KR20200020622A - A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient - Google Patents

Abstract

The present invention relates to a substituted heteroaryl derivative, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating protein kinase-related diseases containing the same as an active component. The substituted heteroaryl derivative has excellent inhibitory activity on various protein kinases containing LRRK2. Therefore, the pharmaceutical composition containing the same as the active component can be usefully used for treating or preventing protein kinase-related diseases.

Description

A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient}

Substituted heteroaryl derivatives, methods for preparing the same, and pharmaceutical compositions for the prophylaxis or treatment of protein kinase related diseases containing the same as an active ingredient.

Protein kinases are enzymes that catalyze the reaction that transfers the terminal phosphate group of adenosine triphosphate (ATP) to specific residues of the protein (tyrosine, serine, threonine) .It is responsible for the activity, growth and differentiation of cells against changes in extracellular mediators and the environment. It is involved in the signal to regulate.

Inappropriately high protein kinase activity is directly or indirectly associated with many diseases resulting from abnormal cellular action. For example, disease may be caused by mutations, over-expression, or failure of the proper regulation of kinases involved in inappropriate enzyme activity, or by the production of excess or deficiency of factors involved in signal transduction upstream or downstream of cytokines or kinases. Can be. Thus, selective inhibition of kinase activity may be a beneficial target of drug development for disease treatment.

Brain cancer is a generic term for primary brain cancers that occur in brain tissue and the brain envelope that surrounds the brain, and secondary brain cancers that have metastasized from cancers that occur in the skull or other parts of the body. Such brain cancer is often distinguished from cancers occurring in other organs. First, lung, stomach, and breast cancers occur in one or two types of organs, and their properties are the same and similar. However, the brain develops a wide variety of cancers. For example, glioblastoma multiforme, malignant gliomas, lymphomas, germ cell tumors, metastatic tumors, and the like.

Parkinson's disease is the result of chronic progressive degeneration of neurons, but the cause is not yet fully understood. Parkinson's disease is characterized by the degeneration of dopaminergic neurons of substantia nigra (SN), although the main cause is unknown. Melanoma is the brain stem or part of the lower brain that helps control the unconscious movement. Dopamine deficiency in the brain due to the loss of these neurons is known to cause observable symptoms. Clinically, Parkinson's disease appears in the form of major symptoms of resting tremor, rigidity, bradykinesia and postural instability. Levodopa, dopamine agonists (eg, rotigotine, pramipexole, bromocriptine, ropinillol, cabergoline, as well as MAO-B inhibitor selegiline and COMT inhibitor entacapone), Pergolides, apomorphine and lyslides), anticholinergic agents, NMDA antagonists and β-blockers are used as drugs to alleviate motor symptoms. Most of these agents are involved in dopamine and / or choline signalling, which affects the typical dyskinesia symptoms of Parkinson's disease. (Patent Document 1: Republic of Korea Patent Publication 10-2009-0117830)

LRRK2 (leucin-rich repeat kinase-2) belongs to the leucin-rich repeat kinase family and consists of 2527 amino acid sequences with high similarity between species. It has both GTPase and Serine-threonine kinase activity. The expressed LRRK2 is observed in various organs and tissues including the brain, and is known to exist in the cytoplasm or cell membrane and mitochondrial outer membrane at the cellular level. Currently, research on the exact in vivo function of LRRK2 is being actively conducted. As it has 5 functionally important domains, cells through autophosphorylation and protein interaction and enzymatic activity Function regulation is expected, especially chaperone machinery, cytoskelecton arrangement, protein translational machinery, synaptic vesicle endocytosis, mitogen-activated protein kinase signaling Mitogen-activated protein kinases signaling cascades and ubiquitin / autophageprotein degradation pathways are known to be regulated by LRRK2.

Most Parkinson's disease occurs sporadically, but 5-10% of patients have a family history, and studies of these patient samples have revealed the locus of PARK 1-16 to date, and mutations in several loci have led to Parkinson's disease. The gene causing the disease has been identified. Parkinson's disease-causing genes caused by mutations are known as parkin, PINK1, DJ-1, α-synuclein, and LRRK2 (leucine-rich repeat kinase 2). Among them, the LRRK2 gene was first reported in 2004 as a dominant gene of the homologous chromosome like α-synuclein. Parkinson's disease patients with LRRK2 mutations, unlike other Parkinson's disease genes, have very similar symptoms to sporadic Parkinson's disease patients. The LRRK2 mutation is found in 1-2% of sporadic Parkinson's disease patients, as well as in patients with family history of Parkinson's disease. Identifying the mechanism of Parkinson's disease caused by mutations in this gene can be helpful in understanding the pathogenesis of Parkinson's disease and in developing therapeutics. .

In addition, LRRK2 is implicated in the imputation of mild cognitive impairment associated with Alzheimer's disease, L-Dopa induced dyskinesia, CNS disorders associated with neuronal progenitor differentiation, cancers such as brain cancer, kidney cancer, breast cancer, prostate cancer, blood cancer and lung cancer, and Compounds and compositions that are known to be associated with acute myeloid leukemia, papillary kidney and thyroid carcinoma, multiple myeloma, amyotrophic lateral sclerosis, rheumatoid arthritis and ankylosing spondylitis, are effective in controlling LRRK2 activity, including neurodegenerative diseases, CNS Therapeutic effects such as disorders, cancer, acute myeloid leukemia and multiple myeloma, and inflammatory diseases.

One object of the present invention is to provide substituted heteroaryl derivatives.

Another object of the present invention is to provide a method for preparing a substituted heteroaryl derivative.

Another object of the present invention to provide a pharmaceutical composition for the prophylaxis or treatment of protein kinase-related diseases.

In order to achieve the above object, according to an aspect of the present invention,

There is provided a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1, A ¹ is CH or N;

R ¹ and R ² are independently hydrogen or straight or branched C _1-6 alkyl, or R ¹ and R ² together with the carbon atom to which they are attached may form pyrrole, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF ₃ ;

R ³ is straight or branched C _1-10 alkyl, straight or branched C _2-10 alkenyl, straight or branched C _2-10 alkynyl or C _3-7 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C _1-6 alkoxy, respectively; And

는

또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 또는 6원자의 헤테로아릴이고, 이때, 상기 헤테로아릴은 직쇄 또는 분지쇄의 C_1-6알킬 또는 알콕시; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 8원자의 헤테로사이클로알킬 또는 헤테로사이클로알킬카보닐;로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고, 이때, 상기 알킬 및 알콕시는 CN으로 하나 이상 치환될 수 있고, 상기 헤테로사이클로알킬 및 헤테로사이클로알킬카보닐은 할로겐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 6원자의 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,

Is

Or 5 or 6 membered heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S, wherein the heteroaryl is straight or branched C _1-6 alkyl or alkoxy; And 3 to 8 atoms of heterocycloalkyl or heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of N, O, and S, and may be substituted with one or more substituents selected from the group consisting of , Wherein the alkyl and alkoxy may be substituted with one or more CN, and the heterocycloalkyl and heterocycloalkylcarbonyl are halogenated and 3 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S May be substituted with one or more substituents selected from the group consisting of heterocycloalkyl of

R ^a and R ^b are independently 3-8 membered heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of hydrogen, halogen or N, O and S, wherein the heterocycloalkylcarbon Neyl may be substituted with one or more substituents selected from the group consisting of halogen and 3 to 6 membered heterocycloalkyl including one or more heteroatoms selected from the group consisting of N, O and S, or R ^a and R ^b may form an unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are attached, wherein the substituted heterocycloalkyl is a straight chain Or one or more substituents selected from the group consisting of branched C _1-6 alkyl and oxo (═O). Can,

R ^c is hydrogen, halogen or straight or branched C _1-6 alkoxy).

According to another aspect of the present invention, as shown in Scheme 1, by reacting the compound represented by the formula (2) and the compound represented by the formula (3), to a compound represented by the formula (4) comprising the step of preparing a compound represented by the formula (4) Methods of making the compounds are provided:

Scheme 1

는 상기 화학식 1에서 정의한 바와 같고; 및 X¹은 할로겐이다). (In Scheme 1, R ¹ , R ² , R ³ , A ¹ And

Is as defined in Formula 1 above; And X ¹ is halogen).

According to another aspect of the present invention, there is provided a pharmaceutical composition for the prophylaxis or treatment of protein kinase-related diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the invention, there is provided a health functional food for the prevention or improvement of protein kinase-related diseases containing the compound represented by the formula (1), the optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, a protein kinase comprising administering to a subject in need thereof a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Methods of preventing or treating a disease are provided.

According to another aspect of the present invention, there is provided a use of a pharmaceutical composition or nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of a protein kinase related disease. do.

Since the compound represented by the formula (1), the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has excellent inhibitory activity against various protein kinases including LRRK2, the pharmaceutical composition containing the same as an active ingredient is a protein It can be usefully used for the treatment or prevention of kinase related diseases.

Figure 1 is a photograph showing the results of the inhibition of LRRK2 phosphorylation in 448T cell line of the compounds according to the present invention.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1, A ¹ is CH or N;

R ¹ and R ² are independently hydrogen or straight or branched C _1-6 alkyl, or R ¹ and R ² together with the carbon atom to which they are attached may form pyrrole, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF ₃ ;

R ³ is straight or branched C _1-10 alkyl, straight or branched C _2-10 alkenyl, straight or branched C _2-10 alkynyl or C _3-7 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C _1-6 alkoxy, respectively; And

는

또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 또는 6원자의 헤테로아릴이고, 이때, 상기 헤테로아릴은 직쇄 또는 분지쇄의 C_1-6알킬 또는 알콕시; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 8원자의 헤테로사이클로알킬 또는 헤테로사이클로알킬카보닐;로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고, 이때, 상기 알킬 및 알콕시는 CN으로 하나 이상 치환될 수 있고, 상기 헤테로사이클로알킬 및 헤테로사이클로알킬카보닐은 할로겐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 6원자의 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,

Is

Or 5 or 6 membered heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S, wherein the heteroaryl is straight or branched C _1-6 alkyl or alkoxy; And 3 to 8 atoms of heterocycloalkyl or heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of N, O, and S, and may be substituted with one or more substituents selected from the group consisting of , Wherein the alkyl and alkoxy may be substituted with one or more CN, and the heterocycloalkyl and heterocycloalkylcarbonyl are halogenated and 3 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S May be substituted with one or more substituents selected from the group consisting of heterocycloalkyl of

R ^a and R ^b are independently 3-8 membered heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of hydrogen, halogen or N, O and S, wherein the heterocycloalkylcarbon Neyl may be substituted with one or more substituents selected from the group consisting of halogen and 3 to 6 membered heterocycloalkyl including one or more heteroatoms selected from the group consisting of N, O and S, or R ^a and R ^b may form an unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are attached, wherein the substituted heterocycloalkyl is a straight chain Or one or more substituents selected from the group consisting of branched C _1-6 alkyl and oxo (═O). Can,

R ^c is hydrogen, halogen or straight or branched C _1-6 alkoxy.

In addition, in Formula 1, A ¹ is CH or N;

R ¹ and R ² are independently hydrogen or straight or branched C _1-4 alkyl, or R ¹ and R ² may form pyrrole with the carbon atoms to which they are attached, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF ₃ ;

R ³ is straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, straight or branched C _2-6 alkynyl or C _3-5 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C _1-4 alkoxy, respectively; And

는

,

,

,

,

및

이고,

Is

,

,

,

,

And

ego,

R ^d , R ^f , R ^g , R ⁱ , R ^j , R ^l , R ^r and R ^x are independently hydrogen, halogen or straight or branched C _1-6 alkyl or alkoxy, wherein said alkyl and Alkoxy may be substituted one or more with CN,

R ^e , R ^h and R ^k are independently 5 or 6 membered heterocycloalkyl or heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of N, O and S, wherein said hetero Cycloalkyl and heterocycloalkylcarbonyl may be substituted with one or more substituents selected from the group consisting of halogen and 3 to 6 membered heterocycloalkyl including one or more heteroatoms selected from the group consisting of N, O and S There is,

R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^v , and R ^w are each hydrogen or straight or branched C _1-6 alkyl, or R ^m , R ⁿ , R ^o Two of which are bonded to the same carbon of R ^p , R ^s , R ^t , R ^v , and R ^w may form carbonyl with the carbon to which they are attached,

R ^q and R ^u can be independently hydrogen or straight or branched C _1-6 alkyl.

In addition, in Formula 1, A ¹ is CH or N;

R ¹ and R ² are independently hydrogen or straight or branched C _1-2 alkyl, or R ¹ and R ² may form pyrrole with the carbon atom to which they are attached, wherein said alkyl is halogen One or more may be substituted, and said pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF ₃ ;

R ³ is straight or branched C _1-4 alkyl, straight or branched C _2-4 alkenyl, straight or branched C _2-4 alkynyl, cyclopropyl or cyclobutyl, said alkyl, alkenyl And alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C _1-2 alkoxy, respectively; And

는

,

,

,

,

및

이고,

Is

,

,

,

,

And

ego,

R ^d , R ^f , R ^g , R ⁱ , R ^j , R ^l , R ^r and R ^x are independently hydrogen, halogen or straight or branched C _1-3 alkyl or alkoxy, wherein said alkyl and Alkoxy may be substituted one or more with CN,

R ^e , R ^h and R ^k are independently morpholinyl, piperidinyl, morpholinylcarbonyl, piperazinylcarbonyl or piperidinylcarbonyl, wherein the morpholinyl, piperidinyl, Morpholinylcarbonyl piperazinylcarbonyl and piperidinylcarbonyl may be substituted with one or more substituents selected from the group consisting of halogen, morpholinyl and oxetanyl,

R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^v , and R ^w are each hydrogen or straight or branched C _1-3 alkyl, or R ^m , R ⁿ , R ^o Two of which are bonded to the same carbon of R ^p , R ^s , R ^t , R ^v , and R ^w may form carbonyl with the carbon to which they are attached,

R ^q and R ^u can be independently hydrogen or straight or branched C _1-3 alkyl.

In addition, in Formula 1, A ¹ is CH or N;

R ¹ and R ² are independently hydrogen or CF _3, or R ¹ and R ² may form pyrrole with the carbon atom to which they are attached, wherein pyrrole is from the group consisting of F, Cl, CN and CF ₃ May be substituted with one or more substituents selected;

R ³ is straight or branched C _1-4 alkyl, vinyl, ethynyl or cyclopropyl, said alkyl substituted with one or more substituents selected from the group consisting of hydroxyl and straight or branched C _1-2 alkoxy Can be; And

는

,

,

,

,

및

이고,

Is

,

,

,

,

And

ego,

이고,R ^d , R ^f , R ^g , R ⁱ , R ^j , R ^l , R ^r and R ^x are independently hydrogen, F, Cl, OMe or

ego,

,

,

또는

이고,R ^e , R ^h and R ^k are independently

,

,

or

ego,

R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^v , and R ^w are each hydrogen or methyl, or R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^{two of the v} , and R ^w bonded to the same carbon may form carbonyl together with the carbon to which they are attached,

R ^q and R ^u can be independently hydrogen or methyl.

In addition, in Formula 1, A ¹ is CH or N;

,

,

또는

를 형성할 수 있고;R ¹ and R ² are independently hydrogen or CF _3, or R ¹ and R ² together with the carbon atom to which they are attached

,

,

or

Can form;

R ³ is methyl, ethyl, i-propyl, t-butyl, i-butyl, hydroxyethyl, methoxyethyl, vinyl, ethynyl or cyclopropyl; And

는

,

,

,

,

,

,

,

,

,

,

,

,

,

또는

일 수 있다.

Is

,

,

,

,

,

,

,

,

,

,

,

,

,

or

Can be.

Examples of the compound represented by Formula 1 according to the present invention include the following compounds:

<1> (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( Morpholino) methanone; <2> (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( 4-morpholinopiperidin-1-yl); <3> (4-((4-cyclopropyl-5- (trifluoromethyl) -H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-fluoro-5- Methoxyphenyl) (morpholino) methanone; <4> 5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2-methyl Isoindolin-1-one; <5> 6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxy-2-methyl Isoindolin-1-one; <6> 6-chloro-5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-methyl is Bovine dollin-1-one; <7> 2- (5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -4-methylthiazole -2-yl) -2-methylpropanenitrile; <8> 7-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2, 2 , 4-trimethyl-2H-benzo [b] [1, 4] oxazin-3 (4H) -one; <9> N- (5-chloro-1-((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazole-4- Yl) -4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-amine; <10> (6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxypyridine-3 -Yl) (morpholino) methanone; <11> (6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxypyridine-3 -Yl) (4-morpholinylpyridin-1-yl) methanone; <12> 4-cyclopropyl-2-((2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbo Nitrile; <13> 4-cyclopropyl-2-((2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrid Midine-5-carbonitrile; <14> 4-cyclopropyl-2-((5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrid Midine-5-carbonitrile; <15> 4-cyclopropyl-2-((6-methoxy-2-methyl-1-oxoisoindol-5-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5- Carbonitrile; <16> 4-cyclopropyl-2-((6-methoxy-2-methyl-3-oxoisoindol-5-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5- Carbonitrile; <17> 2-((6-chloro-2-methyl-1-oxoisoindol-5-yl) amino) -4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidine-5-carbo Nitrile; 2-((2- (2-cyanopropan-2-yl) -4-methylthiazol-5-yl) amino) -4-cyclopropyl-7H-pyrrolo [2, 3-d] Pyrimidine-5-carbonitrile; <19> 4-cyclopropyl-2-((6-methoxy-2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazine -7-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbonitrile; <20> 4-cyclopropyl-2-((3-methoxy-5- (4-morpholinopiperidine-1-carbonyl) pyridin-2-yl) amino) -7H-pyrrolo [2, 3 -d] pyrimidine-5-carbonitrile; <21> (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methane On; <22> (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopi Ferridin-1-yl) methanone; <23> (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-fluoro-5-methoxyphenyl) ( Morpholino) methanone; 5-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2-methylisoindolin-1 -On; (4-((4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone; <26> (4-((4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidine-1 -Yl) methanone; <27> (4-((4-cyclopropyl-5-fluoro-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) Methanone; <28> (4-((4-cyclopropyl-5-fluoro-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morphopoly Nopiperidin-1-yl) methanone; <29> (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( 4- (oxetan-3-yl) piperazin-1-yl) methanone; <30> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (parent Polyno) methanone; <31> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (4 Morpholinopiperidin-1-yl); <32> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-fluoro-5-meth Methoxyphenyl) (morpholino) methanone; 5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -6-methoxy-2-methyl Bovinedan-1-one; 6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxy-2-methyl Bovine dollin-1-one; 6-chloro-5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-methylisoyne Dan-1-one; 5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-methylisoindolin-1- On; <37> (6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxypyridine-3- (I) (morpholino) methanone; (6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxypyridine-3- Yl) (4-morpholinylpiperidin-1-yl) methanone; 7-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -6-methoxy-2, 2, 4-trimethyl-2H-benzo [b] [1, 4] oxazin-3 (4H) -one; 2- (5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -4-methylthiazole- 2-yl) -2-methylpropanenitrile; <41> 4-cyclopropyl-6-((2-methoxy-4- (morpholin-4-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ; <42> 4-cyclopropyl-6-((5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine -3-carbonitrile; 4-cyclopropyl-6-((2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine -3-carbonitrile; 6-((6-methoxy-2-methyl-1-oxoisoindolin-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] pyridine-3-carbo Nitrile; <45> 6-((6-chloro-2-methyl-1-oxoisoindolin-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ; 4-cyclopropyl-6-((6-methoxy-2-methyl-3-oxoisoindol-5-yl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbo Nitrile; 4-Cyclopropyl-6-((3-methoxy-5- (morpholin-4-carbonyl) pyridin-2-yl) amino) -1H-pyrrolo [2, 3-b] pyridine- 3-carbonitrile; <48> 4-cyclopropyl-6-((3-methoxy-5- (4-morpholinopiperidin-1-carbonyl) pyridin-2-yl) amino) -1H-pyrrolo [2, 3 -b] pyridine-3-carbonitrile; 6-((2- (2-cyanopropan-2-yl) -4-methylthiazol-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] Pyridine-3-carbonitrile; <50> 4-cyclopropyl-6-((6-methoxy-2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazine -7-yl) amino) -2H-pyrrolo [2, 3-b] pyridine-3-carbonitrile; <51> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-fluoro-5-meth Methoxyphenyl) (4-morpholinopiperidin-1-yl) methanone; <52> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (4 -(Oxetan-3-yl) piperazin-1-yl) methanone; <53> 4-cyclopropyl-6-((5-fluoro-2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile; <54> 4-cyclopropyl-6-((2-methoxy-4- (4- (oxetan-3-yl) piperazin-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile; (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone; <4-> (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidin-1-yl) Methanone; (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxyphenyl) (morpholino) methanone; 5-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -6-methoxy-2-methylisoindolin-1-one.

The compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, Fluoride, Acetate, Propionate, Decanoate, Caprylate, Acrylate, Formate, Isobutyrate, Caprate, Heptanoate, Propiolate, Oxalate, Malonate, Succinate, Sube Latex, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexane-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro Zensulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and the excess acid may be distilled under reduced pressure, dried and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate). Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.

Another aspect of the present invention, as shown in Scheme 1 below, by reacting the compound represented by the formula (2) and the compound represented by the formula (3), the compound represented by the formula (1) comprising the step of preparing a compound represented by the formula (4) It provides a method for preparing the compound.

Scheme 1

는 상기 화학식 1에서 정의한 바와 같고; 및 X¹은 할로겐이다.In Scheme 1, R ¹ , R ² , R ³ , A ¹ and

Is as defined in Formula 1 above; And X ¹ is halogen.

Hereinafter, the manufacturing method according to the present invention will be described in detail.

The preparation method represented by Scheme 1 of the present invention is a step of reacting a substituted heteroaryl derivative represented by Chemical Formula 2 with a compound represented by Chemical Formula 3, specifically, halogen of the compound represented by Chemical Formula 2 and Chemical Formula 3 The amine of the compound represented by the reaction is a step of preparing a compound represented by the formula (1).

As an example of the preparation method, the reaction may be performed using the compound represented by the formula (2), the compound represented by the formula (3), and the base, and in some cases, a palladium catalyst may be further used as the metal catalyst. In this case, the base includes inorganic bases such as cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydride; Or N, N-diisopropylethylamine (DIPEA), 1, 8-diazabicyclo [5. 4. 0] -7-untetene (DBU), pyridine, triethylamine and other organic bases; and the like or equivalent, can be used alone or in combination. In addition, the palladium catalyst tris (dibenzylidene acetone) palladium (Pd ₂ (dba) ₃ ), tetrakis (triphenylphosphine) palladium (Pd (Ph ₃ P) ₄ ), palladium char (Pd-C ), Bis (triphenylphosphine) palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), [1, 1-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf)), allylpalladium chloride Dimers ([PdCl (allyl)] ₂ ), palladium acetate (Pd (OAc) ₂ ), palladium chloride (PdCl ₂ ), and the like. Furthermore, usable reaction solvents include toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, water, ethyl acetate, acetonitrile; Lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1, 2-dimethoxyethane and the like; Etc., and these may be used alone or in combination.

Another aspect of the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a protein kinase related disease containing the compound represented by Formula 1, the optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The protein kinase is AAK1, ABL1 (E255K) -phosphorylated. ABL1 (F317I) -nonphosphorylated, ABL1 (F317I) -phosphorylated, ABL1 (F317L) -nonphosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) (Q252H) -nonphosphorylated, ABL1 (Q252H) -phosphorylated, ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVRA, ACVRA ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF (V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2K, CAMK2D, , CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CHEKK, CHEKK2 , CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E , CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, DRAK1, DRAK2, DYRK1, DYRK2, DYRK2 -A750del), EGFR (G719C), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHB6 ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H) D835V), FLT3 (D835Y), FLT3 (ITD), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2 (Kin. Dom. 2, S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICK, IGF1R, IKK-alpha, IKK-beta, IKK-epson , INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domain-catalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2 (G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4AP2, MAP4AP2 , MAST1, MEK1, MEK2, MEK3, MEK4, MEK5, MEK6, MELK, MERTK, MET, MET (M1250T), MET (Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKA, MRCKA , MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK, MYLK, MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEKK, NEK9 , NIM1, NLK, OSR1, p38-alpha, p38-beta, p38- delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1 (P. falciparum), PFPK5 (P. falciparum), PFTAIRE2, PFTK1, PHKG1, PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA (C420R), PIK3CA (E542K), PIK3CA (E545A), PIK3CA (47545) (K5453) (H1047Y), PIK3CA (I800L), PIK3CA (M1043I), PIK3CA (Q546K), PIK3CB, PIK3CD, PIK3CG, PIK4CB, PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K2C, PIPK-K2C, PIP5-K2-C , PKMYT1, PKN1, PKN2, M. tuberculosis (PKNB), PLK1, PLK2, PLK3, PLK4, PRKCD, PRKCE, PRKCH, PRKCI, PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PKR, PRKX, PRKX4 QSK, RAF1, RET, RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK2, RIOK3, RIPK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4 (Kin.Dom. 1-N -terminal), RPS6KA4 (Kin. Dom. 2-C-terminal), RPS6KA5 (Kin. Dom. 1-N-terminal), RPS6KA5 (Kin. Dom. 2-C-terminal), RSK1 (Kin. Dom. 1) , N-terminal), RSK1 (Kin. Dom. 2-C-terminal), RSK2 (Kin. Dom. 1-N-terminal), RSK2 (Kin. Dom. 2-C-terminal), RSK3 (Kin. Dom 1-N-terminal), RSK3 (Kin. Dom. 2-C-terminal), RSK4 (Kin. Dom. 1-N-terminal), RSK4 (Kin. Dom. 2-C-terminal) ), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2, SRPK3, STK16, STK33, STK35, STK36, STK39, SYK1, TAK1, TAK1, TAK1 TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TRPM6, TSSK1B, TSSK3, TTK, TXK, TYdomain-2 catalytic), TYK2 (JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, YANK1, NKNK2, YANK3, YES, YSK1, It may be one or more selected from the group consisting of ZAP70.

In addition, the protein kinase-related disease may be at least one selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease. The degenerative brain disease may be at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, and mild cognitive impairment. The inflammatory diseases include dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, colitis, nephritis, systemic edema, local edema, arthritis, keratitis, bronchitis, pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, At least one member selected from the group consisting of cystitis, periodontitis, and gingivitis. The cancer may be brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, intracranial carcinoma, epithelial cell tumor, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal / sinus cancer, nasopharyngeal cancer , Salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small intestine Cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female At least one selected from the group consisting of urethral cancer, and skin cancer.

The compound is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1, CAMK1B, CAMKK2A, CAM2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, EPHA7, EPHALT, EPHALT3 (ITD, F691L), GAK, GCN2 (Kin.Dom. 2, S808G), HIPK2, HIPK3, HIPK4, HUNK, ICK, INSR, INSRR, JNK1, JNK2, JNK3, KIT, KIT (L576P), KIT (V559D) , KIT-autoinhibited, LRRK2, LRRK2 (G2019S), LTK, LYN, MAP3K15, MAP3K2, MAPKAPK2, MAPKAPK5, MEK3, MEK4, MEK5, MEK6, MKK7, MKNK2, MYLK, MYLK2, NIK, NIM1, OSIM38, PHKG1, PHKG2, PIK3C2B, PIK4CB, PIKFYVE, PIP5K1C, PIP5K2C, PLK1, PLK4, PRKCD, PRKD1, PRKD2, PRKD3, PYK2, RIPK4, RIPK5, RPS6KA4 (Kin.Dom. 1-N-terminal), RPS6KA5 (Kin. Dom. 2-C-terminal), RSK3 (Kin. Dom. 2-C-terminal), STK33, STK35, STK39, SYK, TEC, TNK2, TSSK1B, TTK, With TXK, YES, YSK4 and ZAP70 It can exhibit inhibitory activity against one or more kinases selected from the group consisting of.

Compound represented by the formula (1) of the present invention exhibits excellent inhibitory activity against LRRK2, LRRK2 (G2019S), DYRK1A, CLK1 kinase (see Experimental Example 1), so that the disease associated with LRRK2, LRRK2 (G2019S), DYRK1A, CLK1 kinase It can be usefully used as a pharmaceutical composition for treatment or prophylaxis.

In addition, the compound represented by Formula 1 of the present invention is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1 , CAMK1B, CAMK2A, CAMKK2, CHEK2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK1, EPBHA, EPBHA, EPAKHA , FER, FLT3 (D835V), FLT3 (ITD, F691L), GAK, GCN2 (Kin.Dom. 2, S808G), HIPK2, HIPK3, HIPK4, HUNK, ICK, INSR, INSRR, JNK1, JNK2, JNK3, KIT, KIT (L576P), KIT (V559D), KIT-autoinhibited, LRRK2, LRRK2 (G2019S), LTK, LYN, MAP3K15, MAP3K2, MAPKAPK2, MAPKAPK5, MEK3, MEK4, MEK5, MEK6, MKK7, MKNK2, NIKNK2 , NIM1, OSR1, p38-alpha, PHKG1, PHKG2, PIK3C2B, PIK4CB, PIKFYVE, PIP5K1C, PIP5K2C, PLK1, PLK4, PRKCD, PRKD1, PRKD2, PRKD3, PYK2, RIPK4, RIPK4, R6K4C Rin. -terminal), RPS6KA5 (Kin. Dom. 1-N-terminal), RPS6KA5 (Kin. Dom. 2-C-terminal), RSK3 (Kin. Dom. 2-C-terminal), STK33, STK35, STK39, SYK , TEC, TNK 2, the control percentage for TSSK1B, TTK, TXK, YES, YSK4, ZAP70 kinases is less than 35% control (see Experimental Example 2), indicating inhibitory activity against the enzymes listed above, thereby treating or treating the kinase related diseases. It can be usefully used as a prophylactic pharmaceutical composition.

In addition, the compound represented by the formula (1) according to the present invention can effectively be used as a pharmaceutical composition for the treatment or prevention of LRRK2-related diseases by effectively inhibiting LRRK2 phosphorylation in 448T cell line derived from brain tumor patients, in particular, brain cancer Or it may be usefully used as a pharmaceutical composition for treating or preventing Parkinson's disease.

When used in the treatment of cancer, the pharmaceutical composition of the present invention may be administered as a separate therapeutic agent or in combination with other anticancer agents in use.

Another aspect of the present invention, the prevention of a disease selected from the group consisting of cancer, inflammatory diseases and degenerative brain diseases containing the compound represented by the formula (1), optical isomers thereof, or a pharmaceutically acceptable salt thereof as an active ingredient Or it provides a pharmaceutical composition for treatment.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid form preparations include at least one excipient such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used.

Pharmaceutical compositions comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how to do it.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is an ampule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt, etc. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

According to another aspect of the invention, there is provided a health functional food for the prevention or improvement of protein kinase-related diseases containing the compound represented by the formula (1), the optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound represented by Chemical Formula 1 according to the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). In general, the amount of the compound in the health food can be added from 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene or health control, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.

In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Furthermore, in addition to the above, the compound represented by Chemical Formula 1 according to the present invention may be used in various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, such as flavoring agents, coloring agents and neutralizing agents (such as cheese and chocolate) Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. In addition, the compound represented by the formula (1) of the present invention may contain a fruit flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.

According to another aspect of the present invention, a protein kinase comprising administering to a subject in need thereof a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Methods of preventing or treating a disease are provided.

According to another aspect of the present invention, there is provided a use of a pharmaceutical composition or nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of a protein kinase related disease. do.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

Analysis and Purification Conditions

1. HPLC analysis conditions ( A )

Device Name: Shimadzu

Column: YMC-pack pro C18, 150x4.6mm I.D., 5 νm, 40 ° C

Mobile phase: 5%-> 100% acetonitrile / H ₂ O + 0.1% TFA,

Analysis time: 9 minutes, Flow rate: 1ml / min

UV detector: 254nm

2. HPLC analysis conditions ( B )

Instrument Name: Thermo Scientific Ultimate 3000RSLC

Column: Kinetex® 2.6 νM Biphenyl 100ÅA, 100x2.1mm

Mobile phase: 5%-> 100% acetonitrile / H ₂ O + 0.1% TFA,

Analysis time: 4.5 minutes, Flow rate: 1.2ml / min

UV detector: 254nm

3. LC-MS Analysis Conditions

Device Name: Shimadzu LCMS-2020

Column: ACE Excel2 C18, 75x2.1 mm

Mobile phase: Acetonitrile / H ₂ O + 0.1% TFA

Flow rate: 1mL / min

UV detector: 254nm

4. MPLC Purification Conditions

Device Name: CombiFlash®Rf +

UV detector: 254nm

5. Prep-HPLC Purification Conditions

Instrument name: Gilson GX-281, 321 pump, UV / VIS-155

Column: Luna® 10 νM C18 (2) 100 ÅA, 250x21.2 mm

Mobile phase: Acetonitrile / 0.1% TFA H2O

Flow rate: 15 mL / min

UV detector: 254nm

6. ¹ H NMR

Device name: Brucler Avance (400 MHz)

Example 1 (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl Preparation of (morpholino) methanone

Step 1: Preparation of 2, 4-dichloro-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyrimidine

Dissolve CuI (0.25 equiv), KF (3.0 equiv), 1,10-phenanthroline (0.25 equiv) in DMSO (0.25 M), and then trimethyl borate (3.0 equiv), 2,4-dichloro-5- (tri Fluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine (1.0 equiv), trimethyl (trifluoromethyl) silane (3 equiv) were added The temperature was raised to 60 ^° C. and stirred for 12 hours. The reaction was poured into iced water, and the organics were extracted with EtOAc (× 3). The collected organic layer was washed with brine, and then the remaining water was removed using Na ₂ SO ₄ . The reaction was purified through MPLC (EtOAc: Hex) to give the title compound as a yellow liquid. (Yield: 30%)

Step 2: 2-Chloro-4-cyclopropyl-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyrimidine Manufacture

2,4-dichloro-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine (3.0 equiv) , Dissolved in 4-dioxane (0.15 M), and then K ₃ PO ₄ (1.0 equiv), Ag ₂ O (1.0 equiv), Pd (dppf) Cl ₂ (0.1 equiv) and sonicated under nitrogen for 1 min. Gas was removed. The reaction was reacted at 130 ^° C. for 1 hour using microwave. The reaction mixture was filtered through celite and washed with EtOAc and MeOH. The filtrate obtained was concentrated and purified through MPLC (EtOAc: Hex) to give the title compound as a yellow liquid. (Yield: 48%)

Step 3: (4-((4-cyclopropyl-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyri) Preparation of midin-2-yl) amino) methoxyphenyl) (morpholino) methanone

Compound (1.0 equiv), (4-amino-3-methoxyphenyl) (morpholino) methanone (1.0 equiv) and K ₂ CO ₃ (5.0 equiv) prepared in step 2 were added to sec-BuOH (0.1 M). ), And then sonicated for 1 minute to remove the gas. Pd ₂ (dba) ₃ (0.1 equiv) and Xphos (0.1 equiv) were added to the reaction mixture at 100 ^° C., followed by reaction for 1 hour. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. After concentration of the filtrate obtained, the desired compound of the obtained yellow solid was used for the next step without further purification.

Step 4: (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( Preparation of morpholino) methanone

(4-((4-cyclopropyl-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyrimidine-2 -Yl) amino) methoxyphenyl) (morpholino) methanone (1.0 equiv) was dissolved in CH ₂ Cl ₂ (0.05 M) and then TFA (100 equiv) was added at room temperature. After 4 hours reaction, the solvent was removed. The concentrated mixture was again dissolved in THF (0.03 M) and sat. At room temperature. Na ₂ CO ₃ (0.03 M) was added and reacted for 14 hours. After the reaction, the resultant was diluted with EtOAc and washed sequentially with water and brine. The organic layer removed the remaining water with Na ₂ SO ₄ . The mixture was purified via prep-HPLC to give the title compound as a yellow liquid (yield: 35%).

Examples 2 to 28 were prepared in a similar manner to Example 1, and the chemical structures of Examples 1 to 28 are shown in Table 1 below, compound names, mass and UPLC analysis results are summarized in Table 2 below.

Example Chemical structure Example Chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

room
city
Yes Compound name ¹ H NMR, MS yield
(%) HPLC r.t. (min) (analysis condition) One (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino Methanone ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.67 (d, J = 8.28 Hz, 1H), 7.70 (s, 1H), 7.10 (s, 1H), 7.07-7.05 (m, 1H) , 3.99 (s, 3H), 3.79-3.59 (m, 8H), 2.53-2.48 (m, 1H), 1.38-1.35 (m, 2H), 1.28-1.25 (m, 2H); 462 [M + H] ⁺ 35 6.95
100%
(A) 2 (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-mo Polynopiperidin-1-yl) ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.69 (d, J = 8.16 Hz, 1H), 7.69 (s, 1H), 7.09-7.07 (m 2H), 4.11-3.98 (m, 3H ), 4.08 (s, 3H), 3.81-3.76 (m, 2H), 3.61-3.46 (m, 3H), 3.38-3.29 (m, 1H), 3.27-2.94 (m, 4H), 2.56-2.46 (m , 1H), 2.29-2.16 (m, 2H), 1.80-1.65 (m, 2H), 1.37-1.24 (m, 4H); 545 [M + H] ⁺ 34 5.51
100%
(A) 3 (4-((4-cyclopropyl-5- (trifluoromethyl) -H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-fluoro-5-methoxyphenyl (Morpholino) methanone ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 12.44 (s, 1H), 8.46 (d, J = 12.36 Hz, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.02 (d, J = 6.24 Hz, 1H), 3.91 (s, 1H), 3.64-3.56 (m, 8H), 2.37-2.32 (m, 1H), 1.25-1.23 (m, 2H), 1.17-1.15 ( m, 2H); 480 [M + H] ⁺ 23 7.36
99%
(A) 4 5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2-methylisoindolin -1-on ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 12.41 (s, 1H), 8.66 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.24 (s, 1H) , 4.40 (s, 2H), 3.97 (s, 3H), 3.06 (s, 3H), 2.36-2.35 (m, 1H), 1.25-1.24 (m, 2H), 1.15-1.13 (m, 2H); 418 [M + H] ⁺ 25 7.29
100%
(A) 5 6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxy-2-methylisoindolin -1-on ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 12.48 (s, 1H), 8.63 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H) , 4.38 (s, 2H), 3.97 (s, 3H), 3.06 (s, 3H), 2.37-2.29 (m, 1H), 1.24-1.23 (m, 2H), 1.14-1.11 (m, 2H); 418 [M + H] ⁺ 9 6.78
99%
A 6 6-chloro-5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-methylisoindolin- 1-on ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.92 (s, 1H), 7.77 (s, 1H), 7.67 (d, J = 1.08, 1H), 4.49 (s, 2H), 3.18 ( s, 3H), 2.50-2.49 (m, 1H), 1.35-1.29 (m, 4H); 422 [M + H] ⁺ 4 7.60
98%
(A) 7 2- (5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -4-methylthiazol-2- I) -2-methylpropanenitrile ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 12.28 (br s, 1H), 9.60 (br s, 1H), 7.86 (s, 1H), 2.36-2.29 (m, 4H), 1.77 ( s, 6H) 1.34-1.29 (m, 2H), 1.19-1.12 (m, 2H); 407 [M + H] ⁺ 40 7.77
97%
(A) 8 7-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2, 2, 4- Trimethyl-2H-benzo [b] [1, 4] oxazin-3 (4H) -one ¹ H NMR (400 MHz, TFA salt, DMSO- d ₄ ) δ 12.35-12.34 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 3.32 (s, 3H), 2.35-2.28 (m, 1H), 1.39 (s, 6H), 1.23-1.19 (m, 2H), 1.14-1.09 (m, 2H) ; 462 [M + H] ⁺ 8 7.99
98%
(A) 9 N- (5-Chloro-1-((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl)- 4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.09 (s, 1H), 7.54 (s, 1H), 5.24-5.11 (m, 1H), 4.81-4.76 (m, 4H), 4.51- 4.32 (m, 1H), 3.79-3.74 (m, 1H), 3.48-3.30 (m, 2H), 3.13-3.00 (m, 2H), 2.45-2.39 (m, 3H), 1.29-1.19 (m, 2H ), 1.13-1.09 (m, 2 H); 500 [M + H] ⁺ 25 5.67
100%
(A) 10 (6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxypyridin-3-yl) (Morpholino) methanone ¹ H NMR (400 MHz, MeOD) δ 8.04 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 4.07 (s, 3H), 3.75-3.48 (m, 8H), 2.59-2.54 (m, 1 H), 1.35-1, 33 (m, 2H), 1.25-1.14 (m, 2H); 463 [M + H] ⁺ 59 2.05
98%
(B) 11 (6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxypyridin-3-yl) (4-morpholinylpyridin-1-yl) methanone ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.16 (d, J = 1.56 Hz, 1H), 7.99 (s, 1H), 7.79 (d, J = 1.44 Hz, 1H), 4.16 (s , 3H), 4.16-3.99 (m, 4H), 3.98-3.75 (m, 2H), 3.56-3.52 (m, 3H), 3.30-3.18 (m, 4H), 2.68-2.64 (m, 1H), 2.31 -2.19 (m, 2H), 1.88-1.80 (m, 2H), 1.52-1.49 (m, 2H), 1.46-1.39 (m, 2H); 546 [M + H] ⁺ 42 4.67
99%
(A) 12 4-cyclopropyl-2-((2-methoxy-4- (morpholin-4-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbonitrile ¹ H NMR (400 MHz, DMSO- d ₄ ) δ 12.64 (s, 1H), 8.41-8.39 (d, J = 8.2 Hz, 1H), 8.19 (s, 1H), 7.07 (s, 1H), 7.06- 7.01 (d, 1H), 3.61 (s, 4H), 3.53 (s, 4H), 2.67-2.56 (m, 1H), 1.27-1.21 (m, 4H)); 419 [M + H] ⁺ 33 6.52
98%
(A) 13 4-cyclopropyl-2-((2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5 Carbonnitrile ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 8.68-8.66 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H), 7.09 (s, 1H), 7.07-7.06 (d, 1H), 4.13-4.10 (d, 2H), 3.99 (s, 3H), 3.80-3.74 (t, 2H), 3.58-3.48 (m, 4H), 3.27-3.21 (m, 4H), 2.75-2.66 (m, 1H ), 2.75-2.66 (m, 1H), 2.21-2.18 (m, 2H), 1.75-1.67 (m, 2H), 1.38-1.34 (m, 2H); 502 [M + H] ⁺ 41 5.04
97%
(A) 14 4-cyclopropyl-2-((5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5 Carbonnitrile ¹ H NMR (400 MHz, DMSO- d ₄ ) δ 12.72 (s, 1H), 8.42-8.39 (d, J = 12.3 Hz, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.02- 7.00 (d, J = 6.2 Hz, 1H), 3.91 (s, 1H), 3.64 (s, 4H), 3.56 (s, 4H), 2.67 (m, 1H), 1.26-1.21 (m, 4H); 437 [M + H] ⁺ 25 6.86
99%
(A) 15 4-cyclopropyl-2-((6-methoxy-2-methyl-1-oxoisoindol-5-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbonitrile ¹ H NMR (400 MHz, DMSO- d ₄ ) δ 12.71 (s, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.24 (s, 1H), 4.39 ( s, 2H), 3.97 (s, 3H), 3.06 (s, 3H), 2.62-2.55 (m, 1H), 1.28-1.22 (m, 4H); 375 [M + H] ⁺ 8 6.64
90%
(A) 16 4-cyclopropyl-2-((6-methoxy-2-methyl-3-oxoisoindol-5-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbonitrile ¹ H NMR (400 MHz, DMSO- d ₄ ) δ 12.79 (s, 1H), 8.59 (s, 1H), 8.18-8.17 (d, 1H), 7.87 (s, 1H), 7.26 (s, 1H), 7.38 (s, 1 H), 4.37 (s, 2 H), 3.96 (s, 3 H), 3.06 (s, 3 H), 2.60-2.55 (m, 1 H), 1.26-1.19 (m, 4 H); 375 [M + H] ⁺ 8 6.95
98%
(A) 17 2-((6-chloro-2-methyl-1-oxoisoindol-5-yl) amino) -4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidine-5-carbonitrile ¹ H NMR (400 MHz, DMSO- d ₄ ) δ 12.68 (s, 1H), 8.51 (s, 1H), 8.31 (s, 1H), 8.21-8.20 (d, 1H), 7.72 (s, 1H), 4.46 (s, 2H), 3.16 (s, 3H), 3.07 (s, 3H), 2.56-2.54 (s, 3H), 1.23-1.14 (m, 4H); 379 [M + H] ⁺ 6 6.95
91%
(A) 18 2-((2- (2-cyanopropan-2-yl) -4-methylthiazol-5-yl) amino) -4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidine- 5-carbonitrile ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 12.58 (br s, 1H), 9.68 (br s, 1H), 8.19 (d, J = 2.7 Hz, 1H), 2.61-2.55 (m, 1H), 3.33 (s, 3H), 1.77 (s, 6H) 1.34-1.30 (m, 2H), 1.26-1.20 (m, 2H); 364 [M + H] ⁺ 54 2.36
98%
(A) 19 4-cyclopropyl-2-((6-methoxy-2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazine-7- Yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbonitrile ¹ H NMR (400 MHz, TFA salt, DMSO- d ₄ ) δ 12.63-12.62 (s, 1H), 8.15-8.14 (s, 1H), 8.05 (s, 1H), 7.03 (s, 1H), 6.83 ( s, 1H), 3.91 (s, 3H), 3.31 (s, 3H), 2.57-2.54 (m, 1H), 1.39 (s, 6H), 1.22-1.19 (m, 4H); 419 [M + H] ⁺ 41 7.34
98%
(A) 20 4-cyclopropyl-2-((3-methoxy-5- (4-morpholinopiperidine-1-carbonyl) pyridin-2-yl) amino) -7H-pyrrolo [2, 3-d] Pyrimidine-5-carbonitrile ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.20 (s, 1H), 8.16 (d, J = 1.44 Hz, 1H), 7.81 (d, J = 1.40 Hz, 1H), 4.16 (s , 3H), 4.11-4.01 (m, 2H), 3.98-3.75 (m, 2H), 3.60-3.48 (m, 4H), 3.35-3.05 (m, 5H), 2.93-2.89 (m, 1H), 2.31 -2.18 (m, 2H), 1.87-1.76 (m, 2H), 1.52-1.49 (m, 2H), 1.47-1.44 (m, 2H); 503 [M + H] ⁺ 24 4.22
99%
(A) 21 (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.68 (d, J = 8.3 Hz, 1H), 7.24 (s, 1H), 7.12 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H) , 4.02 (s, 3H), 3.88-3.58 (m, 8H), 3.09-3.04 (m, 1H), 1.41-1.37 (m, 2H), 1.35-1.31 (m, 2H); 428 [M + H] ⁺ 39 6.55
98%
(A) 22 (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidine- 1-day) methanone ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.67 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H) , 4.22-4.08 (m, 2H), 4.01 (s, 3H), 3.90-3.74 (m, 2H), 3.62-3.48 (m, 3H), 3.34-3.00 (m, 6H), 2.32-2.14 (m, 2H), 1.80-1.72 (m, 2H), 1.41-1.32 (m, 4H); 511 [M + H] ⁺ 48 5.13
98%
(A) 23 (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-fluoro-5-methoxyphenyl) (morpholino Methanone ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 8.60-5.57 (d, J = 12.5 Hz, 1H), 7.24 (s, 1H), 7.00-6.99 (d, J = 6.0 Hz, 1H), 3.98 ( s, 3H), 3.77 (m, 4H), 3.66 (m, 2H), 3.45 (m, 2H), 3.09-3.03 (m, 1H), 1.40-1.35 (m, 2H), 1.33-1.29 (m, 2H); 446 [M + H] ⁺ 20 7.39
91%
(A) 24 5-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2-methylisoindolin-1-one ¹ H NMR (400 MHz, DMSO- d ₄ ) δ 11.94 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.39-7.38 (d, 2H), 7.23 (s, 1H), 4.39 (s, 2H), 3.97 (s, 3H), 3.06 (s, 3H), 2.89-2.86 (m, 1H), 1.26-1.23 (m, 2H), 1.20-1.13 (m, 2H); 384 [M + H] ⁺ 27 6.86
98%
(A) 25 (4-((4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.66 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 3.8 Hz, 1H), 7.17 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 3.8 Hz, 1H), 4.03 (s, 3H), 3.80-3.48 (m, 8H), 2.59-2.52 (m, 1H), 1.55-1.51 (m, 4H ); 394 [M + H] ⁺ 25 4.77
98%
(A) 26 (4-((4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidin-1-yl) Methanone ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.68 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 3.8 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 3.8 Hz, 1H), 4.25-4.07 (m, 2H), 4.03 (s, 3H), 3.91-3.72 (m, 2H), 3.60-3.49 (m, 3H ), 3.32-2.90 (m, 4H), 2.59-2.52 (m, 1H), 2.35-2.17 (m, 2H), 1.80-1.72 (m, 2H), 1.54-1.51 (m, 4H); 477 [M + H] ⁺ 28 4.18
98%
(A) 27 (4-((4-cyclopropyl-5-fluoro-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.66-8.64 (d, J = 8.3 Hz, 1H), 7.15-7.12 (d, J = 1.6 Hz, 1H), 7.08-7.06 (m, 2H), 4.01 (s, 1 H), 3.70 (m, 8 H), 2.61-2.55 (m, 1 H), 1.43-1.37 (m, 4H); 412 [M + H] ⁺ 35 6.03
95%
(A) 28 (4-((4-cyclopropyl-5-fluoro-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidine -1-yl) methanone ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.70-8.68 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 7.09-7.07 (d, 1H), 6.99-6.98 (d, 1H ), 4.10 (m, 2H), 3.99 (s, 3H), 3.78 (m, 2H), 3.54-3.48 (m, 3H), 3.26 (m, 4H), 2.58-2.52 (m, 1H), 2.21- 2.18 (m, 2H), 1.75-1.67 (m, 2H), 1.40-1.36 (m, 2H), 1.34-1.29 (m, 2H); 495 [M + H] ⁺ 17 4.86
91%
(A) 29 (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4- ( Oxetan-3-yl) piperazin-1-yl) methanone ¹ H NMR (400 MHz, TFA, MeOD) δ 8.74 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.18-7.12 (m, 2H), 4.94-4.89 (m, 2H), 4.85 -4.80 (m, 2H), 4.39-4.30 (m, 1H), 4.02 (s, 3H), 4.02-3.90 (m, 4H), 3.27-3.17 (m, 4H), 2.55-2.48 (m, 1H) , 1.39-1.33 (m, 2H), 1.22-1.15 (m, 2H)
; 517.3 [M + H] ⁺ 37.9 1.41
95%
(A)

Example 30 (4-((4-cyclopropyl-3- (trifluoromethyl) -1 H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) Preparation of (morpholino) methanone

Step 1: Preparation of 4-chloro-3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine

Dissolve 4-chloro-3-iodo-1H-pyrrolo [2, 3-b] pyridine (1.0 equiv) in DMF (0.3 M) under nitrogen, and then NaH (1.2 equiv) in 3-4 at 0 ^o C. Add in portions at once. The reaction mixture was reacted at 20 ^° C. for 1 hour, and further added (2- (chloromethoxy) ethyl) trimethylsilane (1.2 equivalents), followed by further stirring at 20 ^° C. for 2 hours. Ice water was added to the reaction, and the organics were extracted with EtOAc (x3). The collected organic layer was washed with brine, and then the remaining water was removed using Na ₂ SO ₄ . The reaction was purified via MPLC (EtOAc: Hex) to give the title compound as a yellow solid (yield: 75%).

Step 2: Preparation of 4-chloro-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine

The reaction was carried out with CuI (5.0 equiv) and KF (5.0 equiv) maintaining the temperature at 150 ^° C. for 2 hours under reduced pressure close to vacuum. After the reaction was cooled to room temperature, trimethyl (trifluoromethyl) silane (5.0 equiv) was dissolved in DMF and NMP (1: 1 ratio, 0.2 M total) under nitrogen, and then put through a syringe. The reaction mixture is allowed to react for 1 hour at room temperature, further under 4-chloro-3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b ] Pyridine (1.0 equiv) was dissolved in DMF and NMP (1: 1 ratio, 0.2 M total) and then put through a syringe. The reaction was stirred at 50 ^° C. for 14 hours. Ice water was added to the reaction, and the organics were extracted with EtOAc (x3). The collected organic layer was washed with brine, and then the remaining water was removed using Na ₂ SO ₄ . The reaction was purified through MPLC (EtOAc: Hex) to give the title compound as a white solid (yield: 82%).

Step 3: Preparation of 4-cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine

4-Chloro-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine (1.0 equiv) toluene (0.15 M) ), Cyclopropylboronic acid (2.0 equiv), cesium carbonate (2.0 equiv), Pd ₂ (dba) ₃ (0.15 equiv) and Davephos (0.1 equiv) were added and sonicated under nitrogen for 1 minute to remove the gas. It was. The reaction was reacted for 40 minutes at 120 ^° C. using microwave. The reaction mixture was filtered through celite and washed with EtOAc and MeOH. The obtained filtrate was concentrated and purified through MPLC (EtOAc: Hex) to give the title compound as a white solid. (Yield: 60%)

Step 4: 4- (cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-7-oxide Manufacture

4-cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b] pyridine (1.0 equiv) in chloroform (0.15 After dissolving in M), 3-Chloroperbenzoic acid (3.0 equivalents) was added thereto, and the reaction was performed at 75 ^° C. for 16 hours using a reflux apparatus. The reaction was terminated by addition of Na ₂ S ₂ O ₃ and water at 0 ^° C. and the organics extracted with DCM (x3). The collected organic layer was washed with brine, and then the remaining water was removed using Na ₂ SO ₄ . The reaction was purified via MPLC (MeOH: DCM) to give the title compound as a yellow solid (yield: 72%).

Step 5: of 6-chloro-4-cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine Produce

4- (cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-7-oxide (1.0 equiv ) was dissolved in DMF (0.15 M), was added Methanesulfonyl chloride and reacted for 20 minutes at 80 ^o C. the reaction was sikyeotgo terminate the reaction by adding water at 0 ^o C, with the addition aq. NaHCO ₃ After titration of pH 8 the organics were extracted with EtOAc (x3) The combined organic layers were washed with brine and the remaining water was removed using Na ₂ SO ₄ The reaction was purified by MPLC (MeOH: DCM) and ivory The desired compound was obtained as a color solid. (Yield: 74%)

Step 6: (4-((4-cyclopropyl-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyridine Preparation of -2-yl) amino) methoxyphenyl) (morpholino) methanone

Compound (1.0 equiv), (4-amino-3-methoxyphenyl) (morpholino) methanone (1.0 equiv) and K ₂ CO ₃ (5.0 equiv) prepared in step 1 were added to sec-BuOH (0.1 M). ), And then sonicated for 1 minute to remove the gas. Pd ₂ (dba) ₃ (0.1 equiv) and Xphos (0.1 equiv) were added to the reaction mixture at 100 ^° C., followed by reaction for 1 hour. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. After concentration of the filtrate obtained, the desired compound of the obtained yellow solid was used for the next step without further purification.

Step 7: (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyridin-2-yl) amino) -3-methoxyphenyl) (parent Preparation of polyno) methanone

(4-((4-cyclopropyl-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyridine-2- I) amino) methoxyphenyl) (morpholino) methanone (1.0 equiv) was dissolved in CH ₂ Cl ₂ (0.05 M) and then TFA (100 equiv) was added at room temperature. After 4 hours reaction, the solvent was removed. The concentrated mixture was again dissolved in THF (0.03 M) and sat. At room temperature. Na ₂ CO ₃ (0.03 M) was added and reacted for 14 hours. After the reaction, the resultant was diluted with EtOAc and washed sequentially with water and brine. The organic layer removed the remaining water with Na ₂ SO ₄ . The mixture was purified via prep-HPLC to give the title compound as a yellow liquid (yield: 24%).

Examples 31 to 54 were prepared in a similar manner to Example 30, and the chemical structures of Examples 30 to 54 are shown in Table 3 below, the compound names, mass and UPLC analysis results are summarized in Table 4 below.

Example Chemical structure Example Chemical structure 30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

room
city
Yes Compound name ¹ H NMR, MS yield
(%) HPLC r.t. (min) (analysis condition) 30 (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (morpholino) Methanone ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.33 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 6.97 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H) , 6.34 (s, 1H), 3.82 (s, 3H), 3.68-3.38 (m, 8H), 2.24-2.18 (m, 1H), 1.01-0.97 (m, 2H), 0.80-0.76 (m, 2H) ; 461 [M + H] ⁺ 28 2.65
97%
(A) 31 (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (4-morphopoly Nopiperidin-1-yl) ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.50 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 6.95 (s, 1H), 6..94 (d, J = 8.3 Hz , 1H), 6.36 (s, 1H), 4.68-4.14 (m, 2H), 4.04-3.92 (m, 2H), 3.83 (s, 3H), 3.70-3.58 (m, 2H), 3.45-3.32 (m , 3H), 3.15-2.80 (m, 4H), 2.24-2.17 (m, 1H), 2.14-2.04 (m, 2H), 1.63-1.51 (m, 2H), 0.99-0.95 (m, 2H), 0.78 -0.74 (m, 2H); 544 [M + H] ⁺ 28 2.19
94%
(A) 32 (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-fluoro-5-methoxyphenyl) (Morpholino) methanone ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.65 (d, J = 13.0 Hz, 1H), 7.43 (s, 1H), 6.81 (d, J = 6.2 Hz, 1H), 6.41 (s, 1H) , 3.83 (s, 3H), 3.70-3.60 (m, 4H), 3.58-3.50 (m, 2H), 3.38-3.30 (m, 2H), 2.24-2.17 (m, 1H), 0.99-0.95 (m, 2H), 0.79-0.75 (m, 2H); 479 [M + H] ⁺ 23 2.65
97%
(A) 33 5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -6-methoxy-2-methylisoindan- 1-on ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.71 (s, 1H), 7.43 (s, 1H), 7.16 (s, 1H), 6.39 (s, 1H), 4.28 (s, 2H), 3.87 ( s, 3H), 3.05 (s, 3H), 2.24-2.17 (m, 1H), 0.99-0.95 (m, 2H), 0.79-0.75 (m, 2H); 417 [M + H] ⁺ 25 2.53
98%
(A) 34 6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxy-2-methylisoindolin- 1-on ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.60 (s, 1H), 7.41 (s, 1H), 7.09 (s, 1H), 6.32 (s, 1H), 4.32 (s, 2H), 3.88 ( s, 3H), 3.06 (s, 3H), 2.24-2.18 (m, 1H), 1.02-0.97 (m, 2H), 0.80-0.76 (m, 2H); 421 [M + H] ⁺ 13 2.49
94%
(A) 35 6-chloro-5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-methylisoindane-1 -On ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.74 (s, 1H), 7.62 (s, 1H), 7.47 (s, 1H), 6.49 (s, 1H), 4.33 (s, 2H), 3.05 ( s, 3H), 2.26-2.20 (m, 1 H), 0.99-0.95 (m, 2H), 0.81-0.77 (m, 2H); 421 [M + H] ⁺ 18 2.61
97%
(A) 36 5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-methylisoindolin-1-one ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.14 (s, 1H), 7.53-7.47 (m, 2H), 7.41 (s, 1H), 6.21 (s, 1H), 4.33 (s, 2H), 3.05 (s, 3H), 2.24-2.17 (m, 1H), 0.99-0.95 (m, 2H), 0.75-0.71 (m, 2H); 421 [M + H] ⁺ 19 2.39
96%
(A) 37 (6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxypyridin-3-yl) ( Morpholino) methanone ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.93 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 6.95 (s, 1H), 4.10 (s, 3H), 3.77- 3.52 (m, 8H), 2.42-2.38 (m, 1H), 1.19-1.15 (m, 2H), 0.92-0.89 (m, 2H); 462 [M + H] ⁺ 27 2.40
93%
(A) 38 (6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxypyridin-3-yl) ( 4-morpholinylpiperidin-1-yl) methanone ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.08 (d, J = 1.56 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J = 1.48, 1H), 7.06 (s, 1H), 4.17 (s, 3H), 4.15-4.00 (m, 2H), 3.99-3.79 (m, 2H), 3.56-3.48 (m, 4H), 3.35-2.95 (m, 5H), 2.50-2.46 ( m, 1H), 2.35-2.20 (m, 2H), 1.87-1.78 (m, 2H), 1.28-1.23 (m, 2H), 1.00-0.96 (m, 2H); 545 [M + H] ⁺ 19 4.87
98%
(A) 39 7-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -6-methoxy-2, 2, 4-tri Methyl-2H-benzo [b] [1, 4] oxazin-3 (4H) -one ¹ H NMR (400 MHz, TFA salt, DMSO- d ₄ ) δ 12.02 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.64 (s, 1H), 6.01 (s, 1H) , 6.66 (s, 1H), 3.90 (s, 3H), 3.31 (s, 3H), 2.20-2.11 (m, 1H), 1.60-1.01 (m, 2H), 0.84-0.81 (m, 2H); 461 [M + H] ⁺ 45 7.87
99%
(A) 40 2- (5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -4-methylthiazol-2-yl ) -2-methylpropanenitrile ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 12.28 (br s, 1H), 9.60 (br s, 1H), 7.86 (s, 1H), 2.36-2.29 (m, 4H), 1.77 ( s, 6H) 1.34-1.29 (m, 2H), 1.19-1.12 (m, 2H); 407 [M + H] ⁺ 40 7.77
97%
(A) 41 4-cyclopropyl-6-((2-methoxy-4- (morpholin-4-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ 8.66 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.07 (s, 1H), 7.04 (d J = 8.3 Hz, 1H), 6.50 (s, 1H), 3.96 (s, 3H), 3.87-3.58 (m, 8H), 2.58-2.52 (m, 1H), 1.19-1.14 (m, 2H), 0.95-0.91 (m, 2H), 418 [M + H] ⁺ 14 6.20
99%
(A) 42 4-cyclopropyl-6-((5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3- Carbon Nitrile ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ 8.77 (d, J = 13.0 Hz, 1H), 7.82 (s, 1H), 6.93 (s, 1H), 6.55 (d, J = 6.2 Hz , 1H), 3.95 (s, 3H), 3.85-3.62 (m, 6H), 3.52-3.39 (m, 2H), 2.58-2.52 (m, 1H), 1.19-1.14 (m, 2H), 0.95-0.91 (m, 2H); 436 [M + H] ⁺ 8 6.52
100%
(A) 43 4-cyclopropyl-6-((2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3- Carbonitrile ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ 8.69 (d, J = 8.3 Hz, 1H), 7.81 (s, 1H), 7.07 (s, 1H), 7.06 (d J = 8.3 Hz, 1H), 6.52 (s, 1H), 4.18-4.02 (m, 2H), 3.97 (s, 3H), 3.94-3.69 (m, 2H), 3.60-3.44 (m, 3H), 3.29-2.91 (m, 6H), 2.58-2.52 (m, 1H), 2.31-2.18 (m, 2H), 1.78-1.62 (m, 2H), 1.19-1.14 (m, 2H), 0.95-0.91 (m, 2H); 501 [M + H] ⁺ 16 5.04
100%
(A) 44 6-((6-methoxy-2-methyl-1-oxoisoindolin-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ¹ H NMR (400 MHz, TFA salt, DMSO- d ₄ ) δ 8.83 (s, 1H), 8.40 (s, NH), 8.08 (s, 1H), 7.19 (s, 1H), 6.78 (s, 1H) , 4.36 (s, 2H), 3.95 (s, 3H), 3.05 (s, 3H), 2.56-2.53 (m, 1H), 1.21-1.09 (m, 2H), 0.97-0.83 (m, 2H); 374 [M + H] ⁺ 4 6.43
93%
(A) 45 6-((6-chloro-2-methyl-1-oxoisoindolin-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile 378 [M + H] ⁺ 5 6.53
96%
(A) 46 4-cyclopropyl-6-((6-methoxy-2-methyl-3-oxoisoindol-5-yl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ 8.79 (s, 1H), 7.80 (s, 1H), 7.20 (s, 1H), 6.47 (s, 1H), 4.44 (s, 2H) , 4.01 (s, 3H), 3.19 (s, 3H), 2.56-2.53 (m, 1H), 1.26-1.16 (m, 2H), 0.98-0.89 (m, 2H); 374 [M + H] ⁺ 9 6.30
99%
(A) 47 4-cyclopropyl-6-((3-methoxy-5- (morpholin-4-carbonyl) pyridin-2-yl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbo Nitrile ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.04 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 6.96 (s, 1H), 4.10 (s, 3H), 3.77- 3.52 (m, 8H), 2.69-2.58 (m, 1H), 1.28-1.21 (m, 2H), 0.96-0.92 (m, 2H); 419 [M + H] ⁺ 24 2.12
96%
(A) 48 4-cyclopropyl-6-((3-methoxy-5- (4-morpholinopiperidine-1-carbonyl) pyridin-2-yl) amino) -1H-pyrrolo [2, 3-b] Pyridine-3-carbonitrile ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.11 (m, 2H), 7.76 (d, J = 1.4 Hz, 1H), 6.99 (s, 1H), 4.18 (s, 3H), 4.12 -4.01 (m, 2H), 3.89-3.75 (m, 2H), 3.59-3.53 (m, 4H), 3.30-3.01 (m, 5H), 2.73-2.66 (m, 1H), 2.28-2.22 (m, 2H), 1.89-1.78 (m, 2H), 1.34-1.29 (m, 2H), 1.02-0.99 (m, 2H); 502 [M + H] ⁺ 51 4.40
100%
(A) 49 6-((2- (2-cyanopropan-2-yl) -4-methylthiazol-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] pyridine-3 Carbonnitrile ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 12.38 (br s, 1H), 9.30 (br s, 1H), 8.03 (d, J = 2.9 Hz, 1H), 6.47 (s, 1H) , 2.48-2.43 (m, 1H), 2.36 (s, 3H), 1.77 (s, 6H) 1.19-1.13 (m, 2H), 0.86-0.82 (m, 2H); 363 [M + H] ⁺ 24 6.89
97%
(A) 50 4-cyclopropyl-6-((6-methoxy-2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazine-7- Yl) amino) -2H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ¹ H NMR (400 MHz, TFA salt, DMSO- d ₄ ) δ 12.32 (s, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 6.81 (s, 1H) , 6.65 (s, 1H), 3.90 (s, 3H), 3.31 (s, 3H), 2.46-2.39 (m, 1H), 1.38 (s, 6H), 1.14-1.09 (m, 2H), 0.87-0.83 (m, 2H); 418 [M + H] ⁺ 44 7.17
99%
(A) 51 (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-fluoro-5-methoxyphenyl) (4-morpholinopiperidin-1-yl) methanone ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.13 (s, 1H), 8.70 (d, J = 12.6 Hz, 1H), 8.45 (s, 1H), 7.76 (s, 1H), 6.93 (s, 1H ), 6.81 (s, 1H), 4.47 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 5H), 3.34 (s, 3H), 3.05 (t, J = 11.3 Hz , 1H), 2.80 (t, J = 11.5 Hz, 1H), 2.45 (s, 4H), 2.20 (s, 1H), 1.80 (d, J = 42.6 Hz, 2H), 1.33 (s, 2H), 1.07 (s, 2H), 0.85 (s, 2H); 562.4 [M + H] ⁺ 31.8 1.45
95%
(A) 52 (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (4- (jade Cetane-3-yl) piperazin-1-yl) methanone ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.03 (s, 1H), 8.66 (s, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.01 (s, 1H), 6.96 (dd , J = 5.0, 3.0 Hz, 1H), 6.74 (s, 1H), 4.54 (d, J = 4.7 Hz, 2H), 4.44 (d, J = 4.4 Hz, 2H), 3.90 (s, 3H), 3.56 (s, 4H), 3.44 (dd, J = 10.4, 5.1 Hz, 1H), 2.28 (s, 4H), 2.19 (s, 1H), 1.89 (s, 1H), 1.05 (s, 3H), 0.84 ( s, 3H); 516.3 [M + H] ⁺ 28.2 1.46
95%
(A) 53 4-cyclopropyl-6-((5-fluoro-2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b ] Pyridine-3-carbonitrile ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.42 (s, 1H), 8.66 (d, J = 12.1 Hz, 1H), 8.48 (s, 1H), 8.09 (s, 1H), 6.93 (s, 1H ), 6.80 (s, 1H), 4.48 (s, 1H), 3.89 (s, 3H), 3.57 (s, 5H), 3.06 (s, 1H), 2.79 (t, J = 11.8 Hz, 1H), 2.46 (s, 3H), 1.91 (s, 2H), 1.78 (s, 1H), 1.43-1.21 (m, 3H), 1.16 (s, 3H), 0.88 (s, 3H); 519.4 [M + H] ⁺ 26.8 1.30
95%
(A) 54 4-cyclopropyl-6-((2-methoxy-4- (4- (oxetan-3-yl) piperazin-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b ] Pyridine-3-carbonitrile ¹ H NMR (400 MHz, DMSO- d6 ) δ 12.36 (s, 1H), 8.67 (d, J = 4.1 Hz, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.07 (s, 1H ), 7.04 (d, J = 3.6 Hz, 1H), 6.75 (s, 1H), 4.71 (s, 4H), 4.22 (s, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.02 (s, 4H), 2.46 (s, 1H), 1.15 (s, 2H), 0.88 (s, 2H); 473.4 [M + H] ⁺ 48.4 1.26
95%
(A)

Example 55 Preparation of (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

Step 1: Preparation of (4-((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

Dissolve 2,4-dichloro-5- (trifluoromethyl) pyrimidine (1 equiv) in Acetonitrile (0.3M), and then (4-amino-3-methoxyphenyl) (morpholino) methanone at room temperature (1 equiv), sat.sodium bicarbonate solution (3 equiv) were added and stirred for 3 h. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MC. After concentration of the filtrate obtained, the desired compound of the obtained yellow solid was used for the next step without further purification (yield: 100%). MS ( m / z ): 417 [M + l] ^+.

Step 2: Preparation of (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

(4-((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone (1 equiv) to 1,4-dioxane After dissolving in (0.04M), add cyclopropylboronic acid (5 equiv), palladium (II) acetate (0.1 equiv), tricyclohexylphosphine (0.2 equiv) and cesium (I) fluoride salt (3 equiv) at room temperature The gas was removed by sonication under nitrogen for 1 minute. Thereafter, the mixture was stirred at 90 ° C for 12 hours. After the reaction, the resultant was diluted with EtOAc and washed sequentially with water and brine. The organic layer removed the remaining water with Na ₂ SO ₄ . The mixture was purified via prep-HPLC to give the desired compound as a white solid. (Yield: 3%) MS (m / z): 423 [M + l] ^+.

Examples 56 to 58 were prepared in a similar manner to Example 55, and the chemical structures of Examples 55 to 58 are shown in Table 5 below, and the compound names, mass, and UPLC analysis results are summarized in Table 6 below.

Example Chemical structure Example Chemical structure 55

56

57

58

room
city
Yes Compound name ¹ H NMR, MS yield
(%) HPLC r.t. (min) (analysis condition) 55 (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ
8.52 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 7.06 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 3.96 (s, 3H), 3.70 (br s, 8H), 2.28-2.24 (m, 1H), 1.33-1.27 (m, 2H), 1.21-1.18 (m, 2H); 423 [M + H] ⁺ 3 2.59
100%
(B) 56 (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidin-1-yl) methanone ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ 8.53 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 7.07 (dd , J = 8.3 Hz, 1.8 Hz, 1H), 4.10 (d, J = 12.0 Hz, 2H), 3.97 (s, 3H), 3.77 (t, J = 12.2 Hz, 2H), 3.56-3.47 (m, 3H ), 3.22 (t, J = 12.2 Hz, 2H), 2.27-2.21 (m, 3H), 1.76-1.68 (m, 2H), 1.33-1.28 (m, 2H), 1.22-1.17 (m, 2H); 506 [M + H] ⁺ 7 2.19
92%
(B) 57 (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxyphenyl) (morpholino) methanone ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ 8.59 (s, 1H), 8.31 (d, J = 12.1 Hz, 1H), 7.01 (d, J = 6.0 Hz, 1H), 3.96 (s , 3H), 3.77-3.76 (m, 4H), 3.66 (t, J = 4.5 Hz, 2H), 3.43 (br s, 2H), 2.30-2.27 (m, 1H), 1.35-1.27 (m, 2H) , 1.25-1.20 (m, 2 H); 441 [M + H] ⁺ 2 2.65
95%
(B) 58 5-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -6-methoxy-2-methylisoindolin-1-one ¹ H NMR (400 MHz, TFA salt, Methanol- d ₄ ) δ 8.55 (d, J = 6.8 Hz, 2H), 7.34 (s, 1H), 4.43 (s, 2H), 4.01 (s, 3H), 3.18 (s, 3H), 2.28-2.26 (m, 1 H), 1.44-1.31 (m, 2 H), 1.23-1.20 (m, 2H); 379 [M + H] ⁺ 6 2.61
97%
(B)

Experimental Example 1 Evaluation of Enzyme Activity of a Compound According to the Present Invention

In order to evaluate the enzyme activity of the compound represented by Formula 1 according to the present invention, the following experiment was performed. Example compounds prepared in the present invention were used as compounds, and enzymes were used as LRRK2, LRRK2 (G2019S), DYRK1A, CLK1 kinase, and the inhibitory activity against the kinase was evaluated. The specific experimental method is as follows.

Specifically, the substrate was prepared in basic reaction buffer (20 mM Hepes, pH 7.5), 10 mM MgCl _2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na ₃ VO _4, 2 mM DTT, 1%. DMSO) and then added the cofactor necessary for the reaction. Next, LRRK2, LRRK2 (G2019S), DYRK1A, and CLK1 kinase were added and mixed, and each of the example compounds was added using Acoustic technology (Echo550; nanoliter range). After standing at room temperature for 20 minutes, the reaction was started by adding ^33SYK P-ATP (specific activity 10 mCi / ml). After reacting for 2 hours at room temperature, the P81 exchange paper was spotted. After the reaction, kinase activity was detected using a filter-binding method.

Table 7 below shows the inhibitory activities of LRRK2, LRRK2 (G2019S), DYRK1A, and CLK1 of Example compounds.

IC ₅₀ values of the measured kinases are classified as Class A when less than 10 nM, Class C when 10 to 100 nM, and Class B when greater than 100 nM.

Example LRRK2 LRRK2 (G2019S) DYRK1A CLK1 One A A B A 2 A A A A 3 A A B A 4 B B B A 5 C B B B 6 C B B B 7 A A B A 8 C B C B 9 B A A A 10 C C C B 11 B B C B 12 A A B A 13 A A A A 14 A A B A 15 B B B C 16 B B B B 17 C B C C 18 A A B A 19 A A C B 20 B B C C 21 A A B A 22 A A C C 23 A A C B 24 B A C B 25 A A C C 26 NA NA NA NA 27 A A C C 28 B A C C 30 B B B A 31 B B B A 32 C C C B 33 C C C B 34 C C C C 35 C C C B 36 C C C B 37 A A B A 38 B A B A 39 NA NA NA NA 40 A A B A 41 A A B B 42 B B A B 43 A A B B 44 C C C C 45 C C C C 46 C C C C 47 A A B B 48 A A B A 49 B B C C 50 B B C C

In Table 7, NA means no activity.

As shown in Table 7,

Example compounds of the present invention was confirmed to exhibit excellent inhibitory activity against LRRK2, LRRK2 (G2019S), DYRK1A, CLK1 kinase.

Experimental Example 2 Evaluation of Kinase Inhibitory Activity of the Compound According to the Present Invention

In order to evaluate the inhibitory activity against various kinases of the compound represented by Formula 1 according to the present invention, the following experiment was performed. As compounds, the compounds of Examples 1, 12, 30 and 43 prepared in the present invention were used, and enzymes were used as 468 kinases shown in Tables 8-12 below. The results are shown in Table 8-10 below. The specific experimental method is as follows.

Among Example compounds of the nickname, Examples 1, 12, 30, and 43 selected from the company were determined to measure the enzyme (kinase) selectivity by DiscoverX, and the experiment was conducted using a panel for the scanMAX ^TM Kinase assay. At this time, the concentration of the drug treated with the enzyme was set to 1 μM in DMSO, and the percentage control was determined by the same method as in Equation 1 below, and the results are shown in Table 8-10.

[Equation 1]

(Example compound-positive control) / (negative control-positive control) × 100

Herein, the positive control refers to a compound exhibiting a control percentage of 0%, and the negative control indicates a control percentage of 100% with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity for that enzyme if the percentage control for each enzyme was <35% (ie less than 35%).

Kinase Example 1 Example 12 Example 30 Example 43 Kinase Example 1 Example 12 Example 30 Example 43 AAK1 76 49 100 99 CDKL1 100 93 77 78 ABL1 (E255K) -phosphorylated 72 88 93 100 CDKL2 96 100 100 84 ABL1 (F317I) -nonphosphorylated 63 93 100 100 CDKL3 100 100 100 100 ABL1 (F317I) -phosphorylated 50 59 100 77 CDKL5 71 90 100 98 ABL1 (F317L) -nonphosphorylated 61 94 97 95 CHEK1 100 92 86 93 ABL1 (F317L) -phosphorylated 29 67 100 90 CHEK2 1.9 4.3 64 100 ABL1 (H396P) -nonphosphorylated 34 96 100 79 CIT 83 82 100 83 ABL1 (H396P) -phosphorylated 69 92 100 92 CLK1 1.8 1.2 2 2 ABL1 (M351T) -phosphorylated 49 92 100 88 CLK2 3 6 4.7 6.8 ABL1 (Q252H) -nonphosphorylated 26 94 100 72 CLK3 47 35 87 88 ABL1 (Q252H) -phosphorylated 73 91 100 95 CLK4 2.9 4 0.6 1.8 ABL1 (T315I) -nonphosphorylated 84 97 100 100 CSF1R 90 68 100 100 ABL1 (T315I) -phosphorylated 80 92 85 69 CSF1R-autoinhibited 88 12 100 42 ABL1 (Y253F) -phosphorylated 95 100 100 100 CSK 55 83 100 100 ABL1-nonphosphorylated 53 100 65 55 CSNK1A1 58 2 74 8.1 ABL1-phosphorylated 70 97 77 84 CSNK1A1L 82 3.1 100 21 ABL2 97 97 100 100 CSNK1D 41 2.2 68 6.2 ACVR1 100 100 100 100 CSNK1E 47 0.15 70 0.85 ACVR1B 99 96 100 100 CSNK1G1 90 58 100 50 ACVR2A 100 100 100 95 CSNK1G2 100 62 100 35 ACVR2B 100 100 100 100 CSNK1G3 94 24 100 32 ACVRL1 100 100 100 95 CSNK2A1 95 93 100 76 ADCK3 79 90 100 100 CSNK2A2 100 68 100 100 ADCK4 89 98 100 83 CTK 85 95 100 94 AKT1 83 100 100 100 DAPK1 40 13 100 38 AKT2 95 95 100 92 DAPK2 17 6.4 100 33 AKT3 100 97 100 100 DAPK3 29 8.8 100 29 ALK 1.8 6.6 54 20 DCAMKL1 53 86 100 73 ALK (C1156Y) 0.2 2 89 15 DCAMKL2 72 79 100 95 ALK (L1196M) 8.9 28 100 43 DCAMKL3 100 100 100 96 AMPK-alpha1 100 100 100 95 DDR1 79 100 100 94 AMPK-alpha2 96 100 100 100 DDR2 78 69 100 100 ANKK1 78 93 100 87 DLK 94 93 100 100 ARK5 87 68 100 100 DMPK 81 94 100 100 ASK1 99 16 100 100 DMPK2 92 100 100 100 ASK2 69 69 100 82 DRAK1 81 24 98 49 AURKA 100 97 100 98 DRAK2 60 3.6 60 16 AURKB 99 100 100 82 DYRK1A 0 1.6 13 1.6 AURKC 100 71 100 100 DYRK1B 6.9 10 0 12 AXL 98 99 100 83 DYRK2 5 6.5 60 8 BIKE 98 70 85 99 EGFR 84 80 96 100 BLK 96 100 88 100 EGFR (E746-A750del) 90 100 100 100 BMPR1A 100 87 100 100 EGFR (G719C) 78 90 99 100 BMPR1B 100 100 86 74 EGFR (G719S) 75 74 99 100 BMPR2 97 100 100 64 EGFR (L747-E749del, A750P) 77 73 100 100 BMX 83 95 100 100 EGFR (L747-S752del, P753S) 87 100 90 100 BRAF 66 91 100 84 EGFR (L747-T751del, Sins) 70 92 97 100 BRAF (V600E) 69 100 100 80 EGFR (L858R) 71 80 100 100 BRK 87 95 100 100 EGFR (L858R, T790M) 57 52 100 89 BRSK1 100 14 100 100 EGFR (L861Q) 65 95 75 100 BRSK2 100 75 100 100 EGFR (S752-I759del) 83 97 100 100 BTK 84 100 100 64 EGFR (T790M) 67 57 100 100 BUB1 61 15 100 62 EIF2AK1 100 79 100 100 CAMK1 61 52 100 97 EPHA1 89 99 100 100 CAMK1B 28 37 86 94 EPHA2 87 94 100 100 CAMK1D 66 54 100 77 EPHA3 89 97 97 100 CAMK1G 69 67 100 99 EPHA4 93 74 100 91 CAMK2A 24 54 94 93 EPHA5 100 99 100 100 CAMK2B 35 71 100 100 EPHA6 95 96 100 100 CAMK2D 39 76 91 100 EPHA7 100 6.5 95 100 CAMK2G 60 93 100 100 EPHA8 100 13 81 100 CAMK4 94 100 90 96 EPHB1 100 91 98 100 CAMKK1 54 84 100 87 EPHB2 100 100 99 90 CAMKK2 21 61 100 87 EPHB3 94 95 100 97 CASK 77 89 100 82 EPHB4 77 99 100 100 CDC2L1 88 94 98 100 EPHB6 35 100 92 100 CDC2L2 83 86 100 100 ERBB2 79 93 100 71 CDC2L5 77 100 100 95 ERBB3 86 100 100 79 CDK11 100 100 100 100 ERBB4 93 92 100 100 CDK2 100 100 100 100 ERK1 100 100 100 100 CDK3 96 100 100 100 ERK2 99 100 100 97 CDK4 88 94 100 92 ERK3 91 100 75 100 CDK4-cyclinD1 94 100 100 61 ERK4 71 93 70 100 CDK4-cyclinD3 88 91 100 90 ERK5 77 49 100 35 CDK5 100 98 98 100 ERK8 94 62 100 100 CDK7 62 100 100 96 ERN1 46 69 100 70 CDK8 98 100 100 100 FAK 52 33 80 77 CDK9 72 94 100 100 FER 32 11 48 100

Kinase Example 1 Example 12 Example 30 Example 43 Kinase Example 1 Example 12 Example 30 Example 43 FES 74 60 100 100 MAK 85 100 100 100 FGFR1 90 100 100 98 MAP3K1 96 90 100 72 FGFR2 70 69 100 100 MAP3K15 96 6 100 56 FGFR3 86 90 100 100 MAP3K2 31 95 100 63 FGFR3 (G697C) 82 94 100 100 MAP3K3 82 89 100 100 FGFR4 69 62 100 100 MAP3K4 85 88 100 100 FGR 77 99 95 100 MAP4K2 84 84 92 94 FLT1 83 74 100 100 MAP4K3 100 88 100 86 FLT3 98 96 100 88 MAP4K4 88 86 96 93 FLT3 (D835H) 100 96 100 100 MAP4K5 100 97 100 100 FLT3 (D835V) 18 38 100 60 MAPKAPK2 97 12 71 64 FLT3 (D835Y) 62 59 100 95 MAPKAPK5 47 20 100 56 FLT3 (ITD) 65 59 100 100 MARK1 90 86 100 98 FLT3 (ITD, D835V) 37 75 100 54 MARK2 96 75 100 100 FLT3 (ITD, F691L) 53 34 100 50 MARK3 96 100 100 100 FLT3 (K663Q) 88 78 100 100 MARK4 100 87 100 98 FLT3 (N841I) 85 92 100 98 MAST1 100 94 100 100 FLT3 (R834Q) 74 74 100 76 MEK1 80 93 93 79 FLT3-autoinhibited 80 100 99 93 MEK2 89 100 100 75 FLT4 88 96 88 100 MEK3 100 0.4 100 4.3 FRK 88 100 100 100 MEK4 22 0 100 0 FYN 83 100 100 100 MEK5 17 21 85 100 GAK 96 9.1 100 36 MEK6 60 27 100 61 GCN2 (Kin.Dom.2, S808G) 11 100 97 94 MELK 75 46 100 69 GRK1 90 87 92 46 MERTK 100 96 100 100 GRK2 74 83 82 71 MET 85 87 95 99 GRK3 68 74 97 86 MET (M1250T) 75 100 100 100 GRK4 76 71 92 100 MET (Y1235D) 97 48 75 100 GRK7 80 80 100 100 MINK 96 57 100 58 GSK3A 83 90 97 100 MKK7 78 31 100 77 GSK3B 81 97 100 68 MKNK1 95 98 100 70 HASPIN 100 91 95 61 MKNK2 82 32 100 66 HCK 81 100 71 93 MLCK 53 62 100 57 HIPK1 99 26 72 85 MLK1 91 100 100 100 HIPK2 20 20 100 53 MLK2 86 100 100 97 HIPK3 12 25 100 92 MLK3 98 96 72 100 HIPK4 22 89 100 100 MRCKA 94 100 100 83 HPK1 90 100 100 97 MRCKB 92 95 100 100 HUNK 100 6.4 52 15 MST1 96 100 46 100 ICK 8.2 100 100 77 MST1R 100 91 100 100 IGF1R 95 91 81 99 MST2 96 100 100 100 IKK-alpha 83 90 100 84 MST3 90 80 100 100 IKK-beta 92 96 100 87 MST4 72 97 100 86 IKK-epsilon 86 95 100 100 MTOR 91 93 100 100 INSR 94 26 100 93 MUSK 50 100 100 100 INSRR 14 3.2 100 90 MYLK 87 0 9.6 0 IRAK1 59 100 100 84 MYLK2 0 100 100 100 IRAK3 97 100 100 100 MYLK4 100 87 100 94 IRAK4 100 100 100 88 MYO3A 89 71 100 100 ITK 91 98 100 100 MYO3B 69 69 77 86 JAK1 (JH1domain-catalytic) 100 89 100 100 NDR1 66 100 100 56 JAK1 (JH2domain-pseudokinase) 73 37 100 77 NDR2 79 89 100 100 JAK2 (JH1domain-catalytic) 75 91 100 55 NEK1 84 79 100 100 JAK3 (JH1domain-catalytic) 79 87 100 88 NEK10 89 59 99 94 JNK1 78 0 77 0 NEK11 73 83 100 61 JNK2 17 0 95 0 NEK2 83 95 91 100 JNK3 12 0 100 0.05 NEK3 100 79 77 30 KIT 18 25 100 93 NEK4 63 100 100 75 KIT (A829P) 81 70 100 100 NEK5 87 100 100 100 KIT (D816H) 62 99 100 54 NEK6 85 99 100 100 KIT (D816V) 90 55 100 99 NEK7 93 97 75 100 KIT (L576P) 78 8.1 100 58 NEK9 97 93 96 100 KIT (V559D) 86 11 100 69 NIK 99 14 100 22 KIT (V559D, T670I) 90 74 100 97 NIM1 32 90 100 83 KIT (V559D, V654A) 85 59 99 100 NLK 89 54 100 100 KIT-autoinhibited 95 29 98 64 OSR1 71 24 100 74 LATS1 87 88 100 100 p38-alpha 12 100 100 100 LATS2 100 100 100 100 p38-beta 74 86 100 100 LCK 73 99 100 100 p38-delta 100 95 100 95 LIMK1 49 100 100 100 p38-gamma 81 100 47 100 LIMK2 100 100 100 100 PAK1 73 95 91 98 LKB1 92 100 100 100 PAK2 88 92 100 93 LOK 95 100 100 98 PAK3 67 100 85 92 LRRK2 90 0.9 71 1.4 PAK4 100 90 100 100 LRRK2 (G2019S) 1.1 0.6 52 0 PAK6 90 95 100 100 LTK 0.55 29 12 73 PAK7 90 98 100 96 LYN 24 100 100 98 PCTK1 94 100 100 82 LZK 100 87 62 67 PCTK2 92 85 100 86

Kinase Example 1 Example 12 Example 30 Example 43 Kinase Example 1 Example 12 Example 30 Example 43 PCTK3 88 90 97 100 RSK1 (Kin.Dom.1-N-terminal) 77 100 94 100 PDGFRA 79 74 97 100 RSK1 (Kin.Dom.2-C-terminal) 90 62 100 100 PDGFRB 76 81 95 93 RSK2 (Kin.Dom.1-N-terminal) 66 95 100 52 PDPK1 79 84 100 57 RSK2 (Kin.Dom.2-C-terminal) 75 93 100 69 PFCDPK1 (P.falciparum) 89 100 100 78 RSK3 (Kin.Dom.1-N-terminal) 89 100 100 91 PFPK5 (P.falciparum) 100 97 100 77 RSK3 (Kin.Dom.2-C-terminal) 89 28 100 18 PFTAIRE2 80 88 87 100 RSK4 (Kin.Dom.1-N-terminal) 47 89 100 66 PFTK1 93 100 100 100 RSK4 (Kin.Dom.2-C-terminal) 84 73 100 97 PHKG1 84 28 100 67 S6K1 67 95 93 72 PHKG2 48 21 81 25 SBK1 80 97 100 82 PIK3C2B 8.8 100 100 100 SGK 95 37 100 38 PIK3C2G 93 87 100 100 SgK110 83 100 100 100 PIK3CA 87 100 100 100 SGK2 100 93 100 51 PIK3CA (C420R) 100 99 88 100 SGK3 100 94 100 75 PIK3CA (E542K) 91 79 94 88 SIK 78 98 100 100 PIK3CA (E545A) 99 100 67 90 SIK2 84 100 100 100 PIK3CA (E545K) 98 84 85 56 SLK 90 100 100 100 PIK3CA (H1047L) 100 64 99 100 SNARK 85 75 100 89 PIK3CA (H1047Y) 100 100 100 100 SNRK 93 69 100 100 PIK3CA (I800L) 82 86 75 58 SRC 89 95 86 93 PIK3CA (M1043I) 80 96 100 100 SRMS 67 93 100 75 PIK3CA (Q546K) 96 97 100 100 SRPK1 91 76 100 100 PIK3CB 99 71 100 80 SRPK2 86 87 100 78 PIK3CD 100 48 96 97 SRPK3 91 82 98 100 PIK3CG 54 100 100 99 STK16 84 64 74 83 PIK4CB 93 15 100 89 STK33 79 19 43 14 PIKFYVE 34 100 100 74 STK35 22 95 99 100 PIM1 93 94 100 72 STK36 95 100 100 100 PIM2 87 99 89 93 STK39 93 5.2 100 17 PIM3 92 90 99 81 SYK 2.6 23 59 100 PIP5K1A 99 71 100 75 TAK1 79 39 100 91 PIP5K1C 95 26 100 49 TAOK1 73 84 100 90 PIP5K2B 96 81 100 67 TAOK2 87 100 100 86 PIP5K2C 98 4.5 100 5.6 TAOK3 88 86 87 81 PKAC-alpha 37 100 100 99 TBK1 86 95 50 94 PKAC-beta 96 95 100 100 TEC 96 4.3 98 100 PKMYT1 94 75 100 100 TESK1 100 93 100 100 PKN1 86 97 100 100 TGFBR1 84 100 100 100 PKN2 86 97 100 100 TGFBR2 92 100 100 95 MKtuberculosis (PKNB) 87 91 100 100 TIE1 100 47 100 100 PLK1 73 15 100 66 TIE2 65 89 100 100 PLK2 80 91 100 73 TLK1 94 94 100 100 PLK3 95 98 100 78 TLK2 84 100 100 100 PLK4 93 0.9 100 33 TNIK 100 83 100 100 PRKCD 12 98 100 100 TNK1 88 100 62 84 PRKCE 89 99 100 64 TNK2 88 16 100 100 PRKCH 76 98 100 100 TNNI3K 73 71 100 100 PRKCI 93 92 90 98 TRKA 78 100 100 62 PRKCQ 99 81 82 92 TRKB 87 100 100 49 PRKD1 97 30 97 15 TRKC 97 100 100 66 PRKD2 95 22 100 3.4 TRPM6 78 100 100 82 PRKD3 70 17 100 8.7 TSSK1B 88 31 100 94 PRKG1 89 92 100 100 TSSK3 69 65 100 78 PRKG2 92 91 100 98 TTK 94 9.8 31 3.2 PRKR 100 100 100 74 TXK 9.5 98 100 100 PRKX 100 38 100 100 TYK2 (JH1domain-catalytic) 90 95 100 35 PRP4 99 96 100 85 TYK2 (JH2domain-pseudokinase) 88 100 100 81 PYK2 87 16 100 95 TYRO3 97 100 100 100 QSK 67 91 100 68 ULK1 95 81 100 64 RAF1 71 100 100 100 ULK2 84 100 100 75 RET 100 100 93 100 ULK3 100 98 97 53 RET (M918T) 83 100 100 100 VEGFR2 97 97 81 74 RET (V804L) 97 84 100 100 VPS34 94 97 100 95 RET (V804M) 96 88 100 100 VRK2 94 100 100 73 RIOK1 92 49 100 100 WEE1 92 100 99 98 RIOK2 66 82 100 96 WEE2 100 100 100 100 RIOK3 72 46 100 100 WNK1 100 100 100 97 RIPK1 57 97 100 100 WNK2 78 84 100 79 RIPK2 83 80 100 100 WNK3 87 84 100 95 RIPK4 100 100 23 75 WNK4 79 100 100 71 RIPK5 95 12 71 24 YANK1 99 93 100 100 ROCK1 41 90 100 80 YANK2 96 100 100 100 ROCK2 82 75 100 66 YANK3 89 94 100 90 ROS1 84 57 90 100 YES 99 34 100 100 RPS6KA4 (Kin.Dom.1-N-terminal) 54 91 100 100 YSK1 89 79 78 87 RPS6KA4 (Kin.Dom.2-C-terminal) 93 0.1 99 0.55 YSK4 100 5.1 100 44 RPS6KA5 (Kin.Dom.1-N-terminal) 16 94 100 100 ZAK 59 92 100 100 RPS6KA5 (Kin.Dom.2-C-terminal) 100 6.8 100 87 ZAP70 85 18 100 58

As shown in Tables 8 to 12,

Example compounds of the present invention are ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1, CAMK1B, CAMK2A CAMKK2, CHEK2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK1, DRAK2, DYRK1A, DY EP2HA, DY EP1HA, DY EP1 HA, EP D835V), FLT3 (ITD, F691L), GAK, GCN2 (Kin.Dom.2, S808G), HIPK2, HIPK3, HIPK4, HUNK, ICK, INSR, INSRR, JNK1, JNK2, JNK3, KIT, KIT (L576P), KIT (V559D), KIT-autoinhibited, LRRK2, LRRK2 (G2019S), LTK, LYN, MAP3K15, MAP3K2, MAPKAPK2, MAPKAPK5, MEK3, MEK4, MEK5, MEK6, MKK7, MKNK2, MYK, MYLK2, NILK2, NILK2 p38-alpha, PHKG1, PHKG2, PIK3C2B, PIK4CB, PIKFYVE, PIP5K1C, PIP5K2C, PLK1, PLK4, PRKCD, PRKD1, PRKD2, PRKD3, PYK2, RIPK4, RIPK5, RPS6KA4 (2-Cin6D) (Kin.Dom.1-N-terminal), RPS6KA5 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.2-C-terminal), STK33, STK35, STK39, SYK, TEC, TNK2, TSSK1B, TTK, TXK, YES, YSK4, ZAP7 It can be seen that it has a value less than 35% control percentage for 0 kinase.

This indicates that the example compounds of the present invention have inhibitory activity against the enzymes listed above, thereby implying a useful effect when used in diseases associated with the enzymes listed above.

Therefore, the compound represented by Formula 1 according to the present invention is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1, CAMK1B, CAMK2A, CAMKK2, CHEK2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK1, DRAK1, DRK1RK8, DRAK1RK FAK, FER, FLT3 (D835V), FLT3 (ITD, F691L), GAK, GCN2 (Kin.Dom.2, S808G), HIPK2, HIPK3, HIPK4, HUNK, ICK, INSR, INSRR, JNK1, JNK2, JNK3, KIT , KIT (L576P), KIT (V559D), KIT-autoinhibited, LRRK2, LRRK2 (G2019S), LTK, LYN, MAP3K15, MAP3K2, MAPKAPK2, MAPKAPK5, MEK3, MEK4, MEK5, MEK6, MKK7, MKLK, MKLK NIK, NIM1, OSR1, p38-alpha, PHKG1, PHKG2, PIK3C2B, PIK4CB, PIKFYVE, PIP5K1C, PIP5K2C, PLK1, PLK4, PRKCD, PRKD1, PRKD2, PRKD3, PYK2, RIPK4, RIPK5, RIPKA 5 C-terminal), RPS6KA5 (Kin.Dom.1-N-terminal), RPS6KA5 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.2-C-terminal), STK33, STK35, STK39, SYK, TEC, TNK 2, TSSK1B, TTK, TXK, YES, YSK4, ZAP70 can be usefully used as a pharmaceutical composition for the treatment or prevention of kinase-related diseases.

Experimental Example 3 Inhibition of Phosphorylation of a Compound According to the Present Invention in Brain Cancer Cell Lines

In order to evaluate the phosphorylation inhibitory activity of the compound represented by the formula (1) according to the present invention in the brain cancer cell line, the experiment was carried out phosphorylation inhibitory activity in 448T cell line known as brain cancer cell line. Compounds of Examples 1, 2, 3, 4, 9, 12, 13, 15, 21, 22, 23, and 24 prepared in the present invention were used, and the results are shown in FIG. 1. The specific experimental method is as follows.

First, 0.75-1 × 10 ⁶ cells were seeded in a 60 mm dish using a 448T cell line and attached for one day. The final concentration of the compound was added to 100 nM and then incubated for 24 hours in a 37 ℃ CO ₂ incubator. The cells were collected and cultured, followed by protease inhibitor (Roche, 11836153001) and phosphatase inhibitor in RIPA buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 1% Sodium Deoxycholate, 0.1% SDS, 1% Triton X-100). (GenDEPOT, P3200-001) was added to each mixed solution 30 ~ 50 μl. Repeat vortexing three times every 10 minutes with ice. Transfer the supernatant by centrifugation (13000 rpm, 4 ℃, 20 minutes), and measure the protein concentration by BCA quantitative method, 5X sample buffer (1 M Tris-HCl pH 6.8, 10% SDS, 50% Glycerol, 5% beta -mercaptoethanol, 1% Bromophenol blue) was mixed (the final concentration of the sample buffer was 1X). After 5 minutes at 75 ℃ proceed to Western blot.

Western blot method was performed as follows. 20 μg / well was added to the gel, followed by electrophoresis (1 hour at 100V), and the protein was transferred to PVDF membrane (250 mA, 100 minutes). Membrane was blocked with 5% skim milk (room temperature, 1 hour) and then reacted with primary antibodies (p-LRRK2, LRRK2, beta-actin) (4 ° C, 18 hours). The primary antibody was washed with TBST buffer (10 min, 6 times), reacted with a secondary antibody (Goat anti-rabbit IgG-HRP), and then washed with TBST buffer (10 min, 6 h). time). Membrane was reacted with GE ECL plus solution for 5 minutes and then detected by X-ray film.

Figure 1 is a photograph showing the results of the inhibition of LRRK2 phosphorylation in 448T cell line of the compounds according to the present invention.

As shown in Figure 1, when the compound according to the present invention, it can be seen that LRRK2 phosphorylation in the 448T cell line, a cell line derived from a brain tumor patient. In addition, it can be seen that the amount of P-LRRK2 detected is significantly lower than that when the compound according to the present invention is not treated. This means that the compounds according to the invention effectively inhibit the phosphorylation of LRRK2.

Therefore, the compound represented by Formula 1 according to the present invention effectively inhibits LRRK2 phosphorylation in cancer-causing cells, and thus may be usefully used as a pharmaceutical composition for the treatment or prevention of LRRK2-related diseases, in particular for the treatment of brain cancer or Parkinson's disease. It can be useful.

Claims (14)

A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1, A ¹ is CH or N;
R ¹ and R ² are independently hydrogen or straight or branched C _1-6 alkyl, or R ¹ and R ² together with the carbon atom to which they are attached may form pyrrole, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF ₃ ;
R ³ is straight or branched C _1-10 alkyl, straight or branched C _2-10 alkenyl, straight or branched C _2-10 alkynyl or C _3-7 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C _1-6 alkoxy, respectively; And

Is

Or 5 or 6 membered heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S, wherein the heteroaryl is straight or branched C _1-6 alkyl or alkoxy; And 3 to 8 atoms of heterocycloalkyl or heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of N, O, and S, and may be substituted with one or more substituents selected from the group consisting of , Wherein the alkyl and alkoxy may be substituted with one or more CN, and the heterocycloalkyl and heterocycloalkylcarbonyl are halogenated and 3 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S May be substituted with one or more substituents selected from the group consisting of heterocycloalkyl of
R ^a and R ^b are independently 3-8 membered heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of hydrogen, halogen or N, O and S, wherein the heterocycloalkylcarbon Neyl may be substituted with one or more substituents selected from the group consisting of halogen and 3 to 6 membered heterocycloalkyl including one or more heteroatoms selected from the group consisting of N, O and S, or R ^a and R ^b may form an unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are attached, wherein the substituted heterocycloalkyl is a straight chain Or one or more substituents selected from the group consisting of branched C _1-6 alkyl and oxo (═O). Can,
R ^c is hydrogen, halogen or straight or branched C _1-6 alkoxy). The method of claim 1,
A ¹ is CH or N;
R ¹ and R ² are independently hydrogen or straight or branched C _1-4 alkyl, or R ¹ and R ² may form pyrrole with the carbon atoms to which they are attached, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF ₃ ;
R ³ is straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, straight or branched C _2-6 alkynyl or C _3-5 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C _1-4 alkoxy, respectively; And

Is

,

,

,

,

And

ego,
R ^d , R ^f , R ^g , R ⁱ , R ^j , R ^l , R ^r and R ^x are independently hydrogen, halogen or straight or branched C _1-6 alkyl or alkoxy, wherein said alkyl and Alkoxy may be substituted one or more with CN, and R ^e , R ^h and R ^k are independently 5 or 6 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S or Heterocycloalkylcarbonyl, wherein the heterocycloalkyl and heterocycloalkylcarbonyl consist of 3-6 membered heterocycloalkyl including halogen and one or more heteroatoms selected from the group consisting of N, O and S May be substituted with one or more substituents selected from the group,
R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^v , and R ^w are each hydrogen or straight or branched C _1-6 alkyl, or R ^m , R ⁿ , R ^o , R ^{two of p} , R ^s , R ^t , R ^v , and R ^w bonded to the same carbon may form carbonyl with the carbon to which they are attached,
R ^q and R ^u are independently hydrogen or linear or branched C _1-6 alkyl,
Compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof. The method of claim 1,
A ¹ is CH or N;
R ¹ and R ² are independently hydrogen or straight or branched C _1-2 alkyl, or R ¹ and R ² may form pyrrole with the carbon atom to which they are attached, wherein said alkyl is halogen One or more may be substituted, and said pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF ₃ ;
R ³ is straight or branched C _1-4 alkyl, straight or branched C _2-4 alkenyl, straight or branched C _2-4 alkynyl, cyclopropyl or cyclobutyl, said alkyl, alkenyl And alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C _1-2 alkoxy, respectively; And

Is

,

,

,

,

And

ego,
R ^d , R ^f , R ^g , R ⁱ , R ^j , R ^l , R ^r and R ^x are independently hydrogen, halogen or straight or branched C _1-3 alkyl or alkoxy, wherein said alkyl and Alkoxy may be substituted one or more with CN, R ^e , R ^h and R ^k are independently morpholinyl, piperidinyl, morpholinylcarbonyl, piperazinylcarbonyl or piperidinylcarbonyl, In this case, the morpholinyl, piperidinyl, morpholinylcarbonyl piperazinylcarbonyl, and piperidinylcarbonyl may be substituted with one or more substituents selected from the group consisting of halogen, morpholinyl and oxetanyl. Can,
R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^v , and R ^w are each hydrogen or straight or branched C _1-3 alkyl, or R ^m , R ⁿ , R ^o , R ^{two of p} , R ^s , R ^t , R ^v , and R ^w bonded to the same carbon may form carbonyl with the carbon to which they are attached,
R ^q and R ^u are independently hydrogen or a straight or branched C _1-3 alkyl,
Compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof. The method of claim 1,
A ¹ is CH or N;
R ¹ and R ² are independently hydrogen or CF _3, or R ¹ and R ² may form pyrrole with the carbon atom to which they are attached, wherein pyrrole is from the group consisting of F, Cl, CN and CF ₃ May be substituted with one or more substituents selected;
R ³ is straight or branched C _1-4 alkyl, vinyl, ethynyl or cyclopropyl, said alkyl substituted with one or more substituents selected from the group consisting of hydroxyl and straight or branched C _1-2 alkoxy Can be; And

Is

,

,

,

,

And

ego,
R ^d , R ^f , R ^g , R ⁱ , R ^j , R ^l , R ^r and R ^x are independently hydrogen, F, Cl, OMe or

ego,
R ^e , R ^h and R ^k are independently

,

,

or

ego,
R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^v , and R ^w are each hydrogen or methyl, or R ^m , R ⁿ , R ^o , R ^p , R ^s , R ^t , R ^{two of the v} , and R ^w bonded to the same carbon may form carbonyl together with the carbon to which they are attached,
R ^q and R ^u are independently hydrogen or methyl,
Compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof. The method of claim 1,
A ¹ is CH or N;
R ¹ and R ² are independently hydrogen or CF _3, or R ¹ and R ² together with the carbon atom to which they are attached

,

,

or

Can form;
R ³ is methyl, ethyl, i-propyl, t-butyl, i-butyl, hydroxyethyl, methoxyethyl, vinyl, ethynyl or cyclopropyl; And

Is

,

,

,

,

,

,

,

,

,

,

,

,

,

or

It is characterized by
Compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof. The method of claim 1,
Compound represented by the formula (1) is any one selected from the group of compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof:
<1> (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( Morpholino) methanone; <2> (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( 4-morpholinopiperidin-1-yl); <3> (4-((4-cyclopropyl-5- (trifluoromethyl) -H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-fluoro-5- Methoxyphenyl) (morpholino) methanone; <4> 5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2-methyl Isoindolin-1-one; <5> 6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxy-2-methyl Isoindolin-1-one; <6> 6-chloro-5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-methyl is Bovine dollin-1-one; <7> 2- (5-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -4-methylthiazole -2-yl) -2-methylpropanenitrile; <8> 7-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2, 2 , 4-trimethyl-2H-benzo [b] [1, 4] oxazin-3 (4H) -one; <9> N- (5-chloro-1-((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazole-4- Yl) -4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-amine; <10> (6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxypyridine-3 -Yl) (morpholino) methanone; <11> (6-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -5-methoxypyridine-3 -Yl) (4-morpholinylpyridin-1-yl) methanone; <12> 4-cyclopropyl-2-((2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbo Nitrile; <13> 4-cyclopropyl-2-((2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrid Midine-5-carbonitrile; <14> 4-cyclopropyl-2-((5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -7H-pyrrolo [2, 3-d] pyrid Midine-5-carbonitrile; <15> 4-cyclopropyl-2-((6-methoxy-2-methyl-1-oxoisoindol-5-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5- Carbonitrile; <16> 4-cyclopropyl-2-((6-methoxy-2-methyl-3-oxoisoindol-5-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5- Carbonitrile; <17> 2-((6-chloro-2-methyl-1-oxoisoindol-5-yl) amino) -4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidine-5-carbo Nitrile; 2-((2- (2-cyanopropan-2-yl) -4-methylthiazol-5-yl) amino) -4-cyclopropyl-7H-pyrrolo [2, 3-d] Pyrimidine-5-carbonitrile; <19> 4-cyclopropyl-2-((6-methoxy-2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazine -7-yl) amino) -7H-pyrrolo [2, 3-d] pyrimidine-5-carbonitrile; <20> 4-cyclopropyl-2-((3-methoxy-5- (4-morpholinopiperidine-1-carbonyl) pyridin-2-yl) amino) -7H-pyrrolo [2, 3 -d] pyrimidine-5-carbonitrile; <21> (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methane On; <22> (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopi Ferridin-1-yl) methanone; <23> (4-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -2-fluoro-5-methoxyphenyl) ( Morpholino) methanone; 5-((5-chloro-4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -6-methoxy-2-methylisoindolin-1 -On; (4-((4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone; <26> (4-((4-cyclopropyl-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidine-1 -Yl) methanone; <27> (4-((4-cyclopropyl-5-fluoro-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) Methanone; <28> (4-((4-cyclopropyl-5-fluoro-7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morphopoly Nopiperidin-1-yl) methanone; <29> (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( 4- (oxetan-3-yl) piperazin-1-yl) methanone; <30> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (parent Polyno) methanone; <31> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (4 Morpholinopiperidin-1-yl); <32> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-fluoro-5-meth Methoxyphenyl) (morpholino) methanone; 5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -6-methoxy-2-methyl Bovinedan-1-one; 6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxy-2-methyl Bovine dollin-1-one; 6-chloro-5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-methylisoyne Dan-1-one; 5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-methylisoindolin-1- On; <37> (6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxypyridine-3- (I) (morpholino) methanone; (6-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -5-methoxypyridine-3- Yl) (4-morpholinylpiperidin-1-yl) methanone; 7-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -6-methoxy-2, 2, 4-trimethyl-2H-benzo [b] [1, 4] oxazin-3 (4H) -one; 2- (5-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -4-methylthiazole- 2-yl) -2-methylpropanenitrile; <41> 4-cyclopropyl-6-((2-methoxy-4- (morpholin-4-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ; <42> 4-cyclopropyl-6-((5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine -3-carbonitrile; <43> 4-cyclopropyl-6-((2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine -3-carbonitrile; 6-((6-methoxy-2-methyl-1-oxoisoindolin-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] pyridine-3-carbo Nitrile; <45> 6-((6-chloro-2-methyl-1-oxoisoindolin-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile ; 4-cyclopropyl-6-((6-methoxy-2-methyl-3-oxoisoindol-5-yl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbo Nitrile; 4-Cyclopropyl-6-((3-methoxy-5- (morpholin-4-carbonyl) pyridin-2-yl) amino) -1H-pyrrolo [2, 3-b] pyridine- 3-carbonitrile; <48> 4-cyclopropyl-6-((3-methoxy-5- (4-morpholinopiperidin-1-carbonyl) pyridin-2-yl) amino) -1H-pyrrolo [2, 3 -b] pyridine-3-carbonitrile; 6-((2- (2-cyanopropan-2-yl) -4-methylthiazol-5-yl) amino) -4-cyclopropyl-1H-pyrrolo [2, 3-b] Pyridine-3-carbonitrile; <50> 4-cyclopropyl-6-((6-methoxy-2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazine -7-yl) amino) -2H-pyrrolo [2, 3-b] pyridine-3-carbonitrile; <51> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -2-fluoro-5-meth Methoxyphenyl) (4-morpholinopiperidin-1-yl) methanone; <52> (4-((4-cyclopropyl-3- (trifluoromethyl) -1H-pyrrolo [2, 3-b] pyridin-6-yl) amino) -3-methoxyphenyl) (4 -(Oxetan-3-yl) piperazin-1-yl) methanone; <53> 4-cyclopropyl-6-((5-fluoro-2-methoxy-4- (4-morpholinopiperidine-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile; <54> 4-cyclopropyl-6-((2-methoxy-4- (4- (oxetan-3-yl) piperazin-1-carbonyl) phenyl) amino) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile; (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone; <4-> (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (4-morpholinopiperidin-1-yl) Methanone; (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxyphenyl) (morpholino) methanone; And 5-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -6-methoxy-2-methylisoindolin-1-one. As shown in Scheme 1, a method for preparing a compound represented by Formula 1 of claim 1 comprising the step of preparing a compound represented by Formula 4 by reacting a compound represented by Formula 2 with a compound represented by Formula 3 :
Scheme 1

(In Scheme 1, R ¹ , R ² , R ³ , A ¹ And

Is as defined in formula 1 of claim 1; And X ¹ is halogen). A pharmaceutical composition for the prophylaxis or treatment of a protein kinase-related disease containing the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 8,
The protein kinase is AAK1, ABL1 (E255K) -phosphorylated. ABL1 (F317I) -nonphosphorylated, ABL1 (F317I) -phosphorylated, ABL1 (F317L) -nonphosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) (Q252H) -nonphosphorylated, ABL1 (Q252H) -phosphorylated, ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVRA, ACVRA ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF (V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2K, CAMK2D, , CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CHEKK, CHEKK2 , CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E , CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, DRAK1, DRAK2, DYRK1, DYRK2, DYRK2 -A750del), EGFR (G719C), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHB6 ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H) D835V), FLT3 (D835Y), FLT3 (ITD), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2 (Kin.Dom.2, S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICK, IGF1R -alpha, IKK-beta, IKK-epsilon, INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domai n-catalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2 (G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPKAPK2, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MK1, MEK, MEK, MEK, MEK, MEK, MEK MELK, MERTK, MET, MET (M1250T), MET (Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKB, MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK MYLK, MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIK, NIM1, NLK, OSR1, p38-alpha, p38-beta, p38-delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1 (P.falciparum), PFPK5 (P.falciparum), PFKIRE1, PFKIRE2 PHKG1, PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA ( C420R), PIK3CA (E542K), PIK3CA (E545A), PIK3CA (E545K), PIK3CA (H1047L), PIK3CA (H1047Y), PIK3CA (I800L), PIK3CA (M1043I), PIK3CA (Q546K), PIK3CB, PIK3KB , PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKMYT1, PKN1, PKN2, PKNB (M.tuberculosis), PLK1, PLKK, PLK2, PLK2, PLK2 PRKCH, PRKCI, PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PRKR, PRKX, PRP4, PYK2, QSK, RAF1, RET, RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK3, RIOK3 , RIPK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4 (Kin.Dom.1-N-terminal), RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5 (Kin.Dom.1-N -terminal), RPS6KA5 (Kin.Dom.2-C-terminal), RSK1 (Kin.Dom.1, N-terminal), RSK1 (Kin.Dom.2-C-terminal), RSK2 (Kin.Dom.1 -N-terminal), RSK2 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.2-C-terminal), RSK4 (Kin.Dom .1-N-terminal), RSK4 (Kin.Dom.2-C-terminal), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2 , SRPK3, STK16, STK33, STK35, ST K36, STK39, SYK, TAK1, TAOK1, TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TRPMSK TSSK3, TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, WNK4, WNK4, WNK4 Pharmaceutical composition, characterized in that at least one selected from the group consisting of YANK3, YES, YSK1, YSK4, ZAK and ZAP70. The method of claim 8,
The protein kinase-related disease is at least one member selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease. The method of claim 10,
The degenerative brain disease is at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, and mild cognitive impairment. Composition. The method of claim 10,
The inflammatory diseases include dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, colitis, nephritis, systemic edema, local edema, arthritis, keratitis, bronchitis, pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, Pharmaceutical composition, characterized in that at least one member selected from the group consisting of cystitis, periodontitis, and gingivitis. The method of claim 10,
The cancer may be brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, intracranial carcinoma, epithelial cell tumor, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal / sinus cancer, nasopharyngeal cancer , Salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small intestine Cancer, Colorectal cancer, Rectal cancer, Anal cancer, Bladder cancer, Kidney cancer, Male genital tumor, Penile cancer, Prostate cancer, Female genital tumor, Cervical cancer, Endometrial cancer, Ovarian cancer, Uterine sarcoma, Vaginal cancer, Female external genital cancer, Female Pharmaceutical composition, characterized in that at least one member selected from the group consisting of urethral cancer, and skin cancer. The method of claim 8,
The compound is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1, CAMK1B, CAMKK2A, CAM2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, EPHA7, EPHALT, EPHALT3 (ITD, F691L), GAK, GCN2 (Kin.Dom.2, S808G), HIPK2, HIPK3, HIPK4, HUNK, ICK, INSR, INSRR, JNK1, JNK2, JNK3, KIT, KIT (L576P), KIT (V559D) , KIT-autoinhibited, LRRK2, LRRK2 (G2019S), LTK, LYN, MAP3K15, MAP3K2, MAPKAPK2, MAPKAPK5, MEK3, MEK4, MEK5, MEK6, MKK7, MKNK2, MYLK, MYLK2, NIK, NIM1, OSIM38, PHKG1, PHKG2, PIK3C2B, PIK4CB, PIKFYVE, PIP5K1C, PIP5K2C, PLK1, PLK4, PRKCD, PRKD1, PRKD2, PRKD3, PYK2, RIPK4, RIPK5, RPS6KA4 (Kin.Dom5, R-K. .1-N-terminal), RPS6KA5 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.2-C-terminal), STK33, STK35, STK39, SYK, TEC, TNK2, TSSK1B, TTK, Consists of TXK, YES, YSK4 and ZAP70 A pharmaceutical composition, characterized in that it exhibits inhibitory activity against at least one kinase selected from the group.

Images