Pyrrolopyridine derivatives and their use in preventing or treating protein kinase-related diseases

Abstract

The present invention relates to a pyrrolopyridine derivative, and a pharmaceutical composition comprising the pyrrolopyridine derivative as an active ingredient for preventing or treating protein kinase-related diseases. The pyrrolopyridine derivative has excellent inhibitory activity against a variety of protein kinases including LRRK2, DYRK1 and CLK1, and exhibits excellent inhibitory effects on the growth of triple-negative breast cancer cells. The pharmaceutical composition comprising the pyrrolopyridine derivative as an active ingredient can be advantageously used to treat or prevent protein kinase-related diseases, particularly cancer, degenerative brain disease and inflammatory diseases, and is particularly useful for treating triple-negative breast cancer.

Description

Technical Field

[0001] The present application relates to pyrrolopyridine derivatives and their use in preventing or treating protein kinase-related diseases. Background Art

[0002] Protein kinases are enzymes that catalyze the transfer of the terminal phosphate group of adenosine triphosphate (ATP) to specific residues (tyrosine, serine, threonine) of proteins, which are involved in regulating cell activity, growth and differentiation against changing signals from the extracellular medium and environment.

[0003] Inappropriately high protein kinase activity is directly or indirectly associated with many diseases caused by abnormal cellular activity. Diseases can be caused by failure of appropriate regulatory mechanisms of kinases involved in mutations, overexpression or insufficient enzyme activity, or excessive or insufficient production of factors involved in signaling upstream or downstream of cytokines or kinases. Therefore, selective inhibition of kinase activity can be a beneficial target for the development of new drugs for the treatment of diseases.

[0004] Brain cancer is a general term for primary brain cancers that occur in the brain tissue and the meninges surrounding the brain, and secondary brain cancers that occur in the skull or other parts of the body where the cancer has metastasized. This brain cancer is different from cancers that occur in other organs in many ways. First, cancers that occur in the lungs, stomach, breasts, etc. are limited to one or two types for each organ, and their properties are the same or similar. However, there are many different types of cancer in the brain. For example, these cancers are different, such as glioblastoma multiforme, malignant glioma, lymphadenoma, germ cell tumor, metastatic tumors, etc.

[0005] Parkinson's disease is the result of chronic progressive degeneration of neurons, but the cause is still not fully determined. Although the main cause is unknown, Parkinson's disease is characterized by degeneration of dopaminergic neurons in the substantia nigra (SN). The substantia nigra is a part of the lower brain or brainstem that helps control unconscious movements. It is known that dopamine deficiency in the brain can be observed in the symptoms caused by the loss of this neuron. Clinically, Parkinson's disease manifests as the main symptoms such as resting tremor, rigidity, bradykinesia and postural instability. MAO-B inhibitor selegiline and COMT inhibitor entacapone and levodopa, dopamine agonists (for example, rotigotine, pramipexole, bromocriptine, ropinirole, cabergoline, pergolide, apomorphine and lisupriride), anticholinergic drugs, NMDA antagonists and beta-blockers are used as drugs to relieve motor symptoms. Most of these drugs participate in dopamine and / or choline signaling, thereby affecting the typical movement disorder symptoms of Parkinson's disease.

[0006] LRRK2 (Leucine-rich repeat kinase-2) is a protein belonging to the leucine-rich repeat kinase family, consisting of a 2527 amino acid sequence, highly similar between species, and typically has GTP hydrolase (GTPase) and serine-threonine kinase activity in a single protein. It is known that LRRK2 expression is observed in various organs and tissues, including the brain, and is present in the cytoplasm or cell membrane and mitochondrial outer membrane at the cellular level. Currently, the exact in vivo function of LRRK2 has been actively studied, in which it has five functionally important domains, and is therefore expected to have a self-active regulatory effect through autophosphorylation, as well as a cellular function regulatory effect through protein interactions and enzymatic effects, and the clear parts known are that the chaperone mechanism, cytoskeleton arrangement, protein translation mechanism, synaptic vesicle endocytosis, mitogen-activated protein kinase signaling cascade, and ubiquitin / autophagy protein degradation pathway are regulated by LRRK2.

[0007] Parkinson's disease is almost sporadic, but 5%-10% of patients have a family history. From the study of samples of these patients, the gene loci of PARK1-16 have been determined so far, and genes that cause Parkinson's disease through mutations in some of their gene loci have been identified. As Parkinson's disease causative genes that cause Parkinson's disease through mutations, parkin, PINK1, DJ-1, α-synuclein, LRRK2 (leucine-rich repeat kinase-2), etc. are known. Among these genes, the LRRK2 gene was first reported in 2004 as a homologous chromosome dominant gene, similar to α-synuclein. Unlike other Parkinson's disease causative genes, Parkinson's disease patients caused by LRRK2 mutations have symptoms that are very similar to those of sporadic Parkinson's disease patients. LRRK2 mutations are found in 1-2% of sporadic Parkinson's disease patients and those with a family history of Parkinson's disease, so it will be of great help in understanding the pathogenic mechanism of Parkinson's disease and developing therapeutic agents to reveal the pathogenic mechanism of Parkinson's disease caused by mutations in this gene.

[0008] In addition, LRRK2 is known to be involved in mild cognitive impairment associated with Alzheimer's disease, L-dopa-induced dyskinesia, central nervous system diseases associated with neuronal progenitor cell differentiation, cancers (e.g., brain cancer, kidney cancer, breast cancer, prostate cancer, blood cancer, and lung cancer), and the spread of acute myeloid leukemia, papillary renal cancer, and thyroid cancer, multiple myeloma, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis, wherein compounds and compositions that effectively regulate LRRK2 activity can provide therapeutic effects on neurodegenerative diseases, central nervous system diseases, cancer, acute myeloid leukemia and multiple myeloma, and inflammatory diseases, etc.

[0009] DYRK (Dual Specificity Tyrosine Phosphorylation Regulated Kinase) is a serine / threonine kinase that has a higher evolutionary viability and plays multiple roles in central nervous system development and function. Humans have five isoforms, DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4, of which DYRK1A has received the most attention and has been extensively studied in relation to Down syndrome and degenerative brain diseases. The gene for DYRK1A is located in the Down syndrome critical region (DSCR) of human chromosome 21 and has attracted more attention because it has been identified as a determining factor for cognitive impairment, which is typical in Down syndrome patients. For Down syndrome symptom patients, from 35-40 years old, they experience cognitive impairment and memory impairment, which are mainly seen in Alzheimer's disease. Interestingly, it is known that increased expression and activity of DYRK1A occurs not only in Down syndrome, but also in patients with degenerative brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Pick's disease (reviewed by Kimura et al., Hum. Mol. Genet., 2007, 16(1), 15-23 and Wegiel et al., FEBS J., 201 1, 278(2), 236-45).

[0010] In addition, according to recent research results, DYRK1A is also a target for the development of therapeutic agents for type I diabetes. DYRK1A is involved in regulating the proliferation of β cells (insulin-producing cells of the pancreas) through NFAT signal transduction, and several studies have confirmed that inhibition of DYRK1A can activate the proliferation of β cells. In summary, effective inhibitory drugs of DYRK1A activate the proliferation of pancreatic β cells to promote the production and secretion of insulin, thereby expecting a therapeutic effect on patients with type I diabetes (Diabetes. 2016 Jun; 65 (6): 1660-71. doi: 10.2337 / db15-1127).

[0011] In addition, DYRK1A shows high expression in cancer, among which brain tumors and blood cancers are representative examples. It is reported that DYRK1A is involved in the occurrence and progression of cancer through phosphorylation of various intracellular factors (p27, cyclin D1, DREAM, c-myc, Sprouty). Specifically, for Sprouty, it is an important factor in regulating the recycling of EGFR, which is important for maintaining the stemness of cancer stem cells. By inhibiting DYRK1A, it can be expected to produce an anti-cancer effect by inhibiting the stemness of cancer stem cells. J (Cell Mol Med. 2019 Nov; 23 (11): 7427-7437). Therefore, compounds and compositions that can effectively inhibit the activity of DYRK1A can provide therapeutic effects on Down syndrome, central nervous system-related diseases, degenerative encephalopathy, cancer, diabetes, etc.

[0012] [Prior art documents]

[0013] [Non-patent document]

[0014] Kimura et al.,Hum.Mol.Genet.,2007,16(1),15-23

[0015] Wegiel et al.,FEBS J.,201 1,278(2),236-45

[0016] Diabetes.2016Jun;65(6):1660-71

[0017] J Cell Mol Med.2019Nov;23(11):7427-7437 Summary of the invention

[0018] Technical issues

[0019] An object of the present invention is to provide pyrrolopyridine derivatives.

[0020] Another object of the present invention is to provide use of the pyrrolopyridine derivatives in preventing or treating protein kinase-related diseases.

[0021] Technical Solution

[0022] In order to achieve the above goals,

[0023] According to one aspect of the present invention,

[0024] Provided is a compound represented by the following Formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt of the compound:

[0025] [Formula 1]

[0026]

[0027] In the above formula 1,

[0028] A represents a carbon atom or a nitrogen atom,

[0029] R 1 is a straight chain or branched C1-6 alkoxy group, R 2 is hydrogen, or

[0030] R 1 and R 2 Together with the benzene ring including the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S,

[0031] L 1 is sulfonyl, carbonyl or absent;

[0032] When L 1 When R is sulfonyl or carbonyl, 3 is selected from the group consisting of linear or branched C1-6 alkyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctanyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl,

[0033] When L 1 When it does not exist, R 3 is selected from phosphinic acid, azaphosphinane oxide, C1-6 alkylsulfonyl imide and phosphine oxide, wherein R 3 is unsubstituted or substituted by one or more non-hydrogen substituents selected from the group consisting of oxetanyl, C3-9 cycloalkyl, straight or branched C1-6 alkyl, acetyl, tetrahydropyranyl and benzyl, and R 3 The non-hydrogen substituents are unsubstituted or further substituted by C1-6 alkoxy or C1-6 alkyl,

[0034] L 2 is -NH-, -O- or absent;

[0035] When L 2 When it is -NH- or -O-, R 4is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4 is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0036] When L 2 When it does not exist, R 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0037] R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0038] According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a protein kinase-related disease is provided, the pharmaceutical composition containing as an active ingredient a compound represented by Formula 1 above, or an isomer, solvate, hydrate or pharmaceutically acceptable salt of the compound.

[0039] According to another aspect of the present invention, a method for preventing or treating a protein kinase-related disease is provided, the method comprising administering a pharmaceutical composition containing the compound represented by Formula 1 above or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof.

[0040] According to another aspect of the present invention, provided is a use of a pharmaceutical composition containing a compound represented by Formula 1 above or a pharmaceutically acceptable salt thereof in preventing or treating a protein kinase-related disease.

[0041] Beneficial effects

[0042] The pyrrolopyridine derivatives of the present invention have excellent inhibitory activity against multiple protein kinases including LRRK2, DYRK1 and CLK1, and have excellent effects in inhibiting the proliferation of triple-negative breast cancer cells. Therefore, the pharmaceutical composition containing the pyrrolopyridine derivatives as active ingredients can be used to treat or prevent protein kinase-related diseases, especially cancer, degenerative brain disease and inflammatory diseases, and is particularly useful for treating triple-negative breast cancer.

[0043] Description of the drawings

[0044] Figure 1 and 2 The photographs show the results of the LRRK2 phosphorylation inhibition experiment of the compounds of the present invention.

[0045] Embodiments of the invention

[0046] Hereinafter, the present invention is described in detail.

[0047] In the present specification, "halogen" may be F, Cl, Br or I.

[0048] In this specification, "haloalkyl" may refer to a straight or branched alkyl (hydrocarbon) group in which the carbon atoms are substituted by one or more halogen atoms as defined herein. Examples of haloalkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl groups independently substituted by one or more halogen atoms such as F, Cl, Br and I.

[0049] In this specification, "alkyl" may represent a straight or branched non-cyclic saturated hydrocarbon consisting of carbon atoms. Representative -(C1-8 alkyl) may include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl, -n-heptyl and -n-octyl; branched saturated alkyl may include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. -(C1-8 alkyl) may be substituted or may be unsubstituted. For example, C1-8 alkyl may be substituted by phenyl to form benzyl.

[0050] In this specification, "cycloalkyl" may represent a non-aromatic saturated or unsaturated carbocyclic ring. Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cyclohexyl, 1,3-cyclohexadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl and cyclooctadienyl, but are not limited thereto. Cycloalkyl may be substituted or may be unsubstituted. In one embodiment, cycloalkyl may be a C3-8 cycloalkyl.

[0051] In this specification, "heterocycloalkyl" may represent a saturated or partially unsaturated cyclic substituent, with a total number of 3-10 ring atoms, and containing 1-5 heteroatoms selected from N, O and S. Unless otherwise specified, heterocycloalkyl may be a monocyclic, bicyclic, spirocyclic or polycyclic ring. In addition, heterocycloalkyl may include a ring bridged by one or more elements. Heterocycloalkyl may be attached to the rest of the molecule by one or more ring carbons or heteroatoms. Examples of heterocycloalkyl include pyrrolidine, piperidine, N-methylpiperidine, imidazoline, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4 (1H, 3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyrrolidine ... pyrrolidine, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, etc., but not limited thereto.

[0052] In the present specification, "aryl" may mean any functional group or substituent derived by removing 1 hydrogen from an aromatic hydrocarbon ring. The aryl group may be a monocyclic aryl group or a polycyclic aryl group. The number of carbon atoms forming the ring in the aryl group may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of the aryl group may be phenyl, naphthyl, fluorenyl, anthracenyl, phenanthrenyl, biphenyl, terphenyl, quaterphenyl, pentaphenyl, hexaphenyl, triphenylene, pyrenyl, benzofluoranthenyl, The base, etc., are not limited to this.

[0053] In the present specification, "heteroaryl" may be an aryl ring containing one or more of O, N, P, Si and S as hetero elements. The number of carbon atoms forming a ring in the heteroaryl may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroaryl may be a monocyclic heteroaryl or a polycyclic heteroaryl. The polycyclic heteroaryl may have, for example, a bicyclic or tricyclic structure. Examples of heteroaryl groups include thienyl, thiophene, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, bipyridinyl, pyrimidinyl, triazinyl, triazolyl, acridinyl, pyridazinyl, pyrazinyl, quinolyl, quinazolinyl, quinoxalinyl, phenazolyl, phthalazinyl, pyrimidinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrazinopyrazinyl, isoquinoline, indole, carbazole, imidazolyl, imidazolyl, pyridopyridinyl, pyridopyrazinyl, pyrazinopyrazinyl, isoquinoline, The invention also includes pyridinyl, imidazopyrimidinyl, pyrazolpyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazolyl, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuranyl, phenanthroline, isoxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, dibenzothiole and dibenzofuranyl, but is not limited thereto. In one embodiment of the invention, heteroaryl can also include bicyclic heterocyclic-aryl, including aryl ring fused with heterocycloalkyl ring, or heteroaryl fused with cycloalkyl ring.

[0054] The present invention provides

[0055] The compound represented by the following formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt of the compound:

[0056] [Formula 1]

[0057]

[0058] In the above formula 1,

[0059] A represents a carbon atom or a nitrogen atom,

[0060] R 1 is a straight chain or branched C1-6 alkoxy group, R 2 is hydrogen, or

[0061] R 1 and R 2 Together with the benzene ring including the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S,

[0062] L 1 is sulfonyl, carbonyl or absent;

[0063] When L 1 When R is sulfonyl or carbonyl,3 is selected from the group consisting of linear or branched C1-6 alkyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctanyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl,

[0064] When L 1 When R does not exist, 3 is selected from phosphinic acid, azaphosphinane oxide, C1-6 alkylsulfonyl imide and phosphine oxide, wherein R 3 is unsubstituted or substituted by one or more non-hydrogen substituents selected from the group consisting of oxetanyl, C3-9 cycloalkyl, straight or branched C1-6 alkyl, acetyl, tetrahydropyranyl and benzyl, R 3 The non-hydrogen substituents are unsubstituted or further substituted by C1-6 alkoxy or C1-6 alkyl,

[0065] L 2 is -NH-, -O- or absent;

[0066] When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4 is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0067] When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0068] R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0069] In one embodiment of the present invention, a compound of Formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt thereof is provided, wherein

[0070] A represents a carbon atom or a nitrogen atom,

[0071] R 1 is a straight chain or branched C1-6 alkoxy group, R 2 For hydrogen,

[0072] L 1 is sulfonyl, carbonyl or absent;

[0073] When L 1 When R is sulfonyl or carbonyl, 3 is selected from the group consisting of linear or branched C1-6 alkyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl,

[0074] When L 1 When R does not exist, 3 is selected from phosphinic acid, azaphosphinane oxide, C1-6 alkylsulfonyl imide and phosphine oxide, wherein R 3 is unsubstituted or substituted by one or more non-hydrogen substituents selected from the group consisting of oxetanyl, C3-9 cycloalkyl, straight or branched C1-6 alkyl, acetyl, tetrahydropyranyl and benzyl, R 3 The non-hydrogen substituents are unsubstituted or further substituted by C1-6 alkoxy or C1-6 alkyl,

[0075] L 2 is -NH-, -O- or absent;

[0076] When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4 is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0077] When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0078] R5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0079] In another embodiment of the present invention, a compound of Formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt thereof is provided, wherein

[0080] A represents a carbon atom,

[0081] R 1 and R 2 Together with the benzene ring including the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S,

[0082] L 1 is sulfonyl, carbonyl or absent;

[0083] When L 1 When R is sulfonyl or carbonyl, 3 is selected from the group consisting of linear or branched C1-6 alkyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctanyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl,

[0084] When L 1 When R does not exist, 3 is selected from phosphinic acid, azaphosphinane oxide, C1-6 alkylsulfonyl imide and phosphine oxide, wherein R 3 is unsubstituted or substituted by one or more non-hydrogen substituents selected from the group consisting of oxetanyl, C3-9 cycloalkyl, straight or branched C1-6 alkyl, acetyl, tetrahydropyranyl and benzyl, R 3 The non-hydrogen substituents are unsubstituted or further substituted by C1-6 alkoxy or C1-6 alkyl,

[0085] L 2 is -NH-, -O- or absent;

[0086] When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0087] When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0088] R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0089] In another embodiment of the present invention,

[0090] R 1 and R 2 Together with the benzene ring including the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S, wherein the 8-10 membered bicyclic ring may be dihydrobenzodioxin, dihydrobenzofuran or benzodioxole.

[0091] In another embodiment of the present invention, a compound of Formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt thereof is provided, wherein

[0092] A represents a carbon atom,

[0093] R 1 is a straight chain or branched C1-6 alkoxy group, R 2 For hydrogen,

[0094] L 1 is a sulfonyl group,

[0095] R 3 is selected from the group consisting of linear or branched C1-6 alkyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl,

[0096] L 2 is -NH-, -O- or absent;

[0097] When L2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4 is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0098] When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0099] R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0100] In another embodiment of the present invention, a compound of Formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt thereof is provided, wherein

[0101] A represents a carbon atom,

[0102] R 1 is a straight chain or branched C1-6 alkoxy group, R 2 For hydrogen,

[0103] L 1 For does not exist,

[0104] R 3 is selected from phosphinic acid, azaphosphinane oxide, C1-6 alkylsulfonyl imide and phosphine oxide, wherein R3 is unsubstituted or substituted by one or more non-hydrogen substituents selected from the following: oxetanyl, C3-9 cycloalkyl, linear or branched C1-6 alkyl, acetyl, tetrahydropyranyl and benzyl, R 3 The non-hydrogen substituents are unsubstituted or further substituted by C1-6 alkoxy or C1-6 alkyl,

[0105] L 2 is -NH-, -O- or absent;

[0106] When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4 is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0107] When L 2 When R does not exist, 4is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0108] R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0109] In another embodiment of the present invention, a compound of Formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt thereof is provided, wherein

[0110] A represents a carbon atom,

[0111] R 1 and R 2 Together with the benzene ring including the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S,

[0112] L 1 is a sulfonyl group or a carbonyl group,

[0113] R 3 is selected from the group consisting of linear or branched C1-6 alkyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctanyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl,

[0114] L 2 is -NH-, -O- or absent;

[0115] When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4 is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0116] When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0117] R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0118] In another embodiment of the present invention, a compound of Formula 1, or an isomer, solvate, hydrate or pharmaceutically acceptable salt thereof is provided, wherein

[0119] A represents a carbon atom,

[0120] R 1 and R 2 Together with the benzene ring containing the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S, wherein the 8-10 membered bicyclic ring may be dihydrobenzodioxin, dihydrobenzofuran or benzophenone,

[0121] L 1 is a sulfonyl group or a carbonyl group,

[0122] R 3 is selected from the group consisting of linear or branched C1-6 alkyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl,

[0123] L 2 is -NH-, -O- or absent;

[0124] When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl, linear or branched C1-6 alkylamino and allyl, wherein R 4 is unsubstituted or further substituted by one or more non-hydrogen substituents selected from the group consisting of C1-6 alkylsulfonyl, C1-6 alkoxy and C1-6 alkyl,

[0125] When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and

[0126] R5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

[0127] Examples of the compound of Formula 1 of the present invention above may include compounds 1 to 267 listed in [Table 1] of the following embodiments, or pharmaceutically acceptable salts thereof, or free bases (shown as pharmaceutically acceptable salts in Table 1), isomers, solvates, or pharmaceutically acceptable salts:

[0128] The compound of formula 1 of the present invention described above can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed from a pharmaceutically acceptable free acid is useful. Acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid; non-toxic organic acids such as aliphatic monocarboxylates and dicarboxylates, phenyl-substituted alkanoic acid carboxylates, hydroxyalkanoic acid carboxylates and alkandioic acid carboxylates, aromatic acids and aliphatic and aromatic sulfonic acids; and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Types of nontoxic salts of this drug include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, benzylates, sebacates, fumarates, maleates, butyne-1,4-dioates , hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0129] The acid addition salt of the present invention can be prepared by conventional methods, for example, it can be prepared by dissolving the derivative of Formula 1 in an organic solvent (such as methanol, ethanol, acetone, dichloromethane and acetonitrile), adding an organic acid or an inorganic acid thereto, filtering and drying the resulting precipitate, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

[0130] In addition, alkali can be used to prepare pharmaceutically acceptable metal salts. For example, alkali metal or alkaline earth metal salts are obtained by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At the same time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salts in the form of metal salts. The corresponding salts are also obtained by reacting alkali metal or alkaline earth metal salts with suitable negative salts (e.g., silver nitrate).

[0131] Furthermore, the present invention includes not only the compounds of the above formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates and the like, which can be prepared from the compounds of the above formula 1 and pharmaceutically acceptable salts thereof.

[0132] "Hydrate" may refer to a compound of the present application or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces. The hydrate of the compound represented by Formula 1 may contain a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably about 1 equivalent to about 5 equivalents of water. Such a hydrate may be prepared by crystallization of a compound represented by Formula 1 of the present application, an isomer of the compound, or a pharmaceutically acceptable salt from water or an aqueous solvent.

[0133] "Solvate" may refer to a compound of the present application or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Thus, suitable solvents include volatile solvents, non-toxic solvents and / or solvents suitable for administration to humans.

[0134] "Isomers" may refer to compounds or salts thereof of the present application that have the same chemical formula or molecular formula but are structurally or spatially different. Such isomers include structural isomers, such as tautomers, R or S isomers with asymmetric carbon centers, stereoisomers, such as geometric isomers (trans or cis) and optical isomers (enantiomers). All of these isomers and mixtures thereof also fall within the scope of the present application.

[0135] As shown in Scheme A below, another aspect of the present invention provides

[0136] The method for preparing the compound of Formula 1 above comprises: reacting a compound represented by Formula 3 with a compound represented by Formula 4 to prepare a compound represented by Formula 2 (step 1); and

[0137] The compound represented by Formula 2 is reacted to prepare the compound of Formula 1 above (Step 2).

[0138] [Scheme A]

[0139]

[0140] In the above scheme A,

[0141] R 1 , R 2 , R 3 , R 4 , R 5 , L 1 and L 2 As defined in Formula 1 above;

[0142] X is a halogen and SEM represents a protecting group.

[0143] In the preparation method of scheme A,

[0144] Step 1 is a step of preparing a compound represented by Formula 2 (wherein an amine bond is formed) by reacting a halogen of a compound represented by Formula 3 with a primary amine of a compound represented by Formula 4. Step 1 is not limited as long as it is carried out under conditions that allow a halogen to react with an amine to prepare an amine bond, and methods well known to those skilled in the art can be used. In the present invention, the reaction is carried out under the same conditions as in Example 1, but this is only an example and is not limited thereto.

[0145] Step 2 is a step of preparing a compound of Formula 1 by deprotecting the amine protecting group of the compound represented by Formula 2, and Step 2 is not limited as long as it is carried out under conditions capable of removing the amine protecting group, and methods well known to those skilled in the art can be used. In the present invention, the reaction is carried out under the same conditions as in Example 1, but this is only an example and is not limited thereto. Examples of protecting groups may include 2-(trimethylsilyl)ethoxymethyl, trimethylsilyl (TMS), benzyl or acetyl, etc.

[0146] The following examples confirm that the present invention provides a pharmaceutical composition comprising a compound of Formula 1 above or a pharmaceutically acceptable salt thereof for use in preventing or treating a protein kinase-related disease selected from the following: ALK, ALK(C1156Y), ALK(L1196M), CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, GAK, LRRK2, LRRK2(G2019S), MYLK and TTK.

[0147] In addition, the present invention provides a method for preventing or treating a disease associated with a protein kinase selected from the group consisting of ALK, ALK(C1156Y), ALK(L1196M), CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, GAK, LRRK2, LRRK2(G2019S), MYLK and TTK, the method comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0148] In another aspect of the present invention, a pharmaceutical composition for preventing or treating a disease associated with a protein kinase selected from the following: ALK, ALK (C1156Y), ALK (L1196M), CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, GAK, LRRK2, LRRK2 (G2019S), MYLK and TTK is provided, wherein the protein kinase is preferably selected from LRRK2, LRRK2 (G2019S), DYRK1, CLK1 and TTK, and the pharmaceutical composition comprises a compound of formula 1 as an active ingredient, or an isomer, solvate, hydrate or pharmaceutically acceptable salt of the compound.

[0149] The protein kinase-related disease may be one or more selected from cancer, degenerative brain disease and inflammatory disease.

[0150] The degenerative brain disease may be one or more selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, cerebral infarction and mild cognitive impairment.

[0151] The inflammatory disease may be one or more selected from the following: dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, colitis, nephritis, generalized edema, localized edema, arthritis, keratitis, bronchitis, pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, cystitis, periodontitis and gingivitis.

[0152] The cancer may be one or more selected from the following: triple negative breast cancer, brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nose / sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, small intestine cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penis cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer and skin cancer.

[0153] The compound may exhibit inhibitory activity against one or more protein kinases selected from the group consisting of LRRK2, LRRK2(G2019S), DYRK1, CLK1 and TTK.

[0154] Specifically, the compound of Formula 1 of the present invention inhibits the proliferation of triple-negative breast cancer cells and can therefore be used to treat triple-negative breast cancer.

[0155] Furthermore, the compound of Formula 1 of the present invention effectively inhibits DYRK1 phosphorylation in oncogenic cells and thus can be used as a pharmaceutical composition for treating or preventing DYRK1-related diseases.

[0156] The compound of Formula 1 or its pharmaceutically acceptable salt can be applied with various oral and parenteral preparations during clinical administration. In the case of preparation, diluent or excipient is prepared, such as commonly used fillers, extenders, adhesives, wetting agents, disintegrants and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing at least one excipient (such as starch, calcium carbonate, sucrose or lactose and gelatin) in one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc., wherein in addition to commonly used simple diluents (such as water and liquid paraffin), various excipients such as wetting agents, sweeteners, spices and preservatives may also be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions and emulsions. As the non-aqueous solvent and suspending solvent, propylene glycol, polyethylene glycol, vegetable oil (eg olive oil), injectable ester (eg ethyl oleate) and the like can be used.

[0157] The pharmaceutical composition comprising the compound of Formula 1 above or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, wherein the parenteral administration is carried out by the following methods: subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

[0158] In this regard, in order to prepare a preparation for parenteral administration, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or a buffer in water to prepare a solution or suspension, which can be prepared into an ampoule or vial unit dosage form. The composition can be sterile and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifying agents, salts and / or buffers for regulating osmotic pressure, and other therapeutically useful substances, and can be prepared according to the usual methods of mixing, granulation or coating.

[0159] Preparations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, lozenges, etc., and these preparations contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (e.g., silicon dioxide, talc, stearic acid and magnesium or calcium salts of stearic acid and / or polyethylene glycol) in addition to the active ingredient. Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and may optionally contain a disintegrant such as starch, agar, alginic acid or sodium salt of alginic acid, or a boiling mixture and / or an absorbent, a colorant, a flavoring agent and a sweetener.

[0160] 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 contents of the present invention are not limited to the following examples and experimental examples.

[0161] <Analysis and purification conditions>

[0162] The compounds synthesized in the examples of the present invention were purified or subjected to structural analysis by the following methods.

[0163] 1. Medium Pressure Liquid Chromatography (MPLC) Purification

[0164] Medium pressure liquid chromatography was performed using CombiFlash Rf+UV ​​from TELEEDYNE ISCO.

[0165] 2. Analytical HPLC conditions (ACQUITY UPLC H-Class Core System)

[0166] The equipment equipped with a mass QDA detector manufactured by Waters was used in the UPLC system manufactured by Waters (ACQUITY UPLC PDA detector). The column used was the ACQUITY BEH C18 (1.7 μm, 2.1×50 mm) and run at a column temperature of 30° C.

[0167] As mobile phase A, water containing 0.1% formic acid was used, and as mobile phase B, acetonitrile containing 0.1% formic acid was used.

[0168] Gradient conditions (10-100% B for 3 min, moving speed = 0.6 ml / min)

[0169] 3. Preparative LCMS (Preparative Liquid Chromatography Mass Spectrometry) for Purification

[0170] The equipment equipped with a mass QDA detector produced by Waters was used in the automatic purification HPLC system produced by Waters (2767 sample manager, 2545 binary gradient module, 2998 photodiode array detector). The column used was a Waters Prep C18OBD TM (5 μm, 19X50 mm) and run at room temperature column temperature.

[0171] As mobile phase A, water containing 0.035% trifluoroacetic acid was used, and as mobile phase B, methanol containing 0.035% trifluoroacetic acid was used.

[0172] Gradient conditions (15-100% B for 10 min, moving speed = 25 ml / min)

[0173] 4. Preparative Liquid Chromatography UV Spectrometry for Purification (Preparative 150LC System)

[0174] A preparative 150LC system produced by Waters (2545 quaternary gradient module, 2998 photodiode array detector, fraction collector III) was used. The column used was a Waters Prep RP18OBDTM (10 μm, 30x300 mm), and the column temperature was room temperature.

[0175] 5. NMR analysis

[0176] NMR analysis was performed using AVANCE II or AVANCE III 400HD manufactured by Bruker, and the data were expressed as parts per million (ppm) (δ).

[0177] The commercially available reagents used were used without further purification. In the present invention, room temperature refers to a temperature of about 20 to 25° C. For concentration under reduced pressure or solvent distillation removal, a rotary evaporator was used.

[0178] <Preparation Example 1-1> Preparation of 6-chloro-N-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0179] The title compound was prepared by the method shown in Scheme 1 below.

[0180] [Solution 1]

[0181]

[0182] Step 1: Under nitrogen, 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DMF (0.7 M), and then NaH (1.5 eq) was slowly added at 0°C. The reaction mixture was reacted at 0°C for 30 minutes, stirred at 25°C for 2 hours, and (2-(chloromethoxy)ethyl)trimethylsilane (1.2 eq) was further added. Distilled water was added to the reactant, and then the organic matter was extracted with ethyl acetate (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the title compound as a white solid. (Yield: 88%)

[0183] Step 2: Under nitrogen, 4,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in NMP (1.0 M), and cyclopropylamine (2.0 eq) was slowly added thereto. The reaction mixture was stirred at 100°C for 16 hours. Distilled water was added to the reactant, and the organic matter was extracted with EtOAc (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the title compound as a white solid. (Yield: 17%)

[0184] <Preparation Example 1-2> Preparation of 6-chloro-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0185] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 79%)

[0186]

[0187] <Preparation Example 1-3> Preparation of 6-chloro-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0188] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 95%)

[0189]

[0190] <Preparation Example 1-4> Preparation of 6-chloro-n-propyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0191] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 50.6%)

[0192]

[0193] <Preparation Example 1-5> Preparation of 6-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0194] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 37.3%)

[0195]

[0196] <Preparation Example 1-6> Preparation of 6-chloro-N-isobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0197] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 37.6%)

[0198]

[0199] <Preparation Example 1-7> Preparation of 6-chloro-N-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0200] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 78%)

[0201]

[0202] <Preparation Example 1-8> Preparation of 6-chloro-N-cyclopentyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0203] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 53.8%)

[0204]

[0205] <Preparation Example 1-9> Preparation of 6-chloro-N-cyclohexyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0206] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 58.4%)

[0207]

[0208] <Preparation Example 1-10> Preparation of 6-chloro-N-(2-(methylsulfonyl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0209] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 70.8%)

[0210]

[0211] <Preparation Example 1-11> Preparation of 6-chloro-N-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0212] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 60.1%)

[0213]

[0214] <Preparation Example 1-12> Preparation of 6-chloro-N-(2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0215] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 63.6%)

[0216]

[0217] <Preparation Example 1-13> Preparation of (R)-6-chloro-N-(1-methoxypropane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0218] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 30%)

[0219]

[0220] <Preparation Example 1-14> Preparation of 6-chloro-N-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0221] The title compound was prepared in a similar manner to that of Preparation Example 1-1. (Yield: 45.7%)

[0222]

[0223] <Preparation Example 2-1> Preparation of 3,6-dichloro-N-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0224] The title compound was prepared by the method shown in Scheme 2 below.

[0225] [Solution 2]

[0226]

[0227] Step 1: Under nitrogen, 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DMF (0.5 M), and then NCS (1.1 eq) was slowly added at 0°C. The reaction mixture was reacted at 0°C for 10 minutes and stirred at room temperature for 4 hours. After adding ice water to the reactant, the solid target compound was filtered. (Yield: 63%)

[0228] Step 2: Under nitrogen, 3,4,6-trichloro-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DMF (1.1 M), and then NaH (1.5 eq) was slowly added thereto at 0°C. The reaction mixture was reacted at 0°C for 30 minutes, and after further adding (2-(chloromethoxy)ethyl)trimethylsilane (1.2 eq), it was stirred at 20°C for 4 hours. Distilled water was added to the reactant, and then the organic matter was extracted with ethyl acetate (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the target compound as a white solid. (Yield: 59%)

[0229] Step 3: Under nitrogen, 3,4,6-trichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in NMP (1.0 M), and cyclobutylamine (5.0 eq) was slowly added thereto. The reaction mixture was stirred at 100°C for 16 hours. Distilled water was added to the reactant, and the organic matter was extracted with EtOAc (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the target compound as a white solid. (Yield: 98%)

[0230] <Preparation Example 2-2> Preparation of 3,6-dichloro-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0231] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 86%)

[0232]

[0233] <Preparation Example 2-3> Preparation of 3,6-dichloro-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0234] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 62%)

[0235]

[0236] <Preparation Example 2-4> Preparation of 3,6-dichloro-n-propyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0237] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 93%)

[0238]

[0239] <Preparation Example 2-5> Preparation of 3,6-dichloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0240] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 38%)

[0241]

[0242] <Preparation Example 2-6> Preparation of 3,6-dichloro-N-isobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0243] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 84%)

[0244]

[0245] <Preparation Example 2-7> Preparation of 3,6-dichloro-N-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0246] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 79%)

[0247]

[0248] <Preparation Example 2-8> Preparation of 3,6-dichloro-N-cyclopentyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0249] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 84%)

[0250]

[0251] <Preparation Example 2-9> Preparation of 3,6-dichloro-N-cyclohexyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0252] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 53%)

[0253]

[0254] <Preparation Example 2-10> Preparation of 3,6-dichloro-N-(2-(methylsulfonyl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0255] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 46%)

[0256]

[0257] <Preparation Example 2-11> Preparation of 3,6-dichloro-N-(2-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0258] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 79%)

[0259]

[0260] <Preparation Example 2-12> Preparation of 3,6-dichloro-N-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0261] The title compound was prepared in a similar manner to that of Preparation Example 2-1. (Yield: 83%)

[0262]

[0263] <Preparation Example 3-1> Preparation of 6-dichloro-4-(ethylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0264] The title compound was prepared by the method shown in Scheme 3 below.

[0265] [Solution 3]

[0266]

[0267] Step 1: Under nitrogen, 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DCM (0.3 M), and then NIS (1.5 eq) was slowly added thereto at 0°C. The reaction mixture was reacted at 0°C for 10 minutes and stirred at room temperature for 4 hours. After adding ice water to the reactant, the obtained solid target compound was filtered. The filtered target compound was washed with n-hexane to obtain the target compound as a light brown solid. (Yield: 91%)

[0268] Step 2: Under nitrogen, 4,6-dichloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DMF (0.5 M), and then NaH (1.5 eq) was slowly added thereto at 0°C. The reaction mixture was reacted at 0°C for 30 minutes, and then stirred at 20°C for 4 hours after further adding (2-(chloromethoxy)ethyl)trimethylsilane (1.2 eq). Distilled water was added to the reactant, and then the organic matter was extracted with diethyl ether (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the target compound as a white solid. (Yield: 65%)

[0269] Step 3: 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in EtOH (2.0 M), and ethylamine (5.0 eq) was slowly added thereto. The reaction mixture was stirred at 100°C for 16 hours. Distilled water was added to the reactant, and the organic matter was extracted with diethyl ether (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was subjected to MPLC (EtOAc:Hex) to obtain the target compound as a white solid. (Yield: 44%)

[0270] Step 4: 6-Chloro-N-ethyl-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.0 eq) was dissolved in DMF (0.25 M), and then CuI (0.7 eq) and CuCN (2.0 eq) were slowly added thereto. Pd(PPh 3 ) 4 (0.5eq), and the mixture was stirred at 80°C for 16 hours. Distilled water was added to the reactant, and then the organic matter was extracted with EtOAc (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the target compound as a white solid. (Yield: 45%)

[0271] <Preparation Example 3-2> Preparation of 6-chloro-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0272] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 78%)

[0273]

[0274] <Preparation Example 3-3> Preparation of 6-chloro-4-(propylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0275] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 66%)

[0276]

[0277] <Preparation Example 3-4> Preparation of 6-chloro-4-(cyclopentylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0278] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 70%)

[0279]

[0280] <Preparation Example 3-5> Preparation of 6-chloro-4-(cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0281] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 74%)

[0282]

[0283] <Preparation Example 3-6> Preparation of 6-chloro-4-((2-(methylsulfonyl)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0284] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 52%)

[0285]

[0286] <Preparation Example 3-7> Preparation of 6-chloro-4-(cyclopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0287] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 67%)

[0288]

[0289] <Preparation Example 3-8> Preparation of 6-chloro-4-(cyclobutylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0290] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 97%)

[0291]

[0292] <Preparation Example 3-9> Preparation of 6-chloro-4-((2-methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0293] The title compound was prepared in a similar manner to that of Preparation Example 3-1. (Yield: 73%)

[0294]

[0295] <Preparation Example 4-1> Preparation of 6-chloro-N-methyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amino

[0296] The title compound was prepared by the method shown in Scheme 4 below.

[0297] [Solution 4]

[0298]

[0299] Step 1: CuI (5.0 eq) and KF (5.0 eq) were kept at 200 °C under reduced pressure close to vacuum for 2 hours to remove moisture. After the reaction was cooled to room temperature, TMS-CF 3 (5.0eq) was dissolved in DMF and NMP (1:1 ratio, total 0.2M) and then slowly added thereto via a syringe. The reaction mixture was reacted at room temperature for 1 hour, and 4-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0eq) was further dissolved in DMF and NMP (1:1 ratio, total 0.2M) and then slowly added thereto via a syringe. The reaction mixture was stirred at 50°C for 16 hours. Distilled water was added to the reactant, and the organic matter was then extracted with ether (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the target compound as a white solid. (Yield: 74%)

[0300] Step 2: Under nitrogen, 4,6-dichloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DMSO (1.0 M), and K was slowly added thereto. 2 CO 3(3.0 eq) and 33% methylamine in ethanol (5.0 eq). The reaction mixture was stirred at 100°C for 16 hours. Distilled water was added to the reactant, and then the organic matter was extracted with EtOAc (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the title compound as a white solid. (Yield: 52%)

[0301] <Preparation Example 4-2> Preparation of 6-chloro-N-ethyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0302] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 88%)

[0303]

[0304] <Preparation Example 4-3> Preparation of 6-chloro-n-propyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0305] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 61%)

[0306]

[0307] <Preparation Example 4-4> Preparation of n-butyl-6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0308] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 50.2%)

[0309]

[0310] <Preparation Example 4-5> Preparation of 6-chloro-N-isopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0311] The title compound was prepared in a similar manner to that of Example 4-1. (Yield: 57%)

[0312]

[0313] <Preparation Example 4-6> Preparation of 6-chloro-N-isobutyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0314] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 69%)

[0315]

[0316] <Preparation Example 4-7> Preparation of 6-chloro-N-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0317] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 20%)

[0318]

[0319] <Preparation Example 4-8> Preparation of 6-chloro-N-(2-methoxyethyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0320] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 68%)

[0321]

[0322] <Preparation Example 4-9> Preparation of 6-chloro-N-(2-ethoxyethyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0323] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 88%)

[0324]

[0325] <Preparation Example 4-10> Preparation of 6-chloro-N-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0326] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 62%)

[0327]

[0328] <Preparation Example 4-11> Preparation of 6-chloro-N-cyclobutyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0329] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 45.9%)

[0330]

[0331] <Preparation Example 4-12> Preparation of 6-chloro-N-cyclopentyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0332] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 62%)

[0333]

[0334] <Preparation Example 4-13> Preparation of 6-chloro-N-cyclohexyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0335] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 58%)

[0336]

[0337] <Preparation Example 4-14> Preparation of (R)-6-chloro-N-(1-methoxypropane-2-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0338] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 49%)

[0339]

[0340] <Preparation Example 4-15> Preparation of 6-chloro-N-(oxetan-3-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0341] The title compound was prepared in a similar manner to that of Example 4-1. (Yield: 21%)

[0342]

[0343] <Preparation Example 4-16> Preparation of N 1 -(6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N 2 ,N 2 -Dimethylethane-1,2-diamine

[0344] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 14.7%)

[0345]

[0346] <Preparation Example 4-17> Preparation of 6-chloro-N-(2-(isopropylsulfonyl)ethyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0347] The title compound was prepared in a similar manner to that of Preparation Example 4-1. (Yield: 10%)

[0348]

[0349] <Preparation Example 4-18> Preparation of 2-((6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino-N,N-dimethylethane-1-sulfonamide

[0350] The title compound was prepared in a similar manner to that of Example 4-1. (Yield: 15%)

[0351]

[0352] <Preparation Example 5-1> Preparation of 6-chloro-4-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

[0353] The title compound was prepared by the method shown in Scheme 5 below.

[0354] [Solution 5]

[0355]

[0356] Step 1: Under nitrogen, 4-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DMF (0.5 M), and then NaH (1.2 eq) was slowly added thereto at 0°C. The reaction mixture was reacted at 0°C for 30 minutes, and then stirred at 25°C for 2 hours after further adding (2-(chloromethoxy)ethyl)trimethylsilane (1.2 eq). Distilled water was added to the reactant, and then the organic matter was extracted with ethyl acetate (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the target compound as a white solid. (Yield: 81%)

[0357] Step 2: 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq), cyclopropylboronic acid (2.0 eq) and cesium carbonate (2.0 eq) were dissolved in toluene (0.5 M) and then sonicated for 1 min to remove gas. Pd 2 (dba) 3 (0.15eq) and Xantphos (0.1eq) were then reacted at 120°C for 16 hours. The reaction mixture was filtered through Celite and washed with DCM. The filtrate was concentrated and then purified by MPLC (EtOAc: Hex) to give the target compound as a white solid. (Yield: 75%)

[0358] Step 3: Under nitrogen, 4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0eq) was dissolved in DMF (1.5M), and then NIS (1.5eq) was slowly added thereto at 0°C. The reaction mixture was reacted at 0°C for 10 minutes and stirred at room temperature for 2 hours. After adding ice water to the reactant, the obtained solid target compound was filtered. The filtered target compound was washed with n-hexane to obtain the target compound as a light brown solid. (Yield: 53%)

[0359] Step 4: CuI (5.0 eq) and KF (5.0 eq) were kept at 200 °C under reduced pressure close to vacuum for 2 hours to remove moisture. After the reactants were cooled to room temperature, TMS-CF 3(5.0eq) was dissolved in DMF and NMP (1:1 ratio, total 1.0M) and then slowly added thereto via a syringe. The reaction mixture was reacted at room temperature for 1 hour, and 4-cyclopropyl-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0eq) was further dissolved in DMF and NMP (1:1 ratio, total 1.0M) and then slowly added thereto via a syringe. The reaction mixture was stirred at 50°C for 16 hours. Distilled water was added to the reactant, and the organic matter was extracted with ethyl acetate (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the title compound as a white solid. (Yield: 90%)

[0360] Step 5: 4-cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in chloroform (0.25 M), and then 3-chloroperbenzoic acid (3.0 eq) was added thereto, and the reaction was carried out at 75° C. for 16 hours using a reflux apparatus. By adding Na to the reactant at 0° C. 2 S 2 O 3 The reaction was quenched with water and the organic material was extracted with DCM (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was used for the next step without further purification. (Yield: 105%)

[0361] Step 6: 4-(Cyclopropyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.0 eq) was dissolved in DMF (0.3 M), and then methanesulfonyl chloride (4.0 eq) was added thereto and reacted at 80° C. for 30 minutes. The reaction was terminated by adding water to the reactant at 0° C., and NaHCO was further used to 3 After the aqueous solution was titrated to pH 8, the organic material was extracted with EtOAc (x3). The collected organic layer was washed with brine and then with Na 2 SO 4 The remaining water was removed. The reaction was purified by MPLC (EtOAc:Hex) to obtain the target compound as an ivory white solid. (Yield: 38%).

[0362] <Preparation Example 6-1> Preparation of 6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0363] The title compound was prepared by the method shown in Scheme 6 below.

[0364] [Solution 6]

[0365]

[0366] Step 1: 4-Cyclopropyl-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in DMF (0.5 M), and then CuI (0.7 eq) and CuCN (2.0 eq) were slowly added thereto. Pd(PPh 3 ) 4 (0.5eq) and stirred at 80°C for 16 hours. Distilled water was added to the reaction, and then the organic matter was extracted with EtOAc (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the target compound as a white solid. (Yield: 76%)

[0367] Step 2: 4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (1.0 eq) was dissolved in chloroform (0.18 M), and then 3-chloroperbenzoic acid (3.0 eq) was added thereto, and the reaction was carried out at 75° C. for 16 hours using a reflux apparatus. By adding Na 2 S 2 O 3 The reaction was quenched with water and the organic material was extracted with DCM (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was used for the next step without further purification. (Yield: 110%)

[0368] Step 3: 3-Cyano-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (1.0 eq) was dissolved in DMF (0.3 M), and then methanesulfonyl chloride (4.0 eq) was added thereto and reacted at 80°C for 30 minutes. The reaction was terminated by adding water to the reactant at 0°C, and NaHCO was further used. 3 After the aqueous solution was titrated to pH 8, the organic material was extracted with EtOAc (x3). The collected organic layer was washed with brine and then with Na 2 SO 4 The remaining water was removed. The reaction was purified by MPLC (EtOAc:Hex) to obtain the target compound as a white solid. (Yield: 49%)

[0369] <Preparation Example 7-1> Preparation of 6-chloro-4-ethoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

[0370] The title compound was prepared by the method shown in Scheme 7 below.

[0371] [Solution 7]

[0372]

[0373] Step 1: Under nitrogen, 4,6-dichloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.0 eq) was dissolved in THF (1.0 M), and then NaH (1.1 eq) and 33% ethanol (1.5 eq) were slowly added thereto. The reaction mixture was stirred at room temperature for 16 hours. Distilled water was added to the reactant, and then the organic matter was extracted with EtOAc (x3). The collected organic layer was washed with brine and then concentrated under reduced pressure while using Na 2 SO 4 The remaining water was removed. The concentrated mixture was purified by MPLC (EtOAc:Hex) to give the title compound as a white solid. (Yield: 19%)

[0374] <Example 1> Preparation of Compounds of the Present Invention 1

[0375] The pyrrolopyridine derivative compounds of the present invention are prepared in the same manner as shown in Scheme 8 below.

[0376] [Scheme 8]

[0377]

[0378] Step 1: The compound prepared in step 2 of scheme 1 (1.0 eq), 2-methoxy-4-(methylsulfonyl)aniline (1.2 eq) and K 2 CO 3 (5.0 eq) was added to sec-butyl alcohol (0.1 M) and dissolved, and then sonicated for 1 minute to remove gas. Pd 2 (dba) 3 (0.1 eq) and Xphos (0.1 eq) were added to the reaction mixture, which was then stirred at 100°C for 2 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. After concentrating the resulting filtrate, the resulting liquid mixture was used in the next step without further purification. (Yield: 104%)

[0379] Step 2: N 4 -Cyclopropyl-N 6 -(2-Methoxy-4-(methylsulfonyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine (1.0 eq) was dissolved in CH 2 Cl 2 (0.1 M), and then TFA (73 eq) was added at room temperature. After reacting for 2 hours, the solvent was removed. The concentrated mixture was dissolved in 1,4-dioxane (0.1 M), and then NH 4 OH (0.1 M), and the mixture was reacted at 60°C for 2 hours. After the reaction, the solvent was removed by concentration under reduced pressure. The concentrated mixture was purified by preparative HPLC to obtain the target compound as a solid. (Yield: 86%)

[0380] Examples 2-267 were prepared in a manner similar to Example 1. The chemical structures, compound names, and NMR, mass spectrometry, and HPLC analysis results of Examples 1-267 are summarized and shown in Table 1 below.

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470] <Experimental Example 1> Evaluation of Enzyme Inhibitory Activity of the Compounds of the Present Invention 1

[0471] In order to evaluate the inhibitory activity of the compounds of the present invention on LRRK2, LRRK2(G2019S), DYRK1, CLK1 and TTK kinases, the following experiments were performed.

[0472] 1) LRRK2

[0473] The example compounds were reacted with purified human LRRK2 (Invitrogen #PR8604B) enzyme, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer used was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg / ml BSA and 50 μM DTT, and the reactions of all test materials were carried out in reaction buffer. The compounds were diluted with 10 mM DMSO stock solution in 12 steps by a serial dilution method, and the enzyme activity was measured at final compound concentrations of 50, 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256, 0.00000512 and 0.000001024 μM. In the test, human LRRK2 (25 ng) enzyme was reacted with purified ATP (10 μM) and enzyme substrate (0.2 μg) at 25°C for 2 hours, and then in vitro ADP-Glo TM Kinase assay (Promega) was used to identify enzyme activity. The enzyme activity reaction solution, ADP-Glo ​​reaction solution and enzyme potency detection solution were reacted in a ratio of 2:2:1, and the degree of inhibition of enzyme activity was determined by luminescence. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control group not treated with the compound, where the concentration of each compound that inhibited 50% of the enzyme activity was determined as IC 50 The results are shown in Table 2 below.

[0474] 2) LRRK2 G2019S

[0475] The example compounds were reacted with purified human LRRK2G2019S (L10-12GG, SignalChem) enzyme, and the enzyme inhibition ability was evaluated as follows. The reaction buffer used was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5mg / ml BSA and 50μM DTT, and the reactions of all test materials were carried out in reaction buffer. The compounds were diluted with 10mM DMSO stock solution in 12 steps by a serial dilution method, and the enzyme activity was measured at final compound concentrations of 50, 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256, 0.00000512 and 0.000001024μM. In the test, human LRRK2G2019S (16ng) enzyme was reacted with purified ATP (25μM) and enzyme substrate (0.2μg) at 25°C for 2 hours, and then in vitro ADP-Glo TM The enzyme activity was identified by kinase assay (Promega). The enzyme activity reaction solution, ADP-Glo ​​reaction solution and enzyme efficacy detection solution were reacted in a ratio of 2:2:1, and the degree of inhibition of the enzyme activity was determined by luminescence. The degree of inhibition of the enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control group not treated with the compound, where the concentration of each compound that inhibited 50% of the enzyme activity was determined as IC 50 The results are shown in Table 2 below.

[0476] 3) GST-DYRK1A

[0477] The example compounds were reacted with purified human GST-DYRK1A (full length, Thermo scientifics) enzyme, and the enzyme inhibitory ability was evaluated as follows. As the reaction buffer, 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg / mL BSA and 50 μM DTT, and all test materials were reacted in reaction buffer. During the test, human GST-DYRK1A (full length, 10 ng) enzyme, purified ATP (10 uM) and specific substrate solution were reacted at 25°C for 1 hour, and then in vitro ADP-Glo TMThe enzyme activity was identified by using a kinase assay (Promega). Luminescence was measured by reacting an enzyme activity reaction solution, an ADP-Glo ​​reaction solution, and an enzyme potency detection solution at a ratio of 2:2:1. The degree of inhibition of the enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control group not treated with the compound, wherein the concentration of each compound that inhibited the enzyme activity by 50% was determined as IC 50 IC values ​​(nM) were determined for each compound in triplicate data sets. 50 , and obtained using Prism (version 7.01, GraphPad) software.

[0478] 4) GST-CLK1

[0479] The example compounds were reacted with purified human GST-CLK1 (129-end, Signalchem) enzyme, and the enzyme inhibitory ability was evaluated as follows. As the reaction buffer, 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg / mL BSA and 50 μM DTT, and all test materials were reacted in the reaction buffer. During the test, human GST-CLK1 (129-end, 3 ng) enzyme, purified ATP (10 μM) and specific substrate solution were reacted at 25°C for 1 hour, and then in vitro ADP-Glo TM The enzyme activity was identified by kinase assay (Promega). Luminescence was measured by reacting the enzyme activity reaction solution, ADP-Glo ​​reaction solution and enzyme efficacy detection solution at a ratio of 2:2:1. The degree of inhibition of the enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control group not treated with the compound, where the concentration of each compound that inhibited the enzyme activity by 50% was determined as IC 50 IC values ​​(nM) were determined for each compound in triplicate data sets. 50 , and obtained using Prism (version 7.01, GraphPad) software. The results are shown in Table 2 below.

[0480] 5)TTK

[0481] The compounds of the examples were reacted with purified human TTK (Signalchem ​​#T20-10G) enzyme, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer used was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2, 0.1 mg / ml BSA (5X kinase buffer, Signalchem ​​#K03-09) and 50 μM DTT (Signalchem ​​#D86-09B), and all test material reactions were performed in reaction buffer. Compounds were diluted with 10 mM DMSO stock solution in 12 steps by serial dilution method, and enzyme activity was measured at final compound concentrations of 1, 0.333333, 0.1111, 0.037037, 0.012346, 0.004115, 0.001372, 0.000457, 0.000152, 0.000051, and 0.000017 μM. In the test, human TTK (7.5 ng) enzyme was reacted with purified ATP (5 μM, Promega #V6930) and MBP enzyme substrate (0.2 μg, Signalchem ​​M42-51N) at 25°C for 4 hours, and then in vitro ADP-Glo TM Kinase assay (Promega # V6930) was used to identify enzyme activity. The enzyme activity reaction solution, ADP-Glo ​​reaction solution and enzyme efficacy detection solution were reacted at a ratio of 2:2:1, and the degree of inhibition of enzyme activity was determined by luminescence. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the degree of luminescence of the enzyme activity of the solvent control group not treated with the compound, where the concentration of each compound that inhibited 50% of the enzyme activity was determined as IC 50 (nM) values ​​were obtained using Prism (version 8.2, GraphPad) software.

[0482] Meanwhile, enzyme IC of some compounds was performed using Kinase HotSpot service (Reaction Biology Corporation). 50 Measurement; during the test, the ATP concentration was 10 μM, all performed under the same conditions; and the concentration of the compound was measured by giving a 3-fold concentration gradient with a highest concentration of 10 mM, wherein the values ​​measured using the Kinase HotSpot service (Reaction Biology Corporation) are marked with "*".

[0483] All experimental methods were performed as provided in Kinase HotSpot Customer Protocol (http: / / www.reactionbiology.com / / Kinase_Assay_Protocol). The results are shown in Table 2 below.

[0484] In the following table, the enzyme inhibition ability was evaluated using the following designated symbols.

[0485] 0-100nM=A; 101-300nM=B; 301-1000nM=C;

[0486] [Table 2]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492] The values ​​marked with * are data measured using Reaction Biology.

[0493] As shown in Table 2 above,

[0494] It can be seen that the example compounds of the present invention exhibit the effect of inhibiting LRRK2, LRRK2(G2019S), DYRK1, CLK1 and TTK kinases.

[0495] It was thus demonstrated that the Example compounds of the present invention have inhibitory activities against the above-listed enzymes, thereby suggesting that they have useful effects when used in the above-listed enzyme-related diseases.

[0496] Therefore, the compound of formula 1 of the present invention can be used as a pharmaceutical composition for preventing or treating diseases related to LRRK2, LRRK2(G2019S), DYRK1, CLK1 and TTK kinases.

[0497] <Experimental Example 2> Evaluation of MDA-MB-231, MDA-MB-468 and SHP-77 cancer cell proliferation inhibition

[0498] In order to evaluate the cancer cell proliferation inhibitory activity of the compounds of the present invention, the following experiment was performed.

[0499] To evaluate the cancer cell proliferation inhibitory effect, MDA-MB-231 cell line (Korean Cell Line Bank #30026) and MDA-MB-468 cell line as triple-negative breast cancer cell lines, and SHP-77 (ATCC #CRL-2195) as small cell lung cancer cell line were cultured in DMEM (HyClone #SH30243) and RPMI medium (HyClone #SH3027.01), respectively, and cell growth rate analysis was performed. More specifically, the cell lines were seeded at 2000 cells / 100 μl in each well of a 96-well flat-bottom plate (Corning #3903), and then treated with 11 concentrations of the example compounds (1 / 3 dilution, so that the final concentrations were 10.000000, 3.3333, 1.1111, 0.370370, 0.123457, 0.041152, 0.013717, 0.004572, 0.001524, 0.000508 and 0.000169 μM). After 72 hours, 100 μl of Cell Titer-Glo (Promega G7573) was added, incubated at room temperature for 10 minutes, and then luminescence was measured using a microplate reader. The measured luminescence was calculated as GI using Prism (version 8.2, GraphPad) software. 50 .

[0500] In the following table, the proliferation inhibitory activity was evaluated using the following designated symbols.

[0501] 0-50nM=A; 51-100nM=B; 101-300nM=C; 301-1000nM=D;

[0502] [Table 3]

[0503]

[0504] As shown in Table 3, it can be seen that the example compounds of the present invention can inhibit the proliferation of triple-negative breast cancer cells.

[0505] Therefore, the compound of formula 1 of the present invention can be used to treat triple-negative breast cancer.

[0506] <Experimental Example 3> Evaluation of cytokine secretion inhibitory activity of human-derived monocytes

[0507] To evaluate the inhibitory effect of cytokine secretion from monocytes, THP-1 cells (ATCC, #TIB-202), a human monocytic cell line, were cultured in RPMI-1640 (Hyclone, SH30027.01) medium containing 10% fetal bovine serum (Hyclone, SH30084.03), 1% penicillin-streptomycin (Welgene, LS202-02) and 50 μM 2-mercaptoethanol (Gibco, #21985023). 5 Cells / 250 μl / well were dispensed into a 48-well plate (SPL, #30048) and incubated at 37°C and 5% CO 2 Incubate in an incubator for 16 hours, then dilute the compound in DMSO to a final concentration of 0.5 μM. Treat with lipopolysaccharide (LPS) (Sigma, #L6529) 1 hour before treatment. After treatment with the compound, treat LPS to a final concentration of 500 ng / ml, then collect the cell culture fluid after 24 hours of culture, and use each ELISA kit to collect the cytokine IL-6 (R&D system, #D6050) and TNF-α (R&D system, #DTA00D) contained in the culture fluid. After performing the experiment according to the manufacturer's instructions, measure the absorbance at 450 nm and analyze it using a microplate reader.

[0508] [Table 4]

[0509]

[0510]

[0511] <Experimental Example 4> Evaluation of Tau phosphorylation inhibition

[0512] Using ClariCELL in the United States TM Kinase Cell-Based Assay service measures the efficacy of Tau phosphorylation inhibition. The compound is exposed to human embryonic kidney (HEK 293) cells transiently expressing human DYRK1A and Tau, and then the cells are lysed to release cellular proteins. At this point, the released Tau is captured on a plate and the degree of phosphorylation is quantified by ELISA using a Tau phosphorylation-specific antibody.

[0513] [Table 5]

[0514]

[0515]

[0516] <Experimental Example 5> Evaluation of phosphorylation inhibition of LRRK2 (leucine-rich repeat kinase-2)

[0517] In order to evaluate the effect of the compound of formula 1 of the present invention on inhibiting LRRK2 phosphorylation, the following experiment was performed. The results are as follows: Figure 1 and 2 shown.

[0518] Specifically, the NIH3T3 cell line was identified as a fibroblast by Western blotting, and the cells were treated with compounds to inhibit LRRK2 phosphorylation in the cells. The NIH3T3 cell line was seeded in a 6×10 5 The cells were placed in a 60 mm dish and allowed to adhere for one day, and then the compound was added to a final concentration of 100 nM, and DMSO was added to the culture medium to have a content of 0.1%, and then incubated at 37°C CO 2 Cultured in an incubator for 24 hours. After removing the culture medium and washing twice with PBS, the cells were lysed and recovered with 1X RIPA buffer containing phosphatase inhibitors and protease inhibitors. After centrifugation at 4°C and 14000rpm for 15 minutes, the protein in the supernatant was quantified by Bradford test and sampled with 5X sample buffer. The same amount of protein was electrophoresed on SDS PAGE gel and transferred to a nitrocellulose membrane. The membrane was blocked with 5% skim milk for 1 hour, and then anti-LRRK2 (ab133474), anti-LRRK2 (phospho S935, ab133450) and anti-actin primary antibodies were added thereto and refrigerated for 16 hours. After washing with 1×TBS-T buffer (0.05% tween20), secondary antibody was added, incubated for 1 hour, washed, reacted with ECL substrate, and then detected with LAS500. The results are shown in Figure 1 and 2 middle.

[0519] like Figure 1 and 2 As shown, it can be seen that the example compounds according to the present invention significantly inhibit the phosphorylation of LRRK2 in the NIH3T3 cell line, which is a fibroblast. In addition, it can be seen that the amount of P-LRRK2 detected is significantly lower than that in the case where the compound according to the present invention is not treated. This means that the compound of the present invention effectively inhibits the phosphorylation of LRRK2. Figure 1 and 2 As shown, it can be seen that the example compounds of the present invention significantly inhibit the phosphorylation of LRRK2 in the NIH3T3 cell line, which is a fibroblast. In addition, it can be seen that the amount of P-LRRK2 detected is significantly low compared to the case where the compound of the present invention is not treated. This means that the compound of the present invention effectively inhibits the phosphorylation of LRRK2.

[0520] Therefore, the compounds of Formula 1 of the present invention effectively inhibit LRRK2 phosphorylation in oncogenic cells, so that they can be effectively used as pharmaceutical compositions for treating or preventing LRRK2-related diseases.

[0521] <Experimental Example 6> Evaluation of the inhibitory activity of various kinases of the compounds of the present invention

[0522] In order to evaluate the inhibitory activity of the compounds of the present invention on more enzymes, the following experiments were performed.

[0523] Specifically, for Examples 162, 160, 105, 217, 205, 96, 207, 184, 206, 221, 238 and 237 selected from the Example compounds of the present invention, it was decided to measure the enzyme (kinase) selectivity by DiscoverX and use the TM The group of kinase assays was subjected to the experiment. For this, the concentration of the drug treated with the enzyme in DMSO was 1 μM, and the control percentage (% control) was determined in the same manner as in the following equation 1, and the results are shown in the following Table 6.

[0524] [Equation 1]

[0525] (Example compound - positive control) / (negative control - positive control) x 100

[0526] In this regard, the positive control refers to a compound showing a control percentage of 0%, and the negative control is DMSO, showing that the control percentage is 100%. In addition, in the enzyme selectivity of the present invention, if the control percentage of each enzyme is <35% (i.e., less than 35%), it is determined that it has activity against the relevant enzyme.

[0527] [Table 6]

[0528]

[0529] As shown in Table 6 above, the example compounds of the present invention showed a control percentage of less than 35% for ALK, ALK(C1156Y), ALK(L1196M), CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, GAK, LRRK2, LRRK2(G2019S), MYLK or TTK kinases, which shows that they have inhibitory activity against the relevant enzymes.

[0530] Therefore, the compound of formula 1 of the present invention can be used to treat protein kinase-related diseases.

Claims

1. A compound represented by the following formula 1, or a stereoisomer or a pharmaceutically acceptable salt of the compound: [Formula 1] in, A represents a carbon atom or a nitrogen atom, R 1 and R 2 Together with the benzene ring including the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S, wherein the 8-10 membered bicyclic ring is a dihydrobenzodioxin, a dihydrobenzofuran or a benzodioxole; L 1 is sulfonyl or carbonyl; R 3 is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl, L 2 is -NH-, -O- or absent; When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl and allyl, When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

2. The compound of formula 1 according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt of the compound, Where A represents a carbon atom, R 1 and R 2 Together with the benzene ring including the carbon atom to which they are attached, they form an 8-10 membered bicyclic ring containing one or more heteroatoms selected from N, O and S, wherein the 8-10 membered bicyclic ring is a dihydrobenzodioxin, a dihydrobenzofuran or a benzodioxole; L 1 is sulfonyl or carbonyl; R 3 is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, isoxazolidinyl and azaspirooctyl, wherein R 3 is unsubstituted or further substituted with one or more non-hydrogen substituents selected from the group consisting of morpholinyl, oxetanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, phenyl, amino, piperazinyl, piperidinyl, C3-9 cycloalkyl and straight or branched C1-6 alkyl, wherein R 3 The non-hydrogen substituents are unsubstituted or further substituted by substituents selected from the group consisting of halogen, hydroxy, C3-9 cycloalkyl and straight or branched C1-6 alkyl, L 2 is -NH-, -O- or absent; When L 2 When it is -NH- or -O-, R 4 is selected from C3-9 cycloalkyl and allyl, When L 2 When R does not exist, 4 is C3-9 cycloalkyl or amino, wherein R 4 is unsubstituted or further substituted with one or more C1-6 alkyl groups; and R 5 It is hydrogen, cyano, C1-6 haloalkyl or halogen.

3. A compound selected from the following, or a stereoisomer or a pharmaceutically acceptable salt of said compound: <2> (8-((4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <3> (8-((4-(Ethylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone 2,2,2-trifluoroacetate; <4> Morpholino(8-((4-(propylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone 2,2,2-trifluoroacetate; <5> (8-((4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <6> (8-((4-(isobutylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <7> (8-((4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <8> (8-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <9> (8-((4-((2-(methylsulfonyl)ethyl)amino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <33> 4-(Ethylamino)-6-((7-(morpholine-4-carbonyl)benzo[d][1,3]dioxin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <34> 4-(Ethylamino)-6-((7-(4-morpholinopiperidine-1-carbonyl)benzo[d][1,3]dioxol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <35> 4-(Ethylamino)-6-((8-(4-(oxetan-3-yl)piperazine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <36> 4-(Cyclobutylamino)-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <37> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)benzo[d][1,3]dioxol-4-yl)(4-morpholinopiperidin-1-yl)methanone; <38> (7-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)benzo[d][1,3]dioxol-4-yl)(morpholino)methanone; <43> ((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(8-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanone; <44> ((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(8-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanone; <49> (7-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)benzo[d][1,3]dioxol-4-yl)(4-morpholinopiperidin-1-yl)methanone; <50> (8-((4-(dimethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <51> (8-((4-(ethyl(methyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <52> (7-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(morpholino)methanone; <53> (7-((4-(cyclopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(morpholino)methanone; <54> (7-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(morpholino)methanone; <55> (7-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-morpholinopiperidin-1-yl)methanone; <56> (8-((3-chloro-4-(methylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone 2,2,2-trifluoroacetate; <57> (8-((3-chloro-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <58> (8-((3-chloro-4-(propylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <59> (8-((3-chloro-4-(isopropylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <60> (8-((3-chloro-4-(cyclopropylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <61> (8-((3-chloro-4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <62> (8-((3-chloro-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <63> (8-((3-chloro-4-((2-(methylsulfonyl)ethyl)amino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <89> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(morpholino)methanone; <90> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-morpholinopiperidin-1-yl)methanone; <91> (7-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(morpholino)methanone; <92> (7-((4-(cyclopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-morpholinopiperidin-1-yl)methanone; <93> (7-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-morpholinopiperidin-1-yl)methanone; <96> N 4 -ethyl-N 6 -(8-((4-morpholinopiperidin-1-yl)sulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine; <97> N 4 -(2-methoxyethyl)-N 6 -(8-((4-morpholinopiperidin-1-yl)sulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine; <98> N 4 -Methyl-N 6 -(8-(morpholinosulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine; <99> N 4 -ethyl-N 6 -(8-(morpholinosulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine; <100> 4-cyclopropyl-N-(8-(morpholinosulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-amine; <101> (8-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-(oxetan-3-yl)piperazin-1-yl)methanone; <104> N 4 -ethyl-N 6 -(4-((4-morpholinopiperidin-1-yl)sulfonyl)-2,3-dihydrobenzofuran-7-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine; <105> (4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptanyl-5-yl)piperidin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <106> 4-(Methylamino)-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <107> 4-(Ethylamino)-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <108> 6-((8-(Morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <109> 4-((2-methoxyethyl)amino)-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <110> 4-((2-(methylsulfonyl)ethyl)amino)-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <111> 4-(Cyclopropylamino)-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <112> 4-(Cyclopentylamino)-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <113> 4-(Ethylamino)-6-((8-(4-morpholinopiperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <114> 6-((8-(4-morpholinopiperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <115> 4-(Methylamino)-6-((8-(4-morpholinopiperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <116> 4-(Cyclopropylamino)-6-((8-(4-morpholinopiperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <117> 4-(Cyclobutylamino)-6-((8-(4-morpholinopiperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <118> 4-((2-methoxyethyl)amino)-6-((8-(4-morpholinopiperidin-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <149> 4-(Cyclohexylamino)-6-((8-(4-morpholinopiperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <150> N 4 -(Cyclohexylamine)-N 6 -((8-(Morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <152> (8-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <153> (8-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <154> (8-((4-(cyclohexylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <155> (8-((4-(cyclopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone 2,2,2-trifluoroacetate; <156> (8-((4-(isobutylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <157> (8-((4-((2-(methylsulfonyl)ethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <158> (8-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <159> (R)-(8-((4-((1-methoxypropan-2-yl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <160> (8-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <161> (8-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <162> (4-morpholinopiperidin-1-yl)(8-((4-(propylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanone; <163> (8-((4-(cyclopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <164> (8-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <165> (8-((4-((2-(methylsulfonyl)ethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <166> (8-((4-((2-ethoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <167> (8-((4-((2-ethoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <168> (8-((4-(isopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <169> (8-((4-(Butylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <170> (8-((4-(Butylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <171> (8-((4-((2-(dimethylamino)ethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <172> (8-((4-((2-(dimethylamino)ethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <173> (8-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-(oxetan-3-yl)piperazin-1-yl)methanone; <174> Morpholino(8-((4-(propylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methanone; <175> (8-((4-(cyclobutylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone 2,2,2-trifluoroacetate; <176> (8-((4-(cyclobutylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <213> (R)-(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <214> (R)-(7-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <215> (S)-(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <217> (S)-(7-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <220> (8-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <221> (8-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(4-morpholinopiperidin-1-yl)methanone; <225> 4-cyclopropyl-6-((8-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <226> 4-cyclopropyl-6-((8-(4-morpholinopiperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; <231> (8-((4-ethoxy-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)(morpholino)methanone; <233> N 4 -Methyl-N 6 -(8-((4-morpholinopiperidin-1-yl)sulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine; <234> (7-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-morpholinopiperidin-1-yl)methanone; <235> (7-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)benzo[d][1,3]dioxol-4-yl)(4-morpholinopiperidin-1-yl)methanone; <236> (7-((4-(Ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)benzo[d][1,3]dioxol-4-yl)(morpholino)methanone; <237> (S)-(7-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <238> (R)-(7-((4-cyclopropyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <241> (4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptanyl-5-yl)piperidin-1-yl)(7-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <244> (4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanyl-5-yl)piperidin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <245> (R)-(3-(3,5-difluorophenyl)isoxazolin-2-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <246> (S)-(3-(3,5-difluorophenyl)isoxazolin-2-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <247> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone; <248> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-(oxetan-3-yl)piperazin-1-yl)methanone; <249> (4-(dimethylamino)piperidin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <250> (4-cyclopropylpiperazin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <251> (4-cyclopentylpiperazin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <252> (4-allylpiperazin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <253> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone; <254> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-isopropylpiperazin-1-yl)methanone; <255> (7-((4-(allylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(4-morpholinopiperidin-1-yl)methanone; <256> (7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(6-azaspiro[2.5]octan-6-yl)methanone; <257> (4-(cyclopropylmethyl)piperazin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <258> ((2S,6R)-2,6-dimethylmorpholino)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <259> (S)-(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(2-methylmorpholino)methanone; <260> (R)-(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(2-methylmorpholino)methanone; <261> (R)-(7-((4-(allylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <262> (S)-(7-((4-(allylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)(3-morpholinopyrrolidin-1-yl)methanone; <263> (4-((2S,6R)-2,6-dimethylmorpholino)piperidin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone; <264> (4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)(7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanone.

4. A pharmaceutical composition for preventing or treating a disease associated with a protein kinase selected from ALK, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, GAK, LRRK2, MYLK and TTK, the pharmaceutical composition comprising as an active ingredient a compound of formula 1 according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt of the compound.

5. A pharmaceutical composition for preventing or treating a disease associated with a protein kinase selected from ALK C1156Y, ALK L1196M, and LRRK2 G2019S, the pharmaceutical composition comprising as an active ingredient a compound of formula 1 as described in claim 1, or a stereoisomer or a pharmaceutically acceptable salt of the compound.

6. The pharmaceutical composition according to claim 4 or 5, wherein the protein kinase-related disease is one or more diseases selected from cancer, degenerative brain disease and inflammatory disease.

7. The pharmaceutical composition according to claim 6, wherein the degenerative brain disease is one or more diseases selected from the group consisting of dementia and mild cognitive impairment.

8. The pharmaceutical composition according to claim 6, wherein the degenerative brain disease is Alzheimer's disease, Parkinson's disease or Huntington's disease.

9. The pharmaceutical composition of claim 6, wherein the inflammatory disease is one or more selected from the group consisting of dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, nephritis, generalized edema, localized edema, arthritis, keratitis, bronchitis, pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, cystitis, periodontitis, and gingivitis.

10. The pharmaceutical composition according to claim 9, wherein the enteritis is colitis.

11. The pharmaceutical composition of claim 6, wherein the cancer is one or more selected from the group consisting of brain tumors, benign astrocytomas, malignant astrocytomas, meningiomas, oligodendrogliomas, ependymomas, head and neck tumors, laryngeal cancer, oropharyngeal cancer, nose / sinus cancer, nasopharyngeal cancer, thyroid cancer, oral cancer, chest tumors, small cell lung cancer, non-small cell lung cancer, esophageal cancer, breast cancer, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, penis cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female urethral cancer, and skin cancer.

12. The pharmaceutical composition according to claim 11, wherein the breast cancer is triple-negative breast cancer or male breast cancer.

13. The pharmaceutical composition of claim 11, wherein the brain tumor is a pituitary adenoma, a brain lymphoma or a brain stem tumor.

14. The pharmaceutical composition of claim 11, wherein the oral cancer is salivary gland cancer or hypopharyngeal cancer.

15. The pharmaceutical composition according to claim 11, wherein the thoracic tumor is a mediastinal tumor.

16. The pharmaceutical composition of claim 15, wherein the mediastinal tumor is thymic carcinoma.

17. The pharmaceutical composition of claim 4, wherein the compound exhibits inhibitory activity against one or more protein kinases selected from the group consisting of ALK, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, GAK, LRRK2, MYLK, and TTK.

18. The pharmaceutical composition of claim 5, wherein the compound exhibits inhibitory activity against a protein kinase selected from the group consisting of ALK C1156Y, ALK L1196M, and LRRK2 G2019S.

19. Use of the compound of formula 1 as defined in claim 1 or a stereoisomer or a pharmaceutically acceptable salt of the compound in the preparation of a medicament for preventing or treating a disease associated with a protein kinase selected from ALK, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, GAK, LRRK2, MYLK and TTK.

20. Use of the compound represented by formula 1 as defined in claim 1 or a stereoisomer or a pharmaceutically acceptable salt of the compound in the preparation of a medicament for preventing or treating a disease associated with a protein kinase selected from ALK C1156Y, ALK L1196M, and LRRK2 G2019S.

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