that interfere with 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 for binding 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 a covalent bond, which can exhibit stronger inhibitory activity and can also act selectively.

[0004] The most common mutation in AKT is AKT1 E17K (E17K: Glutamic acid at position 17 is mutated to Lysine), which has been reported in 6–8% of breast cancers, 2–6% of colon cancers, and 6% of meningiomas.

[0005] In this patent, we propose a covalent-allosteric AKT inhibitor compound that forms a covalent bond with lysine of AKT1 E17K and exhibits potent and selective inhibitory activity.

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

[0007] Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.

[0008] 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 treating or preventing AKT-related diseases, comprising the heteroaryl derivative compound as an active ingredient.

[0009] Another object of the present invention is to provide a method for treating or preventing an AKT-related disease using the compound or a method for treating or preventing an AKT-related disease comprising a step of administering the compound.

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

[0011] This is described in detail below. All combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific description below.

[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] X1 to X4 are each independently CR X or N;

[0018] R X is -H, -C 1-3 Alkyl, -C 1-3 Aminoalkyl, -NH2, -0H, -OC 1-3 Alkyl, or -halo;

[0019] L1 is Connect ## and L2, and the above L1 is -CR L1 R L2 -, -C(=O)-, -NR L3 -, -O-, or nothing (null);

[0020] R L1 and R L2 are each independently -H, -C 1-3 Alkyl, or -halo, where R L1 and R L2 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms;

[0021] R L3 is -H or -C 1-3 It is alkyl;

[0022] L2 is -C(=O)-NH-, -NH-C(=O)-, -(4-6 membered cycloalkyl), -(4-7 membered heterocycloalkyl), or -(6-11 membered heterobicycloalkyl), wherein the -(4-7 membered heterocycloalkyl) or -(6-11 membered heterobicycloalkyl) contains at least one N atom, and at least one H of the -(4-6 membered cycloalkyl), -(4-7 membered heterocycloalkyl), or -(6-11 membered heterobicycloalkyl) ring is -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC 1-6 Alkyl, -C(=O)-OH, -C(=O)-OC 1-3 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-3 may be substituted with alkyl or -halo;

[0023] L3 connects L2 and Y, and the L3 is -CR L4 R L5 -, -C(=O)-, -NR L6 -, -O-, or nothing (null);

[0024] R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms;

[0025] R L6 is -H or -C 1-3 It is alkyl;

[0026] Y is -CN, -S(=O)2-R Y1, -(4-6 membered cycloalkyl), -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl), wherein -CH2- of the -(4-6 membered cycloalkyl) or -(4-6 membered cycloalkenyl) ring may be replaced with -C(=O)-, and at least one H of the -(4-6 membered cycloalkyl), -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl) ring is -C 1-3 Alkyl, -CN, -OH, -OC 1-3 may be substituted with alkyl, -halo, or -C(=O)H;

[0027] R Y1 Silver -C 1-3 Alkyl or -C 1-3 It is alkenyl;

[0028] W is CH or N;

[0029] R W1 and R W2 are each independently -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;

[0030] Ring Z is -(6-9 membered heteroaryl), wherein at least one H of the -(6-9 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-3 Haloalkyl, -NH2, -C(=O)-NH2, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), -OH, -OC 1-3 may be substituted with alkyl or -halo;

[0031] L4 is -CH2-, -CH=CH-, -C≡C-, -C(=O)-, -NH-, -O-, or nothing (null);

[0032] V is -H, -C1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -NH2, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), -OH, -OC 1-3 Alkyl, -halo, -C(=O)-NH2, -C(=O)-NH-C 1-3 Alkyl, or -R V , and if L2 is -CH2-, -CH=CH-, -C≡C-, -C(=O)-, -NH-, or -O-, then V is -H, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, or -R V and;

[0033] R V is -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), -(7-11 membered heterobicycloalkyl), -phenyl, or -(5-6 membered heteroaryl), wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), or -(7-11 membered heterobicycloalkyl) ring is R V1 may be substituted with, and at least one H of the -phenyl or -(5-6 membered heteroaryl) ring is R V2 can be replaced with;

[0034] R V1 Silver -C 1-3 Alkyl, -C 1-3 Haloalkyl, or -halo;

[0035] R V2 is -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6alkyl)(C 1-6 alkyl), -NH-C(=O)-C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -halo, -C(=O)-R V3 , -S(=O)2-R V4 , -P(=O)(C 1-6 alkyl)(C 1-6 alkyl), -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(3-6 membered cycloalkyl) or -(4-6 membered heterocycloalkyl) ring is -C 1-3 may be substituted with alkyl;

[0036] R V3 and R V4 are each independently -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), -OC 1-3 Alkyl, or -(3-6 membered cycloalkyl).

[0037] According to one specific example of the present invention,

[0038] Chemical formula 1 may be one of the following chemical formulas 1a to 1c;

[0039] [Chemical Formula 1a]

[0040]

[0041] [Chemical Formula 1b]

[0042]

[0043] [Chemical Formula 1c]

[0044]

[0045] Z1 to Z4 are each independently CH or N;

[0046] R Z1 and R Z2 are each independently -C 1-3 Alkyl, -C 1-3Haloalkyl, -NH2, or -halo;

[0047] Ring A may be a five-membered heteroaryl.

[0048] According to one specific example of the present invention,

[0049] Is , , , , , , , or and;

[0050] # is connected to the ring Z;

[0051] ## is L Y is connected with;

[0052] R X is -H, -C 1-3 It can be alkyl or -halo.

[0053] More specifically,

[0054] Is , , or and;

[0055] # is connected to the ring Z;

[0056] ## is L Y is connected with;

[0057] R X is -H, -C 1-3 It can be alkyl or -halo.

[0058] More specifically,

[0059] Is , , , , , , , or and;

[0060] # is connected to the ring Z;

[0061] ## is L Y is connected with;

[0062] R X is -H, -C 1-3 It can be alkyl or -halo.

[0063] According to one specific example of the present invention,

[0064] L1 is Connect ## and L2, and the above L1 is -CR L1 R L2 -, -C(=O)-, -NH-, or nothing (null);

[0065] R L1 and R L2 are each independently -H or -C 1-3 is alkyl, where R L1 and R L2 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms;

[0066] L2 is -C(=O)-NH-, -NH-C(=O)-, -(5-6 membered cycloalkyl), -(5-7 membered heterocycloalkyl), or -(6-10 membered heterobicycloalkyl), wherein the -(5-7 membered heterocycloalkyl) or -(6-10 membered heterobicycloalkyl) contains at least one N atom, and at least one H of the -(5-6 membered cycloalkyl), -(5-7 membered heterocycloalkyl), or -(6-10 membered heterobicycloalkyl) ring is -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC 1-3 Alkyl, -C(=O)-OH, -C(=O)-NH-C 1-3 may be substituted with alkyl or -halo;

[0067] L3 connects L2 and Y, and the L3 is -CR L4 R L5 -, -C(=O)-, -NH-, -N(C 1-3 alkyl)-, -O-, or nothing (null);

[0068] R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 can be linked to each other to form a -(3-4 membered cycloalkyl) ring with the C atoms.

[0069] According to one specific example of the invention,

[0070] Is , , , , , , , , , , , , , , , , , , , , or and;

[0071] L1 is -CR L1 R L2 -, -C(=O)-, -NH-, -O-, or nothing (null);

[0072] R L1 and R L2 are each independently -H, -C 1-3 Alkyl, or -halo, where R L1 and R L2 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms;

[0073] L3 is -CR L4 R L5 -, -C(=O)-, -NR L6 -, -O-, or nothing (null);

[0074] R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 can be linked to each other to form a -(3-4 membered cycloalkyl) ring with the C atom;

[0075] R L6 is -H or -C 1-3 It is alkyl;

[0076] R N1 and R N2 are each independently -H, -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH-C 1-3 It can be alkyl or -halo.

[0077] More specifically,

[0078] Is , , , , , , , , , or and;

[0079] L1 is -CR L1 R L2 -, -C(=O)-, -NH-, or nothing (null);

[0080] R L1 and R L2 are each independently -H or -C 1-3 is alkyl, where R L1 and R L2 can be linked to each other to form a -(3-4 membered cycloalkyl) ring with the C atom;

[0081] L3 is -CR L4 R L5 -, -C(=O)-, -NRL6 -, -O-, or nothing (null);

[0082] R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 can be linked to each other to form a -(3-4 membered cycloalkyl) ring with the C atom;

[0083] R L6 is -H or -C 1-3 It is alkyl;

[0084] R N1 and R N2 are each independently -H, -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC 1-3 Alkyl, -C(=O)-OH, -C(=O)-NH-C 1-3 It can be alkyl or -halo.

[0085] More specifically,

[0086] Is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or and;

[0087] L1 is -CR L1 R L2 -, -C(=O)-, -NH-, or nothing (null);

[0088] R L1 and R L2 are each independently -H or -C 1-3 is alkyl, where R L1 and R L2 can be linked to each other to form a -(3-4 membered cycloalkyl) ring with the C atom;

[0089] L3 is -CR L4 R L5 -, -C(=O)-, -NR L6 -, -O-, or nothing (null);

[0090] R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 can be linked to each other to form a -(3-4 membered cycloalkyl) ring with the C atom;

[0091] R L6 is -H or -C 1-3 It is alkyl;

[0092] R N1 and R N2 are each independently -H, -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC1-3 Alkyl, -C(=O)-OH, -C(=O)-NH-C 1-3 It can be alkyl or -halo.

[0093] According to one specific example of the present invention,

[0094] Y is -CN, -S(=O)2-C 1-3 alkenyl, -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl), wherein -CH2- of the -(4-6 membered cycloalkenyl) ring may be replaced with -C(=O)-, and at least one H of the -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl) ring is -CN, -OH, -OC 1-3 It can be substituted with alkyl, -halo, or -C(=O)H.

[0095] More specifically,

[0096] Y is -CN, -S(=O)2-C 1-3 alkenyl, , , , , , , , , , , , , or and;

[0097] R Y1 is -H or -CN;

[0098] R Y2 Inland R Y4 are each independently -H, -OH, -C(=O)H, or -halo;

[0099] R Y5 is -OC 1-3 It could be an alkyl.

[0100] More specifically,

[0101] Y is -CN, -S(=O)2-C 1-3 alkenyl, , , , , , , , or and;

[0102] R Y1 is -H or -CN;

[0103] R Y2 Inland R Y4 are each independently -H, -OH, -C(=O)H, or -halo;

[0104] R Y5 is -OC 1-3 It could be an alkyl.

[0105] More specifically,

[0106] Y is -CN, -S(=O)2-C 1-3 alkenyl, , , , , , , , , , , , , , , , , , , or and;

[0107] R Y1 is -H or -CN;

[0108] R Y2 Inland R Y4 are each independently -H, -OH, -C(=O)H, or -halo;

[0109] R Y5 is -OC 1-3 It could be an alkyl.

[0110] According to one specific example of the present invention,

[0111] Is or and;

[0112] R W1 and R W2 are each independently -H, -C 1-3 It can be haloalkyl, -NH2, or -halo.

[0113] More specifically,

[0114] Is , , , , , , , , , , or and;

[0115] R W1 and R W2 are each independently -H, -C 1-3 It can be haloalkyl, -NH2, or -halo.

[0116] According to one specific example of the present invention,

[0117] Ring Z is , , , , , , , , or and;

[0118] *Is is connected to #;

[0119] **Is is connected with;

[0120] R Z1 and R Z2 are each independently -C 1-3 Alkyl, -C 1-3 It can be haloalkyl, -NH2, or -halo.

[0121] More specifically,

[0122] Ring Z is , , , , , , , or and;

[0123] *Is is connected to #;

[0124] **Is is connected with;

[0125] R Z1 and R Z2 are each independently -C 1-3 Alkyl, -C 1-3 It can be haloalkyl, -NH2, or -halo.

[0126] More specifically,

[0127] Ring Z is , , , , , , , , , , , , , , , or and;

[0128] *Is is connected to #;

[0129] **Is is connected with;

[0130] R Z1 and R Z2 are each independently -C 1-3 Alkyl, -C 1-3 It can be haloalkyl, -NH2, or -halo.

[0131] According to one specific example of the present invention,

[0132] L4 is -C≡C-, -NH-, -O-, or nothing (null);

[0133] V is -H, -C 1-3 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -NH-C 1-3 Alkyl, -OH, -OC 1-3 Alkyl, -halo, -C(=O)-NH2, -C(=O)NH-C 1-3 Alkyl, or -R V , and if L2 is -C≡C-, -NH-, or -O-, then V is -H, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, or -R V and;

[0134] R V is -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), -(7-11 membered heterobicycloalkyl), -phenyl, or -(5-6 membered heteroaryl), wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), or -(7-11 membered heterobicycloalkyl) ring is R V1 may be substituted with, and one or more H of the -phenyl, or -(5-6 membered heteroaryl) ring is R V2 can be replaced with;

[0135] R V1 Silver -C 1-3 Alkyl or -halo;

[0136] R V2 is -C 1-3 Alkyl, -C 2-3 alkynyl, -C 1-3 Aminoalkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -NH2, -N(C 1-3 alkyl)(C 1-3 alkyl), -NH-C(=O)-C 1-3Alkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -halo, -C(=O)-R V3 , -S(=O)2-R V4 , -P(=O)(C 1-3 alkyl)(C 1-3 alkyl), -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl) ring is -C 1-3 may be substituted with alkyl;

[0137] R V3 is -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), or -OC 1-3 It is alkyl;

[0138] R V4 is -C 1-3 It can be alkyl or -(3-4 membered cycloalkyl).

[0139] According to a specific example of the present invention, the compound represented by the above chemical formula 1 may be selected from the group consisting of compounds listed in Table 1 described below.

[0140] In the present invention, "alkyl" may mean a straight or branched chain, cyclic or saturated hydrocarbon or 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, isopropyl, n-butyl, 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.

[0141] 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 2-6 "Alkenyl" may mean an unsaturated hydrocarbon having 2 to 6 carbon atoms with one or more double bonds, and "C 2-6 "Alkynyl" may mean an unsaturated hydrocarbon having 2 to 6 carbon atoms with one or more triple bonds.

[0142] 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" of 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.

[0143] In the present invention, “halo” may be F, Cl, Br, or I.

[0144] 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.

[0145] In the present invention, "hydroxyalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH). Examples of such hydroxyalkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl independently substituted with -OH.

[0146] 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.

[0147] In the present invention, “cyanoalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0148] In the present invention, "alkylsulfonyl" may mean -(R'-S(=O)2-R"), where R' is a single bond and C 1-6 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.

[0149] 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.

[0150] 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.

[0151] 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 atoms" may mean a heterocycloalkyl having 3 to 12 ring-forming atoms, and as an example, the heterocycloalkyl may be 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, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, It may include, but is not limited to, (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.

[0152] 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.

[0153] 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."

[0154] 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 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 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, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran, but are not limited thereto. 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. As used herein, a residue obtained by removing one hydrogen atom from the above "heteroarene" is referred to as a "heteroaryl".

[0155] In the present invention, “hydroarene” or “hydroaryl” is an aromatic hydrocarbon ring in which at least one double bond is saturated.

[0156] 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."

[0157] 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.

[0158] 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, the compound represented by Chemical Formula 1 of the present invention may include the above stereoisomers of Chemical Formula 1 because the stereochemical structure is not specified. Unless otherwise stated, solid bonds connecting asymmetric carbon atoms A wedge-shaped solid line combination representing the absolute arrangement of the three-dimensional centers or wedge-shaped dotted line combination may include.

[0159] The compound represented by Chemical Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt." Accordingly, the category of the compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by Chemical Formula 1. The term "pharmaceutically acceptable salt" of the present invention means any organic or inorganic acid addition salt of the compound, which has a relatively non-toxic and harmless effective effect in a patient at a concentration, and wherein the side effects caused by the salt do not reduce the beneficial effects of the compound represented by Chemical Formula 1.

[0160] 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.

[0161] 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.

[0162] The above acid addition salt can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 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 acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0163] 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.

[0164] Uses of heteroaryl derivative compounds

[0165] The present invention provides a use of a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0166] [Chemical Formula 1]

[0167]

[0168] The above chemical formula 1 is as defined above.

[0169] The present invention provides uses of compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0170] The compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against AKT.

[0171] According to one specific embodiment of the present invention, the compound of the present invention exhibits excellent inhibitory activity against AKT, and thus can be usefully used for the treatment or prevention of AKT-related diseases, particularly cancer. In particular, the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against AKT mutations (e.g., AKT1-E17K, etc.), and thus can be usefully used for the treatment or prevention of cancers induced by AKT.

[0172] In the present invention, the cancer includes all cancers that can exhibit therapeutic or preventive efficacy due to inhibition of AKT activity, and may be solid cancer or blood cancer, and includes not only primary cancer but also metastatic cancer.

[0173] 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, Ovarian Cancer, Breast Cancer, Gastrointestinal Tract Cancer, Lung and Thoracic Cancer, Genitourinary Cancer, Head and Neck Cancer, Brain and Nervous System Tumor, Endocrine Tumors, Bone and Soft Tissue Tumor, and Skin Cancer.

[0174] The above uterine cancer may be cervical cancer, endometrial cancer, papillary serous carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, or uterine corpus endometrial carcinoma.

[0175] The above ovarian cancer may be serous ovarian cancer or high grade serous ovarian cancer (HGSOC).

[0176] The breast cancer may be Luminal A breast cancer, Luminal B breast cancer, or triple-negative breast cancer (TNBC).

[0177] 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).

[0178] 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.

[0179] The above thymic cancer may be thymoma.

[0180] 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).

[0181] The above head and neck cancer may be head and neck squamous cell carcinoma (HNSCC) or adenoid cystic carcinoma (ACC).

[0182] The above brain and central nervous system tumor may be brain cancer, glioblastoma, glioma, or brain lower grade glioma (LGG).

[0183] The above endocrine tumors may be thyroid cancer, parathyroid cancer, or adrenal cancer.

[0184] The above bone and soft tissue tumor may be bone cancer or soft tissue cancer such as osteosarcoma, Ewing sarcoma, or chondrosarcoma.

[0185] The above skin cancer may be melanoma.

[0186] 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 anaplastic large cell lymphoma (ALCL), lymphoma, or non-Hodgkin lymphoma.

[0187] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for treating or preventing an AKT-related disease, comprising a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the AKT-related disease may be cancer. The type of cancer is as mentioned above.

[0188] 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 compound represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0189] 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.

[0190] In addition, according to one specific example of the present invention, the present invention provides the use of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of an AKT-related disease. The compound of the present invention for the manufacture of a medicament may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be manufactured into a composite formulation together with other active agents to have a synergistic effect of the active ingredients.

[0191] In addition, according to one specific example of the present invention, the present invention provides the use of a compound represented by the above chemical 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 type of cancer is as mentioned above.

[0192] In addition, according to one specific embodiment of the present invention, the present invention provides a method for treating or preventing an AKT-related disease, comprising administering a therapeutically effective amount of a compound represented by the above chemical formula 1, 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 AKT-related disease may be cancer. The type of cancer is as mentioned above.

[0193] 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 the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The type of cancer is as mentioned above.

[0194] In addition, according to one specific example of the present invention, the present invention provides a method for inhibiting AKT, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0195] The term "therapeutically effective amount" as used herein refers to the amount of the compound represented by the above chemical formula 1 that is effective in treating or preventing an AKT-related disease. Specifically, a "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 subject type and severity, 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 can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used in amounts exceeding the determined dosage.

[0196] 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.

[0197] 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 Formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0198] 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.

[0199] 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).

[0200] 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.

[0201] 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.

[0202] Additionally, it can be manufactured as a compound preparation with other active ingredients to have a synergistic effect of the active ingredients.

[0203] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they are contradictory.

[0204] The heteroaryl derivative compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits excellent inhibitory activity against kinases, particularly AKT and / or AKT1 E17K, and therefore can be usefully used for the treatment or prevention of diseases associated with AKT and / or AKT1 E17K overactivation, amplification, or overexpression, and can be particularly usefully used as a therapeutic agent for cancer.

[0205] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following manufacturing examples, examples, and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited thereto.

[0206] <Analysis and purification conditions>

[0207] The compounds synthesized in the manufacturing examples and examples of the present invention were purified or subjected to structural analysis under the following conditions.

[0208] 1. LC-MS, Prep-HPLC, MPLC

[0209] Analytical LC-MS (Liquid Chromatography-Mass Spectrometry)

[0210] 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.

[0211] Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.

[0212] Gradient condition (10-100% B for 3 minutes, flow rate = 0.6 mL / min)

[0213] Preparative Preparative-Liquid chromatography UV spectrometry (Prep-HPLC)

[0214] The ACCQPrep HP150 equipment manufactured by Teledyne was used. The XTERRA from Waters ® Prep RP18 OBD TM (10 ㎛, 30 × 300 mm) column was used, and the column temperature was set to room temperature.

[0215] Gradient condition (10-100% B for 120 min, flow rate = 42 mL / min)

[0216] Medium pressure liquid chromatography (MPLC) for purification

[0217] Medium-pressure liquid chromatography was performed using a CombiFlash Rf +UV from Teledyne ISCO.

[0218] 2. NMR interpretation

[0219] NMR analysis was performed using an NMR AVANCE NEO 400 MHz manufactured by Bruker, and data are expressed in ppm (parts per million(δ)).

[0220] 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°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. Concentration under reduced pressure or solvent distillation was performed using a rotary evaporator.

[0221] Manufacturing Examples 1 to 3: Manufacturing of intermediate compounds of the present invention

[0222] Manufacturing Example 1. Manufacturing of (4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)boronic acid

[0223] [Reaction Formula 1]

[0224]

[0225] [Step 1] Preparation of (4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)phenyl)boronic acid

[0226] (4-(Bromomethyl)phenyl)boronic acid (2 g, 9.31 mmol) was dissolved in tetrahydrofuran (37 mL), and tert-butyl piperidin-4-ylcarbamate (1.86 g, 9.31 mmol) and triethylamine (3.89 mL, 27.90 mmol) were added. The mixture was stirred at room temperature for 4 h. The target compound was identified using LC-MS and concentrated. The concentrated mixture was purified by MPLC (methanol / dichloromethane = 0 / 100 → 1 / 5) to obtain the target compound (3.1 g, 99% yield) as a white solid. MS (ESI): m / z = 335.1 [M+H] +

[0227] [Step 2] Preparation of (4-((4-aminopiperidin-1-yl)methyl)phenyl)boronic acid hydrochloride

[0228] (4-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)phenyl)boronic acid (1 g, 2.99 mmol) prepared in Step 1 was dissolved in methanol (10 mL), then hydrochloric acid / dioxane (4 M, 4 mL) was added, and the mixture was stirred at room temperature for 1 h. After confirming the target compound using LC-MS, the reaction mixture was concentrated to obtain the target compound as a white solid (3.8 g, 100% yield, hydrochloride). MS (ESI): m / z = 235.1 [M+H] +

[0229] [Step 3] Preparation of (4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)boronic acid

[0230] (4-((4-Aminopiperidin-1-yl)methyl)phenyl)boronic acid hydrochloride (0.7 g, 2.99 mmol) prepared in Step 2 was dissolved in ethanol (10 mL), 4-chloropyrimidine-2-carbonitrile (0.5 g, 3.59 mmol) and triethylamine (1.2 g, 11.96 mmol) were added, and the mixture was stirred at 50 °C for 3 h. The target compound was identified using LC-MS and concentrated. The concentrated mixture was purified by MPLC (methanol / ethyl acetate = 0 / 1 → 1 / 1) to obtain the target compound (0.53 g, 52% yield) as a white solid. MS (ESI): m / z = 338.1 [M+H] +

[0231] Manufacturing Example 2. Manufacturing of 2-(4-(1,3-dioxolan-2-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0232] [Reaction Formula 2]

[0233]

[0234] 2-(4-Bromophenyl)-1,3-dioxolane (5.00 g, 21.83 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (8.31 g, 32.74 mmol), and potassium acetate (6.43 g, 65.48 mmol) were dissolved in dioxane (50 mL), and then Pd(dppf)Cl2·CH2Cl2 (1.78 g, 2.18 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. After the target compound was confirmed using LC-MS, ethyl acetate (200 mL) was added, the reaction mixture was filtered, and the filtrate was concentrated. The concentrated mixture was purified by MPLC (ethyl acetate / petroleum ether = 0 / 1 → 1 / 20) to obtain the target compound (4.5 g, 74% yield) as a yellow solid. MS (ESI): m / z = 277.0 [M+H] +

[0235] 1 H NMR (400 MHz, CDCl3): δ 7.83 (d,J= 8.0 Hz, 2H), 7.49 (d,J= 8.0 Hz, 2H), 5.85 (s, 1H), 4.15-4.08 (m, 2H), 4.08-4.01 (m, 2H), 1.35 (s, 12H).

[0236] Manufacturing Example 3. Preparation of 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile trifluoroacetate

[0237] [Reaction Formula 3]

[0238]

[0239] [Step 1] Preparation of tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-1-carboxylate

[0240] 4-Chloropyrimidine-2-carbonitrile (2.8 g, 20.07 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (4.42 g, 22.07 mmol) were dissolved in acetonitrile (28 mL), and N,N-diisopropylethylamine (7.78 g, 60.20 mmol, 10.49 mL) was added. The mixture was stirred at 60 °C for 1 h. After confirming the target compound using LC-MS, the reaction mixture was cooled to room temperature and diluted with water (60 mL). The pH of the mixture was then adjusted to 5–6 using 1 M hydrochloric acid aqueous solution at 0 °C. Afterwards, it was extracted with ethyl acetate, and the collected organic layer was concentrated after removing the remaining water using sodium sulfate to obtain the target compound (6.3 g, 98% yield) in the form of a white solid. MS (ESI): m / z = 304.1 [M+H] +

[0241] 1 H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 6.47 (d,J= 6.0 Hz, 1H), 5.42 (s, 1H), 4.35-3.74 (m, 3H), 2.93 (t,J= 12.0 Hz, 2H), 2.02 (dd,J= 6.0, 11.2 Hz, 2H), 1.46 (s, 9H), 1.40 (d,J= 11.6 Hz, 2H).

[0242] [Step 2] Preparation of 4-(piperidin-4-ylamino)pyrimidine-2-carbonitrile trifluoroacetate

[0243] Trifluoroacetic acid (20 mL) was added dropwise to a solution of tert-butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-1-carboxylate (6 g, 19.78 mmol) prepared in Step 1 in dichloromethane (100 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. After the target compound was identified using LC-MS, the reaction mixture was concentrated to obtain the target compound (6.28 g) as a yellow oil.

[0244] 1 H NMR (400 MHz, DMSO-d6): δ 8.25 (d,J= 7.2 Hz, 1H), 8.17 - 8.08 (m, 1H), 6.70 (d,J= 6.0 Hz, 1H), 4.17-4.05 (m, 1H), 3.30 (d,J= 12.4 Hz, 2H), 3.13-3.01 (m, 2H), 2.07-2.00 (m, 2H), 1.67-1.56 (m, 2H).

[0245] Example: Preparation of the compound of the present invention

[0246] Example 1. Preparation of 4-((1-(4-(3-(2-aminopyridin-3-yl)-6-phenylpyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0247] [Reaction Formula 4]

[0248]

[0249] [Step 1] Preparation of 3-bromo-5-phenylpyrazin-2-amine

[0250] 5-Phenylpyrazin-2-amine (1.00 g, 5.84 mmol) was dissolved in N,N-dimethylformamide (6 mL), N-bromosuccinimide (1.04 g, 5.84 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. The target compound was identified using LC-MS, and the organic matter was extracted with water and ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (petroleum ether / ethyl acetate = 1 / 0 → 4 / 1) to obtain the target compound as a yellow solid (930 mg, 64% yield).

[0251] 1 H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 7.93-7.84 (m, 2H), 7.49-7.42 (m, 2H), 7.41-7.35 (m, 1H), 5.08 (br s, 2H).

[0252] [Step 2] Preparation of 3-bromo-2-chloro-5-phenylpyrazine

[0253] 3-Bromo-5-phenylpyrazin-2-amine (0.60 g, 2.40 mmol) obtained in Step 1 was dissolved in acetonitrile (15 mL), and isopentylprop-2-yn-1-ol (0.56 g, 4.80 mmol) and copper chloride (0.59 g, 6.00 mmol) were added at 0 °C, and the mixture was stirred at 60 °C for 16 h. After confirming the target compound using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by MPLC (petroleum ether / ethyl acetate = 1 / 0 → 50 / 1) to obtain the target compound (0.28 g, 42% yield) as a white solid.

[0254] 1 H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.03-7.98 (m, 2H), 7.56-7.50 (m, 3H); MS (ESI): m / z = 270.8 [M+H] +

[0255] [Step 3] Preparation of 4-((1-(4-(3-chloro-6-phenylpyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0256] 3-Bromo-2-chloro-5-phenylpyrazine (0.28 g, 1.04 mmol) obtained in Step 2 and 4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)boronic acid (0.35 g, 1.04 mmol) obtained in Preparation Example 1 were dissolved in dioxane (8 mL) and water (0.8 mL), and then sodium carbonate (0.22 g, 2.08 mmol) and Pd(dppf)Cl2 (84.84 mg, 103.89 μmol) were added under nitrogen gas. The reaction mixture was stirred at 80 °C for 1.5 h. After confirming the target compound using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by prep-HPLC, and the target compound (0.28 g, 51% yield) was obtained as a white solid. MS (ESI): m / z = 482.2 [M+H] +

[0257] 1 H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.17 (d,J= 6.8 Hz, 1H), 8.08 (dd,J= 1.6, 7.6 Hz, 2H), 7.91 (d,J= 8.0 Hz, 2H), 7.60-7.43 (m, 6H), 6.43 (d,J= 6.0 Hz, 1H), 4.13-3.79 (m, 1H), 3.64 (s, 2H), 2.93 (d,J= 11.2 Hz, 2H), 2.27 (t,J= 10.8 Hz, 2H), 2.09-2.04 (m, 2H), 1.61 (d,J= 10.4 Hz, 2H).

[0258] [Step 4] Preparation of 4-((1-(4-(3-(2-aminopyridin-3-yl)-6-phenylpyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0259] 4-((1-(4-(3-chloro-6-phenylpyrazin-2-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile (100.00 mg, 190.88 μmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (46.21 mg, 209.97 μmol) obtained in step 3 were dissolved in dioxane (6 mL) and water (0.6 mL), and then potassium carbonate (52.76 mg, 381.76 μmol) and Pd(dppf)Cl2 (15.59 mg, 19.09 μmol) were added under nitrogen gas. The reaction mixture was stirred at 100 °C for 2 h. After confirming the target compound using LC-MS, the reaction mixture was filtered through Celite and concentrated. The concentrated mixture was purified by prep-HPLC, yielding the target compound as a white solid (51 mg, 49% yield). MS (ESI): m / z = 540.3 [M+H] +

[0260] Example 32. Preparation of 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0261] [Reaction Formula 5]

[0262]

[0263] [Step 1] Preparation of 5-bromo-6-chloro-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

[0264] 3,5-Dibromo-6-chloro-pyrazin-2-amine (4.70 g, 16.36 mmol) was dissolved in tetrahydrofuran (40 mL), and triethylamine (3.31 g, 32.71 mmol) and copper(I) iodide (311.00 mg, 1.64 mmol) were added. The reaction mixture was degassed, and Pd(PPh3)2Cl2 (574.00 mg, 817 μmol) was added under a nitrogen atmosphere. After the reaction mixture was cooled to -5 °C, ethynyl(trimethyl)silane (1.77 g, 17.99 mmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 3 h. After the target compound was identified using LC-MS, the organic matter was extracted with water and ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (petroleum ether / ethyl acetate = 8 / 1) to obtain the target compound as a yellow solid (4.30 g, 86% yield). MS (ESI): m / z = 305.9 [M+H] +

[0265] 1 H NMR (400 MHz, CDCl3): δ 5.20 (s, 2H), 0.29 (s, 9H).

[0266] [Step 2] Preparation of 2-bromo-3-chloro-5H-pyrrolo[2,3-b]pyrazine

[0267] 5-Bromo-6-chloro-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (4.30 g, 14.1 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (150 mL), and potassium tert-butoxide (1 M, 15.53 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then at 30 °C for 2 h. After confirming the target compound using LC-MS, the organic matter was extracted with water and ethyl acetate. The combined 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 obtain the target compound (1.4 g, 42% yield) as a yellow solid. MS (ESI): m / z = 233.9 [M+H] +

[0268] 1 H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 8.00 (d,J= 3.6 Hz, 1H), 6.68 (d,J= 3.6 Hz, 1H).

[0269] [Step 3] Preparation of 2-bromo-3-chloro-5-phenyl-pyrrolo[2,3-b]pyrazine

[0270] 2-Bromo-3-chloro-5H-pyrrolo[2,3-b]pyrazine (1.40 g, 6.02 mmol), phenylboronic acid (881.00 mg, 7.23 mmol), and copper(II) acetate (218.00 mg, 1.20 mmol) obtained in Step 2 were dissolved in dichloromethane (25 mL), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (916.00 mg, 6.02 mmol) was added, and the mixture was stirred at 30 °C for 12 h under an oxygen atmosphere. After confirming the target compound using LC-MS, the organic matter was extracted with water and ethyl acetate. The combined 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 → 1 / 1) to obtain the target compound as a yellow solid (700 mg, 33% yield). MS (ESI): m / z = 309.9 [M+H] +

[0271] [Step 4] Preparation of 3-(3-chloro-5-phenyl-pyrrolo[2,3-b]pyrazin-2-yl)pyridin-2-amine

[0272] 2-Bromo-3-chloro-5-phenyl-pyrrolo[2,3-b]pyrazine (700.00 mg, 2.27 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (549.00 mg, 2.50 mmol) obtained in Step 3 were dissolved in dioxane (35 mL) and water (7 mL), and then Pd(dppf)Cl2 (165.00 mg, 0.227 mmol) was added. The reaction mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. After the target compound was confirmed using LC-MS, the reaction mixture was filtered through Celite and concentrated. The concentrated mixture was purified by MPLC (petroleum ether / ethyl acetate = 1 / 0 → 0 / 1) to obtain the target compound as a yellow solid (500 mg, 67% yield). MS (ESI): m / z = 321.9 [M+H] +

[0273] [Step 5] Preparation of 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile

[0274] 3-(3-Chloro-5-phenyl-pyrrolo[2,3-b]pyrazin-2-yl)pyridin-2-amine (150.00 mg, 466 μmol) obtained in Step 4 and (4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)boronic acid (471.00 mg, 1.40 mmol) and potassium carbonate (193.00 mg, 1.40 mmol) obtained in Preparation Example 1 were dissolved in dioxane (2 mL) and water (0.5 mL), and then CataCXiumA-Pd-G3 (33.95 mg, 46.6 μmol) was added. The reaction mixture was stirred at 100 °C for 1 h under a nitrogen atmosphere. After the target compound was identified 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 to obtain the target compound (33.17 mg, 12% yield) as a yellow solid. MS (ESI): m / z = 579.3 [M+H] +

[0275] Example 357. Preparation of 6-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)-5-phenylpyridazine-3-carboxamide

[0276] [Reaction Formula 6]

[0277]

[0278] [Step 1] Preparation of methyl 5-bromo-6-hydroxypyridazine-3-carboxylate

[0279] Methyl 6-hydroxypyridazine-3-carboxylate (1.00 g, 6.49 mmol) was dissolved in acetic acid (10 mL), and potassium acetate (2.55 g, 25.95 mmol) and bromine (2.07 g, 12.98 mmol) were added. The mixture was stirred at 80°C for 16 h. After confirming the target compound using LC-MS, the reaction was terminated by adding a saturated aqueous sodium bisulfite solution (10 mL), and the organic matter was extracted using water and ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was suspended in ethyl acetate, stirred for 20 minutes, and the resulting solid was collected to obtain the target compound as a white solid (800 mg, 52% yield). MS (ESI): m / z = 232.9 [M+H] +

[0280] [Step 2] Preparation of methyl 6-hydroxy-5-phenylpyridazine-3-carboxylate

[0281] Methyl 5-bromo-6-hydroxypyridazine-3-carboxylate (700.00 mg, 3.00 mmol) and phenylboronic acid (439.54 mg, 3.60 mmol) obtained in Step 1 were dissolved in dioxane (10 mL) and water (1 mL), and Pd(dppf)Cl2 (122.66 mg, 0.15 mmol) and sodium carbonate (955.19 mg, 9.01 mmol) were added, and the mixture was stirred at 80 °C for 16 h. After confirming the target compound using LC-MS, the reaction mixture was filtered through Celite and concentrated. The concentrated mixture was purified by prep-HPLC, and the target compound (210 mg, 30% yield) was obtained as a white solid. MS (ESI): m / z = 231.0

[0282] [Step 3] Preparation of methyl 6-chloro-5-phenylpyridazine-3-carboxylate

[0283] Methyl 6-hydroxy-5-phenylpyridazine-3-carboxylate (210.00 mg, 912.17 μmol) obtained in step 2 was dissolved in phosphoryl chloride (5 mL) and stirred at 100 °C for 2 h. After confirming the target compound using LC-MS, the reaction mixture was cooled to room temperature and the organic matter was extracted using water and ethyl acetate. The combined organic layer was concentrated to remove the remaining water using sodium sulfate and obtain the target compound as a yellow solid (170 mg, 75% yield). MS (ESI): m / z = 248.9 [M+H]+

[0284] [Step 4] Preparation of 6-chloro-5-phenylpyridazine-3-carboxylic acid

[0285] Methyl 6-chloro-5-phenylpyridazine-3-carboxylate (150.00 mg, 603.22 μmol) obtained in step 3 was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide (126.57 mg, 3.02 mmol) was added. The mixture was stirred at 25 °C for 2 h. After confirming the target compound using LC-MS, the reaction mixture was diluted with water (30 mL). Subsequently, the pH of the mixture was adjusted to 3–4 using 1 M aqueous hydrochloric acid solution. Then, the mixture was extracted with ethyl acetate, and the combined organic layer was concentrated to remove the remaining water using sodium sulfate to obtain the target compound (140 mg, 91% yield) as a white solid. MS (ESI): m / z = 234.9 [M+H] +

[0286] [Step 5] Preparation of 6-chloro-5-phenylpyridazine-3-carboxamide

[0287] 6-Chloro-5-phenylpyridazine-3-carboxylic acid (130.00 mg, 554.04 μmol) obtained in step 4 was dissolved in N,N-dimethylformamide (5 mL), carbonyldiimidazole (CDI, 134.76 mg, 831.07 μmol) was added, and the mixture was stirred at 25 °C for 30 min. Ammonium chloride (296.37 mg, 5.54 mmol) was added to the reaction mixture, and the mixture was stirred at 60 °C for 16 h. After confirming the target compound using LC-MS, the organic matter was extracted using water and ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate to obtain the target compound as a yellow solid (110 mg, 85% yield). MS (ESI): m / z = 234.0

[0288] [Step 6] Preparation of 6-(4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)-5-phenylpyridazine-3-carboxamide

[0289] 6-Chloro-5-phenylpyridazine-3-carboxamide (100.00 mg, 427.98 μmol) obtained in Step 5 and 4-((4-((2-cyanopyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)boronic acid (216.46 mg, 641.98 μmol) obtained in Preparation Example 1 were dissolved in dioxane (5 mL) and water (1 mL), and CataCXium A Pd G3 (15.58 mg, 21.40 μmol) and potassium triphosphate (272.54 mg, 1.28 mmol) were added, and the mixture was stirred at 90 °C for 6 h under a nitrogen atmosphere. After confirming the target compound using LC-MS, the reaction mixture was filtered through Celite and concentrated. The concentrated mixture was purified by prep-HPLC, and the target compound was obtained as a white solid (13.86 mg, 6.53% yield). MS (ESI): m / z = 491.2

[0290] Example 358. Preparation of 4-((1-(4-(8-phenylimidazo[1,2-c]pyrimidin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile formate

[0291] [Reaction Formula 7]

[0292]

[0293] [Step 1] Preparation of 5-phenylpyrimidine-4,6-diol

[0294] Sodium ethoxide (4.32 g, 63.49 mmol) was dissolved in ethanol (50 mL), and formamidine acetate (2.86 g, 27.51 mmol) was added. The mixture was stirred at 25 °C for 30 min. A solution of diethyl 2-phenylmalonate (5.00 g, 21.16 mmol) in ethanol (25 mL) was added dropwise to the reaction mixture, and the mixture was stirred at 60 °C for 12 h. The target compound was identified using LC-MS, and the reaction mixture was concentrated. Water (200 mL) was added to the concentrated mixture, and the pH of the mixture was adjusted to 3–4 with 12 N hydrochloric acid aqueous solution at 0 °C. A yellow precipitate was formed, and the solid was collected by filtration. The collected solid was washed with water and dried to obtain the target compound (2.50 g, 63% yield) as a yellow solid. MS (ESI): m / z = 188.9 [M+H] +

[0295] [Step 2] Preparation of 4,6-dichloro-5-phenylpyrimidine

[0296] 5-Phenylpyrimidine-4,6-diol (1.00 g, 5.31 mmol) obtained in Step 1 was dissolved in phosphoryl chloride (10 mL) and stirred at 90°C for 4 h. After the target compound was identified using LC-MS, the reaction mixture was concentrated. Water (50 mL) was added to the concentrated mixture, and the organic matter was extracted using dichloromethane. The combined organic layer was concentrated to remove the remaining water using sodium sulfate and obtain the target compound as a yellow solid (1 g, 84% yield). MS (ESI): m / z = 224.9

[0297] [Step 3] Preparation of 6-chloro-5-phenylpyrimidin-4-amine

[0298] 4,6-Dichloro-5-phenylpyrimidine (1.00 g, 4.44 mmol) obtained in step 2 was dissolved in ammonia water (40 mL) and acetonitrile (5 mL), and stirred at 80 °C for 12 h. After confirming the target compound using LC-MS, the reaction mixture was concentrated. Water (50 mL) was added to the concentrated mixture, and the resulting yellow precipitate was collected by filtration. The collected solid was washed with water and dried to obtain the target compound (750 mg, 67% yield) as a yellow solid. MS (ESI): m / z = 205.9 [M+H] +

[0299] [Step 4] Preparation of 4-(6-amino-5-phenylpyrimidin-4-yl)benzaldehyde

[0300] 6-Chloro-5-phenylpyrimidin-4-amine (750.00 mg, 3.64 mmol) and (4-formylphenyl)boronic acid (656.22 mg, 4.38 mmol) obtained in step 3 were dissolved in dioxane (20 mL) and water (2 mL), and cesium carbonate (3.56 g, 10.94 mmol) and Pd(dppf)Cl2.CH2Cl2 (297.84 mg, 0.36 mmol) were added, and the mixture was stirred at 90 °C for 4 h under a nitrogen atmosphere. 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 / tetrahydrofuran = 1 / 1 / 1) to obtain the target compound (950 mg, 94% yield) as a yellow solid. MS (ESI): m / z = 276.0 [M+H] +

[0301] [Step 5] Preparation of 4-(8-phenylimidazo[1,2-c]pyrimidin-7-yl)benzaldehyde

[0302] 4-(6-amino-5-phenylpyrimidin-4-yl)benzaldehyde (400.00 mg, 1.45 mmol) obtained in step 4 was dissolved in ethanol (8 mL), and 2-chloroacetaldehyde (1.43 g, 7.26 mmol, 40% aqueous solution) was added dropwise and stirred at 100 °C for 5 h. After confirming the target compound using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by prep-HPLC to obtain the target compound (400 mg, 66% yield) as a white solid. MS (ESI): m / z = 299.9

[0303] [Step 6] Preparation of 4-((1-(4-(8-phenylimidazo[1,2-c]pyrimidin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile formate

[0304] 4-(Piperidin-4-ylamino)pyrimidine-2-carbonitrile trifluoroacetate (127.19 mg, 400.90 μmol) obtained in Preparation Example 3 was dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (43.18 mg, 334.08 μmol) was added, and the pH was adjusted to 7-8, followed by stirring at 25 °C for 10 minutes. To the reaction mixture, 4-(8-phenylimidazo[1,2-c]pyrimidin-7-yl)benzaldehyde (100.00 mg, 427.98 μmol) and acetic acid (2.01 mg, 33.41 μmol) obtained in Step 5 were added, and the mixture was stirred at 25 °C for 30 minutes. Then, sodium cyanoborohydride (31.49 mg, 501.13 μmol) was added to the reaction mixture and stirred at 25°C for 12 h. The target compound was identified using LC-MS and purified by prep-HPLC to obtain the target compound as a white solid (18.84 mg, 11.36% yield). MS (ESI): m / z = 487.2

[0305] <Example 1> to <Example 391>

[0306] All other example compounds of the present invention were prepared in a similar manner to the above-described examples 1, 32, 357, and 358, and the chemical structural formula, compound name, of each example compound are as follows: 1 The results of H NMR and LC-MS analysis are summarized in [Table 1] below.

[0307] [Table 1]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412] Experimental Example 1. Evaluation of growth and proliferation inhibition in AKT1-E17K mutant Ba / F3 cells.

[0413] In order to evaluate the cell proliferation inhibition of the compound of the present invention, the following experiment was performed. Ba / F3-AKT1-E17K cells expressing AKT1-E17K protein were seeded at a concentration of 3,000 cells / well in a White-96-well flat-bottom plate (Corning #3903) and cultured for 16 hours under 37°C, 5% CO2 conditions. The cells were cultured in RPMI1640 medium (Gibco #11875093) containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. The compound was serially diluted 3-fold in 11 concentrations in dimethyl sulfoxide (DMSO) to obtain a final concentration of 1.5 nM - 10 μM. As a control group, DMSO was treated at the same concentration of 0.5% (v / v) as in the compound treatment, and the cells treated with the compounds were cultured at 37°C, 5% CO2 for 72 hours. To check the viability of the cells, 100 μL of Cell Titer-Glo (Promega #G7573) was added to the medium of the cultured cells, cultured for 10 minutes at room temperature, and the luminescence value was measured using a microplate reader (SynergyNeo2, Biotek). The degree of cell proliferation inhibition activity according to the treatment concentration of each compound was calculated based on the luminescence value of the control cells that were not treated with the compounds, and at this time, the concentration at which cell proliferation inhibition activity was 50% was GI 50 (μM) values ​​were calculated using GraphPad Prism 9.3.1 (GraphPad software Inc., San Diego). The results are shown in Table 2 below.

[0414] [Table 2]

[0415]

[0416]

[0417] As shown in Table 2 above, it can be confirmed that the exemplary compounds of the present invention exhibit excellent proliferation inhibitory activity against AKT gene mutant cells.

[0418] While the present invention has been described in detail through preferred embodiments 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 to X4 are each independently CR X or N; R X is -H, -C 1-3 Alkyl, -C 1-3 Aminoalkyl, -NH2, -0H, -OC 1-3 Alkyl, or -halo; L1 is Connect ## and L2, and the above L1 is -CR L1 R L2 -, -C(=O)-, -NR L3 -, -O-, or nothing (null); R L1 and R L2 are each independently -H, -C 1-3 Alkyl, or -halo, where R L1 and R L2 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms; R L3 is -H or -C 1-3 It is alkyl; L2 is -C(=O)-NH-, -NH-C(=O)-, -(4-6 membered cycloalkyl), -(4-7 membered heterocycloalkyl), or -(6-11 membered heterobicycloalkyl), wherein the -(4-7 membered heterocycloalkyl) or -(6-11 membered heterobicycloalkyl) contains at least one N atom, and at least one H of the -(4-6 membered cycloalkyl), -(4-7 membered heterocycloalkyl), or -(6-11 membered heterobicycloalkyl) ring is -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC 1-6 Alkyl, -C(=O)-OH, -C(=O)-OC 1-3 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-3 may be substituted with alkyl or -halo; L3 connects L2 and Y, and the L3 is -CR L4 R L5 -, -C(=O)-, -NR L6 -, -O-, or nothing (null); R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms; R L6 is -H or -C 1-3 It is alkyl; Y is -CN, -S(=O)2-R Y1 , -(4-6 membered cycloalkyl), -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl), wherein -CH2- of the -(4-6 membered cycloalkyl) or -(4-6 membered cycloalkenyl) ring may be replaced with -C(=O)-, and at least one H of the -(4-6 membered cycloalkyl), -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl) ring is -C 1-3 Alkyl, -CN, -OH, -OC 1-3 may be substituted with alkyl, -halo, or -C(=O)H; R Y1 Silver -C 1-3 Alkyl or -C 1-3 It is alkenyl; W is CH or N; R W1 and R W2 are each independently -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; Ring Z is -(6-9 membered heteroaryl), wherein at least one H of the -(6-9 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-3 Haloalkyl, -NH2, -C(=O)-NH2, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), -OH, -OC 1-3 may be substituted with alkyl or -halo; L4 is -CH2-, -CH=CH-, -C≡C-, -C(=O)-, -NH-, -O-, or nothing (null); V is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -NH2, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), -OH, -OC 1-3 Alkyl, -halo, -C(=O)-NH2, -C(=O)-NH-C 1-3 Alkyl, or -R V , and if L2 is -CH2-, -CH=CH-, -C≡C-, -C(=O)-, -NH-, or -O-, then V is -H, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, or -R V and; R V is -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), -(7-11 membered heterobicycloalkyl), -phenyl, or -(5-6 membered heteroaryl), wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), or -(7-11 membered heterobicycloalkyl) ring is R V1 may be substituted with, and at least one H of the -phenyl or -(5-6 membered heteroaryl) ring is R V2 can be replaced with; R V1 Silver -C 1-3 Alkyl, -C 1-3 Haloalkyl, or -halo; R V2 is -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C(=O)-C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -halo, -C(=O)-R V3 , -S(=O)2-R V4 , -P(=O)(C 1-6 alkyl)(C 1-6 alkyl), -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(3-6 membered cycloalkyl) or -(4-6 membered heterocycloalkyl) ring is -C 1-3 may be substituted with alkyl; R V3 and R V4 are each independently -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), -OC 1-3 Alkyl, or -(3-6 membered cycloalkyl).

2. In paragraph 1, Is , , , , , , , or and; # is connected to the ring Z; ## is L Y is connected with; R X is -H, -C 1-3 Alkyl, or -haloine; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, L1 is Connect ## and L2, and the above L1 is -CR L1 R L2 -, -C(=O)-, -NH-, or nothing (null); R L1 and R L2 are each independently -H or -C 1-3 is alkyl, where R L1 and R L2 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms; L2 is -C(=O)-NH-, -NH-C(=O)-, -(5-6 membered cycloalkyl), -(5-7 membered heterocycloalkyl), or -(6-10 membered heterobicycloalkyl), wherein the -(5-7 membered heterocycloalkyl) or -(6-10 membered heterobicycloalkyl) contains at least one N atom, and at least one H of the -(5-6 membered cycloalkyl), -(5-7 membered heterocycloalkyl), or -(6-10 membered heterobicycloalkyl) ring is -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC 1-3 Alkyl, -C(=O)-OH, -C(=O)-NH-C 1-3 may be substituted with alkyl or -halo; L3 connects L2 and Y, and the L3 is -CR L4 R L5 -, -C(=O)-, -NH-, -N(C 1-3 alkyl)-, -O-, or nothing (null); R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 are capable of forming a -(3-4 membered cycloalkyl) ring with the C atoms by linking them together; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. In paragraph 3, Is , , , , , , , , , , , , , , , , , , , , or and; L1 is -CR L1 R L2 -, -C(=O)-, -NH-, -O-, or nothing (null); R L1 and R L2 are each independently -H, -C 1-3 Alkyl, or -halo, where R L1 and R L2 can be linked to each other to form a -(3-6 membered cycloalkyl) ring with the C atoms; L3 is -CR L4 R L5 -, -C(=O)-, -NR L6 -, -O-, or nothing (null); R L4 and R L5 are each independently -H, -C 1-3 Alkyl, or -halo, where R L4 and R L5 can be linked to each other to form a -(3-4 membered cycloalkyl) ring with the C atom; R L6 is -H or -C 1-3 It is alkyl; R N1 and R N2 are each independently -H, -C 1-3 Alkyl, -C 1-3 Hydroxyalkyl, -OH, -OC 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH-C 1-3 Alkyl, or -haloine; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, Y is -CN, -S(=O)2-C 1-3 alkenyl, -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl), wherein -CH2- of the -(4-6 membered cycloalkenyl) ring may be replaced with -C(=O)-, and at least one H of the -(4-6 membered cycloalkenyl), -phenyl, or -(6-10 membered heteroaryl) ring is -CN, -OH, -OC 1-3 which may be substituted with alkyl, -halo, or -C(=O)H; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. In paragraph 5, Y is -CN, -S(=O)2-C 1-3 alkenyl, , , , , , , , , , , , , or and; R Y1 is -H or -CN; R Y2 Inland R Y4 are each independently -H, -OH, -C(=O)H, or -halo; R Y5 is -OC 1-3 alkyl; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, Is or and; R W1 and R W2 are each independently -H, -C 1-3 Haloalkyl, -NH2, or -haloine; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, Ring Z is , , , , , , , , or and; *Is is connected to #; **Is is connected with; R Z1 and R Z2 are each independently -C 1-3 Alkyl, -C 1-3 Haloalkyl, -NH2, or -haloine; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, L4 is -C≡C-, -NH-, -O-, or nothing (null); V is -H, -C 1-3 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -NH-C 1-3 Alkyl, -OH, -OC 1-3 Alkyl, -halo, -C(=O)-NH2, -C(=O)NH-C 1-3 Alkyl, or -R V , and if L2 is -C≡C-, -NH-, or -O-, then V is -H, -C 1-6 Hydroxyalkyl, -C 1-3 Haloalkyl, or -R V and; R V is -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), -(7-11 membered heterobicycloalkyl), -phenyl, or -(5-6 membered heteroaryl), wherein at least one H of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -(4-6 membered heterocycloalkenyl), or -(7-11 membered heterobicycloalkyl) ring is R V1 may be substituted with, and one or more H of the -phenyl, or -(5-6 membered heteroaryl) ring is R V2 can be replaced with; R V1 Silver -C 1-3 Alkyl or -halo; R V2 is -C 1-3 Alkyl, -C 2-3 alkynyl, -C 1-3 Aminoalkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -NH2, -N(C 1-3 alkyl)(C 1-3 alkyl), -NH-C(=O)-C 1-3 Alkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -halo, -C(=O)-R V3 , -S(=O)2-R V4 , -P(=O)(C 1-3 alkyl)(C 1-3 alkyl), -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H of the -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl) ring is -C 1-3 may be substituted with alkyl; R V3 is -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -N(C 1-3 alkyl)(C 1-3 alkyl), or -OC 1-3 It is alkyl; R V4 is -C 1-3 Alkyl or -(3-4 membered cycloalkyl); 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 any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

12. A pharmaceutical composition for preventing or treating cancer, comprising a compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

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

14. In paragraph 12, A pharmaceutical composition, wherein the cancer is a disease associated with overactivation, amplification, or overexpression of AKT and / or AKT1 E17K.

15. In paragraph 14, The above cancers are 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), bile duct cancer, liver cancer, 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, multiple myeloma, lymphoma, non-Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL), prostate cancer, bladder cancer, A pharmaceutical composition comprising at least one selected from the group consisting of testicular cancer, kidney cancer, bone cancer, osteosarcoma, Ewing's 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 medicament for use in the treatment or prevention of AKT and / or AKT1 E17K related diseases.

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 medicament for the treatment or prevention of cancer.

18. A method for treating or preventing an AKT and / or AKT1 E17K related disease, comprising administering to a subject in need thereof 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.

19. A method for treating 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), bile duct cancer, liver cancer, 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, multiple myeloma, comprising administering to a subject in need thereof A method for treating or preventing at least one disease selected from the group consisting of multiple 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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