WO2024035194A1 - Novel heteroaryl-substituted derivative and composition for preventing or treating neurodegenerative disease, cancer, and inflammatory disease comprising same - Google Patents

Novel heteroaryl-substituted derivative and composition for preventing or treating neurodegenerative disease, cancer, and inflammatory disease comprising same Download PDF

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Publication number
WO2024035194A1
WO2024035194A1 PCT/KR2023/011915 KR2023011915W WO2024035194A1 WO 2024035194 A1 WO2024035194 A1 WO 2024035194A1 KR 2023011915 W KR2023011915 W KR 2023011915W WO 2024035194 A1 WO2024035194 A1 WO 2024035194A1
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methyl
chloro
pyrrol
pyrididin
amino
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PCT/KR2023/011915
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French (fr)
Korean (ko)
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신호철
예인해
이규환
윤지수
이그림
유병훈
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환인제약 주식회사
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Priority claimed from KR1020230105159A external-priority patent/KR102651320B1/en
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Publication of WO2024035194A1 publication Critical patent/WO2024035194A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • Neurodegenerative disease is a brain disease that occurs with age and is known to occur due to the accumulation of environmental and genetic factors.
  • Representative examples include Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, and motor neuropathy.
  • Examples include motor neuron disease, spinocerebellar ataxia, spinal muscular atrophy, Creutzfeldt-Jakob disease, and alcohol related dementia.
  • Parkinson's disease along with Alzheimer's disease, is one of the representative neurodegenerative diseases. It is caused by a lack of the neurotransmitter dopamine due to the loss of dopaminergic neurons in the substantia nigra of the brainstem. As a result, protein aggregates called Lewy bodies are formed within nerve cells, causing motor function abnormalities such as stooped posture, tremors, stiffness, and instability, as well as mental symptoms such as depression, anxiety, and sleep disorders.
  • Parkinson's disease Although the exact cause of Parkinson's disease is not known, it is believed to be caused by a combination of factors such as environmental factors, genetic factors, aging, mitochondrial dysfunction, and abnormalities in the processing of unnecessary proteins. Most Parkinson's diseases occur sporadically, but 5-10% are known to be genetic diseases caused by gene mutations.
  • the causative genes include parkin, PINK1, DJ-1, and ⁇ -synuclein. ), LRRK2 (leucine-rich repeat kinase 2), etc. are known.
  • LRRK2 is a protein belonging to the leucin-rich repeat kinase family and consists of a sequence of 2527 amino acids with high similarity between species. , It has both GTPase and serine-threonine kinase activities in one protein. LRRK2 has been reported to be highly expressed in dopaminergic neurons present in the cerebral cortex, substantia nigra, striatum, hippocampus, and cerebellum of the brain, which are related to the pathogenesis of Parkinson's disease. Increased activity of LRRK2 has been shown to affect the onset and progression of Parkinson's disease. It is known.
  • LRRK2 is known to be involved in the transfer of mild cognitive impairment related to Alzheimer's disease, so compounds and compositions effective in regulating LRRK2 activity can provide therapeutic effects for neurodegenerative diseases. Therefore, selective inhibition of LRRK2 activity may be a beneficial target for the development of new drugs for disease treatment.
  • LRRK2 has been reported to be overexpressed in kidney, thyroid, and liver cancer tissues, and it is known that overactivation of LRRK2 due to LRRK2 mutation (particularly G2019S type) increases the risk of breast cancer.
  • LRRK2 mutation particularly G2019S type
  • Voronoi recently received approval to enter phase 1 clinical trials for its LRRK2 inhibitor as a treatment for brain cancer.
  • LRRK2 has been identified as a major genetic susceptibility gene for Crohn's disease, and it has been reported that LRRK2 deficiency increases susceptibility to colitis in animal experiments (Zhihua Liu & Michael J Lenardo, (2012) Cell Research 22:1092 -1094).
  • the LRRK2 expression profile was confirmed to be useful for studying colitis function in experimental models such as dextran sulfate sodium (DSS)-induced colitis, in which innate immune cells play an important role in the pathogenesis of the disease.
  • DSS dextran sulfate sodium
  • LRRK2 inflammatory signaling pathway is believed to be related to the MAPK pathway, and it has recently been demonstrated that LRRK2 kinase activity plays an important role in inflammation and toxicity through activation of the sub-pathway of MAPK signaling in both macrophages and microglia. (Kim, J. et al. (2019) LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.
  • LRRK2 activity as a factor influencing chronic inflammatory changes, especially for Crohn's disease and ulcerative colitis.
  • changes in expression levels may increase intestinal inflammation, which suggests that regulating LRRK2 activity will play a very important role as a treatment for inflammatory diseases in the future.
  • Korean Patent No. 10-1566091 discloses a pyrazole aminopyrimidine derivative as an LRRK2 regulator
  • Korean Patent No. 10-2025451 discloses a 2-(phenyl or pyrid-3-yl) aminopyrimidine derivative as a regulator of the kinase LRRK2 for the treatment of Parkinson's disease
  • Korean Patent No. 10-1208198, LRRK2 A pharmaceutical composition for the treatment or prevention of Parkinson's disease containing a compound with phosphorylation enzyme inhibitory activity as an active ingredient is disclosed, and Korean Patent Publication No.
  • 10-2019-0018676 discloses piri as an LRRK2 inhibitor for use in the treatment of neurodegenerative disorders.
  • Midin-2-ylamino-1H-pyrazole has been disclosed.
  • heteroaryl-substituted derivatives such as Formula 1 of the present invention and their LRRK2 inhibitory activity and the possibility of treating neurodegenerative diseases therefrom.
  • the present inventors confirmed that heteroaryl-substituted derivatives such as Formula 1 of the present invention have excellent LRRK2 inhibitory activity and efficiently pass through the blood brain barrier (BBB), thereby demonstrating the present invention. Completed.
  • BBB blood brain barrier
  • One object of the present invention is to provide novel heteroaryl-substituted derivatives.
  • Another object of the present invention is to provide a method for producing novel heteroaryl-substituted derivatives.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neurodegenerative diseases, cancer, or inflammatory diseases, containing a novel heteroaryl-substituted derivative as an active ingredient.
  • Another object of the present invention is to provide a health functional food for preventing or improving neurodegenerative diseases, cancer, or inflammatory diseases containing a novel heteroaryl-substituted derivative as an active ingredient.
  • a compound represented by the following formula (1) a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • Y is hydrogen, halogen, or unsubstituted or halogen-substituted C 1 -C 6 alkyl
  • Z is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 3 -C 12 heterocycloalkyl, is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C 4 -C 12 aryl, or substituted or unsubstituted C 4 -C 12 heteroaryl;
  • X is unsubstituted or substituted phenyl or heteroaryl of 5-6 atoms
  • the substituted phenyl or heteroaryl of 5-6 atoms is,
  • p is an integer from 0 to 5
  • A is hydrogen or C 1 -C 6 alkyl
  • B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO- B, or -(CH 2 )p-CONAB is C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
  • substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
  • a method for producing a compound represented by Formula 1 of claim 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3:
  • X, Y, and Z are as defined in Formula 1 above.
  • prevention of neurodegenerative diseases, cancer or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient Alternatively, a pharmaceutical composition for treatment is provided.
  • a treatment for neurodegenerative diseases, cancer, or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Health functional foods for prevention or improvement are provided.
  • administering to a subject in need a pharmaceutical composition containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient Provides a method for preventing or treating neurodegenerative diseases, cancer, or inflammatory diseases, including.
  • a compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable compound thereof is used in the prevention or treatment of neurodegenerative diseases, cancer, or inflammatory diseases.
  • a pharmaceutical composition containing a salt is provided.
  • the novel heteroaryl-substituted derivative according to the present invention has excellent LRRK2 inhibitory activity and efficiently passes the blood brain barrier (BBB), making it useful as a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, cancer, or inflammatory diseases. Available.
  • BBB blood brain barrier
  • One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • Y is hydrogen, halogen, or unsubstituted or halogen-substituted C 1 -C 6 alkyl
  • Z is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 3 -C 12 heterocycloalkyl, is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C 4 -C 12 aryl, or substituted or unsubstituted C 4 -C 12 heteroaryl;
  • X is unsubstituted or substituted phenyl or heteroaryl of 5-6 atoms
  • the substituted phenyl or heteroaryl of 5-6 atoms is,
  • p is an integer from 0 to 5
  • A is hydrogen or C 1 -C 6 alkyl
  • B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO- B, or -(CH 2 )p-CONAB is C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
  • substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
  • Ar is phenyl or heteroaryl of 5-6 atoms
  • R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 3 -C 6 cycle. alkyl oxy, unsubstituted or substituted 3-7 membered heterocycloalkyl, or unsubstituted or substituted C 3 -C 6 cycloalkyl;
  • R 2 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO -B, or -(CH 2 )p-CONAB,
  • p is an integer from 0 to 5
  • A is hydrogen or C 1 -C 6 alkyl
  • B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
  • substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
  • Y is halogen or C 1 -C 6 alkyl substituted with halogen
  • R 1a , R 1b , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy , unsubstituted or substituted C 3 -C 6 cycloalkyl oxy, unsubstituted or substituted 3-7 membered heterocycloalkyl, or unsubstituted or substituted C 3 -C 6 cycloalkyl;
  • R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
  • p is an integer from 0 to 5
  • A is hydrogen or C 1 -C 6 alkyl
  • B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
  • substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
  • Y is halogen or C 1 -C 6 alkyl substituted with halogen
  • Z is hydrogen or C 1 -C 6 alkyl
  • R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 5 alkyl, unsubstituted or halogen-substituted C 1 -C 5 alkoxy, unsubstituted or substituted C 3 -C 6 cycle. alkyloxy, unsubstituted or substituted C 3 -C 6 cycloalkyl,
  • R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
  • p is an integer from 0 to 4,
  • A is hydrogen or C 1 -C 5 alkyl
  • B is unsubstituted or substituted C 1 -C 5 alkyl, unsubstituted or substituted C 3 -C 5 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-6 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
  • R 3 is unsubstituted or substituted C 1 -C 5 alkyl, or unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
  • R 4 , R 5 , and R 6 are each independently hydrogen or unsubstituted or substituted C 1 -C 5 alkyl
  • substituted C 1 -C 5 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl, and substituted 3-7 atom heterocycloalkyl are each independently C 1 -C 5 alkyl, C 1 -C 5 alkoxy, cyano, amino substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3-7 unsubstituted or substituted with C 1 -C 6 alkyl
  • the atom is substituted with heterocycloalkyl.
  • Y is halogen or C 1 -C 6 alkyl substituted with halogen
  • Z is hydrogen or C 1 -C 4 alkyl
  • R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or halogen-substituted C 1 -C 4 alkoxy, unsubstituted or substituted C 3 -C 5 cycle. alkyloxy, unsubstituted or substituted C 3 -C 5 cycloalkyl,
  • R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
  • p is an integer from 0 to 3
  • A is hydrogen or C 1 -C 3 alkyl
  • B is unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or substituted C 3 -C 5 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
  • R 3 is unsubstituted or substituted C 1 -C 4 alkyl, or unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
  • R 4 , R 5 , and R 6 are each independently hydrogen or unsubstituted or substituted C 1 -C 4 alkyl
  • substituted C 1 -C 4 alkyl, substituted C 3 -C 5 cycloalkyl, substituted 5-6 atom heteroaryl, and substituted 3-7 atom heterocycloalkyl are each independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3-7 unsubstituted or substituted with C 1 -C 6 alkyl
  • the atom is substituted with heterocycloalkyl.
  • Examples of the compound represented by Formula 1 according to the present invention include the following compounds:
  • the compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate.
  • the acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts.
  • the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (e.g., silver nitrate).
  • the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, stereoisomers, hydrates, etc. that can be prepared therefrom.
  • alkyl refers to a straight or branched chain fully saturated hydrocarbon group
  • examples of alkyl include methyl (Me), ethyl (Et), propyl (e.g. n-propyl and isopropyl groups, butyl (e.g. n -Butyl, isobutyl, s-butyl, t-butyl), pentyl (eg, n-pentyl, isopentyl (Isopentyl group), neopentyl group), etc.
  • cycloalkyl refers to a saturated hydrocarbon group with a ring-shaped single bond.
  • halo and “halogen” are used in their conventional sense to refer to a fluoro (F), chloro (Cl), bromo (Br) or iodo (I) substituent.
  • haloalkyl includes alkyl substituted with one or more halogens, either monosubstituted (eg -CH2F) or multiply substituted (eg -CF3).
  • alkoxy refers to an oxygen group to which a single bond of straight or branched saturated hydrocarbon is bonded. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and 1-methylpropoxy.
  • heterocycloalkyl refers to a ring-shaped, single-bonded saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, Nyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanil, tiazepa These include nil, dioxothiazepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, dioxanyl, dioxolanyl, etc.
  • heteroaryl refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, it may be pyridyl, pyrrolyl, or pyrrolyl.
  • hydrate refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt.
  • the hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the hydrate may contain more than 1 equivalent of water, preferably 1 to 5 equivalents of water.
  • Such hydrates can be prepared by crystallizing the compound represented by Formula 1 of the present invention, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt from water or a water-containing solvent.
  • solvate refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.
  • isomers refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different.
  • isomers include structural isomers, including tautomers, and stereoisomers.
  • Stereoisomers include enatiomers and diastereomers that appear by having one or more asymmetric carbon centers, and geometric isomers. (trans, cis) are all included. All these isomers and mixtures thereof are also included within the scope of the present invention.
  • substituted with one or more substituents means substituted with 1 to 3 substituents among the listed substituents.
  • the compound, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt can inhibit LRRK2.
  • Another aspect of the present invention is the prevention of neurodegenerative diseases, cancer, or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for treatment is provided.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • the neurodegenerative disease refers to a disease that causes various symptoms as degenerative changes occur due to gradual and steady death of neurons in the central nervous system, and includes Parkinson's disease, Alzheimer's disease, and Huntington's disease.
  • disease Pick's disease, amyotrophic lateral sclerosis, Prion disease, Motor neuron disease, Spinocerebellar ataxia, Spinal muscular atrophy It may be selected from the group consisting of muscular atrophy, Creutzfeldt-Jakob disease, and alcohol related dementia, but is not particularly limited thereto.
  • the above cancers include kidney cancer, thyroid cancer, breast cancer, liver cancer, brain cancer, lung cancer, ovarian cancer, colon cancer, melanoma, stomach cancer, gastrointestinal cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine cancer, rectal cancer, It may be selected from the group consisting of colon cancer, esophageal cancer, laryngeal cancer, small intestine cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer, and multiple myeloma, and preferably consists of kidney cancer, thyroid cancer, breast cancer, liver cancer, and brain cancer. It may be selected from the group, but is not particularly limited thereto.
  • the inflammatory diseases include inflammatory bowel disease, ulcerative colitis, inflammatory skin disease, pancreatitis, allergic rhinitis, allergic conjunctivitis, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, ankylosing spondylitis, enteropathy spondylitis, and juvenile spondylitis.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.
  • a pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you do it.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form.
  • a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form.
  • the composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.
  • Dosage forms for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc.
  • These dosage forms contain a diluent (e.g. lactose) in addition to the active ingredient. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol).
  • the tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron agents such as starch, agar, alginic acid or its sodium salt, etc.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron agents such as starch, agar, alginic acid or its sodium salt, etc.
  • the releasing or boiling mixture may contain absorbents, colorants, flavoring agents, and sweeteners.
  • Another aspect of the present invention is the prevention of neurodegenerative diseases, cancer, or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Or provide health functional foods for improvement.
  • the compound represented by Formula 1 according to the present invention exhibits excellent LRRK2 inhibitory ability, and is manufactured as a pharmaceutical composition as a health functional food composition for preventing or improving neurodegenerative diseases, cancer, or inflammatory diseases, or as a food, beverage, etc. It can be added to health functional supplements.
  • the compound represented by Formula 1 according to the present invention can be added as is to food or used together with other foods or food ingredients, and can be used appropriately according to conventional methods.
  • the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention or improvement).
  • the amount of the above compound in health food can be 0.1 to 90 parts by weight of the total weight of the food.
  • the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
  • Another aspect of the present invention is to provide a pharmaceutical composition or health functional food containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.
  • a method for preventing or treating neurodegenerative diseases, cancer, or inflammatory diseases including the step of administering.
  • Another aspect of the present invention is the use of the compound represented by Formula 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt in the prevention or treatment of neurodegenerative diseases, cancer, or inflammatory diseases. Provides a purpose.
  • the compound represented by Formula 1 of the present invention, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt or pharmaceutical composition is administered in a “pharmaceutically effective amount.”
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is determined by the type and severity of the individual, age, It can be determined based on factors including gender, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.
  • effective amounts of 0.001 mg/kg to 1000 mg/kg, 0.01 mg/kg to 100 mg/kg or 0.1 to 20 mg/kg or 0.1 to 500 mg/kg are included.
  • the amount of the pharmaceutical composition of the present invention can be selected and implemented by a person skilled in the art within an appropriate range.
  • the compound represented by Formula 1 of the present invention can be prepared by the following manufacturing method.
  • X, Y, and Z are as defined in Formula 1 above.
  • the coupling reaction of Scheme 1 may proceed by a substitution reaction and may proceed in the presence of a transition metal catalyst. Additionally, the process may be carried out in the presence of a base, and an organic solvent may be used as the solvent.
  • Pd(PPh 3 ) 4 may be used, and the organic solvent may include 1,4-dioxane, tetrahydrofuran, DMF, DMSO, chloroform, etc.
  • Bases include organic or inorganic bases.
  • Organic bases may include primary, secondary, and tertiary amines, and inorganic bases may include carbonates and hydroxides of alkali metals or alkaline earth metals.
  • R 1a , R 1b , Y, Z, p, A and B are as defined in Formula 1 above.
  • Reaction Scheme 2 is an amidation reaction that can be performed in an organic solvent under the conditions of addition of a catalyst or an acid activator.
  • the catalyst may be an acid catalyst and includes an inorganic or organic acid.
  • the acid activator may be a carbodiimide such as EDCl, HOBt, or an acylating agent.
  • a tertiary amine such as DIPEA may be further included as a base.
  • R 1a , R 1b , Y, Z, and p are as defined in Formula 1 above.
  • Reaction Scheme 3 consists of the following steps.
  • Step 1 is a combination reaction of pyrrole derivatives and proceeds as a substitution reaction in an organic solvent in the presence of a catalyst and a base.
  • Step 2 is a substitution reaction with an amine derivative, and the reaction conditions of step 1 can be applied as is.
  • one or more types selected from XantPhos and Pd(OAc) 2 may be used.
  • Step 3 is a hydrolysis reaction of an ester bond, which can be performed under an acid or base catalyst.
  • the base mentioned in Scheme 1 can be applied as is, and the acid can be an inorganic or organic acid.
  • Inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • workup can be performed under acid conditions to obtain the target product in acid form.
  • methyl 4-amino-3-hydroxybenzoate (1.5 g, 8.97 mmol) was dissolved in 100 ml RBF with DMF, and then K 2 CO 3 (1.865 g, 13.5 mmol) and iodoethane (1.469 g) , 9.42 mmol) was added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 50°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (white solid, 1.6 g, 91%).
  • methyl 4-amino-3-hydroxybenzoate (1 g, 5.98 mmol) was completely dissolved in 100 ml RBF with DMF, and then K2CO3 (1.239 g, 8.97 mmol) and 2,2,2-trifluoride.
  • Roethyl trifluoromethanesulfonate (1.666 g, 7.18 mmol) was added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 50°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (white solid, 462 mg, 31%).
  • methyl 4-amino-3-bromobenzoate (1 g, 4.07 mmol) was completely dissolved in 1,4-dioxane in 100 ml RBF, and then cyclopropylbroic acid (457 mg, 5.33 mmol) , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (334 mg, 0.41 mmol), and K 3 PO 4 (3.046 g, 14.4 mmol) were added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 100°C for 3 hours. After completion of the reaction, the mixture was filtered under reduced pressure with celite bad and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (white solid, 555 mg, 66%).
  • Step 1 According to the above reaction formula, methyl 3-fluoro-4-nitrobenzoate (2 g, 10.1 mmol) was completely dissolved in 100 ml RBF with DMF, and then Cs 2 CO 3 (4.913 g. 15.1 mmol) and cyclopropanol. (759 mg, 13.1 mmol) was added at room temperature. The mixture was stirred at room temperature for 5 minutes and then heated at 80°C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure and purified through column chromatography to obtain methyl 3-cyclopropoxy-4-nitrobenzoate (light yellow solid, 1.295 g, 53%).
  • Step 2 Methyl 3-cyclopropoxy-4-nitrobenzoate (1.259 g, 5.31 mmol) was completely dissolved in 100 ml RBF with methanol, then Zn (519 mg. 7.95 mmol), HCO 2 HN 4 (534 mg, 8.48 mmol) mmol) was added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 80°C for 16 hours. After completion of the reaction, the mixture was filtered under reduced pressure with a celite bad, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (yellow solid, 900 mg, 82%).
  • methyl 4-amino-3-hydroxybenzoate 500 mg, 2.99 mmol was completely dissolved in 100 ml RBF with DMF, then K 2 CO 3 (619 mg, 4.48 mmol), 1,1-di Fluoro-2-iodoethane (631 mg. 3.28 mmol) was added at room temperature. The mixture was stirred at 80° C. for 16 hours. After completion of the reaction, extraction was performed several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (yellow solid, 452 mg, 67%).
  • the compound of Example 1 was prepared according to the above reaction scheme.
  • 2,4,5-Trichloropyrimidine (11.5 g, 62.98 mmol) was dissolved in 200 mL of 1,4-dioxane, then 1-methyl-3-(4,4,5,5-tetramethyl-1) ,3,2-dioxaborolan-2-yl)-1H-pyrrole (15 g, 72.4 mmol), Pd(PPh3)4 (946 mg, 0.81 mmol), 2M Na 2 CO 3 solution (50 mL) Add and stir at 105°C for 6 hours. The organic layer extracted by adding ethyl acetate, saturated NaCl aqueous solution, and water is dried, filtered, and concentrated using MgSO 4 . The obtained crude product was separated by column chromatography to obtain 13.55 g (94% yield) of the target compound as a yellow solid.
  • Methyl 4-amino-3-methoxybenzoate (716 mg, 3.95 mmol) was dissolved in 20 mL of 1,4-dioxane, then 2,5-dichloro-4-(1-methyl-1H-pyrrole-3- 1) Add pyrimidine ( 992 mg , 4.35 mmol), Stir for a while. The reaction mixture is filtered under reduced pressure on a Celite pad, and the filtrate is extracted with ethyl acetate, saturated NaCl aqueous solution, and water. The extracted organic layer is dried, filtered, and concentrated using MgSO 4 . The obtained crude product was separated by column chromatography to obtain 1146 mg (77.8% yield) of the target compound as a yellow solid.
  • Step 4) (4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone manufacture of
  • Examples 1 to 108 were prepared using the reaction prepared in Example 1, and the names and NMR spectrum data of the prepared compounds are summarized in Table 1 below, and the structures of the compounds are summarized in Table 2.
  • Example 109 The compound of Example 109 was prepared according to the above reaction scheme.
  • LRRK2 kinase (Signal Chem, Richmond, BC, Canada), 0.2 ug/ul LRRKtide (Signal Chem, Richmond, BC, Canada), and 25 umol/L ATP (Invitrogen, Carlsbad, CA) were added to a 384-well plate.
  • Kinase reaction buffer solution 40 mmol/L TrisHCl, 10 mmol/L MgCl2, and 0.1 ug/uL BSA (bovine serum albumin) was added and mixed.
  • the IC50 value of the measured kinase was classified into grade A if it was less than 10nM, grade B if it was 10 to 100nM, and grade C if it was more than 100nM, and is summarized in Table 5 below. In addition, the grade A compound G2019S enzyme activity % value is was obtained, and the experiment was conducted at a concentration of 100nM.
  • Example Wild type G2019S (enzyme activity%) Example Wild type G2019S (enzyme activity%) Example Wild type G2019S (enzyme activity%)
  • Example Wild type G2019S (enzyme activity%)
  • the test substance was prepared at a dosage of 5 mg/kg, and blood was collected from the heart immediately after sacrificing the animal at 1 and 3 hours after oral administration and centrifuged to prepare plasma samples.
  • the heart was perfused with 20 ml of saline solution containing 10 U/ml heparin, and the brain was removed. PBS buffer 3 times the weight of the brain tissue was added and homogenized.
  • LC-MS/MS (Agilent, Santa Clara, CA, USA) was used for quantitative analysis of the prepared plasma and brain tissue.
  • a mobile phase consisting of 80% acetonitrile and 20% water with 0.1% formic acid was used.
  • the total run time per substance is 3 minutes and the flow rate is 0.3 ml/min.
  • Table 6 The results are shown in Table 6 below.

Abstract

The present invention relates to a novel heteroaryl-substituted derivative and a composition for preventing or treating neurodegenerative diseases, cancer, and inflammatory diseases comprising same. The heteroaryl-substituted derivative according to the present invention has excellent LRRK2 inhibitory activity and can efficiently penetrate through a blood-brain barrier (BBB), and thus can be used as a pharmaceutical composition for preventing or treating neurodegenerative diseases, cancer, and inflammatory diseases.

Description

신규한 헤테로아릴 치환 유도체 및 이를 포함하는 신경퇴행성 질환, 암, 및 염증성 질환의 예방 또는 치료용 조성물Novel heteroaryl-substituted derivatives and compositions containing the same for preventing or treating neurodegenerative diseases, cancer, and inflammatory diseases
신규한 헤테로아릴 치환 유도체 및 이를 포함하는 신경퇴행성 질환, 암, 및 염증성 질환의 예방 또는 치료용 조성물에 관한 것이다.It relates to novel heteroaryl-substituted derivatives and compositions containing the same for preventing or treating neurodegenerative diseases, cancer, and inflammatory diseases.
신경퇴행성 질환(neurodegenerative disease)은 나이가 들어감에 따라 발생하는 뇌 질환으로 환경적, 유전적 요인의 누적으로 인하여 발병하는 것으로 알려져 있다. Neurodegenerative disease is a brain disease that occurs with age and is known to occur due to the accumulation of environmental and genetic factors.
중추 신경계의 신경 세포에 점진적이고 꾸준한 사멸로 인한 퇴행성 변화가 나타나면서 여러 가지 증상을 유발하는 질환을 통칭하며, 세포 손상과 기억 장애를 포함하는 신경 구조와 기능의 손실이 특징적이다. 대표적인 예로는, 파킨슨병(Parkinson's disease), 알츠하이머병(Alzheimer's disease), 헌팅턴병(huntington's disease), 피크병(Pick's disease), 근위축성 축삭경화증(Amyotrophic lateral sclerosis), 프리온병(Prion disease), 운동신경 세포병(Motor neuron disease), 척수 소뇌실조증(Spinocerebellar ataxia), 척수성근위축증(Spinal muscular atrophy), 크로이츠펠트-야콥병(Creutzfeldt-Jakob disease) 및 알코올성 치매(Alcohol related dementia) 등을 들 수 있다. It refers to a disease that causes various symptoms as degenerative changes occur due to gradual and steady death of nerve cells in the central nervous system, and is characterized by loss of nerve structure and function, including cell damage and memory impairment. Representative examples include Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, and motor neuropathy. Examples include motor neuron disease, spinocerebellar ataxia, spinal muscular atrophy, Creutzfeldt-Jakob disease, and alcohol related dementia.
파킨슨병(parkinson's disease)은 알츠하이머병과 함께 대표적인 신경퇴행성 질환 중의 하나로, 뇌간의 흑색질(substantia nigra)에 존재하는 도파민성 신경 세포의 소실로 인해 신경 전달물질인 도파민이 부족하게 되면서 발병한다. 그 결과, 루이소체(Lewy body)라는 단백질 응집체가 신경 세포 내에 형성되게 되어, 구부정한 자세, 떨림, 경직, 불안정 등과 같은 운동기능 이상과 함께 우울증, 불안, 수면장애 등 정신적인 증상도 나타난다. Parkinson's disease, along with Alzheimer's disease, is one of the representative neurodegenerative diseases. It is caused by a lack of the neurotransmitter dopamine due to the loss of dopaminergic neurons in the substantia nigra of the brainstem. As a result, protein aggregates called Lewy bodies are formed within nerve cells, causing motor function abnormalities such as stooped posture, tremors, stiffness, and instability, as well as mental symptoms such as depression, anxiety, and sleep disorders.
파킨슨병의 발병 원인에 대해서는 확실하게 알려져 있지 않지만 환경 요인, 유전요인, 노화, 미토콘드리아 기능 장애, 불필요한 단백질을 처리하는 기능의 이상 등 여러 요인들의 복합적 작용으로 인해 발병한다고 여겨지고 있다. 대부분의 파킨슨병은 산발적으로 일어나지만 5-10%는 유전자의 돌연변이가 원인인 유전병으로 나타나는 것으로 알려졌고, 원인 유전자로는 파킨(parkin), PINK1, DJ-1, α-시누클 레인(α-synuclein), LRRK2(leucine-rich repeat kinase 2) 등이 알려졌다. Although the exact cause of Parkinson's disease is not known, it is believed to be caused by a combination of factors such as environmental factors, genetic factors, aging, mitochondrial dysfunction, and abnormalities in the processing of unnecessary proteins. Most Parkinson's diseases occur sporadically, but 5-10% are known to be genetic diseases caused by gene mutations. The causative genes include parkin, PINK1, DJ-1, and α-synuclein. ), LRRK2 (leucine-rich repeat kinase 2), etc. are known.
이 중 LRRK2 유전자의 G2019S 변이는 우성 유전형으로 가장 빈번하게 나타나 는데, LRRK2는 류신 풍부 반복 키나제 집단(leucin-rich repeat kinase family)에 속하는 단백질이고, 종간 유사성이 높은 2527 개의 아미노산 배열로 구성되어 있으 며, 하나의 단백질 안에 GTP가수분해효소(GTPase)와 세린-트레오닌 키나제(Serinethreonine kinase) 활성을 모두 가지고 있다. LRRK2는 파킨슨병의 병인과 관련된 뇌의 대뇌피질, 흑질, 선조체, 해마, 소뇌 등에 존재하는 도파민신경세포에서 높은 발현이 보고되고 있고, LRRK2의 활성증가가 파킨슨병의 발병 및 진행에 영향을 주는 것으로 알려져 있다. 정상적인 LRRK2가 신경세포 내에서 과발현되면 이로 인해 세포사멸(apoptosis)이 유도되는 것이 확인되고 있으며, LRRK2 과활성 돌연변이 동물에서 파킨슨병 증상과 유사한 도파민 신경세포사멸, 루이소체, 운동장애가 보고 된 바 있고, LRRK2 knock-out 동물의 경우에는 뇌에서 신경돌기 증가(outgrowth) 및 파킨슨병과 밀접한 노화 의존적 α-시누클레인 증가의 억제가 관찰된 바 있어, LRRK2 억제에 의한 파킨슨병 치료가능성이 동물모델에서도 확인되고 있다. 또한, LRRK2는 알츠하이머병과 관련된 경도 인지 손상의 전가 등과도 관련된 것으로 알려져 있어, LRRK2 활성을 조절하는 데에 효과적인 화합물 및 조성물은 신경퇴행성 질환 등의 치료효과를 제공할 수 있다. 따라서, LRRK2 활성의 선택적인 억제는 질병 치료를 위한 신약 개발의 유익한 표적이 될 수 있다. Among these, the G2019S mutation of the LRRK2 gene appears most frequently as a dominant genotype. LRRK2 is a protein belonging to the leucin-rich repeat kinase family and consists of a sequence of 2527 amino acids with high similarity between species. , It has both GTPase and serine-threonine kinase activities in one protein. LRRK2 has been reported to be highly expressed in dopaminergic neurons present in the cerebral cortex, substantia nigra, striatum, hippocampus, and cerebellum of the brain, which are related to the pathogenesis of Parkinson's disease. Increased activity of LRRK2 has been shown to affect the onset and progression of Parkinson's disease. It is known. It has been confirmed that when normal LRRK2 is overexpressed in neurons, it induces apoptosis, and in LRRK2 hyperactive mutant animals, dopaminergic neuron death, Lewy bodies, and movement disorders similar to Parkinson's disease symptoms have been reported. In the case of LRRK2 knock-out animals, neurite outgrowth and inhibition of age-dependent α-synuclein increase, which is closely related to Parkinson's disease, were observed in the brain, and the possibility of treating Parkinson's disease by inhibiting LRRK2 has been confirmed in animal models. . In addition, LRRK2 is known to be involved in the transfer of mild cognitive impairment related to Alzheimer's disease, so compounds and compositions effective in regulating LRRK2 activity can provide therapeutic effects for neurodegenerative diseases. Therefore, selective inhibition of LRRK2 activity may be a beneficial target for the development of new drugs for disease treatment.
위와 같은 신경퇴행성 질환 외에도, 암세포의 증식 억제와 사멸 촉진 기전으로 다양한 암 종에서 LRRK2 저해를 통한 항암 활성이 연구되고 있다. 특히, 신장암과 갑상선암, 간암 조직에서 LRRK2가 과발현되는 것으로 보고되었고, LRRK2 돌연변이 발생(특히 G2019S type)으로 인해 LRRK2가 과활성화되면 유방암의 위험도가 증가되는 것으로 알려져 있다. 또한, 국내 뇌암 환자의 조직에서 LRRK2가 과발현된 환자들은 생존기간이 유의미하게 짧다는 연구결과가 보고된 바 있다. 이와 관련하여 최근 보로노이 사(社)에서는 LRRK2 저해제를 뇌암 치료제로 임상 1상 진입을 승인 받았다. 따라서 LRRK2 활성의 선택적 억제는 신경퇴행성 질환 치료뿐만 아니라, 항암 치료까지 폭넓은 신약 개발 표적이 될 수 있다. 또한 LRRK2는 크론병의 주요 유전적 감수성 유전자로 확인되었으며, LRRK2 의 결핍은 동물실험에서의 대장염에 대한 감수성을 증가시킨다고 보고한 바있다(Zhihua Liu & Michael J Lenardo, (2012) Cell Research 22:1092-1094). LRRK2 발현 프로파일은 선천성 면역 세포가 질병의 발병에 중요한 역할을 하는 덱스트란 황산나트륨 (DSS) 유발 대장염과 같은 실험모델에서의 대장염 기능을 연구하는데 유용하다고 확인하였다. 이는 LRRK2 의 wild-type 마우스와 비교하여 LRRK2 결핍 마우스에서 급격한 체중 감소, 임상증상의 악화 그리고 더 심각한 대장 이상으로 인해 DSS 유도 대장염이 더 쉽게 감염될 수 있다고 밝혔다. LRRK2 의 염증 신호 경로는 MAPK 경로와 관련성이 있는 것으로 여겨지고 있으며 최근에는 LRRK2 키나아제 활성이 대식세포와 미세아교세포 모두에서 MAPK 신호의 하위경로 활성화를 통해 염증 및 독성에 중요한 역할을 한다는 사실이 입증 되었다. (Kim, J. et al. (2019) LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. PLoS One 14) 특히 크론병과 궤양성 대장염에 대한 만성 염증 변화에 영향을 주는 인자로서 LRRK2 활성 또는 발현 수준의 변화가 장내 염증을 증가시킬 수 있으며, 이는 LRRK2 활성 조절이 향후 염증성 질환의 치료제로 매우 중요한 역할을 할 것으로 여겨진다.In addition to the above neurodegenerative diseases, anticancer activity through LRRK2 inhibition is being studied in various cancer types as a mechanism to inhibit proliferation and promote death of cancer cells. In particular, LRRK2 has been reported to be overexpressed in kidney, thyroid, and liver cancer tissues, and it is known that overactivation of LRRK2 due to LRRK2 mutation (particularly G2019S type) increases the risk of breast cancer. In addition, research results have reported that patients with overexpressed LRRK2 in the tissues of domestic brain cancer patients have a significantly shorter survival time. In this regard, Voronoi recently received approval to enter phase 1 clinical trials for its LRRK2 inhibitor as a treatment for brain cancer. Therefore, selective inhibition of LRRK2 activity can be a target for the development of a wide range of new drugs, not only for the treatment of neurodegenerative diseases but also for anti-cancer treatment. Additionally, LRRK2 has been identified as a major genetic susceptibility gene for Crohn's disease, and it has been reported that LRRK2 deficiency increases susceptibility to colitis in animal experiments (Zhihua Liu & Michael J Lenardo, (2012) Cell Research 22:1092 -1094). The LRRK2 expression profile was confirmed to be useful for studying colitis function in experimental models such as dextran sulfate sodium (DSS)-induced colitis, in which innate immune cells play an important role in the pathogenesis of the disease. This revealed that compared to LRRK2 wild-type mice, LRRK2-deficient mice were more susceptible to DSS-induced colitis due to rapid weight loss, worsening clinical symptoms, and more severe colonic abnormalities. The LRRK2 inflammatory signaling pathway is believed to be related to the MAPK pathway, and it has recently been demonstrated that LRRK2 kinase activity plays an important role in inflammation and toxicity through activation of the sub-pathway of MAPK signaling in both macrophages and microglia. (Kim, J. et al. (2019) LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. PLoS One 14) LRRK2 activity as a factor influencing chronic inflammatory changes, especially for Crohn's disease and ulcerative colitis. Alternatively, changes in expression levels may increase intestinal inflammation, which suggests that regulating LRRK2 activity will play a very important role as a treatment for inflammatory diseases in the future.
한편, 헤테로아릴 치환 유도체를 유효성분으로 포함하는 신경퇴행성 질환 예방 또는 치료용 조성물과 관련된 종래 선행문헌으로, 한국등록특허 제10-1566091호에는 LRRK2 조절제로서 피라졸 아미노피리미딘 유도체에 대해 개시하였으며, 한국등록특허 제10-2025451호에는 파킨슨병의 치료를 위한 키나아제 LRRK2 조절제로서 2-(페닐 또는 피리드-3-일) 아미노피리미딘 유도체에 대해 개시하였고, 한국등록특허 제 10-1208198호, LRRK2 인산화 효소 억제 활성을 갖는 화합물을 유효성분으로 함유하는 파킨슨병 치료 또는 예방용 약학조성물에 대해 개시하였으며, 한국공개특허 제 10-2019-0018676호에는 신경퇴행성 장애의 치료에서 사용하기 위한 LRRK2 저해제로서 피리미딘-2-일아미노-1H-피라졸에 대해 개시한 바 있다. 그러나, 본 발명 화학식 1과 같은 헤테로아릴이 치환 유도체 및 상기 유도체의 LRRK2 저해 활성과 이로부터 신경 퇴행성 질환 치료 가능함을 언급한 이전 보고는 없다. 이에 따라, 본 발명자들은 LRRK2 유도체를 연구하는 과정에서, 본 발명 화학식 1과 같은 헤테로아릴 치환 유도체가 LRRK2 저해 활성 효과가 우수하며, 혈액뇌장벽(BBB)을 효율적으로 통과함을 확인함으로써 본 발명을 완성하였다. Meanwhile, as a prior art document related to a composition for preventing or treating neurodegenerative diseases containing a heteroaryl-substituted derivative as an active ingredient, Korean Patent No. 10-1566091 discloses a pyrazole aminopyrimidine derivative as an LRRK2 regulator; Korean Patent No. 10-2025451 discloses a 2-(phenyl or pyrid-3-yl) aminopyrimidine derivative as a regulator of the kinase LRRK2 for the treatment of Parkinson's disease, and Korean Patent No. 10-1208198, LRRK2 A pharmaceutical composition for the treatment or prevention of Parkinson's disease containing a compound with phosphorylation enzyme inhibitory activity as an active ingredient is disclosed, and Korean Patent Publication No. 10-2019-0018676 discloses piri as an LRRK2 inhibitor for use in the treatment of neurodegenerative disorders. Midin-2-ylamino-1H-pyrazole has been disclosed. However, there are no previous reports mentioning heteroaryl-substituted derivatives such as Formula 1 of the present invention and their LRRK2 inhibitory activity and the possibility of treating neurodegenerative diseases therefrom. Accordingly, in the process of studying LRRK2 derivatives, the present inventors confirmed that heteroaryl-substituted derivatives such as Formula 1 of the present invention have excellent LRRK2 inhibitory activity and efficiently pass through the blood brain barrier (BBB), thereby demonstrating the present invention. Completed.
본 발명의 일 목적은, 신규한 헤테로아릴 치환 유도체를 제공하는 것이다.One object of the present invention is to provide novel heteroaryl-substituted derivatives.
본 발명의 다른 목적은, 신규한 헤테로아릴 치환 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing novel heteroaryl-substituted derivatives.
본 발명의 다른 목적은, 신규한 헤테로아릴 치환 유도체를 유효성분으로 함유하는 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neurodegenerative diseases, cancer, or inflammatory diseases, containing a novel heteroaryl-substituted derivative as an active ingredient.
본 발명의 다른 목적은, 신규한 헤테로아릴 치환 유도체를 유효성분으로 함유하는 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다.Another object of the present invention is to provide a health functional food for preventing or improving neurodegenerative diseases, cancer, or inflammatory diseases containing a novel heteroaryl-substituted derivative as an active ingredient.
상기 목적을 달성하기 위하여,In order to achieve the above purpose,
하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.Provided is a compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2023011915-appb-img-000001
Figure PCTKR2023011915-appb-img-000001
Y는 수소, 할로겐, 또는 비치환 또는 할로겐으로 치환된 C1-C6알킬이고;Y is hydrogen, halogen, or unsubstituted or halogen-substituted C 1 -C 6 alkyl;
Z는 수소, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 벤질, 치환 또는 비치환된 C3-C12 사이클로알킬, 치환 또는 비치환된 C3-C12 헤테로사이클로알킬, 치환 또는 비치환된 C4-C12 아릴, 또는 치환 또는 비치환된 C4-C12 헤테로아릴로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,Z is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 3 -C 12 heterocycloalkyl, is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C 4 -C 12 aryl, or substituted or unsubstituted C 4 -C 12 heteroaryl;
상기 치환된 알킬, 벤질, C3-C12 사이클로알킬, C4-C12 아릴, C4-C12 헤테로아릴은 할로겐, 히드록시, 시아노, 아미노, 아미드, 니트로, C1-C6 알킬, C1- C6 알콕시, C3-C12 헤테로 사이클로 알킬, C4-C12 아릴-C1-C6 알콕시, 또는 -C(=O)O-알킬(C1-C6)로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;The substituted alkyl, benzyl, C 3 -C 12 cycloalkyl, C 4 -C 12 aryl, C 4 -C 12 heteroaryl are halogen, hydroxy, cyano, amino, amide, nitro, C 1 -C 6 alkyl. , C 1 -C 6 alkoxy, C 3 -C 12 heterocycloalkyl, C 4 -C 12 aryl-C 1 -C 6 alkoxy, or -C(=O)O-alkyl(C 1 -C 6 ). is substituted with one or more substituents selected from the group;
X는 비치환 또는 치환된 페닐 또는 5-6원자의 헤테로아릴이고,X is unsubstituted or substituted phenyl or heteroaryl of 5-6 atoms,
상기 치환된 페닐 또는 5-6원자의 헤테로아릴은,The substituted phenyl or heteroaryl of 5-6 atoms is,
비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 할로겐으로 치환된 C1-C6 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 할로겐, 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B 및 -(CH2)p-CONAB 중의 하나 이상의 치환기로 치환되고,Unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 3 -C 6 cyclo Alkyloxy, halogen, unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B and -(CH 2 )p- is substituted with one or more substituents of CONAB,
p는 0-5의 정수이고,p is an integer from 0 to 5,
A는 수소 또는 C1-C6 알킬이고,A is hydrogen or C 1 -C 6 alkyl,
B는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO- B, or -(CH 2 )p-CONAB is C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
또는,or,
A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며,A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
여기서, 상기 치환된 C1-C6 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 독립적으로 C1-C6 알킬, C1-C6 알콕시, 시아노, 비치환 또는 C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환된다.Here, the substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이,In addition, the present invention, as shown in Scheme 1 below,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계를 포함하는 제1항의 화학식 1로 표시되는 화합물의 제조방법을 제공한다:Provided is a method for producing a compound represented by Formula 1 of claim 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3:
[반응식 1][Scheme 1]
Figure PCTKR2023011915-appb-img-000002
Figure PCTKR2023011915-appb-img-000002
상기 반응식 1에서 W는 할로겐이고,In Scheme 1, W is halogen,
X, Y, 및 Z는 상기의 화학식 1에서 정의한 바와 같다.X, Y, and Z are as defined in Formula 1 above.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경퇴행성 질환, 암 또는 염증성 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to another aspect of the present invention, prevention of neurodegenerative diseases, cancer or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Alternatively, a pharmaceutical composition for treatment is provided.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 개선용 건강기능식품이 제공된다.According to another aspect of the present invention, a treatment for neurodegenerative diseases, cancer, or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Health functional foods for prevention or improvement are provided.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물을 필요한 대상에게 투여하는 단계를 포함하는 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 치료 방법을 제공한다.According to another aspect of the present invention, administering to a subject in need a pharmaceutical composition containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Provides a method for preventing or treating neurodegenerative diseases, cancer, or inflammatory diseases, including.
본 발명의 다른 측면에 따라, 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물의 용도를 제공한다.According to another aspect of the present invention, a compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable compound thereof is used in the prevention or treatment of neurodegenerative diseases, cancer, or inflammatory diseases. Provided is the use of a pharmaceutical composition containing a salt.
본 발명에 따른 신규한 헤테로아릴 치환 유도체는 LRRK2 저해 활성이 우수하고, 혈액뇌장벽(BBB)을 효율적으로 통과하여, 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 치료용 약학적 조성물로 유용하게 사용가능하다.The novel heteroaryl-substituted derivative according to the present invention has excellent LRRK2 inhibitory activity and efficiently passes the blood brain barrier (BBB), making it useful as a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, cancer, or inflammatory diseases. Available.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 측면은 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2023011915-appb-img-000003
Figure PCTKR2023011915-appb-img-000003
Y는 수소, 할로겐, 또는 비치환 또는 할로겐으로 치환된 C1-C6알킬이고;Y is hydrogen, halogen, or unsubstituted or halogen-substituted C 1 -C 6 alkyl;
Z는 수소, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 벤질, 치환 또는 비치환된 C3-C12 사이클로알킬, 치환 또는 비치환된 C3-C12 헤테로사이클로알킬, 치환 또는 비치환된 C4-C12 아릴, 또는 치환 또는 비치환된 C4-C12 헤테로아릴로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,Z is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 3 -C 12 heterocycloalkyl, is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C 4 -C 12 aryl, or substituted or unsubstituted C 4 -C 12 heteroaryl;
상기 치환된 알킬, 벤질, C3-C12 사이클로알킬, C4-C12 아릴, C4-C12 헤테로아릴은 할로겐, 히드록시, 시아노, 아미노, 아미드, 니트로, C1-C6 알킬, C1- C6 알콕시, C3-C12 헤테로 사이클로 알킬, C4-C12 아릴-C1-C6 알콕시, 또는 -C(=O)O-알킬(C1-C6)로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;The substituted alkyl, benzyl, C 3 -C 12 cycloalkyl, C 4 -C 12 aryl, C 4 -C 12 heteroaryl are halogen, hydroxy, cyano, amino, amide, nitro, C 1 -C 6 alkyl. , C 1 -C 6 alkoxy, C 3 -C 12 heterocycloalkyl, C 4 -C 12 aryl-C 1 -C 6 alkoxy, or -C(=O)O-alkyl(C 1 -C 6 ). is substituted with one or more substituents selected from the group;
X는 비치환 또는 치환된 페닐 또는 5-6원자의 헤테로아릴이고,X is unsubstituted or substituted phenyl or heteroaryl of 5-6 atoms,
상기 치환된 페닐 또는 5-6원자의 헤테로아릴은,The substituted phenyl or heteroaryl of 5-6 atoms is,
비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 할로겐으로 치환된 C1-C6 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 할로겐, 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B 및 -(CH2)p-CONAB 중의 하나 이상의 치환기로 치환되고,Unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 3 -C 6 cyclo Alkyloxy, halogen, unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B and -(CH 2 )p- is substituted with one or more substituents of CONAB,
p는 0-5의 정수이고,p is an integer from 0 to 5,
A는 수소 또는 C1-C6 알킬이고,A is hydrogen or C 1 -C 6 alkyl,
B는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO- B, or -(CH 2 )p-CONAB is C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
또는,or,
A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며,A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
여기서, 상기 치환된 C1-C6알킬, 치환된 C3-C6사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 독립적으로 C1-C6알킬, C1-C6알콕시, 시아노, 비치환 또는 C1-C6알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환된다.Here, the substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
본 발명의 다른 실시형태에서,In another embodiment of the present invention,
상기 X는
Figure PCTKR2023011915-appb-img-000004
이고,The X above is
Figure PCTKR2023011915-appb-img-000004
ego,
상기 Ar은 페닐 또는 5-6원자의 헤테로아릴이고;Ar is phenyl or heteroaryl of 5-6 atoms;
R1a 및 R1b는 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 할로겐으로 치환된 C1-C6 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 비치환 또는 치환된 3-7원자 헤테로사이클로알킬, 또는 비치환 또는 치환된 C3-C6 사이클로알킬이고;R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 3 -C 6 cycle. alkyl oxy, unsubstituted or substituted 3-7 membered heterocycloalkyl, or unsubstituted or substituted C 3 -C 6 cycloalkyl;
R2는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 이고,R 2 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO -B, or -(CH 2 )p-CONAB,
p는 0-5의 정수이고,p is an integer from 0 to 5,
A는 수소 또는 C1-C6 알킬이고,A is hydrogen or C 1 -C 6 alkyl,
B는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB 가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
또는,or,
A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며;A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3 to 7 atoms;
여기서, 상기 치환된 C1-C6 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 독립적으로 C1-C6 알킬, C1-C6 알콕시, 시아노, 비치환 또는 C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환된다.Here, the substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
또한, 본 발명의 다른 실시형태에서,Additionally, in another embodiment of the present invention,
Y는 할로겐, 또는 할로겐으로 치환된 C1-C6알킬이고;Y is halogen or C 1 -C 6 alkyl substituted with halogen;
X는
Figure PCTKR2023011915-appb-img-000005
또는
Figure PCTKR2023011915-appb-img-000006
X is
Figure PCTKR2023011915-appb-img-000005
or
Figure PCTKR2023011915-appb-img-000006
이고;ego;
R1a, R1b, R3, R4, R5, 및 R6 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 할로겐으로 치환된 C1-C6 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 비치환 또는 치환된 3-7원자 헤테로사이클로알킬, 또는 비치환 또는 치환된 C3-C6 사이클로알킬이고;R 1a , R 1b , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy , unsubstituted or substituted C 3 -C 6 cycloalkyl oxy, unsubstituted or substituted 3-7 membered heterocycloalkyl, or unsubstituted or substituted C 3 -C 6 cycloalkyl;
R2는 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 이고,R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
p는 0-5의 정수,p is an integer from 0 to 5,
A는 수소 또는 C1-C6 알킬,A is hydrogen or C 1 -C 6 alkyl,
B는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB 가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
또는,or,
A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며;A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3 to 7 atoms;
여기서, 상기 치환된 C1-C6 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 독립적으로 C1-C6 알킬, C1-C6 알콕시, 시아노, 비치환 또는 C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환된다.Here, the substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
또한, 본 발명의 다른 실시형태에서,Additionally, in another embodiment of the present invention,
Y는 할로겐, 또는 할로겐으로 치환된 C1-C6알킬이고;Y is halogen or C 1 -C 6 alkyl substituted with halogen;
Z는 수소 또는 C1-C6 알킬이고;Z is hydrogen or C 1 -C 6 alkyl;
X는
Figure PCTKR2023011915-appb-img-000007
또는
Figure PCTKR2023011915-appb-img-000008
X is
Figure PCTKR2023011915-appb-img-000007
or
Figure PCTKR2023011915-appb-img-000008
이고,ego,
R1a 및 R1b은 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C5 알킬, 비치환 또는 할로겐으로 치환된 C1-C5 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 비치환 또는 치환된 C3-C6 사이클로알킬이고,R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 5 alkyl, unsubstituted or halogen-substituted C 1 -C 5 alkoxy, unsubstituted or substituted C 3 -C 6 cycle. alkyloxy, unsubstituted or substituted C 3 -C 6 cycloalkyl,
R2는 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 이고,R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
여기서, p는 0-4의 정수,Here, p is an integer from 0 to 4,
A는 수소 또는 C1-C5 알킬,A is hydrogen or C 1 -C 5 alkyl,
B는 비치환 또는 치환된 C1-C5 알킬, 비치환 또는 치환된 C3-C5 사이클로알킬, 비치환 또는 치환된 3-6원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB 가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 5 alkyl, unsubstituted or substituted C 3 -C 5 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-6 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
또는,or,
A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-6원자의 헤테로사이클로알킬을 형성하며,A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3-6 atoms,
R3는 비치환 또는 치환된 C1-C5 알킬, 또는 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬이고,R 3 is unsubstituted or substituted C 1 -C 5 alkyl, or unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
R4, R5, 및 R6은 각각 독립적으로 수소, 또는 비치환 또는 치환된 C1-C5 알킬이고,R 4 , R 5 , and R 6 are each independently hydrogen or unsubstituted or substituted C 1 -C 5 alkyl,
여기서, 상기 치환된 C1-C5 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 각각 독립적으로 C1-C5 알킬, C1-C5 알콕시, 시아노, C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환된다.Here, the substituted C 1 -C 5 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl, and substituted 3-7 atom heterocycloalkyl are each independently C 1 -C 5 alkyl, C 1 -C 5 alkoxy, cyano, amino substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3-7 unsubstituted or substituted with C 1 -C 6 alkyl The atom is substituted with heterocycloalkyl.
또한, 본 발명의 다른 실시형태에서,Additionally, in another embodiment of the present invention,
Y는 할로겐, 또는 할로겐으로 치환된 C1-C6알킬이고;Y is halogen or C 1 -C 6 alkyl substituted with halogen;
Z는 수소 또는 C1-C4 알킬이고;Z is hydrogen or C 1 -C 4 alkyl;
X는
Figure PCTKR2023011915-appb-img-000009
또는
Figure PCTKR2023011915-appb-img-000010
X is
Figure PCTKR2023011915-appb-img-000009
or
Figure PCTKR2023011915-appb-img-000010
이고,ego,
R1a 및 R1b은 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C4 알킬, 비치환 또는 할로겐으로 치환된 C1-C4 알콕시, 비치환 또는 치환된 C3-C5 사이클로알킬 옥시, 비치환 또는 치환된 C3-C5 사이클로알킬이고,R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or halogen-substituted C 1 -C 4 alkoxy, unsubstituted or substituted C 3 -C 5 cycle. alkyloxy, unsubstituted or substituted C 3 -C 5 cycloalkyl,
R2는 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 이고,R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
여기서, p는 0-3의 정수,Here, p is an integer from 0 to 3,
A는 수소 또는 C1-C3 알킬,A is hydrogen or C 1 -C 3 alkyl,
B는 비치환 또는 치환된 C1-C4 알킬, 비치환 또는 치환된 C3-C5 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB 가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or substituted C 3 -C 5 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- B and -(CH 2 )p-CONAB are C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
또는,or,
A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며,A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
R3는 비치환 또는 치환된 C1-C4 알킬, 또는 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬이고,R 3 is unsubstituted or substituted C 1 -C 4 alkyl, or unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
R4, R5, 및 R6은 각각 독립적으로 수소, 또는 비치환 또는 치환된 C1-C4 알킬이고,R 4 , R 5 , and R 6 are each independently hydrogen or unsubstituted or substituted C 1 -C 4 alkyl,
여기서, 상기 치환된 C1-C4 알킬, 치환된 C3-C5 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 각각 독립적으로 C1-C4 알킬, C1-C4 알콕시, 시아노, C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환된다.Here, the substituted C 1 -C 4 alkyl, substituted C 3 -C 5 cycloalkyl, substituted 5-6 atom heteroaryl, and substituted 3-7 atom heterocycloalkyl are each independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3-7 unsubstituted or substituted with C 1 -C 6 alkyl The atom is substituted with heterocycloalkyl.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 예로는 하기의 화합물을 들 수 있다:Examples of the compound represented by Formula 1 according to the present invention include the following compounds:
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온 (실시예 1);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Example 1 );
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 2);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4- 1) Benzamide (Example 2);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 3);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidine -1-yl)methanone (Example 3);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 4);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-(1-methylpiperidin-4- 1) Benzamide (Example 4);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 5);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluorophenyl)(4-(dimethylamino)piperidine -1-yl)methanone (Example 5);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 6);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(1-methylpiperidin-4-yl )Benzamide (Example 6);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 7);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-(dimethylamino)piperidine-1 -1) Methanone (Example 7);
(3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 8);(3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(dimethylamino)piperidine- 1-day)methanone (Example 8);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 9);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(oxetane-3- 1) Benzamide (Example 9);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 10);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-(1-methylpiperidin-4- 1) Benzamide (Example 10);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 11);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 11);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 12);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-(oxetan-3-yl)benzamide (Example 12);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 13);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(oxetane-3- 1) Benzamide (Example 13);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시페닐)(모르폴리노)메탄온 (실시예 14);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxyphenyl)(morpholino)methanone (Example 14);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-(옥세탄-3-일)벤즈아미드 (실시예 15);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-(oxetan-3-yl)benz Amide (Example 15);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-(옥세탄-3-일)벤즈아미드 (실시예 16);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-(oxetan-3-yl)benz Amide (Example 16);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 17);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-methyl-N-(1-methylp peridin-4-yl)benzamide (Example 17);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시페닐)(피롤리딘-1-일)메탄온 (실시예 18);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxyphenyl)(pyrrolidin-1-yl)methane On (Example 18);
(S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드 (실시예 19);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-((tetrahydrofuran- 2-yl)methyl)benzamide (Example 19);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-(옥세탄-3-일)벤즈아미드 (실시예 20);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-(oxetan-3-yl)benzamide (Example 20);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 21);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-methyl-N-( oxetan-3-yl)benzamide (Example 21);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시페닐)(모르폴리노)메탄온 (실시예 22);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino) Methanone (Example 22);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 23);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-methyl-N-( 1-methylpiperidin-4-yl)benzamide (Example 23);
3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 24);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)benzamide ( Example 24);
3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 25);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl )Benzamide (Example 25);
2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 26);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl )Benzamide (Example 26);
2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 27);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidine -4-yl)benzamide (Example 27);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(피롤리딘-1-일)메탄온 (실시예 28);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(pyrrolidin-1-yl)methanone ( Example 28);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시페닐)(모르폴리노)메탄온 (실시예 29);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxyphenyl)(morpholino)methanone (practice Example 29);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 30);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-(oxetan-3-yl)benzamide (Example 30);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 31);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 31);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온 (실시예 32);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluorophenyl)(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)methanone (Example 32);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 33);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-methyl-N-(oxetane-3- 1) Benzamide (Example 33);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온 (실시예 34);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluorophenyl)(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)methanone (Example 34);
2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 35);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(1-methylpiperidin-4-yl )Benzamide (Example 35);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 36);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 36);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-(옥세탄-3-일)벤즈아미드 (실시예 37);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-(oxetan-3-yl)benzamide (Example 37);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 38);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-methyl-N-(oxetane-3- 1) Benzamide (Example 38);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드 (실시예 39);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-((tetrahydrofuran- 2-yl)methyl)benzamide (Example 39);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드 (실시예 40);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)-3-(2,2 ,2-trifluoroethoxy)benzamide (Example 40);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,2-디메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 41);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,2-dimethyl-N-(oxetan-3-yl)benz Amide (Example 41);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,3-디메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 42);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,3-dimethyl-N-(1-methylpiperidin-4 -1)benzamide (Example 42);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸페닐)(피롤리딘-1-일)메탄온 (실시예 43);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methylphenyl)(pyrrolidin-1-yl)methanone ( Example 43);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 44);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methylphenyl)(4-(dimethylamino)piperidine-1 -1) Methanone (Example 44);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 45);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-(1-methylpiperidin-4-yl)benzamide (Example 45);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드 (실시예 46);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-((tetrahydrofuran-2-yl)methyl)benzamide (Example 46);
(2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온 (실시예 47);(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(4-methylpiperazine-1 -yl)piperidin-1-yl)methanone (Example 47);
3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(퓨란-2-일메틸)벤즈아미드 (실시예 48);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(furan-2-ylmethyl)benzamide ( Example 48);
2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 49);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-methyl-N-(ox cetan-3-yl)benzamide (Example 49);
(2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시페닐)(모르폴리노)메탄온 (실시예 50);(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxyphenyl)(morpholino)methane On (Example 50);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드 (실시예 51);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl)-3- (2,2,2-trifluoroethoxy)benzamide (Example 51);
3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 52);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)benzamide ( Example 52);
3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(퓨란-2-일메틸)-N-메틸벤즈아미드 (실시예 53);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(furan-2-ylmethyl)-N- methylbenzamide (Example 53);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필페닐)(모르폴리노)메탄온 (실시예 54);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropylphenyl)(morpholino)methanone (Example 54);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-(옥세탄-3-일)벤즈아미드 (실시예 55);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-(oxetan-3-yl)benzamide (Example 55);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 56);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-methyl-N-(oxetane-3- 1) Benzamide (Example 56);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 57);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(oxetan-3-yl)benzamide ( Example 57);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,3-디메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 58);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,3-dimethyl-N-(oxetan-3-yl)benz Amide (Example 58);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 59);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 59);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 60);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(oxetan-3-yl)benzamide (Example 60);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,2,5-트리메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 61);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,2,5-trimethyl-N-(oxetan-3-yl )Benzamide (Example 61);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(피롤리딘-1-일)메탄온 (실시예 62);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(pyrrolidin-1-yl) Methanone (Example 62);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 63);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-(dimethylamino)piperi din-1-yl)methanone (Example 63);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 64);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-(1-methylpiperidin-4- 1) Benzamide (Example 64);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드 (실시예 65);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidin-4-yl )-3-(2,2,2-trifluoroethoxy)benzamide (Example 65);
2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 66);2-Chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-methyl-N-(1 -methylpiperidin-4-yl)benzamide (Example 66);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 67);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethyl-N-(oxetan-3-yl)benz Amide (Example 67);
(S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 68);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(tetra hydrofuran-3-yl)benzamide (Example 68);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 69);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-(oxetane-3 -1)benzamide (Example 69);
2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 70);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-(oxetane-3- 1) Benzamide (Example 70);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 71);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methyl-N-(oxetan-3-yl)benzamide ( Example 71);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-((1r,3r)-3-메톡시사이클로부틸)벤즈아미드 (실시예 72);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-((1r,3r)-3-meth Toxycyclobutyl)benzamide (Example 72);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(2-메톡시-2-메틸프로필)벤즈아미드 (실시예 73);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(2-methoxy-2-methylpropyl )Benzamide (Example 73);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(1-메톡시-2-메틸프로판-2-일)벤즈아미드 (실시예 74);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(1-methoxy-2-methylpropane -2-yl)benzamide (Example 74);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 75);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidine-1 -1) Methanone (Example 75);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 76);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 76);
3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 77);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidine -4-yl)benzamide (Example 77);
3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(테트라하이드로-2H-피란-4-일)벤즈아미드 (실시예 78);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(tetrahydro-2H-pyran -4-yl)benzamide (Example 78);
(3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 79);(3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(3-morpholinoazetidine-1- 1) Methanone (Example 79);
(S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 80);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-( tetrahydrofuran-3-yl)benzamide (Example 80);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-((1r,3r)-3-메톡시사이클로부틸)벤즈아미드 (실시예 81);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-((1r,3r )-3-methoxycyclobutyl)benzamide (Example 81);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(1-메톡시-2-메틸프로판-2-일)벤즈아미드 (실시예 82);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methoxy -2-methylpropan-2-yl)benzamide (Example 82);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 83);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-morpholy nopiperidin-1-yl)methanone (Example 83);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시페닐)(모르폴리노)메탄온 (실시예 84);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxyphenyl)(morpholino)methanone (practice Example 84);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-(옥세탄-3-일)벤즈아미드 (실시예 85);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-(oxetan-3-yl)benz Amide (Example 85);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 86);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-methyl-N-(oxetane-3 -1)benzamide (Example 86);
4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 87);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-(1-methylpiperidin-4 -1)benzamide (Example 87);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 88);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxyphenyl)(4-(dimethylamino)piperi din-1-yl)methanone (Example 88);
(S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 89);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(tetrahydrofuran-3 -1)benzamide (Example 89);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 90);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidine -1-yl)methanone (Example 90);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 91);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxyphenyl)(4-(dimethylamino)piperi din-1-yl)methanone (Example 91);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 92);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1 -1) Methanone (Example 92);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-(피롤리딘-1-일)피페리딘-1-일)메탄온 (실시예 93);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-(pyrrolidin-1-yl) piperidin-1-yl)methanone (Example 93);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 94);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-morpholinopiperidin-1-yl ) Methanone (Example 94);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 95);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(3-morpholinoazetidin-1-yl ) Methanone (Example 95);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2,2-트리플루오로에톡시)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 96);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2,2-trifluoroethoxy)phenyl )(4-(dimethylamino)piperidin-1-yl)methanone (Example 96);
(2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 97);(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(dimethylamino)piperidine- 1-yl)methanone (Example 97);
2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-N-(옥세탄-3-일)아세트아미드 (실시예 98);2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-N-(oxetane-3 -1)acetamide (Example 98);
2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-1-모르폴리노에탄-1-온 (실시예 99);2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-1-morpholinoethane- 1-one (Example 99);
2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-N-(1-메틸피페리딘-4-일)아세트아미드 (실시예 100);2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-N-(1-methylp peridin-4-yl)acetamide (Example 100);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-(피롤리딘-1-일)피페리딘-1-일)메탄온 (실시예 101);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-(pyrrolidin-1 -yl)piperidin-1-yl)methanone (Example 101);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 102);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-morpholinopiperidine- 1-day)methanone (Example 102);
(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 103);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(3-morpholinoazetidine- 1-yl)methanone (Example 103);
3-메톡시-N-메틸-4-((4-(1-메틸-1H-피롤-3-일)-5-(트리플루오로메틸)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 104);3-methoxy-N-methyl-4-((4-(1-methyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrididin-2-yl)amino)-N-( oxetan-3-yl)benzamide (Example 104);
2-클로로-5-메톡시-N-메틸-4-((4-(1-메틸-1H-피롤-3-일)-5-(트리플루오로메틸)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 105);2-chloro-5-methoxy-N-methyl-4-((4-(1-methyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrididin-2-yl)amino) -N-(oxetan-3-yl)benzamide (Example 105);
(S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 106);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(tetrahydrofuran-3- 1) Benzamide (Example 106);
(4-((5-클로로-4-(1-iso프로필-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온 (실시예 107);(4-((5-chloro-4-(1-isopropyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (practice Example 107);
(R)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 108);(R)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(tetrahydrofuran-3 -1)benzamide (Example 108);
5-클로로-N-(2-메톡시-4-모르폴리노페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 109);5-chloro-N-(2-methoxy-4-morpholinophenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine (Example 109);
5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(1-(테트라하이드로-2H-피란-4-일)-1H-피라졸-4-일)피리디딘-2-아민 (실시예 110);5-chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrididine- 2-amine (Example 110);
5-클로로-N-(4-(2,4-디메틸옥사졸-5-일)-2-메톡시페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 111);5-chloro-N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2- Amines (Example 111);
5-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸이소인돌린-1-온 (실시예 112);5-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylisoindolin-1-one (Example 112);
5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(6-모르폴리노피리딘-3-일)피리디딘-2-아민 (실시예 113);5-chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(6-morpholinopyridin-3-yl)pyrididin-2-amine (Example 113);
2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸-1H-피라졸-1-일)-2-메틸프로판니트릴(실시예 114); 2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropanenitrile (Example 114);
6-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3,4-디하이드로나프탈렌-1(2H)-온 (실시예 115);6-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3,4-dihydronaphthalen-1(2H)-one (Example 115);
5-클로로-N-(1,3-디메틸-1H-피라졸-4-일)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 116);5-chloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine (Example 116);
N-(5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)-5-메틸티아졸-2-아민 (실시예 117)N-(5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)-5-methylthiazol-2-amine (Example 117)
5-클로로-N-(2-플루오로-4-모르폴리노페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 118);5-chloro-N-(2-fluoro-4-morpholinophenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine (Example 118);
5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(4-모르폴리노-2-(트리플루오로메틸)페닐)피리디딘-2-아민 (실시예 119).5-Chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(4-morpholino-2-(trifluoromethyl)phenyl)pyrididin-2-amine (Example 119) .
본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Includes glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다. The acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts. Additionally, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (e.g., silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 입체이성질체, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, stereoisomers, hydrates, etc. that can be prepared therefrom.
용어 "알킬"은 직쇄 또는 분지쇄의 완전포화탄화수소기를 나타내고, 알킬의 예로 메틸(Me), 에틸(Et), 프로필(예를 들어, n-프로필 및 이소프로필기, 부틸(예를 들어, n-부틸, 이소부틸, s-부틸, t-부틸), 펜틸(예를 들어, n-펜틸, 이소펜틸(Isopentyl group), 네오펜틸(neopentyl group)) 등을 포함한다.The term "alkyl" refers to a straight or branched chain fully saturated hydrocarbon group, examples of alkyl include methyl (Me), ethyl (Et), propyl (e.g. n-propyl and isopropyl groups, butyl (e.g. n -Butyl, isobutyl, s-butyl, t-butyl), pentyl (eg, n-pentyl, isopentyl (Isopentyl group), neopentyl group), etc.
용어 “사이클로알킬”은 고리모양의 단일결합의 포화탄화수소기를 의미한다. 예를 들어 시클로프로필, 시클 로부틸, 시클로펜틸, 시클로헥실, 시클로헵틸, 시클로옥틸, 비시클로[3.1.1]헵틸, 스피로[4.5]데실, 스피로 [5.5]운데실, 아다만틸 등을 들 수 있다.The term “cycloalkyl” refers to a saturated hydrocarbon group with a ring-shaped single bond. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptyl, spiro[4.5]decyl, spiro[5.5]undecyl, adamantyl, etc. You can.
용어 "할로" 및 "할로겐"은 플루오로(F), 클로로(Cl), 브로모(Br) 또는 아이오도(I) 치환기를 지칭하기 위해서 통상적인 의미로 사용된다The terms “halo” and “halogen” are used in their conventional sense to refer to a fluoro (F), chloro (Cl), bromo (Br) or iodo (I) substituent.
용어 “할로알킬”은 1 이상의 할로젠으로 치환된 알킬로, 단일치환(예를 들어 -CH2F) 또는 다중 치환(예를 들어 -CF3)된 것을 모두 포함한다.The term “haloalkyl” includes alkyl substituted with one or more halogens, either monosubstituted (eg -CH2F) or multiply substituted (eg -CF3).
용어 “알콕시”는 단일결합의 직쇄 또는 분지쇄의 포화 탄화수소가 결합된 산소기를 의미한다. 예를 들어 메톡시, 에톡시, 프로폭시, n-부톡시, tert-부톡시, 1-메틸프로폭시 등이 있다.The term “alkoxy” refers to an oxygen group to which a single bond of straight or branched saturated hydrocarbon is bonded. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and 1-methylpropoxy.
용어 “헤테로시클로알킬”은 N, O, 또는 S와 같은 헤테로원자를 하나 이상 포함하는 고리모양의 단일결합의 포화탄화수소기를 말하며, 고리에 포함된 헤테로원자의 수 및 종류, 및 탄소수에 따라 아지리디닐, 피롤리디닐, 피페리디닐, 옥소피페리디닐, 모르포리닐, 피페라지닐, 옥소피페라지닐, 모르폴린일, 티오모르포리닐, 아제파닐, 디아제파닐, 옥사제파닐, 티아제파닐, 디옥소티아제파닐, 아조카닐, 테트라히드로푸라닐, 테트라히드로피라닐, 옥사졸리디닐, 디옥사닐, 디옥솔라닐 등이 있다The term “heterocycloalkyl” refers to a ring-shaped, single-bonded saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, Nyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanil, tiazepa These include nil, dioxothiazepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, dioxanyl, dioxolanyl, etc.
용어 “헤테로아릴”은 N, O, 또는 S와 같은 헤테로원자를 하나 이상 포함하는 방향족 고리화합물을 말하며, 고리에 포함된 헤테로원자의 수 및 종류, 및 탄소수에 따라 피리딜, 피롤릴, 피롤리디닐, 피리디닐, 퓨란일, 퀴놀리디닐, 인돌릴, 피리미디닐, 이미다졸릴, 1,2,4-트리아졸릴, 테트라졸릴, 피라닐, 티오페닐, 티아 졸릴, 디벤조티오펜일, 디벤조푸라닐, 디벤조셀레노펜, 티오펜, 벤조푸란, 벤조티오페닐, 벤조셀레노페닐, 카르 바졸일, 인돌로카르바졸일, 피리딜인돌일, 피롤로디피리딘일, 피라졸일, 이미다졸일, 트리아졸일, 옥사졸일, 티아졸일, 옥사디아졸일, 옥사트리아졸일, 디옥사졸일, 티아디아졸일, 피리딘일, 피리다지닐, 피라지닐, 트리아지닐, 옥사진일, 옥사티아진일, 옥사디아진일, 인돌일, 벤즈이미다졸일, 인다졸일, 인독사진일, 벤즈옥사졸일, 벤즈이속사졸일, 벤조티아졸일, 퀴놀린일, 이소퀴놀린일, 시놀린일, 퀴나졸린일, 퀴녹살린일, 나프티리딘일, 프탈라진일, 프테리딘일, 크산텐일, 아크리딘일, 펜아진일, 페노티아진일, 펜옥사진일, 벤조푸로피리딘일, 푸로디피리딘일, 벤조티에노피리딘일, 티에노디피리딘일, 벤조셀레노페노피리딘일 및 셀레노페노디피리딘일 등이 있다.The term “heteroaryl” refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, it may be pyridyl, pyrrolyl, or pyrrolyl. Dinyl, pyridinyl, furanyl, quinolidinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, pyranyl, thiophenyl, thiazolyl, dibenzothiophenyl, Dibenzofuranyl, dibenzoselenophen, thiophene, benzofuran, benzothiophenyl, benzoselenophenyl, carbazolyl, indolocarbazolyl, pyridyl indolyl, pyrrolodipyridinyl, pyrazolyl, imyzolyl Dazolyl, triazolyl, oxazinyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, oxazinyl, oxathiazinyl, oxazolyl diazinyl, indoleyl, benzimidazolyl, indazolyl, indoxazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cynolinyl, quinazolinyl, quinoxalinyl, Naphthyridinyl, phthalazinyl, pteridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzofuropyridinyl, furodipyridinyl, benzothienopyridinyl, thienodiyl. These include pyridinyl, benzoselenophenopyridinyl, and selenophenodipyridinyl.
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecμLar force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 본 발명의 상기 화학식 1로 표시되는 화합물의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 물을 포함할 수 있다. 상기 수화물은 1당량 이상, 바람직하게는, 1당량 내지 5당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이들의 약제학적으로 허용 가능한 염을 결정화시켜 제조될 수 있다.The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain more than 1 equivalent of water, preferably 1 to 5 equivalents of water. Such hydrates can be prepared by crystallizing the compound represented by Formula 1 of the present invention, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt from water or a water-containing solvent.
용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term “solvate” refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.
용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변이성질체(tautomer)까지 포함하는 구조이성질체와, 입체이성질체(stereoisomer)가 포함되며, 입체이성질체에는 비대칭 탄소 중심을 1개 이상 가짐으로써 나타나는 광학이성질체(enatiomer) 및 부분입체이성질체, 그리고 기하이성질체(트랜스, 시스)가 모두 포함된다. 이들 모든 이성체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include structural isomers, including tautomers, and stereoisomers. Stereoisomers include enatiomers and diastereomers that appear by having one or more asymmetric carbon centers, and geometric isomers. (trans, cis) are all included. All these isomers and mixtures thereof are also included within the scope of the present invention.
본 발명에 있어서, “하나 이상의 치환기로 치환”은 열거된 치환기들 중의 1 내지 3개의 치환기로 치환되는 것을 의미한다.In the present invention, “substituted with one or more substituents” means substituted with 1 to 3 substituents among the listed substituents.
또한, 상기 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염은 LRRK2을 억제할 수 있다.Additionally, the compound, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt can inhibit LRRK2.
본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공한다. Another aspect of the present invention is the prevention of neurodegenerative diseases, cancer, or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Alternatively, a pharmaceutical composition for treatment is provided.
약학적 조성물은, 상기 유효성분 외에 약학적으로 허용 가능한 담체를 더 포함할 수 있다.The pharmaceutical composition may further include a pharmaceutically acceptable carrier in addition to the active ingredient.
상기 신경퇴행성 질환은 중추 신경계의 신경세포에 점진적이고 꾸준한 사멸로 인한 퇴행성 변화가 나타나면서 여러 가지 증상을 유발하는 질환을 의미하며, 파킨슨병(Parkinson's disease), 알츠하이머병(Alzheimer's disease), 헌팅턴병(huntington's disease), 피크병(Pick's disease), 근위축성 축삭경화증(Amyotrophic lateral sclerosis), 프리온병(Prion disease), 운동신경세포병(Motor neuron disease), 척수소뇌실조증 (Spinocerebellar ataxia), 척수성근위축증(Spinal muscular atrophy), 크로이츠펠트-야콥병(CreutzfeldtJakob disease) 및 알코올성 치매(Alcohol related dementia)로 이루어진 군에서 선택될 수 있으나 특별히 이에 제한되지는 않는다.The neurodegenerative disease refers to a disease that causes various symptoms as degenerative changes occur due to gradual and steady death of neurons in the central nervous system, and includes Parkinson's disease, Alzheimer's disease, and Huntington's disease. disease, Pick's disease, amyotrophic lateral sclerosis, Prion disease, Motor neuron disease, Spinocerebellar ataxia, Spinal muscular atrophy It may be selected from the group consisting of muscular atrophy, Creutzfeldt-Jakob disease, and alcohol related dementia, but is not particularly limited thereto.
또한 상기 암은 신장암, 갑상선암, 유방암, 간암, 뇌암, 폐암, 난소암, 대장암, 흑색종, 위암, 위장관암, 골암, 췌장암, 피부암, 두경부암, 피부 또는 안구 흑색종, 자궁암, 직장암, 결장암, 식도암, 후두암, 소장암, 연조직의 육종, 요도암, 음경암, 전립선암, 및 다발성 골수종으로 이루어진 군에서 선택될 수 있으며, 바람직하게는 신장암, 갑상선암, 유방암, 간암, 및 뇌암으로 이루어진 군에서 선택될 수 있으나 특별히 이에 제한되지는 않는다.In addition, the above cancers include kidney cancer, thyroid cancer, breast cancer, liver cancer, brain cancer, lung cancer, ovarian cancer, colon cancer, melanoma, stomach cancer, gastrointestinal cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine cancer, rectal cancer, It may be selected from the group consisting of colon cancer, esophageal cancer, laryngeal cancer, small intestine cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer, and multiple myeloma, and preferably consists of kidney cancer, thyroid cancer, breast cancer, liver cancer, and brain cancer. It may be selected from the group, but is not particularly limited thereto.
또한 상기 염증성 질환은 염증성 장 질환, 궤양성 대장염, 염증성 피부 질환, 췌장염, 알러지성 비염, 알러지성 결막염, 급성 기관지염, 만성 기관지염, 급성 세기관지염, 만성 세기관지염, 골관절염, 강직성 척추염, 장질환 척추염, 연소자성 강직성 척추염, 감염성 관절염, 결절성 다발동맥염, 과민성 혈관염, 관절세포 동맥염, 점액낭염, 건초염, 상과염, 신생아발병 다발성 염증성질환(neonatal multisystem inflammatory disease), 접촉성 피부염, 각막염, 결막염, 망막염, 망막혈관염, 포도막염, 안검염, 알레르기 결막염, 다발성 근염(polymyositis), 자가면역성 뇌척수염, 결절성 다발성 동맥염(polyarteritis nodosa) 및 섬유조직염(fibromyalgia syndrome)으로 이루어진 군에서 선택될 수 있으나 특별히 이에 제한되지는 않는다.In addition, the inflammatory diseases include inflammatory bowel disease, ulcerative colitis, inflammatory skin disease, pancreatitis, allergic rhinitis, allergic conjunctivitis, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, ankylosing spondylitis, enteropathy spondylitis, and juvenile spondylitis. Ankylosing spondylitis, infectious arthritis, polyarteritis nodosa, hypersensitivity vasculitis, arthrocellular arteritis, bursitis, tenosynovitis, epicondylitis, neonatal multisystem inflammatory disease, contact dermatitis, keratitis, conjunctivitis, retinitis, retinal vasculitis, uveitis , blepharitis, allergic conjunctivitis, polymyositis, autoimmune encephalomyelitis, polyarteritis nodosa, and fibromyalgia syndrome, but is not particularly limited thereto.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등 이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. A pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you do it.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form. It can be manufactured with The composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Dosage forms for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. These dosage forms contain a diluent (e.g. lactose) in addition to the active ingredient. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron agents such as starch, agar, alginic acid or its sodium salt, etc. The releasing or boiling mixture may contain absorbents, colorants, flavoring agents, and sweeteners.
본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 개선용 건강기능식품을 제공한다.Another aspect of the present invention is the prevention of neurodegenerative diseases, cancer, or inflammatory diseases containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Or provide health functional foods for improvement.
본 발명에 따른 화학식 1로 표시되는 화합물은, 우수한 LRRK2 억제능을 나타냄으로써, 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 개선용 건강기능식품 조성물로 약학적 조성물에 준하여 제조되거나, 식품, 음료 등의 건강기능보조 식품에 첨가할 수 있다.The compound represented by Formula 1 according to the present invention exhibits excellent LRRK2 inhibitory ability, and is manufactured as a pharmaceutical composition as a health functional food composition for preventing or improving neurodegenerative diseases, cancer, or inflammatory diseases, or as a food, beverage, etc. It can be added to health functional supplements.
본 발명에 따른 상기 화학식 1로 표시되는 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound represented by Formula 1 according to the present invention can be added as is to food or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention or improvement). In general, the amount of the above compound in health food can be 0.1 to 90 parts by weight of the total weight of the food. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품을 필요한 대상에게 투여하는 단계를 포함하는 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 치료 방법을 제공한다.Another aspect of the present invention is to provide a pharmaceutical composition or health functional food containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. Provided is a method for preventing or treating neurodegenerative diseases, cancer, or inflammatory diseases, including the step of administering.
본 발명의 다른 측면은, 신경퇴행성 질환, 암, 또는 염증성 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.Another aspect of the present invention is the use of the compound represented by Formula 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt in the prevention or treatment of neurodegenerative diseases, cancer, or inflammatory diseases. Provides a purpose.
본 발명의 상기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염 또는 약학적 조성물은 “약학적으로 유효한 양”으로 투여한다. 본 발명에 있어서, 용어 “약학적으로 유효한 양”이란, 의학적 치료 또는 개선에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 예를 들어, 0.001 mg/kg 내지 1000 mg/kg, 0.01 mg/kg 내지 100 mg/kg 또는 0.1 내지 20 mg/kg 또는 0.1 내지 500 mg/kg의 유효한 양이 포함된다. 본 발명의 약학적 조성물의 양은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.The compound represented by Formula 1 of the present invention, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt or pharmaceutical composition is administered in a “pharmaceutically effective amount.” In the present invention, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is determined by the type and severity of the individual, age, It can be determined based on factors including gender, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts of 0.001 mg/kg to 1000 mg/kg, 0.01 mg/kg to 100 mg/kg or 0.1 to 20 mg/kg or 0.1 to 500 mg/kg are included. The amount of the pharmaceutical composition of the present invention can be selected and implemented by a person skilled in the art within an appropriate range.
본 발명의 상기 화학식 1로 표시되는 화합물은 다음과 같은 제조방법으로 제조될 수 있다.The compound represented by Formula 1 of the present invention can be prepared by the following manufacturing method.
[반응식 1][Scheme 1]
Figure PCTKR2023011915-appb-img-000011
Figure PCTKR2023011915-appb-img-000011
상기 반응식 1에서 W는 할로겐이고,In Scheme 1, W is halogen,
X, Y, 및 Z는 상기의 화학식 1에서 정의한 바와 같다.X, Y, and Z are as defined in Formula 1 above.
상기 반응식 1의 결합 반응은 치환 반응에 의하여 진행될 수 있으며, 전이금속 촉매하에서 진행될 수 있다. 또한, 염기 존재하에 진행될 수 있으며, 용매로서 유기용매를 사용할 수 있다. The coupling reaction of Scheme 1 may proceed by a substitution reaction and may proceed in the presence of a transition metal catalyst. Additionally, the process may be carried out in the presence of a base, and an organic solvent may be used as the solvent.
촉매로서 Pd(PPh3)4 등을 사용할 수 있고, 유기 용매는 1, 4-다이옥세인, 테트라하이드로퓨란, DMF, DMSO, 클로로포름 등을 포함할 수 있다.As a catalyst, Pd(PPh 3 ) 4 may be used, and the organic solvent may include 1,4-dioxane, tetrahydrofuran, DMF, DMSO, chloroform, etc.
염기는 유기 또는 무기염기를 포함하며, 유기염기로는 1, 2, 3차 아민을 포함할 수 있으며, 무기염기로는 알칼리금속 또는 알칼리토금속의 카보네이트, 수산화물 등을 포함할 수 있다.Bases include organic or inorganic bases. Organic bases may include primary, secondary, and tertiary amines, and inorganic bases may include carbonates and hydroxides of alkali metals or alkaline earth metals.
또한, 본 발명의 일부 구체예는 다음의 반응식 2에 의해 제조될 수 있다.Additionally, some embodiments of the present invention can be prepared by Scheme 2 below.
[반응식 2][Scheme 2]
Figure PCTKR2023011915-appb-img-000012
Figure PCTKR2023011915-appb-img-000012
상기 반응식 2에서, Ar, R1a, R1b, Y, Z, p, A 및 B는 상기의 화학식 1에서 정의한 바와 같다.In Scheme 2, Ar, R 1a , R 1b , Y, Z, p, A and B are as defined in Formula 1 above.
상기 반응식 2는 아마이드화 반응으로서, 유기용매하에서 촉매 또는 산 활성화제의 첨가 조건하에서 수행될 수 있다.Reaction Scheme 2 is an amidation reaction that can be performed in an organic solvent under the conditions of addition of a catalyst or an acid activator.
촉매로는 산 촉매를 사용할 수 있으며, 무기 또는 유기산을 포함한다.The catalyst may be an acid catalyst and includes an inorganic or organic acid.
산 활성화제로는 EDCl과 같은 카보다이이미드, HOBt, 또는 아실화제 등이 사용될 수 있다.The acid activator may be a carbodiimide such as EDCl, HOBt, or an acylating agent.
필요에 따라 DIPEA 같은 3차 아민을 염기로서 더 포함할 수 있다.If necessary, a tertiary amine such as DIPEA may be further included as a base.
또한, 상기 반응식 2에 있어서 카르복실산 유도체는 하기 반응식 3에 의해서 제조될 수 있다.Additionally, in Scheme 2, the carboxylic acid derivative can be prepared according to Scheme 3 below.
[반응식 3][Scheme 3]
Figure PCTKR2023011915-appb-img-000013
Figure PCTKR2023011915-appb-img-000013
상기 반응식 3에서, W는 할로겐이고,In Scheme 3, W is halogen,
Ar, R1a, R1b, Y, Z, 및 p는 상기의 화학식 1에서 정의한 바와 같다.Ar, R 1a , R 1b , Y, Z, and p are as defined in Formula 1 above.
상기 반응식 3은 하기의 단계로 구성되어 있다.Reaction Scheme 3 consists of the following steps.
1 단계는 피롤 유도체의 결합 반응으로서 유기용매에서 촉매 및 염기의 존재하에 치환반응으로 진행된다.Step 1 is a combination reaction of pyrrole derivatives and proceeds as a substitution reaction in an organic solvent in the presence of a catalyst and a base.
유기용매, 촉매 및 염기에 대해서는 반응식 1에서 언급된 사항들이 그대로 적용될 수 있다.Regarding organic solvents, catalysts, and bases, the matters mentioned in Scheme 1 can be applied as is.
2 단계는, 아민 유도체에 의한 치환반응이며, 1 단계의 반응 조건이 그대로 적용될 수 있다.Step 2 is a substitution reaction with an amine derivative, and the reaction conditions of step 1 can be applied as is.
촉매로는 XantPhos 및 Pd(OAc)2로부터 선택되는 1 종 이상이 사용될 수 있다.As a catalyst, one or more types selected from XantPhos and Pd(OAc) 2 may be used.
3 단계는 에스테르 결합의 가수분해 반응으로서, 산 또는 염기 촉매하에서 수행될 수 있고, 염기에 대해서는 반응식 1에 언급된 염기가 그대로 적용될 수 있으며, 산은 무기 또는 유기산이 적용될 수 있다. 무기산으로는 염산, 황산, 질산, 인산 등을 포함된다. 염기가 촉매로 사용되는 경우에는 산 형태로의 목적물을 얻기 위하여 산 조건하에서 워크업이 수행될 수 있다.Step 3 is a hydrolysis reaction of an ester bond, which can be performed under an acid or base catalyst. The base mentioned in Scheme 1 can be applied as is, and the acid can be an inorganic or organic acid. Inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. When a base is used as a catalyst, workup can be performed under acid conditions to obtain the target product in acid form.
이하 본 발명을 제조예 및 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail through preparation examples and examples.
단, 하기 제조예 및 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 제조예 및 실시예에 의해서 한정되는 것은 아니다.However, the following preparation examples and examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following preparation examples and examples.
<제조예 1> 메틸 4-아미노-3-에톡시벤조에이트의 제조<Preparation Example 1> Preparation of methyl 4-amino-3-ethoxybenzoate
Figure PCTKR2023011915-appb-img-000014
Figure PCTKR2023011915-appb-img-000014
상기 반응식에 따라, 메틸 4-아미노-3-하이드록시벤조에이트 (1.5 g, 8.97 mmol)을 100ml RBF에 DMF로 녹인 다음, K2CO3 (1.865 g, 13.5 mmol), 아이오도에탄 (1.469 g, 9.42 mmol)을 상온에서 첨가하였다. 혼합물을 상온에서 10분 교반해준 뒤, 50℃에서 16시간동안 가열하였다. 반응 종료 후, 혼합물을 감압 농축한 뒤, 에틸아세테이트로 여러 번 추출하였다. 유기층을 황산마그네슘으로 건조시키고, 여과하여 감압 농축시킨 다음 컬럼 크로마토그래피를 통해서 정제하여 목적화합물(백색 고체, 1.6 g, 91%)을 수득하였다.According to the above reaction formula, methyl 4-amino-3-hydroxybenzoate (1.5 g, 8.97 mmol) was dissolved in 100 ml RBF with DMF, and then K 2 CO 3 (1.865 g, 13.5 mmol) and iodoethane (1.469 g) , 9.42 mmol) was added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 50°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (white solid, 1.6 g, 91%).
<제조예 2> 메틸 4-아미노-3-(2,2,2-트리플루오로에톡시)벤조에이트의 제조<Preparation Example 2> Preparation of methyl 4-amino-3-(2,2,2-trifluoroethoxy)benzoate
Figure PCTKR2023011915-appb-img-000015
Figure PCTKR2023011915-appb-img-000015
상기 반응식에 따라, 메틸 4-아미노-3-하이드록시벤조에이트 (1 g, 5.98 mmol)을 100ml RBF에 DMF로 완전히 녹인 다음, K2CO3 (1.239 g, 8.97 mmol)과 2,2,2-트리플루오로에틸 트리플루오로메탄설포네이트 (1.666 g, 7.18 mmol)을 상온에서 첨가하였다. 혼합물을 상온에서 10분 교반해준 뒤, 50℃에서 16시간동안 가열하였다. 반응 종료 후, 혼합물을 감압 농축한 뒤, 에틸아세테이트로 여러 번 추출하였다. 유기층을 황산마그네슘으로 건조시키고, 여과하여 감압 농축시킨 다음 컬럼 크로마토그래피를 통해서 정제하여 목적화합물(백색 고체, 462 mg, 31%)을 수득하였다.According to the above reaction formula, methyl 4-amino-3-hydroxybenzoate (1 g, 5.98 mmol) was completely dissolved in 100 ml RBF with DMF, and then K2CO3 (1.239 g, 8.97 mmol) and 2,2,2-trifluoride. Roethyl trifluoromethanesulfonate (1.666 g, 7.18 mmol) was added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 50°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (white solid, 462 mg, 31%).
<제조예 3> 메틸 4-아미노-3-사이클로프로필벤조에이트의 제조<Preparation Example 3> Preparation of methyl 4-amino-3-cyclopropylbenzoate
Figure PCTKR2023011915-appb-img-000016
Figure PCTKR2023011915-appb-img-000016
상기 반응식에 따라, 메틸 4-아미노-3-브로모벤조에이트 (1 g, 4.07 mmol)을 100ml RBF에 1,4-디옥산으로 완전히 녹인 다음, 사이클로프로필브로익 산 (457 mg, 5.33 mmol), Pd(dppf)Cl2·CH2Cl2 (334 mg, 0.41 mmol), K3PO4 (3.046 g, 14.4 mmol)을 상온에서 첨가하였다. 혼합물을 상온에서 10분 교반해준 뒤, 100℃에서 3시간동안 가열하였다. 반응 종료 후, 혼합물을 celite bad로 감압 필터한 뒤, 에틸아세테이트로 여러 번 추출하였다. 유기층을 황산마그네슘으로 건조시키고, 여과하여 감압 농축시킨 다음 컬럼 크로마토그래피를 통해서 정제하여 목적화합물(백색 고체, 555 mg, 66%)을 수득하였다.According to the above reaction formula, methyl 4-amino-3-bromobenzoate (1 g, 4.07 mmol) was completely dissolved in 1,4-dioxane in 100 ml RBF, and then cyclopropylbroic acid (457 mg, 5.33 mmol) , Pd(dppf)Cl 2 ·CH 2 Cl 2 (334 mg, 0.41 mmol), and K 3 PO 4 (3.046 g, 14.4 mmol) were added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 100°C for 3 hours. After completion of the reaction, the mixture was filtered under reduced pressure with celite bad and extracted several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (white solid, 555 mg, 66%).
<제조예 4> 4-아미노-3-사이클로프로폭시벤조에이트의 제조<Preparation Example 4> Preparation of 4-amino-3-cyclopropoxybenzoate
Figure PCTKR2023011915-appb-img-000017
Figure PCTKR2023011915-appb-img-000017
상기 반응식에 따라 제조예 4의 화합물을 제조하였다.The compound of Preparation Example 4 was prepared according to the above reaction scheme.
단계 1) 상기 반응식에 따라, 메틸 3-플루오로-4-니트로벤조에이트 (2 g, 10.1 mmol)을 100ml RBF에 DMF로 완전히 녹인 다음, Cs2CO3 (4.913 g. 15.1 mmol), 사이클로프로판올 (759 mg, 13.1 mmol)을 상온에서 첨가하였다. 혼합물을 상온에서 5분 교반해준 뒤, 80℃에서 16시간 동안 가열하였다. 반응 종료 후, 감압 농축시킨 다음 컬럼 크로마토그래피를 통해서 정제하여 메틸 3-사이클로프로폭시-4-니트로벤조에이트 (연노란색 고체, 1.295 g, 53%)을 수득하였다. Step 1) According to the above reaction formula, methyl 3-fluoro-4-nitrobenzoate (2 g, 10.1 mmol) was completely dissolved in 100 ml RBF with DMF, and then Cs 2 CO 3 (4.913 g. 15.1 mmol) and cyclopropanol. (759 mg, 13.1 mmol) was added at room temperature. The mixture was stirred at room temperature for 5 minutes and then heated at 80°C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure and purified through column chromatography to obtain methyl 3-cyclopropoxy-4-nitrobenzoate (light yellow solid, 1.295 g, 53%).
단계 2) 메틸 3-사이클로프로폭시-4-니트로벤조에이트 (1.259g, 5.31 mmol)을 100ml RBF에 메탄올로 완전히 녹인 다음, Zn (519 mg. 7.95 mmol), HCO2HN4 (534 mg, 8.48 mmol)을 상온에서 첨가하였다. 혼합물을 상온에서 10 분 교반해준 뒤, 80℃에서 16시간 동안 가열하였다. 반응 종료 후, 혼합물을 celite bad로 감압 필터한 뒤, 감압 농축시킨 다음 컬럼 크로마토그래피를 통해서 정제하여 목적화합물(노란색 고체, 900 mg, 82%)을 수득하였다. Step 2) Methyl 3-cyclopropoxy-4-nitrobenzoate (1.259 g, 5.31 mmol) was completely dissolved in 100 ml RBF with methanol, then Zn (519 mg. 7.95 mmol), HCO 2 HN 4 (534 mg, 8.48 mmol) mmol) was added at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated at 80°C for 16 hours. After completion of the reaction, the mixture was filtered under reduced pressure with a celite bad, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (yellow solid, 900 mg, 82%).
<제조예 5> 메틸 4-아미노-3-(2,2-디플루오로에톡시)벤조에이트의 제조<Preparation Example 5> Preparation of methyl 4-amino-3-(2,2-difluoroethoxy)benzoate
Figure PCTKR2023011915-appb-img-000018
Figure PCTKR2023011915-appb-img-000018
상기 반응식에 따라, 메틸 4-아미노-3-하이드록시벤조에이트 (500 mg, 2.99 mmol)을 100ml RBF에 DMF로 완전히 녹인 다음, K2CO3 (619 mg, 4.48 mmol), 1,1-디플루오로-2-아이오도에탄 (631 mg. 3.28 mmol)을 상온에서 첨가하였다. 혼합물을 80℃에서 16시간 동안 교반하였다. 반응 종료 후, 에틸아세테이트로 여러 번 추출하였다. 유기층을 황산마그네슘으로 건조시키고, 여과하여 감압 농축시킨 다음 컬럼 크로마토그래피를 통해서 정제하여 목적화합물(노란고체, 452 mg, 67%)을 수득하였다.According to the above reaction formula, methyl 4-amino-3-hydroxybenzoate (500 mg, 2.99 mmol) was completely dissolved in 100 ml RBF with DMF, then K 2 CO 3 (619 mg, 4.48 mmol), 1,1-di Fluoro-2-iodoethane (631 mg. 3.28 mmol) was added at room temperature. The mixture was stirred at 80° C. for 16 hours. After completion of the reaction, extraction was performed several times with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified through column chromatography to obtain the target compound (yellow solid, 452 mg, 67%).
<실시예 1> (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리미딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온의 제조<Example 1> (4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino) Preparation of Methanone
Figure PCTKR2023011915-appb-img-000019
Figure PCTKR2023011915-appb-img-000019
상기 반응식에 따라 실시예 1의 화합물을 제조하였다.The compound of Example 1 was prepared according to the above reaction scheme.
단계 1) 2,5-디클로로-4-(1-메틸-1H-피롤-3-일)피리미딘의 제조Step 1) Preparation of 2,5-dichloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidine
2,4,5-트리크로로피리미딘 (11.5 g, 62.98 mmol)을 1,4-디옥산 200 mL에 녹인 뒤, 1-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피롤 (15 g, 72.4 mmol), Pd(PPh3)4 (946 mg, 0.81 mmol), 2M Na2CO3 용액 (50 mL)을 넣고 105°C에서 6시간 동안 교반한다. 에틸아세테이트와 포화 NaCl 수용액, 물을 가하여 추출 한 유기층을 MgSO4 이용하여 건조, 여과, 농축한다. 얻은 조생성물을 컬럼 크로마토그래피로 분리하여 목적화합물 13.55 g (94% 수율)을 노란색 고체로 얻었다.2,4,5-Trichloropyrimidine (11.5 g, 62.98 mmol) was dissolved in 200 mL of 1,4-dioxane, then 1-methyl-3-(4,4,5,5-tetramethyl-1) ,3,2-dioxaborolan-2-yl)-1H-pyrrole (15 g, 72.4 mmol), Pd(PPh3)4 (946 mg, 0.81 mmol), 2M Na 2 CO 3 solution (50 mL) Add and stir at 105°C for 6 hours. The organic layer extracted by adding ethyl acetate, saturated NaCl aqueous solution, and water is dried, filtered, and concentrated using MgSO 4 . The obtained crude product was separated by column chromatography to obtain 13.55 g (94% yield) of the target compound as a yellow solid.
단계 2) 메틸 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리미딘-2-일)아미노)-3-메톡시벤조에이트의 제조Step 2) Preparation of methyl 4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-yl)amino)-3-methoxybenzoate
메틸 4-아미노-3-메톡시벤조에이트 (716 mg, 3.95 mmol)을 1,4-디옥산 20 mL에 녹인 뒤, 2,5-디클로로-4-(1-메틸-1H-피롤-3-일)피리미딘 (992 mg, 4.35 mmol), XantPhos (457 mg, 0.79 mmol), Pd(OAc)2 (176mg, 0.79 mmol), Cs2CO3 (2571mg, 7.9 mmol)을 넣고 105℃에서 17시간 동안 교반한다. 반응 혼합물을 Celite pad에서 감압 여과한 후 여과액에 에틸아세테이트와 포화 NaCl 수용액, 물을 가하여 추출 한 뒤, 추출한 유기층을 MgSO4 이용하여 건조, 여과, 농축한다. 얻은 조생성물을 컬럼 크로마토그래피로 분리하여 목적화합물 1146 mg (77.8% 수율)을 노란색 고체로 얻었다.Methyl 4-amino-3-methoxybenzoate (716 mg, 3.95 mmol) was dissolved in 20 mL of 1,4-dioxane, then 2,5-dichloro-4-(1-methyl-1H-pyrrole-3- 1) Add pyrimidine ( 992 mg , 4.35 mmol), Stir for a while. The reaction mixture is filtered under reduced pressure on a Celite pad, and the filtrate is extracted with ethyl acetate, saturated NaCl aqueous solution, and water. The extracted organic layer is dried, filtered, and concentrated using MgSO 4 . The obtained crude product was separated by column chromatography to obtain 1146 mg (77.8% yield) of the target compound as a yellow solid.
단계 3) 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리미딘-2-일)아미노)-3-메톡시벤조익 산의 제조Step 3) Preparation of 4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-yl)amino)-3-methoxybenzoic acid
메틸 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리미딘-2-일)아미노)-3-메톡시벤조에이트(1140 mg, 3.05 mmol)을 THF 15mL, MeOH 5mL에 녹인 뒤 H2O 5mL에 녹인 포타슘 하이드록사이드(514 mg, 9.17 mmol)을 넣고 75℃에서 4시간 동안 교반한다. 반응 혼합물을 감압 농축한 뒤 에틸아세테이트와 물을 가하여 추출한다. 추출된 수용액 층에 1N HCl 용액을 pH 2까지 가한 뒤 생성된 고체를 감압 여과하여 거른다. 목적화합물 736 mg (67.2 % 수율)을 흰색 고체로 얻었으며 얻어진 고체는 추가 정제 없이 다음 반응에 이용한다.Methyl 4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-yl)amino)-3-methoxybenzoate (1140 mg, 3.05 mmol) was dissolved in 15 mL of THF. , potassium hydroxide (514 mg, 9.17 mmol) dissolved in 5 mL of MeOH and then dissolved in 5 mL of H2O was added and stirred at 75°C for 4 hours. The reaction mixture is concentrated under reduced pressure and extracted by adding ethyl acetate and water. A 1N HCl solution was added to pH 2 to the extracted aqueous solution layer, and the resulting solid was filtered under reduced pressure. 736 mg (67.2% yield) of the target compound was obtained as a white solid, and the obtained solid was used in the next reaction without further purification.
단계 4) (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리미딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온의 제조Step 4) (4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone manufacture of
메틸 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리미딘-2-일)아미노)-3-메톡시벤조에이트 (350 mg, 0.97 mmol)을 THF 10mL에 녹인 뒤 모르폴린 (169 mg, 1.95 mmol), EDCI-HCl (372 mg, 1.95 mmol), HOBt (65 mg, 0.48 mmol), DIPEA (188 mg, 1.46 mmol)을 넣어준 후 상온에서 12시간 동안 교반한다. 에틸아세테이트와 포화 NaCl 수용액, 물을 가하여 추출한 유기층을 MgSO4 이용하여 건조, 여과, 농축한다. 얻은 조생성물을 컬럼 크로마토그래피로 분리하여 목적 화합물 402 mg (94.1% 수율)을 흰색 고체로 얻었다.Methyl 4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-yl)amino)-3-methoxybenzoate (350 mg, 0.97 mmol) was dissolved in 10 mL of THF. After dissolving in , morpholine (169 mg, 1.95 mmol), EDCI-HCl (372 mg, 1.95 mmol), HOBt (65 mg, 0.48 mmol), and DIPEA (188 mg, 1.46 mmol) were added and incubated at room temperature for 12 hours. Stir. The organic layer extracted by adding ethyl acetate, saturated NaCl aqueous solution, and water is dried using MgSO4, filtered, and concentrated. The obtained crude product was separated by column chromatography to obtain 402 mg (94.1% yield) of the target compound as a white solid.
실시예 1을 제조한 반응을 이용하여 실시예 1 내지 108을 제조하였으며, 제조된 화합물의 명칭 및 NMR 스펙트럼 데이터는 하기 표 1에, 화합물의 구조는 표 2에 정리하였다.Examples 1 to 108 were prepared using the reaction prepared in Example 1, and the names and NMR spectrum data of the prepared compounds are summarized in Table 1 below, and the structures of the compounds are summarized in Table 2.
실시예Example namename NMR assignNMR assignment
1One (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.09 - 7.02 (m, 1H), 7.05 (s, 2H), 6.70 (t, J = 2.5 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.71 (s, 8H). 1H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.09 - 7.02 (m, 1H), 7.05 (s, 2H), 6.70 (t, J = 2.5 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.71 (s, 8H).
22 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.38 - 7.27 (m, 1H), 7.14 - 7.03 (m, 1H), 6.72 - 6.62 (m, 1H), 5.96 (d, J = 8.0 Hz, 1H), 4.10 (s, 1H), 3.99 (s, 2H), 3.91 (s, 1H), 3.76 (s, 2H), 2.83 (s, 2H), 2.31 (d, J = 4.9 Hz, 3H), 2.18 (t, J = 10.6 Hz, 2H), 2.04 (d, J = 4.2 Hz, 3H), 1.30 - 1.22 (m, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.38 - 7.27 (m, 1H), 7.14 - 7.03 (m, 1H), 6.72 - 6.62 (m, 1H), 5.96 (d, J = 8.0 Hz, 1H), 4.10 (s, 1H), 3.99 (s, 2H), 3.91 (s, 1H), 3.76 (s, 2H), 2.83 (s, 2H), 2.31 (d, J = 4.9 Hz, 3H), 2.18 (t , J = 10.6 Hz, 2H), 2.04 (d, J = 4.2 Hz, 3H), 1.30 - 1.22 (m, 1H).
33 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidine -1-day) Methanone 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.82 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.05 (ddd, J = 11.2, 8.1, 1.8 Hz, 3H), 6.69 (t, J = 2.5 Hz, 1H), 3.93 (s, 3H), 3.75 (s, 3H), 2.90 (d, J = 8.2 Hz, 2H), 2.54 - 2.44 (m, 2H), 2.39 (dt, J = 8.1, 3.4 Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H), 1.88 (s, 2H), 1.52 - 1.44 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.82 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.05 (ddd, J = 11.2, 8.1, 1.8 Hz, 3H), 6.69 (t, J = 2.5 Hz, 1H), 3.93 (s, 3H), 3.75 (s, 3H), 2.90 (d, J = 8.2 Hz, 2H), 2.54 - 2.44 (m, 2H), 2.39 (dt, J = 8.1, 3.4 Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H), 1.88 (s, 2H), 1.52 - 1.44 (m, 2H).
44 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-(1-methylpiperidin-4- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.05 (t, J = 8.9 Hz, 1H), 7.96 (dd, J = 15.6, 2.1 Hz, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.29 (s, 1H), 7.19 (dd, J = 8.6, 2.1 Hz, 1H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.74 - 6.67 (m, 1H), 6.62 (dd, J = 13.9, 7.7 Hz, 1H), 4.05 (s, 1H), 3.77 (s, 3H), 2.82 (s, 2H), 2.33 (s, 3H), 2.23 (d, J = 11.4 Hz, 2H), 2.06 (d, J = 10.8 Hz, 2H), 1.65 (t, J = 11.7 Hz, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 8.05 (t, J = 8.9 Hz, 1H), 7.96 (dd, J = 15.6, 2.1 Hz, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.29 (s, 1H), 7.19 (dd, J = 8.6, 2.1 Hz, 1H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.74 - 6.67 (m, 1H), 6.62 (dd, J = 13.9, 7.7 Hz, 1H), 4.05 (s, 1H), 3.77 (s, 3H), 2.82 (s, 2H), 2.33 (s, 3H), 2.23 (d, J = 11.4 Hz) , 2H), 2.06 (d, J = 10.8 Hz, 2H), 1.65 (t, J = 11.7 Hz, 2H).
55 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluorophenyl)(4-(dimethylamino)piperidine -1-day) Methanone 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.87 (d, J = 12.3 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 9.4 Hz, 2H), 7.03 (dd, J = 2.8, 1.8 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 4.82 (d, J = 13.1 Hz, 1H), 3.76 (s, 3H), 2.86 - 2.65 (m, 2H), 2.44 (s, 6H), 2.09 - 1.81 (m, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.31 (s, 1H), 7.87 (d, J = 12.3 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H) , 7.20 (d, J = 9.4 Hz, 2H), 7.03 (dd, J = 2.8, 1.8 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 4.82 (d, J = 13.1 Hz, 1H) , 3.76 (s, 3H), 2.86 - 2.65 (m, 2H), 2.44 (s, 6H), 2.09 - 1.81 (m, 6H).
66 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(1-methylpiperidin-4-yl )Benzamide 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.49 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.72 - 6.66 (m, 1H), 5.63 (d, J = 8.1 Hz, 1H), 3.99 (s, 1H), 3.75 (s, 3H), 2.84 (s, 2H), 2.49 (s, 3H), 2.33 (s, 3H), 2.19 (s, 2H), 2.07 (d, J = 12.6 Hz, 2H), 1.61 (s, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.49 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.72 - 6.66 (m, 1H), 5.63 (d, J = 8.1 Hz, 1H), 3.99 (s, 1H), 3.75 (s, 3H), 2.84 (s, 2H), 2.49 (s, 3H), 2.33 (s, 3H), 2.19 (s, 2H), 2.07 (d, J = 12.6 Hz , 2H), 1.61 (s, 2H).
77 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-(dimethylamino)piperidine-1 -1) Methanone 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.54 (d, J = 9.8 Hz, 2H), 7.21 (s, 1H), 7.14 (s, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.82 (d, J = 13.4 Hz, 1H), 3.75 (s, 3H), 3.65 (d, J = 13.4 Hz, 1H), 3.35 - 3.14 (m, 1H), 2.97 (t, J = 12.9 Hz, 1H), 2.79 (s, 2H), 2.50 (d, J = 12.2 Hz, 1H), 2.35 (s, 6H), 2.31 (s, 3H), 2.00 (d, J = 9.7 Hz, 1H), 1.79 (s, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.54 (d, J = 9.8 Hz, 2H), 7.21 (s, 1H), 7.14 (s, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.82 (d, J = 13.4 Hz, 1H), 3.75 (s, 3H) , 3.65 (d, J = 13.4 Hz, 1H), 3.35 - 3.14 (m, 1H), 2.97 (t, J = 12.9 Hz, 1H), 2.79 (s, 2H), 2.50 (d, J = 12.2 Hz, 1H), 2.35 (s, 6H), 2.31 (s, 3H), 2.00 (d, J = 9.7 Hz, 1H), 1.79 (s, 1H).
88 (3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(dimethylamino)piperidine- 1-day) Methanone 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.75 - 6.62 (m, 1H), 3.76 (s, 3H), 2.40 (t, J = 11.1 Hz, 1H), 2.31 (s, 6H), 1.88 (s, 2H), 1.48 (s, 2H), 1.24 - 1.10 (m, 1H), 0.87 (d, J = 7.1 Hz, 1H). 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.50 ( d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.75 - 6.62 (m, 1H), 3.76 (s) , 3H), 2.40 (t, J = 11.1 Hz, 1H), 2.31 (s, 6H), 1.88 (s, 2H), 1.48 (s, 2H), 1.24 - 1.10 (m, 1H), 0.87 (d, J = 7.1 Hz, 1H).
99 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(oxetane-3- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.11 - 6.96 (m, 3H), 6.70 (t, J = 2.5 Hz, 1H), 5.33 - 5.26 (m, 1H), 4.84 (d, J = 6.8 Hz, 4H), 3.94 (s, 3H), 3.76 (s, 3H), 3.23 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.63 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.11 - 6.96 (m, 3H), 6.70 (t, J = 2.5 Hz, 1H), 5.33 - 5.26 (m, 1H), 4.84 (d, J = 6.8 Hz, 4H), 3.94 (s, 3H), 3.76 ( s, 3H), 3.23 (s, 3H).
1010 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-(1-methylpiperidin-4- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.94 (d, J = 7.9 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 4.05 - 3.92 (m, 1H), 3.76 (s, 3H), 2.89 - 2.78 (m, 2H), 2.32 (s, 3H), 2.23 - 2.12 (m, 2H), 2.10 - 2.04 (m, 2H), 1.72 - 1.55 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.44 ( d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.94 (d, J = 7.9 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 4.05 - 3.92 (m, 1H), 3.76 (s, 3H), 2.89 - 2.78 (m, 2H), 2.32 (s, 3H), 2.23 - 2.12 (m, 2H), 2.10 - 2.04 (m, 2H), 1.72 - 1.55 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H).
1111 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.97 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 2.94 (s, 3H), 2.27 (s, 3H), 1.91 (s, 2H), 1.71 (s, 1H), 1.62 - 1.59 (m, 6H), 1.50 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.05 ( dd, J = 2.9, 1.7 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.97 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 2.94 (s, 3H), 2.27 (s, 3H), 1.91 (s, 2H), 1.71 (s, 1H), 1.62 - 1.59 (m, 6H), 1.50 (t, J = 7.0 Hz, 3H).
1212 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 5.25 (p, J = 7.0 Hz, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.63 (t, J = 6.5 Hz, 2H), 4.21 (q, J = 7.0 Hz, 2H), 1.58 (s, 5H), 1.51 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.43 ( d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 5.25 (p, J = 7.0 Hz, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.63 (t, J = 6.5 Hz, 2H), 4.21 ( q, J = 7.0 Hz, 2H), 1.58 (s, 5H), 1.51 (t, J = 7.0 Hz, 3H).
1313 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(oxetane-3- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 7.00 (s, 2H), 6.69 (t, J = 2.5 Hz, 1H), 5.29 (p, 1H), 4.83 (d, J = 6.9 Hz, 4H), 4.16 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.05 ( dd, J = 2.9, 1.7 Hz, 1H), 7.00 (s, 2H), 6.69 (t, J = 2.5 Hz, 1H), 5.29 (p, 1H), 4.83 (d, J = 6.9 Hz, 4H), 4.16 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H).
1414 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시페닐)(모르폴리노)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxyphenyl)(morpholino)methanone 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.14 - 7.03 (m, 2H), 7.02 (d, J = 1.8 Hz, 1H), 6.69 (dd, J = 2.9, 2.2 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 3.74 - 3.58 (m, 9H), 1.62 (s, 1H), 1.50 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.14 - 7.03 (m, 2H), 7.02 (d, J = 1.8 Hz, 1H), 6.69 (dd, J = 2.9, 2.2 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H) ), 3.74 - 3.58 (m, 9H), 1.62 (s, 1H), 1.50 (t, J = 7.0 Hz, 3H).
1515 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-(oxetan-3-yl)benz amides 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 7.02 (s, 2H), 6.70 (t, J = 2.5 Hz, 1H), 5.32 - 5.24 (m, 1H), 4.84 (d, J = 6.8 Hz, 4H), 4.67 (p, J = 6.1 Hz, 1H), 3.76 (s, 3H), 3.23 (s, 3H), 1.42 (d, J = 6.1 Hz, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 7.02 (s, 2H), 6.70 (t, J = 2.5 Hz, 1H), 5.32 - 5.24 (m, 1H), 4.84 (d, J = 6.8 Hz, 4H), 4.67 (p, J = 6.1 Hz, 1H), 3.76 (s, 3H), 3.23 (s, 3H), 1.42 (d, J = 6.1 Hz, 6H).
1616 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-(oxetan-3-yl)benz amides 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 7.07 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.33 - 5.20 (m, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.76 (p, J = 6.1 Hz, 1H), 4.63 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 1.42 (d, J = 6.1 Hz, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.71 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 7.07 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H) , 5.33 - 5.20 (m, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.76 (p, J = 6.1 Hz, 1H), 4.63 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 1.42 (d, J = 6.1 Hz, 6H).
1717 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-methyl-N-(1-methylp Peridine-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.09 - 6.96 (m, 3H), 6.72 - 6.66 (m, 1H), 4.66 (p, J = 6.1 Hz, 1H), 3.76 (s, 3H), 2.94 (s, 3H), 2.28 (s, 3H), 1.99 - 1.53 (m, 8H), 1.41 (d, J = 6.0 Hz, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.63 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.09 - 6.96 (m, 3H), 6.72 - 6.66 (m, 1H), 4.66 (p, J = 6.1 Hz, 1H), 3.76 (s, 3H), 2.94 (s, 3H), 2.28 (s, 3H), 1.99 - 1.53 (m, 8H), 1.41 (d, J = 6.0 Hz, 6H).
1818 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시페닐)(피롤리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxyphenyl)(pyrrolidin-1-yl)methane on 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.83 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.3, 1.8 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.76 (s, 3H), 3.65 (t, J = 6.9 Hz, 2H), 3.55 (t, J = 6.6 Hz, 2H), 2.00 - 1.81 (m, 4H), 1.49 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.83 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.20 ( dd, J = 8.3, 1.8 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.76 (s, 3H), 3.65 (t, J = 6.9 Hz, 2H), 3.55 (t, J = 6.6 Hz, 2H), 2.00 - 1.81 (m, 4H) ), 1.49 (t, J = 7.0 Hz, 3H).
1919 (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-((tetrahydrofuran- 2-yl)methyl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 - 6.67 (m, 1H), 6.49 (s, 1H), 4.21 (q, J = 7.0 Hz, 2H), 4.08 (qd, J = 7.1, 3.1 Hz, 1H), 3.91 (dt, J = 8.3, 6.7 Hz, 2H), 3.84 - 3.78 (m, 2H), 3.77 (s, 3H), 3.37 (ddd, J = 13.7, 7.3, 4.9 Hz, 2H), 2.04 (td, J = 12.5, 6.7 Hz, 2H), 1.93 (p, J = 6.8 Hz, 2H), 1.69 - 1.60 (m, 1H), 1.50 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.46 ( d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 - 6.67 (m, 1H), 6.49 (s) , 1H), 4.21 (q, J = 7.0 Hz, 2H), 4.08 (qd, J = 7.1, 3.1 Hz, 1H), 3.91 (dt, J = 8.3, 6.7 Hz, 2H), 3.84 - 3.78 (m, 2H), 3.77 (s, 3H), 3.37 (ddd, J = 13.7, 7.3, 4.9 Hz, 2H), 2.04 (td, J = 12.5, 6.7 Hz, 2H), 1.93 (p, J = 6.8 Hz, 2H) ), 1.69 - 1.60 (m, 1H), 1.50 (t, J = 7.0 Hz, 3H).
2020 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.73 (t, J = 8.5 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.46 (d, J = 3.9 Hz, 1H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 5.25 (h, J = 6.9 Hz, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.62 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.73 (t, J = 8.5 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.46 (d, J = 3.9 Hz, 1H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 5.25 (h, J = 6.9 Hz, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.62 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H).
2121 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-methyl-N-( Oxetane-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.53 (t, J = 12.8 Hz, 1H), 8.34 (s, 1H), 7.88 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.05 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 5.04 (s, 1H), 4.98 - 4.77 (m, 4H), 3.92 (s, 3H), 3.77 (s, 3H), 1.25 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.53 (t, J = 12.8 Hz, 1H), 8.34 (s, 1H), 7.88 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.05 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 5.04 (s, 1H), 4.98 - 4.77 (m, 4H), 3.92 (s, 3H), 3.77 (s, 3H), 1.25 (s, 3H).
2222 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시페닐)(모르폴리노)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino) Methanone 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 12.4 Hz, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.8 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 3.93 (s, 3H), 3.80 - 3.66 (br, 6H), 3.77 (s, 3H), 3.46 (s, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.53 (d, J = 12.4 Hz, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.8 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 3.93 (s, 3H), 3.80 - 3.66 (br, 6H), 3.77 (s, 3H), 3.46 (s, 2H).
2323 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-methyl-N-( 1-methylpiperidin-4-yl)benzamide 1H NMR (400 MHz, DMSO) δ 8.51 (d, J = 12.6 Hz, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.43 (t, J = 2.0 Hz, 1H), 6.96 - 6.92 (br, 2H), 6.76 (s, 1H), 3.93 (s, 3H), 3.80 (d, J = 6.1 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 3.30 (s, 3H), 3.22 (m, 1H), 2.34 - 1.91 (br, 4H), 1.37 (m, 7H) 1H NMR (400 MHz, DMSO) δ 8.51 (d, J = 12.6 Hz, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.43 (t, J = 2.0 Hz, 1H), 6.96 - 6.92 (br, 2H), 6.76 (s, 1H), 3.93 (s, 3H), 3.80 (d, J = 6.1 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 3.30 (s) , 3H), 3.22 (m, 1H), 2.34 - 1.91 (br, 4H), 1.37 (m, 7H)
2424 3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 8.7 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.81 - 7.65 (m, 3H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.75 - 6.65 (m, 1H), 6.57 (d, J = 7.4 Hz, 1H), 5.31 - 5.19 (m, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.62 (dd, J = 7.0, 6.0 Hz, 2H), 3.77 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.80 (d, J = 8.7 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.81 - 7.65 (m, 3H) , 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.75 - 6.65 (m, 1H), 6.57 (d, J = 7.4 Hz, 1H), 5.31 - 5.19 (m, 1H), 5.04 (t, J) = 7.1 Hz, 2H), 4.62 (dd, J = 7.0, 6.0 Hz, 2H), 3.77 (s, 3H).
2525 3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)벤즈아미드3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl )Benzamide 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 8.6 Hz, 1H), 8.35 (s, 1H), 7.82 - 7.65 (m, 2H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.41 - 5.15 (m, 1H), 4.83 (q, J = 8.2 Hz, 4H), 3.76 (s, 3H), 3.22 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 8.6 Hz, 1H), 8.35 (s, 1H), 7.82 - 7.65 (m, 2H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H ), 6.70 (t, J = 2.5 Hz, 1H), 5.41 - 5.15 (m, 1H), 4.83 (q, J = 8.2 Hz, 4H), 3.76 (s, 3H), 3.22 (s, 3H).
2626 2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)벤즈아미드2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl )Benzamide 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.09 (s, 1H), 7.73 (s, 1H), 7.45 - 7.37 (m, 1H), 7.20 (dd, J = 16.9, 8.6 Hz, 2H), 7.03 (s, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.61 (d, J = 7.1 Hz, 1H), 4.99 - 4.76 (m, 4H), 4.71 (d, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.38 (s, 2H), 3.05 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (s, 1H), 8.09 (s, 1H), 7.73 (s, 1H), 7.45 - 7.37 (m, 1H), 7.20 (dd, J = 16.9, 8.6 Hz, 2H), 7.03 (s, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.61 (d, J = 7.1 Hz, 1H), 4.99 - 4.76 (m, 4H), 4.71 (d, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.38 (s, 2H), 3.05 (s, 1H).
2727 2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidine -4-day)Benzamide 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 5.2 Hz, 1H), 8.14 - 8.03 (m, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.23 - 7.12 (m, 2H), 7.06 - 7.00 (m, 1H), 6.69 (d, J = 2.7 Hz, 1H), 3.76 (d, J = 2.4 Hz, 3H), 3.03 (s, 2H), 2.77 (s, 2H), 2.33 (s, 3H), 2.25 - 2.13 (m, 4H), 0.88 (t, J = 6.6 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.31 (d, J = 5.2 Hz, 1H), 8.14 - 8.03 (m, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.23 - 7.12 (m, 2H), 7.06 - 7.00 (m, 1H), 6.69 (d, J = 2.7 Hz, 1H), 3.76 (d, J = 2.4 Hz, 3H), 3.03 ( s, 2H), 2.77 (s, 2H), 2.33 (s, 3H), 2.25 - 2.13 (m, 4H), 0.88 (t, J = 6.6 Hz, 3H).
2828 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(피롤리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(pyrrolidin-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.19 (d, J = 8.9 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.68 (t, J = 2.5 Hz, 1H), 3.75 (s, 3H), 3.66 (t, J = 7.0 Hz, 2H), 3.21 (t, J = 6.7 Hz, 2H), 2.35 (s, 3H), 1.98 - 1.93 (m, 2H), 1.89 - 1.84 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.19 (d, J = 8.9 Hz, 1H) , 7.09 - 7.00 (m, 2H), 6.68 (t, J = 2.5 Hz, 1H), 3.75 (s, 3H), 3.66 (t, J = 7.0 Hz, 2H), 3.21 (t, J = 6.7 Hz, 2H), 2.35 (s, 3H), 1.98 - 1.93 (m, 2H), 1.89 - 1.84 (m, 2H).
2929 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시페닐)(모르폴리노)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxyphenyl)(morpholino)methanone 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.08 - 7.01 (m, 3H), 6.70 (t, J = 2.5 Hz, 1H), 4.68 (h, J = 6.2 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 8H), 1.42 (d, J = 6.1 Hz, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.08 - 7.01 (m, 3H), 6.70 (t, J = 2.5 Hz, 1H), 4.68 (h, J = 6.2 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 8H), 1.42 (d, J = 6.1 Hz, 6H).
3030 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.76 - 7.68 (m, 2H), 7.04 (dd, J = 2.9, 1.7 Hz, 2H), 6.70 (t, J = 2.5 Hz, 1H), 6.38 - 5.95 (m, 1H), 5.28 (t, J = 7.2 Hz, 1H), 4.83 (q, J = 6.4 Hz, 4H), 4.32 (td, J = 12.9, 4.0 Hz, 2H), 3.77 (s, 3H), 3.23 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.69 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.76 - 7.68 (m, 2H), 7.04 (dd, J = 2.9, 1.7 Hz, 2H), 6.70 (t, J = 2.5 Hz, 1H), 6.38 - 5.95 (m, 1H), 5.28 (t, J = 7.2 Hz, 1H), 4.83 (q, J = 6.4 Hz, 4H), 4.32 ( td, J = 12.9, 4.0 Hz, 2H), 3.77 (s, 3H), 3.23 (s, 3H).
3131 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-methyl-N-(1-methylpiperi din-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.64 (t, J = 8.3 Hz, 1H), 8.33 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.38 (d, J = 3.7 Hz, 1H), 7.21 (t, J = 10.8 Hz, 2H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.79 - 6.63 (m, 1H), 3.76 (s, 3H), 2.99 (m, 2H), 2.93 (m, 1H), 2.35 (d, J = 14.0 Hz, 3H), 2.31 (m, 3H), 2.03 - 1.89 (m, 4H), 1.72 (s, 2H). 1H NMR (400 MHz, CDCl3) δ 8.64 (t, J = 8.3 Hz, 1H), 8.33 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.38 (d, J = 3.7 Hz, 1H), 7.21 (t, J = 10.8 Hz, 2H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.79 - 6.63 (m, 1H), 3.76 (s, 3H), 2.99 (m, 2H) ), 2.93 (m, 1H), 2.35 (d, J = 14.0 Hz, 3H), 2.31 (m, 3H), 2.03 - 1.89 (m, 4H), 1.72 (s, 2H).
3232 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluorophenyl)(4-(4-methylpiperazine- 1-yl) piperidin-1-yl) methanone 1H NMR (400 MHz, CDCl3) δ 8.63 (t, J = 8.3 Hz, 1H), 8.32 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 3.7 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.76 (s, 3H), 3.06 - 2.76 (m, 4H), 2.71 - 2.41 (m, 5H), 2.31 (s, 3H), 1.97 - 1.42 (m, 8H). 1H NMR (400 MHz, CDCl3) δ 8.63 (t, J = 8.3 Hz, 1H), 8.32 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 3.7 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.76 (s, 3H), 3.06 - 2.76 (m , 4H), 2.71 - 2.41 (m, 5H), 2.31 (s, 3H), 1.97 - 1.42 (m, 8H).
3333 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-methyl-N-(oxetane-3- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.67 (t, J = 8.4 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.40 (d, J = 3.8 Hz, 1H), 7.22 (d, J = 11.4 Hz, 2H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.26 (s, 1H), 4.83 (q, J = 7.6 Hz, 4H), 3.76 (s, 3H), 3.22 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.67 (t, J = 8.4 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.40 (d, J = 3.8 Hz, 1H), 7.22 (d, J = 11.4 Hz, 2H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.26 (s, 1H), 4.83 ( q, J = 7.6 Hz, 4H), 3.76 (s, 3H), 3.22 (s, 3H).
3434 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluorophenyl)(4-(4-methylpiperazine- 1-yl) piperidin-1-yl) methanone 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.92 - 7.81 (m, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.77 (d, J = 13.3 Hz, 1H), 3.75 (s, 3H), 3.16 - 2.79 (m, 2H), 2.68 - 2.43 (m, 8H), 2.29 (s, 3H), 1.96 -1.55 (m, 6H). 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.92 - 7.81 (m, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.77 (d , J = 13.3 Hz, 1H), 3.75 (s, 3H), 3.16 - 2.79 (m, 2H), 2.68 - 2.43 (m, 8H), 2.29 (s, 3H), 1.96 -1.55 (m, 6H).
3535 2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(1-메틸피페리딘-4-일)벤즈아미드2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(1-methylpiperidin-4-yl )Benzamide 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 3.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.41 (dd, J = 8.6, 2.2 Hz, 1H), 7.19 (s, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.71 - 6.69 (m, 1H), 6.32 (d, J = 8.1 Hz, 1H), 4.03 (s, 1H), 3.76 (s, 3H), 2.79 (s, 2H), 2.31 (s, 4H), 2.26 - 2.16 (m, 3H), 2.12 - 2.01 (m, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.32 (d, J = 3.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.41 (dd, J = 8.6, 2.2 Hz, 1H), 7.19 (s, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.71 - 6.69 (m, 1H), 6.32 (d, J = 8.1 Hz, 1H), 4.03 (s, 1H), 3.76 (s, 3H), 2.79 (s, 2H), 2.31 (s, 4H), 2.26 - 2.16 (m, 3H), 2.12 - 2.01 (m, 3H).
3636 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-methyl-N-(1-methylpiperi din-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.36 - 8.25 (m, 1H), 7.86 (dd, J = 12.6, 2.4 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.39 - 7.26 (m, 2H), 7.21 - 7.14 (m, 1H), 7.06 - 7.02 (m, 1H), 6.76 - 6.64 (m, 1H), 4.65 - 4.48 (m, 1H), 3.76 (d, J = 3.4 Hz, 3H), 3.03 - 2.89 (m, 2H), 2.83 (d, J = 1.8 Hz, 3H), 2.31 (d, J = 3.6 Hz, 2H), 2.21 (s, 2H), 2.16 (dd, J = 14.5, 8.7 Hz, 2H), 2.02 - 1.56 (m, 6H). 1 H NMR (400 MHz, CDCl3) δ 8.36 - 8.25 (m, 1H), 7.86 (dd, J = 12.6, 2.4 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.39 - 7.26 (m, 2H) , 7.21 - 7.14 (m, 1H), 7.06 - 7.02 (m, 1H), 6.76 - 6.64 (m, 1H), 4.65 - 4.48 (m, 1H), 3.76 (d, J = 3.4 Hz, 3H), 3.03 - 2.89 (m, 2H), 2.83 (d, J = 1.8 Hz, 3H), 2.31 (d, J = 3.6 Hz, 2H), 2.21 (s, 2H), 2.16 (dd, J = 14.5, 8.7 Hz, 2H), 2.02 - 1.56 (m, 6H).
3737 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.07 - 7.97 (m, 2H), 7.74 (t, J = 2.0 Hz, 1H), 7.34 (s, 1H), 7.25 - 7.15 (m, 2H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 5.28 (td, J = 7.5, 5.5 Hz, 1H), 5.02 (t, J = 7.1 Hz, 2H), 4.63 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.07 - 7.97 (m, 2H), 7.74 (t, J = 2.0 Hz, 1H), 7.34 (s, 1H), 7.25 - 7.15 (m , 2H), 7.03 (dd, J = 2.9, 1.8 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 5.28 (td, J = 7.5, 5.5 Hz, 1H), 5.02 (t, J = 7.1 Hz, 2H), 4.63 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H).
3838 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-methyl-N-(oxetane-3- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.89 (d, J = 12.8 Hz, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.21 - 7.11 (m, 1H), 7.05 - 6.91 (m, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.52 (s, 1H), 5.08 - 4.88 (m, 2H), 4.83 (s, 3H), 3.76 (s, 3H), 3.37 (s, 2H), 3.11 (s, 1H). 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.89 (d, J = 12.8 Hz, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.21 - 7.11 (m, 1H), 7.05 - 6.91 (m, 1H), 6.70 (t, J = 2.5 Hz, 1H), 5.52 (s, 1H), 5.08 - 4.88 (m, 2H), 4.83 (s, 3H), 3.76 (s, 3H), 3.37 (s, 2H), 3.11 (s, 1H).
3939 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-((tetrahydrofuran- 2-yl)methyl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.80 (s, 1H), 7.71 (t, J = 1.9 Hz, 1H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.21 (s, 1H), 4.15 (q, J = 7.0 Hz, 2H), 4.08 - 3.83 (m, 4H), 3.75 (s, 3H), 3.60 - 3.21 (m, 2H), 3.15 (s, 3H), 2.00 - 1.75 (m, 2H), 1.49 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.80 (s, 1H), 7.71 (t, J = 1.9 Hz, 1H), 7.08 ( dd, J = 8.3, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.21 (s, 1H), 4.15 (q, J = 7.0 Hz, 2H), 4.08 - 3.83 (m, 4H), 3.75 (s, 3H), 3.60 - 3.21 (m, 2H), 3.15 (s, 3H) , 2.00 - 1.75 (m, 2H), 1.49 (t, J = 7.0 Hz, 3H).
4040 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)-3-(2,2 ,2-trifluoroethoxy)benzamide 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 7.74 (dd, J = 4.0, 2.1 Hz, 2H), 7.48 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.25 (hept, J = 6.4 Hz, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.62 (dd, J = 7.0, 6.0 Hz, 2H), 4.52 (q, J = 8.0 Hz, 2H), 3.77 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 7.74 (dd, J = 4.0, 2.1 Hz, 2H), 7.48 (d, J = 1.9) Hz, 1H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.25 (hept, J = 6.4 Hz, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.62 (dd, J = 7.0, 6.0 Hz, 2H), 4.52 (q, J = 8.0 Hz, 2H), 3.77 (s, 3H).
4141 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,2-디메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,2-dimethyl-N-(oxetan-3-yl)benz amides 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.71 (t, J = 1.9 Hz, 1H), 7.53 (t, J = 3.6 Hz, 2H), 7.40 (d, J = 17.9 Hz, 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 2H), 6.67 (t, J = 2.5 Hz, 1H), 4.94 (s, 2H), 4.81 (t, J = 6.6 Hz, 1H), 4.71 (s, 2H), 3.73 (d, J = 1.5 Hz, 3H), 3.47 - 2.85 (m, 3H), 2.44 - 2.08 (m, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.71 (t, J = 1.9 Hz, 1H), 7.53 (t, J = 3.6 Hz, 2H), 7.40 (d, J = 17.9 Hz) , 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 2H), 6.67 (t, J = 2.5 Hz, 1H), 4.94 (s, 2H), 4.81 (t, J = 6.6 Hz, 1H), 4.71 (s, 2H), 3.73 (d, J = 1.5 Hz, 3H), 3.47 - 2.85 (m, 3H), 2.44 - 2.08 (m, 3H).
4242 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,3-디메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,3-dimethyl-N-(1-methylpiperidin-4 -1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.38 - 8.23 (m, 2H), 7.70 (q, J = 2.7 Hz, 1H), 7.31 - 7.19 (m, 2H), 7.07 - 6.96 (m, 2H), 6.67 (t, J = 2.6 Hz, 1H), 4.66 (s, 1H), 3.74 (s, 3H), 3.30 (s, 2H), 2.95 (s, 3H), 2.66 - 2.49 (m, 2H), 2.35 (s, 3H), 2.32 - 2.13 (m, 2H), 1.84 (s, 2H), 1.47 (d, J = 6.7 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 - 8.23 (m, 2H), 7.70 (q, J = 2.7 Hz, 1H), 7.31 - 7.19 (m, 2H), 7.07 - 6.96 (m, 2H), 6.67 (t, J = 2.6 Hz, 1H), 4.66 (s, 1H), 3.74 (s, 3H), 3.30 (s, 2H), 2.95 (s, 3H), 2.66 - 2.49 (m, 2H), 2.35 (s, 3H), 2.32 - 2.13 (m, 2H), 1.84 (s, 2H), 1.47 (d, J = 6.7 Hz, 3H).
4343 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸페닐)(피롤리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methylphenyl)(pyrrolidin-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.33 - 8.25 (m, 2H), 7.68 (t, J = 1.9 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.03 - 6.97 (m, 2H), 6.65 (t, J = 2.5 Hz, 1H), 3.72 (s, 3H), 3.64 (t, J = 6.9 Hz, 2H), 3.52 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H), 1.95 (p, J = 6.7 Hz, 2H), 1.86 (p, J = 6.3 Hz, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 - 8.25 (m, 2H), 7.68 (t, J = 1.9 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.03 - 6.97 (m, 2H), 6.65 (t, J = 2.5 Hz, 1H), 3.72 (s, 3H), 3.64 (t, J = 6.9 Hz, 2H), 3.52 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H), 1.95 (p, J = 6.7 Hz, 2H), 1.86 (p, J = 6.3 Hz, 2H).
4444 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methylphenyl)(4-(dimethylamino)piperidine-1 -1) Methanone 1H NMR (400 MHz, CDCl3) δ 8.33 - 8.26 (m, 2H), 7.69 (t, J = 1.9 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.03 - 6.95 (m, 2H), 6.67 (t, J = 2.5 Hz, 1H), 4.47 - 3.84 (m, 2H), 3.73 (s, 3H), 2.91 (s, 2H), 2.54 (tt, J = 10.9, 3.5 Hz, 1H), 2.37 (s, 6H), 2.35 (s, 3H), 1.93 (s, 2H), 1.52 (s, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 - 8.26 (m, 2H), 7.69 (t, J = 1.9 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.03 - 6.95 (m, 2H), 6.67 (t, J = 2.5 Hz, 1H), 4.47 - 3.84 (m, 2H), 3.73 (s, 3H), 2.91 (s, 2H), 2.54 (tt, J = 10.9, 3.5 Hz, 1H), 2.37 (s, 6H), 2.35 (s, 3H), 1.93 (s, 2H), 1.52 (s, 2H).
4545 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-(1-methylpiperidin-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 7.00 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 6.39 - 5.98 (m, 1H), 4.31 (td, J = 12.9, 4.0 Hz, 2H), 3.76 (s, 3H), 2.94 (s, 4H), 2.29 (s, 2H), 1.94 (s, 2H), 1.72 (s, 2H), 1.60 (s, 5H). 1H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 7.00 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 6.39 - 5.98 (m, 1H), 4.31 (td, J = 12.9, 4.0 Hz, 2H), 3.76 (s, 3H), 2.94 (s, 4H), 2.29 (s, 2H), 1.94 (s, 2H), 1.72 (s, 2H) ), 1.60 (s, 5H).
4646 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-((tetrahydrofuran-2-yl)methyl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.67 (s, 1H), 7.18 (dd, J = 8.3, 1.7 Hz, 1H), 7.07 (s, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 - 6.66 (m, 1H), 6.36 - 6.00 (m, 1H), 4.31 (td, J = 12.9, 4.1 Hz, 2H), 3.92 (s, 1H), 3.76 (s, 5H), 3.33 (s, 1H), 3.16 (s, 3H), 2.10 - 1.79 (m, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.67 (s, 1H), 7.18 (dd, J = 8.3, 1.7 Hz, 1H), 7.07 (s, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 - 6.66 (m, 1H), 6.36 - 6.00 (m, 1H) ), 4.31 (td, J = 12.9, 4.1 Hz, 2H), 3.92 (s, 1H), 3.76 (s, 5H), 3.33 (s, 1H), 3.16 (s, 3H), 2.10 - 1.79 (m, 4H).
4747 (2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(4-methylpiperazine-1 -1-yl)piperidine-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.12 - 7.99 (m, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.40 (dd, J = 15.7, 8.3 Hz, 1H), 7.25 - 7.10 (m, 2H), 7.03 (t, J = 2.3 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 4.79 (d, J = 13.6 Hz, 1H), 3.76 (s, 3H), 3.59 (s, 1H), 3.15 - 2.89 (m, 1H), 2.81 (q, J = 13.9 Hz, 1H), 2.63 (s, 2H), 2.49 (s, 2H), 2.31 (s, 3H), 1.98 (d, J = 14.1 Hz, 2H), 1.79 (d, J = 12.9 Hz, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.31 (s, 1H), 8.12 - 7.99 (m, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.40 (dd, J = 15.7, 8.3 Hz, 1H), 7.25 - 7.10 (m, 2H), 7.03 (t, J = 2.3 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 4.79 (d, J = 13.6 Hz, 1H), 3.76 ( s, 3H), 3.59 (s, 1H), 3.15 - 2.89 (m, 1H), 2.81 (q, J = 13.9 Hz, 1H), 2.63 (s, 2H), 2.49 (s, 2H), 2.31 (s , 3H), 1.98 (d, J = 14.1 Hz, 2H), 1.79 (d, J = 12.9 Hz, 2H).
4848 3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(퓨란-2-일메틸)벤즈아미드3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(furan-2-ylmethyl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.79 - 7.65 (m, 3H), 7.40 (dd, J = 1.9, 0.9 Hz, 1H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 6.42 - 6.22 (m, 3H), 4.65 (d, J = 5.4 Hz, 2H), 3.76 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.76 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.79 - 7.65 (m, 3H) , 7.40 (dd, J = 1.9, 0.9 Hz, 1H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 6.42 - 6.22 (m, 3H), 4.65 (d, J = 5.4 Hz, 2H), 3.76 (s, 3H).
4949 2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-methyl-N-(oxo Cetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), 7.74 (t, J = 2.0 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 5.08 - 4.65 (m, 5H), 3.91 (d, J = 3.8 Hz, 3H), 3.76 (s, 3H), 3.39 (s, 2H), 3.07 (s, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.82 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), 7.74 (t , J = 2.0 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 5.08 - 4.65 (m, 5H), 3.91 (d, J = 3.8 Hz) , 3H), 3.76 (s, 3H), 3.39 (s, 2H), 3.07 (s, 1H).
5050 (2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시페닐)(모르폴리노)메탄온(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxyphenyl)(morpholino)methane on 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.32 (s, 1H), 7.75 (d, J = 5.0 Hz, 2H), 7.06 (dd, J = 2.9, 1.8 Hz, 1H), 6.80 (s, 1H), 6.70 (t, J = 2.5 Hz, 1H), 3.92 (s, 4H), 3.83 - 3.76 (m, 4H), 3.76 (s, 3H), 3.60 (ddd, J = 11.2, 6.0, 3.0 Hz, 1H), 3.42 (ddd, J = 13.6, 6.2, 3.1 Hz, 1H), 3.28 (ddd, J = 13.4, 6.9, 3.1 Hz, 1H). 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.32 (s, 1H), 7.75 (d, J = 5.0 Hz, 2H), 7.06 (dd, J = 2.9, 1.8 Hz, 1H), 6.80 (s, 1H), 6.70 (t, J = 2.5 Hz, 1H), 3.92 (s, 4H), 3.83 - 3.76 (m, 4H), 3.76 (s, 3H), 3.60 (ddd, J = 11.2, 6.0, 3.0 Hz, 1H), 3.42 (ddd, J = 13.6, 6.2, 3.1 Hz, 1H), 3.28 (ddd, J = 13.4, 6.9, 3.1 Hz, 1H).
5151 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl)-3- (2,2,2-trifluoroethoxy)benzamide 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.07 - 7.02 (m, 2H), 6.72 - 6.67 (m, 1H), 5.29 - 5.20 (m, 1H), 4.83 (q, J = 7.0 Hz, 4H), 4.48 (q, J = 8.0 Hz, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 1.58 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.07 - 7.02 (m, 2H), 6.72 - 6.67 (m, 1H), 5.29 - 5.20 (m, 1H), 4.83 (q, J = 7.0 Hz, 4H), 4.48 (q, J = 8.0 Hz, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 1.58 (s, 3H).
5252 3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 8.7 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.81 - 7.65 (m, 3H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.75 - 6.65 (m, 1H), 6.57 (d, J = 7.4 Hz, 1H), 5.31 - 5.19 (m, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.62 (dd, J = 7.0, 6.0 Hz, 2H), 3.77 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.80 (d, J = 8.7 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.81 - 7.65 (m, 3H) , 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.75 - 6.65 (m, 1H), 6.57 (d, J = 7.4 Hz, 1H), 5.31 - 5.19 (m, 1H), 5.04 (t, J) = 7.1 Hz, 2H), 4.62 (dd, J = 7.0, 6.0 Hz, 2H), 3.77 (s, 3H).
5353 3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(퓨란-2-일메틸)-N-메틸벤즈아미드3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(furan-2-ylmethyl)-N- Methylbenzamide 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 7.75 - 7.66 (m, 2H), 7.42 (t, J = 1.3 Hz, 1H), 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 6.37 (dd, J = 3.2, 1.9 Hz, 1H), 6.30 (s, 1H), 3.76 (s, 3H), 3.04 (s, 3H), 1.30 - 1.22 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.71 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 7.75 - 7.66 (m, 2H), 7.42 (t, J = 1.3 Hz, 1H) , 7.03 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 6.37 (dd, J = 3.2, 1.9 Hz, 1H), 6.30 (s, 1H), 3.76 ( s, 3H), 3.04 (s, 3H), 1.30 - 1.22 (m, 2H).
5454 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필페닐)(모르폴리노)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropylphenyl)(morpholino)methanone 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.72 (d, J = 1.8 Hz, 2H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 2.9, 1.8 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.76 (s, 3H), 3.73 - 3.56 (m, 8H), 1.85 (ddd, J = 13.7, 8.3, 5.4 Hz, 1H), 1.11 - 1.04 (m, 2H), 0.76 - 0.69 (m, 2H). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.72 (d, J = 1.8 Hz, 2H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 2.9, 1.8 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.76 (s, 3H), 3.73 - 3.56 (m, 8H), 1.85 (ddd, J = 13.7, 8.3, 5.4 Hz, 1H), 1.11 - 1.04 (m, 2H), 0.76 - 0.69 (m, 2H).
5555 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.70 (dd, J = 8.6, 2.3 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 5.26 (p, J = 6.8 Hz, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.62 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 1.91 - 1.81 (m, 1H), 1.14 - 1.07 (m, 2H), 0.79 - 0.72 (m, 2H). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.70 ( dd, J = 8.6, 2.3 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 5.26 (p, J = 6.8 Hz, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.62 (t, J = 6.5 Hz, 2H), 3.77 ( s, 3H), 1.91 - 1.81 (m, 1H), 1.14 - 1.07 (m, 2H), 0.79 - 0.72 (m, 2H).
5656 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-methyl-N-(oxetane-3- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.73 (dd, J = 4.9, 2.9 Hz, 2H), 7.35 - 7.28 (m, 2H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.26 (s, 1H), 4.83 (d, J = 6.8 Hz, 4H), 3.76 (s, 3H), 3.21 (s, 3H), 1.85 (ddd, J = 13.8, 8.4, 5.3 Hz, 1H), 1.12 - 1.04 (m, 2H), 0.75 - 0.68 (m, 2H). 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.73 (dd, J = 4.9, 2.9 Hz, 2H), 7.35 - 7.28 (m, 2H) ), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.26 (s, 1H), 4.83 (d, J = 6.8 Hz, 4H), 3.76 (s , 3H), 3.21 (s, 3H), 1.85 (ddd, J = 13.8, 8.4, 5.3 Hz, 1H), 1.12 - 1.04 (m, 2H), 0.75 - 0.68 (m, 2H).
5757 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CD3OD_SPE) δ 8.28 (s, 1H), 7.80 (s, 1H), 7.72 - 7.63 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.77 (t, J = 2.5 Hz, 1H), 5.48 (s, 1H), 5.11 (t, J = 7.2 Hz, 1H), 4.95 (d, J = 6.7 Hz, 2H), 4.68 (t, J = 6.5 Hz, 2H), 4.61 (s, 1H), 3.75 (s, 3H), 2.43 (s, 3H). 1 H NMR (400 MHz, CD 3 OD_SPE) δ 8.28 (s, 1H), 7.80 (s, 1H), 7.72 - 7.63 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 6.99 (d) , J = 2.0 Hz, 1H), 6.77 (t, J = 2.5 Hz, 1H), 5.48 (s, 1H), 5.11 (t, J = 7.2 Hz, 1H), 4.95 (d, J = 6.7 Hz, 2H) ), 4.68 (t, J = 6.5 Hz, 2H), 4.61 (s, 1H), 3.75 (s, 3H), 2.43 (s, 3H).
5858 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,3-디메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,3-dimethyl-N-(oxetan-3-yl)benz amides 1H NMR (400 MHz, CH2Cl2) δ 8.91 - 8.73 (m, 2H), 8.19 (dp, J = 6.5, 1.8 Hz, 1H), 7.78 (d, J = 4.9 Hz, 2H), 7.56 - 7.46 (m, 2H), 7.16 (ddt, J = 6.5, 4.3, 2.6 Hz, 1H), 5.89 - 5.67 (m, 1H), 5.33 (t, J = 5.6 Hz, 4H), 4.26 - 4.18 (m, 3H), 3.72 (s, 3H), 2.85 (dd, J = 7.1, 3.6 Hz, 3H). 1 H NMR (400 MHz, CH 2 Cl 2 ) δ 8.91 - 8.73 (m, 2H), 8.19 (dp, J = 6.5, 1.8 Hz, 1H), 7.78 (d, J = 4.9 Hz, 2H), 7.56 - 7.46 (m, 2H), 7.16 (ddt, J = 6.5, 4.3, 2.6 Hz, 1H), 5.89 - 5.67 (m, 1H), 5.33 (t, J = 5.6 Hz, 4H), 4.26 - 4.18 (m, 3H), 3.72 (s, 3H), 2.85 (dd, J = 7.1, 3.6 Hz, 3H).
5959 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.08 - 7.00 (m, 2H), 6.99 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 2.93 (s, 3H), 2.54 (s, 1H), 2.34 (s, 3H), 2.04 (s, 4H), 1.97 (d, J = 9.8 Hz, 4H), 1.88 - 1.67 (m, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.08 - 7.00 (m, 2H), 6.99 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 2.93 (s, 3H), 2.54 ( s, 1H), 2.34 (s, 3H), 2.04 (s, 4H), 1.97 (d, J = 9.8 Hz, 4H), 1.88 - 1.67 (m, 4H).
6060 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 5.26 (p, J = 6.8 Hz, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.63 (t, J = 6.5 Hz, 2H), 3.98 (s, 3H), 3.77 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.69 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H) , 6.60 (d, J = 7.4 Hz, 1H), 5.26 (p, J = 6.8 Hz, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.63 (t, J = 6.5 Hz, 2H), 3.98 (s, 3H), 3.77 (s, 3H).
6161 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,2,5-트리메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,2,5-trimethyl-N-(oxetan-3-yl )Benzamide 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.14 (s, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.00 - 6.99 (m, 2H), 6.99 - 6.85 (m, 1H), 6.65 (t, J = 2.5 Hz, 1H), 4.96 - 4.91 (m, 2H), 4.81 (t, J = 6.6 Hz, 1H), 4.71 (s, 2H), 3.71 (s, 3H), 3.42 - 2.86 (m, 3H), 2.34 - 2.16 (m, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 8.14 (s, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.00 - 6.99 (m, 2H), 6.99 - 6.85 ( m, 1H), 6.65 (t, J = 2.5 Hz, 1H), 4.96 - 4.91 (m, 2H), 4.81 (t, J = 6.6 Hz, 1H), 4.71 (s, 2H), 3.71 (s, 3H) ), 3.42 - 2.86 (m, 3H), 2.34 - 2.16 (m, 6H).
6262 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(피롤리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(pyrrolidin-1-yl) methanone 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.11 (s, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.92 (s, 1H), 6.65 (t, J = 2.5 Hz, 1H), 3.71 (s, 3H), 3.65 (t, J = 7.0 Hz, 2H), 3.21 (t, J = 6.7 Hz, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 1.96 (ddd, J = 13.4, 7.3, 5.8 Hz, 2H), 1.90 - 1.79 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.26 (s, 1H), 8.11 (s, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.92 (s, 1H), 6.65 (t, J = 2.5 Hz, 1H), 3.71 (s, 3H), 3.65 (t, J = 7.0 Hz, 2H), 3.21 (t, J = 6.7 Hz, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 1.96 (ddd, J = 13.4, 7.3, 5.8 Hz, 2H), 1.90 - 1.79 (m, 2H).
6363 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-(dimethylamino)piperi din-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.14 (s, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.04 - 6.94 (m, 2H), 6.84 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.84 (d, J = 13.4 Hz, 1H), 3.74 (s, 3H), 3.69 (d, J = 13.9 Hz, 1H), 2.98 (t, J = 12.8 Hz, 1H), 2.80 (t, J = 12.6 Hz, 1H), 2.58 (s, 1H), 2.40 (s, 6H), 2.29 (s, 6H), 2.03 (d, J = 11.9 Hz, 1H), 1.85 (d, J = 12.7 Hz, 1H), 1.54 (s, 1H), 1.39 (d, J = 11.6 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 8.14 (s, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.04 - 6.94 (m, 2H), 6.84 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.84 (d, J = 13.4 Hz, 1H), 3.74 (s, 3H), 3.69 (d, J = 13.9 Hz, 1H), 2.98 (t, J = 12.8 Hz, 1H), 2.80 (t, J = 12.6 Hz, 1H), 2.58 (s, 1H), 2.40 (s, 6H), 2.29 (s, 6H), 2.03 (d, J = 11.9 Hz, 1H), 1.85 (d, J = 12.7 Hz, 1H), 1.54 (s, 1H), 1.39 (d, J = 11.6 Hz, 1H).
6464 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-(1-methylpiperidin-4- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 9.3 Hz, 1H), 8.32 (s, 1H), 7.78 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.64 (d, J = 1.9 Hz, 2H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.89 (d, J = 8.0 Hz, 1H), 4.05 - 3.91 (m, 1H), 3.76 (s, 3H), 2.83 (d, J = 11.4 Hz, 2H), 2.31 (s, 3H), 2.22 - 2.11 (m, 2H), 2.06 (d, J = 8.8 Hz, 2H), 1.85 (ddd, J = 13.8, 8.5, 5.4 Hz, 1H), 1.68 - 1.50 (m, 2H), 1.15 - 1.04 (m, 2H), 0.76 (td, J = 5.8, 4.2 Hz, 2H). 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 9.3 Hz, 1H), 8.32 (s, 1H), 7.78 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.64 ( d, J = 1.9 Hz, 2H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.89 (d, J = 8.0 Hz, 1H), 4.05 - 3.91 (m, 1H), 3.76 (s, 3H), 2.83 (d, J = 11.4 Hz, 2H), 2.31 (s, 3H), 2.22 - 2.11 (m, 2H), 2.06 (d, J = 8.8 Hz) , 2H), 1.85 (ddd, J = 13.8, 8.5, 5.4 Hz, 1H), 1.68 - 1.50 (m, 2H), 1.15 - 1.04 (m, 2H), 0.76 (td, J = 5.8, 4.2 Hz, 2H) ).
6565 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidin-4-yl )-3-(2,2,2-trifluoroethoxy)benzamide 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.65 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 2.8, 1.7 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.47 (q, J = 8.0 Hz, 2H), 3.75 (s, 3H), 2.93 (s, 3H), 2.90 (s, 2H), 2.27 (s, 3H), 1.91 (s, 3H), 1.71 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.65 (s, 1H), 7.13 ( d, J = 8.4 Hz, 1H), 7.04 (dd, J = 2.8, 1.7 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.47 ( q, J = 8.0 Hz, 2H), 3.75 (s, 3H), 2.93 (s, 3H), 2.90 (s, 2H), 2.27 (s, 3H), 1.91 (s, 3H), 1.71 (s, 3H) ).
6666 2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드2-Chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-methyl-N-(1 -methylpiperidin-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.87 - 8.77 (m, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.75 (m, 2H), 7.11 - 7.04 (m, 1H), 6.77 (s, 1H), 6.75 - 6.67 (m, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 3.03 (s, 1H), 2.79 (s, 1H), 2.38 (m, 2H), 2.23 (s, 1H), 1.99 - 1.66 (m, 5H), 1.33 - 1.22 (m, 3H), 0.92 - 0.81 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 - 8.77 (m, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.75 (m, 2H), 7.11 - 7.04 (m, 1H), 6.77 ( s, 1H), 6.75 - 6.67 (m, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 3.03 (s, 1H), 2.79 (s, 1H), 2.38 (m, 2H), 2.23 (s, 1H), 1.99 - 1.66 (m, 5H), 1.33 - 1.22 (m, 3H), 0.92 - 0.81 (m, 2H).
6767 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethyl-N-(oxetan-3-yl)benz amides 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.20 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.25 (s, 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 1H), 6.87 (s, 1H), 6.68 (t, J = 2.5 Hz, 1H), 6.38 - 6.33 (m, 1H), 5.23 (q, J = 6.3 Hz, 1H), 5.02 (t, J = 7.1 Hz, 2H), 4.59 (t, J = 6.5 Hz, 2H), 3.74 (s, 3H), 2.49 (s, 3H), 2.30 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 8.20 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.25 (s, 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 1H), 6.87 (s, 1H), 6.68 (t, J = 2.5 Hz, 1H), 6.38 - 6.33 (m, 1H), 5.23 (q, J = 6.3 Hz, 1H), 5.02 ( t, J = 7.1 Hz, 2H), 4.59 (t, J = 6.5 Hz, 2H), 3.74 (s, 3H), 2.49 (s, 3H), 2.30 (s, 3H).
6868 (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(테트라하이드로퓨란-3-일)벤즈아미드(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(tetra hydrofuran-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.08 - 6.98 (m, 3H), 6.72 - 6.66 (m, 1H), 4.08 (td, J = 8.7, 4.5 Hz, 1H), 3.94 (s, 3H), 3.89 (dd, J = 9.8, 3.9 Hz, 1H), 3.76 (s, 3H), 3.66 (d, J = 8.0 Hz, 1H), 3.02 (s, 3H), 2.25 (s, 1H), 2.04 (q, J = 7.3 Hz, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.08 - 6.98 (m, 3H), 6.72 - 6.66 (m, 1H), 4.08 (td, J = 8.7, 4.5 Hz, 1H), 3.94 (s, 3H), 3.89 (dd, J = 9.8, 3.9 Hz, 1H) ), 3.76 (s, 3H), 3.66 (d, J = 8.0 Hz, 1H), 3.02 (s, 3H), 2.25 (s, 1H), 2.04 (q, J = 7.3 Hz, 2H).
6969 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-(oxetane-3 -1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 15.4 Hz, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 (s, 1H), 5.27 (p, J = 6.6 Hz, 1H), 5.02 (s, 2H), 4.64 (t, J = 6.6 Hz, 2H), 3.96 (s, 3H), 3.78 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 15.4 Hz, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 (s, 1H), 5.27 (p, J = 6.6 Hz, 1H), 5.02 (s) , 2H), 4.64 (t, J = 6.6 Hz, 2H), 3.96 (s, 3H), 3.78 (s, 3H).
7070 2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-(옥세탄-3-일)벤즈아미드2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-(oxetane-3- 1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.76 (t, J = 2.0 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.08 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 (m, 1H), 5.28 (dp, J = 13.6, 6.5 Hz, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.66 (t, J = 6.5 Hz, 2H), 3.96 (s, 3H), 3.77 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.76 (t, J = 2.0 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.08 (dd, J = 2.9, 1.7 Hz, 1H), 6.72 (m, 1H), 5.28 (dp, J = 13.6, 6.5 Hz, 1H), 5.03 (t , J = 7.1 Hz, 2H), 4.66 (t, J = 6.5 Hz, 2H), 3.96 (s, 3H), 3.77 (s, 3H).
7171 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methyl-N-(oxetan-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.49 - 8.42 (m, 1H), 8.31 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.67 (s, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 7.00 (s, 1H), 6.68 (t, J = 2.5 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 5.34 - 5.20 (m, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.62 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H), 2.39 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 - 8.42 (m, 1H), 8.31 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H) , 7.67 (s, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 7.00 (s, 1H), 6.68 (t, J = 2.5 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 5.34 - 5.20 (m, 1H), 5.03 (t, J = 7.1 Hz, 2H), 4.62 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H), 2.39 (s, 3H).
7272 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-((1r,3r)-3-메톡시사이클로부틸)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-((1r,3r)-3-meth Toxycyclobutyl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.5, 1.9 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 6.26 (d, J = 6.6 Hz, 1H), 4.62 (h, J = 6.1 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 3.28 (s, 3H), 2.52 (ddd, J = 12.7, 8.1, 4.1 Hz, 2H), 2.28 (dt, J = 13.0, 6.4 Hz, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.5, 1.9 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H) , 6.26 (d, J = 6.6 Hz, 1H), 4.62 (h, J = 6.1 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 3.28 ( s, 3H), 2.52 (ddd, J = 12.7, 8.1, 4.1 Hz, 2H), 2.28 (dt, J = 13.0, 6.4 Hz, 2H).
7373 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(2-메톡시-2-메틸프로필)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(2-methoxy-2-methylpropyl )Benzamide 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 7.07 (dd, J = 2.8, 1.7 Hz, 1H), 6.73 - 6.67 (m, 1H), 6.45 (d, J = 6.0 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 3.50 (d, J = 5.5 Hz, 2H), 3.26 (s, 3H), 1.24 (s, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 7.07 (dd, J = 2.8, 1.7 Hz, 1H), 6.73 - 6.67 (m, 1H), 6.45 ( d, J = 6.0 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 3.50 (d, J = 5.5 Hz, 2H), 3.26 (s, 3H), 1.24 (s, 6H).
7474 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(1-메톡시-2-메틸프로판-2-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(1-methoxy-2-methylpropane -2-day)Benzamide 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.8 Hz, 1H), 6.69 (t, J = 2.6 Hz, 1H), 6.35 (s, 1H), 3.97 (s, 3H), 3.76 (s, 3H), 3.47 (s, 2H), 3.43 (s, 3H), 1.48 (s, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.8 Hz, 1H), 6.69 (t, J = 2.6 Hz, 1H), 6.35 (s, 1H), 3.97 (s, 3H), 3.76 (s, 3H), 3.47 (s, 2H), 3.43 (s, 3H), 1.48 (s, 6H).
7575 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(3-모르폴리노아제티딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidine-1 -1) Methanone 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 8.4, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.73 - 6.65 (m, 1H), 4.39 - 4.04 (m, 4H), 3.99 (s, 1H), 3.96 (s, 3H), 3.79 - 3.72 (m, 7H), 2.41 (s, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 8.4, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.73 - 6.65 (m, 1H), 4.39 - 4.04 (m, 4H), 3.99 (s, 1H), 3.96 (s, 3H), 3.79 - 3.72 (m, 7H), 2.41 (s, 4H).
7676 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.97 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 2.94 (s, 3H), 2.27 (s, 3H), 1.91 (s, 2H), 1.71 (s, 1H), 1.62 - 1.59 (m, 6H), 1.50 (t, J = 7.0 Hz, 3H). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.05 ( dd, J = 2.9, 1.7 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.97 (s, 1H), 6.69 (t, J = 2.5 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 2.94 (s, 3H), 2.27 (s, 3H), 1.91 (s, 2H), 1.71 (s, 1H), 1.62 - 1.59 (m, 6H), 1.50 (t, J = 7.0 Hz, 3H).
7777 3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidine -4-day)Benzamide 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.47 (s, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.76 (s, 3H), 2.93 (s, 6H), 2.29 (s, 4H), 1.28 (dd, J = 14.9, 7.7 Hz, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.47 (s, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.76 (s, 3H), 2.93 (s, 6H), 2.29 (s, 4H), 1.28 (dd, J = 14.9, 7.7 Hz, 4H).
7878 3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(테트라하이드로-2H-피란-4-일)벤즈아미드3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(tetrahydro-2H-pyran -4-day)Benzamide 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.76 - 7.66 (m, 3H), 7.49 (s, 1H), 7.04 (d, J = 2.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.77 (d, J = 2.8 Hz, 3H), 2.94 (s, 3H), 1.90 (s, 2H), 1.69 (s, 2H), 0.87 (d, J = 7.0 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.71 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.76 - 7.66 (m, 3H), 7.49 (s, 1H) , 7.04 (d, J = 2.7 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 3.77 (d, J = 2.8 Hz, 3H), 2.94 (s, 3H), 1.90 (s, 2H) , 1.69 (s, 2H), 0.87 (d, J = 7.0 Hz, 1H).
7979 (3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(3-모르폴리노아제티딘-1-일)메탄온(3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(3-morpholinoazetidine-1- 1) Methanone 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 7.73 (d, J = 1.9 Hz, 3H), 7.64 - 7.57 (m, 1H), 7.04 (t, J = 2.3 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 3.76 (d, J = 6.0 Hz, 8H), 2.40 (s, 5H), 1.30 (s, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.74 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 7.73 (d, J = 1.9 Hz, 3H), 7.64 - 7.57 (m, 1H) , 7.04 (t, J = 2.3 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 3.76 (d, J = 6.0 Hz, 8H), 2.40 (s, 5H), 1.30 (s, 4H) .
8080 (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-( tetrahydrofuran-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 15.3 Hz, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.97 (dd, J = 15.2, 7.0 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 4.75 (s, 1H), 4.06 - 3.70 (m, 4H), 3.97 (s, 3H), 3.77 (s, 3H), 2.37 (dq, J = 13.7, 7.5 Hz, 1H), 2.07 - 1.88 (m, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.56 (d, J = 15.3 Hz, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.97 (dd, J = 15.2, 7.0 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H) , 4.75 (s, 1H), 4.06 - 3.70 (m, 4H), 3.97 (s, 3H), 3.77 (s, 3H), 2.37 (dq, J = 13.7, 7.5 Hz, 1H), 2.07 - 1.88 (m , 1H).
8181 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-((1r,3r)-3-메톡시사이클로부틸)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-((1r,3r )-3-methoxycyclobutyl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 15.2 Hz, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.55 (d, J = 7.1 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.92 (dd, J = 15.2, 7.4 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 4.26 (dt, J = 9.3, 7.1 Hz, 1H), 3.96 (s, 3H), 3.77 (s, 3H), 3.71 (ddd, J = 13.9, 7.5, 6.5 Hz, 1H), 3.28 (s, 3H), 2.91 - 2.80 (m, 2H), 1.90 (tdd, J = 9.1, 7.4, 2.8 Hz, 2H). 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 15.2 Hz, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.55 ( d, J = 7.1 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.92 (dd, J = 15.2, 7.4 Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H), 4.26 (dt, J = 9.3, 7.1 Hz, 1H), 3.96 (s, 3H), 3.77 (s, 3H), 3.71 (ddd, J = 13.9, 7.5, 6.5 Hz, 1H), 3.28 (s, 3H) , 2.91 - 2.80 (m, 2H), 1.90 (tdd, J = 9.1, 7.4, 2.8 Hz, 2H).
8282 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(1-메톡시-2-메틸프로판-2-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methoxy -2-methylpropan-2-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.34 (s, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.13 (dt, J = 14.3, 5.3 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 3.97 (s, 3H), 3.77 (s, 3H), 3.53 (dd, J = 5.4, 1.5 Hz, 2H), 3.26 (s, 3H), 1.24 (s, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 8.58 (s, 1H), 8.34 (s, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.74 (t, J = 1.9 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.13 (dt, J = 14.3, 5.3 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 3.97 (s, 3H), 3.77 (s, 3H), 3.53 (dd, J = 5.4, 1.5 Hz, 2H), 3.26 (s, 3H), 1.24 (s, 6H).
8383 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시페닐)(4-모르폴리노피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-morpholy nopiperidin-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 12.2 Hz, 1H), 8.33 (s, 1H), 7.85 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.88 (d, J = 5.9 Hz, 1H), 6.71 (dd, J = 2.9, 2.2 Hz, 1H), 4.76 (d, J = 13.4 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 1H), 3.76 (s, 3H), 3.73 (t, J = 4.6 Hz, 4H), 3.08 (s, 1H), 2.83 (t, J = 12.6 Hz, 1H), 2.57 (d, J = 5.5 Hz, 4H), 2.50 - 2.36 (m, 1H), 1.98 (d, J = 12.9 Hz, 1H), 1.83 (d, J = 12.7 Hz, 1H), 1.54 (d, J = 13.5 Hz, 2H). 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 12.2 Hz, 1H), 8.33 (s, 1H), 7.85 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.05 ( dd, J = 2.9, 1.7 Hz, 1H), 6.88 (d, J = 5.9 Hz, 1H), 6.71 (dd, J = 2.9, 2.2 Hz, 1H), 4.76 (d, J = 13.4 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 1H), 3.76 (s, 3H), 3.73 (t, J = 4.6 Hz, 4H), 3.08 (s, 1H), 2.83 (t, J = 12.6 Hz, 1H) ), 2.57 (d, J = 5.5 Hz, 4H), 2.50 - 2.36 (m, 1H), 1.98 (d, J = 12.9 Hz, 1H), 1.83 (d, J = 12.7 Hz, 1H), 1.54 (d , J = 13.5 Hz, 2H).
8484 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시페닐)(모르폴리노)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxyphenyl)(morpholino)methanone 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 7.05 (s, 1H), 6.69 (dd, J = 2.9, 2.1 Hz, 1H), 3.84 (tt, J = 6.0, 3.6 Hz, 1H), 3.76 (s, 3H), 3.74 - 3.59 (m, 8H), 0.95 - 0.83 (m, 4H). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.38 ( d, J = 1.8 Hz, 1H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 7.05 (s, 1H), 6.69 (dd, J = 2.9, 2.1 Hz, 1H), 3.84 (tt, J = 6.0, 3.6 Hz, 1H), 3.76 (s, 3H), 3.74 - 3.59 (m, 8H), 0.95 - 0.83 (m, 4H).
8585 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-(oxetan-3-yl)benz amides 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.5, 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (dd, J = 2.9, 2.2 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 5.35 - 5.19 (m, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.64 (dd, J = 7.0, 6.1 Hz, 2H), 3.89 (tt, J = 6.0, 3.4 Hz, 1H), 3.77 (s, 3H), 0.94 - 0.81 (m, 4H). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.73 ( t, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.5, 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (dd, J = 2.9, 2.2 Hz, 1H) ), 6.59 (d, J = 7.4 Hz, 1H), 5.35 - 5.19 (m, 1H), 5.04 (t, J = 7.1 Hz, 2H), 4.64 (dd, J = 7.0, 6.1 Hz, 2H), 3.89 (tt, J = 6.0, 3.4 Hz, 1H), 3.77 (s, 3H), 0.94 - 0.81 (m, 4H).
8686 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-메틸-N-(옥세탄-3-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-methyl-N-(oxetane-3 -1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.36 (s, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 2H), 6.72 - 6.65 (m, 1H), 5.34 - 5.23 (m, 1H), 4.85 (d, J = 6.9 Hz, 4H), 3.88 - 3.78 (m, 1H), 3.76 (s, 3H), 3.24 (s, 3H), 0.89 - 0.81 (m, 4H). 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.36 ( s, 1H), 7.04 (dd, J = 2.9, 1.7 Hz, 2H), 6.72 - 6.65 (m, 1H), 5.34 - 5.23 (m, 1H), 4.85 (d, J = 6.9 Hz, 4H), 3.88 - 3.78 (m, 1H), 3.76 (s, 3H), 3.24 (s, 3H), 0.89 - 0.81 (m, 4H).
8787 4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-(1-메틸피페리딘-4-일)벤즈아미드4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-(1-methylpiperidin-4 -1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.5 Hz, 1H), 8.31 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.72 (d, J = 1.8 Hz, 2H), 7.32 (dd, J = 8.5, 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.8 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.96 (d, J = 8.0 Hz, 1H), 4.08 - 3.95 (m, 1H), 3.90 (tt, J = 6.1, 3.5 Hz, 1H), 3.76 (s, 3H), 2.85 (d, J = 11.5 Hz, 2H), 2.32 (s, 3H), 2.26 - 2.14 (m, 2H), 2.07 (d, J = 12.7 Hz, 2H), 1.60 (d, J = 13.0 Hz, 2H), 0.88 (dq, J = 5.8, 2.6 Hz, 4H). 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.5 Hz, 1H), 8.31 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.72 (d, J = 1.8 Hz, 2H), 7.32 (dd, J = 8.5, 2.0 Hz, 1H), 7.05 (dd, J = 2.9, 1.8 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.96 (d, J = 8.0 Hz, 1H), 4.08 - 3.95 (m, 1H), 3.90 (tt, J = 6.1, 3.5 Hz, 1H), 3.76 (s, 3H), 2.85 (d, J = 11.5 Hz, 2H), 2.32 (s) , 3H), 2.26 - 2.14 (m, 2H), 2.07 (d, J = 12.7 Hz, 2H), 1.60 (d, J = 13.0 Hz, 2H), 0.88 (dq, J = 5.8, 2.6 Hz, 4H) .
8888 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxyphenyl)(4-(dimethylamino)piperi din-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.65 (s, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.09 (dd, J = 8.3, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (dd, J = 2.9, 2.2 Hz, 1H), 3.83 (tt, J = 6.2, 2.8 Hz, 1H), 3.76 (s, 3H), 2.92 (s, 4H), 2.39 (d, J = 11.1 Hz, 1H), 2.32 (s, 6H), 1.90 (s, 2H), 1.50 (s, 2H), 0.90 - 0.80 (m, 4H). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.65 (s, 1H), 7.36 ( d, J = 1.8 Hz, 1H), 7.09 (dd, J = 8.3, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.69 (dd, J = 2.9, 2.2 Hz, 1H) ), 3.83 (tt, J = 6.2, 2.8 Hz, 1H), 3.76 (s, 3H), 2.92 (s, 4H), 2.39 (d, J = 11.1 Hz, 1H), 2.32 (s, 6H), 1.90 (s, 2H), 1.50 (s, 2H), 0.90 - 0.80 (m, 4H).
8989 (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(tetrahydrofuran-3 -1) Benzamide 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.27 (d, J = 7.4 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.02 (q, J = 7.8 Hz, 1H), 3.98 (s, 3H), 3.93 (dd, J = 9.5, 5.3 Hz, 1H), 3.90 - 3.72 (m, 2H), 3.77 (s, 3H), 2.45 - 2.31 (m, 1H), 2.07 - 1.89 (m, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.5, 1.9 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H) , 6.27 (d, J = 7.4 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.02 (q, J = 7.8 Hz, 1H), 3.98 (s, 3H), 3.93 (dd, J = 9.5, 5.3 Hz, 1H), 3.90 - 3.72 (m, 2H), 3.77 (s, 3H), 2.45 - 2.31 (m, 1H), 2.07 - 1.89 (m, 1H).
9090 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidine -1-day) Methanone 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.09 - 7.00 (m, 3H), 6.69 (t, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 2.92 (s, 2H), 2.56 - 2.45 (m, 2H), 2.36 (s, 6H), 2.17 (s, 1H), 1.92 (s, 2H), 1.51 (s, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.09 - 7.00 (m, 3H), 6.69 (t, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 2.92 (s, 2H), 2.56 - 2.45 (m, 2H), 2.36 (s, 6H), 2.17 (s, 1H), 1.92 (s, 2H), 1.51 (s, 2H).
9191 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxyphenyl)(4-(dimethylamino)piperi din-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 4.67 (p, J = 6.0 Hz, 1H), 3.76 (s, 3H), 2.92 (s, 2H), 2.50 (s, 2H), 2.35 (s, 6H), 2.18 (s, 1H), 1.91 (s, 2H), 1.59 - 1.43 (m, 2H), 1.41 (d, J = 6.1 Hz, 6H). 1H NMR (400 MHz, CDCl 3 ) δ 4.67 (p, J = 6.0 Hz, 1H), 3.76 (s, 3H), 2.92 (s, 2H), 2.50 (s, 2H), 2.35 (s, 6H) , 2.18 (s, 1H), 1.91 (s, 2H), 1.59 - 1.43 (m, 2H), 1.41 (d, J = 6.1 Hz, 6H).
9292 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-모르폴리노피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1 -1) Methanone 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.3 Hz, 1H), 8.32 (d, J = 9.4 Hz, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.03 (dd, J = 10.8, 1.8 Hz, 2H), 6.69 (t, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.75 (d, J = 6.7 Hz, 7H), 2.59 (d, J = 4.8 Hz, 4H), 2.44 (d, J = 11.2 Hz, 1H), 1.99 - 1.44 (m, 8H). 1H NMR (400 MHz, CDCl 3 ) δ 8.60 (d, J = 8.3 Hz, 1H), 8.32 (d, J = 9.4 Hz, 1H), 7.81 (s, 1H), 7.72 (t, J = 2.0 Hz) , 1H), 7.03 (dd, J = 10.8, 1.8 Hz, 2H), 6.69 (t, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.75 (d, J = 6.7 Hz, 7H), 2.59 (d, J = 4.8 Hz, 4H), 2.44 (d, J = 11.2 Hz, 1H), 1.99 - 1.44 (m, 8H).
9393 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-(피롤리딘-1-일)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-(pyrrolidin-1-yl) piperidin-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 7.02 (dd, J = 2.9, 1.8 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 3.75 (s, 3H), 3.60 (d, J = 13.2 Hz, 1H), 2.99 (t, J = 12.5 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.60 (s, 4H), 2.33 (s, 4H), 2.04 (s, 1H), 1.81 (s, 6H), 1.60 (s, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.12 (s, 1H) , 7.07 (s, 1H), 7.02 (dd, J = 2.9, 1.8 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 3.75 (s, 3H), 3.60 (d, J = 13.2 Hz, 1H), 2.99 (t, J = 12.5 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.60 (s, 4H), 2.33 (s, 4H), 2.04 (s, 1H), 1.81 (s, 6H), 1.60 (s, 1H).
9494 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-모르폴리노피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-morpholinopiperidin-1-yl ) Methanone 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.52 (s, 2H), 7.24 (s, 1H), 7.11 (d, J = 17.5 Hz, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.80 (d, J = 13.3 Hz, 1H), 3.74 (s, 3H), 3.73 (t, J = 4.6 Hz, 4H), 3.47 (s, 5H), 2.97 (t, J = 12.7 Hz, 1H), 2.81 (t, J = 12.8 Hz, 1H), 2.55 (q, J = 3.6 Hz, 4H), 2.33 (d, J = 15.9 Hz, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.52 (s, 2H), 7.24 (s, 1H), 7.11 (d, J = 17.5 Hz, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.80 (d, J = 13.3 Hz, 1H), 3.74 (s, 3H) , 3.73 (t, J = 4.6 Hz, 4H), 3.47 (s, 5H), 2.97 (t, J = 12.7 Hz, 1H), 2.81 (t, J = 12.8 Hz, 1H), 2.55 (q, J = 3.6 Hz, 4H), 2.33 (d, J = 15.9 Hz, 4H).
9595 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(3-모르폴리노아제티딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(3-morpholinoazetidin-1-yl ) Methanone 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.33 (s, 1H), 7.28 - 7.21 (m, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.20 (dd, J = 10.1, 7.3 Hz, 1H), 4.03 (dd, J = 10.2, 5.4 Hz, 1H), 3.96 (t, J = 8.1 Hz, 1H), 3.86 (dd, J = 9.2, 5.3 Hz, 1H), 3.74 (s, 3H), 3.73 (d, J = 4.4 Hz, 4H), 3.17 (tt, J = 7.3, 5.4 Hz, 1H), 2.44 (s, 3H), 2.40 - 2.29 (m, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 2.1 Hz) , 1H), 7.33 (s, 1H), 7.28 - 7.21 (m, 1H), 7.02 (dd, J = 2.9, 1.7 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 4.20 (dd, J = 10.1, 7.3 Hz, 1H), 4.03 (dd, J = 10.2, 5.4 Hz, 1H), 3.96 (t, J = 8.1 Hz, 1H), 3.86 (dd, J = 9.2, 5.3 Hz, 1H), 3.74 (s, 3H), 3.73 (d, J = 4.4 Hz, 4H), 3.17 (tt, J = 7.3, 5.4 Hz, 1H), 2.44 (s, 3H), 2.40 - 2.29 (m, 4H).
9696 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2,2-트리플루오로에톡시)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2,2-trifluoroethoxy)phenyl )(4-(dimethylamino)piperidin-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.16 (dd, J = 8.4, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 2H), 6.77 - 6.63 (m, 1H), 4.48 (q, J = 8.0 Hz, 2H), 3.76 (s, 3H), 2.94 (s, 2H), 2.48 - 2.36 (m, 1H), 2.32 (s, 6H), 1.93 - 1.67 (m, 6H), 1.48 (s, 2H). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.16 ( dd, J = 8.4, 1.8 Hz, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 2H), 6.77 - 6.63 (m, 1H), 4.48 (q, J = 8.0 Hz, 2H), 3.76 (s) , 3H), 2.94 (s, 2H), 2.48 - 2.36 (m, 1H), 2.32 (s, 6H), 1.93 - 1.67 (m, 6H), 1.48 (s, 2H).
9797 (2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(dimethylamino)piperidine- 1-day) Methanone 1H NMR (500 MHz, DMSO) δ 10.29 (s, 1H), 10.01 (s, 1H), 8.48 (d, J = 1.0 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 10.0 Hz, 1H), 7.44 - 7.20 (m, 1H), 6.99 - 6.83 (m, 2H), 4.65 (d, J = 13.2 Hz, 1H), 3.75 (s, 3H), 3.46 (d, J = 13.9 Hz, 2H), 3.17 - 2.99 (m, 1H), 2.78 (t, J = 12.7 Hz, 2H), 2.71 (s, 6H), 2.00 (d, J = 9.4 Hz, 2H), 1.68 - 1.42 (m, 3H).1H NMR (500 MHz, DMSO) δ 10.29 (s, 1H), 10.01 (s, 1H), 8.48 (d, J = 1.0 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.87 (d) , J = 2.5 Hz, 1H), 7.73 (d, J = 10.0 Hz, 1H), 7.44 - 7.20 (m, 1H), 6.99 - 6.83 (m, 2H), 4.65 (d, J = 13.2 Hz, 1H) , 3.75 (s, 3H), 3.46 (d, J = 13.9 Hz, 2H), 3.17 - 2.99 (m, 1H), 2.78 (t, J = 12.7 Hz, 2H), 2.71 (s, 6H), 2.00 ( d, J = 9.4 Hz, 2H), 1.68 - 1.42 (m, 3H).
9898 2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-N-(옥세탄-3-일)아세트아미드2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-N-(oxetane-3 -1) Acetamide 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 7.72 (t, J = 1.9 Hz, 2H), 7.05 (dd, J = 2.8, 1.7 Hz, 1H), 6.91 (dd, J = 8.2, 1.9 Hz, 1H), 6.77 (d, J = 1.9 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.94 (d, J = 7.4 Hz, 1H), 5.02 (h, J = 6.8 Hz, 1H), 4.87 (t, J = 7.1 Hz, 2H), 4.39 (dd, J = 7.0, 6.1 Hz, 2H), 3.92 (s, 3H), 3.76 (s, 3H), 3.57 (s, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 7.72 (t, J = 1.9 Hz, 2H), 7.05 (dd, J = 2.8, 1.7 Hz, 1H), 6.91 (dd, J = 8.2, 1.9 Hz, 1H), 6.77 (d, J = 1.9 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.94 (d, J = 7.4 Hz, 1H), 5.02 (h, J = 6.8 Hz, 1H), 4.87 (t, J = 7.1 Hz, 2H), 4.39 (dd, J = 7.0, 6.1 Hz, 2H), 3.92 (s, 3H) , 3.76 (s, 3H), 3.57 (s, 2H).
9999 2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-1-모르폴리노에탄-1-온2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-1-morpholinoethane- 1-on 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.04 (dd, J = 2.8, 1.7 Hz, 1H), 6.85 (dd, J = 8.3, 1.9 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.72 (s, 2H), 3.65 (s, 4H), 3.48 (d, J = 6.3 Hz, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 8.51 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.04 (dd, J = 2.8, 1.7 Hz, 1H), 6.85 (dd, J = 8.3, 1.9 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 6.68 (t, J = 2.5 Hz, 1H) , 3.90 (s, 3H), 3.75 (s, 3H), 3.72 (s, 2H), 3.65 (s, 4H), 3.48 (d, J = 6.3 Hz, 4H).
100100 2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-N-(1-메틸피페리딘-4-일)아세트아미드2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-N-(1-methylp Peridin-4-yl)acetamide 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.2 Hz, 1H), 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.88 (dd, J = 8.2, 1.9 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H), 5.33 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.53 (s, 2H), 2.67 (s, 2H), 2.23 (s, 3H), 2.11 - 2.01 (m, 2H), 1.90 - 1.82 (m, 2H), 1.48 - 1.30 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 8.54 (d, J = 8.2 Hz, 1H), 8.29 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.05 (dd, J = 2.9, 1.7 Hz, 1H), 6.88 (dd, J = 8.2, 1.9 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 6.69 (t, J = 2.5 Hz, 1H) , 5.33 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.53 (s, 2H), 2.67 (s, 2H), 2.23 (s, 3H), 2.11 - 2.01 (m, 2H), 1.90 - 1.82 (m, 2H), 1.48 - 1.30 (m, 2H).
101101 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-(피롤리딘-1-일)피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-(pyrrolidin-1 -1-yl)piperidine-1-yl)methanone 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.88 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.78 (d, J = 13.4 Hz, 1H), 3.74 (s, 3H), 3.71 - 3.60 (m, 1H), 2.99 (t, J = 12.7 Hz, 1H), 2.84 (s, 5H), 2.58 (s, 1H), 2.35 (d, J = 5.1 Hz, 3H), 2.28 (s, 3H), 2.07 (s, 1H), 1.91 (s, 6H), 1.73 (s, 1H), 1.60 (s, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.05 - 6.97 (m, 2H) , 6.88 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.78 (d, J = 13.4 Hz, 1H), 3.74 (s, 3H), 3.71 - 3.60 (m, 1H), 2.99 ( t, J = 12.7 Hz, 1H), 2.84 (s, 5H), 2.58 (s, 1H), 2.35 (d, J = 5.1 Hz, 3H), 2.28 (s, 3H), 2.07 (s, 1H), 1.91 (s, 6H), 1.73 (s, 1H), 1.60 (s, 1H).
102102 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-모르폴리노피페리딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-morpholinopiperidine- 1-day) Methanone 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.13 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.03 - 6.93 (m, 2H), 6.86 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.80 (d, J = 13.4 Hz, 1H), 3.74 (s, 3H), 3.73 - 3.64 (m, 6H), 2.97 (t, J = 12.8 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.59 - 2.50 (m, 4H), 2.35 (s, 2H), 2.29 (d, J = 4.5 Hz, 6H), 1.97 (d, J = 13.2 Hz, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 8.13 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.03 - 6.93 (m, 2H), 6.86 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.80 (d, J = 13.4 Hz, 1H), 3.74 (s, 3H), 3.73 - 3.64 (m, 6H), 2.97 (t, J = 12.8 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.59 - 2.50 (m, 4H), 2.35 (s, 2H), 2.29 (d, J = 4.5 Hz, 6H), 1.97 (d, J = 13.2 Hz) , 2H).
103103 (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(3-모르폴리노아제티딘-1-일)메탄온(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(3-morpholinoazetidine- 1-day) Methanone 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.19 (s, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.10 (s, 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 1H), 6.88 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.20 (dd, J = 10.1, 7.3 Hz, 1H), 4.03 (dd, J = 10.2, 5.4 Hz, 1H), 3.95 (t, J = 8.1 Hz, 1H), 3.86 (dd, J = 9.1, 5.3 Hz, 1H), 3.74 (s, 3H), 3.74 (d, J = 9.1 Hz, 4H), 3.17 (tt, J = 7.1, 5.3 Hz, 1H), 2.44 (s, 3H), 2.35 (td, J = 14.2, 8.2 Hz, 4H), 2.29 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 8.19 (s, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.10 (s, 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 1H), 6.88 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 4.20 (dd, J = 10.1, 7.3 Hz, 1H), 4.03 (dd, J = 10.2, 5.4 Hz, 1H), 3.95 (t, J = 8.1 Hz, 1H), 3.86 (dd, J = 9.1, 5.3 Hz, 1H), 3.74 (s, 3H), 3.74 (d, J = 9.1 Hz, 4H), 3.17 (tt, J = 7.1, 5.3 Hz, 1H), 2.44 (s, 3H), 2.35 (td, J = 14.2, 8.2 Hz, 4H), 2.29 (s, 3H).
104104 3-메톡시-N-메틸-4-((4-(1-메틸-1H-피롤-3-일)-5-(트리플루오로메틸)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드3-methoxy-N-methyl-4-((4-(1-methyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrididin-2-yl)amino)-N-( Oxetane-3-yl)benzamide 1H NMR (400 MHz, CDCl3) δ 8.67 - 8.61 (m, 2H), 8.02 (s, 1H), 7.42 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.67 (t, J = 2.5 Hz, 1H), 5.28 (s, 1H), 4.84 (d, J = 6.8 Hz, 4H), 3.95 (s, 3H), 3.75 (s, 3H), 3.23 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 - 8.61 (m, 2H), 8.02 (s, 1H), 7.42 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.67 ( t, J = 2.5 Hz, 1H), 5.28 (s, 1H), 4.84 (d, J = 6.8 Hz, 4H), 3.95 (s, 3H), 3.75 (s, 3H), 3.23 (s, 3H).
105105 2-클로로-5-메톡시-N-메틸-4-((4-(1-메틸-1H-피롤-3-일)-5-(트리플루오로메틸)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드2-chloro-5-methoxy-N-methyl-4-((4-(1-methyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrididin-2-yl)amino) -N-(oxetan-3-yl)benzamide 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 9.0 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 7.94 (s, 1H), 7.47 (s, 1H), 6.88 - 6.85 (m, 1H), 6.82 - 6.77 (m, 1H), 6.69 (q, J = 2.2 Hz, 1H), 4.98 - 4.81 (m, 4H), 4.73 (d, J = 6.7 Hz, 0H), 3.92 (s, 3H), 3.75 (s, 3H), 3.39 (s, 1H). 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 9.0 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 7.94 (s, 1H), 7.47 (s, 1H), 6.88 - 6.85 (m, 1H), 6.82 - 6.77 (m, 1H), 6.69 (q, J = 2.2 Hz, 1H), 4.98 - 4.81 (m, 4H), 4.73 (d, J = 6.7 Hz, 0H), 3.92 (s, 3H), 3.75 (s, 3H), 3.39 (s, 1H).
106106 (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(테트라하이드로퓨란-3-일)벤즈아미드(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(tetrahydrofuran-3- 1) Benzamide 　1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 2.3 Hz, 1H), 7.71 (s, 1H), 7.58 (t, J = 9.4 Hz, 1H), 7.49 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 6.68 (d, J = 2.9 Hz, 1H), 5.97 (d, J = 7.4 Hz, 1H), 3.98 (q, J = 7.9 Hz, 1H), 3.92 (t, J = 7.3 Hz, 1H), 3.85 (q, J = 7.9 Hz, 2H), 3.79 (d, J = 9.5 Hz, 1H), 3.75 (d, J = 2.2 Hz, 3H), 2.50 (s, 3H), 2.36 (dq, J = 14.8, 7.3 Hz, 2H). 1H NMR (500 MHz, CDCl 3 ) δ 8.28 (d, J = 2.3 Hz, 1H), 7.71 (s, 1H), 7.58 (t, J = 9.4 Hz, 1H), 7.49 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 6.68 (d, J = 2.9 Hz, 1H), 5.97 (d, J = 7.4 Hz, 1H), 3.98 (q, J = 7.9 Hz, 1H), 3.92 (t, J = 7.3 Hz, 1H), 3.85 (q, J = 7.9 Hz, 2H), 3.79 (d, J = 9.5 Hz, 1H), 3.75 (d , J = 2.2 Hz, 3H), 2.50 (s, 3H), 2.36 (dq, J = 14.8, 7.3 Hz, 2H).
107107 (4-((5-클로로-4-(1-iso프로필-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온(4-((5-chloro-4-(1-isopropyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone 　1H NMR (500 MHz, CDCl3) δ 8.50 (d, J = 8.3 Hz, 1H), 8.43 (s, 1H), 7.82 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 2.8 Hz, 1H), 6.31 (t, J = 3.3 Hz, 1H), 5.18 (p, J = 6.7 Hz, 1H), 3.95 (s, 3H), 3.70 (s, 8H), 1.54 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H). 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J = 8.3 Hz, 1H), 8.43 (s, 1H), 7.82 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 2.8 Hz, 1H), 6.31 (t, J = 3.3 Hz, 1H), 5.18 (p, J = 6.7 Hz, 1H), 3.95 ( s, 3H), 3.70 (s, 8H), 1.54 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H).
108108 (R)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드(R)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(tetrahydrofuran-3 -1) Benzamide 　1H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 4.75 (dt, J = 8.1, 2.4 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.98 (s, 3H), 3.93 (dd, J = 9.5, 5.3 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.77 (s, 3H), 2.43 - 2.32 (m, 1H), 2.00 - 1.90 (m, 1H). 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.45 ( d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.06 (dd, J = 2.9, 1.7 Hz, 1H), 6.70 (t, J = 2.5 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 4.75 (dt, J = 8.1, 2.4 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.98 (s, 3H), 3.93 (dd, J = 9.5, 5.3 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.77 (s, 3H), 2.43 - 2.32 (m, 1H), 2.00 - 1.90 (m, 1H).
Figure PCTKR2023011915-appb-img-000020
Figure PCTKR2023011915-appb-img-000020
Figure PCTKR2023011915-appb-img-000021
Figure PCTKR2023011915-appb-img-000021
Figure PCTKR2023011915-appb-img-000022
Figure PCTKR2023011915-appb-img-000022
Figure PCTKR2023011915-appb-img-000023
Figure PCTKR2023011915-appb-img-000023
Figure PCTKR2023011915-appb-img-000024
Figure PCTKR2023011915-appb-img-000024
Figure PCTKR2023011915-appb-img-000025
Figure PCTKR2023011915-appb-img-000025
Figure PCTKR2023011915-appb-img-000026
Figure PCTKR2023011915-appb-img-000026
Figure PCTKR2023011915-appb-img-000027
Figure PCTKR2023011915-appb-img-000027
Figure PCTKR2023011915-appb-img-000028
Figure PCTKR2023011915-appb-img-000028
Figure PCTKR2023011915-appb-img-000029
Figure PCTKR2023011915-appb-img-000029
<실시예 109> 5-클로로-N-(2-메톡시-4-모르폴리노페닐)-4-(1-메틸-1H-피롤-3-일)피리미딘-2-아민의 제조<Example 109> Preparation of 5-chloro-N-(2-methoxy-4-morpholinophenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrimidin-2-amine
Figure PCTKR2023011915-appb-img-000030
Figure PCTKR2023011915-appb-img-000030
상기 반응식에 따라 실시예 109의 화합물을 제조하였다.The compound of Example 109 was prepared according to the above reaction scheme.
2,5-디클로로-4-(1-메틸-1H-피롤-3-일)피리미딘 (100 mg, 0.44 mmol, 1 eq), 2-메톡시-4-모르폴리노아닐린 (100 mg, 0.48 mmol, 1.1 eq), Xantphos (25 mg, 0.044 mmol, 0.1 eq), Pd(OAc)2 (10 mg, 0.044 mmol, 0.1 eq), Cs2CO3 (285 mg, 0.88 mmol, 2 eq)를 RBF에 넣고 1,4-디옥산(5 mL, 0.1M)에 완전히 녹인 후 100℃에서 16시간 동안 교반하였다. 반응 종료 후, 혼합물을 실온으로 식힌 뒤 EtOAc로 추출하고 유기층은 염수으로 씻어주었다. 유기층의 물을 MgSO4를 이용해 제거한 후 여과 감압 농축시켰다. 혼합물은 MPLC(EtOAc:Hex)를 이용해 정제하여 5-클로로-N-(4-(2,4-디메틸옥사졸-5-일)-2-메톡시페닐)-4-(1-메틸-1H-피롤-3-일)피리미딘-2-아민(연노란색 고체, 120mg, 69%)을 수득하였다.2,5-dichloro-4-(1-methyl-1H-pyrrol-3-yl)pyrimidine (100 mg, 0.44 mmol, 1 eq), 2-methoxy-4-morpholinoaniline (100 mg, 0.48 mmol, 1.1 eq), , was completely dissolved in 4-dioxane (5 mL, 0.1M) and stirred at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with EtOAc, and the organic layer was washed with brine. Water in the organic layer was removed using MgSO4, then filtered and concentrated under reduced pressure. The mixture was purified using MPLC (EtOAc:Hex) to obtain 5-chloro-N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-4-(1-methyl-1H -Pyrrol-3-yl)pyrimidin-2-amine (light yellow solid, 120 mg, 69%) was obtained.
실시예 109을 제조한 반응을 이용하여 하기와 같은 화합물을 제조하였으며, 제조된 화합물의 명칭및 NMR 스펙트럼 데이터는 하기 표 3에, 화합물의 구조는 표 4에 정리하였다.The following compounds were prepared using the reaction prepared in Example 109. The names and NMR spectrum data of the prepared compounds are summarized in Table 3 below, and the structures of the compounds are summarized in Table 4.
실시예Example namename NMR assignNMR assignment
109109 5-클로로-N-(2-메톡시-4-모르폴리노페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민5-Chloro-N-(2-methoxy-4-morpholinophenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.45 (s, 1H), 7.04 (dt, J = 3.1, 1.5 Hz, 1H), 6.67 (t, J = 2.5 Hz, 1H), 6.58 (dd, J = 8.8, 2.6 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 3.89 (s, 3H), 3.89 - 3.87 (m, 4H), 3.74 (d, J = 1.5 Hz, 3H), 3.15 - 3.11 (m, 4H). 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.45 (s, 1H), 7.04 (dt, J = 3.1, 1.5 Hz, 1H), 6.67 (t, J = 2.5 Hz, 1H), 6.58 (dd, J = 8.8, 2.6 Hz, 1H), 6.54 (d, J = 2.5) Hz, 1H), 3.89 (s, 3H), 3.89 - 3.87 (m, 4H), 3.74 (d, J = 1.5 Hz, 3H), 3.15 - 3.11 (m, 4H).
110110 5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(1-(테트라하이드로-2H-피란-4-일)-1H-피라졸-4-일)피리디딘-2-아민5-chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrididine- 2-amine 　1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.90 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.56 (s, 1H), 7.01 - 6.94 (m, 2H), 6.67 (d, J = 2.6 Hz, 1H), 4.33 (s, 1H), 4.12 (d, J = 11.2 Hz, 2H), 3.74 (s, 3H), 3.55 (td, J = 11.3, 3.4 Hz, 2H), 2.12 (q, J = 4.5 Hz, 4H). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.90 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.56 (s, 1H), 7.01 - 6.94 (m, 2H) ), 6.67 (d, J = 2.6 Hz, 1H), 4.33 (s, 1H), 4.12 (d, J = 11.2 Hz, 2H), 3.74 (s, 3H), 3.55 (td, J = 11.3, 3.4 Hz) , 2H), 2.12 (q, J = 4.5 Hz, 4H).
111111 5-클로로-N-(4-(2,4-디메틸옥사졸-5-일)-2-메톡시페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민5-chloro-N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2- amine 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 8.5 Hz, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.4, 1.9 Hz, 1H), 7.12 - 7.04 (m, 2H), 6.69 (t, J = 2.5 Hz, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 2.49 (s, 3H), 2.39 (s, 3H). 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 8.5 Hz, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.22 ( dd, J = 8.4, 1.9 Hz, 1H), 7.12 - 7.04 (m, 2H), 6.69 (t, J = 2.5 Hz, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 2.49 (s) , 3H), 2.39 (s, 3H).
112112 5-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸이소인돌린-1-온5-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylisoindolin-1-one 　1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.01 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.5, 1.9 Hz, 1H), 7.25 (s, 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 1H), 6.78 - 6.67 (m, 1H), 4.38 (s, 2H), 3.76 (s, 3H), 3.19 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.01 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.51 ( dd, J = 8.5, 1.9 Hz, 1H), 7.25 (s, 1H), 7.01 (dd, J = 2.9, 1.7 Hz, 1H), 6.78 - 6.67 (m, 1H), 4.38 (s, 2H), 3.76 (s, 3H), 3.19 (s, 3H).
113113 5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(6-모르폴리노피리딘-3-일)피리디딘-2-아민5-chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(6-morpholinopyridin-3-yl)pyrididin-2-amine 　1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.7 Hz, 1H), 8.23 (s, 1H), 7.92 (dd, J = 9.0, 2.7 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 3.0, 1.7 Hz, 1H), 6.87 (s, 1H), 6.69 (d, J = 9.0 Hz, 1H), 6.65 (t, J = 2.6 Hz, 1H), 3.87 - 3.82 (m, 4H), 3.73 (s, 3H), 3.50 - 3.43 (m, 4H). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.7 Hz, 1H), 8.23 (s, 1H), 7.92 (dd, J = 9.0, 2.7 Hz, 1H), 7.67 (d, J = 2.0) Hz, 1H), 6.98 (dd, J = 3.0, 1.7 Hz, 1H), 6.87 (s, 1H), 6.69 (d, J = 9.0 Hz, 1H), 6.65 (t, J = 2.6 Hz, 1H), 3.87 - 3.82 (m, 4H), 3.73 (s, 3H), 3.50 - 3.43 (m, 4H).
114114 2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸-1H-피라졸-1-일)-2-메틸프로판eni트리le2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)- 2-Methylpropanenitrile 　1H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 8.26 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 2.9, 1.6 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 6.55 (s, 1H), 3.74 (s, 3H), 2.29 (s, 3H), 2.00 (s, 6H). 1H NMR (500 MHz, CDCl 3 ) δ 8.31 (s, 1H), 8.26 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 2.9, 1.6 Hz, 1H) , 6.68 (d, J = 2.6 Hz, 1H), 6.55 (s, 1H), 3.74 (s, 3H), 2.29 (s, 3H), 2.00 (s, 6H).
115115 6-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3,4-디하이드로나프탈렌-1(2H)-온6-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3,4-dihydronaphthalen-1(2H)-one 　1H NMR (400 MHz, CDCl3) δ 8.62 - 8.50 (m, 1H), 8.31 - 8.24 (m, 1H), 7.90 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.68 (s, 1H), 7.62 - 7.55 (m, 1H), 7.51 (td, J = 7.8, 2.0 Hz, 2H), 3.01 - 2.86 (m, 2H), 2.30 (s, 3H), 1.99 - 1.89 (m, 2H), 1.48 (qd, J = 11.5, 3.9 Hz, 2H). 1H NMR (400 MHz, CDCl3) δ 8.62 - 8.50 (m, 1H), 8.31 - 8.24 (m, 1H), 7.90 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.68 (s) , 1H), 7.62 - 7.55 (m, 1H), 7.51 (td, J = 7.8, 2.0 Hz, 2H), 3.01 - 2.86 (m, 2H), 2.30 (s, 3H), 1.99 - 1.89 (m, 2H) ), 1.48 (qd, J = 11.5, 3.9 Hz, 2H).
116116 5-클로로-N-(1,3-디메틸-1H-피라졸-4-일)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민5-chloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine 　1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.80 (s, 1H), 7.46 (s, 1H), 6.96 (s, 1H), 6.66 (s, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 2.25 (s, 3H). 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.80 (s, 1H), 7.46 (s, 1H), 6.96 (s, 1H), 6.66 (s, 1H), 3.85 (s, 3H) ), 3.73 (s, 3H), 2.25 (s, 3H).
117117 N-(5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)-5-메틸티아졸-2-아민N-(5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)-5-methylthiazol-2-amine 　1H NMR (500 MHz, CDCl3) δ 10.07 (s, 1H), 8.44 (s, 1H), 7.82 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 2.44 (s, 3H). 1H NMR (500 MHz, CDCl3) δ 10.07 (s, 1H), 8.44 (s, 1H), 7.82 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 6.72 (s, 1H) ), 3.78 (s, 3H), 2.44 (s, 3H).
118118 5-클로로-N-(2-플루오로-4-모르폴리노페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민5-Chloro-N-(2-fluoro-4-morpholinophenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine 　1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 1.2 Hz, 1H), 8.21 (t, J = 9.1 Hz, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.00 (dt, J = 2.8, 1.4 Hz, 1H), 6.97 (s, 1H), 6.76 - 6.64 (m, 3H), 3.87 (dd, J = 5.7, 4.0 Hz, 4H), 3.74 (d, J = 1.2 Hz, 3H), 3.12 (dd, J = 5.7, 3.9 Hz, 4H). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 1.2 Hz, 1H), 8.21 (t, J = 9.1 Hz, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.00 (dt, J = 2.8, 1.4 Hz, 1H), 6.97 (s, 1H), 6.76 - 6.64 (m, 3H), 3.87 (dd, J = 5.7, 4.0 Hz, 4H), 3.74 (d, J = 1.2 Hz, 3H) ), 3.12 (dd, J = 5.7, 3.9 Hz, 4H).
119119 5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(4-모르폴리노-2-(트리플루오로메틸)페닐)피리디딘-2-아민5-chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(4-morpholino-2-(trifluoromethyl)phenyl)pyrididin-2-amine 　1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.01 (s, 1H), 6.97 (dd, J = 2.9, 1.7 Hz, 1H), 6.65 (t, J = 2.5 Hz, 1H), 3.90 - 3.86 (m, 4H), 3.73 (s, 3H), 3.21 - 3.15 (m, 4H). 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.01 (s, 1H), 6.97 (dd, J = 2.9, 1.7 Hz, 1H), 6.65 (t, J = 2.5 Hz, 1H), 3.90 - 3.86 (m, 4H), 3.73 (s, 3H) ), 3.21 - 3.15 (m, 4H).
Figure PCTKR2023011915-appb-img-000031
Figure PCTKR2023011915-appb-img-000031
<실험예 1> LRRK2 저해 활성 확인<Experimental Example 1> Confirmation of LRRK2 inhibitory activity
본 발명에 따른 상기 실시예 1 내지 119의 화합물에 대한 LRRK2 키나제 억제활성을 평가하기 위하여 하기와 같은 실험을 수행하였다.The following experiment was performed to evaluate the LRRK2 kinase inhibitory activity of the compounds of Examples 1 to 119 according to the present invention.
먼저, 384-웰 플레이트에 재조합 LRRK2 키나제(Signal Chem, Richmond, BC, Canada), 0.2 ug/ul LRRKtide(Signal Chem, Richmond, BC, Canada) 및 25 umol/L ATP(Invitrogen, Carlsbad, CA)를 키 나아제 반응 버퍼용액(40 mmol/L TrisHCl, 10 mmol/L MgCl2 및 0.1 ug/uL BSA(bovine serum albumin))에 첨가하여 혼합하였다. 다음으로, 상기 실시예 1 내지 119의 화합물 각각에 대하여 최종 농도를 50 uM, 5 uM, 500 nM, 50 nM, 5 nM, 500 pM, 50 pM, 5 pM, 및 0.5 pM로 첨가한 후, 30°C 인큐베이터에서 2시간 동안 반응시켰다. 반응이 종료된 후, 동량의 키나제-글로(Kinase-Glo, Promega, Madison, WI) 용액을 첨가하여 40분 동안 반응시키고, 탐지(detection) 용액을 첨가하여 상온에서 30분 동안 더 반응시킨 후, 마이크로쓸레이트 효소결합면역톱착검사 판독기(microplate ELISA reader; Bio-Tek)를 이용하여 루시페라제(Luciferase)의 양을 측정하여 키나제의 IC50 값을 산출하였다. (측정된 키나제의 IC50 값을 10nM 미만인 경우 A등급, 10~100nM인 경우 B등급 100nM 초과인 경우 C등급으로 분류하여 하기 표 5에 정리하여 나타내었다. 또한 A 등급의 화합물 G2019S enzyme activity % 값을 구했으며 농도는 100nM 에서의 실험을 진행하였다.)First, recombinant LRRK2 kinase (Signal Chem, Richmond, BC, Canada), 0.2 ug/ul LRRKtide (Signal Chem, Richmond, BC, Canada), and 25 umol/L ATP (Invitrogen, Carlsbad, CA) were added to a 384-well plate. Kinase reaction buffer solution (40 mmol/L TrisHCl, 10 mmol/L MgCl2, and 0.1 ug/uL BSA (bovine serum albumin)) was added and mixed. Next, for each of the compounds of Examples 1 to 119, final concentrations of 50 uM, 5 uM, 500 nM, 50 nM, 5 nM, 500 pM, 50 pM, 5 pM, and 0.5 pM were added, and then The reaction was carried out in a °C incubator for 2 hours. After the reaction was completed, an equal amount of Kinase-Glo (Promega, Madison, WI) solution was added and reacted for 40 minutes, and a detection solution was added and reacted at room temperature for an additional 30 minutes. The amount of luciferase was measured using a microplate ELISA reader (Bio-Tek), and the IC50 value of the kinase was calculated. (The IC50 value of the measured kinase was classified into grade A if it was less than 10nM, grade B if it was 10 to 100nM, and grade C if it was more than 100nM, and is summarized in Table 5 below. In addition, the grade A compound G2019S enzyme activity % value is was obtained, and the experiment was conducted at a concentration of 100nM.)
실시예Example Wild typeWild type G2019S
(enzyme acitivity %)G2019S
(enzyme activity%) 		실시예Example Wild typeWild type G2019S
(enzyme acitivity %)G2019S
(enzyme activity%) 		실시예Example Wild typeWild type G2019S
(enzyme acitivity %)G2019S
(enzyme activity%)
1One BB -- 4646 CC -　- 9191 BB --
22 AA 3.883.88 4747 AA 2.85　2.85 9292 AA 2.922.92
33 AA 2.712.71 4848 CC -　- 9393 AA 0.870.87
44 BB -- 4949 BB -　- 9494 AA 2.592.59
55 BB -- 5050 AA 6.096.09 9595 BB 3.463.46
66 AA 5.505.50 5151 BB -　- 9696 AA 2.52.5
77 AA -- 5252 CC -　- 9797 AA --
88 BB -- 5353 CC -　- 9898 BB --
99 BB -- 5454 CC -　- 9999 CC --
1010 BB 5.965.96 5555 CC -　- 100100 BB 6.726.72
1111 BB -- 5656 CC -　- 101101 AA 3.243.24
1212 BB -- 5757 BB -　- 102102 BB 5.625.62
1313 BB -- 5858 CC -　- 103103 BB --
1414 BB -- 5959 BB -　- 104104 BB --
1515 BB -- 6060 BB -　- 105105 CC --
1616 BB -- 6161 BB -　- 106106 CC --
1717 BB -- 6262 BB -　- 107107 CC --
1818 BB 5.265.26 6363 AA 7.62　7.62 108108 BB --
1919 BB 14.9714.97 6464 BB -　- 109109 BB --
2020 CC -- 6565 BB -　- 110110 BB --
2121 BB 1111 6666 BB -　- 111111 CC --
2222 BB -- 6767 BB -　- 112112 CC --
2323 BB -- 6868 BB -　- 113113 CC --
2424 CC -- 6969 BB -　- 114114 BB --
2525 CC -- 7070 BB 10.42　10.42 115115 CC --
2626 CC -- 7171 BB -　- 116116 BB --
2727 CC -- 7272 BB 3.86　3.86 117117 CC --
2828 BB -- 7373 BB -　- 118118 CC --
2929 CC -- 7474 BB 16.99　16.99 119119 CC --
3030 BB -- 7575 BB 9.54　9.54 　
3131 CC -- 7676 BB 10.6410.64 　
3232 BB -- 7777 BB -- 　
3333 CC -- 7878 CC -- 　
3434 BB 8.098.09 7979 CC -　- 　
3535 BB -　- 8080 BB -　- 　 　
3636 CC -　- 8181 BB 9.87　9.87 　 　
3737 CC -　- 8282 BB -- 　 　
3838 CC -　- 8383 AA 3.213.21 　 　 　
3939 CC -　- 8484 BB -- 　 　 　
4040 CC -　- 8585 BB -　- 　 　 　
4141 BB -　- 8686 BB -　- 　 　 　
4242 BB -　- 8787 BB -　- 　 　 　
4343 CC -　- 8888 AA 2.94　2.94 　 　 　
4444 BB -　- 8989 AA 8.838.83 　 　 　
4545 BB -　- 9090 AA -　- 　 　 　
단백질의 wild type 및 G2019S mutant type에 대하여 매우 우수한 저해 활성을 확인할 수 있다. 따라서, 본 발명에 따른 화합물들은 wild type LRRK2 단백질 또는 G2019S mutant LRRK2 단백질의 과활성화에 기인하는 관련 질환의 예방 또는 치료에 효과적일 것으로 기대된다.<실험예 2> 혈액뇌장벽(BBB; Blood-Brain Barrier) 투과율 평가 Very excellent inhibitory activity can be confirmed against the wild type and G2019S mutant type of the protein. Therefore, the compounds according to the present invention are expected to be effective in preventing or treating related diseases caused by hyperactivation of wild type LRRK2 protein or G2019S mutant LRRK2 protein. <Experimental Example 2> Evaluation of blood-brain barrier (BBB) permeability
혈액뇌장벽 투과율을 평가하기 위하여 다음과 같이 실험하였다.To evaluate the blood-brain barrier permeability, the following experiment was performed.
시험 물질을 5mg/kg의 투여용량으로 조제하여 경구투여 후 1시간 및 3시간 째에 동물을 희생한 직후 심장으로부터 혈액을 채취, 원심분리하여 혈장 샘플을 준비하였다. 체내에 남아있는 혈액을 제거하기 위해 10U/ml heparin이 포함된 식염수 20ml을 이용하여 심장 관류한 후 뇌를 적출하였다. 뇌조직 무게의 3배의 PBS buffer를 첨가하여 균질화하였다. 준비한 혈장과 뇌조직에서의 정량분석을 위해 LC-MS/MS (Agilent, Santa Clara, CA, USA)를 이용하였다. LC에서의 물질의 분리는 80% Acetonitrile과 0.1% formic acid를 첨가한 물 20%로 구성된 이동상을 이용하였다. 물질 당 총 실행 시간은 3분, 유량은 0.3ml/min이다. 그 결과는 하기 표 6에 나타내었다. The test substance was prepared at a dosage of 5 mg/kg, and blood was collected from the heart immediately after sacrificing the animal at 1 and 3 hours after oral administration and centrifuged to prepare plasma samples. To remove blood remaining in the body, the heart was perfused with 20 ml of saline solution containing 10 U/ml heparin, and the brain was removed. PBS buffer 3 times the weight of the brain tissue was added and homogenized. LC-MS/MS (Agilent, Santa Clara, CA, USA) was used for quantitative analysis of the prepared plasma and brain tissue. For separation of substances in LC, a mobile phase consisting of 80% acetonitrile and 20% water with 0.1% formic acid was used. The total run time per substance is 3 minutes and the flow rate is 0.3 ml/min. The results are shown in Table 6 below.
실시예Example Kp valueKp value
1One 1.041.04
33 0.690.69
5050 1.231.23
6868 0.60 0.60
7070 2.792.79
7272 1.461.46
8080 2.032.03
8181 0.720.72
8484 0.540.54
8585 0.470.47
8989 0.670.67

Claims (16)

  1. 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염:A compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2023011915-appb-img-000032
    Figure PCTKR2023011915-appb-img-000032
    Y는 수소, 할로겐, 또는 비치환 또는 할로겐으로 치환된 C1-C6알킬이고;Y is hydrogen, halogen, or unsubstituted or halogen-substituted C 1 -C 6 alkyl;
    Z는 수소, 치환 또는 비치환된 C1-C6 알킬, 치환 또는 비치환된 벤질, 치환 또는 비치환된 C3-C12 사이클로알킬, 치환 또는 비치환된 C3-C12 헤테로사이클로알킬, 치환 또는 비치환된 C4-C12 아릴, 또는 치환 또는 비치환된 C4-C12 헤테로아릴로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,Z is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 3 -C 12 heterocycloalkyl, is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C 4 -C 12 aryl, or substituted or unsubstituted C 4 -C 12 heteroaryl;
    상기 치환된 알킬, 벤질, C3-C12 사이클로알킬, C4-C12 아릴, C4-C12 헤테로아릴은 할로겐, 히드록시, 시아노, 아미노, 아미드, 니트로, C1-C6 알킬, C1- C6 알콕시, C3-C12 헤테로 사이클로 알킬, C4-C12 아릴-C1-C6 알콕시, 또는 -C(=O)O-알킬(C1-C6)로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;The substituted alkyl, benzyl, C 3 -C 12 cycloalkyl, C 4 -C 12 aryl, C 4 -C 12 heteroaryl are halogen, hydroxy, cyano, amino, amide, nitro, C 1 -C 6 alkyl. , C 1 -C 6 alkoxy, C 3 -C 12 heterocycloalkyl, C 4 -C 12 aryl-C 1 -C 6 alkoxy, or -C(=O)O-alkyl(C 1 -C 6 ). is substituted with one or more substituents selected from the group;
    X는 비치환 또는 치환된 페닐 또는 5-6원자의 헤테로아릴이고,X is unsubstituted or substituted phenyl or heteroaryl of 5-6 atoms,
    상기 치환된 페닐 또는 5-6원자의 헤테로아릴은,The substituted phenyl or heteroaryl of 5-6 atoms is,
    비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 할로겐으로 치환된 C1-C6 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 할로겐, 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B 및 -(CH2)p-CONAB 중의 하나 이상의 치환기로 치환되고,Unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 3 -C 6 cyclo Alkyloxy, halogen, unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B and -(CH 2 )p- is substituted with one or more substituents of CONAB,
    p는 0-5의 정수이고,p is an integer from 0 to 5,
    A는 수소 또는 C1-C6 알킬이고,A is hydrogen or C 1 -C 6 alkyl,
    B는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO- B, or -(CH 2 )p-CONAB is C 1 -C 6 alkylene bonded to an atom adjacent to the bonded atom,
    또는,or,
    A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며,A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
    여기서, 상기 치환된 C1-C6 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 독립적으로 C1-C6 알킬, C1-C6 알콕시, 시아노, 비치환 또는 C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환된다.Here, the substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl -Substituted with 7-atom heterocycloalkyl.
  2. 제1항에 있어서,According to paragraph 1,
    상기 X는
    Figure PCTKR2023011915-appb-img-000033
    이고,    The X above is
    Figure PCTKR2023011915-appb-img-000033
    ego,
    상기 Ar은 페닐 또는 5-6원자의 헤테로아릴이고;Ar is phenyl or heteroaryl of 5-6 atoms;
    R1a 및 R1b는 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 할로겐으로 치환된 C1-C6 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 비치환 또는 치환된 3-7원자 헤테로사이클로알킬, 또는 비치환 또는 치환된 C3-C6 사이클로알킬이고;R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 3 -C 6 cycle. alkyl oxy, unsubstituted or substituted 3-7 membered heterocycloalkyl, or unsubstituted or substituted C 3 -C 6 cycloalkyl;
    R2는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 이고,R 2 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO -B, or -(CH 2 )p-CONAB,
    p는 0-5의 정수이고,p is an integer from 0 to 5,
    A는 수소 또는 C1-C6 알킬이고,A is hydrogen or C 1 -C 6 alkyl,
    B는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- is C 1 -C 6 alkylene bonded to an atom adjacent to the atom to which B and -(CH2)p-CONAB are bonded;
    또는,or,
    A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며;A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3 to 7 atoms;
    여기서, 상기 치환된 C1-C6 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 독립적으로 C1-C6 알킬, C1-C6 알콕시, 시아노, 비치환 또는 C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환되는 것을 특징으로 하는,Here, the substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl Characterized by being substituted with -7-atom heterocycloalkyl,
    화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서,According to paragraph 1,
    Y는 할로겐, 또는 할로겐으로 치환된 C1-C6알킬이고;Y is halogen or C 1 -C 6 alkyl substituted with halogen;
    X는
    Figure PCTKR2023011915-appb-img-000034
    또는
    Figure PCTKR2023011915-appb-img-000035
    X is
    Figure PCTKR2023011915-appb-img-000034
    or
    Figure PCTKR2023011915-appb-img-000035
    이고;ego;
    R1a, R1b, R3, R4, R5, 및 R6 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 할로겐으로 치환된 C1-C6 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 비치환 또는 치환된 3-7원자 헤테로사이클로알킬, 또는 비치환 또는 치환된 C3-C6 사이클로알킬이고;R 1a , R 1b , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or halogen-substituted C 1 -C 6 alkoxy , unsubstituted or substituted C 3 -C 6 cycloalkyl oxy, unsubstituted or substituted 3-7 membered heterocycloalkyl, or unsubstituted or substituted C 3 -C 6 cycloalkyl;
    R2는 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB이고,R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
    p는 0-5의 정수,p is an integer from 0 to 5,
    A는 수소 또는 C1-C6 알킬,A is hydrogen or C 1 -C 6 alkyl,
    B는 비치환 또는 치환된 C1-C6 알킬, 비치환 또는 치환된 C3-C6 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- is C 1 -C 6 alkylene bonded to an atom adjacent to the atom to which B and -(CH2)p-CONAB are bonded;
    또는,or,
    A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며;A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3 to 7 atoms;
    여기서, 상기 치환된 C1-C6 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 독립적으로 C1-C6 알킬, C1-C6 알콕시, 시아노, 비치환 또는 C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환되는 것을 특징으로 하는,Here, the substituted C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl and substituted 3-7 atom heterocycloalkyl are independently C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, cyano, amino unsubstituted or substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3 unsubstituted or substituted with C 1 -C 6 alkyl Characterized by being substituted with -7-atom heterocycloalkyl,
    화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,According to paragraph 1,
    Y는 할로겐, 또는 할로겐으로 치환된 C1-C6알킬이고;Y is halogen or C 1 -C 6 alkyl substituted with halogen;
    Z는 수소 또는 C1-C6 알킬이고;Z is hydrogen or C 1 -C 6 alkyl;
    X는
    Figure PCTKR2023011915-appb-img-000036
    또는
    Figure PCTKR2023011915-appb-img-000037
    X is
    Figure PCTKR2023011915-appb-img-000036
    or
    Figure PCTKR2023011915-appb-img-000037
    이고;ego;
    R1a 및 R1b은 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C5 알킬, 비치환 또는 할로겐으로 치환된 C1-C5 알콕시, 비치환 또는 치환된 C3-C6 사이클로알킬 옥시, 비치환 또는 치환된 C3-C6 사이클로알킬이고,R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 5 alkyl, unsubstituted or halogen-substituted C 1 -C 5 alkoxy, unsubstituted or substituted C 3 -C 6 cycle. alkyloxy, unsubstituted or substituted C 3 -C 6 cycloalkyl,
    R2는 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB 이고,R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
    여기서, p는 0-4의 정수,Here, p is an integer from 0 to 4,
    A는 수소 또는 C1-C5 알킬,A is hydrogen or C 1 -C 5 alkyl,
    B는 비치환 또는 치환된 C1-C5 알킬, 비치환 또는 치환된 C3-C5 사이클로알킬, 비치환 또는 치환된 3-6원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 5 alkyl, unsubstituted or substituted C 3 -C 5 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-6 atoms, or -(CH2)p-CO- is C 1 -C 6 alkylene bonded to an atom adjacent to the atom to which B and -(CH2)p-CONAB are bonded;
    또는,or,
    A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-6원자의 헤테로사이클로알킬을 형성하며,A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3-6 atoms,
    R3는 비치환 또는 치환된 C1-C5 알킬, 또는 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬이고,R 3 is unsubstituted or substituted C 1 -C 5 alkyl, or unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
    R4, R5, 및 R6은 각각 독립적으로 수소, 또는 비치환 또는 치환된 C1-C5 알킬이고,R 4 , R 5 , and R 6 are each independently hydrogen or unsubstituted or substituted C 1 -C 5 alkyl,
    여기서, 상기 치환된 C1-C5 알킬, 치환된 C3-C6 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 각각 독립적으로 C1-C5 알킬, C1-C5 알콕시, 시아노, C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환되는 것을 특징으로 하는,Here, the substituted C 1 -C 5 alkyl, substituted C 3 -C 6 cycloalkyl, substituted 5-6 atom heteroaryl, and substituted 3-7 atom heterocycloalkyl are each independently C 1 -C 5 alkyl, C 1 -C 5 alkoxy, cyano, amino substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3-7 unsubstituted or substituted with C 1 -C 6 alkyl Characterized in that the atom is substituted with heterocycloalkyl,
    화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서,According to paragraph 1,
    Y는 할로겐, 또는 할로겐으로 치환된 C1-C6알킬이고;Y is halogen or C 1 -C 6 alkyl substituted with halogen;
    Z는 수소 또는 C1-C4 알킬이고;Z is hydrogen or C 1 -C 4 alkyl;
    X는
    Figure PCTKR2023011915-appb-img-000038
    또는
    Figure PCTKR2023011915-appb-img-000039
    X is
    Figure PCTKR2023011915-appb-img-000038
    or
    Figure PCTKR2023011915-appb-img-000039
    이고,ego,
    R1a 및 R1b은 각각 독립적으로 수소, 할로겐, 비치환 또는 치환된 C1-C4 알킬, 비치환 또는 할로겐으로 치환된 C1-C4 알콕시, 비치환 또는 치환된 C3-C5 사이클로알킬 옥시, 비치환 또는 치환된 C3-C5 사이클로알킬이고,R 1a and R 1b are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or halogen-substituted C 1 -C 4 alkoxy, unsubstituted or substituted C 3 -C 5 cycle. alkyloxy, unsubstituted or substituted C 3 -C 5 cycloalkyl,
    R2는 비치환 또는 치환된 5-6원자의 헤테로아릴, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, -(CH2)p-CO-B, 또는 -(CH2)p-CONAB이고,R 2 is unsubstituted or substituted heteroaryl of 5-6 atoms, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, -(CH 2 )p-CO-B, or -(CH 2 )p-CONAB ego,
    여기서, p는 0-3의 정수,Here, p is an integer from 0 to 3,
    A는 수소 또는 C1-C3 알킬,A is hydrogen or C 1 -C 3 alkyl,
    B는 비치환 또는 치환된 C1-C4 알킬, 비치환 또는 치환된 C3-C5 사이클로알킬, 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬, 또는 -(CH2)p-CO-B 및 -(CH2)p-CONAB가 결합된 원자에 인접한 원자에 결합되는 C1-C6 알킬렌이고,B is unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted or substituted C 3 -C 5 cycloalkyl, unsubstituted or substituted heterocycloalkyl of 3-7 atoms, or -(CH2)p-CO- is C 1 -C 6 alkylene bonded to an atom adjacent to the atom to which B and -(CH 2 )p-CONAB are bonded;
    또는,or,
    A와 B는 각각이 결합된 질소원자와 함께 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬을 형성하며,A and B together with the nitrogen atom to which each is bonded form an unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
    R3는 비치환 또는 치환된 C1-C4 알킬, 또는 비치환 또는 치환된 3-7원자의 헤테로사이클로알킬이고,R 3 is unsubstituted or substituted C 1 -C 4 alkyl, or unsubstituted or substituted heterocycloalkyl of 3-7 atoms,
    R4, R5, 및 R6은 각각 독립적으로 수소, 또는 비치환 또는 치환된 C1-C4 알킬이고,R 4 , R 5 , and R 6 are each independently hydrogen or unsubstituted or substituted C 1 -C 4 alkyl,
    여기서, 상기 치환된 C1-C4 알킬, 치환된 C3-C5 사이클로알킬, 치환된 5-6원자의 헤테로아릴 및 치환된 3-7원자의 헤테로사이클로알킬은 각각 독립적으로 C1-C4 알킬, C1-C4 알콕시, 시아노, C1-C6 알킬로 치환된 아미노, 비치환 5-6원자의 헤테로아릴, 또는 비치환 또는 C1-C6 알킬로 치환된 3-7원자의 헤테로사이클로알킬로 치환되는 것을 특징으로 하는,Here, the substituted C 1 -C 4 alkyl, substituted C 3 -C 5 cycloalkyl, substituted 5-6 atom heteroaryl, and substituted 3-7 atom heterocycloalkyl are each independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, amino substituted with C 1 -C 6 alkyl, unsubstituted heteroaryl of 5-6 atoms, or 3-7 unsubstituted or substituted with C 1 -C 6 alkyl Characterized in that the atom is substituted with heterocycloalkyl,
    화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서,According to paragraph 1,
    상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나의 화합물인 것을 특징으로 하는,The compound represented by Formula 1 is characterized in that it is any one compound selected from the group of compounds below,
    화학물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염:Chemical substance, stereoisomer thereof, solvate thereof, hydrate thereof or pharmaceutically acceptable salt thereof:
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온 (실시예 1);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (Example 1 );
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 2);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4- 1) Benzamide (Example 2);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 3);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidine -1-yl)methanone (Example 3);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 4);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-(1-methylpiperidin-4- 1) Benzamide (Example 4);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 5);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluorophenyl)(4-(dimethylamino)piperidine -1-yl)methanone (Example 5);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 6);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(1-methylpiperidin-4-yl )Benzamide (Example 6);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 7);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-(dimethylamino)piperidine-1 -1) Methanone (Example 7);
    (3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 8);(3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(dimethylamino)piperidine- 1-day)methanone (Example 8);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 9);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(oxetane-3- 1) Benzamide (Example 9);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 10);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-(1-methylpiperidin-4- 1) Benzamide (Example 10);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 11);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 11);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 12);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-(oxetan-3-yl)benzamide (Example 12);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 13);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(oxetane-3- 1) Benzamide (Example 13);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시페닐)(모르폴리노)메탄온 (실시예 14);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxyphenyl)(morpholino)methanone (Example 14);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-(옥세탄-3-일)벤즈아미드 (실시예 15);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-(oxetan-3-yl)benz Amide (Example 15);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-(옥세탄-3-일)벤즈아미드 (실시예 16);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-(oxetan-3-yl)benz Amide (Example 16);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 17);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxy-N-methyl-N-(1-methylp peridin-4-yl)benzamide (Example 17);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시페닐)(피롤리딘-1-일)메탄온 (실시예 18);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxyphenyl)(pyrrolidin-1-yl)methane On (Example 18);
    (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드 (실시예 19);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-((tetrahydrofuran- 2-yl)methyl)benzamide (Example 19);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-(옥세탄-3-일)벤즈아미드 (실시예 20);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-(oxetan-3-yl)benzamide (Example 20);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 21);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-methyl-N-( oxetan-3-yl)benzamide (Example 21);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시페닐)(모르폴리노)메탄온 (실시예 22);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino) Methanone (Example 22);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 23);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-methyl-N-( 1-methylpiperidin-4-yl)benzamide (Example 23);
    3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 24);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)benzamide ( Example 24);
    3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 25);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl )Benzamide (Example 25);
    2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 26);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl )Benzamide (Example 26);
    2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 27);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidine -4-yl)benzamide (Example 27);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(피롤리딘-1-일)메탄온 (실시예 28);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(pyrrolidin-1-yl)methanone ( Example 28);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시페닐)(모르폴리노)메탄온 (실시예 29);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxyphenyl)(morpholino)methanone (practice Example 29);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 30);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-(oxetan-3-yl)benzamide (Example 30);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 31);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 31);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온 (실시예 32);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluorophenyl)(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)methanone (Example 32);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-플루오로-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 33);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-fluoro-N-methyl-N-(oxetane-3- 1) Benzamide (Example 33);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온 (실시예 34);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluorophenyl)(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)methanone (Example 34);
    2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 35);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(1-methylpiperidin-4-yl )Benzamide (Example 35);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 36);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 36);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-(옥세탄-3-일)벤즈아미드 (실시예 37);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-(oxetan-3-yl)benzamide (Example 37);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 38);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-N-methyl-N-(oxetane-3- 1) Benzamide (Example 38);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드 (실시예 39);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-((tetrahydrofuran- 2-yl)methyl)benzamide (Example 39);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드 (실시예 40);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)-3-(2,2 ,2-trifluoroethoxy)benzamide (Example 40);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,2-디메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 41);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,2-dimethyl-N-(oxetan-3-yl)benz Amide (Example 41);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,3-디메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 42);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,3-dimethyl-N-(1-methylpiperidin-4 -1)benzamide (Example 42);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸페닐)(피롤리딘-1-일)메탄온 (실시예 43);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methylphenyl)(pyrrolidin-1-yl)methanone ( Example 43);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 44);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methylphenyl)(4-(dimethylamino)piperidine-1 -1) Methanone (Example 44);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 45);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-(1-methylpiperidin-4-yl)benzamide (Example 45);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2-디플루오로에톡시)-N-메틸-N-((테트라하이드로퓨란-2-일)메틸)벤즈아미드 (실시예 46);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2-difluoroethoxy)-N-methyl -N-((tetrahydrofuran-2-yl)methyl)benzamide (Example 46);
    (2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(4-메틸피페라진-1-일)피페리딘-1-일)메탄온 (실시예 47);(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(4-methylpiperazine-1 -yl)piperidin-1-yl)methanone (Example 47);
    3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(퓨란-2-일메틸)벤즈아미드 (실시예 48);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(furan-2-ylmethyl)benzamide ( Example 48);
    2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 49);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-methyl-N-(ox cetan-3-yl)benzamide (Example 49);
    (2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시페닐)(모르폴리노)메탄온 (실시예 50);(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxyphenyl)(morpholino)methane On (Example 50);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(옥세탄-3-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드 (실시예 51);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(oxetan-3-yl)-3- (2,2,2-trifluoroethoxy)benzamide (Example 51);
    3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 52);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(oxetan-3-yl)benzamide ( Example 52);
    3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-(퓨란-2-일메틸)-N-메틸벤즈아미드 (실시예 53);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-(furan-2-ylmethyl)-N- methylbenzamide (Example 53);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필페닐)(모르폴리노)메탄온 (실시예 54);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropylphenyl)(morpholino)methanone (Example 54);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-(옥세탄-3-일)벤즈아미드 (실시예 55);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-(oxetan-3-yl)benzamide (Example 55);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 56);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-methyl-N-(oxetane-3- 1) Benzamide (Example 56);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 57);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(oxetan-3-yl)benzamide ( Example 57);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,3-디메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 58);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,3-dimethyl-N-(oxetan-3-yl)benz Amide (Example 58);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 59);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 59);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 60);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(oxetan-3-yl)benzamide (Example 60);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N,2,5-트리메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 61);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N,2,5-trimethyl-N-(oxetan-3-yl )Benzamide (Example 61);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(피롤리딘-1-일)메탄온 (실시예 62);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(pyrrolidin-1-yl) Methanone (Example 62);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 63);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-(dimethylamino)piperi din-1-yl)methanone (Example 63);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로필-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 64);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropyl-N-(1-methylpiperidin-4- 1) Benzamide (Example 64);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)-3-(2,2,2-트리플루오로에톡시)벤즈아미드 (실시예 65);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidin-4-yl )-3-(2,2,2-trifluoroethoxy)benzamide (Example 65);
    2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 66);2-Chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-methyl-N-(1 -methylpiperidin-4-yl)benzamide (Example 66);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 67);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethyl-N-(oxetan-3-yl)benz Amide (Example 67);
    (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-메틸-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 68);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-methyl-N-(tetra hydrofuran-3-yl)benzamide (Example 68);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 69);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-(oxetane-3 -1)benzamide (Example 69);
    2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-5-메톡시-N-(옥세탄-3-일)벤즈아미드 (실시예 70);2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-5-methoxy-N-(oxetane-3- 1) Benzamide (Example 70);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 71);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methyl-N-(oxetan-3-yl)benzamide ( Example 71);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-((1r,3r)-3-메톡시사이클로부틸)벤즈아미드 (실시예 72);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-((1r,3r)-3-meth Toxycyclobutyl)benzamide (Example 72);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(2-메톡시-2-메틸프로필)벤즈아미드 (실시예 73);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(2-methoxy-2-methylpropyl )Benzamide (Example 73);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(1-메톡시-2-메틸프로판-2-일)벤즈아미드 (실시예 74);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(1-methoxy-2-methylpropane -2-yl)benzamide (Example 74);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 75);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidine-1 -1) Methanone (Example 75);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-에톡시-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 76);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-ethoxy-N-methyl-N-(1-methylpiperi din-4-yl)benzamide (Example 76);
    3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 77);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(1-methylpiperidine -4-yl)benzamide (Example 77);
    3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-N-메틸-N-(테트라하이드로-2H-피란-4-일)벤즈아미드 (실시예 78);3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-N-methyl-N-(tetrahydro-2H-pyran -4-yl)benzamide (Example 78);
    (3-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 79);(3-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(3-morpholinoazetidine-1- 1) Methanone (Example 79);
    (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 80);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-( tetrahydrofuran-3-yl)benzamide (Example 80);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-((1r,3r)-3-메톡시사이클로부틸)벤즈아미드 (실시예 81);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-((1r,3r )-3-methoxycyclobutyl)benzamide (Example 81);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시-N-(1-메톡시-2-메틸프로판-2-일)벤즈아미드 (실시예 82);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methoxy -2-methylpropan-2-yl)benzamide (Example 82);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-플루오로-5-메톡시페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 83);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-morpholy nopiperidin-1-yl)methanone (Example 83);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시페닐)(모르폴리노)메탄온 (실시예 84);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxyphenyl)(morpholino)methanone (practice Example 84);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-(옥세탄-3-일)벤즈아미드 (실시예 85);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-(oxetan-3-yl)benz Amide (Example 85);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-메틸-N-(옥세탄-3-일)벤즈아미드 (실시예 86);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-methyl-N-(oxetane-3 -1)benzamide (Example 86);
    4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시-N-(1-메틸피페리딘-4-일)벤즈아미드 (실시예 87);4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxy-N-(1-methylpiperidin-4 -1)benzamide (Example 87);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-사이클로프로폭시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 88);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-cyclopropoxyphenyl)(4-(dimethylamino)piperi din-1-yl)methanone (Example 88);
    (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 89);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(tetrahydrofuran-3 -1)benzamide (Example 89);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 90);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidine -1-yl)methanone (Example 90);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-이소프로폭시페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 91);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-isopropoxyphenyl)(4-(dimethylamino)piperi din-1-yl)methanone (Example 91);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 92);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1 -1) Methanone (Example 92);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-(피롤리딘-1-일)피페리딘-1-일)메탄온 (실시예 93);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-(pyrrolidin-1-yl) piperidin-1-yl)methanone (Example 93);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 94);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(4-morpholinopiperidin-1-yl ) Methanone (Example 94);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 95);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylphenyl)(3-morpholinoazetidin-1-yl ) Methanone (Example 95);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-(2,2,2-트리플루오로에톡시)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 96);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-(2,2,2-trifluoroethoxy)phenyl )(4-(dimethylamino)piperidin-1-yl)methanone (Example 96);
    (2-클로로-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)페닐)(4-(디메틸아미노)피페리딘-1-일)메탄온 (실시예 97);(2-chloro-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)phenyl)(4-(dimethylamino)piperidine- 1-yl)methanone (Example 97);
    2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-N-(옥세탄-3-일)아세트아미드 (실시예 98);2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-N-(oxetane-3 -1)acetamide (Example 98);
    2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-1-모르폴리노에탄-1-온 (실시예 99);2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-1-morpholinoethane- 1-one (Example 99);
    2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)-N-(1-메틸피페리딘-4-일)아세트아미드 (실시예 100);2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)-N-(1-methylp peridin-4-yl)acetamide (Example 100);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-(피롤리딘-1-일)피페리딘-1-일)메탄온 (실시예 101);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-(pyrrolidin-1 -yl)piperidin-1-yl)methanone (Example 101);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(4-모르폴리노피페리딘-1-일)메탄온 (실시예 102);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(4-morpholinopiperidine- 1-day)methanone (Example 102);
    (4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2,5-디메틸페닐)(3-모르폴리노아제티딘-1-일)메탄온 (실시예 103);(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2,5-dimethylphenyl)(3-morpholinoazetidine- 1-yl)methanone (Example 103);
    3-메톡시-N-메틸-4-((4-(1-메틸-1H-피롤-3-일)-5-(트리플루오로메틸)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 104);3-methoxy-N-methyl-4-((4-(1-methyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrididin-2-yl)amino)-N-( oxetan-3-yl)benzamide (Example 104);
    2-클로로-5-메톡시-N-메틸-4-((4-(1-메틸-1H-피롤-3-일)-5-(트리플루오로메틸)피리디딘-2-일)아미노)-N-(옥세탄-3-일)벤즈아미드 (실시예 105);2-chloro-5-methoxy-N-methyl-4-((4-(1-methyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)pyrididin-2-yl)amino) -N-(oxetan-3-yl)benzamide (Example 105);
    (S)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 106);(S)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methyl-N-(tetrahydrofuran-3- 1) Benzamide (Example 106);
    (4-((5-클로로-4-(1-iso프로필-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시페닐)(모르폴리노)메탄온 (실시예 107);(4-((5-chloro-4-(1-isopropyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (practice Example 107);
    (R)-4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메톡시-N-(테트라하이드로퓨란-3-일)벤즈아미드 (실시예 108);(R)-4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methoxy-N-(tetrahydrofuran-3 -1)benzamide (Example 108);
    5-클로로-N-(2-메톡시-4-모르폴리노페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 109);5-chloro-N-(2-methoxy-4-morpholinophenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine (Example 109);
    5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(1-(테트라하이드로-2H-피란-4-일)-1H-피라졸-4-일)피리디딘-2-아민 (실시예 110);5-chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrididine- 2-amine (Example 110);
    5-클로로-N-(4-(2,4-디메틸옥사졸-5-일)-2-메톡시페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 111);5-chloro-N-(4-(2,4-dimethyloxazol-5-yl)-2-methoxyphenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2- Amines (Example 111);
    5-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-2-메틸이소인돌린-1-온 (실시예 112);5-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-2-methylisoindolin-1-one (Example 112);
    5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(6-모르폴리노피리딘-3-일)피리디딘-2-아민 (실시예 113);5-chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(6-morpholinopyridin-3-yl)pyrididin-2-amine (Example 113);
    2-(4-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3-메틸-1H-피라졸-1-일)-2-메틸프로판니트릴(실시예 114); 2-(4-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)- 2-methylpropanenitrile (Example 114);
    6-((5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)아미노)-3,4-디하이드로나프탈렌-1(2H)-온 (실시예 115);6-((5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)amino)-3,4-dihydronaphthalen-1(2H)-one (Example 115);
    5-클로로-N-(1,3-디메틸-1H-피라졸-4-일)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 116);5-chloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine (Example 116);
    N-(5-클로로-4-(1-메틸-1H-피롤-3-일)피리디딘-2-일)-5-메틸티아졸-2-아민 (실시예 117)N-(5-chloro-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-yl)-5-methylthiazol-2-amine (Example 117)
    5-클로로-N-(2-플루오로-4-모르폴리노페닐)-4-(1-메틸-1H-피롤-3-일)피리디딘-2-아민 (실시예 118);5-chloro-N-(2-fluoro-4-morpholinophenyl)-4-(1-methyl-1H-pyrrol-3-yl)pyrididin-2-amine (Example 118);
    5-클로로-4-(1-메틸-1H-피롤-3-일)-N-(4-모르폴리노-2-(트리플루오로메틸)페닐)피리디딘-2-아민 (실시예 119).5-Chloro-4-(1-methyl-1H-pyrrol-3-yl)-N-(4-morpholino-2-(trifluoromethyl)phenyl)pyrididin-2-amine (Example 119) .
  7. 제1항에 있어서,According to paragraph 1,
    상기 화합물은 LRRK2(leucine-rich repeat kinase 2) 활성을 저해하는 것을 특징으로 하는, 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.The compound is a compound characterized in that it inhibits LRRK2 (leucine-rich repeat kinase 2) activity, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  8. 하기 반응식 1에 나타낸 바와 같이,As shown in Scheme 1 below,
    화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 제조하는 단계를 포함하는 제1항의 화학식 1로 표시되는 화합물의 제조방법:A method for producing a compound represented by Formula 1 of claim 1, comprising the step of reacting a compound represented by Formula 2 with a compound represented by Formula 3 to prepare a compound represented by Formula 1:
    [반응식 1][Scheme 1]
    Figure PCTKR2023011915-appb-img-000040
    Figure PCTKR2023011915-appb-img-000040
    상기 반응식 1에서 W는 할로겐이고,In Scheme 1, W is halogen,
    X, Y, 및 Z는 제1항의 화학식 1에서 정의한 바와 같다.X, Y, and Z are as defined in Formula 1 of Clause 1.
  9. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경퇴행성 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  10. 제9항에 있어서,According to clause 9,
    상기 신경퇴행성 질환은 파킨슨병(Parkinson's disease), 알츠하이머병(Alzheimer's disease), 헌팅턴병(huntington's disease), 피크병(Pick's disease), 근위축성 축삭경화증(Amyotrophic lateral sclerosis), 프리온병(Prion disease), 운동신경 세포병(Motor neuron disease), 척수 소뇌실조증(Spinocerebellar ataxia), 척수성근위축증(Spinal muscular atrophy), 크로이츠펠트-야콥병(Creutzfeldt-Jakob disease) 및 알코올성 치매(Alcohol related dementia)로 이루어진 군으로부터 선택되는 1종 이상인 것을 특징으로 하는, 신경퇴행성 질환의 예방 또는 치료용 약학적 조성물.The neurodegenerative diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, and exercise. Motor neuron disease, Spinocerebellar ataxia, Spinal muscular atrophy, Creutzfeldt-Jakob disease, and Alcohol related dementia. A pharmaceutical composition for preventing or treating neurodegenerative diseases, characterized in that it contains one or more types.
  11. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경 퇴행성 질환의 예방 또는 개선용 건강기능식품.A health functional food for preventing or improving neurodegenerative diseases containing the compound represented by Formula 1 of claim 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient.
  12. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  13. 제12항에 있어서,According to clause 12,
    상기 암은 신장암, 갑상선암, 유방암, 간암, 뇌암, 폐암, 난소암, 대장암, 흑색종, 위암, 위장관암, 골암, 췌장암, 피부암, 두경부암, 피부 또는 안구 흑색종, 자궁암, 직장암, 결장암, 식도암, 후두암, 소장암, 연조직의 육종, 요도암, 음경암, 전립선암, 및 다발성 골수종으로 이루어진 군에서 선택되는 것을 특징으로 하는, 암의 예방 또는 치료용 약학적 조성물.The above cancers include kidney cancer, thyroid cancer, breast cancer, liver cancer, brain cancer, lung cancer, ovarian cancer, colon cancer, melanoma, stomach cancer, gastrointestinal cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine cancer, rectal cancer, and colon cancer. A pharmaceutical composition for the prevention or treatment of cancer, characterized in that it is selected from the group consisting of esophageal cancer, laryngeal cancer, small intestine cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, and multiple myeloma.
  14. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 개선용 건강기능식품.A health functional food for preventing or improving cancer containing the compound represented by Formula 1 of claim 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient.
  15. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 염증성 질환의 예방 또는 치료용 약학적 조성물로서,A pharmaceutical composition for the prevention or treatment of inflammatory diseases containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
    상기 염증성 질환은 염증성 장 질환, 궤양성 대장염, 염증성 피부 질환, 췌장염, 알러지성 비염, 알러지성 결막염, 급성 기관지염, 만성 기관지염, 급성 세기관지염, 만성 세기관지염, 골관절염, 강직성 척추염, 장질환 척추염, 연소자성 강직성 척추염, 감염성 관절염, 결절성 다발동맥염, 과민성 혈관염, 관절세포 동맥염, 점액낭염, 건초염, 상과염, 신생아발병 다발성 염증성질환(neonatal multisystem inflammatory disease), 접촉성 피부염, 각막염, 결막염, 망막염, 망막혈관염, 포도막염, 안검염, 알레르기 결막염, 다발성 근염(polymyositis), 자가면역성 뇌척수염, 결절성 다발성 동맥염(polyarteritis nodosa) 및 섬유조직염(fibromyalgia syndrome)으로 이루어진 군에서 선택되는 것을 특징으로 하는, 염증성 질환의 예방 또는 치료용 약학적 조성물.The inflammatory diseases include inflammatory bowel disease, ulcerative colitis, inflammatory skin disease, pancreatitis, allergic rhinitis, allergic conjunctivitis, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, ankylosing spondylitis, enteropathy spondylitis, and juvenile ankylosing spondylitis. Spondylitis, infectious arthritis, polyarteritis nodosa, hypersensitivity vasculitis, arthrocellular arteritis, bursitis, tenosynovitis, epicondylitis, neonatal multisystem inflammatory disease, contact dermatitis, keratitis, conjunctivitis, retinitis, retinal vasculitis, uveitis, A pharmaceutical composition for the prevention or treatment of inflammatory diseases, characterized in that it is selected from the group consisting of blepharitis, allergic conjunctivitis, polymyositis, autoimmune encephalomyelitis, polyarteritis nodosa, and fibromyalgia syndrome. .
  16. 제1항의 화학식 1로 표시되는 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 염증성 질환의 예방 또는 개선용 건강기능식품으로서,A health functional food for preventing or improving inflammatory diseases containing the compound represented by Formula 1 of claim 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient,
    상기 염증성 질환은 염증성 장 질환, 궤양성 대장염, 염증성 피부 질환, 췌장염, 알러지성 비염, 알러지성 결막염, 급성 기관지염, 만성 기관지염, 급성 세기관지염, 만성 세기관지염, 골관절염, 강직성 척추염, 장질환 척추염, 연소자성 강직성 척추염, 감염성 관절염, 결절성 다발동맥염, 과민성 혈관염, 관절세포 동맥염, 점액낭염, 건초염, 상과염, 신생아발병 다발성 염증성질환(neonatal multisystem inflammatory disease), 접촉성 피부염, 각막염, 결막염, 망막염, 망막혈관염, 포도막염, 안검염, 알레르기 결막염, 다발성 근염(polymyositis), 자가면역성 뇌척수염, 결절성 다발성 동맥염(polyarteritis nodosa) 및 섬유조직염(fibromyalgia syndrome)으로 이루어진 군에서 선택되는 것을 특징으로 하는, 염증성 질환의 예방 또는 개선용 건강기능식품.The inflammatory diseases include inflammatory bowel disease, ulcerative colitis, inflammatory skin disease, pancreatitis, allergic rhinitis, allergic conjunctivitis, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, ankylosing spondylitis, enteropathy spondylitis, and juvenile ankylosing spondylitis. Spondylitis, infectious arthritis, polyarteritis nodosa, hypersensitivity vasculitis, arthrocellular arteritis, bursitis, tenosynovitis, epicondylitis, neonatal multisystem inflammatory disease, contact dermatitis, keratitis, conjunctivitis, retinitis, retinal vasculitis, uveitis, A health functional food for preventing or improving inflammatory diseases, characterized in that it is selected from the group consisting of blepharitis, allergic conjunctivitis, polymyositis, autoimmune encephalomyelitis, polyarteritis nodosa, and fibromyalgia syndrome. .
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WO2007042784A2 (en) * 2005-10-14 2007-04-19 Cyclacel Limited Pyrimidin-4-yl-3, 4-dihydr0-2h- pyrrolo [1, 2a] pyrazin-1-one compounds
WO2010042337A1 (en) * 2008-10-07 2010-04-15 Merck Sharp & Dohme Corp. Novel 6-azaindole aminopyrimidine derivatives having nik inhibitory activity
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