Compounds as protein kinase inhibitors and pharmaceutical compositions containing the same

Abstract

The present invention provides novel compounds having protein kinase inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof. Due to the protein kinase inhibitory activity, the compounds according to the present invention, stereoisomers thereof or pharmaceutically acceptable salts thereof can effectively prevent or treat protein kinase-related diseases, such as cancer, autoimmune diseases, neurological diseases, metabolic diseases and infections, etc.

Description

Technical Field

[0001] The present invention relates to a novel compound as a protein kinase inhibitor, a pharmaceutical composition comprising the same, and a pharmaceutical use thereof, which novel compound inhibits the activity of protein kinase as a phosphatase and can therefore be valuable for preventing or treating diseases associated therewith. Background Art

[0002] Protein kinases are enzymes that control various processes within cells by phosphorylating other proteins, thereby regulating the activity, location and function of proteins. Abnormalities in the control functions of these protein kinases are closely related to the mechanisms of diseases such as cancer, autoimmune diseases, neurological diseases, metabolic diseases, and infections.

[0003] Janus kinase (JAK) is a kinase that plays an important role in the signal transduction system of cytokines. JAK plays a key role in hematopoiesis, innate immunity and acquired immunity, and therefore becomes an important target for therapeutic agents for treating diseases such as cancer, autoimmune diseases, neurological diseases, metabolic diseases, infections, etc.

[0004] JAK is a protein composed of about 1,150 amino acids and has a molecular weight of about 120 to 130 kDa, and JAK is classified into four types: JAK1, JAK2, JAK3 and TYK2. JAK is located in the intracellular receptors of inflammatory cytokines. Inflammatory cytokines (IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, GM-CSF, G-CSF, EPO, TPO, IFN-a (IFN-α), IFN-b (IFN-β), IFN-G (IFN-γ), etc.) bind to receptors, then phosphorylate, and then deliver the signal of inflammatory cytokines to cells through the action of STAT molecules. Excessive activation of signal transduction by such different inflammatory cells causes the human immune system to attack the human body, and thus leads to the occurrence of autoimmune diseases.

[0005] Therefore, it is expected that by developing a drug for inhibiting the receptor kinase of such inflammatory cytokines, improved therapeutic effects on autoimmune diseases compared with existing therapeutic agents will be found. Summary of the invention

[0006] Technical issues

[0007] The object of the present invention is to provide a novel compound having protein kinase inhibitory activity, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0008] Furthermore, an object of the present invention is to provide a process for preparing the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof.

[0009] Furthermore, an object of the present invention is to provide a pharmaceutical composition for treating or preventing a protein kinase-related disease, which comprises the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] Furthermore, an object of the present invention is to provide a method for preventing or treating a protein kinase-related disease, which comprises the step of administering a therapeutically effective amount of the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof to an individual.

[0011] In addition, the present invention aims to provide a use of the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a protein kinase-related disease.

[0012] In addition, the present invention also aims to provide a use of the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof for preventing or treating protein kinase-related diseases.

[0013] Solution to the problem

[0014] Protein kinase inhibitor compounds and methods for preparing the same

[0015] In order to solve the above problems, the present invention provides a compound represented by the following formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0016] [Formula 1]

[0017]

[0018] In formula 1,

[0019] R1 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, aryl or heteroaryl;

[0020] X is C-A1 or N,

[0021] Y is C-A2 or N-A4,

[0022] Z is C-A3 or N-A5, wherein at least one of X, Y and Z includes N;

[0023] at least one of the bond between X and Y or the bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, then A1 or A4 is absent;

[0024] A1 to A5 are each independently H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, -C(=O)-NC 1-6 haloalkyl, aryl or heteroaryl;

[0025] R2 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, aryl or heteroaryl;

[0026] n and m are each independently 0, 1, 2 or 3;

[0027] B1 is -C(=O)-, -C(=S)-, -C(=O)-NR3- or a single bond;

[0028] B2 is C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0029] B3 is H or C 1-6 alkyl;

[0030] D1 is -NR3-;

[0031] D2 is -C(=O)-, -C(=S)-, -S(=O)2- or a single bond;

[0032] D3 is -NR3-, or single key;

[0033] D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0034] Among them C1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Haloalkyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, aryl, heteroaryl or cyano,

[0035] C 3-7 At least one H in the cycloalkyl or 5- to 6-membered heterocycloalkyl group may be replaced by a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 substituted with cyanoalkyl, cyano or halogen, and

[0036] At least one H in the aryl or heteroaryl group may be replaced by a C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 alkylthio, hydroxy, cyano, nitro or halogen substitution; and

[0037] R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0038] According to one embodiment of the present invention, the compound represented by Formula 1 may include one of the compounds represented by the following Formula 1-1, Formula 1-2, and Formula 1-3:

[0039] [Formula 1-1]

[0040]

[0041] [Formula 1-2]

[0042]

[0043] [Formula 1-3]

[0044]

[0045] In these formulas,

[0046] R1 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, aryl or heteroaryl;

[0047] A2 to A5 are each independently H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, -C(=O)-NC 1-6 haloalkyl, aryl or heteroaryl;

[0048] R2 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, aryl or heteroaryl;

[0049] n and m are each independently 0, 1, 2 or 3;

[0050] B1 is -C(=O)-, -C(=S)-, -C(=O)-NR3- or a single bond;

[0051] B2 is C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0052] B3 is H or C 1-6 alkyl;

[0053] D1 is -NR3-;

[0054] D2 is -C(=O)-, -C(=S)-, -S(=O)2- or a single bond;

[0055] D3 is -NR3-, or single key;

[0056] D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0057] Among them C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Haloalkyl or C1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, aryl, heteroaryl or cyano,

[0058] C 3-7 At least one H in the cycloalkyl or 5- to 6-membered heterocycloalkyl group may be replaced by a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 substituted with cyanoalkyl, cyano or halogen, and

[0059] At least one H in the aryl or heteroaryl group may be replaced by a C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 alkylthio, hydroxy, cyano, nitro or halogen substitution; and

[0060] R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0061] According to one embodiment of the present invention, the compound represented by Formula 1 may include a compound represented by the following Formula 2:

[0062] [Formula 2]

[0063]

[0064] In formula 2,

[0065] R1 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, aryl or heteroaryl;

[0066] X is C-A1 or N,

[0067] Y is C-A2 or N-A4,

[0068] Z is C-A3 or N-A5, wherein at least one of X, Y and Z includes N;

[0069] at least one of the bond between X and Y or the bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, then A1 or A4 is absent;

[0070] A1 to A5 are each independently H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, -C(=O)-NC 1-6 haloalkyl, aryl or heteroaryl;

[0071] R2 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, aryl or heteroaryl;

[0072] n and m are each independently 0 or 1;

[0073] D2 is -C(=O)-, -C(=S)-, -S(=O)2- or a single bond;

[0074] D3 is -NR3-, or single key;

[0075] D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0076] Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, aryl, heteroaryl or cyano,

[0077] C 3-7 At least one H in the cycloalkyl or 5- to 6-membered heterocycloalkyl group may be replaced by a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 substituted with cyanoalkyl, cyano or halogen, and

[0078] At least one H in the aryl or heteroaryl group may be replaced by a C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 alkylthio, hydroxy, cyano, nitro or halogen substitution; and

[0079] R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0080] According to another embodiment of the present invention, in Formula 1,

[0081] R1 is H, C 1-6 Alkyl or C 1-6 Alkoxy;

[0082] X is C-A1 or N,

[0083] Y is C-A2 or N-A4,

[0084] Z is C-A3 or N-A5, wherein at least one of X, Y and Z includes N;

[0085] at least one of the bond between X and Y or the bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, then A1 or A4 is absent;

[0086] A1 to A5 are each independently H, C 1-6 Alkyl or -C(=O)-NC 1-6 Haloalkyl;

[0087] R2 is H, C 1-6 Alkyl or C 1-6 heteroaryl;

[0088] n and m are each independently 0 or 1;

[0089] D2 is -C(=O)-;

[0090] D3 is -NR3-, or single key;

[0091] D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0092] Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, aryl, heteroaryl or cyano,

[0093] C 3-7 At least one H in the cycloalkyl or 4- to 6-membered heterocycloalkyl group may be replaced by a C 1-6 Alkyl, C 1-6 cyanoalkyl or cyano substituted, and

[0094] At least one H in the aryl or heteroaryl group may be replaced by a C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl or cyano substituted; and

[0095] R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0096] According to another embodiment of the present invention, in Formula 1,

[0097] R1 is H;

[0098] X is N;

[0099] Y is C-A2;

[0100] Z is C-A3;

[0101] The bond between Y and Z is a double bond;

[0102] A2 and A3 are each independently H;

[0103] R2 is H;

[0104] n and m are each independently 0;

[0105] D2 is -C(=O)-;

[0106] D3 is -NR3-, or single key;

[0107] D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0108] Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one H in the cyanoalkyl group may be substituted by an aryl group, a heteroaryl group or a cyano group.

[0109] C 3-7 At least one H in the cycloalkyl or 5- to 6-membered heterocycloalkyl group may be replaced by a C 1-6 cyanoalkyl or cyano substituted, and

[0110] At least one H in the aryl or heteroaryl group may be replaced by a C 1-6 Alkyl, C 1-6 Alkoxy, cyano, nitro or halogen substitution; and

[0111] R3 and R4 are each independently H or C 1-6 alkyl.

[0112] According to another embodiment of the present invention, in Formula 1,

[0113] R1 is H, C 1-6 Alkyl or C 1-6 Alkoxy;

[0114] X is C-A1;

[0115] Y is C-A2;

[0116] Z is N-A5, wherein at least one of X, Y and Z includes N;

[0117] The bond between X and Y is a double bond, and if the bond between X and Y is a double bond, then A1 is not present;

[0118] A2 and A5 are each independently H, C 1-6 Alkyl or -C(=O)-NC 1-6 Halogenated alkyl.

[0119] R2 is H or C 1-6 alkyl;

[0120] n and m are each independently 0 or 1;

[0121] D2 is -C(=O)-;

[0122] D3 is -NR3-, or single key;

[0123] D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl, aryl or heteroaryl;

[0124] Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, heteroaryl or cyano,

[0125] C 3-7 At least one H in the cycloalkyl or 5- to 6-membered heterocycloalkyl group may be replaced by a C 1-6alkyl or cyano substituted, and

[0126] At least one H in the aryl or heteroaryl group may be replaced by a C 1-6 Alkyl, C 1-6 haloalkyl or cyano substituted; and

[0127] R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0128] According to another embodiment of the present invention, in Formula 1,

[0129] R1 is H;

[0130] X is C-A1;

[0131] Y is N-A4;

[0132] Z is N-A5;

[0133] The bond between X and Y is a double bond;

[0134] A1, A4 and A5 are each independently H;

[0135] R2 is H;

[0136] n and m are each independently 0;

[0137] D2 is -C(=O)-;

[0138] D3 is a single bond;

[0139] D4 is C 1-6 Alkenyl, where C 1-6 At least one H in the alkenyl group may be substituted with a cyano group; and

[0140] R3 is H.

[0141] Throughout this specification, the following defined concepts are used when defining the compounds of Formula 1 and Formula 2. Unless specifically indicated otherwise, the following definitions also apply to the terms used throughout this specification either individually or as part of a larger group thereof.

[0142] The term "alkyl" refers to a straight chain, branched chain or cyclic hydrocarbon group when used independently or in combination with "heteroalkyl", wherein each carbon atom may be arbitrarily substituted by at least one of cyano, hydroxy, alkoxy, oxo, halogen, carbonyl, sulfonyl, cyanyl, etc.

[0143] The term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above.

[0144] The term "heteroalkyl" refers to an alkyl group including at least one heteroatom selected from N, O and S.

[0145] The term "aryl" refers to an aromatic group including phenyl, naphthyl, and the like, and may be arbitrarily substituted with at least one of alkyl, alkoxy, halogen, hydroxy, carbonyl, sulfonyl, cyanyl, and the like.

[0146] The term "heteroaryl" refers to: a 5- to 7-membered aromatic monocyclic ring including at least one heteroatom selected from N, O and S, such as 1 to 4 heteroatoms, or in some exemplary embodiments, 1 to 3 heteroatoms, and wherein the remaining ring atoms are carbon; an 8- to 12-membered bicyclic ring including at least one heteroatom selected from N, O and S, such as 1 to 4 heteroatoms, or in some exemplary embodiments, 1 to 3 heteroatoms, and wherein the remaining ring atoms are carbon, at least one ring is aromatic, and at least one heteroatom is present in the aromatic ring; and an 11- to 14-membered tricyclic ring including at least one heteroatom selected from N, O and S, such as 1 to 4 heteroatoms, or in some exemplary embodiments, 1 to 3 heteroatoms, and wherein the remaining ring atoms are carbon, at least one ring is aromatic, and at least one heteroatom is present in the aromatic ring. Examples of heteroaryl groups include pyridyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furanyl, benzofuranyl, benzimidazolyl, indolyl, indolyl, pyrrolyl, phenylthio, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, pyrrolopyridinyl, pyrazolopyridinyl, benzoxazolyl, benzothiazolyl, indazolyl, and 5,6,7,8-tetrahydroisoquinoline, but are not limited thereto.

[0147] The term "heterocycloalkyl" refers to a group including 1 to 4 heteroatoms selected from N, O and S, which may be fused with benzo or cycloalkyl, and is saturated or partially saturated or aromatic. Suitable heterocycloalkyl groups may include, for example, piperidinyl, piperazinyl, tetrahydrofuranyl, pyrrolidinyl, pyranyl, etc., but are not limited thereto.

[0148] The term "halo" refers to a substituent selected from fluoro, chloro, bromo and iodo.

[0149] Also, in Formula 1, Formulas 1-1 to 1-3, and Formula 2, "n" refers to the number of substituents that may be substituted. If n is 0, it means that all hydrogen atoms are substituted.

[0150] Furthermore, in the present invention, the expression that a monovalent substituent may become zero by removing one hydrogen means “absence”, and the expression that a divalent substituent may become zero by removing two hydrogens means “single bond”.

[0151] In addition, unless otherwise defined, the terms and abbreviations used in this specification have their original meanings.

[0152] In the present invention, examples of the compound represented by Formula 1 are as follows.

[0153]

[0154]

[0155] Meanwhile, the compound according to the present invention may have an asymmetric carbon and may exist in the form of an R or S isomer, a racemate, a mixture of diastereomers, and a single diastereomer, and all isomers and mixtures are included within the scope of the present invention. In other words, if an asymmetric carbon is included in the structure of Formula 1, it should be appreciated that unless its direction is otherwise described, stereoisomers are all included therein.

[0156] Hereinafter, for a better understanding of the present invention, a method for preparing a compound represented by Formula 2 is described based on an exemplary reaction formula, which is an embodiment of Formula 1. However, it should be recognized by those skilled in the art that the compound of Formula 1 or Formula 2 can be prepared by various methods based on the structure of Formula 1 or Formula 2, and such methods are all included within the scope of the present invention. In other words, it should be recognized that the compound according to the present invention can be prepared by any combination of various synthesis methods described in this specification or disclosed in the prior art, and this belongs to the scope of the present invention. In the following reaction formula, unless otherwise indicated, all substituents are the same as defined above.

[0157] As the acid, base and reaction solvent used in the compounds of the present invention, those commonly used in the art can be used without restriction. For example, as an acid, the following can be used: inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, adipic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc.; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc. As a base, the following can be used: NaH, K2CO3, Na2CO3, NaHCO3, K3PO4, KOH, NaOH, LiOH, n-BuLi, sec-BuLi, LiHMDS, etc. As a reaction solvent, the following can be used: DCM, THF, dioxane, MeOH, EtOH, hexane, EtOAC, ether, DMF, DMSO, toluene, xylene, etc., or a mixed solvent thereof, etc.

[0158] In one embodiment, the method for synthesizing the compound of Formula 2 according to the present invention can be illustrated by the following reaction formula 1:

[0159] [Reaction 1]

[0160]

[0161] In reaction formula 1,

[0162] R1, R2, X, Y and Z are the same as defined in Formula 2, wherein R1 may be substituted with up to m, and R2 may be substituted with up to n, wherein m and n are the same as defined in Formula 2;

[0163] A refers to a halogen atom, which includes F, Cl, Br, I, etc.; and

[0164] D is an analog of D2-D3-D4 as defined in combined formula 2, or D2-D3-D4 itself.

[0165] In Reaction Scheme 1, Step 1 is to prepare Compound (V) by reacting Compound (IV) with N-bromosuccinimide (NBS).

[0166] In Reaction Scheme 1, Step 2 is to prepare Compound (VI) from Compound (V) via bis(pinacolato)diboron.

[0167] In Reaction Scheme 1, step 3 is to prepare compound (VII) by reducing the NO2 group of compound (VI) to an NH2 group.

[0168] In Reaction Scheme 1, Step 4 is to prepare Compound (VIII) by Suzuki coupling reaction between Compound (VII) and Compound (III).

[0169] In Reaction Scheme 1, Step 5 is to prepare Compound (IX), which is obtained by inserting a derivative into Compound (VIII).

[0170] In Reaction Formula 1, compound (III) can be synthesized by the method of the following Reaction Formula 1-1:

[0171] [Reaction formula 1-1]

[0172]

[0173] According to Reaction Formula 1-1, compound (III) is prepared by reacting compound (I) with compound (II).

[0174] In addition to the method of Reaction Formula 1, the synthesis can also be carried out through Reaction Formula 2.

[0175] In one embodiment, the method for synthesizing the compound of Formula 2 according to the present invention can be illustrated by the following reaction formula 2:

[0176] [Reaction 2]

[0177]

[0178] In reaction formula 2,

[0179] R1, R2, X, Y and Z are the same as defined in Formula 2, wherein R1 may be substituted with up to m, and R2 may be substituted with up to n, wherein m and n are the same as defined in Formula 2;

[0180] A refers to a halogen atom, which includes F, Cl, Br, I, etc.; and

[0181] D is an analog of D2-D3-D4 as defined in combined formula 2, or D2-D3-D4 itself.

[0182] In reaction formula 2, step 1 is to react compound (IV') with compound (III) by S N Ar reaction to prepare compound (V').

[0183] In Reaction Scheme 2, Step 2 is to prepare Compound (VI') by reducing the NO2 group of Compound (V') to an NH2 group.

[0184] In Reaction Scheme 2, Step 3 is to prepare Compound (VIII'), wherein Compound (VIII') is obtained by inserting a derivative into Compound (VII').

[0185] In Reaction Formulas 1 and 2, if compound (IV) (in the case of X═CH) is used as a starting material, Reaction Formula 1 is preferably followed. If compound (IV') (in the case of X═NH) is used as a starting material, Reaction Formula 2 is preferably followed.

[0186] In Reaction Formula 1, Reaction Formula 1-1 or Reaction Formula 2, compounds (I), (II), (IV) and (IV') can be purchased or synthesized conventionally.

[0187] The compound of Formula 1 according to the present invention can be separated or purified from the products of Reaction Formulas 1 and 2 by various methods such as crystallization, silica gel column chromatography, etc. Therefore, the compound according to the present invention, the initiator, intermediate, etc. used to prepare the compound can be synthesized by various methods, and it should be recognized that such methods are included in the scope of the present invention with respect to the preparation of the compound of Formula 1.

[0188] Compositions containing compounds of formula 1 and uses thereof

[0189] The present invention provides a pharmaceutical composition and a use for treating or preventing a protein kinase-related disease, wherein the composition comprises a compound represented by the following formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient:

[0190] [Formula 1]

[0191]

[0192] Formula 1 is the same as defined above.

[0193] As used herein, the term "prevention" refers to all actions to inhibit protein kinase-related diseases or delay their occurrence by administering the pharmaceutical composition according to the present invention.

[0194] As used herein, the term "treatment" refers to all actions that improve or improve the symptoms of a protein kinase-related disease by administering the pharmaceutical composition according to the present invention.

[0195] By showing protein kinase inhibitory activity, the compound of Formula 1 according to the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof has a significant effect on preventing or treating protein kinase-related diseases.

[0196] In the present invention, the protein kinase may be janus kinase (JAK), but is not limited thereto.

[0197] In the present invention, the protein kinase-related diseases include: cancer; autoimmune diseases, such as psoriasis, rheumatoid arthritis, lupus, inflammatory bowel disease, chronic obstructive pulmonary disease, etc.; neurological diseases; metabolic diseases; or infections.

[0198] In the present invention, pharmaceutically acceptable salts refer to salts conventionally used in the pharmaceutical industry, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid, sulfuric acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonates prepared from methanesulfonic acid, ethylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picolinate, etc.; and the like, but the types of salts referred to in the present invention are not limited to those listed salts. In the present invention, preferred salts include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

[0199] In order to administer the pharmaceutical composition, in addition to the compound represented by Formula 1, its stereoisomer or its pharmaceutically acceptable salt, the pharmaceutical composition of the present invention may further contain at least one type of pharmaceutically acceptable carrier. And if necessary, it can also be used by adding other conventional additives such as antioxidants, buffer solutions, antibacterial agents, etc. Moreover, such a pharmaceutical composition can be prepared in a manner that a diluent, a dispersant, a surfactant, a binder and a lubricant are additionally added to the pharmaceutical composition.

[0200] The composition of the present invention can be orally administered or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to a predetermined method, wherein the dosage range thereof varies depending on the patient's weight, age, sex, health status and diet, administration time, administration method, excretion rate, severity of disease, etc. The daily dose of the compound represented by Formula 1 of the present invention is about 0.001 to 1000 mg / kg, and can be administered once a day or divided into several doses.

[0201] In addition to the compound represented by Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present invention may further contain at least one active ingredient having the same or similar pharmaceutical effect as the compound.

[0202] The present invention provides a method for preventing or treating a protein kinase-related disease, which comprises administering a therapeutically effective amount of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to an individual.

[0203] As used herein, "subject" refers to mammals including humans, and "administering" refers to providing a predetermined material to a patient by any appropriate method.

[0204] As used herein, the term "therapeutically effective amount" refers to an amount of the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is effective for preventing or treating a protein kinase-related disease.

[0205] The method for preventing or treating a protein kinase-related disease according to the present invention includes not only treating the disease itself before the symptoms are expressed, but also inhibiting or avoiding such symptoms by administering a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In controlling a disease, the preventive or therapeutic dosage of a certain active ingredient may vary according to the nature and severity of the disease or condition and the route of administration of the active ingredient. Its dosage and frequency may vary according to the age, weight, and response of the individual patient. Those skilled in the art naturally take such factors into consideration and can easily select a suitable dosage and dose. Moreover, the method for preventing or treating a protein kinase-related disease according to the present invention may further include administering an additional active agent in a therapeutically effective amount that helps treat the disease together with a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the additional active agent may exhibit a synergistic effect or an additive effect together with a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0206] In order to prepare drugs, the compound represented by Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof can be combined with acceptable adjuvants, diluents, carriers, etc., and can be prepared into a composite preparation together with other active agents, and thus have a synergistic effect of the active ingredients.

[0207] The matters mentioned in the uses, compositions and methods of treatment of the present invention can be equally applied if they do not contradict each other.

[0208] Beneficial effects

[0209] Due to the protein kinase inhibitory activity, the compound represented by Formula 1 according to the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof has a remarkably excellent effect on preventing or treating protein kinase-related diseases. DETAILED DESCRIPTION

[0210] Hereinafter, preferred embodiments are provided to better understand the present invention. However, the following embodiments are provided only for the purpose of illustrating the present invention, and therefore the present invention is not limited thereto. When preparing the compounds of the present invention, the reaction sequence can be appropriately modified. In other words, any reaction step can be performed earlier than described herein, or any substituent can be inserted to change, and any reagent other than the exemplary reagent can be used if necessary.

[0211] Various synthetic methods known for starting materials are used to synthesize the compounds of the present invention. If the starting material is commercially available, such material can be purchased from its supplier and used. As reagent suppliers, there are companies such as Sigma-Aldrich, TCI, Wako, Kanto, Fluchem, Acros, Alfa, Fluka, Combi-Blocks, Dae-Jung, but are not limited thereto. Moreover, unless otherwise specified, all commercial materials are used without any additional purification.

[0212] First, as shown in the following preparation examples, the compounds used for the synthesis in the following examples were prepared. Those skilled in the art can appropriately change and modify the following examples within the scope of the present invention.

[0213] Example 1: Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0214]

[0215] [Step 1] Synthesis of N-(4-bromopyridin-2-yl)cyclopropanecarboxamide

[0216]

[0217] 4-Bromopyridin-2-amine (2.0 g, 11.56 mmol) was dissolved in dichloromethane, and pyridine (1.8 ml) and cyclopropanecarbonyl chloride (1.2 ml, 13.87 mmol) were then added dropwise thereto at 0° C., followed by stirring at the same temperature for one hour. The reaction mixture was added to water (100 ml), and the resulting solid was then filtered and then dried under reduced pressure to obtain the title compound (2.1 g, 8.7 mmol).

[0218] 1 H NMR (400MHz, DMSO-d6) δ10.99-11.14(m,1H),8.33(d,J=1.83Hz,1H),8.22(d ,J=5.31Hz,1H),7.29-7.42(m,1H),1.94-2.07(m,1H),0.83(d,J=6.04Hz,4H)

[0219] MS (ESI+) m / z 241, 243 (M+H) +

[0220] [Step 2] Synthesis of 7-nitro-1-toluenesulfonyl-1H-indole

[0221]

[0222] 7-Nitro-1H-indole (20 g, 123.3 mmol) was dissolved in dimethylformamide (1.2 L), and sodium hydride (3.2 g, 135.6 mmol) was then slowly added dropwise thereto at 0°C, so as toluenesulfonyl chloride (26 g, 135.6 mmol) was slowly added dropwise thereto, and stirred for two hours. Dichloromethane (300 ml) was added to the resulting mixture, then washed with water (300 ml, twice), then dried over anhydrous magnesium sulfate, then filtered, and then the resulting filtrate was distilled under reduced pressure. Ether was added to the resulting vacuum distilled filtrate, and then the resulting solid was filtered, and then dried under reduced pressure to obtain the title compound (21 g, 66.4 mmol).

[0223] 1 H NMR (400MHz, DMSO-d6) δ8.05(d,J=3.66Hz,1H),7.97(d,J=7.68Hz,1H),7.82(d,J=7.87 Hz,1H),7.78(d,J=8.42Hz,2H),7.40-7.50(m,3H),7.08(d,J=3.66Hz,1H),2.37(s,3H)

[0224] MS (ESI+) m / z 317 (M+H) +

[0225] [Step 3] Synthesis of 3-bromo-7-nitro-1-toluenesulfonyl-1H-indole

[0226]

[0227] 7-Nitro-1-tosyl-1H-indole (21 g, 66.4 mmol) was dissolved in acetonitrile (664 ml), to which N-bromosuccinimide (24 g, 132.78 mmol) was then added, followed by heating to 50° C. for 18 hours. The resulting mixture was cooled to room temperature, and the resulting solid was filtered and then dried under reduced pressure to obtain the title compound (24.9 g, 63 mmol).

[0228] 1 H NMR (400MHz, DMSO-d6) δ8.44-8.51(m,1H),7.94-8.00(m,1H),7.84-7.90(m,3H),7.57-7.64(m,1H),7.45-7.52(m,2H),2.40(s,3H)

[0229] MS (ESI+) m / z 395,397 (M+H) +

[0230] [Step 4] Synthesis of 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole

[0231]

[0232] 3-Bromo-7-nitro-1-tosyl-1H-indole (24.9 g, 63 mmol), divinyl alcohol borane (32 g, 126 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (5.2 g, 6.4 mmol), potassium acetate (12 g, 122.2 mmol) were added to dioxane (630 ml), and then heated to 100 ° C for two hours. The resulting mixture was cooled to room temperature and then distilled under reduced pressure, followed by addition of dichloromethane (300 ml) and then washed with distilled water (300 ml, twice). The separated organic layer was dried over anhydrous magnesium sulfate, then filtered, and the resulting filtrate was then distilled under reduced pressure. Column chromatography was used to separate to obtain the title compound (16.9 g, 38.2 mmol).

[0233] 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.16-8.21(m,1H),7.95-8.01(m,2H),7.84-7.90(m,1H),7.47-7.57(m,3H),2.42(s,3H),1.34(s,12H)

[0234] MS (ESI+) m / z 443 (M+H) +

[0235] [Step 5] Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-7-amine

[0236]

[0237] 7-Nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (16.9 g, 38.2 mmol) was dissolved in ethanol / distilled water (2 / 1, 330 ml), and then iron (6.4 g, 114.6 mmol) and ammonium chloride (20 g, 382 mmol) were added thereto, and then heated to 80° C. for three hours. The resulting mixture was cooled to room temperature, and then methanol was added thereto, and then filtered to remove iron therefrom. The resulting filtrate was distilled under reduced pressure and then separated by column chromatography to obtain the title compound (7.4 g, 17.9 mmol).

[0238] 1 H NMR (400MHz, DMSO-d6) δ7.80-7.83(m,1H),7.75-7.80(m,2H),7.59-7.62(m,1H),7.37-7.43(m,2H),7. 32-7.36(m,1H),7.03-7.09(m,1H),2.31-2.34(m,3H),2.28-2.30(m,1H)1.30(s,12H)1.14-1.19(m,4H)

[0239] MS (ESI+) m / z 413 (M+H) +

[0240] [Step 6] Synthesis of N-(4-(7-amino-1-tosyl-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0241]

[0242] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-7-amine (7.4 g, 17.9 mmol) was dissolved in a dimethylformamide / distilled water (2:1) solution, and then N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (5.1 g, 21.48 mmol) obtained in Preparation Example 1, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (2.2 g, 2.68 mmol) and potassium phosphate (4.7 g, 21.48 mmol) were added thereto, and then stirred at 100° C. for one hour. When the reaction was completed, the mixture was cooled to room temperature, and then water was added thereto to extract with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the resulting residue. The residue was separated by column chromatography to obtain the title compound (5 g, 11.2 mmol).

[0243] MS (ESI+) m / z 447 (M+H) +

[0244] [Step 7] Synthesis of N-(4-(7-amino-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0245]

[0246] N-(4-(7-amino-1-tosyl-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide (5 g, 11.2 mmol) was added to tetrahydrofuran / methanol (1 / 1, 100 ml), followed by addition of 2N sodium hydroxide aqueous solution, followed by stirring at 30 to 40° C. for three hours. When the reaction was complete, the mixture was cooled to room temperature, followed by addition of saturated NH4Cl aqueous solution while stirring. The organic layer was extracted with dichloromethane, then concentrated under reduced pressure, and the resulting residue was then separated by column chromatography to obtain the title compound (2.7 g, 9.2 mmol).

[0247] 1 H NMR(DMSO-d6,400MHz)δ11.24(br s,1H),10.71(s,1H),8.53(s,1H),8.22(d,1H,J=5.3Hz),7.90(d,1H,J=2.7Hz),7.37(dd,1H,J=1.3,5.3 Hz),7.22(d,1H,J=8.1Hz),6.88(t,1H,J=7.8Hz),6.42(d,1H,J=7.5Hz),1.9-2.1(m,1H),0.8-0.9(m,4H)

[0248] MS (ESI+) m / z 293 (M+H) +

[0249] [Step 8] Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0250]

[0251] 1.5 equivalents of 2-cyano-3-methylbut-2-enoic acid, 1.5 equivalents of HATU, 2 equivalents of DIPEA, and synthesized N-(4-(7-amino-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide (100 mg) were added to a dichloromethane solution and then stirred at room temperature. After the reaction was complete, H2O was added to the mixture and then extracted with dichloromethane to separate the organic layer. After the mixture was concentrated, the resulting concentrate was separated by column chromatography to obtain the product, i.e., N-(4-(7-(2-cyano-3-methylbut-2-enoylamide)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide.

[0252] 1 H NMR(DMSO-d6,400MHz)δ10.79(br s,1H),10.34(br d,1H,J=0.9Hz),8.55(brs,1H),8.27(s,1H),7.98(br s,1H),7.42(br d,1H,J=4.8Hz),7.37(br s,1H),7.1-7.2(m,1H),2.24(br s,3H),2.18(br s,3H),2.0-2.0(m,1H),0.8-0.9(m,4H)

[0253] MS (ESI+) m / z 400 (M+H) +

[0254] Examples 2 to 41

[0255] Hereinafter, the compounds in Examples 2 to 41 were prepared by the same method as shown in Example 1, but using appropriate reactants in consideration of Reaction Formula 1 and the structures of the compounds to be prepared.

[0256] Example 2: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-3,5-difluorobenzamide

[0257]

[0258] 1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.79(s,1H),10.39(s,1H),8.58(s,1H),8.2-8.3(m,1H),8.01(s,1H),7.8-7.9(m,1H),7.80(br s,2H),7.5-7.6(m,1H),7.4-7.5(m,1H),7.3-7.4(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0259] MS (ESI+) m / z 433 (M+H) +

[0260] Example 3: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)cyclohexanecarboxamide

[0261]

[0262] 1 H NMR(DMSO-d6,400MHz)δ11.04(s,1H),8.5-8.6(m,1H),8.5-8.5(m,1H),8.4-8.5(m,1H),8.1-8.2(m,1H),7.5- 7.6(m,1H),7.4-7.5(m,1H),6.9-7.0(m,1H),2.0-2.1(m,1H),1.2-1.3(m,8H),1.1-1.2(m,2H),0.8-0.9(m,4H)

[0263] MS (ESI+) m / z 403 (M+H) +

[0264] Example 4: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-2-fluoroisonicotinamide

[0265]

[0266] 1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.8-10.8(m,1H),10.5-10.6(m,1H),8.5-8.6(m,1H),8.5- 8.5(m,1H),8.2-8.3(m,1H),8.0-8.1(m,1H),7.9-8.0(m,1H),7.9-7.9(m,1H),7.8-7.8(m,1H),7.44(br d,1H,J=1.5Hz),7.36(br s,1H),7.21(br s,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0267] MS (ESI+) m / z 416 (M+H) +

[0268] Example 5: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-3,5-dimethylbenzamide

[0269]

[0270] 1 H NMR(DMSO-d6,400MHz)δ 11.0-11.1(m,1H),8.5-8.6(m,1H),8.5-8.5(m,1H),8.5-8.5(m,1H),8.1-8.2(m,1H),7.5- 7.6(m,1H),7.4-7.5(m,1H),6.94(d,1H,J=4.0Hz),2.0-2.1(m,1H),1.06(s,10H),0.85(br s,4H),0.7-0.7(m,1H)

[0271] MS (ESI+) m / z 425 (M+H) +

[0272] Example 6: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)thiazole-5-carboxamide

[0273]

[0274] 1H NMR(DMSO-d6,400MHz)δ11.48(br s,1H),10.79(s,1H),10.15(s,1H),8.58(s,1H),8.4-8.5(m,1H),8.27(d,1H,J=5.5Hz),7.96(d,1H,J=2.7Hz),7. 82(d,1H,J=7.7Hz),7.67(s,2H),7.3-7.5(m,2H),7.25(s,1H),7.17(t,1H,J=7.9Hz),2.33(m,1H),0.6-0.9(m,4H)

[0275] MS (ESI+) m / z 404 (M+H) +

[0276] Example 7: Synthesis of N-(4-(7-butyramido-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0277]

[0278] 1 H NMR(DMSO-d6,400MHz)δ11.2-11.3(m,1H),10.6-10.8(m,1H),9.6-9.8(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),7.9-8.0(m,1H),7.7-7.8 (m,1H),7.4-7.5(m,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),2.4-2.4(m,2H),2.0-2.1(m,1H),1.6-1.8(m,2H),0.97(s,3H),0.8-0.9(m,4H)

[0279] MS (ESI+) m / z 363 (M+H) +

[0280] Example 8: Synthesis of N-(4-(7-(2-cyanoacetamido)-1H-indol-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

[0281]

[0282] 1H NMR (400 MHz, chloroform-d) δ 11.29-11.40 (m, 1H), 10.71-10.80 (m, 1H), 10.08-10.24 (m, 1H), 8.33-8.43 (m, 1H), 7.94-8.02 (m, 1H), 7.77-7.86 (m, 1H), 7.24-7.34 (m, 2H), 7.09-7.17 (m, 1H), 3.92-4.03 (m, 2H), 2.42-2.47 (m, 3H), 2.00-2.10 (m, 1H), 0.77-0.88 (m, 4H)

[0283] MS (ESI+) m / z 374 (M+H) +

[0284] Example 9: Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)-6-methylpyridin-2-yl)cyclopropanecarboxamide

[0285]

[0286] 1 H NMR(400MHz,CHLOROFORM-d)δ11.14-11.30(m,1H),10.71(s,1H),10.34(s,1H),8.23(s,2H),7.63-7.76(m,1H),7.45-7.55(m,1H) ),7.32-7.41(m,1H),7.03-7.15(m,1H),2.68(s,6H),2.28-2.34(m,3H),2.14-2.27(m,6H),1.95-2.06(m,1H),0.75-0.87(m,4H)

[0287] MS (ESI+) m / z 414 (M+H) +

[0288] Example 10: Synthesis of N-(4-(7-(2-cyanoacetamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0289]

[0290] 1H NMR(DMSO-d6,400MHz)δ11.37(br s,1H),10.7-10.8(m,1H),10.1-10.2(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),8.0-8.0(m,1H ),7.8-7.9(m,1H),7.4-7.5(m,1H),7.3-7.3(m,1H),7.2-7.3(m,1H),7.1-7.2(m,1H),3.98(br s,2H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0291] MS (ESI+) m / z 360 (M+H) +

[0292] Example 11: Synthesis of 4-cyano-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)tetrahydro-2H-pyran-4-carboxamide

[0293]

[0294] 1 H NMR(DMSO-d6,400MHz)δ11.3-11.4(m,1H),11.3-11.3(m,1H),10.8-10.8(m,1H),10.1-10.2(m, 1H),8.5-8.6(m,1H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.8-7.9(m,1H),7.4-7.5(m,1H),7.17(br d,2H,J=3.1Hz),4.0-4.1(m,2H),3.5-3.6(m,2H),2.2-2.3(m,4H),1.9-2.1(m,1H),0.8-0.9(m,4H)

[0295] MS (ESI+) m / z 430 (M+H) +

[0296] Example 12: Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

[0297]

[0298] MS (ESI+) m / z 414 (M+H) +

[0299] Example 13: Synthesis of N-(4-(7-(2-(1-cyanocyclopropyl)acetamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0300]

[0301] 1 H NMR(DMSO-d6,400MHz)δ11.41(br s,1H),10.79(s,1H),9.92(s,1H),8.55(s,1H),8.27(d,1H,J=5.3Hz),8.01(d,1H,J=2.7Hz),7.76(d,1H,J=7.9Hz),7.54(d ,1H,J=7.5Hz),7.41(d,1H,J=5.4Hz),7.14(t,1H,J=7.8Hz),2.72(s,2H),2.0-2.1(m,1H),1.2-1.2(m,4H),0.8-0.9(m,4H)

[0302] MS (ESI+) m / z 400 (M+H) +

[0303] Example 14: Synthesis of N-(4-(7-(2-cyanopropionamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0304]

[0305] 1 H NMR(DMSO-d6,400MHz)δ10.80(s,1H),10.23(s,1H),8.55(s,1H),8.27(d,1H,J=5.3Hz),8.02(d,1H,J =2.9Hz),7.82(d,1H,J=8.1Hz),7.43(d,1H,J=5.4Hz),7.34(d,1H,J=7.5Hz),7.1-7.2(m,1H),1.99(br d,1H,J=7.3Hz),1.62(d,3H,J=7.3Hz),0.8-0.9(m,4H)

[0306] MS (ESI+) m / z 374 (M+H) +

[0307] Example 15: Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-5-methyl-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0308]

[0309] 1 H NMR(DMSO-d6,400MHz)δ11.20(br s,1H),10.76(s,1H),10.28(br s,1H),8.48(br s,1H),8.27(br d,1H,J=5.7Hz),7.89(br s,1H),7.61(br s,1H),7.4-7.5(m,1H),7.26(br s,1H),2.42(br s,3H),2.23(br s,2H),2.1-2.2(m,2H),0.8-0.9(m,4H)

[0310] MS (ESI+) m / z 414 (M+H) +

[0311] Example 16: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-methyl-1H-indol-7-yl)-5-methylpyrazine-2-carboxamide

[0312]

[0313] 1 H NMR(DMSO-d6,400MHz)δ11.50(br s,1H),10.76(br s,1H),10.63(br s,1H),9.19(br s,1H),8.75(br s,1H),8.50(br s,1H),8.27(br d,1H,J=5.3Hz),7.88(br s,1H),7.65(br s,1H),7.43(br d,1H,J=4.8Hz),7.32(br s,1H),2.5-2.7(m,4H),2.4-2.5(m,6H),2.05(br s,1H),0.7-0.9(m,4H)

[0314] MS (ESI+) m / z 427 (M+H) +

[0315] Example 17: Synthesis of N-(4-(7-(2,3-dimethylbut-2-enamido)-3H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0316]

[0317] 1H NMR(DMSO-d6,400MHz)δ11.3-11.3(m,1H),10.78(s,1H),9.7-9.7(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),7.9-8.0(m,1H),7.7-7. 8(m,1H),7.6-7.7(m,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),1.91(s,3H),1.82(s,3H),1.76(s,3H),0.8-0.9(m,4H)

[0318] MS (ESI+) m / z 389 (M+H) +

[0319] Example 18: Synthesis of N-(4-(7-(2-(4-methylpiperazin-1-yl)propionamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0320]

[0321] 1 H NMR(DMSO-d6,400MHz)δ11.4-11.4(m,1H),10.78(s,1H),9.7-9.8(m,1H),8 .5-8.6(m,1H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.7-7.8(m,1H),7.5-7.5(m ,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),2.7-2.7(m,1H),2.69(s,3H),2.4-2 .4(m,3H),2.3-2.3(m,1H),2.0-2.1(m,1H),1.2-1.3(m,8H),0.8-0.9(m,4H)

[0322] MS (ESI+) m / z 447 (M+H) +

[0323] Example 19: Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)-6-methoxypyridin-2-yl)cyclopropanecarboxamide

[0324]

[0325] 1H NMR (400MHz, DMSO-d6) δ11.12-11.27(m,1H),10.52-10.71(m,1H),10.29(s,1H),8.47-8.61(m,1H),8.09-8.19(m,1H),7.44-7.54(m,1 H),7.30-7.39(m,1H),7.08-7.18(m,2H),3.86-3.90(m,3H),2.23-2.26(m,3H),2.17-2.20(m,3H),2.10-2.15(m,1H),0.83-0.87(m,4H)

[0326] MS (ESI+) m / z 430 (M+H) +

[0327] Example 20: Synthesis of N-(4-(7-(2-cyanoacetamido)-1H-indol-3-yl)-6-methoxypyridin-2-yl)cyclopropanecarboxamide

[0328]

[0329] 1 H NMR (400MHz, DMSO-d6) δ11.11-11.26(m,1H),10.50-10.63(m,1H),10.05-10.12(m,1H),8.51-8.59(m,1H),8.12-8.20(m,1 H),7.48-7.57(m,1H),7.19-7.28(m,1H),7.05-7.16(m,2H),3.97(s,2H),3.86(s,3H),2.09-2.19(m,1H),0.79-0.90(m,4H)

[0330] MS (ESI+) m / z 390 (M+H) +

[0331] Example 21: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-4-(trifluoromethyl)thiazole-2-carboxamide

[0332]

[0333] 1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.99(s,1H),10.8-10.9(m,1H),8.8-8.9(m,1H),8.5-8.6(m,1H),8.2-8.3(m ,1H),7.9-8.1(m,1H),7.9-7.9(m,1H),7.4-7.5(m,1H),7.2-7.3(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0334] MS (ESI+) m / z 472 (M+H) +

[0335] Example 22: Synthesis of (E)-N-(4-(7-(2-cyano-3-phenylacrylamide)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0336]

[0337] 1 H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.7-10.8(m,1H),10.4-10.5(m,1H),8.5-8.6(m,1H),8.2-8.3(m,4H),8.0-8.1(m,2H),8.00(br s,1H),7.86(br dd,1H,J=3.7,8.2Hz),7.4-7.5(m,1H),7.3-7.4(m,1H),7.1-7.2(m,1H),3.5-3.7(m,1H),3.0-3.2(m,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0338] MS (ESI+) m / z 448 (M+H) +

[0339] Example 23: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-1H-pyrrole-2-carboxamide

[0340]

[0341] 1H NMR(DMSO-d6,400MHz)δ11.7-11.8(m,1H),11.48(br s,1H),10.78(br s,1H),9.73(s,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),7.9-8.0(m,1H),7.7-7.8(m,1H),7.4-7.5(m,2H),7.14(br d,2H,J=19.4Hz),6.99(br d,1H,J=2.0Hz),6.2-6.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0342] MS (ESI+) m / z 386 (M+H) +

[0343] Example 24: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-4-methylnicotinamide

[0344]

[0345] 1 H NMR(DMSO-d6,400MHz)δ11.4-11.5(m,1H),10.7-10.8(m,1H),10.34(s,1H),8.8-8.9(m,1H),8.58(br s,2H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.8-7.9(m,1H),7.5-7.6(m,1H),7.4 -7.5(m,2H),7.1-7.2(m,1H),3.4-3.4(m,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0346] MS (ESI+) m / z 412 (M+H) +

[0347] Example 25: Synthesis of (E)-N-(4-(7-(2-cyano-3-(thiophen-2-yl)acrylamide)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0348]

[0349] 1H NMR(DMSO-d6,400MHz)δ11.5-11.5(m,1H),10.7-10.8(m,1H),10.29(s,1H),8.59(d,2H,J=19.2 Hz),8.2-8.3(m,1H),8.1-8.2(m,1H),7.9-8.0(m,2H),7.8-7.9(m,1H),7.3-7.5(m,2H),7.20(br d,2H,J=19.0Hz),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0350] MS (ESI+) m / z 454 (M+H) +

[0351] Example 26: Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1-methyl-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0352]

[0353] 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),10.43(s,1H),8.49-8.54(m,1H),8.25-8.31(m,1H),8.17-8.23(m,1H),7.91(s,1H),7 .32-7.37(m,1H),7.17-7.23(m,1H),7.01-7.08(m,1H),2.21(s,3H),2.01-2.08(m,1H),1.16-1.26(m,6H),0.78-0.87(m,4H)

[0354] MS (ESI+) m / z 414 (M+H) +

[0355] Example 27: Synthesis of 4-cyano-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)benzamide

[0356]

[0357] 1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.7-10.9(m,1H),10.4-10.5(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),8.22(br d,2H,J=8.1Hz),8.07(d,2H,J=8.2Hz),8.00(d,1H,J=2.6Hz),7.8-7.9(m,1H),7. 4-7.5(m,1H),7.38(d,1H,J=7.5Hz),7.20(s,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0358] MS (ESI+) m / z 422 (M+H) +

[0359] Example 28: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-6-methylnicotinamide

[0360]

[0361] 1 H NMR(DMSO-d6,400MHz)δ11.53(br s,1H),10.79(s,1H),10.34(s,1H),9.0-9.1(m,1H),8.58(s,1H),8.27(br d,2H,J=5.3Hz),7.99(d,1H,J=2.4Hz),7.8-7.9(m,1H),7.4-7.5(m,2H) ,7.38(s,1H),7.19(s,1H),2.58(s,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0362] MS (ESI+) m / z 412 (M+H) +

[0363] Example 29: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-6-(trifluoromethyl)nicotinamide

[0364]

[0365] 1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.80(s,1H),10.75(s,1H),9.0-9.1(m,1H),8.6-8.6(m,1H),8.4-8.5(m,1H),8.2- 8.3(m,2H),8.0-8.1(m,1H),7.9-7.9(m,1H),7.4-7.5(m,1H),7.3-7.4(m,1H),7.2-7.3(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0366] MS (ESI+) m / z 466 (M+H) +

[0367] Example 30: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-5,6-difluoronicotinamide

[0368]

[0369] 1 H NMR(DMSO-d6,400MHz)δ11.4-11.5(m,1H),10.80(s,1H),10.67(s,1H),8.58(s,1H),8.27(s,2H),8.04(d,1H,J=1.8Hz),7.8-7.9(m,2H),7.44(br d,2H,J=6.8Hz),7.21(s,1H),2.0-2.1(m,1H),0.7-0.9(m,4H)

[0370] MS (ESI+) m / z 434 (M+H) +

[0371] Example 31: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-5-fluoronicotinamide

[0372]

[0373] 1H NMR(DMSO-d6,400MHz)δ11.4-11.5(m,1H),10.8-10.8(m,1H),8.8-8.8(m,1H),8.6-8.7(m,1 H),8.6-8.7(m,1H),8.5-8.6(m,1H),8.57(s,1H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.87(br s,2H),7.5-7.5(m,1H),7.4-7.4(m,1H),7.2-7.3(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0374] MS (ESI+) m / z 416 (M+H) +

[0375] Example 32: Synthesis of 6-chloro-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)nicotinamide

[0376]

[0377] 1 H NMR(DMSO-d6,400MHz)δ8.61-8.69(m,1H),8.31-8.39(m,1H),8.26(d,1H,J=5.1Hz),8.12(s,1H),7.98(br s,2H),7.8-7.8(m,1H),7.62(br d,1H,J=1.1Hz),7.4-7.5(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),0.87(br d,4H,J=1.1Hz)

[0378] MS (ESI+) m / z 433 (M+H) +

[0379] Example 33: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-1H-pyrazole-3-carboxamide

[0380]

[0381] 1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.7-10.8(m,1H),10.0-10.1(m,1H),8.57(s,1H),8.2-8.3(m,1H),7.93(br d,1H,J=1.8Hz),7.9-8.0(m,1H),7.8-7.8(m,1H),7.5-7.5(m,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),6.83(br s,1H),2.05(br d,1H,J=2.4Hz),0.8-0.9(m,4H)

[0382] MS (ESI+) m / z 387 (M+H) +

[0383] Example 34: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0384]

[0385] 1 H NMR(DMSO-d6,400MHz)δ12.08(s,1H),11.3-11.5(m,1H),10.8-11.0(m,1H),8.50(br dd,2H,J=2.1,7.2Hz),8.26(br d,2H,J=5.5Hz),7.9-8.0(m,1H),7.83(s,1H),7.4-7.5(m,1H),7.31(s,1H) ),7.19(s,1H),6.64(s,1H),3.68(s,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0386] MS (ESI+) m / z 428 (M+H) +

[0387] Example 35: Synthesis of 2-cyano-N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)isonicotinamide

[0388]

[0389] 1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.8-10.8(m,1H),10.7-10.7(m,1H),9.0-9.1(m,1H),8.6-8.7(m,1H),8.5-8.6(m,1H) ,8.29(s,2H),8.0-8.1(m,1H),7.9-7.9(m,1H),7.4-7.5(m,1H),7.4-7.4(m,1H),7.2-7.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0390] MS (ESI+) m / z 423 (M+H) +

[0391] Example 36: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-4-ethyl-1H-pyrrole-2-carboxamide

[0392]

[0393] 1 H NMR(DMSO-d6,400MHz)δ11.5-11.5(m,1H),11.4-11.5(m,1H),10.7-10.8(m,1H),9.5-9.7(m,1H),8.57(s,1H),8.2-8.3(m, 1H),7.95(s,1H),7.7-7.8(m,1H),7.43(s,2H),7.1-7.2(m,1H),7.0-7.0(m,1H),6.8-6.8(m,1H),2.0-2.1(m,1H),1.23(br s,2H),1.18(t,4H,J=7.6Hz),0.85(br d,4H,J=14.3Hz)

[0394] MS (ESI+) m / z 414 (M+H) +

[0395] Example 37: Synthesis of 3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-N-(2,2,2-trifluoroethyl)-7-(3-(2,2,2-trifluoroethyl)ureido)-1H-indole-1-carboxamide

[0396]

[0397] 1H NMR(DMSO-d6,400MHz)δ11.98(br s,1H),10.79(s,1H),8.58(s,1H),8.2-8.3(m,2H),8.03(d,1H,J=8.2Hz),7.96(s,1H),7.44(br d,1H,J=5.3Hz),7.25(t,1H,J=8.0Hz),7.05(d,1H,J=7.7Hz),3.8-4.0(m,4H),2.0-2.1(m,1H),0.8-0.9(m,4H)

[0398] MS (ESI+) m / z 543 (M+H) +

[0399] Example 38: Synthesis of N-(3-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-7-yl)-3-fluorobenzamide

[0400]

[0401] 1 H NMR(DMSO-d6,400MHz)δ11.24(br s,1H),10.71(s,1H),8.53(s,1H),8.22(d,1H,J=5.3Hz),7.90(d,1H,J=2.7Hz),7.37(dd,1H,J=1.3,5.3 Hz),7.22(d,1H,J=8.1Hz),6.88(t,1H,J=7.8Hz),6.42(d,1H,J=7.5Hz),1.9-2.1(m,1H),0.8-0.9(m,4H)

[0402] MS (ESI+) m / z 415 (M+H) +

[0403] Example 39: Synthesis of N-(4-(7-(3-(2,2,2-trifluoroethyl)ureido)-3H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0404]

[0405] 1H NMR(400MHz,DMSO-d6)δ11.21-11.33(m,1H),10.71-10.80(m,1H),8.67- 8.76(m,1H),8.51-8.56(m,1H),8.21-8.29(m,1H),7.90-7.95(m,1H),7.6 5-7.71(m,1H),7.36-7.43(m,1H),7.23-7.29(m,1H),7.05-7.12(m,1H),6 .89-6.96(m,1H),3.92-4.03(m,2H),1.99-2.09(m,1H),0.79-0.88(m,4H)

[0406] MS (ESI+) m / z 418 (M+H) +

[0407] Example 40: Synthesis of N-(4-(4-(2-cyano-3-methylbut-2-enamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0408]

[0409] [Step 1] Synthesis of N-(4-fluoropyridin-2-yl)cyclopropanecarboxamide

[0410]

[0411] 2-Amino-4-fluoropyridine (5 g, 44.6 mmol) was dissolved in dichloromethane, and pyridine (10.5 mL) and cyclopropanecarbonyl chloride (4.9 mL, 53.5 mmol) were slowly added dropwise thereto at 0° C., and then stirred at the same temperature for two hours. The reaction mixture was added to water, and the resulting solid was then filtered and then dried under reduced pressure to obtain the title compound (5.67 g, 90.1 mmol) (70%).

[0412] MS (ESI+) m / z 181 (M+H) +

[0413] [Step 2] Synthesis of N-(4-(4-nitro-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0414]

[0415] 4-nitro-1H-indole (4.3g, 26.6mmol) was dissolved in dimethylformamide (50mL), and then 60%NaH (1.1g, 26.6mmol) in oil was slowly added thereto at 0°C. N-(4-fluoropyridin-2-yl)cyclopropanecarboxamide (4.0g, 22.2mmol) was added thereto, so that after the reaction mixture was stirred, the resulting mixture was stirred for 0.5 hours. When the reaction was complete, the mixture was stirred at room temperature, and then saturated NH4Cl aqueous solution was added thereto while stirring. The organic layer was extracted with dichloromethane, then concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound.

[0416] 1 H NMR (400MHz, DMSO-d6) δ11.09-11.27(m,1H),8.46-8.56(m,1H),8.34-8.42(m,1H),8.13-8.24(m, 3H),7.46-7.55(m,1H),7.39-7.46(m,1H),7.30-7.37(m,1H),1.99-2.12(m,1H),0.79-0.93(m,4H)

[0417] MS (ESI+) m / z 323 (M+H) +

[0418] [Step 3] Synthesis of N-(4-(4-amino-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0419]

[0420] N-[4-(4-nitroindol-1-yl)-2-pyridyl]cyclopropanecarboxamide (5 g, 15.5 mmol) was inserted into methanol (100 mL), and Pd / C (500 mg) was subsequently added thereto, followed by stirring at 40 to 50° C. under a hydrogen atmosphere for six hours. When the reaction was complete, the mixture was cooled to room temperature and then filtered with Celite. The resulting filtrate was distilled under reduced pressure and then separated by column chromatography to obtain the title compound (3.9 g, 87%).

[0421] MS (ESI+) m / z 293 (M+H) +

[0422] [Step 4] Synthesis of N-(4-(4-(2-cyano-3-methylbut-2-enamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0423] The same process as in step 8 of Example 1 was performed to obtain the product, i.e., N-(4-(4-(2-cyano-3-methylbut-2-enamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide.

[0424] 1 H NMR (400MHz, DMSO-d6) δ11.04-11.12(m,1H),10.41-10.54(m,1H),8.42-8.48(m,1H),8.38-8.42(m,1H),7.75-7.80(m,1H),7.58-7.66(m,2H ),7.36-7.40(m,1H),7.24-7.30(m,1H)6.91-6.98(m,1H),2.20(s,3H) ,2.13(s,3H),2.02-2.07(m,1H),1.19-1.26(m,2H),0.83-0.87(m,4H).

[0425] MS (ESI+) m / z 400 (M+H) +

[0426] Examples 41 to 62

[0427] Hereinafter, the compounds in Examples 41 to 62 were prepared by the same method as shown in Example 40, but using appropriate reactants in consideration of Reaction Formula 2 and the structures of the compounds to be prepared.

[0428] Example 41: Synthesis of N-(4-(4-(2-cyanoacetamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0429]

[0430] 1 H NMR (400MHz, DMSO-d6) δ10.99-11.17(m,1H),10.03-10.22(m,1H),8.42-8.48(m,1H),8.37-8.42(m,1H),7.75-7.81(m,1H),7.67-7.73(m ,1H),7.54-7.60(m,1H),7.34-7.41(m,1H),7.21-7.30(m,1H),6.97- 7.05(m,1H),3.99-4.10(m,2H),2.00-2.09(m,1H),0.77-0.89(m,4H)

[0431] MS (ESI+) m / z 360 (M+H) +

[0432] Example 42: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-1H-pyrrole-2-carboxamide

[0433]

[0434] 1 H NMR(400MHz,DMSO-d6)δ11.67-11.80(m,1H),10.98-11.13(m,1H),9.66-9.8 1(m,1H),8.43(s,2H),7.71-7.80(m,1H),7.56-7.64(m,1H),7.48-7.56(m,1H ),7.35-7.42(m,1H),7.22-7.32(m,1H),7.11-7.21(m,1H),6.95-7.02(m,1H ),6.85-6.95(m,1H),6.11-6.25(m,1H),1.97-2.14(m,1H),0.77-0.94(m,4H)

[0435] MS (ESI+) m / z 386 (M+H) +

[0436] Example 43: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-2-methylthiazole-5-carboxamide

[0437]

[0438] 1 H NMR (400MHz, DMSO-d6) δ11.02-11.14(m,1H),10.03-10.15(m,1H),8.40-8.49(m,2H),8.33(s,1H),7.75-7.83(m,1H),7.67-7. 73(m,1H),7.59-7.66(m,1H),7.36-7.45(m,1H),7.26-7.34(m,1H),6.75-6.84(m,1H),2.80(s,3H),1.99-2.11(m,1H),0.86(br d,J=4.76Hz,4H)

[0439] MS (ESI+) m / z 418 (M+H) +

[0440] Example 44: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-3,5-difluorobenzamide

[0441]

[0442] 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.45(s,1H),8.44(s,2H),7.78(s,3H),7.64-7.70(m,1H),7.48-7 .59(m,2H),7.37-7.43(m,1H),7.26-7.35(m,1H),6.89-6.99(m,1H),2.00-2.10(m,1H),0.80-0.91(m,4H)

[0443] MS (ESI+) m / z 433 (M+H) +

[0444] Example 45: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0445]

[0446] 1 H NMR (400MHz, DMSO-d6) δ12.71-12.87(m,1H),10.96-11.22(m,1H),8.38-8.62(m,3H),8.16-8.26(m,2H),7.78-7.94(m,1H),7.48-7.66(m ,1H),7.34-7.45(m,1H),7.23-7.33(m,1H),6.83-6.97(m,1H),6.55- 6.72(m,1H),3.64-3.76(m,3H),1.97-2.17(m,1H),0.77-0.96(m,4H)

[0447] MS (ESI+) m / z 428 (M+H) +

[0448] Example 46: Synthesis of N-(4-(4-(2-cyano-3-(thiophen-2-yl)acrylamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0449]

[0450] 1H NMR(400MHz,DMSO-d6)δ11.02-11.12(m,1H),10.25-10.40(m,1H),8.57- 8.64(m,1H),8.40-8.49(m,2H),8.11-8.20(m,1H),7.94-8.01(m,1H),7.7 6-7.83(m,1H),7.61-7.70(m,1H),7.45-7.50(m,1H),7.34-7.42(m,2H),7 .24-7.33(m,1H),6.85-6.93(m,1H),2.00-2.13(m,1H),0.73-0.92(m,4H)

[0451] MS (ESI+) m / z 454 (M+H) +

[0452] Example 47: Synthesis of 4-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)benzamide

[0453]

[0454] 1 H NMR (400MHz, DMSO-d6) δ11.04-11.14(m,1H),10.48-10.62(m,1H),8.40-8.49(m,2H),8.14-8.23(m,2H),7.99-8.09(m,2H),7.74-7.83(m ,1H),7.61-7.70(m,1H),7.52-7.60(m,1H),7.35-7.42(m,1H),7.26- 7.34(m,1H),6.91-6.97(m,1H),2.00-2.11(m,1H),0.80-0.90(m,4H)

[0455] MS (ESI+) m / z 422 (M+H) +

[0456] Example 48: Synthesis of N-(4-(4-(2-cyano-3-phenylacrylamide)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0457]

[0458] 1H NMR (400MHz, DMSO-d6) δ11.05-11.14(m,1H),10.37-10.49(m,1H),8.41-8.49(m,2H),8.35-8.40(m,1H),8.00-8.09(m,2H),7.78-7.84(m ,1H),7.60-7.69(m,4H),7.47-7.54(m,1H),7.38-7.43(m,1H),7.26- 7.34(m,1H),6.90-6.98(m,1H),1.98-2.11(m,1H),0.79-0.90(m,4H)

[0459] MS (ESI+) m / z 448 (M+H) +

[0460] Example 49: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-1-methyl-1H-indole-2-carboxamide

[0461]

[0462] 1 H NMR(400MHz,DMSO-d6)δ11.04-11.12(m,1H),10.31-10.40(m,1H),8.40-8 .48(m,2H),7.76-7.82(m,1H),7.69-7.74(m,1H),7.61-7.67(m,1H),7.52- 7.61(m,2H),7.37-7.44(m,2H),7.27-7.35(m,2H),7.09-7.19(m,1H),6.92 -7.01(m,1H),3.99-4.10(m,3H),2.00-2.11(m,1H),0.78-0.89(m,4H)ppm.

[0463] MS (ESI+) m / z 450 (M+H) +

[0464] Example 50: Synthesis of 4-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)tetrahydro-2H-pyran-4-carboxamide

[0465]

[0466] 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.22-10.38(m,1H),8.37-8.49(m,2H),7.79(d,J=3.48Hz,1H),7. 61-7.71(m,1H),7.34-7.42(m,1H),7.22-7.31(m,2H),7.00-7.09(m,1H),6.76(d,J=3.48Hz,1H),3.99(br d,J=11.89Hz,2H),3.54-3.68(m,2H),2.12-2.29(m,4H),1.99-2.10(m,1H),0.86(br d,J=4.03Hz,4H)

[0467] MS (ESI+) m / z 430 (M+H) +

[0468] Example 51: Synthesis of 2-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)isonicotinamide

[0469]

[0470] 1 H NMR (400MHz, DMSO-d6) δ11.03-11.15(m,1H),10.65-10.80(m,1H),8.92-9.04(m,1H),8.60(s,1H),8.39-8.48(m,2H),8.21-8.28(m,1H ),7.75-7.84(m,1H),7.55-7.72(m,2H),7.37-7.44(m,1H),7.25-7.34(m,1H),6.97-7.07(m,1H),2.00-2.12(m,1H),0.74-0.92(m,4H)

[0471] MS (ESI+) m / z 423 (M+H) +

[0472] Example 52: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-2-fluoroisonicotinamide

[0473]

[0474] 1H NMR (400MHz, DMSO-d6) δ11.01-11.16(m,1H),10.54-10.68(m,1H),8.41-8.51(m,3H),7.86-7.98(m,1H),7.72-7.83(m,2H) ,7.61-7.68(m,1H),7.52-7.60(m,1H),7.36-7.44(m,1H),7.26-7.36(m,1H),6.90-7.00(m,1H),1.99-2.10(m,1H),0.86(br s,4H)

[0475] MS (ESI+) m / z 416 (M+H) +

[0476] Example 53: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-2,3-difluoroisonicotinamide

[0477]

[0478] 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.52-10.81(m,1H),8.35-8.53(m,2H),8.14-8.29(m,1H),7.79(br d,J=3.48Hz,2H),7.70-7.76(m,1H),7.64(d,J=8.42Hz,1H),7.34-7.43( m,1H),7.22-7.34(m,1H),6.91-7.06(m,1H),2.00-2.10(m,1H),0.86(br d,J=4.21Hz,4H)

[0479] MS (ESI+) m / z 434 (M+H) +

[0480] Example 54: Synthesis of N-(4-(4-(2-cyanopropionamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0481]

[0482] 1H NMR(400MHz,DMSO-d6)δ11.08(br s,1H),10.12-10.37(m,1H),8.36-8.49(m,2H),7.74-7.85(m,1H),7.64-7.71(m,1H),7.54-7.63(m,1H),7.34-7.44 (m,1H),7.20-7.31(m,1H),6.93-7.05(m,1H),4.11-4.24(m,1H,1.97-2.13(m,1H),1.57(d,J=7.14Hz,3H),0.85(br s,4H)

[0483] MS (ESI+) m / z 374 (M+H) +

[0484] Example 55: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-1H-pyrazole-3-carboxamide

[0485]

[0486] 1 H NMR (400MHz, DMSO-d6) δ10.99-11.18(m,1H),9.68-10.13(m,1H),8.35-8.52(m,2H),7.83-7.95(m,1H),7.71-7.82(m, 1H),7.55-7.71(m,2H),7.35-7.46(m,1H),7.21-7.35(m,1H),6.71-6.93(m,2H),1.98-2.13(m,1H),0.73-0.92(m,4H)

[0487] MS (ESI+) m / z 387 (M+H) +

[0488] Example 56: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-3-fluoro-4-methoxybenzamide

[0489]

[0490] 1H NMR (400MHz, DMSO-d6) δ11.01-11.17(m,1H),10.10-10.30(m,1H),8.39-8.51(m,2H),7.87-8.02(m,2H),7.72-7.80(m,1 H),7.59-7.68(m,1H),7.45-7.53(m,1H),7.24-7.42(m,3H),6.85-6.98(m,1H),3.94(s,3H),2.00-2.10(m,1H),0.86(br d,J=3.84Hz,4H)

[0491] MS (ESI+) m / z 445 (M+H) +

[0492] Example 57: Synthesis of (1R,2S)-2-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)cyclopropane-1-carboxamide

[0493]

[0494] 1 H NMR (400MHz, DMSO-d6) δ10.97-11.19(m,1H),10.25-10.47(m,1H),8.34-8.54(m,2H),7.70-7.85(m,2H),7.50-7.62(m,1H),7.34-7. 42(m,1H),7.20-7.28(m,1H),7.03-7.12(m,1H),2.56-2.71(m,2H),2.21-2.35(m,1H),1.99-2.10(m,1H),1.40-1.56(m,2H),0.86(br d,J=3.84Hz,4H)

[0495] MS (ESI+) m / z 386 (M+H) +

[0496] Example 58: Synthesis of N-(4-(4-(2-(1-cyanocyclopropyl)acetamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0497]

[0498] 1H NMR(400MHz,DMSO-d6)δ11.00-11.10(m,1H),9.80-9.91(m,1H),8.38-8.48(m,2H),7.72-7.81(m,2H),7.50-7 .58(m,1H),7.32-7.41(m,1H),7.19-7.27(m,1H),6.99-7.07(m,1H),2.75(s,2H),2.02-2.11(m,1H),0.85(br s,4H)

[0499] MS (ESI+) m / z 400 (M+H) +

[0500] Example 59: Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-6-methylnicotinamide

[0501]

[0502] 1 H NMR(400MHz,DMSO-d6)δ10.99-11.14(m,1H),10.31-10.47(m,1H),8.98-9.11(m, 1H),8.38-8.48(m,2H),8.20-8.33(m,1H),7.72-7.82(m,1H),7.61-7.67(m,1H),7 .53-7.58(m,1H),7.42-7.47(m,1H),7.37-7.42(m,1H),7.24-7.34(m,1H),6.90- 7.00(m,1H),2.58(s,3H),2.02-2.11(m,1H),1.22-1.31(m,5H),0.80-0.92(m,4H)

[0503] MS (ESI+) m / z 412 (M+H) +

[0504] Example 60: Synthesis of N-(4-(4-(2,3-dimethylbut-2-enamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0505]

[0506] 1H NMR (400MHz, DMSO-d6) δ10.97-11.15(m,1H),9.69-9.87(m,1H),8.35-8.51(m,2H),7.65-7.78(m,2H),7.50-7.61(m,1H),7.31-7.41(m,1H) ,7.15-7.28(m,1H),6.96-7.07(m,1H),2.68(s,6H),2.00-2.10(m,1H) ,1.85-1.92(m,3H),1.78-1.85(m,3H),1.74(s,3H),0.77-0.91(m,4H)

[0507] MS (ESI+) m / z 389 (M+H) +

[0508] Example 61: Synthesis of N-(4-(4-(3-(2,4-difluorophenyl)ureido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0509]

[0510] 1 H NMR(400MHz,DMSO-d6)δ8.98-9.08(m,1H),8.80-8.91(m,1H),8.38-8.49(m,2H),8.10-8.30(m,1H),7.81-7.92(m,1H),7.74-7.81 (m,1H),7.42-7.51(m,1H),7.28-7.42(m,2H),7.17-7.27(m,1H),7.03-7.13(m,1H),6.86-6.97(m,1H),2.01-2.12(m,1H),0.86(br d,J=4.39Hz,4H)

[0511] MS (ESI+) m / z 448 (M+H) +

[0512] Example 62: Synthesis of N-(4-(4-(3-(2,2,2-trifluoroethyl)ureido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

[0513]

[0514] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.64-8.77(m,1H),8.35-8.52(m,2H),7.71-7.86(m,2H),7.32-7.49(m,2H),7.12- 7.23(m,1H),6.93-7.05(m,1H),6.73-6.90(m,3H),3.93-4.08(m,2H),3.84(m,4H),1.98-2.09(m,1H),0.78-0.93(m,4H)

[0515] MS (ESI+) m / z 418 (M+H) +

[0516] Hereinafter, the compound in Example 63 was prepared in such a manner that the synthesis was performed by the same method as shown in Example 1, or using appropriate reactants, taking into account Reaction Formula 1 and the structure of the compound to be prepared.

[0517] Example 63: Synthesis of N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indazol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

[0518]

[0519] 1 H NMR (400MHz, DMSO-d6) δ11.25-11.42(m,1H),10.95-11.03(m,1H),8.79(s,1H),8.39-8.47(m,1H),7.81-7.90(m,1H),7.65-7.73(m ,1H),7.32-7.41(m,1H),7.13-7.28(m,1H),4.96-5.48(m,1H),2.68(s,6H),2.02-2.10(m,1H),1.96-2.23(m,3H),0.81-0.91(m,4H)

[0520] MS (ESI+) m / z 401 (M+H) +

[0521] Experimental Example 1: Analysis of JAK1 Activity Inhibition Ability (ADP-Glo TM Kinase assay)

[0522] The inhibitory effect of the compounds of the present invention on JAK was identified as follows.

[0523] The control material and the test material were prepared by diluting each concentration using DMSO. Meanwhile, ATP (250uM) and substrates of JAK (JAK1, IRS-1tide 40ng / mL) were prepared by diluting in kinase buffer (40mM Tris-HCl pH 7.5, 20mMMgCl2, 0.5mg / mL BSA, 50uM DTT).

[0524] Each concentration of the test drug, substrate, ATP and JAK enzyme were mixed in an eppendorf tube and then reacted in an incubator at 30°C for 40 minutes.

[0525] ADP-Glo ​​◎ reagent included in the ADP-GloTM Kinase Enzyme System (Promega, USA, V9571) was added to each eppendorf tube, and then the reaction was carried out in an incubator at 30° C. for 40 minutes.

[0526] The kinase detection reagent included in the ADP-GloTM kinase enzyme system was added to an eppendorf tube, and then the luminescence was measured using a Wallac Victor 2TM (integration time set to 1 second) to analyze the inhibitory ability of the test material on JAK phosphorylation. Compared with the control group, the compound concentration at which 50% inhibition of JAK enzyme activity occurred was determined as the IC50 (nM) of the inhibitor. The results are shown in Table 1 below.

[0527] [Table 1]:

[0528]

[0529]

[0530] Industrial Applicability

[0531] Due to the protein kinase inhibitory activity, the compound represented by Formula 1 according to the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof has a remarkably excellent effect on preventing or treating protein kinase-related diseases, and thus can be expected to be valuable in the relevant pharmaceutical industry.

Claims

1. A compound represented by the following formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Formula 1] In formula 1, R1 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, or S(=O)2-C 1-6 alkyl; XYZ is C=CA2-NA5, N-CA2=CA3 or C=N-NA5; A2, A3 and A5 are each independently H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, or -C(=O)-NH-C 1-6 Haloalkyl; R2 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, or S(=O)2-C 1-6 alkyl; n and m are each independently 0, 1, 2 or 3; B1 is -C(=O)-; B2 is cyclopropyl; B3 is H; D1 is -NR3-; D2 is -C(=O)-; D3 is -NR3-, or single key; D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, phenyl, or 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; Among them C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Haloalkyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, phenyl, 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or cyano, C 3-7 At least one H in the cycloalkyl group or the 5- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 substituted with cyanoalkyl, cyano or halogen, and At least one H in the phenyl group or the 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 alkylthio, hydroxy, cyano, nitro or halogen substitution; and R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

2. The compound represented by Formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Formula 1 is a compound represented by the following Formula 2: [Formula 2] In formula 2, R1 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, or S(=O)2-C 1-6 alkyl; XYZ is C=CA2-NA5, N-CA2=CA3 or C=N-NA5; A2, A3 and A5 are each independently H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C(=O)-OH, C(=O)-OC 1-6 Alkyl, S(=O)2-C 1-6 Alkyl, or -C(=O)-NH-C 1-6 Haloalkyl; R2 is H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, hydroxy, cyano, halogen, C(=O)-OH, C(=O)-OC 1-6 Alkyl, or S(=O)2-C 1-6 alkyl; n and m are each independently 0 or 1; D2 is -C(=O)-; D3 is -NR3-, or single key; D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, phenyl, or 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, phenyl, 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or cyano, C 3-7 At least one H in the cycloalkyl group or the 5- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 substituted with cyanoalkyl, cyano or halogen, and At least one H in the phenyl group or the 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 alkylthio, hydroxy, cyano, nitro or halogen substitution; and R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

3. The compound represented by formula 1 according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R1 is H, C 1-6 Alkyl or C 1-6 Alkoxy; XYZ is C=CA2-NA5, N-CA2=CA3 or C=N-NA5; A2, A3 and A5 are each independently H, C 1-6 Alkyl or -C(=O)-NH-C 1-6 Haloalkyl; R2 is H or C 1-6 alkyl; n and m are each independently 0 or 1; D2 is -C(=O)-; D3 is -NR3-, or single key; D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, phenyl, or 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, phenyl, 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or cyano, C 3-7 At least one H in the cycloalkyl group or the 5- to 6-membered heterocycloalkyl group containing 1 to 4 atoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 cyanoalkyl or cyano substituted, and At least one H in the phenyl group or the 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, cyano, nitro or halogen substituted; and R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

4. The compound represented by formula 1 according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R1 is H; XYZ is N-CH=CH; R2 is H; n and m are each independently 0; D2 is -C(=O)-; D3 is -NR3-, or single key; D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, phenyl, or 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one H in the cyanoalkyl group may be substituted by a phenyl group, a 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, or a cyano group, C 3-7 At least one H in the cycloalkyl group or the 5- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S may be replaced by C 1-6 cyanoalkyl or cyano substituted, and At least one H in the phenyl group or the 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 Alkoxy, cyano, nitro or halogen substitution; and R3 and R4 are each independently H or C 1-6 alkyl.

5. The compound represented by formula 1 according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R1 is H, C 1-6 Alkyl or C 1-6 Alkoxy; XYZ is C=CA2-NA5; A2 and A5 are each independently H, C 1-6 Alkyl or -C(=O)-NH-C 1-6 Haloalkyl; R2 is H or C 1-6 alkyl; n and m are each independently 0 or 1; D2 is -C(=O)-; D3 is -NR3-, or single key; D4 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Cyanoalkyl, C 3-7 Cycloalkyl, 5- to 6-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, phenyl, or 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; Among them C 1-6 Alkyl, C 1-6 Alkenyl or C 1-6 At least one of the H atoms in the cyanoalkyl group may be replaced by a C 3-7 substituted by cycloalkyl, 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or cyano, C 3-7 At least one H in the cycloalkyl group or the 5- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S may be replaced by C 1-6 alkyl or cyano substituted, and At least one H in the phenyl group or the 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be replaced by C 1-6 Alkyl, C 1-6 haloalkyl or cyano substitution; and R3 and R4 are each independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

6. The compound represented by Formula 1 according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R1 is H; XYZ is C=N-NH; R2 is H; n and m are each independently 0; D2 is -C(=O)-; D3 is a single bond; D4 is C 1-6 Alkenyl, where C 1-6 At least one H in the alkenyl group may be substituted with a cyano group; and R3 is H.

7. A compound selected from the following compounds 1) to 63), their stereoisomers or their pharmaceutically acceptable salts:

8. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is used for preventing or treating protein kinase-related diseases.

10. The pharmaceutical composition according to claim 9, wherein the protein kinase-related disease is selected from cancer, autoimmune disease, neurological disease, metabolic disease and infection.

11. Use of the compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a Janus kinase-1 related disease.

12. The use according to claim 11, wherein the Janus kinase-1 related disease is selected from cancer, autoimmune disease, neurological disease, metabolic disease and infection.

13. The use according to claim 11, wherein the Janus kinase-1 related disease is selected from cancer, psoriasis, rheumatoid arthritis, lupus, inflammatory bowel disease, and chronic obstructive pulmonary disease.

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