Heteroaryl derivative compound and uses thereof

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

Heteroaryl derivative compounds and uses thereof

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to heteroaryl derivative compounds having PKMYT1 and / or CCNE1 inhibitory activity.

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

[0003] In particular, PKMYT1 (MYT1; membrane-associated tyrosine and threonine specific cdc2 inhibitory kinase) belongs to the WEE1 kinase family and, together with WEE1, acts as a key regulator of the gateway to mitosis at the G2 checkpoint in the cell cycle. When DNA damage occurs in cancer cells, PKMYT1 plays a role in DNA damage repair (DDR) at the G2 checkpoint (Molecules, 2017, 22(12), 2045). Therefore, inhibition of PKMYT1 can suppress the activity of cancer cells by suppressing the G2 / M checkpoint function of cancer cells and inducing mitotic catastrophe (Journal of Hematology & Oncology, 2020, 13, 126).

[0004] Many patients with solid tumors do not respond to chemotherapy, which is attributed to cell cycle regulation and DDR in cancer cells. Furthermore, PKMYT1 is overexpressed in solid tumors such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), gastric cancer, hepatocellular carcinoma, glioblastoma, and breast cancer (Cell Proliferation, 2020, 53, e12741), and its overexpression in NSCLC patients is known to promote cancer progression and metastasis, leading to a poor prognosis (Eur Rev Med Pharmacol Sci., 2019, 23(10), 4210-4219).

[0005] Synthetic lethality is a phenomenon in which a single gene alone does not induce cell death, but the combined effects of two or more genes, mutated, suppressed, or overexpressed, lead to cell death. Because synthetic lethality can target a variety of cellular defects, including alterations in DNA repair, cell cycle regulation, and metabolism, it is attracting attention as a technology for developing new anticancer drugs that specifically kill cancer cells.

[0006] Overexpression of CCNE1, a cell cycle regulator, induces DNA damage during DNA replication. At this time, cells are arrested in the G2 phase to correct the damaged DNA and undergo DNA repair. PKMYT1, a G2 checkpoint regulator, is upregulated in expression and activity through CCNE1 hyperactivation, amplification, or overexpression. While inhibition of PKMYT1 alone does not induce apoptosis, inhibition of PKMYT1 in cancer cells with increased DNA damage due to CCNE1 hyperactivation, amplification, or overexpression can induce synthetic lethality and promote apoptosis.

[0007] As described above, PKMYT1 exhibits CCNE1-dependent activity, which can be divided into CCNE1-intrinsic dependent activity caused by overactivation, amplification, or overexpression of the CCNE1 gene and CCNE1-induced dependent activity caused by extrinsic overactivation, amplification, or overexpression induced by chemotherapy, etc.

[0008] Therefore, there is a growing need for novel compounds that can be useful in the treatment of PKMYT1-associated diseases and diseases caused by CCNE1 hyperactivation, amplification, and overexpression.

[0009] An object of the present invention is to provide a novel structural heteroaryl derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0010] Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.

[0011] 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 a disease associated with PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression, comprising the heteroaryl derivative compound as an active ingredient, a use for treating or preventing a disease associated with PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression using the compound, or a method for treating or preventing a disease associated with PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression, comprising a step of administering the compound.

[0012] In order to achieve the above purpose, the inventors of the present invention completed the present invention by confirming through research efforts that heteroaryl derivative compounds represented by the chemical formula 1 mentioned below inhibit the proliferation of cells in which PKMYT1 and / or CCNE1 are overactivated, amplified, or overexpressed.

[0013] Heteroaryl derivative compounds

[0014] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1,

[0018] X is CH or N;

[0019] R X1 and R X2 are each independently -H, -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, -NH(C 1-6 alkyl), -N(C1-6 alkyl)(C 1-6 alkyl), -O-(C 1-6 alkyl), -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -phenyl, or -(5-6 membered heteroaryl), wherein at least one H in the ring of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -phenyl, or -(5-6 membered heteroaryl) is -C 1-6 may be substituted with alkyl; or R X1 and R X2 are combined with each other to form a 12-13 membered aromatic fused ring;

[0020] Ring Y is -(5-10 membered heteroaryl), wherein said -(5-10 membered heteroaryl) ring may include one or more N, O, or S atoms in the ring, and one or more H in the ring of said -(5-10 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -(CH2)mR a , -NH-R b , -OR c , -halo, -(3-6 membered cycloalkyl), -C(=O)-(3-6 membered cycloalkyl), -S(=O)2-C 1-6 Alkyl, or -P(=O)-(C 1-6 alkyl)(C 1-6 may be substituted with alkyl);

[0021] m is 0, 1, 2, 3, or 4;

[0022] R a is -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl), wherein at least one H in the -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl) ring is -C1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered heterocycloalkyl);

[0023] R b and R c are each independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered heterocycloalkyl), or -(CH2)n-(5-6 membered heteroaryl), wherein at least one H in the -(CH2)n-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered heterocycloalkyl), or -(CH2)n-(5-6 membered heteroaryl) ring is -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered cycloalkyl);

[0024] n is 0, 1, 2, 3, or 4;

[0025] Z1 to Z5 are each independently -H, -C 1-6 Alkyl, -OH, or -halo.

[0026] According to a specific example of the present invention, Is , , or and;

[0027] R X1 and R X2 are each independently -H, -C 1-6Alkyl, -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(3-6 membered cycloalkyl) or -(4-6 membered heterocycloalkyl) is -C 1-3 It can be substituted with alkyl.

[0028] According to a specific example of the present invention,

[0029] Ring Y is -(8-9 membered heteroaryl);

[0030] Z1 and Z2 are each independently -C 1-6 Alkyl, preferably -C 1-3 is alkyl, more preferably methyl;

[0031] One of Z3 and Z4 is -OH and the other is -H;

[0032] Z5 is -H or -halo.

[0033] According to a specific example of the present invention, Is and Z1, Z2, and Z5 are as defined above, and may be a compound of the S form in the present specification.

[0034] According to another specific embodiment of the present invention, Is and Z1, Z2, and Z5 are as defined above and may be a compound of the R form in the present specification.

[0035] In addition, according to a specific example of the present invention, may be a racemic mixture.

[0036] According to a specific example of the present invention, ring Y is , , , , , , , , , , , , , , , , , , or and wherein at least one H in the ring of the above ring Y is -C 1-3 Alkyl, -C 1-3 Aminoalkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -(CH2)mR a , -NH-R b , -OR c , -halo, -(3-6 membered cycloalkyl), -C(=O)-(3-6 membered cycloalkyl), -S(=O)2-C 1-3 Alkyl, or -P(=O)-(C 1-3 alkyl)(C 1-3 may be substituted with alkyl);

[0037] m is 0 or 1;

[0038] R a is -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl), wherein at least one H in the -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl) ring is -C 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered heterocycloalkyl);

[0039] R b and R c are each independently -C 1-3 Alkyl, -C 1-3 Haloalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-3Alkyl, -S(=O)2-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl) is -C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered cycloalkyl);

[0040] n is 0, 1, or 2.

[0041] 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.

[0042] In the present invention, "alkyl" may mean a straight or branched chain acyclic, cyclic or saturated hydrocarbon with a combination thereof, unless otherwise specified. For example, "C 1-6 "Alkyl" may mean alkyl having 1 to 6 carbon atoms. Acyclic alkyl may include, but is not limited to, methyl, ethyl, n-propyl, 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.

[0043] 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.

[0044] In the present invention, “alkoxy” may mean an alkyl ether group -(R′-OR″), where R′ represents 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 1-6 Alkoxy may mean, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0045] In the present invention, “halo” may be F, Cl, Br, or I.

[0046] In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more carbon atoms substituted with halo as defined herein. Examples of such haloalkyl 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.

[0047] 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.

[0048] In the present invention, “alkylamino” or “aminoalkyl” may mean -(NR′R″), where 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. 1-6 Amino 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.

[0049] In the present invention, “cyanoalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0050] 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, 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. 1-6A 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.

[0051] In the present invention, "alkylcarbonyl" may mean -(R′-C(=O)-R″), where R′ represents 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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."

[0056] 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".

[0057] In the present invention, “hydroarene” or “hydroaryl” is an aromatic hydrocarbon ring in which at least one double bond is saturated.

[0058] 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."

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] Method for producing heteroaryl derivative compounds

[0067] The present invention provides a method for preparing a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0068] [Chemical Formula 1]

[0069]

[0070] According to a specific example of the present invention, the manufacturing method may include the steps represented by the following reaction scheme I:

[0071] [Reaction Formula I]

[0072]

[0073] In the above reaction formula I,

[0074] R X1 and R X2are each independently -H, -C 1-6 Alkyl, -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(3-6 membered cycloalkyl) or -(4-6 membered heterocycloalkyl) is -C 1-3 may be substituted with alkyl;

[0075] R X3 is -halo;

[0076] Ring Y is , , , , , , , , , , , , , , , , , , or and wherein at least one H in the ring of the above ring Y is -C 1-3 Alkyl, -C 1-3 Aminoalkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -(CH2)mR a , -NH-R b , -OR c , -halo, -(3-6 membered cycloalkyl), -C(=O)-(3-6 membered cycloalkyl), -S(=O)2-C 1-3 Alkyl, or -P(=O)-(C 1-3 alkyl)(C 1-3 may be substituted with alkyl);

[0077] m is 0 or 1;

[0078] R ais -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl), wherein at least one H in the -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl) ring is -C 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered heterocycloalkyl);

[0079] R b and R c are each independently -C 1-3 Alkyl, -C 1-3 Haloalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-3 Alkyl, -S(=O)2-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl) is -C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered cycloalkyl);

[0080] n is 0, 1, or 2;

[0081] Z1 and Z2 are each independently -C 1-3 It is alkyl;

[0082] Z4 is -H;

[0083] Z5 is -H or -halo;

[0084] PG is an -OH protecting group.

[0085] In the present invention, the -OH protecting group may be MOM (methoxymethyl) or SEM (2-(trimethylsilyl)ethoxymethyl). However, it is not limited thereto.

[0086] According to another specific embodiment of the present invention, the manufacturing method may include the steps represented by the following reaction scheme II:

[0087] [Reaction Formula II]

[0088]

[0089] In the above reaction formula II,

[0090] R X1 Inland R X3 , rings Y, Z1, Z2, Z4, Z5 and PG are as summarized in Scheme I.

[0091] Uses of heteroaryl derivative compounds

[0092] 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.

[0093] [Chemical Formula 1]

[0094]

[0095] The above chemical formula 1 is as defined above.

[0096] The compound represented by chemical formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against various kinases.

[0097] According to one specific example of the present invention, it was confirmed that the heteroaryl derivative represented by the above chemical formula 1 exhibits high inhibitory activity against PKMYT1 and inhibits the proliferation of cells in which PKMYT1 is activated. In addition, the heteroaryl derivative represented by the above chemical formula 1 of the present invention also exhibits high inhibitory activity against cells in which CCNE1 is overactivated, amplified, or overexpressed. Therefore, it can be usefully used for the treatment or prevention of diseases associated with PKMYT1 and / or CCNE1 overactivation, amplification, or overexpression.

[0098] The disease associated with the above PKMYT1 and / or CCNE1 overactivation, amplification, or overexpression may be, for example, cancer. The cancer may be a malignant tumor that includes an abnormality that activates PKMYT1, such as a disease or disorder associated with PKMYT1, or a malignant tumor characterized by the overactivation, amplification, or overexpression of CCNE1. The cancer may be a solid tumor or a hematological cancer, and includes not only primary cancer but also metastatic cancer.

[0099] As a specific example, the solid cancer may be one or more selected from the group consisting of, but is not limited to, Uterine Cancer, Cervical Cancer, Ovarian Cancer, Breast Cancer, Gastrointestinal Tract Cancer, Biliary Tract Cancer, Lung and Thoracic Cancer, Thymic Cancer, Genitourinary Cancer, Head and Neck Cancer, Brain and Nervous System Tumor, Neuroendocrine Tumor, Bone and Soft Tissue Tumor, and Skin Cancer.

[0100] The above uterine cancer may be endometrial cancer, papillary serous carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, or uterine corpus endometrial carcinoma.

[0101] The above ovarian cancer may be serous ovarian cancer or high grade serous ovarian cancer (HGSOC).

[0102] The above breast cancer may be triple-negative breast cancer (TNBC).

[0103] The above gastrointestinal tract cancer may be pancreatic cancer such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), rectal cancer, gastric cancer, esophageal cancer, or liver cancer such as liver hepatocellular carcinoma (LIHC).

[0104] The above lung cancer may be small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), or squamous cell carcinoma of the lung.

[0105] The above thymic cancer may be thymoma.

[0106] 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).

[0107] The above head and neck cancer may be head and neck squamous cell carcinoma (HNSCC) or adenoid cystic carcinoma (ACC).

[0108] The above brain and central nervous system tumor may be brain cancer, glioblastoma, glioma, or brain lower grade glioma (LGG).

[0109] The above bone and soft tissue tumor may be bone cancer or soft tissue cancer such as osteosarcoma, Ewing sarcoma, or chondrosarcoma.

[0110] The above skin cancer may be melanoma.

[0111] As a specific example, the blood cancer may be leukemia, such as chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma, or lymphoma.

[0112] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for treating or preventing a disease associated with PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression, 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 disease associated with PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression may be cancer. The type of cancer is as mentioned above.

[0113] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for treating or preventing a disease associated with an inactivating mutation of PPP2R1A and / or FBXW7, 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 disease associated with the inactivating mutation of PPP2R1A and / or FBXW7 may be cancer. The type of cancer is as mentioned above.

[0114] 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.

[0115] 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.

[0116] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disease associated with PKMYT1 and / or CCNE1 overactivation, amplification, or overexpression. Specifically, the disease associated with PKMYT1 and / or CCNE1 overactivation, amplification, or overexpression may be cancer. The type of cancer is as mentioned above.

[0117] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing cancer. The type of cancer is as mentioned above.

[0118] In addition, according to one specific example of the present invention, a method for treating or preventing a disease associated with PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression is provided, 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 disease associated with the above PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression may be cancer. The type of cancer is as mentioned above.

[0119] In addition, according to one specific embodiment of the present invention, the present invention provides a method for treating or preventing 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.

[0120] In addition, according to one specific example of the present invention, the present invention provides a method for inhibiting PKMYT1 and / or CCNE1, 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.

[0121] 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 a disease associated with PKMYT1 and / or CCNE1 overactivation, amplification, or overexpression. Specifically, the "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and it can be easily determined by a person skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by a specialist based on various factors, such as the patient's condition, age, sex, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used in doses exceeding the determined dosage.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] The 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).

[0126] 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.

[0127] 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.

[0128] Additionally, it can be manufactured as a compound preparation with other active ingredients to have a synergistic effect of the active ingredients.

[0129] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they are contradictory.

[0130] The heteroaryl derivative compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits excellent inhibitory activity against kinases, particularly PKMYT1 and / or CCNE1, and therefore can be usefully used for the treatment or prevention of diseases associated with PKMYT1 and / or CCNE1 overactivation, amplification, or overexpression, and can be particularly usefully used as a therapeutic agent for cancer.

[0131] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0132] <Analysis and purification conditions>

[0133] The compounds synthesized in the manufacturing examples and examples of the present invention were purified or subjected to structural analysis under the following conditions.

[0134] 1. LC-MS, Prep-HPLC, MPLC

[0135] Analytical LC-MS (Liquid Chromatography-Mass Spectrometry)

[0136] 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.

[0137] Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.

[0138] Gradient condition (10-100% B for 3 min, flow rate = 0.6 mL / min)

[0139] Preparative Preparative-Liquid chromatography UV spectrometry (Prep-HPLC)

[0140] The ACCQPrep HP150 equipment manufactured by Teledyne was used. Water's XTERRA ® Prep RP18 OBD TM (10 ㎛, 30 Х 300 mm) column was used, and the column temperature was set to room temperature.

[0141] Medium pressure liquid chromatography (MPLC) for purification

[0142] Medium-pressure liquid chromatography was performed using a CombiFlash Rf +UV instrument from Teledyne ISCO.

[0143] 2. NMR interpretation

[0144] NMR analysis was performed using an NMR AVANCE NEO 400 MHz manufactured by Bruker, and data are expressed in ppm (parts per million(δ)).

[0145] The commercially available reagents used were used without further purification. In the present invention, room temperature or ambient temperature refers to a temperature of 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.

[0146] Manufacturing example: Manufacturing of intermediate compound of the present invention

[0147] Manufacturing Example 1. Manufacturing of 3-(methoxymethoxy)-2,6-dimethylaniline

[0148] [Reaction Formula 1]

[0149]

[0150] [Step 1] Preparation of 1-bromo-2,4-dimethyl-3-nitrobenzene

[0151] 1,3-Dimethyl-2-nitrobenzene (20 g, 132 mmol) was dissolved in dichloromethane (66 mL), and then iron (1.85 g, 33.1 mmol) and anhydrous iron(III) bromide (0.78 g, 2.65 mmol) were added. Bromine (23.26 g, 146 mmol, 7.5 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred for 3 hours. The reaction mixture was slowly diluted with ice water, and the organic layer was extracted with ethyl ether (50 mL Х 3). The combined organic layers were washed with a 20% aqueous sodium thiosulfate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained target compound (30.31 g, crude) was used in the next reaction without further purification.

[0152] [Step 2] Preparation of 1-methoxy-2,4-dimethyl-3-nitrobenzene

[0153] 1-Bromo-2,4-dimethyl-3-nitrobenzene (30 g, 130 mmol) prepared in Step 1 was dissolved in dimethylformamide (87 mL), and then copper bromide (1.87 g, 13.04 mmol) was added. 25% sodium methoxide (89 mL, methanol solution, 391 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 95 °C for 2 hours. Saturated ammonium chloride aqueous solution (500 mL) was added to the reaction mixture, and the organic layer was extracted with ethyl ether (200 mL Х 3). The combined organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The product was purified with hexane:ethyl acetate (0-50%), and the target compound (20.5 g, 87% yield) was obtained.

[0154] [Step 3] Preparation of 2,4-dimethyl-3-nitrophenol

[0155] 1-Methoxy-2,4-dimethyl-3-nitrobenzene (21.81 g, 120 mmol) prepared in Step 2 was dissolved in dichloromethane (120 mL), and then 1 M boron tribromide (181 mL, 181 mmol) dissolved in dichloromethane at -78 °C was slowly added dropwise. The reaction mixture was stirred at room temperature for 16 h and then slowly poured into a saturated aqueous sodium bicarbonate solution at 0 °C. The organic layer was extracted with dichloromethane (500 mL Х 3). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained target compound (19.52 g, 97% yield) was used in the next reaction without further purification.

[0156] [Step 4] Preparation of 1-(methoxymethoxy)-2,4-dimethyl-3-nitrobenzene

[0157] 2,4-Dimethyl-3-nitrophenol (20.38 g, 122 mmol) prepared in Step 3 was dissolved in dichloromethane (406 mL), and N,N-diisopropylethylamine (39.4 g, 305 mmol, 53.2 mL) was added. Chloromethyl methyl ether (9.81 g, 122 mmol, 9.26 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LC-MS, dichloromethane (1 L) was additionally added to the reaction mixture, and the mixture was washed with water and 0.1 M hydrochloric acid aqueous solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The target compound (24.41 g, 95% yield) was obtained by purification with hexane:ethyl acetate (0-40%).

[0158] [Step 5] Preparation of 3-(methoxymethoxy)-2,6-dimethylaniline

[0159] 1-(Methoxymethoxy)-2,4-dimethyl-3-nitrobenzene (24.41 g, 116 mmol) prepared in step 4 was dissolved in methanol (385 mL), Pd / C (2.46 g, 10% purity) was added, and the mixture was stirred under hydrogen gas for 16 h. After confirming the target compound using LC-MS, the reaction mixture was filtered through Celite and concentrated. The obtained target compound (18.93 g, 90% yield) was used in the next reaction without further purification. MS (ESI): m / z 182 [M+H] +

[0160] Manufacturing Example 2. Preparation of 3-fluoro-2,6-dimethyl-5-(2-trimethylsilyl)ethoxy)aniline

[0161] [Reaction Formula 2]

[0162]

[0163] [Step 1] Preparation of 1-fluoro-2,4-dimethyl-3-nitrobenzene

[0164] 1-Bromo-4-fluoro-3-methyl-2-nitrobenzene (1 g, 4.27 mmol) was dissolved in 1,4-dioxane (20 mL), then water (4 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivorineine (0.54 g, 4.27 mmol), potassium carbonate (1.18 g, 8.55 mmol), Pd(dppf)Cl2·dichloromethane (0.35 g, 0.43 mmol) was added. The reaction mixture was stirred at 110 °C for 1 h, cooled to room temperature, water (100 mL) was added, and extracted with ethyl acetate (60 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The concentrated mixture was purified by MPLC (SiO 2, The target compound (400 mg, 50% yield) was obtained by purification with petroleum ether:ethyl acetate 0-5%).

[0165] 1H NMR (400 MHz, DMSO-d6): δ 7.43 - 7.32 (m, 2H), 2.23 (s, 3H), 2.15 (d,J= 2.0 Hz, 3H).

[0166] [Step 2] Preparation of 1-bromo-5-fluoro-2,4-dimethyl-3-nitrobenzene

[0167] 1-Fluoro-2,4-dimethyl-3-nitrobenzene (350 mg, 2.07 mmol) prepared in Step 1 was dissolved in sulfuric acid (3.5 mL), and then trifluoroacetic acid (1 mL) and N-bromosuccinimide (368 mg, 2.07 mmol) were added. The mixture was stirred at room temperature for 12 h, and the reaction mixture was slowly added dropwise to ice water (20 mL). The mixture was extracted with ethyl acetate (10 mL Х 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The target compound (360 mg, 70% yield) was obtained by purification with petroleum ether:ethyl acetate 0-5%).

[0168] 1 H NMR (400 MHz, CDCl3): δ 7.42 (d,J= 8.4 Hz, 1H), 2.31 (s, 3H), 2.17 (d,J= 2.0 Hz, 3H).

[0169] [Step 3] Preparation of (2-(5-fluoro-2,4-dimethyl-3-nitrophenoxy)ethyl)trimethylsilane

[0170] 1-Bromo-5-fluoro-2,4-dimethyl-3-nitrobenzene (100 mg, 0.40 mmol) prepared in step 2 and 2-trimethylsilylethanol (234 mg, 1.98 mmol) were dissolved in 1,4-dioxane (5 mL), and cesium carbonate (193 mg, 0.59 mmol) and t-BuBrettPhos Pd G3 (17 mg) were added. The reaction mixture was stirred at 80 °C for 16 h, filtered through Celite, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO2, The target compound (50 mg, 40% yield) was obtained by purification with petroleum ether:ethyl acetate 0-5%).

[0171] 1 H NMR (400 MHz, DMSO-d6): δ 7.19 (d,J= 11.6 Hz, 1H), 4.13 (t,J= 8.0 Hz, 2H), 2.09 - 1.97 (m, 6H), 1.10 (t,J= 8.0 Hz, 2H), 0.06 (s, 9H).

[0172] [Step 4] Preparation of 3-fluoro-2,6-dimethyl-5-(2-(trimethylsilyl)ethoxy)aniline

[0173] (2-(5-Fluoro-2,4-dimethyl-3-nitrophenoxy)ethyl)trimethylsilane (50 mg, 0.16 mmol) prepared in Step 3 was dissolved in 2-propanol (5 mL), and Pd / C (17 mg, 10% purity) was added. The reaction mixture was stirred at room temperature under hydrogen gas for 2 hours. After confirming the completion of the reaction by LC-MS, the mixture was filtered through Celite and concentrated under reduced pressure to obtain the target compound (50 mg, 90% purity).

[0174] 1 H NMR (400 MHz, CDCl3): δ 6.11 (d,J= 11.6 Hz, 1H), 4.00 (t,J= 8.0 Hz, 2H), 3.70 (s, 2H), 2.04 (d,J= 1.6 Hz, 3H), 2.02 (s, 3H), 1.17 - 1.11 (m, 2H), 0.08 (s, 9H).

[0175] Example: Preparation of the compound of the present invention

[0176] Examples 1 and 2. Preparation of (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone and (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0177] [Reaction Formula 3]

[0178]

[0179] [Step 1] Preparation of 3-(1H-indol-2-yl)-3-oxopropanenitrile

[0180] Methyl 1H-indole-2-carboxylate (5 g, 28.54 mmol) was dissolved in tetrahydrofuran (50 mL), and acetonitrile (6.44 g, 156.98 mmol, 8.26 mL) was added. The temperature of the reaction mixture was lowered to -78 °C, and lithium bis(trimethylsilyl)amide (LiHMDS; 1 M, tetrahydrofuran solution, 85.62 mL) was slowly added dropwise under nitrogen gas, and the mixture was stirred for 2 h. At 0 °C, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (300 mL) and extracted with ethyl acetate (200 mL Х 2). The combined organic layer was washed with saturated brine (200 mL), and the remaining water was removed using anhydrous sodium sulfate, followed by concentration. The concentrated mixture was purified by MPLC (SiO 2, The target compound (3 g, 57% yield) was obtained by purification with petroleum ether:ethyl acetate (0-30%). MS (ESI): m / z = 185.0 [M+H] +

[0181] [Step 2] Preparation of 3-chloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine

[0182] 2,3-Dichloropyrazine (1.64 g, 11.04 mmol) and 3-(methoxymethoxy)-2,6-dimethylamine (2 g, 11.04 mmol) obtained in Preparation Example 1 were dissolved in toluene (20 mL), and then potassium tert-butoxide (t-BuOK; 1.86 g, 16.55 mmol), Xantphos (319.27 mg, 0.552 mmol), and Pd2(dba)3 (1.01 g, 1.10 mmol) were added and stirred at 80 °C for 12 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by MPLC (SiO2, The product was purified using petroleum ether:ethyl acetate (0-15%) and further purified by prep-HPLC to obtain the target compound (500 mg, 15% yield). MS (ESI): m / z = 294.0 [M+H] +

[0183] [Step 3] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0184] 3-(1H-Indol-2-yl)-3-oxo-propanenitrile (62.7 mg, 0.34 mmol) prepared in Step 1 was dissolved in dioxane (5 mL), and then sodium tert-butoxide (98.15 mg, 1.02 mmol) was added at 0 °C and stirred for 30 minutes. 3-Chloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (100 mg, 0.34 mmol) and BINAP Pd G3 (33.82 mg, 0.034 mmol) prepared in Step 2 were added and stirred at 100 °C for 12 hours. The reaction mixture was concentrated and then purified by MPLC (SiO2, petroleum ether:ethyl acetate 0-50%) to obtain the target compound (30 mg, 17% yield) as a yellow oil.

[0185] 1H NMR (400 MHz, DMSO-d6): δ 13.80 (s, 1H), 9.14 - 8.49 (m, 1H), 8.44 (d,J= 3.2 Hz, 1H), 7.96 (d,J= 2.8 Hz, 1H), 7.88 (s, 1H), 7.72 (s, 1H), 7.68 (d,J= 8.4 Hz, 1H), 7.36 - 7.20 (m, 3H), 7.12 (t,J= 7.6 Hz, 1H), 3.44 (s, 3H), 1.88 (s, 3H), 1.84 (s, 3H).

[0186] [Step 4] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0187] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone (30 mg, 0.058 mmol) prepared in step 3 above was dissolved in methanol (2 mL), 2N hydrochloric acid (0.6 mL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC to obtain the target compound (10 mg, 44% yield).

[0188] 1 H NMR (400 MHz, DMSO-d6): δ 13.84 (s, 1H), 9.68 (s, 1H), 8.42 (d,J= 2.8 Hz, 1H), 7.96 (d,J= 3.2 Hz, 1H), 7.84 (d,J= 1.2 Hz, 1H), 7.72 (d,J= 8.0 Hz, 1H), 7.68 (d,J= 8.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.15 - 7.07 (m, 2H), 6.96 (d,J= 8.4 Hz, 1H), 1.84 (s, 3H), 1.76 (s, 3).

[0189] [Step 5] Preparation of (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone and (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0190] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone (95 mg, 0.239 mmol) obtained in the above step 4 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / EtOH (0.1 % NH3H2O)]) to obtain compounds of Examples 1 and 2.

[0191] Example 1. ((S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone)

[0192] Second elution; 43.1 mg, 43% yield; 1 H NMR (400 MHz, MeOD): δ 8.42 (d,J= 1.6 Hz, 1H), 7.96 (d,J= 2.8 Hz, 1H), 7.72 (d,J= 8.2 Hz, 1H), 7.64 (d,J= 8.2 Hz, 1H), 7.56 (s, 1H), 7.32 (t,J= 7.5 Hz, 1H), 7.17 - 7.06 (m, 2H), 6.96 (br d,J= 8.1 Hz, 1H), 1.92 (s, 3H), 1.87 (s, 3H); MS (ESI): m / z = 398.1 [M+H] +

[0193] Example 2. ((R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone)

[0194] First elution; 41.2 mg, 42% yield;1 H NMR (400 MHz, MeOD): δ 8.42 (d,J= 1.6 Hz, 1H), 7.96 (d,J= 2.8 Hz, 1H), 7.72 (d,J= 8.2 Hz, 1H), 7.64 (d,J= 8.2 Hz, 1H), 7.56 (s, 1H), 7.32 (t,J= 7.5 Hz, 1H), 7.17 - 7.06 (m, 2H), 6.96 (br d,J= 8.1 Hz, 1H), 1.92 (s, 3H), 1.87 (s, 3H); MS (ESI): m / z = 398.1 [M+H] +

[0195] Examples 11 and 12. Preparation of (S)-(2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone and (R)-(2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone

[0196] [Reaction Formula 4]

[0197]

[0198] [Step 1] Preparation of 3-(1H-benzo[d]imidazol-2-yl)-3-oxopropanenitrile

[0199] Methyl 1H-benzo[d]imidazole-2-carboxylate (3.7 g, 21 mmol) was dissolved in tetrahydrofuran (40 mL), and acetonitrile (5.17 g, 126 mmol) was added. The temperature of the reaction mixture was lowered to -78 °C, and LiHMDS (1 M, tetrahydrofuran solution, 84.01 mL) was slowly added dropwise under nitrogen gas, and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution at 0 °C and purified by prep-HPLC to obtain the target compound (1.37 g, 35% yield). MS (ESI): m / z 186.1 = [M+H] +

[0200] 1 H NMR (400 MHz, CDCl3): δ 10.32 (s, 1H), 7.92 (d,J= 8.4 Hz, 1H), 7.64-7.56 (m, 1H), 7.52 (t,J= 7.6 Hz, 1H), 7.46 - 7.40 (m, 1H), 4.48 (s, 2H).

[0201] [Step 2] Preparation of 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine

[0202] 3-(methoxymethoxy)-2,6-dimethylaniline (1 g, 5.52 mmol) prepared in the above Preparation Example 1 was dissolved in toluene (50 mL), then 2,3-dibromo-5,6-dimethylpyridine (1.61 g, 6.07 mmol), Xantphos (319 mg, 0.552 mmol), cesium carbonate (5.39 g, 16.55 mmol), and Pd2(dba)3 (505 mg, 0.552 mmol) were added and stirred at 100°C for 12 hours. The reaction mixture was concentrated and then analyzed by MPLC (SiO 2, The target compound (1.5 g, 69% yield) was obtained by purification with petroleum ether:ethyl acetate (0-25%). MS (ESI): m / z = 365.1 [M+H] +

[0203] [Step 3] Preparation of (2-amino-1-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone

[0204] 3-(1H-Benzo[d]imidazol-2-yl)-3-oxopropanenitrile (38.02 mg, 0.205 mmol) prepared in the above step 1 and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (50 mg, 0.137 mmol) prepared in the above step 2 were dissolved in dioxane (1 mL), then BINAP Pd G3 (13.60 mg, 0.014 mmol) and tribasic potassium phosphate (87.17 mg, 0.411 mmol) were added and stirred at 100 °C for 12 h. The reaction mixture was concentrated and then analyzed by MPLC (SiO 2, The target compound (50 mg, 16% yield) was obtained by purification with petroleum ether:ethyl acetate (0-50%). MS (ESI): m / z = 470.2 [M+H] +

[0205] [Step 4] Preparation of (2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone

[0206] (2-Amino-1-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone (74 mg, 157.60 μmol) prepared in the above step 3 was dissolved in methanol (3 mL), 4N hydrochloric acid (3 mL) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated and purified by perp-HPLC to obtain the target compound (20 mg, 30% yield). MS (ESI): m / z = 426.1 [M+H] +

[0207] [Step 5] Preparation of (S)-(2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone and (R)-(2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone

[0208] (2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone (20 mg, 0.047 mmol) obtained in the above step 4 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK OD (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / methanol (0.1 % NH3H2O)]) to obtain compounds of Examples 11 and 12.

[0209] Example 11. ((S)-(2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone)

[0210] Second extraction; 8.4 mg (42% yield); 1 H NMR (400 MHz, MeOD): δ 8.72 - 8.41 (m, 1H), 7.76 (dd,J= 2.8, 6.0 Hz, 2H), 7.48 (s, 2H), 7.36 - 7.21 (m, 2H), 7.04 (d,J= 8.4 Hz, 1H), 2.48 (s, 3H), 2.36 (s, 3H), 1.92 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 426.1 [M+H] +

[0211] Example 12. ((R)-(2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(1H-benzo[d]imidazol-2-yl)methanone)

[0212] First elution; 6.8 mg (34% yield); 1 H NMR (400 MHz, MeOD): δ 8.66 - 8.35 (m, 1H), 7.72 (dd,J= 2.8, 6.0 Hz, 2H), 7.44 (d,J= 8.4 Hz, 2H), 7.30 - 7.15 (m, 2H), 7.00 (d,J= 8.4 Hz, 1H), 2.44 (s, 3H), 2.32 (s, 3H), 1.88 (s, 3H), 1.84 (s, 3H); MS (ESI): m / z = 426.1 [M+H] +

[0213] Examples 56 and 57. Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone

[0214] [Reaction Formula 5]

[0215]

[0216] [Step 1] Preparation of 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine

[0217] 2,3-Dibromopyrazine (10 g, 42 mmol) and 3-(methoxymethoxy)-2,6-dimethylaniline (7.6 g, 42 mmol) obtained in Preparation Example 1 were dissolved in tetrahydrofuran (100 mL), and then LiHMDS (1 M tetrahydrofuran solution, 63 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, and after confirming the completion of the reaction by LC-MS, aqueous ammonium chloride solution (200 mL) was slowly added at 0 °C to terminate the reaction. Then, the organic layer was extracted using ethyl acetate (100 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by prep-HPLC to obtain the target compound (10.5 g, 74% yield). MS (ESI): m / z = 338.0 [M+H] +

[0218] [Step 2] Preparation of 3-methyl-3-((3-nitrophenoxy)methyl)oxetane

[0219] (3-Methyloxetan-3-yl)methanol (50.18 g, 491.35 mmol, 48.53 mL) was dissolved in dimethylformamide (500 mL), and then sodium hydride (18.14 g, 60% purity) was slowly added at 0 °C over 30 minutes, and the mixture was stirred at 0 °C for 30 minutes. Then, 1-fluoro-3-nitro-benzene (53.33 g, 377.96 mmol, 40.25 mL) was slowly added dropwise to the reaction mixture over 30 minutes, and the mixture was stirred at room temperature for 12 hours under nitrogen gas. After confirming the completion of the reaction by LC-MS, water (5 L) was poured into the reaction mixture, and the organic layer was extracted using ethyl acetate (1 L Х 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by MPLC (SiO 2, The product was purified using petroleum ether:ethyl acetate (0-25%) to obtain the target compound (45 g, 53% yield).

[0220] 1H NMR (400 MHz, DMSO-d6): δ 7.83 (dd,J= 1.6, 8.0 Hz, 1H), 7.75 (t,J= 2.0 Hz, 1H), 7.59 (t,J= 8.4 Hz, 1H), 7.46 (dd,J= 2.4, 8.4 Hz, 1H), 4.51 (d,J= 6.0 Hz, 2H), 4.31 (d,J= 5.6 Hz, 2H), 4.18 (s, 2H), 1.37 (s, 3H).

[0221] [Step 3] Preparation of 3-((3-methyloxetan-3-yl)methoxy)aniline

[0222] 3-Methyl-3-((3-nitrophenoxy)methyl)oxetane (30 g, 134.39 mmol) prepared in the above step 2 was dissolved in tetrahydrofuran (500 mL), Pd / C (5 g, 10% purity) was added, and the mixture was stirred at room temperature for 12 hours under hydrogen gas. After confirming the completion of the reaction by LC-MS, the mixture was filtered through Celite. The organic layer obtained by filtration was concentrated under reduced pressure to obtain the target compound (27 g).

[0223] 1 H NMR (400 MHz, DMSO-d6): δ 6.90 (t,J= 8.0 Hz, 1H), 6.21 - 6.14 (m, 2H), 6.12 (dd,J= 1.6, 8.8 Hz, 1H), 4.46 (d,J= 5.6 Hz, 2H), 4.28 (d,J= 5.6 Hz, 2H), 3.92 (s, 2H), 1.34 (s, 3H).

[0224] [Step 4] Preparation of ethyl 6-((3-methyloxetan-3-yl)methoxy)-1H-indole-2-carboxylate

[0225] 3-((3-methyloxetan-3-yl)methoxy)aniline (5 g, 25.87 mmol) prepared in Step 3 above was dissolved in dimethyl sulfoxide (100 mL), and ethyl 2-oxopropanoate (6.01 g, 51.75 mmol, 5.75 mL), acetic acid (6.22 g, 103.50 mmol, 5.92 mL), 4 Å MS (10 g), and Pd(OAc)2 (581 mg, 2.59 mmol) were added. The reaction mixture was stirred at 80 °C under oxygen gas for 12 h. After confirming the completion of the reaction by LC-MS, water (2 L) was poured into the reaction mixture, and the organic layer was extracted using ethyl acetate (500 mL Х 3). The collected organic layer was washed with saturated brine (500 mL), dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC (SiO2, petroleum ether:ethyl acetate 0-35%) to obtain the target compound (3.14 g, 42% yield).

[0226] 1 H NMR (400 MHz, DMSO-d6): δ 11.70 (s, 1H), 7.53 (d,J= 8.8 Hz, 1H), 7.08 (d,J= 2.0 Hz, 1H), 6.92 (d,J= 1.6 Hz, 1H), 6.78 (dd,J= 2.0, 8.8 Hz, 1H), 4.52 (d,J= 5.6 Hz, 2H), 4.31 (d,J= 6.4 Hz, 4H), 4.05 (s, 2H), 1.38 (s, 3H), 1.33 (t,J= 7.2 Hz, 3H).

[0227] [Step 5] Preparation of 3-(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)-3-oxopropanenitrile

[0228] Ethyl 6-((3-methyloxetan-3-yl)methoxy)-1H-indole-2-carboxylate (3.14 g, 10.85 mmol) prepared in the above step 4 was dissolved in tetrahydrofuran (120 mL), and then LiHMDS (1 M tetrahydrofuran solution, 41 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. After confirming the completion of the reaction by LC-MS, aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, and the organic layer was extracted using ethyl acetate (30 mL Х 3). After drying over sodium sulfate and concentrating under reduced pressure, the target compound (2.09 g, 68% yield) was obtained. MS (ESI): m / z = 283.2 [MH] -

[0229] [Step 6] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone

[0230] 3-(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)-3-oxopropanenitrile (2.09 g, 7.35 mmol) prepared in Step 5 above and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (2.48 g, 7.35 mmol) prepared in Step 1 above were dissolved in 1,4-dioxane (500 mL), and then cesium carbonate (6.88 g, 21.1 mmol) and BINAP Pd G3 (0.7 g) were added. The reaction mixture was then stirred at 100 °C for 12 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure and purified by MPLC (SiO2, petroleum ether:ethyl acetate 0-50%) to obtain the target compound (1.75 g, 44% yield).

[0231] [Step 7] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone

[0232] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone (1 g, 1.85 mmol) prepared in Step 6 was dissolved in water (100 mL) and trifluoroacetic acid (100 mL), and the mixture was stirred at room temperature for 2 h. After confirming the completion of the reaction by LC-MS, water (200 mL) was poured into the reaction mixture, and the pH was adjusted to 8 with potassium carbonate. The organic layer was then extracted with ethyl acetate (50 mL X 3), and the combined organic layers were washed with saturated brine (100 mL X 2). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by prep-HPLC to obtain the target compound (0.43 g, 47% yield). MS (ESI): m / z = 498.2 [M+H] +

[0233] [Step 8] Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone

[0234] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone (0.43 g, 0.86 mmol) prepared in step 7 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm Х 30 mm, 10 μm); mobile phase: [CO2-acetonitrile / isopropanol (0.1 % NH3H2O)]) to give compounds of Examples 56 and 57.

[0235] Example 56. (R)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone

[0236] First elution; 162 mg, 38% yield; 1 H NMR (400 MHz, MeOD): δ 8.41 (d,J= 3.2 Hz, 1H), 7.94 (d,J= 3.2 Hz, 1H), 7.58 (d,J= 8.8 Hz, 1H), 7.51 (s, 1H), 7.19 (s, 1H), 7.15 (d,J= 8.4 Hz, 1H), 7.01 - 6.93 (m, 1H), 6.83 (dd,J= 2.0, 8.8 Hz, 1H), 4.73 (d,J= 6.0 Hz, 2H), 4.48 (d,J= 6.0 Hz, 2H), 4.14 (s, 2H), 1.92 (s, 3H), 1.87 (s, 3H), 1.48 (s, 3H); MS (ESI): m / z = 498.2 [M+H] +

[0237] Example 57. (S)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(6-((3-methyloxetan-3-yl)methoxy)-1H-indol-2-yl)methanone

[0238] Second extraction; 158 mg; 37% yield; 1H NMR (400 MHz, MeOD): δ 8.41 (d,J= 3.2 Hz, 1H), 7.94 (d,J= 3.2 Hz, 1H), 7.58 (d,J= 8.8 Hz, 1H), 7.51 (s, 1H), 7.20 (s, 1H), 7.15 (d,J= 8.4 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.83 (dd,J= 2.0, 8.8 Hz, 1H), 4.73 (d,J= 6.0 Hz, 2H), 4.49 (d,J= 6.0 Hz, 2H), 4.14 (s, 2H), 1.92 (s, 3H), 1.88 (s, 3H), 1.48 (s, 3H); MS (ESI): m / z = 498.2 [M+H] +

[0239] Examples 58 and 59. Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0240] [Reaction Formula 6]

[0241]

[0242] [Step 1] Preparation of 3-chloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5,6-dimethylpyrazin-2-amine

[0243] 2,3-Dichloro-5,6-dimethyl-pyrazine (5 g, 28.24 mmol) and 3-(methoxymethoxy)-2,6-dimethylaniline (3.41 g, 18.83 mmol) obtained in Preparation Example 1 were dissolved in toluene (350 mL), and then K3PO4 (4.0 g, 18.83 mmol) and Xantphos Pd G4 (1.8 g, 1.88 mmol) were added. The reaction mixture was stirred at 100 °C for 12 h. After confirming the completion of the reaction by LC-MS, the mixture was filtered through Celite and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The target compound (1.1 g, 18% yield) was obtained by purification with petroleum ether:ethyl acetate (0-20%).

[0244] 1 H NMR (400 MHz, CDCl3): δ 7.09 - 7.02 (m, 1H), 7.01 - 6.94 (m, 1H), 6.26 (s, 1H), 5.21 (s, 2H), 3.51 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H).

[0245] [Step 2] Preparation of 3-oxo-3-(1H-pyrrolo[3,2-b]pyridin-2-yl)propanenitrile

[0246] Ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate (10 g, 52.58 mmol) was dissolved in 2-methyltetrahydrofuran (200 mL), and acetonitrile (15 mL) was added. Then, LiHMDS (1 M tetrahydrofuran solution, 184 mL) was slowly added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and after confirming the completion of the reaction by LC-MS, water (400 mL) was slowly added at 0 °C to terminate the reaction. Then, the organic layer was extracted using 2-MeTHF (300 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (8 g, 82% yield).

[0247] 1 H NMR (400 MHz, MeOD): δ 8.24 (dd,J= 1.2, 4.8 Hz, 1H), 7.80 (d,J= 8.0 Hz, 1H), 7.13 (dd,J= 4.8, 8.0 Hz, 1H), 6.82 (s, 1H), 4.85 (s, 2H).

[0248] [Step 3] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0249] 3-Chloro-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5,6-dimethylpyrazin-2-amine (1.1 g, 3.42 mmol) prepared in step 1 above and 3-oxo-3-(1H-pyrrolo[3,2-b]pyridin-2-yl)propanenitrile (1.27 g, 6.86 mmol) prepared in step 2 above were dissolved in 1,4-dioxane (150 mL), and then cesium carbonate (3.3 g, 10.26 mmol) and BINAP Pd G3 (0.34 g, 0.34 mmol) were added. The reaction mixture was then stirred at 100°C for 12 hours, and after confirming the completion of the reaction by LC-MS, water (100 mL) was poured into the reaction mixture and extracted with ethyl acetate (100 mL Х 3). The collected organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by prep-HPLC to obtain the target compound (144 mg, 9% yield). MS (ESI): m / z = 471.1 [M+H] +

[0250] [Step 4] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0251] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone (144 mg, 0.31 mmol) prepared in Step 3 above was dissolved in HCl (4 M, 1,4-dioxane solution, 40 mL) and stirred at room temperature for 1 hour. After confirming the completion of the reaction by LC-MS, the pH was adjusted to 6 using solid sodium bicarbonate. Then, water was added to the reaction mixture, and it was extracted using ethyl acetate (50 mL Х 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (124 mg, 95% yield).

[0252] [Step 5] Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0253] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone (124 mg, 0.29 mmol) prepared in the above step 4 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK OD (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / methanol (0.1% NH3H2O)]) to obtain compounds of Examples 58 and 59.

[0254] Example 58. (R)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0255] First elution; 40 mg (32% yield); 1 H NMR (400 MHz, MeOD): δ 8.45 (dd,J= 1.2, 4.8 Hz, 1H), 8.15 (d,J= 8.4 Hz, 1H), 7.60 (s, 1H), 7.37 (dd,J= 4.8, 8.4 Hz, 1H), 7.16 (d,J= 8.4 Hz, 1H), 6.98 (d,J= 8.4 Hz, 1H), 2.79 (s, 3H), 2.50 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 427.1 [M+H] +

[0256] Example 59. (S)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0257] Second extraction; 45 mg (36% yield); 1 H NMR (400 MHz, MeOD): δ 8.45 (dd,J= 1.2, 4.8 Hz, 1H), 8.15 (d,J= 8.4 Hz, 1H), 7.60 (s, 1H), 7.37 (dd,J= 4.8, 8.4 Hz, 1H), 7.16 (d,J= 8.4 Hz, 1H), 6.98 (d,J= 8.4 Hz, 1H), 2.79 (s, 3H), 2.50 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 427.1 [M+H] +

[0258] Examples 82 and 83. Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone

[0259] [Reaction Formula 7]

[0260]

[0261] [Step 1] Preparation of 3-(7-chloro-1H-indol-2-yl)-3-oxopropanenitrile

[0262] Ethyl 7-chloro-1H-indole-2-carboxylate (10 g, 44.71 mmol) was dissolved in tetrahydrofuran (100 mL), and acetonitrile (13 mL) was added. Then, LiHMDS (1 M tetrahydrofuran solution, 196 mL) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. After confirming the completion of the reaction by LC-MS, water (300 mL) was added to the reaction mixture, and 2-methyltetrahydrofuran (150 mL Х 3) was extracted. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (23 g, crude). MS (ESI): m / z = 217.1 [MH] -

[0263] [Step 2] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-chloro-1H-indol-2-yl)methanone

[0264] 3-(7-chloro-1H-indol-2-yl)-3-oxopropanenitrile (5.82 g, 26.61 mmol) prepared in Step 1 above and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (5 g, 14.78 mmol) prepared in Step 1 of Examples 56 and 57 above were dissolved in 1,4-dioxane (150 mL), and then cesium carbonate (14.45 g, 44.35 mmol) and BINAP Pd G3 (1.47 g, 1.48 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours, and the completion of the reaction was confirmed by LC-MS, and filtered through Celite. The filtered organic layer was concentrated under reduced pressure and then purified by MPLC (SiO 2, The target compound (1.8 g, 24% yield) was obtained by purification with petroleum ether:ethyl acetate (0-30%). MS (ESI): m / z = 476.1 [M+H] +

[0265] [Step 3] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl))methyl)amino)-1H-indol-2-yl)methanone

[0266] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-chloro-1H-indol-2-yl)methanone (300 mg, 0.63 mmol) prepared in the above step 2 was dissolved in toluene (15 mL), and then (3-methyloxetan-3-yl)methanamine (637 mg, 6.30 mmol), sodium tert-butoxide (420 mg, 4.37 mmol), and Pd-PEPPSI쪠-IPent (50 mg) were added. The reaction mixture was stirred at 100 °C for 12 h, and the completion of the reaction was confirmed by LC-MS, and filtered through Celite. The filtered organic layer was concentrated under reduced pressure and then analyzed by MPLC (SiO 2, The target compound (300 mg, 88% yield) was obtained by purification with petroleum ether:ethyl acetate (0-25%). MS (ESI): m / z = 541.3 [M+H] +

[0267] [Step 4] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone

[0268] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl))methyl)amino)-1H-indol-2-yl)methanone (150 mg, 0.28 mmol) prepared in Step 3 above was dissolved in water (90 mL) and trifluoroacetic acid (90 mL), and the mixture was stirred at room temperature for 1 h. The completion of the reaction was confirmed by LC-MS, and the pH of the reaction mixture was adjusted to 8 using sodium bicarbonate. The organic layer was then extracted using dichloromethane (150 mL Х 3), and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC to obtain the target compound (35 mg, 13% yield). MS (ESI): m / z = 497.3 [M+H] +

[0269] [Step 5] Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone

[0270] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone (35 mg, 0.07 mmol) prepared in the above step 4 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm Х 30 mm, 10 μm); mobile phase: [CO2-acetonitrile / isopropanol (0.1 % NH3H2O)]) to obtain compounds of Examples 82 and 83.

[0271] Example 82. (R)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone

[0272] First elution; 16.8 mg (48% yield); 1 H NMR (400 MHz, MeOD): δ 8.42 (d,J= 2.8 Hz, 1H), 7.94 (d,J= 3.2 Hz, 1H), 7.58 (s, 1H), 7.22 - 7.10 (m, 2H), 7.03 - 6.94 (m, 2H), 6.63 (d,J= 7.6 Hz, 1H), 4.81 (d,J= 6.0 Hz, 2H), 4.54 (d,J= 6.0 Hz, 2H), 3.51 (s, 2H), 1.93 (s, 3H), 1.88 (s, 3H), 1.56 (s, 3H); MS (ESI): m / z = 497.2 [M+H] +

[0273] Example 83. (S)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(7-(((3-methyloxetan-3-yl)methyl)amino)-1H-indol-2-yl)methanone

[0274] Second elution; 15.7 mg (45% yield); 1 H NMR (400 MHz, MeOD): δ 8.42 (d,J= 3.2 Hz, 1H), 7.94 (d,J= 3.2 Hz, 1H), 7.58 (s, 1H), 7.15 (dd,J= 8.4, 10.8 Hz, 2H), 7.03 - 6.94 (m, 2H), 6.63 (d,J= 7.6 Hz, 1H), 4.81 (d,J= 6.0 Hz, 2H), 4.54 (d,J= 6.0 Hz, 2H), 3.51 (s, 2H), 1.93 (s, 3H), 1.88 (s, 3H), 1.56 (s, 3H); MS (ESI): m / z = 497.2 [M+H] +

[0275] Examples 142 and 143. Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone

[0276] [Reaction Formula 8]

[0277]

[0278] [Step 1] Preparation of 3-(4-chloro-1H-indol-2-yl)-3-oxopropanenitrile

[0279] Ethyl 4-chloro-1H-indole-2-carboxylate (4 g, 17.88 mmol) was dissolved in tetrahydrofuran (40 mL), and acetonitrile (5 mL) was added. Then, LiHMDS (1 M tetrahydrofuran solution, 80 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and after confirming the completion of the reaction by LC-MS, aqueous ammonium chloride solution (200 mL) was slowly added at 0 °C to terminate the reaction. Then, the organic layer was extracted using ethyl acetate (100 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (4.5 g, crude). MS (ESI): m / z = 217.1 [MH] -

[0280] [Step 2] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-chloro-1H-indol-2-yl)methanone

[0281] 3-(4-Chloro-1H-indol-2-yl)-3-oxopropanenitrile (4.5 g, 20.58 mmol) prepared in Step 1 and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (3.87 g, 11.43 mmol) prepared in Step 1 of Examples 56 and 57 were dissolved in 1,4-dioxane (200 mL), and then cesium carbonate (11.18 g, 34.30 mmol) and BINAP Pd G3 (1.14 g, 1.14 mmol) were added. The reaction mixture was then stirred at 100 °C for 12 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC to obtain the target compound (3.2 g, 58% yield). MS (ESI): m / z = 476.1 [M+H] +

[0282] [Step 3] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone

[0283] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-chloro-1H-indol-2-yl)methanone (300 mg, 0.62 mmol) prepared in step 2, potassium trifluoro(morpholinomethyl)borate were dissolved in 1,4-dioxane (20 mL), and then water (0.2 mL), potassium carbonate (0.55 mg, 3.94 mmol), and RhPhos Pd G3 (52 mg) were added. The reaction mixture was stirred at 100 °C for 12 h. Water (30 mL) was poured into the reaction mixture, and extracted with ethyl acetate (100 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by MPLC (SiO 2,The target compound (230 mg, 68% yield) was obtained by purification with petroleum ether:ethyl acetate (0-80%). MS (ESI): m / z = 541.3 [M+H] +

[0284] 1 H NMR (400 MHz, CDCl3): δ 8.37 (d,J= 2.8 Hz, 1H), 8.05 (d,J= 2.8 Hz, 1H), 7.78 (s, 1H), 7.60 (d,J= 8.0 Hz, 1H), 7.36-7.27 (m, 2H), 7.24 (s, 1H), 7.20-7.10 (m, 1H), 5.31-5.22 (m, 2H), 3.91 (d,J= 2.0 Hz, 2H), 3.80-3.72 (m, 4H), 3.54 (s, 3H), 2.71-2.52 (m, 4H), 2.00 (s, 3H), 1.95 (s, 3H).

[0285] [Step 4] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone

[0286] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone (220 mg, 0.40 mmol) prepared in step 3 was dissolved in HCl (4 M, 1,4-dioxane solution, 25 mL) and stirred at room temperature for 30 min. Then, aqueous sodium bicarbonate solution (100 mL) was poured into the reaction mixture and extracted with ethyl acetate (100 mLХ3). The collected organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (200 mg). MS (ESI): m / z = 497.2 [M+H] +

[0287] [Step 5] Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone

[0288] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone (85 mg, 0.17 mmol) prepared in step 4 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm Х 30 mm, 10 μm); mobile phase: [CO2-acetonitrile / isopropanol (0.1 % NH3H2O)]) to give compounds of Examples 142 and 143.

[0289] Example 142. (R)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone

[0290] First elution; 39.4 mg (45% yield); 1 H NMR (400 MHz, MeOD): δ 8.41 (d,J= 3.2 Hz, 1H), 7.97 (d,J= 3.2 Hz, 1H), 7.79 (d,J= 0.8 Hz, 1H), 7.61 (d,J= 8.4 Hz, 1H), 7.34-7.25 (m, 1H), 7.17 (d,J= 8.4 Hz, 1H), 7.11 (d,J= 7.2 Hz, 1H), 6.98 (d,J= 8.4 Hz, 1H), 3.93 (s, 2H), 3.73 (t,J= 4.8 Hz, 4H), 2.63 (s, 4H), 1.93 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 497.3 [M+H] +

[0291] Example 143. (S)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-(morpholinomethyl)-1H-indol-2-yl)methanone

[0292] Second elution; 39.6 mg (46% yield); 1 H NMR (400 MHz, MeOD): δ 8.41 (d,J= 3.2 Hz, 1H), 7.96 (d,J= 3.2 Hz, 1H), 7.78 (s, 1H), 7.59 (d,J= 8.4 Hz, 1H), 7.35-7.23 (m, 1H), 7.16 (d,J= 8.4 Hz, 1H), 7.10 (d,J= 7.2 Hz, 1H), 6.98 (d,J= 8.4 Hz, 1H), 3.87 (s, 2H), 3.71 (t,J= 4.8 Hz, 4H), 2.57 (s, 4H), 1.92 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 497.3 [M+H] +

[0293] Examples 240 and 241. Preparation of (R)-(6-amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone and (S)-(6-amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0294] [Reaction Formula 9]

[0295]

[0296] [Step 1] Preparation of 5-bromo-6-methylpyrazin-2-amine

[0297] 6-Methylpyrazin-2-amine (6 g, 54.98 mmol) was dissolved in dimethyl sulfoxide (300 mL) and water (12 mL), and then N-bromosuccinimide (10.76 g, 60.48 mmol) was added. The reaction mixture was stirred at room temperature for 10 h, and after confirming the completion of the reaction by LC-MS, water (500 mL) was poured into the reaction mixture and extracted with ethyl acetate (200 mL X 2). The collected organic layer was washed with saturated aqueous sodium carbonate solution (300 mL) and saturated brine (500 mL X 3), dried over sodium sulfate, and filtered. The organic layer was then concentrated under reduced pressure and purified by MPLC (SiO 2, The target compound (10 g, 97% yield) was obtained by purification with petroleum ether:ethyl acetate (0-30%).

[0298] 1 H NMR (400 MHz, DMSO-d6): δ 7.49 (s, 1H), 6.54 (s, 2H), 2.33 (s, 3H).

[0299] [Step 2] Preparation of 5-cyclopropyl-6-methylpyrazin-2-amine

[0300] 5-Bromo-6-methylpyrazin-2-amine (10 g, 53.18 mmol) and cyclopropylboronic acid (9.14 g, 106.37 mmol) prepared in Step 1 above were dissolved in 1,4-dioxane (300 mL) and water (100 mL), and then potassium carbonate (22.05 g, 159.55 mmol) and Pd(dppf)Cl2·dichloromethane (6.5 g) were added. The reaction mixture was stirred at 100 °C for 18 h. After confirming the completion of the reaction by LC-MS, the filtrate was filtered through Celite, and water (200 mL) was poured into the obtained filtrate, and extracted with ethyl acetate (200 mL Х 3). The collected organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2,The target compound (3.92 g, 41% yield) was obtained by purification with petroleum ether:ethyl acetate 0-20%).

[0301] 1 H NMR (400 MHz, DMSO-d6): δ 7.56 (s, 1H), 5.92 (s, 2H), 2.36 (s, 3H), 2.02 - 1.91 (m, 1H), 0.82 - 0.76 (m, 2H), 0.75 - 0.69 (m, 2H).

[0302] [Step 3] Preparation of 3-bromo-5-cyclopropyl-6-methylpyrazin-2-amine

[0303] 5-Cyclopropyl-6-methylpyrazin-2-amine (3.76 g, 25.20 mmol) prepared in Step 2 was dissolved in acetonitrile (80 mL), and N-bromosuccinimide (4.93 g, 27.72 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and after confirming the completion of the reaction by LC-MS, saturated aqueous sodium carbonate solution (100 mL) was slowly poured. Then, ethyl acetate (80 mL Х 2) was used for extraction, and the organic layer was washed with saturated brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (5.67 g, 99% yield).

[0304] 1 H NMR (400 MHz, DMSO-d6): δ 6.23 (s, 2H), 2.37 (s, 3H), 2.00 - 1.93 (m, 1H), 0.88 - 0.81 (m, 2H), 0.74 - 0.67 (m, 2H).

[0305] [Step 4] Preparation of 2-bromo-6-cyclopropyl-3-iodo-5-methylpyrazine

[0306] 3-Bromo-5-cyclopropyl-6-methylpyrazin-2-amine (3.4 g, 14.91 mmol) prepared in the above step 3 was dissolved in tetrahydrofuran (90 mL), and isopentyl nitrite (6.02 mL, 44.72 mmol) was slowly added at 0 °C. Then, CuI (4.26 g, 22.36 mmol) and I2 (4.5 mL, 22.36 mmol) were added at 0 °C, and the reaction mixture was stirred at 60 °C for 1 h. After confirming the completion of the reaction by LC-MS, saturated aqueous sodium bicarbonate solution (200 mL) was slowly added. The organic layer was extracted using ethyl acetate (50 mL Х 4), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The target compound (2.4 g, 44% yield) was obtained by purification with petroleum ether:ethyl acetate 0-10%).

[0307] 1 H NMR (400 MHz, CDCl3): δ 2.60 (s, 3H), 2.01 - 1.93 (m, 1H), 1.13 - 1.05 (m, 4H).

[0308] [Step 5] Preparation of 3-bromo-5-cyclopropyl-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-6-methylpyrazin-2-amine

[0309] 2-Bromo-6-cyclopropyl-3-iodo-5-methylpyrazine (1 g, 2.95 mmol) prepared in the above step 4 and 3-(methoxymethoxy)-2,6-dimethylaniline (0.54 g, 2.95 mmol) obtained in the above preparation example 1 were dissolved in toluene (20 mL), and then cesium carbonate (2.88 g, 8.85 mmol), XantPhos (0.34 g, 0.59 mmol), and Pd2(dba)3 (0.27 g, 0.3 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours, and after confirming the completion of the reaction by LC-MS, it was filtered through Celite. The filtrate obtained after filtration was concentrated under reduced pressure and analyzed by MPLC (SiO 2, The target compound (0.68 g, 58% yield) was obtained by purification with petroleum ether:ethyl acetate 0-20%).

[0310] 1 H NMR (400 MHz, CDCl3): δ 7.08 - 7.01 (m, 1H), 7.00 - 6.93 (m, 1H), 6.29 (s, 1H), 5.21 (s, 2H), 3.51 (s, 3H), 2.36 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 1.94 - 1.86 (m, 1H), 0.97 - 0.88 (m, 4H).

[0311] [Step 6] Preparation of (6-amino-2-cyclopropyl-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0312] 3-Bromo-5-cyclopropyl-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)-6-methylpyrazin-2-amine (350 mg, 0.89 mmol) prepared in step 5 and 3-(1H-indol-2-yl)-3-oxopropanenitrile (164 mg, 0.89 mmol) prepared in step 1 of Examples 1 and 2 were dissolved in tert-amyl alcohol (100 mL), and then cesium carbonate (1.45 mg, 4.45 mmol) and BINAP Pd G3 (91 mg) were added. The reaction mixture was stirred at 100 °C for 12 h, filtered through Celite, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The target compound (220 mg, 50% yield) was obtained by purification with petroleum ether:ethyl acetate (15-100%).

[0313] 1 H NMR (400 MHz, CDCl3): δ 14.55 (s, 1H), 7.80 (dd,J= 5.2, 8.0 Hz, 2H), 7.54 (d,J= 1.2 Hz, 1H), 7.37 (t,J= 7.6 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.18 (t,J= 7.6 Hz, 1H), 5.32 - 5.21 (m, 2H), 3.55 (s, 3H), 2.66 (s, 3H), 2.42 - 2.29 (m, 1H), 1.96 (d,J= 18.8 Hz, 6H), 1.46 - 1.39 (m, 2H), 1.38 - 1.32 (m, 2H).

[0314] [Step 7] Preparation of (6-amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0315] (6-Amino-2-cyclopropyl-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone (100 mg, 0.20 mmol) prepared in the above step 6 was dissolved in trifluoroacetic acid (100 mL) and water (100 mL), and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (2500 mL) was slowly added to the reaction mixture, and extraction was performed using ethyl acetate (150 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated mixture was purified using prep-HPLC to obtain the target compound (100 mg, 89% yield). MS (ESI): m / z = 452.2 [M+H] +

[0316] [Step 8] Preparation of (R)-(6-amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone and (S)-(6-amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0317] (6-Amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone (100 mg, 0.22 mmol) prepared in the above step 7 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm Х 30 mm, 10 μm); mobile phase: [CO2-acetonitrile / isopropanol (0.1 % NH3H2O)]) to obtain compounds of Examples 240 and 241.

[0318] Example 240. (R)-(6-Amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0319] First elution; 22.6 mg (23% yield); 1 H NMR (400 MHz, MeOD): δ 7.76 (d,J= 8.4 Hz, 1H), 7.71 (d,J= 8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (t,J= 7.6 Hz, 1H), 7.18 - 7.09 (m, 2H), 6.97 (d,J= 8.0 Hz, 1H), 2.63 (s, 3H), 2.50 - 2.41 (m, 1H), 1.92 (s, 3H), 1.87 (s, 3H), 1.39 - 1.32 (m, 4H); MS (ESI): m / z = 452.2 [M+H] +

[0320] Example 241. (S)-(6-Amino-2-cyclopropyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(1H-indol-2-yl)methanone

[0321] Second elution; 24.4 mg (24% yield); 1 H NMR (400 MHz, MeOD): δ 7.76 (d,J= 8.4 Hz, 1H), 7.71 (d,J= 8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (t,J= 7.6 Hz, 1H), 7.18 - 7.09 (m, 2H), 6.97 (d,J= 8.0 Hz, 1H), 2.63 (s, 3H), 2.49 - 2.41 (m, 1H), 1.92 (s, 3H), 1.87 (s, 3H), 1.38 - 1.32 (m, 4H); MS (ESI): m / z = 452.2 [M+H] +

[0322] Examples 258 and 259. Preparation of (R)-(6-amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone and (S)-(6-amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0323] [Reaction Formula 10]

[0324]

[0325] [Step 1] Preparation of 3-bromo-N-(3-fluoro-2,6-dimethyl-5-(2-(trimethylsilyl)ethoxy)phenyl)pyrazin-2-amine

[0326] 3-Fluoro-2,6-dimethyl-5-(2-trimethylsilyl)ethoxy)aniline (50 mg, 0.16 mmol) and 2,3-dibromopyrazine (47 mg, 0.16 mmol) obtained in Preparation Example 2 were dissolved in tetrahydrofuran (3 mL), and then LiHMDS (1 M tetrahydrofuran solution, 0.4 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and after confirming the completion of the reaction by LC-MS, ammonium chloride aqueous solution (10 mL) was slowly added at 0 °C to terminate the reaction. Then, the organic layer was extracted using ethyl acetate (5 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (80 mg, 99% yield). MS (ESI): m / z = 412.0 [M+H] +

[0327] [Step 2] Preparation of 3-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-3-oxopropanenitrile

[0328] Ethyl 5-methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (0.5 g, 2.27 mmol) was dissolved in tetrahydrofuran (10 mL), and acetonitrile (1 mL) was added. The temperature of the reaction mixture was cooled to 0 °C, and LiHMDS (1 M, tetrahydrofuran solution, 6 mL) was slowly added dropwise, and the mixture was stirred for 1 h. Saturated ammonium chloride solution (50 mL) was added to the reaction mixture at 0 °C, and then extracted with ethyl acetate (25 mL Х 3). The collected organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (0.34 g, 70% yield). MS (ESI): m / z = 216.1 [M+H] +

[0329] [Step 3] Preparation of (6-amino-5-(3-fluoro-2,6-dimethyl-5-(2-(trimethylsilyl)ethoxy)phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0330] 3-Bromo-N-(3-fluoro-2,6-dimethyl-5-(2-(trimethylsilyl)ethoxy)phenyl)pyrazin-2-amine (80 mg, 0.19 mmol) prepared in the above step 1 and 3-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-3-oxopropanenitrile (63 mg, 0.29 mmol) prepared in the above step 2 were dissolved in tert-amyl alcohol (5 mL), and then cesium carbonate (189 mg, 0.58 mmol) and BINAP Pd G3 (19 mg) were added. The reaction mixture was stirred at 100 °C for 12 h, filtered through Celite, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The target compound (62 mg, 57% yield) was obtained by purification with petroleum ether:ethyl acetate (0-30%). MS (ESI): m / z = 547.2 [M+H] +

[0331] [Step 4] Preparation of (6-amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0332] (6-Amino-5-(3-fluoro-2,6-dimethyl-5-(2-(trimethylsilyl)ethoxy)phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone (60 mg, 0.11 mmol) prepared in Step 3 above was dissolved in trifluoroacetic acid (6 mL) and stirred at room temperature for 1 hour. After confirming the completion of the reaction by LC-MS, saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7. Then, ethyl acetate (10 mL Х 3) was extracted, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC to obtain the target compound (45 mg, 95% yield). MS (ESI): m / z = 447.1 [M+H] +

[0333] [Step 5] Preparation of (R)-(6-amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone and (S)-(6-amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0334] (6-Amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone (45 mg, 0.10 mmol) prepared in the above step 4 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / isopropanol (0.1% NH3H2O)]) to obtain compounds of Examples 258 and 259.

[0335] Example 258. (R)-(6-Amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0336] First elution; 15.6 mg (35% yield); 1 H NMR (400 MHz, MeOD): δ 8.40 (d,J= 3.2 Hz, 1H), 8.03 (d,J= 8.8 Hz, 1H), 7.98 (d,J= 3.2 Hz, 1H), 7.53 (s, 1H), 6.81 (d,J= 8.8 Hz, 1H), 6.76 (d,J= 11.2 Hz, 1H), 3.99 (s, 3H), 1.82 (s, 6H); MS (ESI): m / z = 447.2 [M+H] +

[0337] Example 259. (S)-(6-Amino-5-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0338] Second extraction; 19.5 mg (43% yield); 1H NMR (400 MHz, MeOD): δ 8.41 (d,J= 3.2 Hz, 1H), 8.04 (d,J= 8.8 Hz, 1H), 7.99 (d,J= 3.2 Hz, 1H), 7.53 (d,J= 0.8 Hz, 1H), 6.83 (d,J= 2.4 Hz, 1H), 6.81 (d,J= 4.4 Hz, 1H), 4.00 (s, 3H), 1.85 (s, 6H); MS (ESI): m / z = 447.2 [M+H] +

[0339] Examples 394 and 395. Preparation of (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone and (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone

[0340] [Reaction Formula 11]

[0341]

[0342] [Step 1] Preparation of 6-chloro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridazin-4-amine

[0343] 3,6-Dichloropyridazin-4-amine (5.00 g, 30.49 mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (10.68 g, 76.22 mmol) were dissolved in acetonitrile (100 mL), and then triethylamine (15.43 g, 152.45 mmol), Pd(PPh3)2Cl2 (2.14 g, 3.05 mmol), and CuI (580.67 mg, 3.05 mmol) were added to the reaction mixture. The reaction mixture was stirred at 60 °C for 4 h. After confirming that all the substrates were consumed, the mixture was concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2,The target compound (3.6 g, 43% yield) was obtained by purification with petroleum ether:ethyl acetate (0-100%).

[0344] 1 H NMR (400 MHz, DMSO-d6): δ 6.94 (br s, 2H), 6.80 (s, 1H), 4.83 (s, 1H), 4.67 - 4.45 (m, 2H), 3.85 - 3.71 (m, 1H), 3.56 - 3.45 (m, 1H), 1.77 - 1.62 (m, 2H), 1.59 - 1.42 (m, 4H).

[0345] [Step 2] Preparation of 3-chloro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-c]pyridazine

[0346] 6-Chloro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridazin-4-amine (3.20 g, 11.71 mmol) prepared in Step 1 above and potassium tert-butoxide (3.29 g, 29.29 mmol) were dissolved in dimethylacetamide (120 mL) and stirred at 100 °C for 12 hours. After cooling the reaction mixture to room temperature, water (200 mL) was poured into it and extracted with ethyl acetate (150 mL X 3). The collected organic layer was washed with saturated brine (200 mL X 2), dried over sodium sulfate and filtered. The organic layer was then concentrated under reduced pressure to obtain the target compound (2.7 g, 80% yield).

[0347] 1H NMR (400 MHz, DMSO-d6): δ 12.03 (s, 1H), 7.71 (s, 1H), 6.84 (s, 1H), 4.84 (d,J= 13.6 Hz, 1H), 4.74 (t,J= 3.2 Hz, 1H), 4.69 (d,J= 13.6 Hz, 1H), 3.86 - 3.76 (m, 1H), 3.55 - 3.45 (m, 1H), 1.79 - 1.64 (m, 2H), 1.61 - 1.44 (m, 4H).

[0348] [Step 3] Preparation of 3-methyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-c]pyridazine

[0349] 3-Chloro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-c]pyridazine (1.5 g, 5.60 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivorine (14.07 g, 56.03 mmol), and potassium carbonate (2.32 g, 16.81 mmol) prepared in Step 2 above were dissolved in dioxane (40 mL) and water (2 mL), and then Pd(dppf)Cl2 (0.41 g, 0.56 mmol) was added. The reaction mixture was stirred at 90 °C for 21 h. After confirming that all substrates were consumed, water (200 mL) was added to the reaction mixture, and extracted with ethyl acetate (100 mLХ3). The collected organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated mixture was purified by MPLC (SiO 2, The target compound (0.86 g, 49% yield) was obtained by purification with ethyl acetate:methanol 0~10%). MS (ESI): m / z = 248.1 [M+H] +

[0350] [Step 4] Preparation of (3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanol

[0351] 3-Methyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-c]pyridazine (0.66 g, 2.67 mmol) prepared in step 3 above was dissolved in hydrochloric acid (2 M, dioxane solution, 18 mL) and stirred at room temperature for 3 hours. The resulting solid was filtered to obtain the target compound (0.45 g, 99% yield).

[0352] 1 H NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 8.14 (s, 1H), 6.95 (s, 1H), 4.81 (s, 2H), 2.85 (s, 3H).

[0353] [Step 5] Preparation of 3-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylic acid

[0354] (3-Methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanol (600 mg, 3.68 mmol) prepared in Step 4 above was dissolved in dimethylformamide (15 mL), and then sodium hydroxide (294.14 mg, 7.35 mmol) and (1-hydroxycyclohexyl)-phenyl-methanone (1.50 g, 7.35 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. The resulting solid was filtered, washed with methyl tert-butyl ether (60 mL), and dried to obtain the target compound (442 mg, 68% yield).

[0355] 1 H NMR (400 MHz, DMSO-d6): δ 7.25 (s, 1H), 6.77 (s, 1H), 2.64 (s, 3H).

[0356] [Step 6] Preparation of methyl 3-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylate

[0357] 3-Methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylic acid (442 mg, 2.50 mmol) prepared in Step 5 above was dissolved in methanol (10 mL), and thionyl chloride (594 mg, 4.99 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h. After confirming that all the substrate was consumed, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate (30 mL) was slowly added to the concentrated mixture at 0 °C. Then, ethyl acetate (60 mL Х 5) was extracted, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (305 mg, 64% yield).

[0358] 1 H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 7.49 (s, 1H), 7.48 (s, 1H), 3.93 (s, 3H), 2.74 (s, 3H).

[0359] [Step 7] Preparation of 3-(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)-3-oxopropanenitrile

[0360] Methyl 3-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylate (200 mg, 1.05 mmol) prepared in Step 6 above and acetonitrile (257.67 mg, 6.28 mmol) were dissolved in tetrahydrofuran (5 mL), and LiHMDS (1 M tetrahydrofuran solution, 5.23 mL) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and water (10 mL) was added. The aqueous layer was washed with petroleum ether (15 mL Х 3), collected, concentrated under reduced pressure, and purified by Prep-HPLC to obtain the target compound (180 mg, 90% yield).

[0361] 1H NMR (400 MHz, MeOD): δ 7.37 (d,J= 3.6 Hz, 1H), 7.02 (d,J= 4.0 Hz, 1H), 5.04 (s, 2H), 2.68 (d,J= 4.0 Hz, 3H).

[0362] [Step 8] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone

[0363] This reaction was performed in seven parallel batches.

[0364] 3-(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)-3-oxopropanenitrile (30 mg, 0.149 mmol) prepared in step 7 above and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (25.34 mg, 74.93 μmol) prepared in step 1 of Examples 56 and 57 above were dissolved in tert-amyl alcohol (12 mL), then cesium carbonate (244.12 mg, 749.26 μmol) and BINAP Pd G3 (14.87 mg, 14.99 μmol) were added, and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction mixture was cooled to room temperature, water (80 mL) was added and extracted with ethyl acetate (50 mL Х 4). The collected organic layer was concentrated under reduced pressure and purified by MPLC (SiO 2, The product was purified using petroleum ether:ethyl acetate (0-50%) to obtain the target compound (100 mg, 20% yield).

[0365] 1H NMR (400 MHz, MeOD): δ 8.41 (d,J= 3.2 Hz, 1H), 8.05 (s, 1H), 8.00 (d,J= 3.2 Hz, 1H), 7.87 (s, 1H), 7.31 (d,J= 2.0 Hz, 2H), 5.30 (s, 2H), 3.51 (s, 3H), 2.85 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H).

[0366] [Step 9] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone

[0367] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone (90 mg, 196.73 μmol) prepared in the above step 8 was dissolved in HCl (2 M, dioxane solution, 9 mL) and stirred at 25°C for 1 hour. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (30 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (85 mg, 98% yield). MS (ESI): m / z = 414.1 [M+H] +

[0368] [Step 10] Preparation of (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone and (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone

[0369] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone (90 mg, 217.69 μmol) obtained in the above step 9 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / ethanol (0.1% NH3H2O)]) to obtain compounds of Examples 394 and 395.

[0370] Example 394. (S)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone

[0371] First elution; 17 mg (18% yield); 1 H NMR (400 MHz, MeOD): δ 8.40 (d,J= 3.2 Hz, 1H), 8.03 (s, 1H), 8.00 (d,J= 3.2 Hz, 1H), 7.87 (s, 1H), 7.17 (d,J= 8.4 Hz, 1H), 6.99 (d,J= 8.4 Hz, 1H), 2.85 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 414.1 [M+H] +

[0372] Example 395. (R)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(3-methyl-5H-pyrrolo[3,2-c]pyridazin-6-yl)methanone

[0373] Second extraction; 27 mg (28% yield); 1H NMR (400 MHz, MeOD): δ 8.39 (d,J= 3.2 Hz, 1H), 8.02 (s, 1H), 8.00 (d,J= 3.2 Hz, 1H), 7.88 (s, 1H), 7.17 (d,J= 8.4 Hz, 1H), 6.99 (d,J= 8.4 Hz, 1H), 2.85 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 414.0 [M+H] +

[0374] Examples 416 and 417. Preparation of (6-amino-5-((S)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone and (6-amino-5-((R)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0375] [Reaction Formula 12]

[0376]

[0377] [Step 1] Preparation of tert-butyl (S)-3,3-difluoro-4-((4-methyl-5-nitropyridin-2-yl)oxy)pyrrolidine-1-carboxylate

[0378] 2-Fluoro-4-methyl-5-nitropyridine (560 mg, 3.59 mmol) and tert-butyl (S)-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (800 mg, 3.59 mmol) were dissolved in tetrahydrofuran (10 mL), and cesium carbonate (2.34 g, 7.17 mmol) was added. The reaction mixture was stirred at 65°C for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2,The target compound (900 mg, 70% yield) was obtained by purification with petroleum ether:ethyl acetate (0-50%). MS (ESI): m / z = 304.0 [M+H-56] +

[0379] 1 H NMR (400 MHz, CDCl3): δ 8.91 (s, 1H), 6.78 (s, 1H), 5.72 (s, 1H), 3.93 - 3.83 (m, 3H), 3.70 - 3.59 (m, 1H), 2.65 (s, 3H), 1.48 (s, 9H).

[0380] [Step 2] Preparation of tert-butyl (S)-4-((5-amino-4-methylpyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate

[0381] Tert-Butyl (S)-3,3-difluoro-4-((4-methyl-5-nitropyridin-2-yl)oxy)pyrrolidine-1-carboxylate (760 mg, 2.12 mmol) prepared in Step 1 above was dissolved in tetrahydrofuran (16 mL) and water (4 mL), and then ammonium chloride (565 mg, 10.58 mmol) and Zn-Cu couple (1.36 g, 10.58 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After confirming that all substrates were consumed by LC-MS, the reaction mixture was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (700 mg, crude), which was used in the next reaction without further purification. MS (ESI): m / z = 330.2 [M+H] +

[0382] [Step 3] Preparation of tert-butyl (S)-4-((5-amino-6-bromo-4-methylpyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate

[0383] Tert-butyl (S)-4-((5-amino-4-methylpyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate (700 mg, 2.13 mmol) prepared in the above step 2 was dissolved in acetic acid (8 mL), and pyridinium perbromide (680 mg, 2.13 mmol) was added. The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was slowly poured into ice water (50 mL), and the pH was adjusted to 7–8 with sodium carbonate. Then, ethyl acetate (40 mL Х 3) was extracted, and the organic layers were combined, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by MPLC (SiO 2, The target compound (600 mg, 62% yield) was obtained by purification with petroleum ether:ethyl acetate (0-25%). MS (ESI): m / z = 352.0 [M+H-56] +

[0384] [Step 4] Preparation of (S)-5-((1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid

[0385] This reaction was performed in two parallel batches.

[0386] Tert-Butyl (S)-4-((5-amino-6-bromo-4-methylpyridin-2-yl)oxy)-3,3-difluoropyrrolidine-1-carboxylate (250 mg, 0.612 mmol), DABCO (206 mg, 1.84 mmol), and Pd(dppf)Cl2·dichloromethane (50 mg, 0.061 mmol) prepared in Step 3 above were dissolved in dimethylformamide (7.5 mL) and stirred at 100 °C for 12 h under nitrogen gas. The reaction mixture was poured into water (100 mL), and the pH was adjusted to 9 with 1 N sodium hydroxide aqueous solution. The aqueous layer was then washed with ethyl acetate (50 mL Х 3). The pH of the aqueous layer was adjusted to 5 with 3N hydrochloric acid, extracted with 2-methyltetrahydrofuran (50 mL X 3), and the combined organic layer was washed with saturated brine (100 mL X 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (500 mL, crude), which was used in the next reaction without further purification. MS (ESI): m / z = 398.1 [M+H] +

[0387] [Step 5] Preparation of methyl (S)-5-((4,4-difluoropyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0388] (S)-5-((1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (500 mg, 1.26 mmol) prepared in the above step 4 was dissolved in hydrochloric acid (2 M, methanol solution, 25 mL) and stirred at 35°C for 12 h. After confirming that all substrates were consumed by LC-MS, the mixture was concentrated under reduced pressure to obtain the target compound (400 mg, crude), which was used in the next reaction without further purification. MS (ESI): m / z = 312.1 [M+H] +

[0389] [Step 6] Preparation of methyl (S)-5-((4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate

[0390] Methyl (S)-5-((4,4-difluoropyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (500 mg, 1.61 mmol) prepared in Step 5 above was dissolved in methanol, and then formaldehyde aqueous solution (37%, 0.48 mL) was added and stirred at room temperature for 10 minutes. Then, NaBH3CN (302 mg, 4.82 mmol) was slowly added and stirred at room temperature for 1 hour. Water (60 mL) was poured into the reaction mixture, and the pH was adjusted to 7-8 with sodium bicarbonate. Then, ethyl acetate (50 mL Х 3) was extracted, and the organic layer was combined, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by prep-HPLC to obtain the target compound (220 mg, 42% yield). MS (ESI): m / z = 326.1 [M+H] +

[0391] 1 H NMR (400 MHz, CDCl3): δ 8.87 (br s, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 5.74 - 5.61 (m, 1H), 3.96 (s, 3H), 3.34 (dd,J= 6.4, 10.4 Hz, 1H), 3.11 - 2.97 (m, 2H), 2.78 (dd,J= 4.0, 10.8 Hz, 1H), 2.49 (s, 3H), 2.43 (s, 3H).

[0392] [Step 7] Preparation of (S)-3-(5-((4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-3-oxopropanenitrile

[0393] Methyl (S)-5-((4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (200 mg, 0.615 mmol) prepared in the above step 6 and acetonitrile (126 mg, 3.07 mmol) were dissolved in tetrahydrofuran (1.2 mL), and then LiHMDS (1 M, tetrahydrofuran solution, 2.46 mL) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Then, water (3 mL) was added at 0 °C, and the aqueous layer was washed with petroleum ether (5 mL Х 2). The pH of the aqueous layer was adjusted to 6 with 1 N HCl, and the resulting solid was collected by filtration to obtain the target compound (80 mg, crude). MS (ESI): m / z = 335.1 [M+H] +

[0394] 1 H NMR (400 MHz, DMSO-d6): δ 12.21 (s, 1H), 7.37 (d, J= 2.0 Hz, 1H), 6.73 (s, 1H), 5.60 - 5.47 (m, 1H), 4.68 (s, 2H), 2.30 (s, 3H).

[0395] [Step 8] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0396] This reaction was performed in two parallel batches.

[0397] (S)-3-(5-((4,4-Difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)-3-oxopropanenitrile (35 mg, 0.105 mmol) prepared in step 7 above and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (35.4 mg, 0.105 mmol) prepared in step 1 of Examples 56 and 57 above were dissolved in tert-amyl alcohol (3.5 mL), and then BINAP Pd G3 (10.4 mg, 0.015 mmol) and cesium carbonate (170 mg, 0.523 mmol) were added. The reaction mixture was stirred at 100°C under nitrogen gas for 12 h. Water (20 mL) was added to the reaction mixture, and extracted with ethyl acetate (30 mL Х 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The residue was purified using petroleum ether:ethyl acetate (10-60%) and the target compound (60 mg, 48% yield) was obtained. MS (ESI): m / z = 592.3 [M+H] +

[0398] 1 H NMR (400 MHz, CDCl3): δ 15.06 (s, 1H), 8.31 (d,J= 3.2 Hz, 1H), 8.04 (d,J= 2.8 Hz, 1H), 7.49 (s, 1H), 7.26 - 7.18 (m, 2H), 6.73 (s, 1H), 5.85 - 5.68 (m, 1H), 5.30 - 5.23 (m, 2H), 3.54 (s, 3H), 3.48 - 3.36 (m, 1H), 3.13 - 3.05 (m, 1H), 2.72 (s, 3H), 2.46 (s, 2H), 2.07 - 2.01 (m, 3H), 1.99 (s, 3H), 1.95 (s, 3H).

[0399] [Step 9] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0400] 6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone (60 mg, 0.101 mmol) prepared in the above step 8 was dissolved in hydrochloric acid (2 M, dioxane solution, 12 mL) and stirred at room temperature for 1 hour. Water (20 mL) was poured into the reaction mixture, and potassium carbonate was slowly added at 0 °C to adjust the pH to 7–8. Then, ethyl acetate (20 mL Х 3) was extracted. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated reaction mixture was purified by prep-HPLC to obtain the target compound (50 mg, 88% yield). MS (ESI): m / z = 548.3 [M+H] +

[0401] [Step 10] Preparation of (6-amino-5-((S)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone and (6-amino-5-((R)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0402] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone (50 mg) obtained in the above step 9 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK OX (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / ethanol (0.1% NH3H2O)]) to obtain compounds of Examples 416 and 417.

[0403] Example 416. (6-Amino-5-((S)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0404] First elution; 15 mg (29% yield); 1 H NMR (400 MHz, MeOD): δ 8.36 (d,J= 3.2 Hz, 1H), 7.99 (d,J= 3.2 Hz, 1H), 7.36 (s, 1H), 7.17 (d,J= 8.4 Hz, 1H), 6.99 (d,J= 8.4 Hz, 1H), 6.72 (s, 1H), 5.71 - 5.56 (m, 1H), 3.40 (dd,J= 6.4, 10.4 Hz, 1H), 3.16 - 2.94 (m, 2H), 2.78 (dd,J= 4.8, 11.2 Hz, 1H), 2.74 (s, 3H), 2.42 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 548.2 [M+H] +

[0405] Example 417. (6-Amino-5-((R)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(5-(((S)-4,4-difluoro-1-methylpyrrolidin-3-yl)oxy)-7-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)methanone

[0406] Second extraction; 16.5 mg (31% yield); 1 H NMR (400 MHz, MeOD: δ 8.36 (d,J= 3.2 Hz, 1H), 7.99 (d,J= 3.2 Hz, 1H), 7.37 (s, 1H), 7.17 (d,J= 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 5.72 - 5.58 (m, 1H), 3.44 (dd,J= 6.4, 10.8 Hz, 1H), 3.20 - 3.01 (m, 2H), 2.88 - 2.81 (m, 1H), 2.75 (s, 3H), 2.46 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H); MS (ESI): m / z = 548.2 [M+H] +

[0407] Examples 524 and 525. Preparation of (R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0408] [Reaction Formula 13]

[0409]

[0410] [Step 1] Preparation of 4-chloro-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidin-5-amine

[0411] 4,6-Dichloro-2-methyl-pyrimidin-5-amine (9.00 g, 50.56 mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (6.38 g, 45.50 mmol) were dissolved in acetonitrile (180 mL), and then CuI (481.42 mg, 2.53 mmol), triethylamine (15.35 g, 151.67 mmol), and Pd(PPh3)2Cl2 (1.77 g, 2.53 mmol) were added. The reaction mixture was stirred at 50 °C under nitrogen gas for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (5.3 g, 37% yield) was obtained by purification with petroleum ether:ethyl acetate (0-25%).

[0412] 1 H NMR (400 MHz, CDCl3): δ 4.87 (t,J= 3.2 Hz, 1H), 4.57 (s, 2H), 3.91 - 3.85 (m, 1H), 3.62 - 3.51 (m, 1H), 2.57 (s, 3H), 1.86 - 1.74 (m, 2H), 1.68 - 1.61 (m, 2H), 1.59 - 1.54 (m, 2H).

[0413] [Step 2] Preparation of 4-chloro-2-methyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine

[0414] 4-Chloro-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidin-5-amine (4.30 g, 15.26 mmol) obtained in the above step 1 was dissolved in N-methyl-2-pyrrolidone (45 mL), and potassium tert-butoxide (3.43 g, 30.52 mmol) was added at 0 °C. The reaction mixture was then stirred at 0 °C for 1 h. After confirming the completion of the reaction by LC-MS, water (500 mL) was poured into the reaction mixture, and ethyl acetate (100 mL Х 3) was extracted. The collected organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated target compound (4.2 g, crude) was used in the next reaction without purification. MS (ESI): m / z = 281.9 [M+H] +

[0415] [Step 3] Preparation of 4-cyclopropyl-2-methyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine

[0416] 4-Chloro-2-methyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (4.2 g, 14.91 mmol), cyclopropylboronic acid (32.01 g, 372.69 mmol), potassium carbonate (20.60 g, 149.07 mmol) obtained in step 2 above were dissolved in 1,4-dioxane (50 mL), water (5 mL), and then cataCXium ® A Pd G3 (1.09 g, 1.49 mmol) was added. The reaction mixture was stirred at 110 °C for 12 h under nitrogen gas. After confirming the completion of the reaction by LC-MS, water (1000 mL) was poured into the reaction mixture and extracted with ethyl acetate (200 mL Х 3). The collected organic layer was washed with saturated brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2,The target compound (2.40 g, 56% yield) was obtained by purification with petroleum ether:ethyl acetate (0-50%). MS (ESI): m / z = 288.0 [M+H] +

[0417] [Step 4] Preparation of (4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol

[0418] 4-Cyclopropyl-2-methyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (1.30 g, 4.52 mmol) obtained in the above step 3 was dissolved in dichloromethane (15 mL), and then trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at 20 °C for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure to obtain the target compound (900 mg, crude), which was used in the next reaction without purification. MS (ESI): m / z = 204.0 [M+H] +

[0419] [Step 5] Preparation of 4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid

[0420] (4-Cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol (900 mg, 4.43 mmol) and (1-hydroxycyclohexyl)-phenyl-methanone (1.81 g, 8.86 mmol) obtained in the above step 4 were dissolved in dimethoxyethane (30 mL), and then sodium hydroxide (708.47 mg, 17.71 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered. The solid obtained by filtration was washed with dimethoxyethane (20 mL) and dried to obtain the target compound (960 mg, crude). MS (ESI): m / z = 218.0 [M+H] +

[0421] [Step 6] Preparation of methyl 4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate

[0422] 4-Cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid (960 mg, 4.42 mmol) obtained in the above step 5 was dissolved in methanol (20 mL), and sulfuric acid (1.33 g, 13.26 mmol) was slowly added dropwise at 25°C. The reaction mixture was stirred at 70°C for 12 h. After confirming the completion of the reaction by LC-MS, the mixture was concentrated under reduced pressure to remove methanol. Saturated sodium bicarbonate solution was added to the concentrated mixture to adjust the pH to 8. Water (30 mL) was poured into the reaction mixture, and ethyl acetate (30 mL X 3) was extracted. The combined organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (240 mg, 23% yield) was obtained by purification with petroleum ether:ethyl acetate (0-50%). MS (ESI): m / z = 232.0 [M+H] +

[0423] [Step 7] Preparation of 3-(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-3-oxopropanenitrile

[0424] Methyl 4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate (240 mg, 1.04 mmol) and acetonitrile (255.63 mg, 6.23 mmol) obtained in the above step 6 were dissolved in tetrahydrofuran (5 mL), and LiHMDS (1 M, tetrahydrofuran solution, 4.15 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Ice water (2 mL) was slowly added to the reaction mixture to terminate the reaction, and the aqueous layer was washed with petroleum ether (10 mL) and recovered. The recovered aqueous layer was concentrated under reduced pressure and purified by Prep-HPLC to obtain the target compound (130 mg, 52%). MS (ESI): m / z = 239.0 [M+H] +

[0425] [Step 8] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0426] 3-(4-Cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-3-oxopropanenitrile (127.89 mg, 532.23 μmol) obtained in step 7 above and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (120 mg, 354.82 μmol) prepared in step 1 of Examples 56 and 57 were dissolved in tert-amyl alcohol (20 mL), and then cesium carbonate (346.82 mg, 1.06 mmol) and BINAP Pd G3 (35.25 mg) were added. The reaction mixture was stirred at 100 °C for 4 hours, filtered through Celite, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (158 mg, 89% yield) was obtained by purification with petroleum ether: ethyl acetate: tetrahydrofuran (1:0:0 ~ 2:1:1). MS (ESI): m / z = 498.1 [M+H]+

[0427] [Step 9] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0428] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone (155 mg, 317.56 μmol) obtained in step 8 above was dissolved in trifluoroacetic acid (1 mL) and water (1 mL), and stirred at 25°C for 2 hours. The reaction mixture was poured into iced water (20 mL), and the pH was adjusted to 8 with potassium carbonate. Then, ethyl acetate (20 mL X 3) was extracted. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated reaction mixture was purified by prep-HPLC to obtain the target compound (90 mg, 62% yield). MS (ESI): m / z = 454.1 [M+H] +

[0429] [Step 10] Preparation of ((R)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone and (S)-(6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0430] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone (90 mg) obtained in the above step 9 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK OD (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / methanol (0.1% NH3H2O)]) to obtain compounds of Examples 524 and 525.

[0431] Example 524. ((R)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0432] First elution; 28 mg (30% yield); 1 H NMR (400 MHz, DMSO-d6): δ 15.13 (s, 1H), 9.80 (s, 1H), 8.45 (d,J= 2.8 Hz, 1H), 8.04 (d,J= 2.8 Hz, 1H), 7.48 (d,J= 2.0 Hz, 1H), 7.13 (d,J= 8.4 Hz, 1H), 7.00 (d,J= 8.4 Hz, 1H), 2.67 - 2.66 (m, 1H), 2.58 (s, 3H), 1.83 (s, 3H), 1.76 (s, 3H), 1.32 - 1.26 (m, 4H); MS (ESI): m / z = 454.2 [M+H] +

[0433] Example 525. ((S)-(6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0434] Second extraction; 33 mg (34% yield); 1H NMR (400 MHz, DMSO-d6): δ 15.13 (s, 1H), 9.74 (s, 1H), 8.45 (d,J= 3.2 Hz, 1H), 8.04 (d,J= 2.8 Hz, 1H), 7.48 (d,J= 1.6 Hz, 1H), 7.13 (d,J= 8.0 Hz, 1H), 7.00 (d,J= 8.4 Hz, 1H), 2.68 - 2.65 (m, 1H), 2.58 (s, 3H), 1.83 (s, 3H), 1.76 (s, 3H), 1.31 - 1.25 (m, 4H); MS (ESI): m / z = 454.2 [M+H] +

[0435] Examples 532 and 533. Preparation of (6-amino-5-((R)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone and (6-amino-5-((S)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0436] [Reaction Formula 14]

[0437]

[0438] [Step 1] Preparation of 4-chloro-6-cyclopropyl-2-(methylthio)-5-nitropyrimidine

[0439] This reaction was performed in three parallel batches.

[0440] 4,6-Dichloro-2-(methylthio)-5-nitropyrimidine (20 g, 83.31 mmol), cyclopropylboronic acid (7.16 g, 83.31 mmol), and sodium carbonate (26.49 g, 249.93 mmol) were dissolved in toluene (400 mL) and water (40 mL), and then Pd(PPh3)4 (9.63 g, 8.33 mmol) was added. The reaction mixture was stirred at 80 °C under nitrogen gas for 12 h. After confirming the completion of the reaction by LC-MS, ethyl acetate (500 mL) and water (1000 mL) were added to the reaction mixture, and the filtrate was collected by filtration. The collected filtrate was extracted with ethyl acetate (500 mL × 2). The combined organic layer was washed with saturated brine (2000 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (46.00 g, 75% yield) was obtained by purification with petroleum ether:ethyl acetate (0~5%). MS (ESI): m / z = 245.8 [M+H] +

[0441] [Step 2] Preparation of 4-cyclopropyl-6-methyl-2-(methylthio)-5-nitropyrimidine

[0442] This reaction was performed in two parallel batches.

[0443] 4-Chloro-6-cyclopropyl-2-(methylthio)-5-nitropyrimidine (23 g, 93.62 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivorine (51.71 g, 205.95 mmol), and potassium carbonate (38.81 g, 280.85 mmol) obtained in Step 1 above were dissolved in 1,4-dioxane (300 mL) and water (30 mL), and then Pd(dppf)Cl2·dichloromethane (7.64 g, 9.36 mmol) was added. The reaction mixture was stirred at 90 °C for 12 hours under nitrogen gas. After confirming the completion of the reaction by LC-MS, ethyl acetate (500 mL) and water (1000 mL) were added to the reaction mixture, filtered, and the filtrate was recovered. The recovered filtrate was extracted with ethyl acetate (500 mL × 2). The collected organic layer was washed with saturated brine (2000 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (17.00 g, 40% yield) was obtained by purification with petroleum ether:ethyl acetate (0~4%). MS (ESI): m / z = 225.9 [M+H] +

[0444] [Step 3] Preparation of 4-cyclopropyl-6-methyl-2-(methylsulfonyl)-5-nitropyrimidine

[0445] 4-Cyclopropyl-6-methyl-2-(methylthio)-5-nitropyrimidine (15.50 g, 68.81 mmol) obtained in the above step 2 was dissolved in dichloromethane (300 mL), and 3-chloroperoxybenzoic acid (34.92 g, 172.02 mmol, 85% purity) was slowly added at 0°C. The reaction mixture was then stirred at 20°C for 2 hours. The reaction mixture was cooled to 0°C and slowly poured into a saturated aqueous sodium thiosulfate solution (500 mL), followed by the addition of a saturated aqueous sodium carbonate solution (500 mL). The reaction mixture was extracted with dichloromethane (500 mL × 2), and the collected organic layer was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (17.00 g, 96% yield) was obtained by purification with petroleum ether:ethyl acetate (0-25%).

[0446] 1 H NMR (400 MHz, CDCl3): δ 3.33 (s, 3H), 2.65 (s, 3H), 2.12 - 2.05 (m, 1H), 1.49 - 1.42 (m, 2H), 1.42 - 1.35 (m, 2H); MS (ESI): m / z = 257.9 [M+H] +

[0447] [Step 4] Preparation of tert-butyl (3S,4R)-3-((4-cyclopropyl-6-methyl-5-nitropyrimidin-2-yl)oxy)-4-fluoropyrrolidine-1-carboxylate

[0448] This reaction was performed in three parallel batches.

[0449] tert-Butyl (3R,4S)-3-fluoro-4-hydroxy-pyrrolidine-1-carboxylate (730 mg, 3.56 mmol) was dissolved in tetrahydrofuran (50 mL), and potassium tert-butoxide (1 M, tetrahydrofuran solution, 7.11 mL) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and cooled to -60 °C. 4-Cyclopropyl-6-methyl-2-(methylsulfonyl)-5-nitropyrimidine (915.11 mg, 3.56 mmol) obtained in Step 3 was slowly added. After confirming the completion of the reaction by LC-MS, the reaction was terminated by adding a saturated ammonium chloride aqueous solution (200 mL). The reaction mixture was extracted with ethyl acetate (50 mL × 3), and the collected organic layer was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrated reaction mixture was analyzed by MPLC (SiO 2, The target compound (2.1 g, 40% yield) was obtained by purification with petroleum ether:ethyl acetate (0-33%). MS (ESI): m / z = 327.0 [M+H-tBu] +

[0450] [Step 5] Preparation of tert-butyl (3S,4R)-3-((4-cyclopropyl-6-(3-ethoxy-2,3-dioxopropyl)-5-nitropyrimidin-2-yl)oxy)-4-fluoropyrrolidine-1-carboxylate

[0451] This reaction was performed in two parallel batches.

[0452] Diethyl oxalate (496.84 mg, 3.40 mmol) was dissolved in tetrahydrofuran (50 mL), and potassium tert-butoxide (1 M, tetrahydrofuran solution, 3.14 mL) was slowly added dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min, and tert-butyl (3S,4R)-3-((4-cyclopropyl-6-methyl-5-nitropyrimidin-2-yl)oxy)-4-fluoropyrrolidine-1-carboxylate (1.00 g, 2.62 mmol) obtained in Step 4 was slowly added. The reaction mixture was stirred at 0 °C for 30 min, and after confirming the completion of the reaction by LC-MS, water (200 mL) was added. The reaction mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic layer was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the target compound (3.00 g, crude), which was used in the next reaction without further purification. MS (ESI): m / z = 483.1 [M+H] +

[0453] [Step 6] Preparation of ethyl 2-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-4-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate

[0454] Tert-butyl (3S,4R)-3-((4-cyclopropyl-6-(3-ethoxy-2,3-dioxopropyl)-5-nitropyrimidin-2-yl)oxy)-4-fluoropyrrolidine-1-carboxylate (3.00 g, 6.22 mmol) obtained in the above step 5 was dissolved in acetic acid (100 mL), and then iron (Fe, 1.39 g, 24.87 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h, and after confirming the completion of the reaction by LC-MS, it was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution (100 mL) was added to the concentrated mixture, and ethyl acetate (50 mL × 3) was extracted. The combined organic layer was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (1.40 g, 33% yield) was obtained by purification with petroleum ether:ethyl acetate (0-50%). MS (ESI): m / z = 435.2 [M+H] +

[0455] [Step 7] Preparation of ethyl 4-cyclopropyl-2-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate

[0456] Ethyl 2-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)-4-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate (1.40 g, 3.22 mmol) obtained in the above step 6 was dissolved in hydrochloric acid solution (2 M, methanol solution, 50 mL) and stirred at 25°C for 3 hours. After confirming the completion of the reaction by LC-MS, the mixture was concentrated under reduced pressure to obtain the target compound (1.10 g, 92% yield, HCl salt). MS (ESI): m / z = 335.0 [M+H] +

[0457] [Step 8] Preparation of ethyl 4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate

[0458] Ethyl 4-cyclopropyl-2-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate (1.10 g, 2.97 mmol, HCl salt) obtained in step 7 above was dissolved in methanol (50 mL), and then 37% aqueous formaldehyde solution (1.20 g, 14.83 mmol) was added. The reaction mixture was stirred at 25°C for 30 minutes, after which sodium cyanoborohydride (372.84 mg, 5.93 mmol) was added and stirred for 10 minutes. Water (300 mL) was poured into the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The collected organic layer was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the target compound (1.00 g, crude). The obtained target compound was used in the next reaction without further purification. MS (ESI): m / z = 349.1 [M+H] +

[0459] [Step 9] Preparation of 3-(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-3-oxopropanenitrile

[0460] Ethyl 4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxylate (900.00 mg, 2.58 mmol) obtained in the above step 8 was dissolved in tetrahydrofuran (50 mL), acetonitrile (530.28 mg, 12.92 mmol) was added, and LiHMDS (1 M, tetrahydrofuran solution, 12.92 mL) was slowly added dropwise at 0 °C, followed by stirring for 2 hours. At 0 °C, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (50 mL), and the aqueous layer was washed with hexane (30 mL × 3) and concentrated under reduced pressure. The concentrated reaction mixture was purified by perp-HPLC to obtain the target compound (500 mg, 51% yield). MS (ESI): m / z = 342.1 [M+H] +

[0461] [Step 10] Preparation of (6-amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0462] This reaction was performed in five parallel batches.

[0463] 3-(4-Cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-3-oxopropanenitrile (100 mg, 291.24 μmol) obtained in step 9 above and 3-bromo-N-(3-(methoxymethoxy)-2,6-dimethylphenyl)pyrazin-2-amine (98.50 mg, 291.24 μmol) prepared in step 1 of Examples 56 and 57 were dissolved in tert-amyl alcohol (10 mL), and then cesium carbonate (284.68 mg, 873.73 μmol) and BINAP Pd G3 (28.89 mg) were added. The reaction mixture was stirred at 100°C for 2 hours, filtered through Celite, and concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (SiO 2, The target compound (500 mg, 50% yield) was obtained by purification with hexane:tetrahydrofuran (0-100%). MS (ESI): m / z = 601.4 [M+H] +

[0464] [Step 11] Preparation of (6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0465] This reaction was performed in five parallel batches.

[0466] (6-Amino-5-(3-(methoxymethoxy)-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone (100 mg, 166.49 μmol) obtained in the above step 9 was dissolved in a hydrochloric acid solution (2 M, 1,4-dioxane solution, 50 mL) and stirred at 25°C for 1 hour. After confirming the completion of the reaction by LC-MS, the mixture was concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC to obtain the target compound (400 mg, 85% yield). MS (ESI): m / z = 557.3 [M+H] +

[0467] [Step 12] Preparation of (6-amino-5-((R)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone and (6-amino-5-((S)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0468] (6-Amino-5-(3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone (90 mg) obtained in the above step 11 was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK OD (250 mm Х 30 mm, 10 μm); mobile phase: [CO2 / isopropanol (0.1% NH3H2O)]) to obtain compounds of Examples 532 and 533.

[0469] Example 532. (6-Amino-5-((R)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0470] First elution; 39.50 mg (43% yield); 1 H NMR (400 MHz, MeOD): δ 8.32 (t,J= 3.6 Hz, 1H), 8.06 - 7.87 (m, 1H), 7.25 - 7.13 (m, 2H), 6.98 (d,J= 8.4 Hz, 1H), 5.49 - 5.26 (m, 2H), 3.18 - 2.95 (m, 4H), 2.59 - 2.51 (m, 1H), 2.47 (s, 3H), 1.94 (s, 3H), 1.89 (s, 3H), 1.45 (d,J= 2.8 Hz, 2H), 1.41 - 1.34 (m, 2H); MS (ESI): m / z = 557.3 [M+H] +

[0471] Example 533. (6-Amino-5-((S)-3-hydroxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4-cyclopropyl-2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanone

[0472] Second elution; 39.04 mg (41% yield); 1H NMR (400 MHz, MeOD): δ 8.32 (d,J= 9.6 Hz, 1H), 8.06 - 7.87 (m, 1H), 7.24 - 7.15 (m, 2H), 7.00 (d,J= 8.4 Hz, 1H), 5.59 - 5.31 (m, 2H), 3.30 - 3.08 (m, 4H), 2.61 - 2.50 (m, 4H), 1.95 (s, 3H), 1.91 (s, 3H), 1.49 - 1.43 (m, 2H), 1.43 - 1.37 (m, 2H); MS (ESI): m / z = 557.3 [M+H] +

[0473] <Example 1> to <Example 539>

[0474] All other example compounds of the present invention were prepared in a similar manner to Examples 1, 2, 11, 12, 56, 57, 58, 59, 82, 83, 142, 143, 240, 241, 258, 259, 394, 395, 416, 417, 524, 525, 532, and 533 described above, and the chemical structural formulas, compound names, NMR, and LC-MS analysis results of each example compound are summarized and shown in [Table 1] below.

[0475] [Table 1]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596] Experimental Example 1: PKMYT1 Thermal Shift Analysis Evaluation of Example Compounds

[0597] The degree of binding of the compounds of the present invention to the PKMYT1 kinase domain was tested through a thermal shift assay. 100 μM compounds were diluted in 50 mM Tris (pH 7.5) at a concentration of 2 μM for each protein. SYPRO was added to the solution. TM Orange dye was added and the plate was transferred to a QuantStudio3 real-time PCR system (Applied Biosystems by Thermo Fisher Scientific). The temperature was increased from 25°C to 99°C by 0.1°C per second, and the transformation temperature (Tm) was calculated using Protein Thermal Shift software (version 1.3) (Applied Biosystems, Grand Island, NY). The degree of protein transformation temperature in the presence of the compound compared to DMSO was calculated according to the following equation 1.

[0598] [Formula 1]

[0599] ΔTm = Tm (temperature of the example compound) - Tm (temperature of DMSO)

[0600] The above ΔTm value is a value that has a significant correlation with cell activity, and the results are shown in Table 2 below.

[0601] [Table 2]

[0602]

[0603]

[0604]

[0605]

[0606] Experimental Example 2: Evaluation of inhibitory activity against PKMYT1 kinase by example compounds

[0607] In order to evaluate the inhibitory activity of the compound of the present invention against PKMYT1 kinase, the compound of the present invention was reacted with purified human PKMYT1 enzyme and evaluated by the following method.

[0608] The reaction buffer used was composed of 200 mM Tris-HCl pH 7.4, 100 mM MgCl2, 0.5 mg / mL BSA, and 0.25 mM DTT, and all test reactions were performed in the reaction buffer. The compounds were diluted from a 10 mM DMSO stock using a 12-step serial dilution method, and the enzyme activity was measured at a final compound concentration of 10 to 0.00005645 μM. After reacting with the appropriate concentration of PKMYT1 enzyme, purified ATP, and enzyme substrate (CDK1) at 25°C for 1 hour, the enzyme activity was confirmed using an in vitro ADP-GloTM kinase assay (Promega). The enzyme activity reaction solution, ADP-Glo ​​reaction solution, and enzyme activity detection solution were reacted at a ratio of 2:2:1, and the degree of enzyme activity inhibition was measured by luminescence. The degree of enzyme activity inhibition according to the treatment concentration of each compound was calculated based on the fluorescence of enzyme activity for the solvent control group that was not treated with the compound. At this time, the concentration of each compound that inhibits enzyme activity by 50% was IC 50 (nM) value and was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) software. The results are shown in Table 3 below.

[0609] [Table 3]

[0610]

[0611]

[0612] Experimental Example 3: Evaluation of tumor cell proliferation inhibition by the example compound

[0613] In order to evaluate the cell proliferation inhibitory activity of the compounds of the present invention, the following experiments were performed. CCNE1-positive cell lines, HCC1569 cell lines (Korea Cell Line Bank #9S1569) and MKN1 cell lines (Korea Cell Line Bank #80101), were cultured in RPMI1640 medium (Gibco #11875093) containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin, respectively, and cell viability analysis was performed. When performing the test, HCC1569 cell lines or MKN1 cell lines were dispensed into 96-well flat-bottom plates (Corning #3903) at a concentration of 5,000 cells / well or 3,000 cells / well, respectively, and cultured for 24 hours at 37°C and 5% CO2 conditions. Compounds were treated in 11 concentrations in each well at a 3-fold concentration gradient starting from the highest concentration of 10 μM. As a control, dimethyl sulfoxide (DMSO) was treated at the same concentration of 0.5% (v / v) as when the compounds were treated, and the cells treated with the compounds were cultured for 144 or 72 hours. To check the viability of the cells, 100 μL of Cell Titer-Glo (Promega #G7573) was added to the medium of each cultured cell, incubated for 10 minutes at room temperature, and the luminescence value was measured using a microplate reader. 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 the concentration at which cell proliferation inhibition activity was 50% was designated as GI. 50 (μM) value was determined. GI 50 The (μM) values ​​were calculated using Prism (version 8.4.3 #GraphPad) software, and the results are shown in Table 4 below.

[0614] [Table 4]

[0615]

[0616]

[0617] Through the results of the above experimental examples, it was confirmed that the exemplary compounds of the present invention exhibit high inhibitory activity against PKMYT1 and have high cell proliferation inhibition ability through induction of synthetic lethality due to PKMYT1 inhibition in cells in which CCNE1 is overactivated, amplified, or overexpressed.

[0618] 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, X is CH or N; R X1 and R X2 are each independently -H, -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, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -O-(C 1-6 alkyl), -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -phenyl, or -(5-6 membered heteroaryl), wherein at least one H in the ring of the -(3-6 membered cycloalkyl), -(4-6 membered heterocycloalkyl), -phenyl, or -(5-6 membered heteroaryl) is -C 1-6 may be substituted with alkyl; or R X1 and R X2 are combined with each other to form a 12-13 membered aromatic fused ring; Ring Y is -(5-10 membered heteroaryl), wherein said -(5-10 membered heteroaryl) ring may include one or more N, O, or S atoms in the ring, and one or more H in the ring of said -(5-10 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -CN, -(CH2)mR a , -NH-R b , -OR c , -halo, -(3-6 membered cycloalkyl), -C(=O)-(3-6 membered cycloalkyl), -S(=O)2-C 1-6 Alkyl, or -P(=O)-(C 1-6 alkyl)(C 1-6 may be substituted with alkyl); m is 0, 1, 2, 3, or 4; R a is -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl), wherein at least one H in the -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl) ring is -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered heterocycloalkyl); R b and R c are each independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)2-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered heterocycloalkyl), or -(CH2)n-(5-6 membered heteroaryl), wherein at least one H in the -(CH2)n-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered heterocycloalkyl), or -(CH2)n-(5-6 membered heteroaryl) ring is -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered cycloalkyl); n is 0, 1, 2, 3, or 4; Z1 to Z5 are each independently -H, -C 1-6 Alkyl, -OH, or -halo.

2. In paragraph 1, Is , , or And, R X1 and R X2 are each independently -H, -C 1-6 Alkyl, -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(3-6 membered cycloalkyl) or -(4-6 membered heterocycloalkyl) is -C 1-3 may be substituted with alkyl; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, Ring Y is -(8-9 membered heteroaryl); Z1 and Z2 are each independently -C 1-3 It is alkyl; One of Z3 and Z4 is -OH and the other is -H; Z5 is -H or -Halloween, A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, Ring Y is , , , , , , , , , , , , , , , , , , or and wherein at least one H in the ring of the above ring Y is -C 1-3 Alkyl, -C 1-3 Aminoalkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -(CH2)mR a , -NH-R b , -OR c , -halo, -(3-6 membered cycloalkyl), -C(=O)-(3-6 membered cycloalkyl), -S(=O)2-C 1-3 Alkyl, or -P(=O)-(C 1-3 alkyl)(C 1-3 may be substituted with alkyl); m is 0 or 1; R a is -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl), wherein at least one H in the -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl) ring is -C 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered heterocycloalkyl); R b and R c are each independently -C 1-3 Alkyl, -C 1-3 Haloalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-3 Alkyl, -S(=O)2-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl) is -C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered cycloalkyl); n is 0, 1, or 2; A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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

6. A method for preparing a compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps represented by the following reaction scheme I or II: [Reaction Formula I] [Reaction Formula II] In the above reaction scheme I or II, R X1 and R X2 are each independently -H, -C 1-6 Alkyl, -(3-6 membered cycloalkyl), or -(4-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(3-6 membered cycloalkyl) or -(4-6 membered heterocycloalkyl) is -C 1-3 may be substituted with alkyl; R X3 is -halo; Ring Y is , , , , , , , , , , , , , , , , , , or and wherein at least one H in the ring of the above ring Y is -C 1-3 Alkyl, -C 1-3 Aminoalkyl, -C 1-3 Hydroxyalkyl, -C 1-3 Haloalkyl, -CN, -(CH2)mR a , -NH-R b , -OR c , -halo, -(3-6 membered cycloalkyl), -C(=O)-(3-6 membered cycloalkyl), -S(=O)2-C 1-3 Alkyl, or -P(=O)-(C 1-3 alkyl)(C 1-3 may be substituted with alkyl); m is 0 or 1; R a is -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl), wherein at least one H in the -(3-6 membered heterocycloalkyl), -(7-12 membered heterobicycloalkyl), -(3-6 membered heterocycloalkenyl), or -(5-6 membered heteroaryl) ring is -C 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered heterocycloalkyl); R b and R c are each independently -C 1-3 Alkyl, -C 1-3 Haloalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Alkyl-OC 1-3 Alkyl, -S(=O)2-(3-6 membered cycloalkyl), -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl), wherein at least one H in the ring of the -(CH2)n-(3-6 membered cycloalkyl) or -(CH2)n-(3-6 membered heterocycloalkyl) is -C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-6 may be substituted with haloalkyl, -halo, or -(3-6 membered cycloalkyl); n is 0, 1, or 2; Z1 and Z2 are each independently -C 1-3 It is alkyl; Z4 is -H; Z5 is -H or -halo; PG is an -OH protecting group.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

8. A pharmaceutical composition for preventing or treating cancer, containing a compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

9. In paragraph 8, A pharmaceutical composition that inhibits PKMYT1 and / or CCNE1.

10. In paragraph 8, A pharmaceutical composition, wherein the cancer is associated with hyperactivation, amplification, or overexpression of PKMYT1 and / or CCNE1.

11. In paragraph 8, A pharmaceutical composition, wherein the cancer is associated with an inactivating mutation of PPP2R1A and / or FBXW7.

12. In paragraph 8, The cancers above are uterine cancer, endometrial cancer, papillary serous carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, uterine corpus endometrial carcinoma, cervical cancer, ovarian cancer, serous ovarian cancer, high-grade serous ovarian cancer (HGSOC), breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), rectal cancer, gastric cancer, esophageal cancer, liver cancer, hepatocellular carcinoma (LIHC), lung cancer, non-small cell lung cancer (NSCLC), lung squamous cell carcinoma, leukemia, and chronic myeloid leukemia. A pharmaceutical composition comprising at least one selected from the group consisting of leukemia, lymphoma, prostate cancer, bladder cancer, testicular cancer, kidney cancer, kidney renal papillary cell carcinoma (KIRP), kidney renal clear cell carcinoma (KIRC), bone cancer, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue cancer, brain cancer, glioblastoma, glioma, brain lower grade glioma (LGG), head and neck cancer, adenoid cystic carcinoma (ACC), skin cancer, melanoma, and thymoma.

13. Use of a compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of diseases associated with overactivation, amplification, or overexpression of PKMYT1 and / or CCNE1.

14. A method for treating or preventing a disease associated with PKMYT1 and / or CCNE1 hyperactivation, amplification, or overexpression, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

15. A method for treating uterine cancer, endometrial cancer, papillary serous carcinoma (UPSC), uterine carcinosarcoma, uterine corpus cancer, uterine corpus endometrial carcinoma, cervical cancer, ovarian cancer, serous ovarian cancer, high grade serous ovarian cancer (HGSOC), breast cancer, triple negative breast cancer (TNBC), pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), rectal cancer, gastric cancer, esophageal cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. A method for treating or preventing at least one disease selected from the group consisting of liver cancer, liver hepatocellular carcinoma (LIHC), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung squamous cell carcinoma, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphoma, prostate cancer, bladder cancer, testicular cancer, kidney cancer, kidney renal papillary cell carcinoma (KIRP), kidney renal clear cell carcinoma (KIRC), bone cancer, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue cancer, brain cancer, glioblastoma, glioma, brain lower grade glioma (LGG), head and neck cancer, adenoid cystic carcinoma (ACC), skin cancer, melanoma, and thymoma.