RU2785734C1 - New compound as a protein kinase inhibitor and pharmaceutical composition containing said compound - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound by the formula 1, stereoisomers or pharmaceutically acceptable salts thereof exhibiting the ability to inhibit the activity of Janus kinase 1 (JAK1). In formula 1, R₁ constitutes H, a C_1-6alkyl, or a C_1-6alkoxy; X constitutes C-A₁ or N, Y constitutes C-A₂ or N-A₄, Z constitutes C-A₃ or N-A₅, wherein at least one from X, Y, and Z includes N; at least one bond between X and Y or bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, A₁ or A₄ is absent; each of substitutes from A₁ to A₄ independently constitutes H; A₅ independently constitutes H, a C_1-6alkyl, or a -C(=O)-NH-C_1-6halogenalkyl; R₂ constitutes H or a C_1-6alkyl; each of n and m independently equals 0, 1, 2, or 3; B₁ constitutes -C(=O)-; B₂ constitutes a C_3-7cycloalkyl; B₃ constitutes H; D₁ constitutes -NR₃-; D₂ constitutes -C(=O)-; D₃ constitutes -NR₃-,

,

, or a single bond; D₄ constitutes H, a C_1-6alkyl, a C_1-6alkenyl, a C_1-6halogenalkyl, a C_1-6cyanoalkyl, a C_3-7cycloalkyl, a 5-6-membered heterocycloalkyl, a C_1-6alkyl, wherein one H is substituted with methylpiperazine, a 6-membered aryl, or a 5-6-membered heteroaryl; wherein when D₄ constitutes a C_1-6alkyl wherein one H is substituted with methylpiperazine, then D₃ constitutes a single bond, where at least one H contained in the C_1-6alkyl or C_1-6alkenyl can be substituted with a C_3-7cycloalkyl, a 6-membered aryl, a 5-6-membered heteroaryl, or cyano, at least one H contained in the C_3-7cycloalkyl or 5-6-membered heterocycloalkyl can be substituted with a C_1-6alkyl or cyano, and at least one H contained in the 6-membered aryl or 5-6-membered heteroaryl can be substituted with a C_1-6alkyl, C_1-6alkoxy, C_1-6halogenalkyl, cyano or halogen; and each of R₃ and R₄ independently constitutes H or a C_1-6alkyl, and where the 5-6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S, the 5-6-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O, and S, and wherein the remaining ring atoms are carbon atoms. Invention also relates to a pharmaceutical composition containing said compounds, an application thereof for preventing or treating diseases associated with Janus kinase 1, and a method for preventing or treating diseases associated with Janus kinase 1.

EFFECT: creation of a compound applicable in treatment of diseases associated with Janus kinase 1.

14 cl, 1 tbl, 63 ex

Description

Technical field

The present invention relates to a novel compound as a protein kinase inhibitor, a pharmaceutical composition containing the same, and a pharmaceutical use thereof, wherein the compound inhibits the activity of a protein kinase as a phosphoenzyme and can therefore be effectively used to prevent or treat related diseases.

Prior Art

Protein kinases are enzymes that control various intracellular processes by phosphorylation of other proteins and thus by regulating the activity, position and function of proteins. Disruption of the control function of such protein kinases is closely related to the development mechanism of diseases such as cancer, autoimmune diseases, neurological diseases, metabolic diseases, infections and the like.

Janus kinase (JAK) is a kinase that plays a key role in the cytokine signaling system. JAK plays an important role in hematopoiesis, innate immunity and adaptive immunity and thus becomes an important target as a therapeutic agent for diseases such as cancer, autoimmune diseases, neurological diseases, metabolic diseases, infections and the like.

JAK is a protein that consists of about 1150 amino acids and has a molecular weight of about 120-130 kDa, and JAK is represented by four types: JAK1, JAK2, JAK3 and TYK2. JAK is located on the intracellular inflammatory cytokine receptor. Inflammatory cytokines (IL-2 (interleukin-2), IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, GM-CSF (granulocyte-macrophage colony stimulating factor), G-CSF (granulocyte colony stimulating factor), EPO (erythropoietin), TPO (thrombopoetin), IFN-a (IFN-alpha (tumor necrosis factor-alpha)), IFN-b (IFN-beta), IFN-g (IFN-gamma), and etc.) bind to receptors, which are then phosphorylated and then signal inflammatory cytokines to cells through interaction with STAT (signal transducer and transcription activator) molecules. Over-activation of signal transduction by these various inflammatory cytokines causes our body's immune system to attack its own body and thus leads to autoimmune diseases.

Thus, drug development for inhibiting the receptor kinase of such inflammatory cytokines is expected to reveal a stronger therapeutic effect against autoimmune diseases compared to existing therapeutic agents.

Disclosure of the essence of the invention

Technical problem

The object of the present invention is to provide a novel compound exhibiting protein kinase inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof.

It is also an object of the present invention to provide a process for the preparation of a compound of the present invention, stereoisomers thereof or pharmaceutically acceptable salts thereof.

In addition, the object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of diseases associated with protein kinase, containing the compound of the present invention, its stereoisomers or its pharmaceutically acceptable salts as an active ingredient.

Furthermore, it is an object of the present invention to provide a method for preventing or treating protein kinase-related diseases, comprising the step of administering to a subject a therapeutically effective amount of a compound of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

It is further an object of the present invention to provide the use of a compound of the present invention, stereoisomers thereof or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention or treatment of protein kinase related diseases.

Furthermore, it is an object of the present invention to provide the use of a compound of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof, for the prevention or treatment of protein kinase-associated diseases.

Solution

Protein kinase inhibitor compound and method for preparing the same

To solve the above problems according to the present invention proposed the compound of the following formula 1, its stereoisomers or its pharmaceutically acceptable salts:

In formula 1:

R ₁ 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, aryl or heteroaryl;

X is CA ₁ or N,

Y is C-A ₂ or NA ₄ ,

Z is C-A ₃ or N-A ₅ where at least one of X, Y and Z includes N;

at least one bond between X and Y or a bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, A ₁ or A ₄ is absent;

each of the substituents A ₁ to A ₅ is 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, -C(=O)-N-C _1-6 haloalkyl, aryl or heteroaryl;

R ₂ 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, aryl or heteroaryl;

each of n and m is independently 0, 1, 2, or 3;

B ₁ represents -C(=O)-, -C(=S)-, -C(=O)-NR ₃ - or a single bond;

B ₂ is C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl or heteroaryl;

B ₃ is H or C _1-6 alkyl;

D ₁ is -NR ₃ -;

D ₂ is -C(=O)-, -C(=S)-, -S(=O) ₂ - or a single bond;

или одинарную связь;D ₃ is -NR ₃ -,

or a single bond;

D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl or heteroaryl;

where at least one H in the composition of C _1-6 alkyl, C _1-6 alkenyl, C _1-6 haloalkyl or C _1-6 cyanoalkyl may be substituted with C _3-7 cycloalkyl, aryl, heteroaryl or cyano,

at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, cyano or halogen, and

at least one H in an aryl or heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 thioalkyl, hydroxy , cyano, nitro or halogen; and

each of R ₃ and R ₄ independently represents H, C _1-6 alkyl or C _1-6 haloalkyl.

According to one embodiment of the present invention, the compound of formula 1 may include one of the compounds of the following formula 1-1, formula 1-2 and formula 1-3:

In formulas:

R ₁ 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, aryl or heteroaryl;

each of the substituents A ₂ to A ₅ is 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, -C(=O)-N-C _1-6 haloalkyl, aryl or heteroaryl;

R ₂ 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, aryl or heteroaryl;

each of n and m is independently 0, 1, 2, or 3;

B ₁ represents -C(=O)-, -C(=S)-, -C(=O)-NR ₃ - or a single bond;

B ₂ is C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl or heteroaryl;

B ₃ is H or C _1-6 alkyl;

D ₁ is -NR ₃ -;

D ₂ is -C(=O)-, -C(=S)-, -S(=O) ₂ - or a single bond;

или одинарную связь;D ₃ is -NR ₃ -,

or a single bond;

D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl or heteroaryl;

where at least one H in the composition of C _1-6 alkyl, C _1-6 alkenyl, C _1-6 haloalkyl or C _1-6 cyanoalkyl may be substituted with C _3-7 cycloalkyl, aryl, heteroaryl or cyano,

at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, cyano or halogen, and

at least one H in an aryl or heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 thioalkyl, hydroxy , cyano, nitro or halogen; and

each of R ₃ and R ₄ independently represents H, C _1-6 alkyl or C _1-6 haloalkyl.

According to one embodiment of the present invention,

a compound of formula 1 may include a compound of the following formula 2:

In formula 2:

R ₁ 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, aryl or heteroaryl;

X is CA ₁ or N,

Y is C-A ₂ or N-A4,

Z is C-A ₃ or N-A ₅ where at least one of X, Y and Z includes N;

at least one bond between X and Y or a bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, A ₁ or A ₄ is absent;

each of the substituents A ₁ to A ₅ is 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, -C(=O)-N-C _1-6 haloalkyl, aryl or heteroaryl;

R ₂ 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)-O-C _1-6 alkyl, S(=O) ₂ -C _1-6 alkyl, aryl or heteroaryl;

each of n and m is independently 0 or 1;

D ₂ is -C(=O)-, -C(=S)-, -S(=O) ₂ - or a single bond;

или одинарную связь;D ₃ is -NR ₃ -,

or a single bond;

D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl;

where at least one H in the composition of C _1-6 alkyl, C _1-6 alkenyl or C _1-6 cyanoalkyl may be substituted with C _3-7 cycloalkyl, aryl, heteroaryl or cyano,

at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, cyano or halogen, and

at least one H in an aryl or heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, C _1-6 thioalkyl, hydroxy , cyano, nitro or halogen; and

each of R ₃ and R ₄ independently represents H, C _1-6 alkyl or C _1-6 haloalkyl.

According to another aspect of the embodiment of the present invention in formula 1:

R ₁ is H, C _1-6 alkyl or C _1-6 alkoxy;

X is CA ₁ or N,

Y is C-A ₂ or NA ₄ ,

Z represents C-A ₃ or N-A ₅ where at least one of X, Y and Z includes N;

at least one bond between X and Y or a bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, A ₁ or A ₄ is absent;

each of the substituents from A ₁ to A ₅ independently represents H, C _1-6 alkyl or -C(=O)-N-C _1-6 haloalkyl;

R ₂ is H, C _1-6 alkyl or C _1-6 heteroaryl;

each of n and m is independently 0 or 1;

D ₂ represents -C(=O)-;

или одинарную связь;D ₃ is -NR ₃ -,

or a single bond;

D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl;

where at least one H in the composition of C _1-6 alkyl, C _1-6 alkenyl or C _1-6 cyanoalkyl may be substituted with C _3-7 cycloalkyl, aryl, heteroaryl or cyano,

at least one H in C _3-7 cycloalkyl or 4-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl, C _1-6 cyanoalkyl or piano, and

at least one H in the aryl or heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or cyano; and

each of R ₃ and R ₄ independently represents H, C _1-6 alkyl or C _1-6 haloalkyl.

According to another aspect of the embodiment of the present invention in formula 1:

R ₁ is H;

X is N;

Y is C-A ₂ ;

Z is C-A ₃ ;

the bond between Y and Z is a double bond;

each of A ₂ and A ₃ independently represents H;

R ₂ is H;

each of n and m is independently 0;

D ₂ represents -C(=O)-;

или одинарную связь;D ₃ is -NR ₃ -,

or a single bond;

D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl;

where at least one H in the composition of C _1-6 alkyl, C _1-6 alkenyl or C _1-6 cyanoalkyl may be substituted by aryl, heteroaryl or cyano,

at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 cyanoalkyl or cyano, and

at least one H in aryl or heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, cyano, nitro, or halogen; and

each of R ₃ and R ₄ independently represents H or C _1-6 alkyl.

According to another aspect of the embodiment of the present invention in formula 1:

R ₁ is H, C _1-6 alkyl or C _1-6 alkoxy;

X is CA ₁ ;

Y is C-A ₂ ;

Z is N-A ₅ where at least one of X, Y and Z includes N;

the bond between X and Y is a double bond, and if the bond between X and Y is a double bond, A ₁ is absent;

each of A ₂ and A ₅ independently represents H, C _1-6 alkyl or —C(=O)-N-C _1-6 haloalkyl;

R ₂ is H or C _1-6 alkyl;

each of n and m is independently 0 or 1;

D ₂ represents -C(=O)-;

или одинарную связь;D ₃ is -NR ₃ -,

or a single bond;

D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl;

where at least one H in the composition of C _1-6 alkyl, C _1-6 alkenyl or C _1-6 cyanoalkyl may be substituted with C _3-7 cycloalkyl, heteroaryl or cyano,

at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl or cyano, and

at least one H in the aryl or heteroaryl may be substituted with C _1-6 alkyl, C _1-6 haloalkyl or cyano; and

each of R ₃ and R ₄ is independently H, C _1-6 alkyl, or C _1-6 haloalkyl.

According to another aspect of the embodiment of the present invention in formula 1:

R ₁ is H;

X is CA ₁ ;

Y is NA ₄ ;

Z is N-A ₅ ;

the bond between X and Y is a double bond;

each of A ₁ , A ₄ and A ₅ independently represents H;

R ₂ is H;

each of n and m is independently 0;

D ₂ represents -C(=O)-;

D ₃ is a single bond;

D ₄ is C _1-6 alkenyl, where at least one H in the C _1-6 alkenyl may be substituted with cyano; and

R ₃ is H.

In the present description, when determining the compounds of formula 1 and formula 2 use the following data. The following definitions also apply herein to terms used either alone or as part of a larger group, unless otherwise indicated.

The term "alkyl" means a straight, branched or cyclic hydrocarbon radical, respectively, when used alone or in combination with "heteroalkyl", in which each carbon atom may be optionally substituted with at least one of cyano, hydroxy, alkoxy, oxo, halogen, carbonyl, sulfonyl, cyanyl and so on.

The term "alkoxy" refers to -O-alkyl, in which alkyl is as defined above.

The term "heteroalkyl" means alkyl containing at least one heteroatom selected from N, O and S.

The term "aryl" means an aromatic group which includes phenyl, naphthyl, and so on, and may optionally be substituted with at least one of alkyl, alkoxy, halogen, hydroxy, carbonyl, sulfonyl, cyanyl, and so on.

The term "heteroaryl" refers to a 5-7 membered aromatic monocyclic ring containing at least one heteroatom, such as 1 to 4, or in some illustrative embodiments, 1 to 3 heteroatoms selected from N, O, and S, and in which the remaining ring atoms are carbon atoms; An 8-12 membered bicyclic ring containing at least one heteroatom, such as 1 to 4, or in some illustrative embodiments, 1 to 3 heteroatoms selected from N, O and S, and in which the remaining ring atoms are carbon atoms, at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and an 11-14 membered tricyclic ring containing at least one heteroatom, such as 1 to 4, or in some illustrative embodiments, 1 to 3 heteroatoms selected from N, O, and S, and in which the remaining ring atoms are carbon atoms , at least one ring is aromatic, and at least one heteroatom is present in the aromatic ring. An example of a heteroaryl group includes pyridyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, indolinyl, but not limited to pyrrolyl, thiophenyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, pyrrolopyridinyl, pyrazolopyridinyl, benzoxazolyl, benzothiazolyl, indazolyl, and 5,6,7,8-tetrahydroisoquinoline.

The term "heterocycloalkyl" refers to a structure that contains from 1 to 4 heteroatoms selected from N, O and S, may be optionally fused to benzo or cycloalkyl, and is saturated or partially saturated or aromatic. The corresponding heterocycloalkyl may include, for example, but is not limited to piperidinyl, piperazinyl, tetrahydrofuranyl, pyrrolidinyl, pyranyl, and so on.

The term "halo(gene)" means a substituent selected from fluorine, chlorine, bromine and

iodine.

Also, in formula 1, formulas 1-1 to 1-3 and formula 2, "n" means the number of substituents that can be substituted. If n is 0, it means that all hydrogen atoms have been replaced.

In addition, in the present invention, the expression that a monovalent substituent except for one hydrogen atom may be absent means "not present", and the expression that a divalent substituent except for two hydrogen atoms may be absent means "single bond".

In addition, the terms and abbreviations used in the present description have their original meanings, unless otherwise indicated.

In the present invention, examples of compounds of formula 1 are as follows:

At the same time, the compounds of the present invention may have an asymmetric carbon atom and may be in the form of R or S isomers, racemates, mixtures of diastereomers and individual diastereomers, and all isomers and mixtures are included in the scope of the present invention. In other words, if asymmetric(e) carbon atom(s) is included(s) in the structure of formula 1, it should be understood that it includes all stereoisomers, unless otherwise indicated.

The following describes a method for obtaining a compound of formula 2, which is one of the embodiments of formula 1, using an illustrative reaction scheme for a better understanding of the present invention. However, those skilled in the art to which the present invention pertains will appreciate that a compound of formula 1 or formula 2 can be prepared using various methods based on the structure of formula 1 or formula 2, and all such methods are included within the scope of the present invention. In other words, it should be understood that the compound of the present invention can be obtained by possibly combining various synthetic methods that are described in the present description or disclosed in the prior art, and this is within the scope of the present invention. In the following reaction scheme, all substituents are as defined above unless otherwise indicated.

As the acid, base, and reaction solvent used to prepare the compounds of the present invention, those commonly used in the art can be used without limitation. For example, the following can be used as the acid: inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and so on; 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, and so on; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, naphthalenesulfonic acid or the like. The following can be used as a base: NaH, K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ , K ₃ PO ₄ , KOH, NaOH, LiOH, n-BuLi, sec-BuLi, LiHMDS and so on. The following substances can be used as the reaction solvent: DCM (dichloromethane), THF (tetrahydrofuran), dioxane, MeOH, EtOH, hexane, EtOAC, ether, DMF (dimethylformamide), DMSO (dimethyl sulfoxide), toluene, xylene, etc. or mixtures of these solvents, and so on.

In one embodiment, the method for synthesizing a compound of formula 2 of the present invention can be illustrated using the following reaction scheme 1:

[Reaction Scheme 1]

In reaction scheme 1:

R ₁ , R ₂ , X, Y and Z are as defined in formula 2, where R ₁ can be substituted m times, and R ₂ can be substituted n times, where the type is as defined in formula 2;

A means a halogen atom, including F, Cl, Br, I, and the like; and

D is analogous to include the substituent sequence D ₂ -D ₃ -D ₄ as defined in formula 2, or D ₂ -D ₃ -D ₄ itself.

Reaction Scheme 1 in step 1 shows the preparation of compound (V) by reacting compound (IV) with N-bromosuccinimide (NBS).

Reaction Scheme 1 in step 2 shows the preparation of compound (VI) from compound (V) using bis(pinacolato)diboron.

Reaction Scheme 1 in step 3 shows the preparation of compound (VII) by reducing the NO ₂ group of compound (VI) to an NH ₂ group.

Reaction Scheme 1 in Step 4 shows the preparation of compound (VIII) by performing a Suzuki coupling reaction between compound (VII) and compound (III).

Reaction Scheme 1 in step 5 shows the preparation of compound (IX) which includes a derivative of compound (VIII).

In Reaction Scheme 1, Compound (III) can be synthesized by the method described in the following Reaction Scheme 1-1:

According to Reaction Scheme 1-1, compound (III) is obtained by reacting said compound (I) with compound (II).

In addition to the method described in reaction scheme 1, the synthesis can be carried out according to reaction scheme 2.

In one embodiment, the method for synthesizing a compound of formula 2 of the present invention can be illustrated by the following reaction scheme 2:

In reaction scheme 2:

R ₁ , R ₂ , X, Y and Z are as defined in formula 2, where R ₁ can be substituted m times, and R ₂ can be substituted n times, where the type is as defined in formula 2;

A means a halogen atom, including F, Cl, Br, I, and the like; and

D is analogous to include the substituent sequence D ₂ -D ₃ -D ₄ as defined in formula 2, or D ₂ -D ₃ -D ₄ itself.

Reaction Scheme 2 in Step 1 shows the preparation of compound (V) by carrying out an S _N Ar (aromatic nucleophilic substitution) reaction between compound (IV') and compound (III).

Reaction Scheme 2 in step 2 shows the preparation of compound (VI') by reducing the NO ₂ group of compound (V') to an NH ₂ group.

Reaction Scheme 2 in Step 3 shows the preparation of compound (VIII') which includes a derivative of compound (VII').

In reaction schemes 1 and 2, if the compound (IV) (in the case when X is CH) is used as the starting material, it is preferable to follow the reaction scheme 1. If the compound (IV') (in the case when X is NH) used as starting material, it is preferable to follow Reaction Scheme 2.

In Reaction Scheme 1, Reaction Scheme 1-1 or Reaction Scheme 2, compounds (I), (II), (IV) and (IV') can be purchased or synthesized in a conventional manner.

The compound of formula 1 of the present invention can be separated or purified from the products obtained by reaction schemes 1 and 2 using various methods such as crystallization, silica gel column chromatography, and so on. As such, the compound of the present invention, the starting material thereof, the intermediate, etc., can be synthesized by various methods, and it is to be understood that such methods are included within the scope of the present invention with respect to the preparation of the compound of formula 1.

Composition containing a compound of formula 1 and its use

The present invention provides a pharmaceutical composition and its use for the treatment or prevention of protein kinase related diseases, wherein said composition contains a compound of the following formula 1, stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient:

Formula 1 is as defined above.

As used herein, the term "prevention" refers to all actions that inhibit or delay the onset of protein kinase-associated diseases upon administration of a pharmaceutical composition of the present invention.

As used herein, the term "treatment" means all actions that alleviate or reverse the symptoms of protein kinase-associated diseases when a pharmaceutical composition of the present invention is administered.

The compound of formula 1 of the present invention, its stereoisomers or its pharmaceutically acceptable salts have a significant effect on the prevention or treatment of protein kinase-related diseases by demonstrating protein kinase inhibitory activity.

In the present invention, the protein kinase may be Janus kinase (JAK), but is not limited to this.

In the present invention, these diseases associated with protein kinase include cancer; autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, inflammatory bowel disease, chronic obstructive pulmonary disease, and so on; neurological diseases; metabolic diseases; or infections.

In the present invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, salts formed with inorganic ions such as calcium, potassium, sodium, magnesium and the like; inorganic acid salts formed with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid, sulfuric acid and the like; salts of organic acids formed by 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 and so on; sulfonic acid salts formed from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like; amino acid salts formed by glycine, arginine, lysine, and so on; amine salts formed by trimethylamine, triethylamine, ammonia, pyridine, picoline, and so on; and the like, but the kinds of salts contemplated in the present invention are not limited to the 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.

For its administration, the pharmaceutical composition of the present invention, in addition to the compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts, may additionally contain at least one kind of pharmaceutically acceptable carrier, and, if necessary, the addition of other conventional excipients such as antioxidants, buffers solutions, bacteriostatic agents and so on. Also, such a pharmaceutical composition can be made in such a way that diluents, dispersing agents, surfactants, binders and lubricants are additionally added to it.

The composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) in accordance with the intended method, in which its dosage varies within a certain range depending on the weight, age, sex, health and nutrition of the patient, time administration, route of administration, excretion rate, disease severity, and the like. The daily dose of the compound of formula 1 according to the present invention is from about 0.001 to 1000 mg/kg and can be administered once a day or divided into several doses.

In addition to the compound of formula 1, stereoisomers thereof, or pharmaceutically acceptable salts thereof, said pharmaceutical composition of the present invention may further contain at least one active ingredient which exhibits the same or similar therapeutic effect.

The present invention provides a method for preventing or treating protein kinase-related diseases, comprising administering to a subject a therapeutically effective amount of a compound of Formula 1, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

The term "subject" as used herein means a mammal, including humans, and "administration" means receiving a predetermined substance by a patient using any suitable method.

The term "therapeutically effective amount" as used herein refers to an amount of a compound of formula 1, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which is effective in preventing or treating protein kinase-related diseases.

The method for preventing or treating protein kinase-related diseases of the present invention includes not only combating the diseases themselves before their symptoms appear, but also suppressing or eliminating such symptoms by administering a compound of formula 1, stereoisomers thereof, or pharmaceutically acceptable salts thereof. In the treatment of diseases, the prophylactic or therapeutic dose of a particular active ingredient may vary depending on the nature and severity of the diseases or conditions and the route of administration of the active ingredient. The dose and frequency of its administration may vary depending on the age, weight and response of the individual patient. A suitable dosage and application can be readily selected by those skilled in the art, of course, taking into account such factors. Also, the method for preventing or treating protein kinase related diseases of the present invention may further comprise administering a therapeutically effective amount of an additional active agent that is useful in treating the disease along with a compound of Formula 1, stereoisomers thereof, or pharmaceutically acceptable salts thereof, and the additional active agent may show a synergistic effect or an additive effect together with the compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts.

For the manufacture of a medicament, a compound of formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof, may be combined with suitable adjuvants, diluents, carriers, etc., and may be formulated together with other active agents and thus have a synergistic effect of the active agents. components.

The objects mentioned in the use, composition and therapeutic method of the present invention are used in the same way, unless they contradict each other.

Useful effects of the invention

The compound of formula 1 of the present invention, its stereoisomers, or its pharmaceutically acceptable salts have a markedly superior effect in preventing or treating protein kinase-related diseases by demonstrating protein kinase inhibitory activity.

Method for carrying out the invention

Below are preferred examples for a better understanding of the present invention. However, the following examples are presented for the purpose of illustrating the present invention only, and thus the present invention is not limited to them. Upon receipt of the compounds of the present invention, the sequence of interactions can be changed accordingly. In other words, any reaction step may be carried out earlier than described here, or any substituent substitution may be introduced, and if necessary, any reagent other than that used in the examples may be used.

Various methods for the synthesis of the starting material are known for the synthesis of the compound of the present invention. If said starting material is commercially available, such material can be purchased and used from a supplier. Reagent suppliers include, but are not limited to, Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Combi-Blocks, Dae-Jung, and others. Also, all materials purchased were used without any further purification unless otherwise indicated.

First of all, the compounds used for the synthesis in the examples below were obtained as shown in the following production example. The following examples may be appropriately altered and modified by those skilled in the art within the scope of the present invention.

Example 1 Synthesis of N-(4-(7-(2-cyano-3-methylout-2-enamido)-1H-indol-3-yl)-pyridin-2-yl)cyclopropanecarboxamide

[Step 1] Synthesis of N-(4-bromoshfidin-2-yl)1-sclopropanecarboxamide

4-Bromopyridine-2-amine (2.0 g; 11.56 mmol) was dissolved in dichloromethane, after which pyridine (1.8 ml) and cyclopropanecarbonyl chloride (1.2 ml; 13.87 mmol) were added dropwise at 0° C and then stirred at this temperature for one hour. The reaction mixture was added to water (100 ml), after which the resulting solid was filtered and then dried under reduced pressure to obtain the title compound (2.1 g, 8.7 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99-11.14 (m, 1H), 8.33 (d, J=1.83 Hz, 1H), 8.22 (d, J=5.31 Hz, 1H), 7.29-7.42 (m, 1H), 1.94-2.07 (m, 1H), 0.83 (d, J=6.04 Hz, 4H).

MS ((mass spectrometry)(ESI (electrospray ionization)+) m/z 241, 243 (M+H) ⁺ .

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

7-Nitro-1H-indole (20 g; 123.3 mmol) was dissolved in dimethylformamide (1.2 L), after which sodium hydride (3.2 g; 135.6 mmol) was slowly added dropwise at 0°C, then tosyl chloride (26 g; 135.6 mmol) was slowly added dropwise and stirred for two hours. To the resulting mixture was added dichloromethane (300 ml), then washed with water (300 ml; twice), then dried with anhydrous magnesium sulfate, and then filtered, after which the resulting filtrate was distilled under reduced pressure. Ethyl ether was added to the resulting vacuum distilled filtrate, after which the resulting solid was filtered off and then dried under reduced pressure to give the title compound (21 g, 66.4 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J=3.66 Hz, 1H), 7.97 (d, J=7.68 Hz, 1H), 7.82 (d, J=7.87 Hz, 1H), 7.78 (d, J=8.42 Hz, 2H), 7.40-7.50 (m, 3H), 7.08 (d, J=3.66 Hz, 1H), 2.37 (s, 3H).

MS(ERI+) m/z 317 (M+H) ⁺ .

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

7-Nitro-1-tosyl-1H-indole (21 g; 66.4 mmol) was dissolved in acetonitrile (664 ml), after which N-bromosuccinimide (24 g; 132.78 mmol) was added and then heated to 50°C within 18 hours. The resulting mixture was cooled to room temperature, after which the resulting solid was filtered off and then dried under reduced pressure to give the title compound (24.9 g, 63 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44-8.51 (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).

MS(ERI+) m/z 395, 397 (M+H) ⁺ .

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

3-Bromo-7-nitro-1-tosyl-1H-indole (24.9 g; 63 mmol), dipinacolborane (32 g; 126 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (5, 2 g; 6.4 mmol), potassium acetate (12 g; 122.2 mmol) was 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, after which dichloromethane (300 ml) was added and then washed with distilled water (300 ml; twice). The separated organic layer was dried with anhydrous magnesium sulfate and then filtered, after which the resulting filtrate was distilled under reduced pressure. Separation was performed by column chromatography to give the title compound (16.9 g, 38.2 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (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).

MS(ERI+) m/z 443 (M+H) ⁺ .

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

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) followed by addition of iron (6.4 g; 114.6 mmol) and ammonium chloride (20 g; 382 mmol) and then heated to 80°C for three hours . The resulting mixture was cooled to room temperature, after which methanol was added and then filtered to remove iron. The resulting filtrate was distilled under reduced pressure and then separated by column chromatography to give the title compound (7.4 g, 17.9 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80-7.83 (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).

MS(ERI+) m/z 413 (M+H) ⁺ .

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

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole-7-amine (7.4 g; 17.9 mmol) was dissolved in solution of dimethylformamide in distilled water (2:1), after which was added N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (5.1 g; 21.48 mmol) obtained in step 1 of example 1, [1,1' -bis(diphenylphosphino)-ferrocene]dichloropalladium (2.2 g; 2.68 mmol) and potassium phosphate (4.7 g; 21.48 mmol) and then stirred at 100° C. for one hour. After completion of the reaction, this mixture was cooled to room temperature, after which water was added and extraction was performed with ethyl acetate. The solution of the extracted substances was dried with anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a residue as a result. The residue was separated by column chromatography to give the title compound (5 g, 11.2 mmol).

MS(ERI+) m/z 447 (M+H) ⁺ .

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

N-(4-(7-Amino-1-tosyl-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide (5 g; 11.2 mmol) was introduced into a mixture of tetrahydrofuran/methanol (1/1; 100 ml), after which 2 N. an aqueous solution of sodium hydroxide and then stirred at 30-40°C for three hours. After completion of the reaction, this mixture was cooled to room temperature, after which a saturated aqueous solution of NH ₄ Cl was added with stirring. The organic layer was extracted with dichloromethane and then concentrated under reduced pressure, after which the resulting residue was separated by column chromatography to obtain the title compound (2.7 g, 9.2 mmol).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.24 (br s, 1H), 10.71 (s, 1H), 8.53 (s, 1H), 8.22 (d, 1H, J=5.3 Hz), 7.90 (d, 1H, J=2.7 Hz), 7.37 (dd, 1H, J=1.3, 5.3 Hz), 7.22 (d, 1H, J=8.1 Hz), 6.88 (t, 1H , J=7.8 Hz), 6.42 (d, 1H, J=7.5 Hz), 1.9-2.1 (m, 1H), 0.8-0.9 (m, 4H).

MS(ERI+) m/z 293 (M+H) ⁺ .

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

1.5 equivalents 2-cyano-3-methylbut-2-enoic acid, 1.5 equivalents HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea) , 2 equivalents of DIPEA (N,N-diisopropylethylamine) and synthesized N-(4-(7-amino-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide (100 mg) were introduced into a dichloromethane solution and then stirred at room temperature. After completion of the reaction, H ₂ O was added to this mixture, followed by extraction with dichloromethane to separate the organic layer. After concentrating the mixture, the resulting concentrate was separated by column chromatography to obtain the product, i.e. N-(4-(7-(2-cyano-3-methylbut-2-enamido)-1H-indol-3-yl)-pyridine-2 -yl)cyclopropanecarboxamide.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 10.79 (br s, 1H), 10.34 (br d, 1H, J=0.9 Hz), 8.55 (br s, 1H), 8.27 (s, 1H) , 7.98 (br s, 1H), 7.42 (br d, 1Н, J=4.8 Hz), 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).

MS(ERI+) m/z 400 (M+H) ⁺ .

Examples 2-41

Further, the compounds of Examples 2-41 were obtained in the same way as shown in Example 1, but with the appropriate reagent, taking into account the reaction scheme 1 and the structure of the compound to be obtained.

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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, 1Н), 7.1-7.2 (m, 1H), 2.0-2.1 (m, 1H), 0.8-0.9 (m, 4Н).

MS(ERI+) m/z 433 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.04 (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).

MS(ERI+) m/z 403 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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=1.5 Hz), 7.36 (br s, 1H), 7.21 (br s, 1H), 2.0-2.1 (m, 1H), 0.8-0.9 (m, 4H ).

MS(ERI+) m/z 416 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) 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=4.0 Hz), 2.0-2.1 (m, 1H), 1.06 (s, 10H), 0.85 (br s, 4H), 0.7–0.7 (m, 1H).

MS(ERI+) m/z 425 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.48 (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=5.5 Hz), 7.96 (d, 1H, J=2.7 Hz), 7.82 (d, 1H, J=7.7 Hz), 7.67 (s, 2H), 7.3-7.5 (m, 2H), 7.25 (s, 1H), 7.17 (t, 1H, J=7.9 Hz), 2.33(m, 1H), 0.6-0.9 (m, 4H).

MS(ERI+) m/z 404 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.2-11.3 (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).

MS(ERI+) m/z 363 (M+H) ⁺ .

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

¹ H 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).

MS(ERI+) m/z 374 (M+H) ⁺ .

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

¹ H NMR (400 MHz, CHLOROFORM-d) δ 11.14-11.30 (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, 6Н), 1.95-2.06 (m, 1Н), 0.75-0.87 (m, 4Н).

MS(ERI+) m/z 414 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.37 (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).

MS(ERI+) m/z 360 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.3-11.4 (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=3.1 Hz), 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).

MS(ERI+) m/z 430 (M+H) ⁺ .

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

MS(ERI+) m/z 414 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.41 (br s, 1H), 10.79 (s, 1H), 9.92 (s, 1H), 8.55 (s, 1H 8.27 (d, 1H, J=5, 3 Hz), 8.01 (d, 1H, J=2.7 Hz), 7.76 (d, 1H, J=7.9 Hz), 7.54 (d, 1H, J=7.5 Hz), 7.41 (d, 1H, J=5.4 Hz), 7.14 (t, 1H, J=7.8 Hz), 2.72 (s, 2H), 2.0-2.1 (m, 1H), 1.2-1.2 (m, 4H), 0.8 -0.9 (m, 4H).

MS(ERI+) m/z 400 (M+H) ⁺ .

Example 14: Synthesis of N-(4-(7-(2-cyanopropanamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 10.80 (s, 1H), 10.23 (s, 1H), 8.55 (s, 1H), 8.27 (d, 1H, J=5.3 Hz), 8.02 ( d, 1H, J=2.9 Hz), 7.82 (d, 1H, J=8.1 Hz), 7.43 (d, 1H, J=5.4 Hz), 7.34 (d, 1H, J=7, 5 Hz), 7.1-7.2 (m, 1H), 1.99 (br d, 1H, J=7.3 Hz), 1.62 (d, 3H, J=7.3 Hz), 0.8-0.9 (m, 4H) .

MS(ERI+) m/z 374 (M+H) ^- .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.20 (br s, 1H), 10.76 (s, 1H), 10.28 (br s, 1H), 8.48 (br s, 1H), 8.27 (br d, 1H , J=5.7 Hz), 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).

MS(ERI+) m/z 414 (M+H) ^- .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.50 (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=5.3 Hz), 7.88 (br s, 1H), 7.65 (br s, 1H), 7.43 (br d, 1H, J =4.8 Hz), 7.32 (brs, 1H), 2.5-2.7 (m, 4H), 2.4-2.5 (m, 6H), 2.05 (brs, 1H), 0.7-0.9 (m, 4H).

MS(ERI+) m/z 427 (M+H) ^- .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11 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).

MS(ERI+) m/z 389 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.4-11.4 (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, 8Н), 0.8-0.9 (m, 4Н).

MS(ERI+) m/z 447 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12-11.27 (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, 1H), 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).

MS(ERI+) m/z 430 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11-11.26 (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, 1H), 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).

MS(ERI+) m/z 390 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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).

MS(ERI+) m/z 472 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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, 8.2 Hz), 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).

MS(ERI+) m/z 448 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.7-11.8 (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, 24, J=19 .4 Hz), 6.99 (br d, 1H, J=2.0 Hz), 6.2-6 2 (m, 1H), 2.0-2.1 (m, 1H), 0.8-0.9 (m, 4H).

MS(ERI+) m/z 386 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.4-11.5 (m, 1H), 10.7-10.8 (m, 1H), 10.34 (s, 1H), 8.8-8.9 (m, 1H), 8.58 (br s, 2Н), 8.2-8.3 (m, 1Н), 8.0-8.0 (m, 1Н), 7.8-7.9 (m, 1Н), 7.5-7.6 (m, 1Н), 7.4-7.5 (m, 2Н), 7.1-7.2 (m, 1H), 3.4-3.4 (m, 3H), 2.0-2.1 (m, 1H), 0.8-0.9 (m, 4H).

MS(ERI+) m/z 412 (M+H) ⁺ .

Example 25 Synthesis of (E)-N-(4-(7-(2-cyano-3-(thiophen-2-yl)acrylamido)-1H-indol-3-yl)pyridin-2-yl)cyclopropanecarboxamide

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.5 (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=19.0 Hz), 2.0-2.1 (m, 1H), 0.8-0.9 (m, 4H).

MS(ERI+) m/z 454 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.80 (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, 3Н), 2.01-2.08 (m , 1H), 1.16–1.26 (m, 6H), 0.78–0.87 (m, 4H).

MS(ERI+) m/z 414 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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=8.1 Hz), 8.07 (d, 2H, J=8.2 Hz), 8.00 (d, 1H, J=2.6 Hz) , 7.8-7.9 (m, 1H), 7.4-7.5 (m, 1H), 7.38 (d, 1H, J=7.5 Hz), 7.20 (s, 1H), 2.0-2.1 (m, 1H), 0.8 -0.9 (m, 4H).

MS(ERI+) m/z 422 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.53 (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=5.3 Hz), 7.99 (d, 1H, J=2.4 Hz), 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).

MS(ERI+) m/z 412 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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).

MS(ERI+) m/z 466 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.4-11.5 (m, 1H), 10.80 (s, 1H), 10.67 (s, 1H), 8.58 (s, 1H), 8.27 (s, 2H), 8.04 (d, 1H, J=1.8 Hz), 7.8-7.9 (m, 2H), 7.44 (br d, 2H, J=6.8 Hz), 7.21 (s, 1H), 2.0-2.1 (m , 1Н), 0.7–0.9 (m, 4Н).

MS(ERI+) m/z 434 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11 4-11.5 (m, 1H), 10.8-10.8 (m, 1H), 8.8-8.8 (m, 1H), 8.6-8.7 (m, 1H), 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).

MS(ERI+) m/z 416 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.61-8.69 (m, 1H), 8.31-8.39 (m, 1H), 8.26 (d, 1H, J=5.1 Hz), 8.12 (s, 1H ), 7.98 (br s, 2Н), 7.8-7.8 (m, 1Н), 7.62 (br d, 1H, J=1.1 Hz), 7.4-7.5 (m, 1H), 7.1-7 2 (m, 1H), 2.0-2.1 (m, 1H), 0.87 (br d, 4H, J=1.1 Hz).

MS(ERI+) m/z 433 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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=1.8 Hz), 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=2.4 Hz), 0.8-0.9 (m, 4H).

MS(ERI+) m/z 387 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.08 (s, 1H), 11.3-11.5 (m, 1H), 10.8-11.0 (m, 1H), 8.50 (br dd, 2H, J=2,l , 7.2 Hz), 8.26 (br d, 2H, J=5.5 Hz), 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).

MS(ERI+) m/z 428 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.6 (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).

MS(ERI+) m/z 423 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.5-11.5 (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=7.6 Hz), 0.85 (br d , 4H, J=14.3 Hz).

MS(ERI+) m/z 414 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.98 (br s, 1H), 10.79 (s, 1H), 8.58 (s, 1H), 8.2-8.3 (m, 2H), 8.03 (d, 1H, J=8.2 Hz), 7.96 (s, 1H), 7.44 (br d, 1H, J=5.3 Hz), 7.25 (t, 1H, J=8.0 Hz), 7.05 (d, 1H, J=7.7 Hz), 3.8-4.0 (m, 4H), 2.0-2.1 (m, 1H), 0.8-0.9 (m, 4H).

MS(ERI+) m/z 543 (M+H) ⁺ .

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

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.24 (br s, 1H), 10.71 (s, 1H), 8.53 (s, 1H), 8.22 (d, 1H, J=5.3 Hz), 7.90 (d, 1H, J=2.7 Hz), 7.37 (dd, 1H, J=1.3, 5.3 Hz), 7.22 (d, 1H, J=8.1 Hz), 6.88 (t, 1H , J=7.8 Hz), 6.42 (d, 1H, J=7.5 Hz), 1.9-2.1 (m, 1H), 0.8-0.9 (m, 4H).

MS(ERI+) m/z 415 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.21-11.33 (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), 7.65-7.71 (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).

MS(ERI+) m/z 418 (M+H) ⁺ .

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

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

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

MS(ERI+) m/z 181 (M+H) ⁺ .

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

4-Nitro-1H-indole (4.3 g; 26.6 mmol) was dissolved in dimethylformamide (50 ml), after which 60% NaH in oil (1.1 g; 26.6 mmol) was slowly added at 0 °C. The resulting mixture was stirred for 0.5 hour, then N-(4-fluoropyridin-2-yl)cyclopropanecarboxamide (4.0 g; 22.2 mmol) was added and the reaction mixture was stirred. After completion of the reaction, this mixture was stirred at room temperature, after which a saturated aqueous solution of NH ₄ Cl was added with stirring. The organic layer was extracted with dichloromethane and then concentrated under reduced pressure, after which the resulting residue was separated by column chromatography to obtain the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09-11.27 (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).

MS(ERI+) m/z 323 (M+H) ⁺ .

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

N-[4-(4-Nitroindol-1-yl)-2-pyridyl]cyclopropanecarboxamide (5 g; 15.5 mmol) was added to methanol (100 ml) followed by Pd/C (500 mg) and then stirred at 40-50°C in a hydrogen atmosphere for six hours. After completion of the reaction, this mixture was cooled to room temperature and then filtered through celite. The resulting filtrate was distilled under reduced pressure and then separated by column chromatography to give the title compound (3.9 g, 87%).

MS(ERI+) m/z 293 (M+H) ⁺ .

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04-11.12 (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).

MS(ERI+) m/z 400 (M+H) ⁺ .

Examples 41-62

Further, the compounds of Examples 41-62 were obtained in the same way as shown in Example 40, but with the appropriate reagent, taking into account the reaction scheme 2 and the structure of the compound to be obtained.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99-11.17 (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).

MS(ERI+) m/z 360 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.67-11.80 (m, 1H), 10.98-11.13(m, 1H), 9.66-9.81 (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).

MS(ERI+) m/z 386 (M+H) ⁺ .

Example 43 Synthesis of N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)-2-methylthiazol-5-carboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.02-11.14 (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=4.76 Hz, 4H).

MS(ERI+) m/z 418 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (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).

MS(ERI+) m/z 433 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.71-12.87 (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).

MS(ERI+) m/z 428 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMS0-d ₆ ) δ 11.02-11.12 (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), 7.76-7.83 (m, 1H), 7.61-7.70 (m, 1H), 7.45-7.50 (m, 1H), 7.34-7.42 (m, 2Н), 7.24-7.33 (m, 1H), 6.85-6.93 (m, 1H), 2.00-2.13 (m, 1H), 0.73-0.92 (m, 4Н).

MS(ERI+) m/z 454 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04-11.14 (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).

MS(ERI+) m/z 422 (M+H) ⁺ .

Example 48: Synthesis of N-(4-(4-(2-cyano-3-phenylacrylamido)-1H-indol-1-yl)-pyridin-2-yl)cyclopropanecarboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.05-11.14 (in, 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).

MS(ERI+) m/z 448 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04-11.12 (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

MS(ERI+) m/z 450 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 10.22-10.38 (m, 1H), 8.37-8.49 (m, 2H), 7.79 (d, J=3.48 Hz, 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=3.48 Hz, 1H ), 3.99 (br d, J=11.89 Hz, 2H), 3.54-3.68 (m, 2H), 2.12-2.29 (m, 4H), 1.99-2.10 (m, 1H), 0.86 (br d, J =4.03 Hz, 4H).

MS(ERI+) m/z 430 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.03-11.15 (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).

MS(ERI+) m/z 423 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.01-11.16 (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).

MS(ERI+) m/z 416 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (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=3.48 Hz, 2H), 7.70-7.76 (m, 1H), 7.64 (d, J=8.42 Hz, 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=4.21 Hz, 4H).

MS(ERI+) m/z 434 (M+H) ⁺ .

Example 54 Synthesis of N-(4-(4-(2-cyanopropanamido)-1H-indol-1-yl)pyridin-2-yl)cyclopropanecarboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (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=7.14 Hz, 3H), 0.85 (br s, 4H).

MS(ERI+) m/z 374 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99-11.18 (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).

MS(ERI+) m/z 387 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.01-11.17 (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, 1H), 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=3.84 Hz, 4H).

MS(ERI+) m/z 445 (M+H) ⁺ .

Example 57 Synthesis of (1R,2S)-2-cyano-N-(1-(2-(cyclopropanecarboxamido)pyridin-4-yl)-1H-indol-4-yl)cyclopropan-1-carboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97-11.19 (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=3.84 Hz, 4H).

MS(ERI+) m/z 386 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00-11.10 (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 (brs, 4H).

MS(ERI+) m/z 400 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.99-11.14 (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), 2.5S(s, 3H), 2.02-2.11 (m, 1H), 1.22-1.31 (m, 5H), 0.80-0.92 (m, 4H).

MS(ERI+) m/z 412 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97-11.15 (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).

MS(ERI+) m/z 389 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98-9.08 (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=4.39 Hz, 4H).

MS(ERI+) m/z 448 (M+H) ⁺ .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (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, 2Н), 7.12-7.23 (m, 1H), 6.93-7.05 (m, 1H), 6.73-6.90 (m, 3Н), 3.93-4.08 (m, 2Н), 3.84 (m, 4Н), 1.98 -2.09 (m, 1H), 0.78-0.93 (m, 4H).

MS(ERI+) m/z 418 (M+H) ⁺ .

Further, the compound of Example 63 was obtained by carrying out the synthesis in the same manner as shown in Example 1, or using an appropriate reagent, taking into account the reaction scheme 1 and the structure of the compound to be obtained.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.25-11.42 (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).

MS(ERI+) m/z 401 (M+H) ⁺ .

Experimental Example 1: JAK1 Activity Inhibitory Assay (ADP-Glo™ Kinase assay)

The inhibitory effect of the compound of the invention against JAK was determined as follows.

Control substance and test substance were prepared by dilution at each concentration using DMSO. ATP (adenosine triphosphate) (250 μM) and JAK substrate (JAK1, IRS-ltide 40 ng/ml) were prepared simultaneously by dilution in kinase buffer (40 mM Tris-HCl (tris(hydroxymethyl)aminomethane) pH 7.5, 20 mM MgCl ₂ , 0.5 mg/ml BSA (bovine serum albumin), 50 μM DTT (dithiothreitol)).

The test drug for each concentration, substrate, ATP and JAK enzymes were mixed in an Eppendorf tube and then reacted in an incubator at 30° C. for 40 minutes.

The ADP-Glo® reagent included in the ADP-GloTM Kinase Enzyme System (Promega, USA, V9571) was added to each Eppendorf tube and then reacted in an incubator at 30° C. for 40 minutes.

The kinase detection reagent included in the ADP-GloTM Kinase Enzyme System was placed in an Eppendorf tube, after which the luminescence was measured using a Wallac Victor 2TM analyzer with an integration time set to 1 second, and the inhibitory ability of the test substance against JAK phosphorylation was analyzed. The concentration of the compound at which 50% inhibition of JAK enzyme activity occurs compared to the control group was defined as the IC50 (nM) of the inhibitor. The results are presented in the following Table 1.

Industrial Applicability

The compound of formula 1 of the present invention, its stereoisomers, or its pharmaceutically acceptable salts, has a markedly superior effect in preventing or treating protein kinase-related diseases by exhibiting protein kinase inhibitory activity, and thus can be expected to be extremely useful when used in the related pharmaceutical industry.

Claims (146)

1. The compound of the following formula 1, its stereoisomers or its pharmaceutically acceptable salts

where in formula 1 R ₁ is H, C _1-6 alkyl or C _1-6 alkoxy; X is CA ₁ or N, Y is C-A ₂ or NA ₄ , Z represents SA ₃ or NA ₅ where at least one of X, Y and Z includes N; at least one bond between X and Y or a bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, A ₁ or A ₄ is absent; each of the substituents A ₁ to A ₄ independently represents H; A ₅ is independently H, C _1-6 alkyl or -C(=O)-NH-C _1-6 haloalkyl; R ₂ is H or C _1-6 alkyl; each of n and m is independently 0, 1, 2, or 3; B ₁ represents -C(=O)-; B ₂ is C _3-7 cycloalkyl; B ₃ is H; D ₁ is -NR ₃ -; D ₂ represents -C(=O)-; D ₃ is -NR ₃ -,

,

or a single bond; D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, C _1-6 alkyl, in in which one H is substituted with methylpiperazinyl, 6-membered aryl or 5-6-membered heteroaryl; where when D ₄ is C _1-6 alkyl in which one H is substituted with methylpiperazinyl then D ₃ is a single bond, where at least one H in the composition of C _1-6 alkyl or C _1-6 alkenyl may be substituted with C _3-7 cycloalkyl, 6-membered aryl, 5-6-membered heteroaryl or cyano, at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl or cyano, and at least one H in the 6-membered aryl or 5-6-membered heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, cyano or halogen; and each of R ₃ and R ₄ is independently H or C _1-6 alkyl, and where the 5-6 membered heterocycloalkyl contains from 1 to 3 heteroatoms selected from N, O and S, the 5-6 membered heteroaryl contains from 1 to 3 heteroatoms selected from N, O and S, and in which the remaining ring atoms are carbon atoms. 2. The compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where the compound of the above formula 1 is one of the compounds of the following formulas 1-1, 1-2 and 1-3:

where in formulas R ₁ is H, C _1-6 alkyl or C _1-6 alkoxy; each of the substituents A ₁ to A ₄ independently represents H; A ₅ is independently H, C _1-6 alkyl or -C(=O)-NH-C _1-6 haloalkyl; R ₂ is H or C _1-6 alkyl; each of n and m is independently 0, 1, 2, or 3; B ₁ represents -C(=O)-; B ₂ is C _3-7 cycloalkyl; B ₃ is H; D ₁ is -NR ₃ -; D ₂ represents -C(=O)-; D ₃ is -NR ₃ -,

,

or a single bond; D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, C _1-6 alkyl, in in which one H is substituted with methylpiperazinyl, 6-membered aryl or 5-6-membered heteroaryl; where when D ₄ is C _1-6 alkyl in which one H is substituted with methylpiperazinyl then D ₃ is a single bond, where at least one H in the composition of C _1-6 alkyl or C _1-6 alkenyl may be substituted with C _3-7 cycloalkyl, 6-membered aryl, 5-membered heteroaryl or cyano, at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl or cyano, and at least one H in the 6-membered aryl or 5-6-membered heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, cyano or halogen; and each of R ₃ and R ₄ is independently H or C _1-6 alkyl, and where the 5-6 membered heterocycloalkyl contains from 1 to 3 heteroatoms selected from N, O and S, the 5-6 membered heteroaryl contains from 1 to 3 heteroatoms selected from N, O and S, and in which the remaining ring atoms are carbon atoms. 3. The compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where the compound of formula 1 is a compound of the following formula 2:

where in formula 2 R ₁ is H, C _1-6 alkyl or C _1-6 alkoxy; X is CA ₁ or N, Y is C-A ₂ or NA ₄ , Z represents SA ₃ or NA ₅ where at least one of X, Y and Z includes N; at least one bond between X and Y or a bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, A ₁ or A ₄ is absent; each of the substituents A ₁ to A ₄ independently represents H; A ₅ is independently H, C _1-6 alkyl or —C(=O)-NH—C _1-6 haloalkyl; R ₂ is H or C _1-6 alkyl; each of n and m is independently 0 or 1; D ₂ represents -C(=O)-; D ₃ is -NR ₃ -,

,

or a single bond; D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, C _1-6 alkyl, in which one H is substituted by methylpiperazinyl, 6-membered aryl or 5-6-membered heteroaryl; where when D ₄ is C _1-6 alkyl in which one H is substituted with methylpiperazinyl then D ₃ is a single bond, where at least one H in the composition of C _1-6 alkyl or C _1-6 alkenyl may be substituted with C _3-7 cycloalkyl, 6-membered aryl, 5-6-membered heteroaryl or cyano, at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl or cyano, and at least one H in the 6-membered aryl or 5-6-membered heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, cyano or halogen; and each of R ₃ and R ₄ independently represents H or C _1-6 alkyl. 4. The compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where R ₁ is H, C _1-6 alkyl or C _1-6 alkoxy; X is CA ₁ or N, Y is C-A ₂ or N-A ₄ , Z represents SA ₃ or NA ₅ where at least one of X, Y and Z includes N; at least one bond between X and Y or a bond between Y and Z is a double bond, and if the bond between X and Y is a double bond, A ₁ or A ₄ is absent; each of the substituents A ₁ to A ₄ independently represents H; A ₅ is independently H, C _1-6 alkyl or —C(=O)-NH—C _1-6 haloalkyl; R ₂ is H or C _1-6 alkyl; each of n and m is independently 0 or 1; D ₂ represents -C(=O)-; D ₃ is -NR ₃ -,

,

or a single bond; D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, C _1-6 alkyl, in which one H is substituted by methylpiperazinyl, 6-membered aryl or 5-6-membered heteroaryl; where when D ₄ is C _1-6 alkyl in which one H is substituted with methylpiperazinyl then D ₃ is a single bond, where at least one H in the composition of C _1-6 alkyl or C _1-6 alkenyl may be substituted with C _3-7 cycloalkyl, 6-membered aryl, 5-6-membered heteroaryl or cyano, at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl or cyano, and at least one H in the 6-membered aryl or 5-6-membered heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl or cyano; and each of R ₃ and R ₄ independently represents H or C _1-6 alkyl. 5. The compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts according to claim 4, where R ₁ is H; X is N; Y is C-A ₂ ; Z is C-A ₃ ; the bond between Y and Z is a double bond; each of A ₂ and A ₃ independently represents H; R ₂ is H; each of n and m is independently 0; D ₂ represents -C(=O)-; D ₃ is -NR ₃ -,

,

or a single bond; D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, 6 membered aryl, or 5-6 membered heteroaryl; where at least one H in the composition of C _1-6 alkyl or C _1-6 alkenyl may be substituted by 6-membered aryl, 5-6 membered heteroaryl or cyano, at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with cyano, and at least one H in the 6-membered aryl or 5-6-membered heteroaryl may be substituted with C _1-6 alkyl, C _1-6 alkoxy, cyano or halogen; and each of R ₃ and R ₄ independently represents H or C _1-6 alkyl. 6. The compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts according to claim 4, where R ₁ is H, C _1-6 alkyl or C _1-6 alkoxy; X is CA ₁ ; Y is C-A ₂ ; Z is NA ₅ where at least one of X, Y and Z includes N; the bond between X and Y is a double bond, and if the bond between X and Y is a double bond, A ₁ is absent; each of the substituents A ₂ to A ₄ independently represents H; A ₅ is independently H, C _1-6 alkyl or —C(=O)-NH—C _1-6 haloalkyl; R ₂ is H or C _1-6 alkyl; each of n and m is independently 0 or 1; D ₂ represents -C(=O)-; D ₃ is -NR ₃ -,

or a single bond; D ₄ is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, 5-6 membered heterocycloalkyl, C _1-6 alkyl, in which one H is substituted by methylpiperazinyl, 6-membered aryl or 5-6-membered heteroaryl; where when D ₄ is C _1-6 alkyl in which one H is substituted with methylpiperazinyl then D ₃ is a single bond, where at least one H in the composition of C _1-6 alkyl or C _1-6 alkenyl may be substituted with C _3-7 cycloalkyl, 5-6 membered heteroaryl or cyano, at least one H in C _3-7 cycloalkyl or 5-6 membered heterocycloalkyl may be substituted with C _1-6 alkyl or cyano, and at least one H in the 6-membered aryl or 5-6-membered heteroaryl may be substituted with C _1-6 alkyl, C _1-6 haloalkyl or cyano; and each of R ₃ and R ₄ independently represents H or C _1-6 alkyl. 7. The compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts according to claim 4, where R ₁ is H; X is CA ₁ ; Y is NA ₄ ; Z is NA ₅ ; the bond between X and Y is a double bond; each of A ₁ , A ₄ and A ₅ independently represents H; R ₂ is H; each of n and m is independently 0; D ₂ represents -C(=O)-; D ₃ is a single bond; D ₄ is C _1-6 alkenyl, where at least one H in the C _1-6 alkenyl may be substituted with cyano; and R ₃ is H. 8. The compound of formula 1, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where the compound is selected from the group consisting of the following compounds:

9. Pharmaceutical composition with the ability to inhibit the activity of Janus kinase 1 (JAK1), containing a therapeutically effective amount of the compound according to any one of paragraphs. 1-8, its stereoisomers or its pharmaceutically acceptable salts as an active ingredient and a pharmaceutically acceptable carrier. 10. A pharmaceutical composition according to claim 9 for the prevention or treatment of Janus kinase 1 related diseases. 11. The pharmaceutical composition of claim 10 wherein the Janus kinase 1 related diseases are selected from the group consisting of cancer, autoimmune diseases, neurological diseases, metabolic diseases and infections. 12. The use of a compound according to any one of paragraphs. 1-8, stereoisomers thereof, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the prevention or treatment of Janus kinase 1 related diseases in a therapeutically effective amount. 13. A method for preventing or treating Janus kinase 1 related diseases, comprising the step of administering to a subject a therapeutically effective amount of a compound according to any one of paragraphs. 1-8, its stereoisomers or its pharmaceutically acceptable salts. 14. The use of a compound according to any one of paragraphs. 1-8, stereoisomers thereof, or pharmaceutically acceptable salts thereof, for the prevention or treatment of Janus kinase 1 related diseases in a therapeutically effective amount.