WO2021096314A1 - Novel benzimidazole derivative and use thereof - Google Patents

Novel benzimidazole derivative and use thereof Download PDF

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WO2021096314A1
WO2021096314A1 PCT/KR2020/016038 KR2020016038W WO2021096314A1 WO 2021096314 A1 WO2021096314 A1 WO 2021096314A1 KR 2020016038 W KR2020016038 W KR 2020016038W WO 2021096314 A1 WO2021096314 A1 WO 2021096314A1
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benzo
imidazol
piperidine
carboxamide
mmol
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PCT/KR2020/016038
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French (fr)
Korean (ko)
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서승용
김선여
맹한주
이재혁
이산하
이빛
이정은
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가천대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to novel benzimidazole-based compounds and uses thereof.
  • the novel benzimidazole-based compound of the present invention inhibits the production of advanced glycation end products (AGEs) and decomposes the resulting final glycation products, so it is suitable for the prevention or treatment of diseases caused by the final glycation products. It can be usefully used.
  • AGEs advanced glycation end products
  • Diabetes is a metabolic disease in which insulin secretion is insufficient or high blood sugar levels persist for a long period of time due to insulin resistance. As the state of elevated blood sugar in the body persists for a long time, the product of glycosylation invades large and small blood vessels in the retina, kidneys, nerves, or whole body, leading to chronic complications. Because diabetes is more dangerous for complications than itself, the primary goal of diabetes treatment today is to prevent the initiation or progression of diabetic complications. Typical diabetic complications include ulcerative colitis, inflammatory bowel disease, diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic atherosclerosis, and sarcopenia. .
  • the mechanisms that induce these diabetes complications are largely due to oxidative stress caused by free radicals, non-enzymatic glycation of protein, and osmotic pressure due to changes in the mechanisms of the polyol pathway. It is explained by stress, etc.
  • Oxidative stress which is the cause of diabetes complications, refers to a reaction that occurs when the removal function of free radicals occurring in the human body decreases or the production of free radicals is rapidly increased due to environmental factors.
  • oxidative stress increases due to hyperglycemia, increases insulin resistance, and causes cell damage such as blood vessels, kidneys, and retinas.
  • advanced glycation end products (AGEs) produced by oxidative stress are a major cause of diabetes complications.
  • the saccharification reaction is a non-enzymatic reaction between the aldehyde group of sugars present in blood or cell fluid and the free amino group of proteins inside and outside the cell.
  • nonalcoholic steatohepatitis NASH disease
  • the pathogenesis of non-alcoholic steatohepatitis has not been fully elucidated, but it is widely accepted that at least it is closely related to insulin resistance.
  • FAA free fatty acid
  • Free fatty acids are converted into non-toxic triglycerides (TG) in hepatocytes, leading to a state of simple steatosis (Hepatology, 2007 Jun:45(6):1366-74; Hepatology, 2004 Jul:40(1)). :185-94).
  • non-alcoholic steatohepatitis is often accompanied by type 2 diabetes, another insulin resistance-related disease, which suggests a link between the final glycated product, which is known to be a major causative agent of diabetic complications, and non-alcoholic steatohepatitis.
  • glyceraldehyde (GA)-derived final glycosylation products (GAAGEs) are the most toxic among final glycosylation products produced in the body, so they are called TAGEs (toxic AGEs).
  • TAGEs are the serum and liver of patients with non-alcoholic steatohepatitis. It has been found to be present in high concentrations in the tissues.
  • Aminoguanidine is a nucleophilic hydrazine that binds to the product of the condensation reaction and inhibits the production of the final glycated product and prevents the development of diabetes complications. This is the most promising drug for the prevention and treatment of diabetic complications, and has been conducted up to phase 3 clinical trials, but there is a problem that toxicity is induced when administered for a long period of time, so the development of a safer drug is required.
  • Korean Patent Registration No. 10-1899234 discloses a fir extract for the treatment of diabetes complications, which is a disease related to the final glycation product
  • Korean Patent Publication No. 10-2018-0024825 discloses homoiso, which has inhibitory and crushing activity of final glycation products Flavonoid compounds are disclosed.
  • the present invention was completed by developing a novel substance having an activity to inhibit or decompose the formation of a final saccharified product.
  • An object of the present invention is to provide a novel compound having excellent inhibition or decomposition activity of the final glycation product.
  • the present invention is also to provide a pharmaceutical composition comprising the novel compound.
  • the present invention also aims to provide a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising the novel compound.
  • the present invention also aims to provide a food composition comprising the novel compound.
  • the present invention also aims to provide a food composition for preventing or improving diseases related to final saccharification products comprising the novel compound.
  • the present invention provides a compound of the following formula (I) (hereinafter also referred to as a'benzimidazole compound') or a pharmaceutically acceptable salt thereof.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
  • R 1 , R 2 , and R 3 may each independently be one or more;
  • Ra or Rb are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -N(Rc) 2 , -ORc, -SRc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each Rc is independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0 to 4.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition for preventing or improving diseases related to final saccharification products comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the final glycated product-related disease is a group consisting of aging, diabetes, diabetes complications, degenerative brain disease, arteriosclerosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, skin fibrosis, pulmonary fibrosis, renal fibrosis, and heart fibrosis. It may be selected from. Preferably, it is a diabetic complication or non-alcoholic steatohepatitis.
  • the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, It may be selected from the group consisting of diabetic osteoporosis, and sarcopenia.
  • the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, Progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early stage dementia, temporal lobe epilepsy, and stroke.
  • the present invention relates to a novel benzimidazole compound or a pharmaceutically acceptable salt thereof, and the benzimidazole compound according to the present invention has the effect of inhibiting the production of final saccharified products and decomposing the resulting final saccharified products. , It can be usefully used as a pharmaceutical composition for the prevention or treatment of diseases caused by the final glycation product.
  • novel benzimidazole compounds of the present invention are particularly useful for the prevention or treatment of diabetic complications or non-alcoholic steatohepatitis.
  • 1A and 1B are graphs showing the decomposition effect of the compounds of the present invention on the final glycosylated products MGO-AGEs and GO-AGEs, respectively.
  • 2A and 2B are graphs showing the decomposition effects of the compounds of the present invention on the final glycosylated products GA-AGEs and GC-AGEs, respectively.
  • 3 is a graph showing the result of measuring the amount of lipid droplets in the cell.
  • 4A to 4D are graphs showing results of measuring the generated NO concentration.
  • Figure 4e is a graph showing the expression level of iNOS to GAPDH as a ratio to the normal group.
  • Figure 4f is a graph showing the expression level of COX2 to GAPDH as a ratio to the normal group.
  • 5A to 5E are graphs showing the results of measuring cell viability.
  • 6A shows the results of confirming the expression level of ⁇ -SMA by immunoblotting.
  • 6B is a graph showing the expression level of ⁇ -SMA to ⁇ -Tubulin as a ratio of the normal group.
  • 8A and 8B are graphs showing the results of measuring blood glucose concentration and AUC according to time during the oral glucose tolerance test (OGTT).
  • 8C and 8D are graphs showing the results of measuring blood glucose concentration and AUC according to time during the insulin resistance test (ITT).
  • 9 is a graph showing the results of measuring GO values.
  • 10A shows the results of confirming the expression levels of p-ACC and ACC by immunoblotting.
  • Figure 10b is a graph showing the expression levels of p-ACC and ACC.
  • 11A shows the results of confirming the expression levels of FAS, SREBP1C, and C/EBP ⁇ by immunoblotting.
  • 11B is a graph showing the expression levels of FAS, SREBP1C, and C/EBP ⁇ .
  • 12B is a graph showing the expression level of PPAR ⁇ as a ratio of the normal group.
  • 13A shows the result of confirming the expression level of SIRT1 by immunoblotting.
  • 13B is a graph showing the expression level of SIRT1 to ⁇ -Tubulin as a ratio of the normal group.
  • 15A is a photograph showing lipid droplets, lipid accumulation, and collagen expression in liver tissue by staining.
  • 15B is a graph showing the results of measuring the area of lipid droplets in liver tissue.
  • 15C is a graph showing the results of measuring the degree of lipid accumulation in liver tissue.
  • 15D is a graph showing the results of measuring the level of collagen expression in liver tissue.
  • 16A is a photograph showing the shape of the glomerulus, the number of mesangial matrices, and the expression of collagen in kidney tissue by staining.
  • 16B is a graph showing the number of mesangial matrices in kidney tissue as a ratio of the normal group.
  • 16C is a graph showing the results of measuring the level of collagen expression in kidney tissue.
  • 17A and 17B show the results of measuring cell viability in C2C12 cells, which are muscle cells.
  • HIEC-6 cells which are human small intestine epithelial cells.
  • HIEC-6 cells which are human small intestine epithelial cells.
  • 19B to 19D show results of measuring cell mobility related factors (relative wound density, wound confluence, and wound width).
  • the present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt thereof.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
  • R 1 , R 2 , and R 3 may each independently be one or more;
  • Ra or Rb are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -N(Rc) 2 , -ORc, -SRc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each Rc is independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0 to 4.
  • the present invention in one embodiment, the present invention
  • the present invention in one embodiment, the present invention
  • Ring A is 5- or 6-membered heterocycloalkyl
  • Ring B is or ego
  • X is C or N
  • R 3 is hydrogen, halo, -N(Ra)(Rb), -NO 2 , or -ORa;
  • the present invention provides a compound of the following formula (II) or a pharmaceutically acceptable salt thereof.
  • Ring B is or ego
  • X is C or N
  • One of Y and Z is N and the other is C;
  • R 3 is hydrogen, halo or -ORa
  • R 1 , R 2 , and R 3 may each independently be one or more;
  • Each Ra is independently C 1-6 alkyl unsubstituted or substituted with a halo group
  • n 1 or 2.
  • the present invention in one embodiment, the present invention
  • R3 is hydrogen, halo or -OCH 3 to provide a compound of formula II or a pharmaceutically acceptable salt thereof.
  • the present invention may be selected from the group consisting of the following compounds 1) to 49).
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may further include conventional pharmaceutically acceptable additives, such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or bulking agents.
  • conventional pharmaceutically acceptable additives such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or bulking agents.
  • the formulation of the pharmaceutical composition may be selected from the group consisting of powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, and injections.
  • the final glycated product-related disease is a group consisting of aging, diabetes, diabetes complications, degenerative brain disease, arteriosclerosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, skin fibrosis, pulmonary fibrosis, renal fibrosis, and heart fibrosis. It may be selected from. Preferably, it is a diabetic complication or non-alcoholic steatohepatitis.
  • the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, It may be selected from the group consisting of diabetic osteoporosis, and sarcopenia.
  • the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, Progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early stage dementia, temporal lobe epilepsy, and stroke.
  • the present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition for preventing or improving diseases related to final saccharification products comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the food composition may be a health functional food, a dairy product, a fermented product or a food additive.
  • the food composition is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid, and Salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may further be included.
  • nutrients vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid, and Salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may further be included.
  • Alkyl as used herein is a hydrocarbon having substituted or unsubstituted primary, secondary, tertiary and/or quaternary carbon atoms, and saturated aliphatic, which may be straight chain, branched, cyclic, or a combination thereof. Includes a flag.
  • an alkyl group has 1 to 20 carbon atoms (i.e. C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e. C 1 -C 10 alkyl), or 1 to 6 carbon atoms (i.e. C 1 -C 6 alkyl).
  • alkyl refers to C 1 -C 6 alkyl.
  • alkyl groups are methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i -Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH
  • alkyl as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-tri It refers to an alkyl moiety having a substituent that replaces hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as fluoroethyl, and the like.
  • C xy or "C x -C y ", when used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to a group containing x to y carbons in the chain. It is believed to contain. For example, a (C 1 -C 6 )alkyl group contains 1 to 6 carbon atoms in the chain.
  • Alkenyl has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, ie, carbon- It is a hydrocarbon with a carbon sp 2 double bond.
  • an alkenyl group has 2 to 20 carbon atoms (i.e. C 2 -C 20 alkenyl), 2 to 12 carbon atoms (i.e. C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( That is, C 2 -C 10 alkenyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkenyl).
  • Alkynyl has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and has one or more carbon-carbon sp triple bonds. It is a hydrocarbon having.
  • an alkynyl group has 2 to 20 carbon atoms (i.e. C 2 -C 20 alkynyl), 2 to 12 carbon atoms (i.e. C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( That is, C 2 -C 10 alkynyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • Cycloalkyl refers to a monovalent or divalent, saturated or partially saturated non-aromatic ring, which may be substituted or unsubstituted monocyclic, bicyclic or polycyclic and each atom of the ring is carbon. . Further, “cycloalkyl” may have 3 to 7 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 20 carbon atoms when polycyclic. Bicyclic or polycyclic ring systems may be fused, bridging, or spiro ring systems.
  • heterocycloalkyl is monocyclic, bicyclic or containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms within the ring It refers to a polycyclic, substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring.
  • heterocycloalkyl is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is heterocyclic, and
  • the click ring can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Bicyclic or polycyclic ring systems may be fused, bridging, or spiro ring systems.
  • “Heterocycloalkyl” includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like, each of which may be substituted or unsubstituted.
  • halo means halogen and includes chloro, fluoro, bromo, and iodo.
  • aryl includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic or polycyclic.
  • Aryl is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is aromatic, and the other cyclic ring is for example For example, it may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Aryl may be, for example, benzene, naphthalene, phenanthrene, anthracene, indene, indan, phenol, aniline, and the like, each of which may be substituted or unsubstituted.
  • heteroaryl refers to a substituted or unsubstituted monovalent or divalent aromatic group, which is monocyclic, bicyclic or polycyclic, containing one or more heteroatoms within the ring.
  • suitable heteroatoms include oxygen, sulfur and nitrogen.
  • Heteroaryl is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is heteroaromatic, and the other cyclic ring is For example, it may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
  • Heteroaryl is, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyra Sol, pyridine, pyrazine, pyridazine, and pyrimidine, and the like, each of which may be substituted or unsubstituted.
  • substituted refers to a specific moiety of a compound of the present invention having one or more substituents.
  • substituted for example "substituted alkyl” or “substituted heterocycloalkyl” for alkyl, heterocycloalkyl, etc. means that one or more hydrogen atoms of the alkyl or heterocycloalkyl are each independently by a non-hydrogen substituent. Means replaced.
  • the term “pharmaceutically acceptable salt” is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient.
  • exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid.
  • Acids benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid.
  • Monoacid or diacid salts may be formed, and these salts may exist in hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of the compounds of the present invention are more soluble in water and in various hydrophilic organic solvents compared to their free base form, and generally exhibit a higher melting point.
  • suitable salts is known to those skilled in the art.
  • diabetes complication refers to a symptom that occurs when diabetes lasts for a long time.
  • the "diabetic complication” is evaluated on a criterion different from the criteria for onset and judgment of diabetes.
  • the benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 1 below or a modification thereof. All starting materials and reagents were commercially available and did not undergo further purification. Reactions sensitive to air and moisture were carried out under a nitrogen atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvents. Thin film chromatography was performed using a 0.25 mm silica gel plate (Merck). 1 H and 13 C NMR spectra were recorded on a Bruker 600 MHz spectrometer with a solution in dimethylsulfoxide-d6, chloroform-d or methanol-d4.
  • N- (3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in a CH 2 Cl 2 solution (5 mL) of 1-( N , N -dimethylsulfamoyl ) Piperidine-4-carboxylic acid (26 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 ⁇ mol), DIPEA (40 ⁇ L, 0.3 mmol), and DMAP (2 mg , 8 ⁇ mol) was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine.
  • the benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 2 below or a modification thereof.
  • the benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 3 below or a modification thereof.
  • the final glycated product is produced through a non-enzymatic reaction in which the free amine end of the protein is covalently modified by reactive glucose or other carbonyl-containing molecules. Therefore, in this experimental example, by measuring the amount of free amine, which is a decomposition product of the final saccharified product, using a TNBSA (2,4,6-trinitrobenzene sulfonic acid) assay, the final saccharified product (AGEs ) The decomposition effect was evaluated.
  • TNBSA 2,4,6-trinitrobenzene sulfonic acid
  • Methylglyoxal (MGO) or glyoxal (GO) is mixed with bovine serum albumin (BSA) and sodium azide, and then stored at 37°C for 7 days to produce final glycation products (AGEs).
  • BSA bovine serum albumin
  • AGEs final glycation products
  • MGO-AGEs or GO-AGEs 1 mg/ml of the final glycosylated product was treated with the compound of the present invention at a concentration of 0.4 mM for 24 hours.
  • aminoguanidine AG
  • AGEs an inhibitor of final glycosylated products
  • TNBSA 2,4,6-trinitrobenzene sulfonic acid
  • sodium bicarbonate reagent were added to react, followed by 10% sodium dedecyl sulfate and 1N hydrochloric acid solution. Stopped.
  • the compound of the present invention increased the amount of free amine compared to the negative control (MGO-AGEs or GO-AGEs) treated with only the final glycosylated product.
  • MGO-AGEs or GO-AGEs the negative control
  • SA the compound of Example 11
  • the compound of the present invention increased the amount of free amine compared to the negative control group (MGO-AGEs) treated with only the final glycosylated product.
  • the compounds of Examples 56 and 60 exhibited similar values when compared to the positive control (aminoguanidine 1 nM), and the compound (SA) of Example 11 was 0.4 mM at a lower concentration when compared to the positive control (aminoguanidine 1 nM). It was reconfirmed that the degree of decomposition of the final glycation product MGO-AGEs was very good.
  • the benzimidazole compound of the present invention increased the amount of free amine compared to the negative control, in particular compared to the positive control Alagebrium using the same concentration as the compound of the present invention. It indicated a higher amount of free amine. From this, it was confirmed that the compound (SA) of the present invention has excellent resolution of the final saccharified product.
  • Glyceraldehyde (GA) or glycoaldehyde (GC) is mixed with bovine serum albumin (BSA) and sodium azide, and then stored at 37°C for 7 days to final glycated product (AGEs).
  • BSA bovine serum albumin
  • AGEs final glycated product
  • the final glycated product derived from glyceraaldehyde (GA) was referred to as GA-AGEs
  • the final glycated product derived from glycoaldehyde (GC) was referred to as GC-AGEs.
  • the benzimidazole compound (SA) of the present invention increased the amount of free amine compared to the negative control, and in particular, when comparing the degree of decomposition of GA-AGEs with the positive control, the present Treatment with the inventive compound (SA) showed a higher amount of free amine even at a lower concentration. From this, it was confirmed that the benzimidazole compound of the present invention has excellent resolution of the final saccharified product.
  • the benzimidazole compound (SA) of the present invention reduced the amount of lipid accumulation compared to the negative control, and in particular, when 10 ⁇ M was treated, the amount of lipid accumulation was at the level of the normal group. Decreased.
  • the compound of the present invention inhibits lipid accumulation.
  • Raw 264.7 cells which are macrophages, were seeded in a 96-well plate at 5 ⁇ 10 4 each and incubated in an incubator at 37° C. and 5% CO 2 for 24 hours, followed by pretreatment with 10 ⁇ M of the compound (SA) of Example 11 for 30 minutes, and then 100 It was stimulated with ng/ml LPS for 24 hours. After 24 hours, 50 ⁇ l of the supernatant was taken and transferred to a 96-well plate, and then Griess reagent (50 ⁇ l,% sulfanilamide in 5% phosphoric acid and 50 ⁇ l 0.1% N-1-napthylethylenediamine dihydrochloride in water) was added 1:1.
  • SA compound
  • Raw 264.7 cells were seeded in a 60 ⁇ dish with 1 ⁇ 10 6 each and incubated for 24 hours in a 37° C., 5% CO 2 incubator, and then the compound (SA) of Example 11 was pretreated for each concentration and incubated for 30 minutes, and LPS was It was treated at a concentration of 100 ng/ml and incubated for 24 hours.
  • After collecting the cultured cells spin down the cell pellet with a centrifuge (5,000 rpm, 5 min, 4°C), add lysis buffer, dissolve for 1 day, and then centrifuge (12,000 rpm, 25 min, 4°C) Cell membrane components and the like were removed. After denatured separation by SDS-PAGE, it was transferred to a PVDF membrane. Thereafter, after reacting with the primary antibody overnight, the secondary antibody was bound and the expression of iNOS and COX2 was measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
  • the compound (SA) of Example 11 decreased the expression of iNOS and COX2 compared to the negative control.
  • the compound of the present invention has an excellent anti-inflammatory effect.
  • Raw 264.7 cells which are macrophages, were seeded in a 96-well plate at 5 ⁇ 10 4 each and incubated in an incubator at 37° C. and 5% CO 2 for 24 hours, and then compound (SA) of Example 11 0.1, 1, 10 ⁇ M and positive control L -NMMA (20 ⁇ M) was pretreated for 30 minutes and then stimulated with 100 ng/ml LPS for 24 hours. After incubation for 24 hours, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 ⁇ l of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
  • SA compound
  • MTT solution 3-[4,5-dimethylthiazol-2-yl]-2,5-bromide
  • the LPS 100 ng / ml inducing group exhibited cytotoxicity, and the compounds of Examples 11, 44, 56 and 60 exhibited a cytoprotective effect.
  • LX2 cells Human stellate cells
  • SA compound 1 + 5 and 10 ⁇ M of Example 11
  • Pretreatment was performed and incubated for 1 hour, and TGF- ⁇ was treated at a concentration of 2 ng/ml and incubated for 24 hours.
  • spin down the cell pellet with a centrifuge (5,000 rpm, 5 min, 4°C), add lysis buffer, dissolve for 1 day, and then centrifuge (12,000 rpm, 25 min, 4°C)
  • a centrifuge 5,000 rpm, 5 min, 4°C
  • lysis buffer dissolve for 1 day
  • centrifuge (12,000 rpm, 25 min, 4°C
  • the compound of the present invention exhibits anti-fibrotic activity and can be used for the treatment of liver fibrosis, skin fibrosis, pulmonary fibrosis, renal fibrosis, or cardiac fibrosis.
  • OGTT Oral glucose tolerance test
  • ITT insulin tolerance test
  • an in vivo experiment was performed as shown in FIG. 7 using a male C57BL/6J mouse.
  • the negative control group (DMC; Diabetes mellitus control) and the experimental group were fed a high-fat diet containing 60% kcal of fat, and the normal group (CON or C) was fed a normal diet of tongue odors.
  • STZ streptozotocin 60 mg/kg was administered, and in the case of the normal group, only citrate buffer was administered.
  • 10 mg/kg of the compound of Example 11 (SA) was administered from the 11th week after the start of the experiment.
  • mice were subjected to an oral glucose tolerance test (OGTT) and an insulin resistance test (ITT) to measure blood glucose levels.
  • OGTT oral glucose tolerance test
  • ITT insulin resistance test
  • ITT insulin resistance test
  • Glyoxal is known to be one of the substances that cause diabetes complications. Accordingly, in this experimental example, the effect of reducing the GO level of the compound of the present invention was evaluated to determine whether the compound of the present invention can be used in the treatment of diabetic complications.
  • the GO level was decreased in the group treated with the compound (SA) of Example 11 of the present invention.
  • SA negative control
  • the GO level was reduced to a degree similar to that of the normal group. Accordingly, it was confirmed that the compound of the present invention can be effectively used in the treatment of diabetic complications.
  • Hepatic lipid metabolism related hepatic protein level measurement ( in vivo test)
  • liver protein related to liver lipid metabolism was measured. Specifically, it was attempted to determine whether the compound of the present invention can be effectively used in the treatment of fatty liver, especially non-alcoholic steatohepatitis, by measuring whether or not the protein expression related to adipogenesis or lipolysis is decreased.
  • Acetyl-CoA carboxylase is known to be a factor that oxidizes fatty acids and is reduced during adipogenesis, and FAS, SREBP1c, and C/EBP ⁇ are known to be highly expressed during adipogenesis as adipogenesis factors.
  • the liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins.
  • a sample was prepared after quantification through the Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Thereafter, after reacting the primary antibody overnight, the secondary antibody is bound and Acetyl-CoA carboxylase (ACC), FAS, SREBP1c, C/EBP is used using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA). The expression of the ⁇ protein was measured.
  • Figs. 10 and 11 the ratio of p-ACC to ACC was increased in the group treated with the compound (SA) of Example 11 of the present invention (Figs. 10a and 10b), FAS, SREBP1c, C /EBP ⁇ protein expression was decreased (Figs. 11A and 11B).
  • the compounds of the present invention can be effectively used in the treatment of fatty liver, particularly non-alcoholic steatohepatitis, by reducing the expression of proteins associated with adipogenesis or lipolysis.
  • liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins.
  • a sample was prepared after quantification through a Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Thereafter, after reacting with the primary antibody overnight, the secondary antibody was combined and the expression level of Sirt1 protein in liver tissue was measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
  • the expression level of the Sirt1 protein was increased in the group treated with the compound (SA) of Example 11 of the present invention. This confirmed the applicability of the compound of the present invention for the treatment of non-alcoholic steatohepatitis.
  • liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins.
  • a sample was prepared after quantification through a Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Then, after reacting with the primary antibody overnight, the secondary antibody was combined and the expression levels of iNOS and COX2 in the liver tissue of mice were measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
  • the expression level of iNOS decreased in the group treated with the compound (SA) of Example 11 of the present invention. Accordingly, it was confirmed that the compound of the present invention can be effectively used in the treatment of non-alcoholic steatohepatitis, diabetes, and diabetic complications.
  • hepatic steatosis Representative features of hepatic steatosis are that lipid droplets are observed in liver tissue, lipid accumulation is confirmed, and collagen is expressed. Accordingly, in this experimental example, the degree of lipid droplets, accumulation of lipids, and collagen expression in liver tissues were checked to determine whether the compound of the present invention can be used for the treatment of hepatic steatosis, particularly non-alcoholic fatty liver or non-alcoholic steatohepatitis.
  • liver tissue of the mouse at 23 weeks of ingestion of the high fat diet of Experimental Example 6 was stained with hematoxylin eosin (H&E) or PAS to identify lipid droplets, stained with Oil Red O to confirm lipid accumulation, and stained with Masson's trichrome. Thus, collagen expression was confirmed.
  • H&E hematoxylin eosin
  • PAS hematoxylin eosin
  • lipid droplets, lipid accumulation, and collagen expression were decreased in the group administered with the compound (SA) of Example 11 of the present invention compared to the negative control group. From this, it was confirmed that the compound of the present invention can be effectively used in the treatment of hepatic steatosis, in particular, non-alcoholic fatty liver or non-alcoholic steatohepatitis.
  • a typical characteristic of diabetic nephropathy is that the shape of the glomerulus is deformed, and the number of mesangial matrix and the expression of collagen are increased. Therefore, in this experimental example, the shape of the glomerulus in the kidney tissue was observed, the number of mesangial matrices and the degree of collagen expression were checked to determine whether the compound of the present invention can be used in the treatment of diabetic nephropathy. I wanted to.
  • kidney tissue of the mouse at 23 weeks after ingestion of the high fat diet of Experimental Example 6 was stained with hematoxylin eosin (H&E) to confirm the glomerulus, stained with PAS to confirm the mesangial matrix, and with Masso' trichrome. By staining, collagen expression in the kidneys was confirmed.
  • H&E hematoxylin eosin
  • Diabetic complications are accompanied by sarcopenia.
  • cell viability and cell morphology are observed to confirm whether the compound of the present invention exhibits a cell protective effect due to treatment with methylglyoxal (MGO), which is highly toxic among glycotoxin substances.
  • MGO methylglyoxal
  • C2C12 cells which are muscle cells, were seeded in a 6-well plate at 2.5 ⁇ 10 5 each, incubated in a 37° C., 5% CO 2 incubator for 24 hours, and then differentiated for 4 days after replacement with 2% horse serum medium. After 4 days, 10 ⁇ M of the compounds of Examples 11 (SA), 44, 56, and 60 were each pretreated for 1 hour, followed by stimulation with 1.5 mM MGO for 24 hours. After 24 hours, after observing the cell morphology using IncuCyte imaging program, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 ⁇ l of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
  • SA compounds of Examples 11
  • MGO methylglyoxal
  • HIEC-6 cells which are human small intestine epithelial cells, were seeded in a 96-well plate at 2.0X10 4 and 8.0X10 4 , respectively, and cultured in an incubator at 37°C and 5% CO 2 for 24 hours. ), 10 ⁇ M of compounds of 44, 56 and 60 were pretreated for 1 hour and then stimulated with 1.0 mM MGO for 24 hours. After 24 hours, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5- bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 ⁇ l of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
  • MTT solution 3-[4,5-dimethylthiazol-2-yl]-2,5- bromide
  • the effect of cell migration was evaluated as the effect of restoring the inhibition of cell migration by treatment with MGO, and it was confirmed that the compounds of Examples 11, 44, 56 and 60 exhibit the effect of restoring the suppressed cell migration to MGO, In particular, as shown in Figs. 19A to 19D, it was confirmed that the compounds of Examples 56 and 60 have excellent cell migration recovery effects.
  • the compound of the present invention can be effectively used for the treatment of ulcerative colitis and inflammatory bowel disease.

Abstract

The present invention relates to novel benzimidazole-based compounds and uses thereof. The novel benzimidazole-based compounds of the present invention inhibit the formation of advanced glycation end products (AGEs), and break down formed AGEs, and thus can be useful in the prevention or treatment of diseases caused by AGEs.

Description

신규한 벤즈이미다졸 유도체 및 이의 용도New benzimidazole derivatives and uses thereof
본 발명은 신규한 벤즈이미다졸계 화합물 및 이의 용도에 관한 것이다. 본 발명의 신규한 벤즈이미다졸계 화합물은 최종당화산물(Advanced glycation end product; AGEs)의 생성을 억제하고, 생성된 최종당화산물을 분해하므로, 최종당화산물에 의해 유발되는 질병의 예방 또는 치료에 유용하게 사용될 수 있다. The present invention relates to novel benzimidazole-based compounds and uses thereof. The novel benzimidazole-based compound of the present invention inhibits the production of advanced glycation end products (AGEs) and decomposes the resulting final glycation products, so it is suitable for the prevention or treatment of diseases caused by the final glycation products. It can be usefully used.
당뇨병은 인슐린의 분비량이 부족하거나 인슐린 저항성으로 인해 높은 혈당 수치가 오랜 기간 지속되는 대사 질환이다. 체내 혈당이 높아진 상태가 장기간 지속됨에 따라, 당화 산물이 망막, 신장, 신경 또는 전신의 크고 작은 혈관들을 침범하면서 만성 합병증이 발병하게 된다. 당뇨병은 그 자체보다 당뇨 합병증이 더 위험하기 때문에, 오늘날 당뇨병 치료에 있어서 가장 큰 목표는 당뇨 합병증의 유발이나 진행을 억제하는 데에 있다. 대표적인 당뇨 합병증으로는 궤양성 대장염, 염증성 장질환, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신장병증, 당뇨병성 신경병증, 당뇨병성 심장병, 당뇨병성 골다공증, 당뇨병성 아테롬성 동맥경화, 근감소증 등이 있다.Diabetes is a metabolic disease in which insulin secretion is insufficient or high blood sugar levels persist for a long period of time due to insulin resistance. As the state of elevated blood sugar in the body persists for a long time, the product of glycosylation invades large and small blood vessels in the retina, kidneys, nerves, or whole body, leading to chronic complications. Because diabetes is more dangerous for complications than itself, the primary goal of diabetes treatment today is to prevent the initiation or progression of diabetic complications. Typical diabetic complications include ulcerative colitis, inflammatory bowel disease, diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart disease, diabetic osteoporosis, diabetic atherosclerosis, and sarcopenia. .
이러한 당뇨 합병증을 유발하는 기전으로는 크게 자유라디칼에 의한 산화적 스트레스(oxidative stress), 단백질의 비효소적 당화 반응(non-enzymatic glycation of protein)과 폴리올 경로(polyol pathway)의 기작 변화에 의한 삼투압 스트레스 등으로 설명되고 있다.The mechanisms that induce these diabetes complications are largely due to oxidative stress caused by free radicals, non-enzymatic glycation of protein, and osmotic pressure due to changes in the mechanisms of the polyol pathway. It is explained by stress, etc.
당뇨 합병증을 일으키는 원인인 산화적 스트레스란 인체 내에서 발생하는 활성산소의 제거기능이 저하되거나 환경적인 요인으로 활성산소 생성이 급격하게 증가되어 일어나는 반응을 일컫는다. 당뇨 환자의 경우 고혈당에 의해 산화적 스트레스가 상승하여 인슐린 저항성을 증가시키고 혈관, 신장, 망막 등의 세포 손상을 발생시킨다고 알려져 있다. 이 뿐만 아니라 산화적 스트레스로 인하여 생성되는 최종당화산물 (advanced glycation end products, AGEs)은 당뇨합병증의 주요한 원인이 되고 있다. 당화 반응은 혈액이나 세포액에 존재하는 당류의 aldehyde group과 세포 내외의 단백질의 free amino group 사이의 비효소적 반응으로, 당과 단백질이 반응하여 초기당화산물이 생성되고 이 초기당화산물이 분해되지 않고 재배열된 후 다른 단백질과 교차 결합하여 AGEs를 생성하는 일련의 반응을 일컫는다. 이 반응은 반응 시작 단계에서 에너지 공급 없이 거의 자연발생적으로 일어나므로 식품이나 우리의 신체 내에서 일어나며, 일정단계 이후 비가역적인 특징을 가진다. 따라서 최종당화산물은 일단 생성되면 혈당이 정상으로 회복되어도 분해되지 않고, 단백질 생존 기간 동안 조직에 축적되어 조직의 구조와 기능을 비정상적으로 변화시킨다. 이처럼 비효소적 단백질 당화반응에 의하여 기저막, 혈장 알부민, 수정체 단백질, 피브린, 콜라겐 등의 단백질에서 당화가 일어나며, 생성된 최종당화산물(AGEs)은 조직의 구조와 기능을 비정상적으로 변화시켜 만성 당뇨 합병증을 유발시킨다.Oxidative stress, which is the cause of diabetes complications, refers to a reaction that occurs when the removal function of free radicals occurring in the human body decreases or the production of free radicals is rapidly increased due to environmental factors. In diabetic patients, it is known that oxidative stress increases due to hyperglycemia, increases insulin resistance, and causes cell damage such as blood vessels, kidneys, and retinas. In addition, advanced glycation end products (AGEs) produced by oxidative stress are a major cause of diabetes complications. The saccharification reaction is a non-enzymatic reaction between the aldehyde group of sugars present in blood or cell fluid and the free amino group of proteins inside and outside the cell. It refers to a series of reactions that are rearranged and cross-linked with other proteins to produce AGEs. Since this reaction occurs almost spontaneously without supplying energy at the beginning of the reaction, it occurs in food or in our body, and has an irreversible characteristic after a certain stage. Therefore, once the final glycated product is produced, it is not degraded even if blood sugar is restored to normal, but accumulates in the tissue during the protein survival period, causing abnormal changes in the structure and function of the tissue. As described above, by the non-enzymatic protein saccharification reaction, saccharification occurs in proteins such as basement membrane, plasma albumin, lens protein, fibrin, and collagen, and the resulting final glycated products (AGEs) abnormally change the structure and function of tissues, resulting in complications of chronic diabetes. Causes.
따라서, 당뇨 합병증의 발병을 지연시키거나 예방 또는 치료하기 위해서는 산화적 스트레스를 막는 역할을 하거나 최종당화산물의 생성 억제 또는 분해 효과를 가지는 것이 중요하다.Therefore, in order to delay, prevent or treat the onset of diabetic complications, it is important to prevent oxidative stress or have an effect of inhibiting or decomposing the final glycation product.
최종당화산물은 당뇨 합병증 외에도 비알코올성 지방간염(nonalcoholic steatohepatitis, NASH) 질환과 관련이 있다고 최근 밝혀졌다. 비알코올성 지방간염의 발병 기전은 완전히 밝혀지지는 않았지만, 적어도 인슐린 저항성과 밀접한 관련이 있는 것으로 널리 받아들여지고 있다. 유전적 요인과 더불어 식이 및 운동 등 생활습관과 관련된 환경적 요인의 복합 작용으로 인슐린 저항이 증가하면, 간에서 과도한 유리 지방산(free fatty acid, FAA)이 생성된다. 유리 지방산은 간세포 안에서 독성이 없는 중성 지방(triglyceride, TG)으로 전환되어 일차적으로 단순 지방증의 상태가 된다 (Hepatology, 2007 Jun:45(6):1366-74; Hepatology, 2004 Jul:40(1):185-94). 다양한 산화적 스트레스가 추가되면서 지방과산화와 염증 사이토카인의 과생성으로 간세포 손상 및 염증반응이 일어나 비알코올성 지방간염으로 발전한다는 것으로 알려져 있다. 흥미롭게도 비알코올성 지방간염은 또다른 인슐린 저항성 관련 질환인 제2형 당뇨병을 흔히 동반하는데, 이러한 사실은 당뇨 합병증의 주요 원인 물질로 알려진 최종당화산물과 비알코올성 지방간염의 연관성을 제안한다. 특히 글리세르알데하이드(glyceraldehyde, GA) 유래 최종당화산물(GAAGEs)은 체내에서 생성되는 최종당화산물 중 가장 독성이 높아, TAGEs(toxic AGEs)라고 불리는데, 최근 TAGEs가 비알코올성 지방간염 환자의 혈청 및 간 조직에서 고농도로 존재한다고 밝혀졌다.The final glycated product was recently found to be associated with nonalcoholic steatohepatitis (NASH) disease in addition to diabetic complications. The pathogenesis of non-alcoholic steatohepatitis has not been fully elucidated, but it is widely accepted that at least it is closely related to insulin resistance. When insulin resistance increases due to a combination of genetic factors and environmental factors related to lifestyle such as diet and exercise, excess free fatty acid (FAA) is produced in the liver. Free fatty acids are converted into non-toxic triglycerides (TG) in hepatocytes, leading to a state of simple steatosis (Hepatology, 2007 Jun:45(6):1366-74; Hepatology, 2004 Jul:40(1)). :185-94). With the addition of various oxidative stresses, it is known that fat peroxidation and overproduction of inflammatory cytokines lead to liver cell damage and inflammatory reactions, leading to non-alcoholic steatohepatitis. Interestingly, non-alcoholic steatohepatitis is often accompanied by type 2 diabetes, another insulin resistance-related disease, which suggests a link between the final glycated product, which is known to be a major causative agent of diabetic complications, and non-alcoholic steatohepatitis. In particular, glyceraldehyde (GA)-derived final glycosylation products (GAAGEs) are the most toxic among final glycosylation products produced in the body, so they are called TAGEs (toxic AGEs). Recently, TAGEs are the serum and liver of patients with non-alcoholic steatohepatitis. It has been found to be present in high concentrations in the tissues.
현재, 체내 최종당화산물의 생성을 억제하는 화합물질들이 많은 연구자들에 의해 개발되고 있다. 대표적으로는 아미노구아니딘(aminoguanidine), 피리독사민(pyridoxamin), 알라게브리움(Alagebrium; ALT-711), 티아졸리디네디온(thiazolidinediones) 등이 있다(Am JNephrol 2009;30:323-35.). 아미노구아니딘 (Aminoguanidine)은 친핵성 히드라진 (hydrazine)으로 축합반응의 산물과 결합하여 최종당화산물의 생성을 억제하여 당뇨 합병증으로 진전되는 것을 방지한다. 이는 당뇨 합병증의 예방 및 치료에 가장 유망한 의약품으로 제3상 임상시험까지 진행되었으나, 장기간 투여 시 독성이 유발되는 문제점이 있어 더욱 안전한 약제의 개발이 필요한 실정이다. 나아가 비알코올성 지방간염은 간이식 외에는 뚜렷한 치료 방법이 없으므로 이러한 문제점을 해결할 수 있는 보다 안전한 새로운 치료법에 대한 개발이 요구되고 있다. 한국등록특허 제10-1899234호에는 최종당화산물 관련 질환인 당뇨 합병증 치료용 전나무 추출물이 개시되어 있고, 한국공개특허 제10-2018-0024825호에는 최종당화산물의 생성 억제 및 파쇄 활성을 갖는 호모이소플라보노이드계 화합물이 개시되어 있다.Currently, compounds that inhibit the production of final glycation products in the body are being developed by many researchers. Representative examples include aminoguanidine, pyridoxamine, Alagebrium (ALT-711), and thiazolidinediones (Am JNephrol 2009; 30:323-35.). Aminoguanidine is a nucleophilic hydrazine that binds to the product of the condensation reaction and inhibits the production of the final glycated product and prevents the development of diabetes complications. This is the most promising drug for the prevention and treatment of diabetic complications, and has been conducted up to phase 3 clinical trials, but there is a problem that toxicity is induced when administered for a long period of time, so the development of a safer drug is required. Furthermore, since there is no clear treatment method for non-alcoholic steatohepatitis other than liver transplantation, there is a demand for the development of a safer new treatment that can solve this problem. Korean Patent Registration No. 10-1899234 discloses a fir extract for the treatment of diabetes complications, which is a disease related to the final glycation product, and Korean Patent Publication No. 10-2018-0024825 discloses homoiso, which has inhibitory and crushing activity of final glycation products Flavonoid compounds are disclosed.
이에 최종당화산물의 생성 억제 또는 분해 활성을 갖는 신규한 물질을 개발하여 본 발명을 완성하였다.Accordingly, the present invention was completed by developing a novel substance having an activity to inhibit or decompose the formation of a final saccharified product.
[선행기술문헌][Prior technical literature]
[특허문헌][Patent Literature]
한국등록특허 제10-1899234호Korean Patent Registration No. 10-1899234
한국공개특허 제10-2018-0024825호Korean Patent Publication No. 10-2018-0024825
본 발명은 최종당화산물의 생성 억제 또는 분해 활성이 우수한 신규한 화합물을 제공하고자 한다.An object of the present invention is to provide a novel compound having excellent inhibition or decomposition activity of the final glycation product.
본 발명은 또한 상기 신규한 화합물을 포함하는 약학 조성물을 제공하고자 한다.The present invention is also to provide a pharmaceutical composition comprising the novel compound.
본 발명은 또한 상기 신규한 화합물을 포함하는 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물을 제공하고자 한다.The present invention also aims to provide a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising the novel compound.
본 발명은 또한 상기 신규한 화합물을 포함하는 식품 조성물을 제공하고자 한다.The present invention also aims to provide a food composition comprising the novel compound.
본 발명은 또한 상기 신규한 화합물을 포함하는 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물을 제공하고자 한다.The present invention also aims to provide a food composition for preventing or improving diseases related to final saccharification products comprising the novel compound.
본 발명은 하기 화학식 I의 화합물(이하 '벤즈이미다졸 화합물'이라고도 한다) 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound of the following formula (I) (hereinafter also referred to as a'benzimidazole compound') or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
Figure PCTKR2020016038-appb-img-000001
Figure PCTKR2020016038-appb-img-000001
상기 식에서,In the above formula,
고리 A는 시클로알킬, 헤테로시클로알킬, 아릴, 헤테로아릴, 또는 바이시클로알킬이고;Ring A is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
고리 B는 시클로알킬, 헤테로시클로알킬, 아릴, 헤테로아릴, 또는 바이시클로알킬이고;Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
W는 단일결합이거나, -NR 4C(=O)-, 또는 -NR 4알킬-이고;W is a single bond, -NR 4 C(=O)-, or -NR 4 alkyl-;
R 1, R 2, R 3, 또는 R 4는 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O) 2Rb, -NO 2, -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2Ra, -S(=O) 2N(Ra)(Rb), 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고;R 1 , R 2 , R 3, or R 4 are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Ra, -C(=O)N(Ra)( Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S (=O) 2 Rb, -NO 2 , -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S( =O) 2 Ra, -S(=O) 2 N(Ra)(Rb), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 1, R 2, 및 R 3는 각각 독립적으로 하나 이상일 수 있으며;R 1 , R 2 , and R 3 may each independently be one or more;
Ra 또는 Rb는 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -N(Rc) 2, -ORc, -SRc, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고, 이 때 Rc는 각각 독립적으로 수소, 할로, 알킬, 알케닐, 알키닐, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고;Ra or Rb are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -N(Rc) 2 , -ORc, -SRc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each Rc is independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
n은 0 내지 4이며;n is 0 to 4;
여기서 상기 알킬, 알케닐, 알키닐, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴은 각각 독립적으로 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Rd, -C(=O)N(Rd)(Re), -C(=O)ORd, -N(Rd)(Re), -N(Rd)C(=O)Re, -N(Rd)S(=O)Re, -N(Rd)S(=O) 2Re, -NO 2, -ORd, -OC(=O)Rd, -SRd, -S(=O)Rd, -S(=O)N(Rd)(Re), -S(=O) 2Rd, -S(=O) 2N(Rd)(Re), 시클로알킬, 헤테로시클로알킬, 아릴, 및 헤테로아릴로 이루어진 군으로부터 선택된 하나 이상의 기로 치환되거나 치환되지 않으며, 이 때 Rd 또는 Re는 각각 독립적으로 수소, 할로, 또는 알킬이다.Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are each independently halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Rd, -C( =O)N(Rd)(Re), -C(=O)ORd, -N(Rd)(Re), -N(Rd)C(=O)Re, -N(Rd)S(=O) Re, -N(Rd)S(=O) 2 Re, -NO 2 , -ORd, -OC(=O)Rd, -SRd, -S(=O)Rd, -S(=O)N(Rd )(Re), -S(=O) 2 Rd, -S(=O) 2 N(Rd)(Re), cycloalkyl, heterocycloalkyl, aryl, and substituted with one or more groups selected from the group consisting of heteroaryl Or not substituted, wherein Rd or Re is each independently hydrogen, halo, or alkyl.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 식품 조성물을 제공한다.The present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물을 제공한다.The present invention provides a food composition for preventing or improving diseases related to final saccharification products comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
일 실시태양에서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 퇴행성 뇌질환, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것일 수 있다. 바람직하게는, 당뇨 합병증 또는 비알코올성 지방간염이다.In one embodiment, the final glycated product-related disease is a group consisting of aging, diabetes, diabetes complications, degenerative brain disease, arteriosclerosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, skin fibrosis, pulmonary fibrosis, renal fibrosis, and heart fibrosis. It may be selected from. Preferably, it is a diabetic complication or non-alcoholic steatohepatitis.
일 실시태양에서, 상기 당뇨 합병증은 궤양성 대장염, 염증성 장질환, 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 및 근감소증으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, It may be selected from the group consisting of diabetic osteoporosis, and sarcopenia.
일 실시태양에서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, Progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early stage dementia, temporal lobe epilepsy, and stroke.
본 발명은 신규한 벤즈이미다졸 화합물 또는 이의 약학적으로 허용가능한 염에 관한 것으로, 본 발명에 따른 벤즈이미다졸 화합물은 최종당화산물의 생성을 억제하고 생성된 최종당화산물을 분해하는 효과를 가지므로, 최종당화산물에 의해 유발되는 질환의 예방 또는 치료용 약학 조성물로 유용하게 사용될 수 있다.The present invention relates to a novel benzimidazole compound or a pharmaceutically acceptable salt thereof, and the benzimidazole compound according to the present invention has the effect of inhibiting the production of final saccharified products and decomposing the resulting final saccharified products. , It can be usefully used as a pharmaceutical composition for the prevention or treatment of diseases caused by the final glycation product.
본 발명의 신규한 벤즈이미다졸 화합물은 특히 당뇨 합병증 또는 비알코올성 지방간염의 예방 또는 치료에 유용하다.The novel benzimidazole compounds of the present invention are particularly useful for the prevention or treatment of diabetic complications or non-alcoholic steatohepatitis.
도 1a 및 1b는 각각 최종당화산물 MGO-AGEs 및 GO-AGEs에 대한 본 발명의 화합물의 분해 효과를 나타내는 그래프이다.1A and 1B are graphs showing the decomposition effect of the compounds of the present invention on the final glycosylated products MGO-AGEs and GO-AGEs, respectively.
도 2a 및 2b는 각각 최종당화산물 GA-AGEs 및 GC-AGEs에 대한 본 발명의 화합물의 분해 효과를 나타내는 그래프이다.2A and 2B are graphs showing the decomposition effects of the compounds of the present invention on the final glycosylated products GA-AGEs and GC-AGEs, respectively.
도 3은 세포 내 지질방울의 양을 측정한 결과를 나타내는 그래프이다.3 is a graph showing the result of measuring the amount of lipid droplets in the cell.
도 4a 내지 도 4d는 생성된 NO 농도를 측정한 결과를 나타내는 그래프이다.4A to 4D are graphs showing results of measuring the generated NO concentration.
도 4e는 GAPDH에 대한 iNOS의 발현량을 정상군에 대한 비율로 나타낸 그래프이다.Figure 4e is a graph showing the expression level of iNOS to GAPDH as a ratio to the normal group.
도 4f는 GAPDH에 대한 COX2의 발현량을 정상군에 대한 비율로 나타낸 그래프이다.Figure 4f is a graph showing the expression level of COX2 to GAPDH as a ratio to the normal group.
도 5a 내지 5e는 세포 생존율을 측정한 결과를 나타내는 그래프이다.5A to 5E are graphs showing the results of measuring cell viability.
도 6a는 α-SMA 발현 정도를 면역블롯팅으로 확인한 결과를 나타낸다.6A shows the results of confirming the expression level of α-SMA by immunoblotting.
도 6b는 α-Tubulin에 대한 α-SMA의 발현량을 정상군에 대한 비율로 나타낸 그래프이다.6B is a graph showing the expression level of α-SMA to α-Tubulin as a ratio of the normal group.
도 7은 in vivo 실험을 위한 본 발명의 화합물의 투여 스케줄 및 식이 섭취 스케줄을 나타낸다.7 shows the administration schedule and dietary intake schedule of the compound of the present invention for in vivo experiments.
도 8a 및 8b는 경구내당능 검사시(OGTT) 시간에 따른 혈중 포도당 농도 및 AUC를 측정한 결과를 나타내는 그래프이다.8A and 8B are graphs showing the results of measuring blood glucose concentration and AUC according to time during the oral glucose tolerance test (OGTT).
도 8c 및 8d는 인슐린내성 검사시(ITT) 시간에 따른 혈중 포도당 농도 및 AUC를 측정한 결과를 나타내는 그래프이다.8C and 8D are graphs showing the results of measuring blood glucose concentration and AUC according to time during the insulin resistance test (ITT).
도 9는 GO 수치를 측정한 결과를 나타내는 그래프이다.9 is a graph showing the results of measuring GO values.
도 10a는 p-ACC 및 ACC의 발현 정도를 면역블롯팅으로 확인한 결과를 나타낸다.10A shows the results of confirming the expression levels of p-ACC and ACC by immunoblotting.
도 10b는 p-ACC 및 ACC의 발현량을 나타낸 그래프이다.Figure 10b is a graph showing the expression levels of p-ACC and ACC.
도 11a는 FAS, SREBP1C, 및 C/EBPα의 발현 정도를 면역블롯팅으로 확인한 결과를 나타낸다.11A shows the results of confirming the expression levels of FAS, SREBP1C, and C/EBPα by immunoblotting.
도 11b는 FAS, SREBP1C, 및 C/EBPα의 발현량을 나타낸 그래프이다.11B is a graph showing the expression levels of FAS, SREBP1C, and C/EBPα.
도 12a는 PPARα의 발현 정도를 면역블롯팅으로 확인한 결과를 나타낸다.12A shows the results of confirming the expression level of PPARα by immunoblotting.
도 12b는 PPARα의 발현량을 정상군에 대한 비율로 나타낸 그래프이다.12B is a graph showing the expression level of PPARα as a ratio of the normal group.
도 13a는 SIRT1의 발현 정도를 면역블롯팅으로 확인한 결과를 나타낸다.13A shows the result of confirming the expression level of SIRT1 by immunoblotting.
도 13b는 α-Tubulin에 대한 SIRT1의 발현량을 정상군에 대한 비율로 나타낸 그래프이다.13B is a graph showing the expression level of SIRT1 to α-Tubulin as a ratio of the normal group.
도 14는 α-Tubulin에 대한 iNOS의 발현량을 나타낸 그래프이다.14 is a graph showing the expression level of iNOS against α-Tubulin.
도 15a는 간 조직에서의 지질방울, 지질 축적, 콜라겐 발현을 염색법으로 확인한 사진이다.15A is a photograph showing lipid droplets, lipid accumulation, and collagen expression in liver tissue by staining.
도 15b는 간 조직에서 지질방울의 면적을 측정한 결과를 나타내는 그래프이다.15B is a graph showing the results of measuring the area of lipid droplets in liver tissue.
도 15c는 간 조직에서 지질 축적 정도를 측정한 결과를 나타내는 그래프이다.15C is a graph showing the results of measuring the degree of lipid accumulation in liver tissue.
도 15d는 간 조직에서 콜라겐 발현 정도를 측정한 결과를 나타내는 그래프이다.15D is a graph showing the results of measuring the level of collagen expression in liver tissue.
도 16a는 신장 조직에서 사구체(glomerulus)의 모양, 혈관사이바탕질(mesangial matrix)의 수, 및 콜라겐 발현을 염색법으로 확인한 사진이다.16A is a photograph showing the shape of the glomerulus, the number of mesangial matrices, and the expression of collagen in kidney tissue by staining.
도 16b는 신장 조직에서 혈관사이바탕질(mesangial matrix)의 수를 정상군에 대한 비율로 나타낸 그래프이다.16B is a graph showing the number of mesangial matrices in kidney tissue as a ratio of the normal group.
도 16c는 신장 조직에서 콜라겐 발현 정도를 측정한 결과를 나타내는 그래프이다.16C is a graph showing the results of measuring the level of collagen expression in kidney tissue.
도 17a 및 도 17b는 근육세포인 C2C12 세포에서 세포 생존율(cell viability)을 측정한 결과를 나타낸다.17A and 17B show the results of measuring cell viability in C2C12 cells, which are muscle cells.
도 18a 및 도 18b는 인간 소장 상피세포인 HIEC-6 세포에서 세포 생존율(cell viability)을 측정한 결과를 나타낸다.18A and 18B show the results of measuring cell viability in HIEC-6 cells, which are human small intestine epithelial cells.
도 19a는 인간 소장 상피세포인 HIEC-6 세포에서 세포이동성 형태학적 관찰 결과를 나타낸다.19A shows the results of morphological observation of cell mobility in HIEC-6 cells, which are human small intestine epithelial cells.
도 19b 내지 도 19d는 세포이동성 관련 요소 (relative wound density, wound confluence 및 wound width)를 측정한 결과를 나타낸다.19B to 19D show results of measuring cell mobility related factors (relative wound density, wound confluence, and wound width).
이하, 첨부한 도면을 참조하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본원의 실시태양 및 실시예를 상세히 설명한다. 그러나 본원은 여러 가지 형태로 구현될 수 있으며 여기에서 설명하는 실시태양 및 실시예에 한정되지 않는다. Hereinafter, embodiments and examples of the present disclosure will be described in detail with reference to the accompanying drawings so that those of ordinary skill in the art may easily implement the present disclosure. However, the present application may be implemented in various forms and is not limited to the embodiments and examples described herein.
본원 명세서 전체에서, 어떤 부분이 어떤 구성 요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성 요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In the entire specification of the present application, when a certain part "includes" a certain constituent element, it means that other constituent elements may be further included rather than excluding other constituent elements unless otherwise specified.
본 발명은 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt thereof.
[화학식 I][Formula I]
Figure PCTKR2020016038-appb-img-000002
Figure PCTKR2020016038-appb-img-000002
상기 식에서,In the above formula,
고리 A는 시클로알킬, 헤테로시클로알킬, 아릴, 헤테로아릴, 또는 바이시클로알킬이고;Ring A is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
고리 B는 시클로알킬, 헤테로시클로알킬, 아릴, 헤테로아릴, 또는 바이시클로알킬이고;Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
W는 단일결합이거나, -NR 4C(=O)-, 또는 -NR 4알킬-이고;W is a single bond, -NR 4 C(=O)-, or -NR 4 alkyl-;
R 1, R 2, R 3, 또는 R 4는 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O) 2Rb, -NO 2, -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2Ra, -S(=O) 2N(Ra)(Rb), 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고;R 1 , R 2 , R 3, or R 4 are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Ra, -C(=O)N(Ra)( Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S (=O) 2 Rb, -NO 2 , -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S( =O) 2 Ra, -S(=O) 2 N(Ra)(Rb), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 1, R 2, 및 R 3는 각각 독립적으로 하나 이상일 수 있으며;R 1 , R 2 , and R 3 may each independently be one or more;
Ra 또는 Rb는 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -N(Rc) 2, -ORc, -SRc, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고, 이 때 Rc는 각각 독립적으로 수소, 할로, 알킬, 알케닐, 알키닐, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고;Ra or Rb are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -N(Rc) 2 , -ORc, -SRc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each Rc is independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
n은 0 내지 4이며;n is 0 to 4;
여기서 상기 알킬, 알케닐, 알키닐, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴은 각각 독립적으로 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Rd, -C(=O)N(Rd)(Re), -C(=O)ORd, -N(Rd)(Re), -N(Rd)C(=O)Re, -N(Rd)S(=O)Re, -N(Rd)S(=O) 2Re, -NO 2, -ORd, -OC(=O)Rd, -SRd, -S(=O)Rd, -S(=O)N(Rd)(Re), -S(=O) 2Rd, -S(=O) 2N(Rd)(Re), 시클로알킬, 헤테로시클로알킬, 아릴, 및 헤테로아릴로 이루어진 군으로부터 선택된 하나 이상의 기로 치환되거나 치환되지 않으며, 이 때 Rd 또는 Re는 각각 독립적으로 수소, 할로, 또는 알킬이다.Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are each independently halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Rd, -C( =O)N(Rd)(Re), -C(=O)ORd, -N(Rd)(Re), -N(Rd)C(=O)Re, -N(Rd)S(=O) Re, -N(Rd)S(=O) 2 Re, -NO 2 , -ORd, -OC(=O)Rd, -SRd, -S(=O)Rd, -S(=O)N(Rd )(Re), -S(=O) 2 Rd, -S(=O) 2 N(Rd)(Re), cycloalkyl, heterocycloalkyl, aryl, and substituted with one or more groups selected from the group consisting of heteroaryl Or not substituted, wherein Rd or Re is each independently hydrogen, halo, or alkyl.
일 실시태양에서, 본 발명은 In one embodiment, the present invention
W는 단일결합이거나, -NHC(=O)-, 또는 -NH알킬-이고,W is a single bond, -NHC(=O)-, or -NHalkyl-,
R 1, R 2, 또는 R 3은 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O) 2Rb, -NO 2, -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2Ra, -S(=O) 2N(Ra)(Rb), 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴인, 상기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.R 1 , R 2 , or R 3 are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O ) 2 Rb, -NO 2 , -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2 Ra, -S(=O) 2 N(Ra)(Rb), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is provided.
일 실시태양에서, 본 발명은In one embodiment, the present invention
고리 A는 5- 또는 6-원 헤테로시클로알킬이고;Ring A is 5- or 6-membered heterocycloalkyl;
고리 B는
Figure PCTKR2020016038-appb-img-000003
또는
Figure PCTKR2020016038-appb-img-000004
이고;Ring B is
Figure PCTKR2020016038-appb-img-000003
or
Figure PCTKR2020016038-appb-img-000004
ego;
X는 C 또는 N이며;X is C or N;
W는 단일결합이거나, -NHC(=O)-, 또는 -NH알킬-이고;W is a single bond, -NHC(=O)-, or -NHalkyl-;
R 1은 -C(=O)Ra, -C(=O)ORa, -S(=O) 2Ra, 또는 -S(=O) 2N(Ra)(Rb)이고;R 1 is -C(=O)Ra, -C(=O)ORa, -S(=O) 2 Ra, or -S(=O) 2 N(Ra)(Rb);
R 2는 수소, 할로, 알킬, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O) 2Rb, -NO 2, -ORa, 또는 아릴이고; R 2 is hydrogen, halo, alkyl, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O) 2 Rb, -NO 2 , -ORa, Or aryl;
R 3는 수소, 할로, -N(Ra)(Rb), -NO 2, 또는 -ORa이고;R 3 is hydrogen, halo, -N(Ra)(Rb), -NO 2 , or -ORa;
Ra 또는 Rb는 각각 독립적으로 수소; 할로기로 치환되거나 비치환된 C 1-6알킬; 또는 -S(=O) 2N(Rd)(Re)로 치환되거나 비치환된 5- 또는 6-원 헤테로시클로알킬이며, 이 때 Rd 또는 Re는 각각 독립적으로 수소 또는 C 1-6알킬인, 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.Ra or Rb are each independently hydrogen; C 1-6 alkyl unsubstituted or substituted with halo group; Or -S(=O) 2 N(Rd)(Re) substituted or unsubstituted 5- or 6-membered heterocycloalkyl, wherein Rd or Re are each independently hydrogen or C 1-6 alkyl, And a pharmaceutically acceptable salt thereof.
본 발명은 하기 화학식 II의 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound of the following formula (II) or a pharmaceutically acceptable salt thereof.
[화학식 II][Formula II]
Figure PCTKR2020016038-appb-img-000005
Figure PCTKR2020016038-appb-img-000005
상기 식에서,In the above formula,
고리 B는
Figure PCTKR2020016038-appb-img-000006
또는
Figure PCTKR2020016038-appb-img-000007
이고;Ring B is
Figure PCTKR2020016038-appb-img-000006
or
Figure PCTKR2020016038-appb-img-000007
ego;
X는 C 또는 N이고;X is C or N;
Y 및 Z 중 하나는 N, 나머지는 C이고;One of Y and Z is N and the other is C;
W는 단일결합이거나, -NHC(=O)-, 또는 -NHC 1-6알킬-이고;W is a single bond, -NHC(=O)-, or -NHC 1-6 alkyl-;
R 1는 -C(=O)-C 1-6알킬, -C(=O)O-C 1-6알킬, -S(=O) 2-C 1-6알킬, 또는 -S(=O) 2N-(C 1-6알킬) 2이고;R 1 is -C(=O)-C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, or -S(=O) 2 N-(C 1-6 alkyl) 2 ;
R 2는 수소, C 1-6알킬, -NH(Rb), -NHC(=O)Rb, -NHS(=O) 2Rb, -NO 2, -ORa, 또는 페닐이고;R 2 is hydrogen, C 1-6 alkyl, -NH(Rb), -NHC(=O)Rb, -NHS(=O) 2 Rb, -NO 2 , -ORa, or phenyl;
R 3는 수소, 할로 또는 -ORa이고;R 3 is hydrogen, halo or -ORa;
R 1, R 2, 및 R 3는 각각 독립적으로 하나 이상일 수 있으며;R 1 , R 2 , and R 3 may each independently be one or more;
Ra는 각각 독립적으로 할로기로 치환되거나 비치환된 C 1-6알킬이고; Each Ra is independently C 1-6 alkyl unsubstituted or substituted with a halo group;
Rb는 각각 독립적으로 수소; C 1-6알킬; 또는 -S(=O) 2N-(C 1-6알킬) 2로 치환되거나 비치환된 피페리딘이며;Each Rb is independently hydrogen; C 1-6 alkyl; Or piperidine unsubstituted or substituted with -S(=O) 2 N-(C 1-6 alkyl) 2;
n은 1 또는 2이다.n is 1 or 2.
일 실시태양에서, 본 발명은 In one embodiment, the present invention
W는 단일결합이거나, -NHC(=O)-, 또는 -NHCH 2-이고;W is a single bond, -NHC(=O)-, or -NHCH 2 -;
R 1은 -C(=O)CH 3, -C(=O)OC(CH 3) 3, -S(=O) 2CH 3, -S(=O) 2CH(CH 3) 2 또는 -S(=O) 2N(CH 3) 2이고;R 1 is -C(=O)CH 3 , -C(=O)OC(CH 3 ) 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH(CH 3 ) 2 or- S(=O) 2 N(CH 3 ) 2 ;
R2는 수소, -CH 3, -NH 2, -NHC(=O)CH 3,
Figure PCTKR2020016038-appb-img-000008
, -NHS(=O) 2CH 3, -NO 2, -OCH 3, -OCF 3, 또는 페닐이고; R2 is hydrogen, -CH 3 , -NH 2 , -NHC(=O)CH 3 ,
Figure PCTKR2020016038-appb-img-000008
, -NHS (= O) 2 CH 3, -NO 2, -OCH 3, -OCF 3, or phenyl;
R3는 수소, 할로 또는 -OCH 3인, 화학식 II의 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.R3 is hydrogen, halo or -OCH 3 to provide a compound of formula II or a pharmaceutically acceptable salt thereof.
본 발명은 하기 화합물 1) 내지 49)로 이루어진 군으로부터 선택되는 것일 수 있다.The present invention may be selected from the group consisting of the following compounds 1) to 49).
1) 1-아세틸-N-(1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;1) 1-acetyl-N-(1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
2) tert-부틸 4-((1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;2) tert-butyl 4-((1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
3) tert-부틸 3-((1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;3) tert-butyl 3-((1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
4) N-(1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)-1-(메틸설포닐)피페리딘-4-카르복스아미드;4) N-(1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;
5) N-(1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드;5) N-(1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide;
6) tert-부틸 4-((1-(4-아미노페네틸)-1H-벤조[d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;6) tert-butyl 4-((1-(4-aminophenethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
7) N-(1-(4-아미노페네틸)-1H-벤조[d]이미다졸-2-일)-1-(메틸설포닐)피페리딘-4-카르복스아미드;7) N-(1-(4-aminophenethyl)-1H-benzo[d]imidazol-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;
8) 1-(N,N-디메틸설파모일)-N-(3-((2-(1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미도)-1H-벤조[d]이미다졸-1-일)메틸)페닐)피페리딘-4-카르복스아미드;8) 1-(N,N-dimethylsulfamoyl)-N-(3-((2-(1-(N,N-dimethylsulfamoyl) piperidine-4-carboxamido)-1H-benzo [d]imidazol-1-yl)methyl)phenyl)piperidine-4-carboxamide;
9) N-(1-(3-아세트아미도벤질)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드;9) N-(1-(3-acetamidobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide ;
10) 1-(N,N-디메틸설파모일)-N-(1-(3-(메틸설폰아미도)벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;10) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-(methylsulfonamido)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4- Carboxamide;
11) 1-(N,N-디메틸설파모일)-N-(1-(3-니트로벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;11) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-nitrobenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
12) 1-(N,N-디메틸설파모일)-N-(1-(4-니트로벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;12) 1-(N,N-dimethylsulfamoyl)-N-(1-(4-nitrobenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
13) 1-(N,N-디메틸설파모일)-N-(1-(3-니트로페네틸)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;13) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-nitrophenethyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
14) N-(1-(4-아미노벤질)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드;14) N-(1-(4-aminobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide;
15) N-(1-(3-아미노페네틸)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드; 15) N-(1-(3-aminophenethyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide;
16) 1-(N,N-디메틸설파모일)-N-(1-(4-니트로페네틸)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;16) 1-(N,N-dimethylsulfamoyl)-N-(1-(4-nitrophenethyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
17) 1-(N,N-디메틸설파모일)-N-(1-(피리딘-3-일메틸)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;17) 1-(N,N-dimethylsulfamoyl)-N-(1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide ;
18) 1-(N,N-디메틸설파모일)-N-(1-(3-메틸벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;18) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-methylbenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
19) 1-(N,N-디메틸설파모일)-N-(1-(3-(트리플루오로메톡시)벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;19) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-(trifluoromethoxy)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4- Carboxamide;
20) 1-(N,N-디메틸설파모일)-N-(1-(3-메톡시벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;20) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
21) N-(1-(3-아미노-4-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)-1-( N, N-디메틸술파모일)피페리딘-4-카르복스아미드;21) N- (1-(3-amino-4-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-( N , N -dimethylsulfamoyl)piperidin-4- Carboxamide;
22) tert-부틸 4-((1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;22) tert -butyl 4-((1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate ;
23) 1-(이소프로필설포닐)- N-(1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;23) 1- (isopropylsulfonyl) - N - (1- (3- ( trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide, amides;
24) tert-부틸 4-((1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;24) tert -butyl 4-((1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
25) 1-(이소프로필설포닐)- N-(1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카복스아미드;25) 1- (isopropylsulfonyl) - N - (1- (3- methyl-benzyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide;
26) tert-부틸 4-((1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;26) tert -butyl 4-((1-(pyridin-3-ylmethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
27) 1-(이소프로필설포닐)- N-(1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;27) 1- (isopropylsulfonyl) - N - (1- (pyridin-3-ylmethyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide;
28) tert-부틸 4-((1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;28) tert -butyl 4-((1-(thiazol-4-ylmethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
29) 1-(이소프로필설포닐)- N-(1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카복스아미드;29) 1- (isopropylsulfonyl) - N - (1- (4-ylmethyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide;
30) 1-( N, N-디메틸술파모일)- N-(1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;30) 1- (N, N - dimethyl sulfamoyl) - N - (1- (4-ylmethyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxylic Boxamide;
31) tert-부틸 4-((1-((6-메틸피리딘-2-일)메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;31) tert -butyl 4-((1-((6-methylpyridin-2-yl)methyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidin-1-car Boxylate;
32) 1-(이소프로필설포닐)- N-(1-((6-메틸피리딘-2-일)메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;32) 1- (isopropylsulfonyl) - N - (1 - ( (6- methylpyridin-2-yl) methyl) -1 H - benzo [d] imidazol-2-yl) piperidin-4 Carboxamide;
33) tert-부틸 4-((1-(2-(4-페닐피페라진-1-일)에틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;33) tert -Butyl 4-((1-(2-(4-phenylpiperazin-1-yl)ethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
34) 1-(이소프로필설포닐)- N-(1-(2-(4-페닐피페라진-1-일)에틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카복스아미드;34) 1- (isopropylsulfonyl) - N - (1- (2- (4- phenyl-piperazin-1-yl) ethyl) -1 H - benzo [d] imidazol-2-yl) piperidine -4-carboxamide;
35) 1-( N, N-디메틸설파모일)- N-(6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;35) 1- (N, N - dimethyl sulfamoyl) - N - (6- fluoro-1 - (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) Piperidine-4-carboxamide;
36) 1-( N, N-디메틸설파모일)- N-(5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;36) 1- (N, N - dimethyl sulfamoyl) - N - (5-fluoro-1- (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) Piperidine-4-carboxamide;
37) tert-부틸 4-((6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;37) tert -Butyl 4-((6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
38) tert-부틸 4-((5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;38) tert -Butyl 4-((5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
39) N-(6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)-1-(이소프로필술포닐)피페리딘-4-카르복스아미드;39) N- (6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-(isopropylsulfonyl)piperidine -4-carboxamide;
40) N-(5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)-1-(이소프로필술포닐)피페리딘-4-카르복스아미드;40) N- (5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-(isopropylsulfonyl)piperidine -4-carboxamide;
41) 1-( N, N-디메틸설파모일)- N-(5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;41) 1- (N, N - dimethyl sulfamoyl) - N - (5- methoxy-1- (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) Piperidine-4-carboxamide;
42) tert-부틸 4-((5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;42) tert -Butyl 4-((5-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
43) 1-(이소프로필설포닐)- N-(5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;43) 1- (isopropylsulfonyl) - N - (5- methoxy-1- (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) piperidine -4-carboxamide;
44) 4-(((1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-일)아미노)메틸)- N, N-디메틸피페리딘-1-설폰아미드;44) 4-(((1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-yl)amino)methyl) -N , N -dimethylpiperidine-1-sulfonamide;
45) N, N-디메틸-4-(((1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)아미노)메틸)피페리딘-1-설폰아미드;45) N , N -dimethyl-4-(((1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)amino)methyl)piperidine-1-sulfonamide;
46) N, N-디메틸-4-(((1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)아미노)메틸)피페리딘-1-설폰아미드;46) N , N -dimethyl-4-(((1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)amino)methyl)piperidine-1 -Sulfonamide;
47) 4-(1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-일)- N, N-디메틸피페리딘-1-설폰아미드;47) 4-(1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-yl) -N , N -dimethylpiperidine-1-sulfonamide;
48) N, N-디메틸-4-(1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-1-설포나미드; 및48) N , N -dimethyl-4-(1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)piperidine-1-sulfonamide; And
49) N, N-디메틸-4-(1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-1-설폰아미드.49) N , N -dimethyl-4-(1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)piperidine-1-sulfonamide.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating diseases related to final glycosylated products comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
일 실시태양에서 상기 약학 조성물에 약제학적으로 허용 가능한 통상의 첨가제, 예를 들어 부형제, 결합제, 붕해제, 활택제, 가용화제, 현탁화제, 보존제 또는 증량제 등이 더 포함될 수 있다.In one embodiment, the pharmaceutical composition may further include conventional pharmaceutically acceptable additives, such as excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or bulking agents.
일 실시태양에서 상기 약학 조성물의 제형은 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 슬러리제, 현탁액, 및 주사제로 이루어진　군으로부터 선택될 수 있다.In one embodiment, the formulation of the pharmaceutical composition may be selected from the group consisting of powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, and injections.
일 실시태양에서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 퇴행성 뇌질환, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것일 수 있다. 바람직하게는, 당뇨 합병증 또는 비알코올성 지방간염이다.In one embodiment, the final glycated product-related disease is a group consisting of aging, diabetes, diabetes complications, degenerative brain disease, arteriosclerosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, skin fibrosis, pulmonary fibrosis, renal fibrosis, and heart fibrosis. It may be selected from. Preferably, it is a diabetic complication or non-alcoholic steatohepatitis.
일 실시태양에서, 상기 당뇨 합병증은 궤양성 대장염, 염증성 장질환, 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 및 근감소증으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis, It may be selected from the group consisting of diabetic osteoporosis, and sarcopenia.
일 실시태양에서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것일 수 있다.In one embodiment, the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia, Progressive supranuclear palsy, cognitive dysfunction, senile dementia, Lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early stage dementia, temporal lobe epilepsy, and stroke.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 식품 조성물을 제공한다.The present invention provides a food composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
본 발명은 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물을 제공한다.The present invention provides a food composition for preventing or improving diseases related to final saccharification products comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
일 실시태양에서 상기 식품 조성물은 건강기능식품, 유제품, 발효제품 또는 식품첨가물일 수 있다.In one embodiment, the food composition may be a health functional food, a dairy product, a fermented product or a food additive.
일 실시태양에서 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 추가로 포함할 수 있다.In one embodiment, the food composition is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid, and Salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may further be included.
정의Justice
달리 정의되지 않는 한, 본원에서 사용되는 모든 기술용어는 본 발명이 속한 분야의 당업자가 일반적으로 이해하는 바와 동일한 의미를 갖는다. 더욱이, 본원에 기재된 수치는 명백히 언급되지 않는 한 "약"의 의미를 포함하는 것으로 간주한다. 본원에서 사용되는 잔기 및 치환기의 정의를 하기 제공한다. 달리 명시하지 않는 한, 각각의 잔기는 하기 정의를 가지며, 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다.Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Moreover, the numerical values set forth herein are considered to be inclusive of the meaning of “about” unless expressly stated. The definitions of moieties and substituents as used herein are provided below. Unless otherwise specified, each moiety has the following definition and is used in the meaning as commonly understood by one of ordinary skill in the art.
당업계에서 사용되는 관습에 따라, 본원의 화학식에 사용된 "
Figure PCTKR2020016038-appb-img-000009
"은 잔기 또는 치환기 "R"이 골격 구조에 부착되어 있는 것을 나타내는데 사용된다.According to the conventions used in the art, as used in the formulas herein, "
Figure PCTKR2020016038-appb-img-000009
"Is used to indicate that a moiety or substituent "R" is attached to a framework structure.
본원에 사용된 "알킬"은 치환 또는 비치환된 1차, 2차, 3차 및/또는 4차 탄소 원자를 갖는 탄화수소이며, 직쇄형, 분지형, 환형, 또는 이들의 조합일 수 있는 포화 지방족기를 포함한다. 예를 들어, 알킬 기는 1 내지 20개의 탄소 원자 (즉, C 1-C 20 알킬), 1 내지 10개의 탄소 원자 (즉, C 1-C 10 알킬), 또는 1 내지 6개의 탄소 원자 (즉, C 1-C 6 알킬)를 가질 수 있다. 달리 정의되지 않는 한, 바람직한 실시양태에서, 알킬은 C 1-C 6 알킬을 지칭한다. 적합한 알킬 기의 예로는 메틸 (Me, -CH 3), 에틸 (Et, -CH 2CH 3), 1-프로필 (n-Pr, n-프로필, -CH 2CH 2CH 3), 2-프로필 (i-Pr, i-프로필, -CH(CH 3) 2), 1-부틸 (n-Bu, n-부틸, -CH 2CH 2CH 2CH 3), 2-메틸-1-프로필 (i-Bu, i-부틸, -CH 2CH(CH 3) 2), 2-부틸 (s-Bu, s-부틸, -CH(CH 3)CH 2CH 3), 2-메틸-2-프로필 (t-Bu, t-부틸, -C(CH 3) 3), 1-펜틸 (n-펜틸, -CH 2CH 2CH 2CH 2CH 3), 2-펜틸 (-CH(CH 3)CH 2CH 2CH 3), 3-펜틸 (-CH(CH 2CH 3) 2), 2-메틸-2-부틸 (-C(CH 3) 2CH 2CH 3), 3-메틸-2-부틸 (-CH(CH 3)CH(CH 3) 2), 3-메틸-1-부틸 (-CH 2CH 2CH(CH 3) 2), 2-메틸-1-부틸 (-CH 2CH(CH 3)CH 2CH 3), 1-헥실 (-CH 2CH 2CH 2CH 2CH 2CH 3), 2-헥실 (-CH(CH 3)CH 2CH 2CH 2CH 3), 3-헥실 (-CH(CH 2CH 3)(CH 2CH 2CH 3)), 2-메틸-2-펜틸 (-C(CH 3) 2CH 2CH 2CH 3), 3-메틸-2-펜틸 (-CH(CH 3)CH(CH 3)CH 2CH 3), 4-메틸-2-펜틸 (-CH(CH 3)CH 2CH(CH 3) 2), 3-메틸-3-펜틸 (-C(CH 3)(CH 2CH 3) 2), 2-메틸-3-펜틸 (-CH(CH 2CH 3)CH(CH 3) 2), 2,3-디메틸-2-부틸 (-C(CH 3) 2CH(CH 3) 2), 3,3-디메틸-2-부틸 (-CH(CH 3)C(CH 3) 3), 및 옥틸 (-(CH 2) 7CH 3)을 들 수 있으나 이에 제한되는 것은 아니다.“Alkyl” as used herein is a hydrocarbon having substituted or unsubstituted primary, secondary, tertiary and/or quaternary carbon atoms, and saturated aliphatic, which may be straight chain, branched, cyclic, or a combination thereof. Includes a flag. For example, an alkyl group has 1 to 20 carbon atoms (i.e. C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e. C 1 -C 10 alkyl), or 1 to 6 carbon atoms (i.e. C 1 -C 6 alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to C 1 -C 6 alkyl. Examples of suitable alkyl groups are methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i -Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl ( -CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl ( -CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (- CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C (CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C( CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), and octyl (-(CH 2 ) 7 CH 3 ) However, it is not limited thereto.
더욱이, 명세서, 실시예 및 청구항 전반에 걸쳐 사용되는 용어 "알킬"은 비치환된 및 치환된 알킬 기 모두를 포함하는 것으로 의도되며, 이들 중 후자는 트리플루오로메틸 및 2,2,2-트리플루오로에틸과 같은 할로알킬 기 등을 포함하는, 탄화수소 골격의 1개 이상의 탄소 상의 수소를 대체하는 치환기를 갖는 알킬 잔기를 지칭한다. Moreover, the term "alkyl" as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-tri It refers to an alkyl moiety having a substituent that replaces hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as fluoroethyl, and the like.
용어 "C x-y" 또는 "C x-C y"는, 아실, 아실옥시, 알킬, 알케닐, 알키닐 또는 알콕시와 같은 화학적 잔기와 함께 사용되는 경우, 사슬 내에 x 내지 y개의 탄소를 함유하는 기를 포함하는 것으로 여겨진다. 예를 들어, (C 1-C 6)알킬 기는 사슬 내에 1 내지 6개의 탄소 원자를 함유한다.The term "C xy "or "C x -C y ", when used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to a group containing x to y carbons in the chain. It is believed to contain. For example, a (C 1 -C 6 )alkyl group contains 1 to 6 carbon atoms in the chain.
"알케닐"은 1차, 2차, 3차 및/또는 4차 탄소 원자를 갖고, 직쇄형, 분지형 및 환형 기, 또는 이들의 조합을 포함하고, 1개 이상의 불포화 영역, 즉, 탄소-탄소 sp 2 이중 결합을 갖는 탄화수소이다. 예를 들어, 알케닐 기는 2 내지 20개의 탄소 원자 (즉, C 2-C 20 알케닐), 2 내지 12개의 탄소 원자 (즉, C 2-C 12 알케닐), 2 내지 10개의 탄소 원자 (즉, C 2-C 10 알케닐), 또는 2 내지 6개의 탄소 원자 (즉, C 2-C 6 알케닐)를 가질 수 있다. 적합한 알케닐 기의 예로는 비닐 (-CH=CH 2), 알릴 (-CH 2CH=CH 2), 시클로펜테닐 (-C 5H 7), 및 5-헥세닐 (-CH 2CH 2CH 2CH 2CH=CH 2)을 들 수 있으나 이에 제한되는 것은 아니다.“Alkenyl” has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, ie, carbon- It is a hydrocarbon with a carbon sp 2 double bond. For example, an alkenyl group has 2 to 20 carbon atoms (i.e. C 2 -C 20 alkenyl), 2 to 12 carbon atoms (i.e. C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( That is, C 2 -C 10 alkenyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkenyl). Examples of suitable alkenyl groups are vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ), and 5-hexenyl (-CH 2 CH 2 CH 2 CH 2 CH=CH 2 ), but is not limited thereto.
"알키닐"은 1차, 2차, 3차 및/또는 4차 탄소 원자를 갖고, 직쇄형, 분지형 및 환형 기, 또는 이들의 조합을 포함하고, 1개 이상의 탄소-탄소 sp 삼중 결합을 갖는 탄화수소이다. 예를 들어, 알키닐 기는 2 내지 20개의 탄소 원자 (즉, C 2-C 20 알키닐), 2 내지 12개의 탄소 원자 (즉, C 2-C 12 알키닐), 2 내지 10개의 탄소 원자 (즉, C 2-C 10 알키닐), 또는 2 내지 6개의 탄소 원자 (즉, C 2-C 6 알키닐)를 가질 수 있다. 적합한 알키닐 기의 예로는 아세틸레닉 (-C≡CH) 및 프로파르길 (-CH 2C≡CH)을 들 수 있으나 이에 제한되는 것은 아니다."Alkynyl" has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and has one or more carbon-carbon sp triple bonds. It is a hydrocarbon having. For example, an alkynyl group has 2 to 20 carbon atoms (i.e. C 2 -C 20 alkynyl), 2 to 12 carbon atoms (i.e. C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( That is, C 2 -C 10 alkynyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH 2 C≡CH).
본원에 사용된 "시클로알킬"은 치환 또는 비치환된 모노시클릭, 바이시클릭 또는 폴리시클릭일 수 있고 고리의 원자 각각이 탄소인 1가 또는 2가, 포화 또는 부분 포화 비방향족 고리를 지칭한다. 또한 "시클로알킬"은 모노시클릭일 때 3 내지 7개의 탄소 원자, 바이시클릭일 때 7 내지 12개의 탄소 원자, 및 폴리시클릭일 때 약 20개 이하의 탄소 원자를 가질 수 있다. 바이시클릭 또는 폴리시클릭 고리계는 융합, 다리, 또는 스피로 고리계일 수 있다.“Cycloalkyl” as used herein refers to a monovalent or divalent, saturated or partially saturated non-aromatic ring, which may be substituted or unsubstituted monocyclic, bicyclic or polycyclic and each atom of the ring is carbon. . Further, “cycloalkyl” may have 3 to 7 carbon atoms when monocyclic, 7 to 12 carbon atoms when bicyclic, and up to about 20 carbon atoms when polycyclic. Bicyclic or polycyclic ring systems may be fused, bridging, or spiro ring systems.
본원에 사용된 "헤테로시클로알킬"은 고리 내에 1개 이상의 헤테로원자, 바람직하게는 1 내지 4개의 헤테로원자, 보다 바람직하게는 1 내지 2개의 헤테로원자를 함유하는, 모노시클릭, 바이시클릭 또는 폴리시클릭인, 치환 또는 비치환된 1가 또는 2가, 포화 또는 부분 포화 비방향족 고리를 지칭한다. 또한 "헤테로시클로알킬"은 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 갖는 바이시클릭 또는 폴리시클릭 고리계일 경우, 고리 중 1개 이상은 헤테로시클릭이고, 다른 시클릭 고리는 예를 들어, 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클로알킬일 수 있다. 바이시클릭 또는 폴리시클릭 고리계는 융합, 다리, 또는 스피로 고리계일 수 있다. "헤테로시클로알킬"은 예를 들어, 피페리딘, 피페라진, 피롤리딘, 모르폴린, 락톤, 락탐 등 (이들 각각은 치환되거나 또는 비치환된 것일 수 있음)을 포함한다.As used herein, "heterocycloalkyl" is monocyclic, bicyclic or containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms within the ring It refers to a polycyclic, substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring. In addition, "heterocycloalkyl" is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is heterocyclic, and The click ring can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. Bicyclic or polycyclic ring systems may be fused, bridging, or spiro ring systems. “Heterocycloalkyl” includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like, each of which may be substituted or unsubstituted.
본원에 사용된 "할로"는 할로겐을 의미하고, 클로로, 플루오로, 브로모, 및 요오도를 포함한다.As used herein, “halo” means halogen and includes chloro, fluoro, bromo, and iodo.
본원에 사용된 용어 "아릴"은 고리의 원자 각각이 탄소인, 모노시클릭, 바이시클릭 또는 폴리시클릭인, 치환 또는 비치환된 1가 또는 2가 방향족 탄화수소기를 포함한다. "아릴"은 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 갖는 바이시클릭 또는 폴리시클릭 고리계일 경우, 고리 중 1개 이상은 방향족이고, 다른 시클릭 고리는 예를 들어, 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클로알킬일 수 있다. "아릴"은 예를 들어, 벤젠, 나프탈렌, 페난트렌, 안트라센, 인덴, 인단, 페놀, 아닐린 등 (이들 각각은 치환되거나 또는 비치환된 것일 수 있음)일 수 있다.As used herein, the term “aryl” includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic or polycyclic. "Aryl" is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is aromatic, and the other cyclic ring is for example For example, it may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl. “Aryl” may be, for example, benzene, naphthalene, phenanthrene, anthracene, indene, indan, phenol, aniline, and the like, each of which may be substituted or unsubstituted.
본원에 사용된 용어 "헤테로아릴"은 고리 내에 1개 이상의 헤테로원자를 함유하는, 모노시클릭, 바이시클릭 또는 폴리시클릭인, 치환 또는 비치환된 1가 또는 2가 방향족기를 지칭한다. 방향족 고리에 함유될 수 있는 적합한 헤테로원자의 비제한적인 예로는 산소, 황 및 질소를 들 수 있다. "헤테로아릴"은 2개 이상의 탄소가 2개의 인접한 고리에 공통인 2개 이상의 시클릭 고리를 갖는 바이시클릭 또는 폴리시클릭 고리계일 경우, 고리 중 1개 이상은 헤테로방향족이고, 다른 시클릭 고리는 예를 들어, 시클로알킬, 시클로알케닐, 시클로알키닐, 아릴, 헤테로아릴, 및/또는 헤테로시클릴일 수 있다. "헤테로아릴"은 예를 들어, 벤조푸란, 벤조티오펜, 피롤, 푸란, 티오펜, 이미다졸, 인돌, 이소인돌, 이속사졸, 이소티아졸, 옥사졸, 티아졸, 퀴놀린, 이소퀴놀린, 피라졸, 피리딘, 피라진, 피리다진, 및 피리미딘 등 (이들 각각은 치환되거나 또는 비치환된 것일 수 있음)을 포함한다.The term “heteroaryl” as used herein refers to a substituted or unsubstituted monovalent or divalent aromatic group, which is monocyclic, bicyclic or polycyclic, containing one or more heteroatoms within the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur and nitrogen. "Heteroaryl" is a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is heteroaromatic, and the other cyclic ring is For example, it may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. "Heteroaryl" is, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyra Sol, pyridine, pyrazine, pyridazine, and pyrimidine, and the like, each of which may be substituted or unsubstituted.
본원에 사용된 용어 "치환된"은 1개 이상의 치환기를 갖는 본 발명의 화합물의 특정 잔기를 지칭한다. 알킬, 헤테로시클로알킬 등에 대하여 용어 "치환된", 예를 들어 "치환된 알킬" 또는 "치환된 헤테로시클로알킬"은 알킬 또는 헤테로시클로알킬의 1개 이상의 수소 원자가 각각 독립적으로 비-수소 치환기에 의해 대체된 것을 의미한다. As used herein, the term “substituted” refers to a specific moiety of a compound of the present invention having one or more substituents. The term "substituted", for example "substituted alkyl" or "substituted heterocycloalkyl" for alkyl, heterocycloalkyl, etc. means that one or more hydrogen atoms of the alkyl or heterocycloalkyl are each independently by a non-hydrogen substituent. Means replaced.
본원에 사용된 용어 "약학적으로 허용가능한 염"은 본원에서 환자의 치료에 적합한 또는 상용성이 있는 산부가염 또는 염기부가염을 지칭하는데 사용된다. 적합한 염을 형성하는 예시적 무기산으로는 염산, 브롬화수소산, 황산 및 인산, 뿐만 아니라 금속 염, 예컨대 오르토인산 일수소 나트륨 및 황산수소칼륨을 들 수 있다. 적합한 염을 형성하는 예시적 유기산으로는 모노-, 디- 및 트리카르복실산, 예컨대 글리콜산, 락트산, 피루브산, 말론산, 숙신산, 글루타르산, 푸마르산, 말산, 타르타르산, 시트르산, 아스코르브산, 말레산, 벤조산, 페닐아세트산, 신남산 및 살리실산, 뿐만 아니라 술폰산, 예컨대 p-톨루엔 술폰산 및 메탄술폰산을 들 수 있다. 일산 또는 이산 염이 형성될 수 있으며, 이러한 염은 수화, 용매화 또는 실질적으로 무수 형태로 존재할 수 있다. 일반적으로, 본 발명의 화합물의 산부가염은 이의 유리 염기 형태와 비교하여 물 및 다양한 친수성 유기 용매에 더욱 가용성이고, 일반적으로 더 높은 융점을 나타낸다. 적절한 염의 선택은 당업자에게 공지되어 있다.As used herein, the term “pharmaceutically acceptable salt” is used herein to refer to an acid or base addition salt suitable or compatible with the treatment of a patient. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid. Acids, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluene sulfonic acid and methanesulfonic acid. Monoacid or diacid salts may be formed, and these salts may exist in hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of the compounds of the present invention are more soluble in water and in various hydrophilic organic solvents compared to their free base form, and generally exhibit a higher melting point. The selection of suitable salts is known to those skilled in the art.
본원에 사용된 용어 "당뇨 합병증"은, 당뇨병이 장기간 지속되는 경우 유발되는 증상을 의미한다. "당뇨 합병증"은, 당뇨병의 발병 기준 및 판단 기준과 상이한 기준으로 평가된다.The term “diabetic complication” as used herein refers to a symptom that occurs when diabetes lasts for a long time. The "diabetic complication" is evaluated on a criterion different from the criteria for onset and judgment of diabetes.
이하 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며 본원 발명의 범위를 한정하고자 하는 것은 아니다. The present invention is to be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
일반적인 합성방법General synthesis method
본 발명에 따른 벤즈이미다졸계 화합물은 하기 반응식 1의 합성 프로토콜 또는 이의 변형을 이용해서 합성될 수 있다. 모든 출발 물질 및 시약은 시판되고 있는 것을 사용하였으며, 추가의 정제 과정을 거치지 않았다. 공기 및 수분에 민감한 반응들은 질소 대기 하에서 수행되었다. 플래시 컬럼 크로마토그래피는 표시된 용매들로 실리카 겔 60 (230-400 메쉬, Merck)을 사용하여 수행되었다. 0.25 mm 실리카 겔 플레이트(Merck)를 사용하여 박막 크로마토그래피를 수행하였다. 디메틸술폭시드-d6, 클로로폼-d 또는 메탄올-d4 중의 용액으로 Bruker 600MHz 분광기에서 1H 및 13C NMR 스펙트럼을 기록하였다. 화학적 이동, 다중도(s, singlet; d, doublet; t, triplet; m, multiplet 및/또는 multiple resonances), 양성자 개수 및 헤르츠(Hz) 단위의 커플링 상수( J)의 순서로 1H NMR 데이터를 기록하였다.The benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 1 below or a modification thereof. All starting materials and reagents were commercially available and did not undergo further purification. Reactions sensitive to air and moisture were carried out under a nitrogen atmosphere. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvents. Thin film chromatography was performed using a 0.25 mm silica gel plate (Merck). 1 H and 13 C NMR spectra were recorded on a Bruker 600 MHz spectrometer with a solution in dimethylsulfoxide-d6, chloroform-d or methanol-d4. 1 H NMR data in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet and/or multiple resonances), number of protons, and coupling constant ( J) in Hertz (Hz) Was recorded.
[반응식 1][Scheme 1]
Figure PCTKR2020016038-appb-img-000010
Figure PCTKR2020016038-appb-img-000010
a) K 2CO 3, THF, 0 ℃, overnight; b) KOH, KI, acetone, rt, 30 min; C) K 2CO 3, THF, DMSO, overnight; d) Pd/C, H 2, MeOH, 3 h; e) EDCI, HOBt, DIPEA, DMAP, CH 2Cl 2, overnight; Y=N, Z=CH 2 or Y=CH 2, Z=N.a) K 2 CO 3 , THF, 0° C., overnight; b) KOH, KI, acetone, rt, 30 min; C) K 2 CO 3 , THF, DMSO, overnight; d) Pd/C, H 2 , MeOH, 3 h; e) EDCI, HOBt, DIPEA, DMAP, CH 2 Cl 2 , overnight; Y=N, Z=CH 2 or Y=CH 2 , Z=N.
[실시예 1] [Example 1]
1-(3-니트로벤질)-11-(3-nitrobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민의 제조]Preparation of imidazol-2-amine
Figure PCTKR2020016038-appb-img-000011
Figure PCTKR2020016038-appb-img-000011
1 H-벤조[ d]이미다졸-2-아민(2.0 g, 15.0 mmol)의 아세톤(65 mL) 용액에 KOH (1.7 g, 30.0 mmol), KI (1.2 g, 0.5 mmol), 1-(브로모메틸)-3-니트로벤젠(3.2 g, 7.5 mmol)을 차례로 넣고 30분 동안 실온에서 교반하였다. 상기 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 증류수 또는 brine을 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 그 후, 용매를 감압 하에 제거하고, 실리카겔(MeOH / CH 2Cl 2 = 1 : 15) 상에서 플래시 컬럼 크로마토그래피로 정제하여 목적 화합물을 수득하였다(3.8 g, 95%). In a solution of 1 H -benzo[ d ]imidazol-2-amine (2.0 g, 15.0 mmol) in acetone (65 mL), KOH (1.7 g, 30.0 mmol), KI (1.2 g, 0.5 mmol), 1-(bro Momethyl)-3-nitrobenzene (3.2 g, 7.5 mmol) was sequentially added and stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate. After washing the organic layer with distilled water or brine in the mixture, water molecules were removed with anhydrous Na 2 SO 4. Then, the solvent was removed under reduced pressure, and purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 15) to obtain the title compound (3.8 g, 95%).
1H NMR (600 MHz, DMSO- d6) δ 8.13 (m, 1H), 8.09 (m, 1H), 7.6 (m, 2H), 7.15 (d, 1H, J = 7.6 Hz), 7.11 (d, 1H, J = 7.4 Hz), 6.94 (m, 1H), 6.84 (m, 1H), 6.61 (s, 1H), 5.41 (s, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 154.9, 139.6, 134.0, 133.7, 130.2, 122.4, 121.7, 120.8, 118.3, 115.0, 107.8, 44.0. 1 H NMR (600 MHz, DMSO- d6 ) δ 8.13 (m, 1H), 8.09 (m, 1H), 7.6 (m, 2H), 7.15 (d, 1H, J = 7.6 Hz), 7.11 (d, 1H) , J = 7.4 Hz), 6.94 (m, 1H), 6.84 (m, 1H), 6.61 (s, 1H), 5.41 (s, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 154.9, 139.6, 134.0, 133.7, 130.2, 122.4, 121.7, 120.8, 118.3, 115.0, 107.8, 44.0.
[실시예 2] [Example 2]
1-(3-아미노벤질)-11-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민의 제조]Preparation of imidazol-2-amine
Figure PCTKR2020016038-appb-img-000012
Figure PCTKR2020016038-appb-img-000012
1-(3-니트로벤질)-1 H-벤조[ d]이미다졸-2-아민(1.0 g, 3.7 mmol)의 메틸 알코올 용액 및 5% wet Pd/C (0.2 g, 1.9 mmol)를 수소 대기하에서 반응시켰다. 3시간 동안 교반시킨 후, 반응 혼합물을 메틸 알코올로 희석시키고, celite pad로 여과한 후 갑압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 15) 상에서 플래시 컬럼 크로마토그래피로 정제하여 목적 화합물을 수득하였다(0.9 g, 95%). 1-(3-nitrobenzyl)-1 H -benzo[ d ]imidazol-2-amine (1.0 g, 3.7 mmol) in methyl alcohol solution and 5% wet Pd/C (0.2 g, 1.9 mmol) in hydrogen atmosphere Reacted under. After stirring for 3 hours, the reaction mixture was diluted with methyl alcohol, filtered through a celite pad, and concentrated under pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 15) to obtain the title compound (0.9 g, 95%).
1H NMR (600 MHz, DMSO- d6) δ 8.13 (m, 1H), 8.09 (m, 1H), 7.6 (m, 2H), 7.15 (d, 1H, J = 7.6 Hz), 7.11 (d, 1H, J = 7.4 Hz), 6.94 (m, 1H), 6.84 (m, 1H), 6.61 (s, 1H), 5.41 (s, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 155.1, 148.9, 142.9, 137.7, 134.3, 128.9, 120.3, 117.9, 114.7, 114.3, 112.9, 111.9, 107.9, 45.0. 1 H NMR (600 MHz, DMSO- d6 ) δ 8.13 (m, 1H), 8.09 (m, 1H), 7.6 (m, 2H), 7.15 (d, 1H, J = 7.6 Hz), 7.11 (d, 1H) , J = 7.4 Hz), 6.94 (m, 1H), 6.84 (m, 1H), 6.61 (s, 1H), 5.41 (s, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 155.1, 148.9, 142.9, 137.7, 134.3, 128.9, 120.3, 117.9, 114.7, 114.3, 112.9, 111.9, 107.9, 45.0.
[실시예 3] [Example 3]
1-(4-니트로페네틸)-11-(4-nitrophenethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민의 제조]Preparation of imidazol-2-amine
Figure PCTKR2020016038-appb-img-000013
Figure PCTKR2020016038-appb-img-000013
1 H-벤조[ d]이미다졸-2-아민(0.1 g, 0.8 mmol)의 THF 및 DMSO (6:1, 7 mL) 혼합 용액에 K 2CO 3 (0.3 mg, 2.3 mmol)과 1-(2-브로모에틸)-4-니트로벤젠(0.2 g, 0.8 mmol)을 첨가하였다. 80 ℃에서 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH 4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(MeOH / CH 2Cl 2 = 1 : 8) 상에서 플래시 컬럼 크로마토그래피로 정제하여 1-(4-니트로페네틸)-1 H-벤조[ d]이미다졸-2-아민을 수득하였다(0.1 g, 50%).In a mixed solution of 1 H -benzo[ d ]imidazol-2-amine (0.1 g, 0.8 mmol) in THF and DMSO (6:1, 7 mL), K 2 CO 3 (0.3 mg, 2.3 mmol) and 1-( 2-Bromoethyl)-4-nitrobenzene (0.2 g, 0.8 mmol) was added. After stirring at 80° C. overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with a saturated aqueous NH 4 Cl solution and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 8) to 1-(4-nitrophenethyl)-1 H -benzo[ d ]imidazol-2-amine. Was obtained (0.1 g, 50%).
1H NMR (600 MHz, DMSO- d6) δ 8.14 (d, 2H, J = 7.4 Hz), 7.57 (d, 2H, J = 7.6 Hz), 7.11 (t, 2H, J = 6.8 Hz), 6.91 (t, 1H, J = 7.5 Hz), 6.83 (t, 1H, J = 7.5 Hz), 6.44 (s, 2H), 4.24 (t, 2H, J = 7.5 Hz), 3.07 (t, 2H, J = 7.5 Hz). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 154.6, 146.6, 146.2, 142.6, 133.9, 130.5, 123.3, 120.3, 118.0, 114.7, 107.6, 42.2, 34.1. 1 H NMR (600 MHz, DMSO- d6 ) δ 8.14 (d, 2H, J = 7.4 Hz), 7.57 (d, 2H, J = 7.6 Hz), 7.11 (t, 2H, J = 6.8 Hz), 6.91 ( t, 1H, J = 7.5 Hz), 6.83 (t, 1H, J = 7.5 Hz), 6.44 (s, 2H), 4.24 (t, 2H, J = 7.5 Hz), 3.07 (t, 2H, J = 7.5 Hz). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 154.6, 146.6, 146.2, 142.6, 133.9, 130.5, 123.3, 120.3, 118.0, 114.7, 107.6, 42.2, 34.1.
[실시예 4] [Example 4]
1-(4-아미노페네틸)-11-(4-aminophenethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민의 제조]Preparation of imidazol-2-amine
Figure PCTKR2020016038-appb-img-000014
Figure PCTKR2020016038-appb-img-000014
1-(4-니트로페네틸)-1 H-벤조[ d]이미다졸-2-아민(0.7 g, 2.5 mmol)의 메틸 알코올 용액에 10% Pd/C (0.2 g)을 넣고 수소 대기 하에서 교반시켰다. 60분 동안 교반시킨 후, 반응 혼합물을 메틸 알코올로 희석시키고, celite pad로 여과한 후 갑압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아민 화합물을 수득하였다(0.5 g, 82%). 1-(4-nitrophenethyl)-1 H -benzo[ d ]imidazol-2-amine (0.7 g, 2.5 mmol) in a methyl alcohol solution of 10% Pd/C (0.2 g) and stirred under a hydrogen atmosphere Made it. After stirring for 60 minutes, the reaction mixture was diluted with methyl alcohol, filtered through a celite pad, and concentrated under pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to obtain an amine compound (0.5 g, 82%).
[실시예 5] [Example 5]
1-(One-( NN ,, NN -디메틸설파모일)피페리딘-4-카르복실산의 제조Preparation of -dimethylsulfamoyl)piperidine-4-carboxylic acid
Figure PCTKR2020016038-appb-img-000015
Figure PCTKR2020016038-appb-img-000015
이소니페코트산 (0.6 g, 5.0 mmol)의 디에틸에테르 및 물 혼합 용액(1:1, 20 mL)에 NaOH (0.4 g, 10.0 mmol)를 첨가하고 밤새 교반시켰다. 그 후, 수성층에 1N HCl을 첨가하여 pH를 3으로 조절하였다. 침전물을 여과하고 EtOAc에 용해시켰다. 상기 용액을 감압농축시켜 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산을 수득하였다(0.6 g, 50 %). NaOH (0.4 g, 10.0 mmol) was added to a mixed solution of diethyl ether and water (1:1, 20 mL) of isonipecotic acid (0.6 g, 5.0 mmol) and stirred overnight. Then, 1N HCl was added to the aqueous layer to adjust the pH to 3. The precipitate was filtered and dissolved in EtOAc. The solution was concentrated under reduced pressure to obtain 1-( N , N -dimethylsulfamoyl)piperidine-4-carboxylic acid (0.6 g, 50%).
1H NMR (600 MHz, CDCl 3) δ 3.64 (m, 2H), 2.93 (m, 2H), 2.81 (d, 6H, J = 2.1 Hz), 2.48 (m, 1H), 2.01 (m, 2H), 1.79 (m, 2H). 13C{ 1H} NMR (150 MHz, CDCl 3) δ 179.8, 45.7, 40.2, 38.3, 27.6. 1 H NMR (600 MHz, CDCl 3 ) δ 3.64 (m, 2H), 2.93 (m, 2H), 2.81 (d, 6H, J = 2.1 Hz), 2.48 (m, 1H), 2.01 (m, 2H) , 1.79 (m, 2H). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ) δ 179.8, 45.7, 40.2, 38.3, 27.6.
[실시예 6] [Example 6]
NN -(1-(One HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(]Imidazol-2-yl)-1-( NN ,, NN -디메틸설파모일)피페리딘-4-카르복스아미드의 제조Preparation of -dimethylsulfamoyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000016
Figure PCTKR2020016038-appb-img-000016
1 H-벤조[ d]이미다졸-2-아민(0.3 g, 2.3 mmol)의 CH 2Cl 2 용액(8 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.8 g, 3.4 mmol), EDCI (2.2 g, 11.3 mmol), HOBt (0.3 g, 2.3 mmol) 및 DMAP (55 mg, 0.5 mmol)을 첨가하였다. DIPEA (2 mL, 13.5 mmol)을 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온시키고 밤새 교반시켰다. 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 물 및 brine으로 세척하고, 수성 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(Acetone / EtOAc = 1 : 10) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(0.6 g, 76%).1 H -benzo[ d ]imidazol-2-amine (0.3 g, 2.3 mmol) in CH 2 Cl 2 solution (8 mL) 1-( N , N -dimethylsulfamoyl) piperidine-4-carboxyl Acid (0.8 g, 3.4 mmol), EDCI (2.2 g, 11.3 mmol), HOBt (0.3 g, 2.3 mmol) and DMAP (55 mg, 0.5 mmol) were added. DIPEA (2 mL, 13.5 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. Reaction mixture to CH 2 Cl 2 After dilution, the organic layer was washed with water and brine , water molecules were removed with aqueous Na 2 SO 4, and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Acetone / EtOAc = 1: 10) to give an amide compound (0.6 g, 76%).
1H NMR (600 MHz, DMSO- d6) δ 12.05 (s, 1H), 11.65 (s, 1H), 7.45 (m, 2H), 7.08 (m, 2H), 3.62 (d, 2H, J = 12.5 Hz), 2.85 (m, 2H), 2.74 (s, 6H), 2.66 (m, 1H), 1.91 (m, 2H), 1.68 (m, 2H). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.05 (s, 1H), 11.65 (s, 1H), 7.45 (m, 2H), 7.08 (m, 2H), 3.62 (d, 2H, J = 12.5 Hz ), 2.85 (m, 2H), 2.74 (s, 6H), 2.66 (m, 1H), 1.91 (m, 2H), 1.68 (m, 2H).
[실시예 7] [Example 7]
1-아세틸-1-acetyl- NN -(1-(3-아미노벤질)-1-(1-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드의 제조] Preparation of imidazol-2-yl) piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000017
Figure PCTKR2020016038-appb-img-000017
(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-아민(20 mg, 0.1 mmol)의 CH 2Cl 2 용액 (5 mL)에 1-아세틸 피페리딘-4-카르복실산(19 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol) 및 DMAP (2 mg, 8 μmol)을 첨가하였다. 17 시간 동안 교반한 후, 반응 혼합물을 CH 2Cl 2로 희석하고 물 및 brine으로 세척하고, 무수 MgSO 4 상에서 건조시키고 감압농축시켰다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(20 mg, 62%). (3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in CH 2 Cl 2 solution (5 mL) of 1-acetyl piperidine-4-carboxylic acid (19 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol) and DMAP (2 mg, 8 μmol) were added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 , washed with water and brine, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (20 mg, 62%).
1H NMR (600 MHz, CDCl 3) δ 7.25 (s, 1H), 7.20 (m, 4H), 6.71 (d, 1H, J = 7.2 Hz), 6.69 (d, 2H, J = 4.2 Hz), 5.23 (s, 2H), 4.52 (d, 1H, J = 13.8 Hz), 3.84 (d, 1H, J = 13.8 Hz), 3.17 (m, 1H), 2.79 (m, 1H), 2.64 (m, 1H), 2.11 (s, 3H), 2.05 (m, 2H), 1.78 (m, 2H); HRMS (EI): mass calcd for C 22H 25N 5O 2 [M+H] +, 392.2081; found, 392.2117. 1 H NMR (600 MHz, CDCl 3 ) δ 7.25 (s, 1H), 7.20 (m, 4H), 6.71 (d, 1H, J = 7.2 Hz), 6.69 (d, 2H, J = 4.2 Hz), 5.23 (s, 2H), 4.52 (d, 1H, J = 13.8 Hz), 3.84 (d, 1H, J = 13.8 Hz), 3.17 (m, 1H), 2.79 (m, 1H), 2.64 (m, 1H) , 2.11 (s, 3H), 2.05 (m, 2H), 1.78 (m, 2H); HRMS (EI): mass calcd for C 22 H 25 N 5 O 2 [M+H] + , 392.2081; found, 392.2117.
[실시예 8] [Example 8]
terttert -부틸 4-((1-(3-아미노벤질)-1-Butyl 4-((1-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트의 제조]Preparation of imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000018
Figure PCTKR2020016038-appb-img-000018
1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-아민(20 mg, 0.1 mmol)의 CH 2Cl 2 용액(5 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(25 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (50 μL, 0.3 mmol), 및 DMAP (2 mg, 8 μmol)를 첨가하였다. 17시간 동안 교반한 후, 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 MgSO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(29 mg, 77%). 1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in a CH 2 Cl 2 solution (5 mL) of 1-( tert -butoxycarbonyl) Piperidine-4-carboxylic acid (25 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (50 μL, 0.3 mmol), and DMAP (2 mg, 8 μmol) was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (29 mg, 77%).
1H NMR (400 MHz, CDCl 3) δ 7.21 (d, 1H, J = 6.8 Hz), 7.14 (m, 5H), 6.69 (d, 1H, J = 7.6 Hz), 6.57 (d, 2H, J = 12 Hz), 5.19 (s, 2H), 4.06 (bs, 2H), 2.84 (t, 2H, J = 12 Hz), 2.54 (m, 1H), 1.97 (d, 2H, J = 9.6 Hz), 1.76 (m, 2H), 1.44 (s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 (d, 1H, J = 6.8 Hz), 7.14 (m, 5H), 6.69 (d, 1H, J = 7.6 Hz), 6.57 (d, 2H, J = 12 Hz), 5.19 (s, 2H), 4.06 (bs, 2H), 2.84 (t, 2H, J = 12 Hz), 2.54 (m, 1H), 1.97 (d, 2H, J = 9.6 Hz), 1.76 (m, 2H), 1.44 (s, 9H).
[실시예 9] [Example 9]
terttert -부틸 3-((1-(3-아미노벤질)-1-Butyl 3-((1-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트의 제조]Preparation of imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000019
Figure PCTKR2020016038-appb-img-000019
1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-아민(19 mg, 0.1 mmol)의 CH 2Cl 2 용액(5 mL)에 1-( tert-부톡시카르보닐)피페리딘-3-카르복실산(24 mg, 0.1 mmol), EDCI (39 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol), 및 DMAP (2 mg, 8 μmol)를 첨가하였다. 17시간 동안 교반한 후, 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 MgSO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(34 mg, 95%). 1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (19 mg, 0.1 mmol) in a CH 2 Cl 2 solution (5 mL) of 1-( tert -butoxycarbonyl) Piperidine-3-carboxylic acid (24 mg, 0.1 mmol), EDCI (39 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol), and DMAP (2 mg, 8 μmol) was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (34 mg, 95%).
1H NMR (600 MHz, DMSO- d6) δ 12.57 (s, 1H), 7.47 (d, 1H, J = 5.2 Hz), 7.26 (s, 1H), 7.17 (m, 2H), 6.95 (t, 1H, J = 7.6 Hz), 6.54 (m, 2H), 6.44 (d, 1H, J = 7.7 Hz), 5.19 (s, 2H), 5.06 (s, 2H), 4.18 (s, 1H), 3.84 (d, 1H, J = 12.1 Hz), 2.86 (m, 3H), 2.33 (t, 1H, J = 10.3 Hz), 1.67 (d, 1H, J = 9.1 Hz), 1.58 (dd, 2H, J = 21.7, 9.7 Hz), 1.39 (s, 9H).; HRMS (EI): mass calcd for C 25H 31N 5O 3 [M+H] + 450.2500; found, 450.2567. 1 H NMR (600 MHz, DMSO- d6 ) δ 12.57 (s, 1H), 7.47 (d, 1H, J = 5.2 Hz), 7.26 (s, 1H), 7.17 (m, 2H), 6.95 (t, 1H , J = 7.6 Hz), 6.54 (m, 2H), 6.44 (d, 1H, J = 7.7 Hz), 5.19 (s, 2H), 5.06 (s, 2H), 4.18 (s, 1H), 3.84 (d , 1H, J = 12.1 Hz), 2.86 (m, 3H), 2.33 (t, 1H, J = 10.3 Hz), 1.67 (d, 1H, J = 9.1 Hz), 1.58 (dd, 2H, J = 21.7, 9.7 Hz), 1.39 (s, 9H).; HRMS (EI): mass calcd for C 25 H 31 N 5 O 3 [M+H] + 450.2500; found, 450.2567.
[실시예 10] [Example 10]
NN -(1-(3-아미노벤질)-1-(1-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(메틸설포닐)피페리딘-4-카르복스아미드의 제조]Preparation of imidazol-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000020
Figure PCTKR2020016038-appb-img-000020
1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-아민(20 mg, 0.1 mmol)의 CH 2Cl 2 용액(5 mL)에 1-(메틸설포닐)피페리딘-4-카르복실산(22 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol), 및 DMAP (2 mg, 8 μmol)를 첨가하였다. 17시간 동안 교반한 후, 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 MgSO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(19 mg, 54%). 1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in CH 2 Cl 2 solution (5 mL) of 1-(methylsulfonyl) piperidine -4-carboxylic acid (22 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol), and DMAP (2 mg, 8 μmol) Was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (19 mg, 54%).
1H NMR (400 MHz, CDCl 3) δ 7.26 (d, 1H, J = 1.6 Hz), 7.20 (m, 3H), 7.09 (t, 1H, J = 8 Hz), 6.68 (d, 1H, J = 7.6 Hz), 6.57 (m, 2H), 5.21 (s, 2H), 3.72 (d, 2H, J = 12.4 Hz), 2.87 (m, 2H), 2.75 (s, 3H), 2.52 (m, 1H), 2.12 (dd, 2H, J = 13.6, 3.6 Hz), 2.0 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (d, 1H, J = 1.6 Hz), 7.20 (m, 3H), 7.09 (t, 1H, J = 8 Hz), 6.68 (d, 1H, J = 7.6 Hz), 6.57 (m, 2H), 5.21 (s, 2H), 3.72 (d, 2H, J = 12.4 Hz), 2.87 (m, 2H), 2.75 (s, 3H), 2.52 (m, 1H) , 2.12 (dd, 2H, J = 13.6, 3.6 Hz), 2.0 (m, 2H).
[실시예 11] [Example 11]
NN -(1-(3-아미노벤질)-1-(1-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(]Imidazol-2-yl)-1-( NN ,, NN -디메틸설파모일)피페리딘-4-카르복스아미드(SA)의 제조Preparation of -dimethylsulfamoyl)piperidine-4-carboxamide (SA)
Figure PCTKR2020016038-appb-img-000021
Figure PCTKR2020016038-appb-img-000021
N-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-아민(20 mg, 0.1 mmol)의 CH 2Cl 2 용액(5 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(26 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol), 및 DMAP (2 mg, 8 μmol)를 첨가하였다. 17시간 동안 교반한 후, 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 MgSO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물(SA)을 수득하였다(23 mg, 60%). N- (3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in a CH 2 Cl 2 solution (5 mL) of 1-( N , N -dimethylsulfamoyl ) Piperidine-4-carboxylic acid (26 mg, 0.1 mmol), EDCI (40 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.3 mmol), and DMAP (2 mg , 8 μmol) was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (SA) (23 mg, 60%).
1H NMR (600 MHz, DMSO- d6) δ 12.57 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 7.21 - 7.10 (m, 2H), 6.94 (t, 1H, J = 7.3 Hz), 6.50 (s, 1H), 6.43 (d, 2H, J = 7.8 Hz), 5.18 (s, 2H), 5.06 (s, 2H), 3.55 (d, 2H, J = 11.4 Hz), 2.91 (s, 2H), 2.74 (s, 6H), 2.43 (s, 1H), 1.95 (m, 2H), 1.66 (d, 2H, J = 10.0 Hz).; HRMS (EI): mass calcd for C 22H 28N 6O 3S [M+Na] +, 479.1836; found, 479.1880. 1 H NMR (600 MHz, DMSO- d6 ) δ 12.57 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 7.21-7.10 (m, 2H), 6.94 (t, 1H, J = 7.3 Hz), 6.50 (s, 1H), 6.43 (d, 2H, J = 7.8 Hz), 5.18 (s, 2H), 5.06 (s, 2H), 3.55 (d, 2H, J = 11.4 Hz), 2.91 (s, 2H), 2.74 (s, 6H), 2.43 (s, 1H), 1.95 (m, 2H), 1.66 (d, 2H, J = 10.0 Hz).; HRMS (EI): mass calcd for C 22 H 28 N 6 O 3 S [M+Na] + , 479.1836; found, 479.1880.
[실시예 12] [Example 12]
terttert -부틸 4-((1-(4-아미노페네틸)-1-Butyl 4-((1-(4-aminophenethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트의 제조]Preparation of imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000022
Figure PCTKR2020016038-appb-img-000022
1-(4-아미노페네틸)-1 H-벤조[ d]이미다졸-2-아민(25.5 mg, 0.10 mmol)의 CH 2Cl 2 용액(5 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(30 mg, 0.1 mmol), EDCI (48 mg, 0.3 mmol), HOBt (7 mg, 0.1 mmol), DIPEA (50 μL, 0.3 mmol), 및 DMAP (2 mg, 8 μmol)를 첨가하였다. 17시간 동안 교반한 후, 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 MgSO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(34 mg, 74%). 1-(4-aminophenethyl)-1 H -benzo[ d ]imidazol-2-amine (25.5 mg, 0.10 mmol) in CH 2 Cl 2 solution (5 mL) of 1-( tert -butoxycarbonyl ) Piperidine-4-carboxylic acid (30 mg, 0.1 mmol), EDCI (48 mg, 0.3 mmol), HOBt (7 mg, 0.1 mmol), DIPEA (50 μL, 0.3 mmol), and DMAP (2 mg , 8 μmol) was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (34 mg, 74%).
1H NMR (400 MHz, CDCl 3) δ 7.24 (m, 3H), 7.08 (m, 2H), 6.92 (d, 2H, J = 8.4 Hz), 6.56 (d, 2H, J = 8.4 Hz), 4.25 (t, 2H, J = 7.2 Hz), 4.04 (bs, 2H), 2.95 (t, 2H, J = 7.2 Hz), 2.87 (t, 2H, J = 11.2 Hz), 2.5 (m, 2H), 2.11 (d, 2H, J = 11.6 Hz), 1.73 (m, 2H) 1.46 (s, 9H); HRMS (EI): mass calcd for C 26H 33N 5O 3 [M+H] +, 464.2656; found, 464.2737. 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 (m, 3H), 7.08 (m, 2H), 6.92 (d, 2H, J = 8.4 Hz), 6.56 (d, 2H, J = 8.4 Hz), 4.25 (t, 2H, J = 7.2 Hz), 4.04 (bs, 2H), 2.95 (t, 2H, J = 7.2 Hz), 2.87 (t, 2H, J = 11.2 Hz), 2.5 (m, 2H), 2.11 (d, 2H, J = 11.6 Hz), 1.73 (m, 2H) 1.46 (s, 9H); HRMS (EI): mass calcd for C 26 H 33 N 5 O 3 [M+H] + , 464.2656; found, 464.2737.
[실시예 13] [Example 13]
NN -(1-(4-아미노페네틸)-1-(1-(4-aminophenethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(메틸설포닐)피페리딘-4-카르복스아미드의 제조]Preparation of imidazol-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000023
Figure PCTKR2020016038-appb-img-000023
1-(4-아미노페네틸)-1 H-벤조[ d]이미다졸-2-아민(20 mg, 0.1 mmol)의 CH 2Cl 2 용액(5 mL)에 1-(메틸설포닐)피페리딘-4-카르복실산(22 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.2 mmol), 및 DMAP (2 mg, 8 μmol)를 첨가하였다. 17시간 동안 교반한 후 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 MgSO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(19 mg, 54%). 1-(4-aminophenethyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in CH 2 Cl 2 solution (5 mL) of 1-(methylsulfonyl) piperi Din-4-carboxylic acid (22 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol), HOBt (6 mg, 40 μmol), DIPEA (40 μL, 0.2 mmol), and DMAP (2 mg, 8 μmol ) Was added. After stirring for 17 hours, the reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (19 mg, 54%).
1H NMR (400 MHz, CDCl 3) δ 7.22 (m, 3H), 7.12 (m, 1H), 6.91 (d, 2H, J = 8.4 Hz), 6.58 (d, 2H, J = 8.4 Hz), 4.27 (t, 2H, J = 7.6 Hz), 3.73 (m, 2H), 2.96 (t, 2H, J = 7.6 Hz), 2.89 (m, 2H), 2.78 (s, 3H), 2.47 (m, 1H), 2.09 (dd, 2H, J = 13.6, 3.6 Hz), 1.97 (m, 2H); HRMS (EI): mass calcd for C 22H 27N 5O 3S [M+H] +, 442.1907; found, 442.1951. 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 (m, 3H), 7.12 (m, 1H), 6.91 (d, 2H, J = 8.4 Hz), 6.58 (d, 2H, J = 8.4 Hz), 4.27 (t, 2H, J = 7.6 Hz), 3.73 (m, 2H), 2.96 (t, 2H, J = 7.6 Hz), 2.89 (m, 2H), 2.78 (s, 3H), 2.47 (m, 1H) , 2.09 (dd, 2H, J = 13.6, 3.6 Hz), 1.97 (m, 2H); HRMS (EI): mass calcd for C 22 H 27 N 5 O 3 S [M+H] + , 442.1907; found, 442.1951.
[실시예 14] [Example 14]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(3-((2-(1-(-(3-((2-(1-( NN ,, NN -디메틸설파모일)피페리딘-4-카르복스아미도)-1-Dimethylsulfamoyl)piperidine-4-carboxamido)-1 HH -벤조[-Benzo[ dd ]이미다졸-1-일)메틸)페닐)피페리딘-4-카르복스아미드의 제조]Preparation of imidazol-1-yl)methyl)phenyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000024
Figure PCTKR2020016038-appb-img-000024
1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-아민(0.5 g, 2.2 mmol)의 DMF 용액(3 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.5 g, 2.2 mmol), EDCI (0.8 g, 5.6 mmol), HOBt (0.3 g, 2.2 mmol), 및 DMAP (27 mg, 0.2 mmol)를 첨가하였다. DIPEA (1 mL, 6.7 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온한 후 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석시키고 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 MgSO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(0.5 g, 33%).1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-amine (0.5 g, 2.2 mmol) in a DMF solution (3 mL) of 1-( N , N -dimethylsulfamoyl) piperi Din-4-carboxylic acid (0.5 g, 2.2 mmol), EDCI (0.8 g, 5.6 mmol), HOBt (0.3 g, 2.2 mmol), and DMAP (27 mg, 0.2 mmol) were added. DIPEA (1 mL, 6.7 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and then stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20) to give an amide compound (0.5 g, 33%).
[실시예 15] [Example 15]
NN -(1-(3-아세트아미도벤질)-1-(1-(3-acetamidobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(]Imidazol-2-yl)-1-( NN ,, NN -디메틸설파모일)피페리딘-4-카르복스아미드의 제조Preparation of -dimethylsulfamoyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000025
Figure PCTKR2020016038-appb-img-000025
N-(1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-일)-1-( N, N-디메틸설파모일)피페리딘-4-카르복스아미드(30 mg, 0.1 mmol)의 CH 2Cl 2 (1 mL) 용액에 Et 3N (10 μL, 0.1 mmol)를 첨가한 후, 아세틸 클로라이드(6 μL, 0.1 mmol)를 0 ℃에서 적가하였다. 생성된 혼합물을 실온으로 가온하고 2시간 동안 교반하였다. 그 후, 상기 반응 혼합물을 1 N HCl 용액으로 반응을 종결하고, 디클로로메탄으로 희석하였다. 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 70) 상에서 플래시 컬럼 크로마토그래피로 정제하여 목적 화합물을 수득하였다(5 mg, 15%). N- (1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-( N , N -dimethylsulfamoyl)piperidine-4-carboxamide (30 mg , 0.1 mmol) of CH 2 Cl 2 (1 mL) was added Et 3 N (10 μL, 0.1 mmol), and then acetyl chloride (6 μL, 0.1 mmol) was added dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Thereafter, the reaction mixture was terminated with 1 N HCl solution and diluted with dichloromethane. The organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 70) to obtain the title compound (5 mg, 15%).
1H NMR (600 MHz, DMSO- d6) δ 12.57 (s, 2H), 9.90 (s, 1H), 7.49 (d, 2H, J = 7.9 Hz), 7.45 (s, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 7.16 (m, 2H), 6.98 (s, 1H), 5.30 (s, 2H), 3.53 (d, 2H, J = 12.3 Hz), 2.89 (t, 2H, J = 11.2 Hz), 2.73 (s, 6H), 2.46 (s, 1H), 1.98 (s, 3H, J = 6.6 Hz), 1.93 (d, 2H, J = 10.2 Hz), 1.64 (m, 2H). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.57 (s, 2H), 9.90 (s, 1H), 7.49 (d, 2H, J = 7.9 Hz), 7.45 (s, 1H), 7.32 (s, 1H) ), 7.23 (s, 1H), 7.16 (m, 2H), 6.98 (s, 1H), 5.30 (s, 2H), 3.53 (d, 2H, J = 12.3 Hz), 2.89 (t, 2H, J = 11.2 Hz), 2.73 (s, 6H), 2.46 (s, 1H), 1.98 (s, 3H, J = 6.6 Hz), 1.93 (d, 2H, J = 10.2 Hz), 1.64 (m, 2H).
[실시예 16] [Example 16]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(3-(메틸설폰아미도)벤질)-1-(1-(3-(methylsulfonamido)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드의 제조] Preparation of imidazol-2-yl) piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000026
Figure PCTKR2020016038-appb-img-000026
N-(1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-일)-1-( N, N-디메틸설파모일)피페리딘-4-카르복스아미드(30 mg, 0.1 mmol)의 CH 2Cl 2 용액(1 mL)에 Et 3N (10 μL, 0.1 mmol)를 첨가한 후, 메탄설포닐 클로라이드(8 μL, 0.1 mmol)를 0 ℃에서 적가하였다. 생성된 혼합물을 실온으로 가온하고 2시간 동안 교반하였다. 그 후, 상기 반응 혼합물을 NH 4Cl 용액으로 반응을 종결하고, CH 2Cl 2으로 희석하였다. 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 50) 상에서 플래시 컬럼 크로마토그래피로 정제하여 목적 화합물을 수득하였다(6 mg, 17%). N- (1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-( N , N -dimethylsulfamoyl)piperidine-4-carboxamide (30 mg , 0.1 mmol) of CH 2 Cl 2 solution (1 mL) was added Et 3 N (10 μL, 0.1 mmol), and then methanesulfonyl chloride (8 μL, 0.1 mmol) was added dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. Then, the reaction mixture was terminated with an NH 4 Cl solution, and then diluted with CH 2 Cl 2. The organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 50) to obtain the title compound (6 mg, 17%).
1H NMR (600 MHz, DMSO- d6) δ 12.58 (s, 1H), 9.75 (s, 1H), 7.47 (m, 1H), 7.35 (m, 1H), 7.28 (t, 1H, J = 7.9 Hz), 7.22 (s, 1H), 7.16 (m, 2H), 7.09 (d, 2H, J = 7.9 Hz), 5.32 (s, 2H), 3.53 (d, 2H, J = 12.2 Hz), 2.91 (m, 5H), 2.74 (s, 6H), 2.43 (m, 1H), 1.97 (d, 2H, J = 10.5 Hz), 1.66 (m, 2H). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.58 (s, 1H), 9.75 (s, 1H), 7.47 (m, 1H), 7.35 (m, 1H), 7.28 (t, 1H, J = 7.9 Hz ), 7.22 (s, 1H), 7.16 (m, 2H), 7.09 (d, 2H, J = 7.9 Hz), 5.32 (s, 2H), 3.53 (d, 2H, J = 12.2 Hz), 2.91 (m , 5H), 2.74 (s, 6H), 2.43 (m, 1H), 1.97 (d, 2H, J = 10.5 Hz), 1.66 (m, 2H).
[실시예 17] [Example 17]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(3-니트로벤질)-1-(1-(3-nitrobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드의 제조] Preparation of imidazol-2-yl) piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000027
Figure PCTKR2020016038-appb-img-000027
1-(3-니트로벤질)-1 H-벤조[ d]이미다졸-2-아민(15 mg, 0.056 mmol)의 CH 2Cl 2 용액(1 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(20 mg, 0.1 mmol), EDCI (53 mg, 0.3 mmol), HOBt (8 mg, 0.1 mmol), 및 DMAP (1 mg, 10 μmol)를 첨가하였다. DIPEA (60 μL, 0.3 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 7시간 동안 교반한 후, 반응 혼합물을 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 50, 소량의 NH 4OH) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(3 mg, 11%). 1-(3-nitrobenzyl)-1 H -benzo[ d ]imidazol-2-amine (15 mg, 0.056 mmol) in a CH 2 Cl 2 solution (1 mL) of 1-( N , N -dimethylsulfamoyl ) Piperidine-4-carboxylic acid (20 mg, 0.1 mmol), EDCI (53 mg, 0.3 mmol), HOBt (8 mg, 0.1 mmol), and DMAP (1 mg, 10 μmol) were added. DIPEA (60 μL, 0.3 mmol) was added to the reaction mixture at 0 °C. After stirring for 7 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 50, a small amount of NH 4 OH) to give an amide compound (3 mg, 11%).
1H NMR (600 MHz, DMSO- d6) δ 12.61 (s, 1H), 8.38 (s, 1H), 8.15 (m, 1H), 7.84 (s, 1H), 7.64 (t, 1H, J = 8.0 Hz), 7.50 (d, 2H, J = 16.9 Hz), 7.2 (m, 2H), 5.48 (s, 2H), 3.54 (d, 2H, J = 11.9 Hz), 2.91 (m, 2H), 2.74 (s, 6H), 2.43 (d, 1H, J = 15.8 Hz), 1.97 (s, 2H), 1.66 (d, 2H, J = 10.3 Hz). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.61 (s, 1H), 8.38 (s, 1H), 8.15 (m, 1H), 7.84 (s, 1H), 7.64 (t, 1H, J = 8.0 Hz ), 7.50 (d, 2H, J = 16.9 Hz), 7.2 (m, 2H), 5.48 (s, 2H), 3.54 (d, 2H, J = 11.9 Hz), 2.91 (m, 2H), 2.74 (s , 6H), 2.43 (d, 1H, J = 15.8 Hz), 1.97 (s, 2H), 1.66 (d, 2H, J = 10.3 Hz).
[실시예 18] [Example 18]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(4-니트로벤질)-1-(1-(4-nitrobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드의 제조] Preparation of imidazol-2-yl) piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000028
Figure PCTKR2020016038-appb-img-000028
1-(4-니트로벤질)-1 H-벤조[ d]이미다졸-2-아민(0.2 g, 0.8 mmol)의 CH 2Cl 2 용액(3 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.2 g, 1.0 mmol), EDCI (0.3 g, 1.9 mmol), HOBt (50 mg, 0.4 mmol), 및 DMAP (9 mg, 0.1 mmol)를 첨가하였다. DIPEA (0.4 mL, 2.2 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 50) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(0.1 mg, 33%). 1-(4-nitrobenzyl)-1 H -benzo[ d ]imidazol-2-amine (0.2 g, 0.8 mmol) in a CH 2 Cl 2 solution (3 mL) of 1-( N , N -dimethylsulfamoyl ) Piperidine-4-carboxylic acid (0.2 g, 1.0 mmol), EDCI (0.3 g, 1.9 mmol), HOBt (50 mg, 0.4 mmol), and DMAP (9 mg, 0.1 mmol) were added. DIPEA (0.4 mL, 2.2 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 50) to give an amide compound (0.1 mg, 33%).
1H NMR (600 MHz, DMSO- d6) δ 12.62 (s, 1H), 8.20 (d, 2H, J = 8.5 Hz), 7.59 (d, 2H, J = 8.2 Hz), 7.48 (d, 1H, J = 6.6 Hz), 7.39 (dd, 1H, J = 6.3, 2.3 Hz), 7.18 (d, 2H, J = 3.3 Hz), 5.49 (s, 2H), 3.51 (d, 2H, J = 11.8 Hz), 2.90 (t, 2H, J = 11.0 Hz), 2.73 (s, 6H), 2.42 (m, 1H), 1.93 (d, 2H, J = 11.5 Hz), 1.64 (d, 2H, J = 10.5 Hz). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.62 (s, 1H), 8.20 (d, 2H, J = 8.5 Hz), 7.59 (d, 2H, J = 8.2 Hz), 7.48 (d, 1H, J = 6.6 Hz), 7.39 (dd, 1H, J = 6.3, 2.3 Hz), 7.18 (d, 2H, J = 3.3 Hz), 5.49 (s, 2H), 3.51 (d, 2H, J = 11.8 Hz), 2.90 (t, 2H, J = 11.0 Hz), 2.73 (s, 6H), 2.42 (m, 1H), 1.93 (d, 2H, J = 11.5 Hz), 1.64 (d, 2H, J = 10.5 Hz).
[실시예 19] [Example 19]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(3-니트로페네틸)-1-(1-(3-nitrophenethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드의 제조] Preparation of imidazol-2-yl) piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000029
Figure PCTKR2020016038-appb-img-000029
1-(3-니트로페네틸)-1 H-벤조[ d]이미다졸-2-아민(20 mg, 0.1 mmol)의 CH 2Cl 2 용액(1 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(25 mg, 0.1 mmol), EDCI (68 mg, 0.4 mmol), HOBt (11 mg, 0.1 mmol), 및 DMAP (2 mg, 10 μmol)를 첨가하였다. DIPEA (0.7 mL, 0.4 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20, 소량 NH 4OH) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(18 mg, 51%). 1-(3-nitrophenethyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in a CH 2 Cl 2 solution (1 mL) of 1-( N , N -dimethylsulfa Moyl) piperidine-4-carboxylic acid (25 mg, 0.1 mmol), EDCI (68 mg, 0.4 mmol), HOBt (11 mg, 0.1 mmol), and DMAP (2 mg, 10 μmol) were added. DIPEA (0.7 mL, 0.4 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20, a small amount of NH 4 OH) to give an amide compound (18 mg, 51%).
1H NMR (600 MHz, DMSO- d6) δ 12.41 (s, 1H), 8.06 (m, 2H), 7.48 (m, 4H), 7.18 (m, 2H), 4.42 (t, 2H, J = 6.5 Hz), 3.53 (d, 2H, J = 11.9 Hz), 3.21 (t, 2H, J = 6.8 Hz), 2.88 (t, 2H, J = 10.8 Hz), 2.75 (s, 6H), 2.29 (t, 1H, J = 10.8 Hz), 1.89 (m, 2H), 1.58 (m, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 183.2, 152.0, 147.7, 140.6, 135.8, 129.7, 128.8, 128.7, 123.7, 122.4, 121.4, 111.8, 109.6, 45.8, 45.5, 44.3, 42.2, 40.1, 33.1, 28.7, 27.9. 1 H NMR (600 MHz, DMSO- d6 ) δ 12.41 (s, 1H), 8.06 (m, 2H), 7.48 (m, 4H), 7.18 (m, 2H), 4.42 (t, 2H, J = 6.5 Hz ), 3.53 (d, 2H, J = 11.9 Hz), 3.21 (t, 2H, J = 6.8 Hz), 2.88 (t, 2H, J = 10.8 Hz), 2.75 (s, 6H), 2.29 (t, 1H , J = 10.8 Hz), 1.89 (m, 2H), 1.58 (m, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 183.2, 152.0, 147.7, 140.6, 135.8, 129.7, 128.8, 128.7, 123.7, 122.4, 121.4, 111.8, 109.6, 45.8, 45.5, 44.3, 42.2, 40.1, 33.1, 28.7, 27.9.
[실시예 20] [Example 20]
NN -(1-(4-아미노벤질)-1-(1-(4-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(]Imidazol-2-yl)-1-( NN ,, NN -디메틸설파모일)피페리딘-4-카르복스아미드의 제조Preparation of -dimethylsulfamoyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000030
Figure PCTKR2020016038-appb-img-000030
1-( N, N-디메틸설파모일)-N-(1-(4-니트로벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드(30 mg, 0.1 mmol)의 메틸 알코올 용액 및 10% wt Pd/C (10 mg)를 수소 대기하에 두었다. 70분 동안 교반한 후, 반응 혼합물을 메틸 알코올로 희석시키고, celite pad로 여과한 후 갑압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 30) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아민 화합물을 수득하였다(5 mg, 19%). 1-( N , N -dimethylsulfamoyl)-N-(1-(4-nitrobenzyl)-1 H -benzo[ d ]imidazol-2-yl)piperidine-4-carboxamide (30 mg , 0.1 mmol) of methyl alcohol solution and 10% wt Pd/C (10 mg) were placed under a hydrogen atmosphere. After stirring for 70 minutes, the reaction mixture was diluted with methyl alcohol, filtered through a celite pad, and concentrated under pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 30) to obtain an amine compound (5 mg, 19%).
1H NMR (600 MHz, DMSO- d6) δ 12.52 (s, 1H), 7.42 (d, 2H, J = 27.3 Hz), 7.13 (m, 4H), 6.47 (d, 2H, J = 8.2 Hz), 5.12 (s, 2H), 5.05 (s, 2H), 3.56 (d, 2H, J = 10.1 Hz), 2.94 (s, 2H), 2.76 (m, 6H), 2.45 (s, 1H), 1.98 (m, 2H), 1.69 (d, 2H, J = 9.1 Hz). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.52 (s, 1H), 7.42 (d, 2H, J = 27.3 Hz), 7.13 (m, 4H), 6.47 (d, 2H, J = 8.2 Hz), 5.12 (s, 2H), 5.05 (s, 2H), 3.56 (d, 2H, J = 10.1 Hz), 2.94 (s, 2H), 2.76 (m, 6H), 2.45 (s, 1H), 1.98 (m , 2H), 1.69 (d, 2H, J = 9.1 Hz).
[실시예 21] [Example 21]
NN -(1-(3-아미노페네틸)-1-(1-(3-aminophenethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(]Imidazol-2-yl)-1-( NN ,, NN -디메틸설파모일)피페리딘-4-카르복스아미드의 제조Preparation of -dimethylsulfamoyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000031
Figure PCTKR2020016038-appb-img-000031
1-( N, N-디메틸설파모일)- N-(1-(3-니트로페네틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드(7 mg, 10 μmol)의 메틸 알코올 용액 및 10% wt Pd/C (2 mg)를 수소 대기하에 두었다. 70분 동안 교반한 후, 반응 혼합물을 메틸 알코올로 희석시키고, celite pad로 여과한 후 갑압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 30) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아민 화합물을 수득하였다(2 mg, 30%). 1- (N, N - dimethyl sulfamoyl) - N - (1- (3- nitro-phenethyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide (7 mg, 10 μmol) of methyl alcohol solution and 10% wt Pd/C (2 mg) were placed under a hydrogen atmosphere. After stirring for 70 minutes, the reaction mixture was diluted with methyl alcohol, filtered through a celite pad, and concentrated under pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 30) to obtain an amine compound (2 mg, 30%).
1H NMR (600 MHz, DMSO- d6) δ 12.46 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.18 (m, 2H), 6.90 (t, 1H, J = 7.7 Hz), 6.44 (s, 1H), 6.38 (m, 2H), 4.96 (s, 2H), 4.24 (s, 2H), 3.58 (d, 2H, J = 11.2 Hz), 2.94 (m, 2H), 2.84 (m, 2H), 2.75 (s, 6H), 2.38 (m, 1H), 1.96 (m, 2H), 1.68 (m, 2H). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.46 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.18 (m, 2H), 6.90 (t, 1H, J = 7.7 Hz ), 6.44 (s, 1H), 6.38 (m, 2H), 4.96 (s, 2H), 4.24 (s, 2H), 3.58 (d, 2H, J = 11.2 Hz), 2.94 (m, 2H), 2.84 (m, 2H), 2.75 (s, 6H), 2.38 (m, 1H), 1.96 (m, 2H), 1.68 (m, 2H).
[실시예 22] [Example 22]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(4-니트로페네틸)-1-(1-(4-nitrophenethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드의 제조] Preparation of imidazol-2-yl) piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000032
Figure PCTKR2020016038-appb-img-000032
1-(4-니트로페네틸)-1 H-벤조[ d]이미다졸-2-아민(20 mg, 0.1 mmol)의 CH 2Cl 2 용액(3 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(25 mg, 0.1 mmol), EDCI (68 mg, 0.4 mmol), HOBt (11 mg, 0.1 mmol), 및 DMAP (2 mg, 0.01 mmol)를 첨가하였다. DIPEA (0.1 mL, 0.4 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(MeOH / CH 2Cl 2 = 1 : 20, 소량 NH 4OH) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아미드 화합물을 수득하였다(32 mg, 89%).1-(4-nitrophenethyl)-1 H -benzo[ d ]imidazol-2-amine (20 mg, 0.1 mmol) in a CH 2 Cl 2 solution (3 mL) of 1-( N , N -dimethylsulfa Moyl) piperidine-4-carboxylic acid (25 mg, 0.1 mmol), EDCI (68 mg, 0.4 mmol), HOBt (11 mg, 0.1 mmol), and DMAP (2 mg, 0.01 mmol) were added. DIPEA (0.1 mL, 0.4 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 20, a small amount of NH 4 OH) to give an amide compound (32 mg, 89%).
1H NMR (600 MHz, DMSO- d6) δ 12.43 (s, 1H), 8.09 (d, 2H, J = 8.5 Hz), 7.45 (m, 4H), 7.18 (m, 2H), 4.41 (t, 2H, J = 6.3 Hz), 3.53 (d, 2H, J = 12.0 Hz), 3.20 (m, 2H), 2.90 (m, 2H), 2.75 (s, 6H), 2.31 (t, 1H, J = 10.6 Hz), 1.88 (m, 2H), 1.58 (m, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 183.3, 152.0, 146.7, 146.2, 130.3, 123.3, 122.4, 111.8, 109.5, 79.2, 45.8, 44.2, 42.1, 37.9, 33.4, 28.7. 1 H NMR (600 MHz, DMSO- d6 ) δ 12.43 (s, 1H), 8.09 (d, 2H, J = 8.5 Hz), 7.45 (m, 4H), 7.18 (m, 2H), 4.41 (t, 2H) , J = 6.3 Hz), 3.53 (d, 2H, J = 12.0 Hz), 3.20 (m, 2H), 2.90 (m, 2H), 2.75 (s, 6H), 2.31 (t, 1H, J = 10.6 Hz ), 1.88 (m, 2H), 1.58 (m, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 183.3, 152.0, 146.7, 146.2, 130.3, 123.3, 122.4, 111.8, 109.5, 79.2, 45.8, 44.2, 42.1, 37.9, 33.4, 28.7.
[실시예 23][Example 23]
1-(피리딘-3-일메틸)-11-(pyridin-3-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민의 제조 ]Preparation of imidazol-2-amine
Figure PCTKR2020016038-appb-img-000033
Figure PCTKR2020016038-appb-img-000033
1 H-벤조[ d]이미다졸-2-아민(0.1 g, 0.8 mmol)의 THF 및 DMSO (6:1, 7 mL) 혼합 용액에 K 2CO 3 (0.3 g, 2.3 mmol) 및 3-(브로모메틸)피리딘(0.2 g, 0.8 mmol)을 첨가하였다. 0 ℃에서 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH 4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(MeOH / CH 2Cl 2 = 1 : 8) 상에서 플래시 컬럼 크로마토그래피로 정제하여 1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-아민을 수득하였다(45 mg, 27%). In a mixed solution of 1 H -benzo[ d ]imidazol-2-amine (0.1 g, 0.8 mmol) in THF and DMSO (6:1, 7 mL), K 2 CO 3 (0.3 g, 2.3 mmol) and 3-( Bromomethyl)pyridine (0.2 g, 0.8 mmol) was added. After stirring at 0° C. overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with a saturated aqueous NH 4 Cl solution and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 8) to 1-(pyridin-3-ylmethyl)-1 H -benzo[ d ]imidazole-2- An amine was obtained (45 mg, 27%).
1H NMR (600 MHz, DMSO- d6) δ 8.5 (m, 1H), 8.46 (d, 1H, J = 4.7 Hz), 7.54 (d, 1H, J = 7.9 Hz), 7.34 (m, 1H), 7.13 (t, 2H, J = 8.5 Hz), 6.94 (t, 1H, J = 7.6 Hz), 6.84 (t,1H, J = 7.6 Hz), 6.63 (s, 2H), 5.31 (s, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 154.8, 148.6, 148.5, 142.7, 134.8, 133.9, 132.8, 123.7, 120.7, 118.3, 114.9, 107.8, 42.4. 1 H NMR (600 MHz, DMSO- d6 ) δ 8.5 (m, 1H), 8.46 (d, 1H, J = 4.7 Hz), 7.54 (d, 1H, J = 7.9 Hz), 7.34 (m, 1H), 7.13 (t, 2H, J = 8.5 Hz), 6.94 (t, 1H, J = 7.6 Hz), 6.84 (t,1H, J = 7.6 Hz), 6.63 (s, 2H), 5.31 (s, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 154.8, 148.6, 148.5, 142.7, 134.8, 133.9, 132.8, 123.7, 120.7, 118.3, 114.9, 107.8, 42.4.
[실시예 24][Example 24]
1-(One-( NN ,, NN -디메틸설파모일)-N-(1-(피리딘-3-일메틸)-1-Dimethylsulfamoyl)-N-(1-(pyridin-3-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000034
Figure PCTKR2020016038-appb-img-000034
1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-아민(30 mg, 0.1 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(32 mg, 0.1 mmol), EDCI (128 mg, 0.7 mmol), HOBt (18 mg, 0.1 mmol), 및 DMAP (3 mg, 0.3 mmol)를 첨가하였다. DIPEA (0.1 mL, 0.8 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 이틀동안 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc / CH 2Cl 2 = 1 : 4) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(25 mg, 43%). 1-(pyridin-3-ylmethyl)-1 H -benzo[ d ]imidazol-2-amine (30 mg, 0.1 mmol) in CH 2 Cl 2 solution (2 mL) of 1-( N , N -dimethyl Sulfamoyl) piperidine-4-carboxylic acid (32 mg, 0.1 mmol), EDCI (128 mg, 0.7 mmol), HOBt (18 mg, 0.1 mmol), and DMAP (3 mg, 0.3 mmol) were added. . DIPEA (0.1 mL, 0.8 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for two days. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc / CH 2 Cl 2 = 1: 4) to obtain a compound (25 mg, 43%).
1H NMR (600 MHz, DMSO- d6) δ 12.54 (s, 1H), 8.64 (s, 1H), 8.48 (dd, 1H, J = 4.8, 1.6 Hz), 7.71 (s, 1H), 7.50 (m, 2H), 7.34 (m, 1H), 7.19 (m, 2H), 5.38 (s, 2H), 3.56 (m, 2H), 2.91 (t, 2H, J = 10.9 Hz), 2.74 (s, 6H), 2.46 (m, 1H), 1.95 (d, 2H, J = 11.5 Hz), 1.66 (m, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 149.0, 135.4, 132.3, 123.8, 122.6, 109.8, 54.9, 45.7, 37.9, 28.5. 1 H NMR (600 MHz, DMSO- d6 ) δ 12.54 (s, 1H), 8.64 (s, 1H), 8.48 (dd, 1H, J = 4.8, 1.6 Hz), 7.71 (s, 1H), 7.50 (m , 2H), 7.34 (m, 1H), 7.19 (m, 2H), 5.38 (s, 2H), 3.56 (m, 2H), 2.91 (t, 2H, J = 10.9 Hz), 2.74 (s, 6H) , 2.46 (m, 1H), 1.95 (d, 2H, J = 11.5 Hz), 1.66 (m, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 149.0, 135.4, 132.3, 123.8, 122.6, 109.8, 54.9, 45.7, 37.9, 28.5.
[실시예 25][Example 25]
1-(3-메틸벤질)-11-(3-methylbenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민 ]Imidazol-2-amine
Figure PCTKR2020016038-appb-img-000035
Figure PCTKR2020016038-appb-img-000035
1 H-벤조[ d]이미다졸-2-아민(0.1 g, 0.8 mmol)의 THF 및 DMSO (6:1, 7 mL) 혼합 용액에 K 2CO 3 (0.3 g, 2.3 mmol) 및 1-(브로모메틸)-3-메틸벤젠(0.1 mL, 0.8 mmol)을 첨가하였다. 0 ℃에서 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH 4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(MeOH / CH 2Cl 2 = 1 : 15) 상에서 플래시 컬럼 크로마토그래피로 정제하여 1-(3-메틸벤질)-1H-벤조[ d]이미다졸-2-아민을 수득하였다(0.1 g, 62%). In a mixed solution of 1 H -benzo[ d ]imidazol-2-amine (0.1 g, 0.8 mmol) in THF and DMSO (6:1, 7 mL), K 2 CO 3 (0.3 g, 2.3 mmol) and 1-( Bromomethyl)-3-methylbenzene (0.1 mL, 0.8 mmol) was added. After stirring at 0° C. overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with a saturated aqueous NH 4 Cl solution and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 15) to give 1-(3-methylbenzyl)-1H-benzo[ d ]imidazol-2-amine. (0.1 g, 62%).
1H NMR (600 MHz, DMSO- d6) δ 7.19 (m, 3H), 6.99 (m, 4H), 6.84 (m, 1H), 6.70 (s, 2H), 5.23 (s, 2H), 2.24 (s, 3H). 1 H NMR (600 MHz, DMSO- d6 ) δ 7.19 (m, 3H), 6.99 (m, 4H), 6.84 (m, 1H), 6.70 (s, 2H), 5.23 (s, 2H), 2.24 (s , 3H).
[실시예 26][Example 26]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(3-메틸벤질)-1-(1-(3-methylbenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드 ]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000036
Figure PCTKR2020016038-appb-img-000036
1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-아민(32 mg, 0.1 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(32 mg, 0.1 mmol), EDCI (0.1 g, 0.7 mmol), HOBt (18 mg, 0.1 mmol), 및 DMAP (3 mg, 0.3 mmol)를 첨가하였다. DIPEA (0.1 mL, 0.8 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 이틀동안 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc / CH 2Cl 2 = 1 : 4) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(36 mg, 61%).1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-amine (32 mg, 0.1 mmol) in a CH 2 Cl 2 solution (2 mL) of 1-( N , N -dimethylsulfamoyl ) Piperidine-4-carboxylic acid (32 mg, 0.1 mmol), EDCI (0.1 g, 0.7 mmol), HOBt (18 mg, 0.1 mmol), and DMAP (3 mg, 0.3 mmol) were added. DIPEA (0.1 mL, 0.8 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for two days. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc / CH 2 Cl 2 = 1: 4) to obtain a compound (36 mg, 61%).
1H NMR (600 MHz, DMSO- d6) δ 12.57 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 7.15 (m, 6H), 5.29 (s, 2H), 3.55 (d, 2H, J = 12.2 Hz), 2.91 (t, 2H, J = 9.8 Hz), 2.74 (s, 6H), 2.45 (m, 1H), 2.24 (s, 3H), 1.94 (s, 2H), 1.67 (d, 2H, J = 10.4 Hz). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.57 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 7.15 (m, 6H), 5.29 (s, 2H), 3.55 (d , 2H, J = 12.2 Hz), 2.91 (t, 2H, J = 9.8 Hz), 2.74 (s, 6H), 2.45 (m, 1H), 2.24 (s, 3H), 1.94 (s, 2H), 1.67 (d, 2H, J = 10.4 Hz).
[실시예 27][Example 27]
1-(3-(트리플루오로메톡시)벤질)-11-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민 ]Imidazol-2-amine
Figure PCTKR2020016038-appb-img-000037
Figure PCTKR2020016038-appb-img-000037
1 H-벤조[ d]이미다졸-2-아민(0.1 g, 0.8 mmol)의 THF (6 mL)에 K 2CO 3 (0.3g, 2.3 mmol) 및 1-(브로모메틸)-3-(트리플루오로메톡시)벤젠(0.1 mL, 0.8 mmol)을 첨가하였다. 0 ℃에서 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH 4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(MeOH / CH 2Cl 2 = 1 : 15) 상에서 플래시 컬럼 크로마토그래피로 정제하여 1-(3-(트리플루오로메톡시)벤질)-1H-벤조[ d]이미다졸-2-아민을 수득하였다(0.1 g, 52%).1 H -benzo[ d ]imidazol-2-amine (0.1 g, 0.8 mmol) in THF (6 mL) K 2 CO 3 (0.3 g, 2.3 mmol) and 1-(bromomethyl)-3-( Trifluoromethoxy)benzene (0.1 mL, 0.8 mmol) was added. After stirring at 0° C. overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with a saturated aqueous NH 4 Cl solution and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 15) to 1-(3-(trifluoromethoxy)benzyl)-1H-benzo[ d ]imidazole- 2-amine was obtained (0.1 g, 52%).
1H NMR (600 MHz, DMSO- d6) δ 7.45 (m, 1H), 7.25 (d, 1H, J = 8.2 Hz), 7.21 (s, 1H), 7.16 (t, 2H, J = 8.4 Hz), 7.08 (d, 1H, J = 7.7 Hz), 6.94 (m, 1H), 6.83 (m, 1H), 6.60 (s, 2H), 5.33 (s, 2H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 155.0, 148.5, 142.9, 140.1, 134.0, 130.6, 126.0, 120.7, 119.8, 119.5, 118.2, 114.9, 107.8, 44.1. 1 H NMR (600 MHz, DMSO- d6 ) δ 7.45 (m, 1H), 7.25 (d, 1H, J = 8.2 Hz), 7.21 (s, 1H), 7.16 (t, 2H, J = 8.4 Hz), 7.08 (d, 1H, J = 7.7 Hz), 6.94 (m, 1H), 6.83 (m, 1H), 6.60 (s, 2H), 5.33 (s, 2H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 155.0, 148.5, 142.9, 140.1, 134.0, 130.6, 126.0, 120.7, 119.8, 119.5, 118.2, 114.9, 107.8, 44.1.
[실시예 28][Example 28]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(3-(트리플루오로메톡시)벤질)-1-(1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000038
Figure PCTKR2020016038-appb-img-000038
1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민(41 mg, 0.1 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(32 mg, 0.1 mmol), EDCI (0.1 g, 0.7 mmol), HOBt (18 mg, 0.1 mmol), 및 DMAP (3 mg, 0.3 mmol)를 첨가하였다. DIPEA (0.1 mL, 0.8 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 이틀동안 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc / CH 2Cl 2 = 1 : 4) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(32 mg, 47%).1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-amine (41 mg, 0.1 mmol) in CH 2 Cl 2 solution (2 mL) of 1-( N , N -dimethylsulfamoyl) piperidine-4-carboxylic acid (32 mg, 0.1 mmol), EDCI (0.1 g, 0.7 mmol), HOBt (18 mg, 0.1 mmol), and DMAP (3 mg, 0.3 mmol) Was added. DIPEA (0.1 mL, 0.8 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for two days. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc / CH 2 Cl 2 = 1: 4) to obtain a compound (32 mg, 47%).
1H NMR (600 MHz, DMSO- d6) δ 12.60 (s, 1H), 7.47 (d, 4H, J = 7.0 Hz), 7.40 (d, 1H, J = 5.9 Hz), 7.27 (d, 1H, J = 7.7 Hz), 7.18 (m, 2H), 5.39 (s, 2H), 3.53 (d, 2H, J = 10.7 Hz), 2.91 (t, 2H, J = 10.6 Hz), 2.42 (s, 1H), 1.96 (d, 2H, J = 11.0 Hz), 1.66 (d, 2H, J = 10.5 Hz). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.60 (s, 1H), 7.47 (d, 4H, J = 7.0 Hz), 7.40 (d, 1H, J = 5.9 Hz), 7.27 (d, 1H, J = 7.7 Hz), 7.18 (m, 2H), 5.39 (s, 2H), 3.53 (d, 2H, J = 10.7 Hz), 2.91 (t, 2H, J = 10.6 Hz), 2.42 (s, 1H), 1.96 (d, 2H, J = 11.0 Hz), 1.66 (d, 2H, J = 10.5 Hz).
[실시예 29][Example 29]
1-(3-메톡시벤질)-11-(3-methoxybenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민 ]Imidazol-2-amine
Figure PCTKR2020016038-appb-img-000039
Figure PCTKR2020016038-appb-img-000039
1 H-벤조[ d]이미다졸-2-아민(0.1 g, 0.8 mmol)의 THF (6 mL) 혼합 용액에 K 2CO 3 (0.3 g, 2.3 mmol) 및 1-(브로모메틸)-3-메톡시벤젠(0.1 mL, 0.8 mmol)을 첨가하였다. 0 ℃에서 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH 4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(MeOH / CH 2Cl 2 = 1 : 15) 상에서 플래시 컬럼 크로마토그래피로 정제하여 1-(3-메톡시벤질)-1 H-벤조[ d]이미다졸-2-아민을 수득하였다(81 mg, 43%).In a mixed solution of 1 H -benzo[ d ]imidazol-2-amine (0.1 g, 0.8 mmol) in THF (6 mL), K 2 CO 3 (0.3 g, 2.3 mmol) and 1-(bromomethyl)-3 -Methoxybenzene (0.1 mL, 0.8 mmol) was added. After stirring at 0° C. overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with a saturated aqueous NH 4 Cl solution and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH / CH 2 Cl 2 = 1: 15) to 1-(3-methoxybenzyl)-1 H -benzo[ d ]imidazol-2-amine. Was obtained (81 mg, 43%).
1H NMR (600 MHz, DMSO- d6) δ 7.22 (t, 1H, J = 7.9 Hz), 7.15 (d, 1H, J = 7.6 Hz), 7.06 (d, 1H, J = 7.7 Hz), 6.93 (m, 1H), 6.83 (m, 2H), 6.79 (m, 1H), 6.74 (m, 1H), 6.59 (s, 2H), 5.23 (s, 2H), 3.69 (s, 3H). 13C{ 1H} NMR (150 MHz, DMSO- d6) δ 159.3, 155.0, 142.8, 138.8, 134.2, 129.7, 120.5, 119.1, 118.1, 114.7, 113.2, 112.2, 107.9, 55.0, 44.6 1 H NMR (600 MHz, DMSO- d6 ) δ 7.22 (t, 1H, J = 7.9 Hz), 7.15 (d, 1H, J = 7.6 Hz), 7.06 (d, 1H, J = 7.7 Hz), 6.93 ( m, 1H), 6.83 (m, 2H), 6.79 (m, 1H), 6.74 (m, 1H), 6.59 (s, 2H), 5.23 (s, 2H), 3.69 (s, 3H). 13 C{ 1 H} NMR (150 MHz, DMSO- d6 ) δ 159.3, 155.0, 142.8, 138.8, 134.2, 129.7, 120.5, 119.1, 118.1, 114.7, 113.2, 112.2, 107.9, 55.0, 44.6
[실시예 30][Example 30]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(1-(3-메톡시벤질)-1-(1-(3-methoxybenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000040
Figure PCTKR2020016038-appb-img-000040
1-(3-메톡시벤질)-1 H-벤조[ d]이미다졸-2-아민(34 mg, 0.1 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(32 mg, 0.1 mmol), EDCI (0.1 g, 0.7 mmol), HOBt (18 mg, 0.1 mmol), 및 DMAP (3 mg, 0.3 mmol)를 첨가하였다. DIPEA (0.1 mL, 0.8 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 이틀동안 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc / CH 2Cl 2 = 1 : 4) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(31 mg, 51%).1-(3-methoxybenzyl)-1 H -benzo[ d ]imidazol-2-amine (34 mg, 0.1 mmol) in a CH 2 Cl 2 solution (2 mL) of 1-( N , N -dimethylsulfa Moyl) piperidine-4-carboxylic acid (32 mg, 0.1 mmol), EDCI (0.1 g, 0.7 mmol), HOBt (18 mg, 0.1 mmol), and DMAP (3 mg, 0.3 mmol) were added. DIPEA (0.1 mL, 0.8 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred for two days. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc / CH 2 Cl 2 = 1: 4) to obtain a compound (31 mg, 51%).
1H NMR (600 MHz, DMSO- d6) δ 12.57 (s, 1H), 7.46 (d, 1H, J = 3.0 Hz), 7.39 (d, 1H, J = 2.9 Hz), 7.22 (t, 1H, J = 7.8 Hz), 7.16 (d, 2H, J = 2.9 Hz), 6.99 (s, 1H), 6.91 (d, 1H, J = 7.4 Hz), 6.82 (d, 1H, J = 6.7 Hz), 5.29 (s, 2H), 3.69 (s, 3H), 3.52 (d, 2H, J = 12.1 Hz), 2.91 (t, 2H, J = 11.0 Hz), 2.72 (s, 6H), 2.42 (t, 1H, J = 10.7 Hz), 1.96 (d, 2H, J = 15.4 Hz), 1.67(m, 2H). 1 H NMR (600 MHz, DMSO- d6 ) δ 12.57 (s, 1H), 7.46 (d, 1H, J = 3.0 Hz), 7.39 (d, 1H, J = 2.9 Hz), 7.22 (t, 1H, J = 7.8 Hz), 7.16 (d, 2H, J = 2.9 Hz), 6.99 (s, 1H), 6.91 (d, 1H, J = 7.4 Hz), 6.82 (d, 1H, J = 6.7 Hz), 5.29 ( s, 2H), 3.69 (s, 3H), 3.52 (d, 2H, J = 12.1 Hz), 2.91 (t, 2H, J = 11.0 Hz), 2.72 (s, 6H), 2.42 (t, 1H, J = 10.7 Hz), 1.96 (d, 2H, J = 15.4 Hz), 1.67 (m, 2H).
[실시예 31][Example 31]
NN -(1-(3-아미노-4-메틸벤질)-1-(1-(3-amino-4-methylbenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(]Imidazol-2-yl)-1-( NN ,, NN -디메틸술파모일)피페리딘-4-카르복스아미드-Dimethylsulfamoyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000041
Figure PCTKR2020016038-appb-img-000041
1-(3-아미노-4-메틸벤질)-1 H-벤조[ d]이미다졸-2-아민(0.01 g, 0.04 mmol)의 CH 2Cl 2 용액(1 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.01 g, 0.04 mmol), EDCI (0.04 g, 0.22 mmol), HOBt (0.01 g, 0.04 mmol), 및 DMAP (1 mg, 0.01 mmol)를 첨가하였다. DIPEA (0.05 mL, 0.26 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/CH 2Cl 2 = 1 : 4) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(8 mg, 38%).1-(3-amino-4-methylbenzyl)-1 H -benzo[ d ]imidazol-2-amine (0.01 g, 0.04 mmol) in CH 2 Cl 2 solution (1 mL) of 1-( N , N -Dimethylsulfamoyl)piperidine-4-carboxylic acid (0.01 g, 0.04 mmol), EDCI (0.04 g, 0.22 mmol), HOBt (0.01 g, 0.04 mmol), and DMAP (1 mg, 0.01 mmol) Added. DIPEA (0.05 mL, 0.26 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/CH 2 Cl 2 = 1: 4) to give a compound (8 mg, 38%).
1H NMR (600 MHz, DMSO- d 6) δ 12.56 (s, 1H), 7.46 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.84 (d, 1H, J = 7.1 Hz), 6.49 (m, 2H), 5.17 (s, 2H), 4.82 (s, 2H), 3.55 (d, 2H, J = 11.3 Hz), 2.92 (t, 2H, J = 11.1 Hz), 2.74 (s, 6H), 2.43 (s, 1H), 1.97 (s, 5H), 1.65 (m, 2H). 13C NMR (150 MHz, DMSO- d 6) δ 183.6, 152.3, 146.7, 134.5, 130.0, 128.9, 122.4, 120.4, 115.2, 112.5, 111.8, 109.9, 45.8, 44.3, 37.9, 28.7, 17.1. 1 H NMR (600 MHz, DMSO- d 6 ) δ 12.56 (s, 1H), 7.46 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.84 (d, 1H, J = 7.1 Hz), 6.49 (m, 2H), 5.17 (s, 2H), 4.82 (s, 2H), 3.55 (d, 2H, J = 11.3 Hz), 2.92 (t, 2H, J = 11.1 Hz), 2.74 ( s, 6H), 2.43 (s, 1H), 1.97 (s, 5H), 1.65 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6 ) δ 183.6, 152.3, 146.7, 134.5, 130.0, 128.9, 122.4, 120.4, 115.2, 112.5, 111.8, 109.9, 45.8, 44.3, 37.9, 28.7, 17.1.
[실시예 32][Example 32]
terttert -부틸 4-((1-(3-(트리플루오로메톡시)벤질)-1-Butyl 4-((1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000042
Figure PCTKR2020016038-appb-img-000042
1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민(0.10 g, 0.33 mmol)의 CH 2Cl 2 용액(6 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.11 g, 0.49 mmol), EDCI (0.3 g, 1.63 mmol), HOBt (0.04 g, 0.33 mmol), 및 DMAP (0.01 g, 0.07 mmol)를 첨가하였다. DIPEA (0.34 mL, 1.95 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(140 mg, 82%).1- (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] 1 - (tert-imidazol-2-amine in CH 2 Cl 2 solution (6 mL) of (0.10 g, 0.33 mmol) - Butoxycarbonyl) piperidine-4-carboxylic acid (0.11 g, 0.49 mmol), EDCI (0.3 g, 1.63 mmol), HOBt (0.04 g, 0.33 mmol), and DMAP (0.01 g, 0.07 mmol) Added. DIPEA (0.34 mL, 1.95 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (140 mg, 82%).
1H NMR (500 MHz, CDCl 3) δ 7.37 (m, 5H), 7.23 (s, 2H), 7.16 (m, 1H), 5.60 (s, 2H), 4.11 (s, 2H), 2.86 (s, 3H), 1.99 (d, 2H, J = 11.9 Hz), 1.69 (d, 2H, J = 12.3 Hz), 1.46 (s, 9H); HRMS (EI): mass calcd for C 26H 29F 3N 4O 4 [M+H] +, 518.2141; found, 518.2138. 1 H NMR (500 MHz, CDCl 3 ) δ 7.37 (m, 5H), 7.23 (s, 2H), 7.16 (m, 1H), 5.60 (s, 2H), 4.11 (s, 2H), 2.86 (s, 3H), 1.99 (d, 2H, J = 11.9 Hz), 1.69 (d, 2H, J = 12.3 Hz), 1.46 (s, 9H); HRMS (EI): mass calcd for C 26 H 29 F 3 N 4 O 4 [M+H] + , 518.2141; found, 518.2138.
[실시예 33][Example 33]
1-(이소프로필설포닐)-1-(isopropylsulfonyl)- NN -(1-(3-(트리플루오로메톡시)벤질)-1-(1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000043
Figure PCTKR2020016038-appb-img-000043
tert-부틸 4-((1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트(0.03 g, 0.06 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.01 mL, 0.09 mmol)과 DIPEA (0.02 mL, 0.12 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(21 mg, 30%). tert -butyl 4-((1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate (0.03 g, 0.06 mmol) of CH 2 Cl 2 solution (2 mL) was added TFA (excess). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.01 mL, 0.09 mmol) and DIPEA (0.02 mL, 0.12 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (21 mg, 30%).
1H NMR (400 MHz, CDCl 3) δ 7.35 (t, 1H, J = 7.9 Hz), 7.28 (d, 1H, J = 6.0 Hz), 7.17 (m, 6H), 5.33 (s, 2H), 3.81 (m, 2H), 3.18 (m, 1H), 3.00 (m, 2H), 2.52 (m, 1H), 2.06 (m, 2H), 1.86 (m, 2H), 1.34 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 24H 27F 3N 4O 4S [M+H] +, 524.1705; found, 524.1708. 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (t, 1H, J = 7.9 Hz), 7.28 (d, 1H, J = 6.0 Hz), 7.17 (m, 6H), 5.33 (s, 2H), 3.81 (m, 2H), 3.18 (m, 1H), 3.00 (m, 2H), 2.52 (m, 1H), 2.06 (m, 2H), 1.86 (m, 2H), 1.34 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 24 H 27 F 3 N 4 O 4 S [M+H] + , 524.1705; found, 524.1708.
[실시예 34][Example 34]
1-((6-메틸피리딘-2-일)메틸)-11-((6-methylpyridin-2-yl)methyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민]Imidazol-2-amine
Figure PCTKR2020016038-appb-img-000044
Figure PCTKR2020016038-appb-img-000044
1H-벤조[ d]이미다졸-2-아민(0.2 g, 1.13 mmol)의 THF (6 mL) 혼합 용액에 K2CO3 (0.3 g, 2.3 mmol) 및 2-(브로모메틸)-6-메틸 피리딘(0.1 mL, 0.8 mmol)을 첨가하였다. 0 ℃에서 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na2SO4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(MeOH / CH2Cl2 = 1 : 15) 상에서 플래시 컬럼 크로마토그래피로 정제하여1-((6-메틸피리딘-2-일)메틸)-1H-벤조[d]이미다졸-2-아민을 수득하였다(63 mg, 40%).In a mixed solution of 1H-benzo[ d ]imidazol-2-amine (0.2 g, 1.13 mmol) in THF (6 mL), K2CO3 (0.3 g, 2.3 mmol) and 2-(bromomethyl)-6-methyl pyridine ( 0.1 mL, 0.8 mmol) was added. After stirring at 0° C. overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with saturated aqueous NH4Cl and distilled water, and water molecules were removed with anhydrous Na2SO4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH / CH2Cl2 = 1: 15) to obtain 1-((6-methylpyridin-2-yl)methyl)-1H-benzo[d]imidazole-2. -Amine was obtained (63 mg, 40%).
1H NMR (600 MHz, MeOD) δ 7.56 (t, 1H, J = 7.7 Hz), 7.26 (d, 1H, J = 8.0 Hz), 7.13 (d, 1H, J = 7.7 Hz), 7.04 (m, 1H), 6.96 (m, 1H), 6.83 (d, 1H, J = 7.8 Hz), 5.25 (s, 2H). 13C NMR (150 MHz, MeOD) δ 159.7, 156.5, 156.4, 142.2, 139.2, 135.0, 123.8, 122.8, 121.0, 119.5, 116.0, 109.1, 48.3, 24.1. 1 H NMR (600 MHz, MeOD) δ 7.56 (t, 1H, J = 7.7 Hz), 7.26 (d, 1H, J = 8.0 Hz), 7.13 (d, 1H, J = 7.7 Hz), 7.04 (m, 1H), 6.96 (m, 1H), 6.83 (d, 1H, J = 7.8 Hz), 5.25 (s, 2H). 13 C NMR (150 MHz, MeOD) δ 159.7, 156.5, 156.4, 142.2, 139.2, 135.0, 123.8, 122.8, 121.0, 119.5, 116.0, 109.1, 48.3, 24.1.
[실시예 35][Example 35]
terttert -부틸 4-((1-(3-메틸벤질)-1-Butyl 4-((1-(3-methylbenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000045
Figure PCTKR2020016038-appb-img-000045
1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-아민 (0.10 g, 0.42 mmol)의 CH 2Cl 2 용액(6 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.15 g, 0.63 mmol), EDCI (0.40 g, 2.11 mmol), HOBt (0.06 g, 0.42 mmol), 및 DMAP (0.01 g, 0.08 mmol)를 첨가하였다. DIPEA (0.44 mL, 2.53 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(150 mg, 80%).1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-amine (0.10 g, 0.42 mmol) in a CH 2 Cl 2 solution (6 mL) of 1-( tert -butoxycarbonyl) Piperidine-4-carboxylic acid (0.15 g, 0.63 mmol), EDCI (0.40 g, 2.11 mmol), HOBt (0.06 g, 0.42 mmol), and DMAP (0.01 g, 0.08 mmol) were added. DIPEA (0.44 mL, 2.53 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (150 mg, 80%).
1H NMR (500 MHz, CDCl 3) δ 7.33 (d, 1H, J = 7.2 Hz), 7.20 (m, 5H), 7.10 (m, 2H), 5.47 (s, 2H), 4.12 (d, 2H, J = 7.2 Hz), 2.86 (s, 1H), 2.31 (s, 3H), 2.00 (d, 2H, J = 13.3 Hz), 1.72 (m, 2H), 1.46 (s, 9H); HRMS (EI): mass calcd for C 26H 32N 4O 3 [M+H] +, 448.2474; found, 448.2470. 1 H NMR (500 MHz, CDCl 3 ) δ 7.33 (d, 1H, J = 7.2 Hz), 7.20 (m, 5H), 7.10 (m, 2H), 5.47 (s, 2H), 4.12 (d, 2H, J = 7.2 Hz), 2.86 (s, 1H), 2.31 (s, 3H), 2.00 (d, 2H, J = 13.3 Hz), 1.72 (m, 2H), 1.46 (s, 9H); HRMS (EI): mass calcd for C 26 H 32 N 4 O 3 [M+H] + , 448.2474; found, 448.2470.
[실시예 36][Example 36]
1-(이소프로필설포닐)-1-(isopropylsulfonyl)- NN -(1-(3-메틸벤질)-1-(1-(3-methylbenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000046
Figure PCTKR2020016038-appb-img-000046
tert-부틸 4-((1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트(0.03 g, 0.07 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.01 mL, 0.1 mmol)과 DIPEA (0.02 mL, 0.13 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(22 mg, 74%). tert -Butyl 4-((1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate (0.03 g, 0.07 mmol) TFA (excess) was added to a solution of CH 2 Cl 2 (2 mL). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.01 mL, 0.1 mmol) and DIPEA (0.02 mL, 0.13 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (22 mg, 74%).
1H NMR (400 MHz, CDCl 3) δ 7.24 (s, 1H), 7.12 (m, 7H), 5.27 (s, 2H), 3.78 (m, 2H), 3.16 (m, 1H), 3.00 (m, 2H), 2.52 (m, 1H), 2.29 (s, 3H), 2.05 (m, 3H), 1.87 (m, 2H), 1.32 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 24H 30N 4O 3S [M+H] +, 454.2039; found, 454.2035. 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 (s, 1H), 7.12 (m, 7H), 5.27 (s, 2H), 3.78 (m, 2H), 3.16 (m, 1H), 3.00 (m, 2H), 2.52 (m, 1H), 2.29 (s, 3H), 2.05 (m, 3H), 1.87 (m, 2H), 1.32 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 24 H 30 N 4 O 3 S [M+H] + , 454.2039; found, 454.2035.
[실시예 37][Example 37]
terttert -부틸 4-((1-(피리딘-3-일메틸)-1-Butyl 4-((1-(pyridin-3-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000047
Figure PCTKR2020016038-appb-img-000047
1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-아민(0.10 g, 0.45 mmol)의 CH 2Cl 2 용액(6 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.16 g, 0.68 mmol), EDCI (0.43 g, 2.25 mmol), HOBt (0.06 g, 0.45 mmol), 및 DMAP (0.01 g, 0.09 mmol)를 첨가하였다. DIPEA (0.47 mL, 2.70 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(130 mg, 66%).1-(pyridin-3-ylmethyl)-1 H -benzo[ d ]imidazol-2-amine (0.10 g, 0.45 mmol) in a CH 2 Cl 2 solution (6 mL) of 1-( tert -butoxycar) Bonyl) piperidine-4-carboxylic acid (0.16 g, 0.68 mmol), EDCI (0.43 g, 2.25 mmol), HOBt (0.06 g, 0.45 mmol), and DMAP (0.01 g, 0.09 mmol) were added. DIPEA (0.47 mL, 2.70 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (130 mg, 66%).
1H NMR (600 MHz, MeOD) δ 8.64 (s, 1H), 8.42 (m, 1H), 7.84 (s, 1H), 7.42 (m, 3H), 7. 24 (m, 2H), 5.46 (s, 2H), 4.07 (d, 2H, J = 13.1 Hz), 2.88 (s, 2H), 2.56 (s, 1H), 1.93 (s, 2H), 1.67 (s, 2H), 1.46 (d, 9H, J = 3.0 Hz); HRMS (EI): mass calcd for C 24H 29N 5O 3 [M+H] +, 435.2270; found, 435.2275. 1 H NMR (600 MHz, MeOD) δ 8.64 (s, 1H), 8.42 (m, 1H), 7.84 (s, 1H), 7.42 (m, 3H), 7.24 (m, 2H), 5.46 (s , 2H), 4.07 (d, 2H, J = 13.1 Hz), 2.88 (s, 2H), 2.56 (s, 1H), 1.93 (s, 2H), 1.67 (s, 2H), 1.46 (d, 9H, J = 3.0 Hz); HRMS (EI): mass calcd for C 24 H 29 N 5 O 3 [M+H] + , 435.2270; found, 435.2275.
[실시예 38][Example 38]
1-(이소프로필설포닐)-1-(isopropylsulfonyl)- NN -(1-(피리딘-3-일메틸)-1-(1-(pyridin-3-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000048
Figure PCTKR2020016038-appb-img-000048
tert-부틸 4-((1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트(0.03 g, 0.07 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.01 mL, 0.1 mmol)과 DIPEA (0.02 mL, 0.14 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(18 mg, 58%). tert -Butyl 4-((1-(pyridin-3-ylmethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate (0.03 g, 0.07 mmol) CH 2 Cl 2 solution (2 mL) was added TFA (excess). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.01 mL, 0.1 mmol) and DIPEA (0.02 mL, 0.14 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (18 mg, 58%).
1H NMR (600 MHz, MeOD) δ 8.60 (s, 1H), 8.46 (m, 1H), 7.79 (d, 1H, J = 7.8 Hz), 7.49 (m, 1H), 7.40 (m, 2H), 7.26 (m, 2H), 5.46 (s, 2H), 3.79 (m, 2H), 2.99 (m, 2H), 2.55 (m, 1H), 1.99 (m, 2H), 1.80 (m, 2H), 1.30 (d, 6H, J = 6.8 Hz) ; HRMS (EI): mass calcd for C 22H 27N 5O 3S [M+H] +, 441.1835; found, 441.1835. 1 H NMR (600 MHz, MeOD) δ 8.60 (s, 1H), 8.46 (m, 1H), 7.79 (d, 1H, J = 7.8 Hz), 7.49 (m, 1H), 7.40 (m, 2H), 7.26 (m, 2H), 5.46 (s, 2H), 3.79 (m, 2H), 2.99 (m, 2H), 2.55 (m, 1H), 1.99 (m, 2H), 1.80 (m, 2H), 1.30 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 22 H 27 N 5 O 3 S [M+H] + , 441.1835; found, 441.1835.
[실시예 39][Example 39]
1-(티아졸-4-일메틸)-11-(thiazol-4-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-아민]Imidazol-2-amine
Figure PCTKR2020016038-appb-img-000049
Figure PCTKR2020016038-appb-img-000049
1H-벤조[d]이미다졸-2-아민(0.2 g, 1.13 mmol)의 THF (6 mL) 혼합 용액에 K2CO3 (0.3 g, 2.3 mmol) 및 4- (브로 모 메틸) 티아 졸(0.1 mL, 0.8 mmol)을 첨가하였다. 0 ℃에서 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na2SO4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(MeOH / CH2Cl2 = 1 : 15) 상에서 플래시 컬럼 크로마토그래피로 정제하여 1-(티아졸-4-일메틸)-1H-벤조[d]이미다졸-2-아민을 수득하였다(102 mg, 51%).In a mixed solution of 1H-benzo[d]imidazol-2-amine (0.2 g, 1.13 mmol) in THF (6 mL), K2CO3 (0.3 g, 2.3 mmol) and 4- (bromomethyl) thiazole (0.1 mL, 0.8 mmol) was added. After stirring at 0° C. overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with saturated aqueous NH4Cl and distilled water, and then water molecules were removed with anhydrous Na2SO4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (MeOH / CH2Cl2 = 1: 15) to give 1-(thiazol-4-ylmethyl)-1H-benzo[d]imidazol-2-amine. (102 mg, 51%).
1H NMR (600 MHz, MeOD) δ 8.92 (d, 1H, J = 2.0 Hz), 7.30 (m, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.96 (m, 1H), 5.33 (d, 2H, J = 0.9 Hz. 13C NMR (150 MHz, MeOD) δ 156.2, 156.0, 153.3, 142.4, 134.9, 122.7, 120.9, 117.6, 116.0, 109.2, 42.8. 1 H NMR (600 MHz, MeOD) δ 8.92 (d, 1H, J = 2.0 Hz), 7.30 (m, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.96 (m, 1H), 5.33 (d, 2H, J = 0.9 Hz. 13 C NMR (150 MHz, MeOD) δ 156.2, 156.0, 153.3, 142.4, 134.9, 122.7, 120.9, 117.6, 116.0, 109.2, 42.8.
[실시예 40][Example 40]
terttert -부틸 4-((1-(티아졸-4-일메틸)-1-Butyl 4-((1-(thiazol-4-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000050
Figure PCTKR2020016038-appb-img-000050
1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-아민(0.03 g, 0.14 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.05 g, 0.21 mmol), EDCI (0.13 g, 0.70 mmol), HOBt (0.02 g, 0.14 mmol), 및 DMAP (0.004 g, 0.03 mmol)를 첨가하였다. DIPEA (0.15 mL, 0.84 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(33 mg, 53%).1-(thiazol-4-ylmethyl)-1 H -benzo[ d ]imidazol-2-amine (0.03 g, 0.14 mmol) in CH 2 Cl 2 solution (2 mL) of 1-( tert -butoxy Carbonyl) piperidine-4-carboxylic acid (0.05 g, 0.21 mmol), EDCI (0.13 g, 0.70 mmol), HOBt (0.02 g, 0.14 mmol), and DMAP (0.004 g, 0.03 mmol) were added. . DIPEA (0.15 mL, 0.84 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (33 mg, 53%).
1H NMR (600 MHz, CDCl 3) δ 8.76 (d, 1H, J = 2.1 Hz), 7.35 (m, 1H), 7.22 (m, 4H), 5.50 (s, 2H), 4.10 (s, 2H), 2.84 (s, 2H), 2.54 (m, 1H), 1.96 (m, 2H), 1.71 (m, 2H), 1.46 (s, 9H). 13C NMR (150 MHz, CDCl 3) δ 186.8, 155.0, 153.4, 151.9, 129.3, 128.4, 123.3, 123.3, 116.9, 111.3, 110.2, 79.4, 46.2, 44.1, 43.4, 41.6, 29.3, 28.6, 28.5; HRMS (EI): mass calcd for C 22H 27N 5O 3S [M+H] +, 441.1835; found, 441.1832. 1 H NMR (600 MHz, CDCl 3 ) δ 8.76 (d, 1H, J = 2.1 Hz), 7.35 (m, 1H), 7.22 (m, 4H), 5.50 (s, 2H), 4.10 (s, 2H) , 2.84 (s, 2H), 2.54 (m, 1H), 1.96 (m, 2H), 1.71 (m, 2H), 1.46 (s, 9H). 13 C NMR (150 MHz, CDCl 3 ) δ 186.8, 155.0, 153.4, 151.9, 129.3, 128.4, 123.3, 123.3, 116.9, 111.3, 110.2, 79.4, 46.2, 44.1, 43.4, 41.6, 29.3, 28.6, 28.5; HRMS (EI): mass calcd for C 22 H 27 N 5 O 3 S [M+H] + , 441.1835; found, 441.1832.
[실시예 41] [Example 41]
1-(이소프로필설포닐)-1-(isopropylsulfonyl)- NN -(1-(티아졸-4-일메틸)-1-(1-(thiazol-4-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000051
Figure PCTKR2020016038-appb-img-000051
tert-부틸 4-((1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트(0.03 g, 0.07 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.1 mL, 0.01 mmol)과 DIPEA (0.02 mL, 0.14 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(16 mg, 53%). tert -butyl 4-((1-(thiazol-4-ylmethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate (0.03 g, 0.07 mmol) of CH 2 Cl 2 solution (2 mL) was added TFA (excess). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.1 mL, 0.01 mmol) and DIPEA (0.02 mL, 0.14 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (16 mg, 53%).
1H NMR (600 MHz, CDCl 3) δ 8.77 (d, 1H, J = 2.0 Hz), 7.37 (m, 1H), 7.28 (m, 1H), 7.22 (m, 3H), 5.50 (s, 2H), 3.82 (m, 2H), 3.19 (m, 1H), 3.01 (m, 2H), 2.53 (m, 1H), 2.06 (m, 2H), 1.87 (m, 2H), 1.34 (d, 6H, J = 6.9 Hz). 13C NMR (150 MHz, CDCl 3) δ 186.2, 153.5, 151.8, 129.3, 128.3, 123.5, 123.4, 116.9, 111.3, 110.3, 53.3, 46.3, 45.5, 41.7, 29.7, 17.0; HRMS (EI): mass calcd for C 20H 25N 5O 3S 2 [M+H] +, 447.1399; found, 447.1399. 1 H NMR (600 MHz, CDCl 3 ) δ 8.77 (d, 1H, J = 2.0 Hz), 7.37 (m, 1H), 7.28 (m, 1H), 7.22 (m, 3H), 5.50 (s, 2H) , 3.82 (m, 2H), 3.19 (m, 1H), 3.01 (m, 2H), 2.53 (m, 1H), 2.06 (m, 2H), 1.87 (m, 2H), 1.34 (d, 6H, J = 6.9 Hz). 13 C NMR (150 MHz, CDCl 3 ) δ 186.2, 153.5, 151.8, 129.3, 128.3, 123.5, 123.4, 116.9, 111.3, 110.3, 53.3, 46.3, 45.5, 41.7, 29.7, 17.0; HRMS (EI): mass calcd for C 20 H 25 N 5 O 3 S 2 [M+H] + , 447.1399; found, 447.1399.
[실시예 42][Example 42]
1-(One-( NN ,, NN -디메틸술파모일)--Dimethylsulfamoyl)- NN -(1-(티아졸-4-일메틸)-1-(1-(thiazol-4-ylmethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000052
Figure PCTKR2020016038-appb-img-000052
1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-아민(0.05 g, 0.22 mmol)의 CH 2Cl 2 용액(1 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.5 g, 0.22 mmol), EDCI (0.21 g, 1.10 mmol), HOBt (0.03 g, 0.22 mmol), 및 DMAP (0.01 g, 0.04 mmol)를 첨가하였다. DIPEA (0.23 mL, 1.32 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2.5 : 0.1)상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(40 mg, 40%).1-(thiazol-4-ylmethyl)-1 H -benzo[ d ]imidazol-2-amine (0.05 g, 0.22 mmol) in CH 2 Cl 2 solution (1 mL) of 1-( N , N- Dimethylsulfamoyl) piperidine-4-carboxylic acid (0.5 g, 0.22 mmol), EDCI (0.21 g, 1.10 mmol), HOBt (0.03 g, 0.22 mmol), and DMAP (0.01 g, 0.04 mmol) were added. I did. DIPEA (0.23 mL, 1.32 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2.5: 0.1) to give a compound (40 mg, 40%).
1H NMR (600 MHz, CDCl 3) δ 8.77 (d, 1H, J = 2.0 Hz), 7.40 (m, 1H), 7.32 (s, 1H), 7.29 (m, 1H), 7.24 (m, 2H), 5.56 (s, 2H), 3.71 (m, 2H), 2.93 (m, 2H), 2.82 (s, 6H), 2.58 (s, 1H), 2.07 (m, 2H), 1.86 (m, 2H). 13C NMR (150 MHz, CDCl 3) δ 153.5, 151.7, 129.3, 128.2, 123.6, 123.6, 117.1, 111.4, 110.5, 46.3, 45.2, 41.8, 38.4, 29.0. 1 H NMR (600 MHz, CDCl 3 ) δ 8.77 (d, 1H, J = 2.0 Hz), 7.40 (m, 1H), 7.32 (s, 1H), 7.29 (m, 1H), 7.24 (m, 2H) , 5.56 (s, 2H), 3.71 (m, 2H), 2.93 (m, 2H), 2.82 (s, 6H), 2.58 (s, 1H), 2.07 (m, 2H), 1.86 (m, 2H). 13 C NMR (150 MHz, CDCl 3 ) δ 153.5, 151.7, 129.3, 128.2, 123.6, 123.6, 117.1, 111.4, 110.5, 46.3, 45.2, 41.8, 38.4, 29.0.
[실시예 43][Example 43]
terttert -부틸 4-((1-((6-메틸피리딘-2-일)메틸)-1-Butyl 4-((1-((6-methylpyridin-2-yl)methyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000053
Figure PCTKR2020016038-appb-img-000053
1-((6-메틸피리딘-2-일메틸)-1 H-벤조[ d]이미다졸-2-아민(0.04 g, 0.17 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.06 g, 0.26 mmol), EDCI (0.16 g, 0.85 mmol), HOBt (0.02 g, 0.17 mmol), 및 DMAP (4 mg, 0.03 mmol)를 첨가하였다. DIPEA (0.18 mL, 1.02 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(42 mg, 62%).1-((6-methylpyridin-2-ylmethyl)-1 H -benzo[ d ]imidazol-2-amine (0.04 g, 0.17 mmol) in CH 2 Cl 2 solution (2 mL) of 1-( tert -Butoxycarbonyl)piperidine-4-carboxylic acid (0.06 g, 0.26 mmol), EDCI (0.16 g, 0.85 mmol), HOBt (0.02 g, 0.17 mmol), and DMAP (4 mg, 0.03 mmol) DIPEA (0.18 mL, 1.02 mmol) was added to the reaction mixture at 0° C. The resulting mixture was warmed to room temperature and stirred overnight, The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was distilled water and brine. Thereafter, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound Was obtained (42 mg, 62%).
1H NMR (600 MHz, CDCl 3) δ 7.46 (t, 1H, J = 7.7 Hz,), 7.27 (s, 1H), 7.22 (m, 1H), 7.16 (m, 2H), 7.04 (d, 1H, J = 7.6 Hz), 6.87 (d, 1H, J = 7.7 Hz), 5.39 (s, 2H), 4.06 (s, 2H), 3.45 (s, 3H), 2.81 (s, 2H), 2.55 (s, 3H), 2.50 (s, 1H), 1.94 (d, 2H, J = 13.2 Hz), 1.69 (m, 2H), 1.44 (s, 9H). 13C NMR (150 MHz, CDCl 3) δ 186.6, 158.3, 155.0, 154.9, 153.5, 137.4, 129.6, 128.8, 123.2, 122.6, 118.6, 111.4, 110.3, 79.4, 50.6, 47.6, 46.1, 44.0, 43.3, 29.2, 28.7, 28.5, 28.5, 24.4; HRMS (EI): mass calcd for C 25H 31N 5O 3 [M+H] +, 449.2427; found, 449.2431. 1 H NMR (600 MHz, CDCl 3 ) δ 7.46 (t, 1H, J = 7.7 Hz,), 7.27 (s, 1H), 7.22 (m, 1H), 7.16 (m, 2H), 7.04 (d, 1H) , J = 7.6 Hz), 6.87 (d, 1H, J = 7.7 Hz), 5.39 (s, 2H), 4.06 (s, 2H), 3.45 (s, 3H), 2.81 (s, 2H), 2.55 (s , 3H), 2.50 (s, 1H), 1.94 (d, 2H, J = 13.2 Hz), 1.69 (m, 2H), 1.44 (s, 9H). 13 C NMR (150 MHz, CDCl 3 ) δ 186.6, 158.3, 155.0, 154.9, 153.5, 137.4, 129.6, 128.8, 123.2, 122.6, 118.6, 111.4, 110.3, 79.4, 50.6, 47.6, 46.1, 44.0, 43.3, 29.2 , 28.7, 28.5, 28.5, 24.4; HRMS (EI): mass calcd for C 25 H 31 N 5 O 3 [M+H] + , 449.2427; found, 449.2431.
[실시예 44][Example 44]
1-(이소프로필설포닐)-1-(isopropylsulfonyl)- NN -(1-((6-메틸피리딘-2-일)메틸)-1-(1-((6-methylpyridin-2-yl)methyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000054
Figure PCTKR2020016038-appb-img-000054
tert-부틸 4-((1-((6-메틸피리딘-2-일)메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트(0.04 g, 0.09 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.2 mL, 0.01 mmol)과 DIPEA (0.03 mL, 0.19 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(20 mg, 49%). tert -Butyl 4-((1-((6-methylpyridin-2-yl)methyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate TFA (excess) was added to (0.04 g, 0.09 mmol) of CH 2 Cl 2 solution (2 mL). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.2 mL, 0.01 mmol) and DIPEA (0.03 mL, 0.19 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (20 mg, 49%).
1H NMR (600 MHz, CDCl 3) δ 7.48 (t, 1H, J = 7.7 Hz), 7.28 (m, 2H), 7.20 (m, 2H), 7.06 (d, 1H, J = 7.6 Hz), 6.90 (d, 1H, J = 7.8 Hz), 5.44 (s, 2H), 3.80 (m, 2H), 3.17 (m, 1H), 3.00 (m, 2H), 2.56 (s, 4H), 2.05 (m, 2H), 1.85 (m, 2H), 1.33 (d, 6H, J = 6.8 Hz). 13C NMR (150 MHz, CDCl 3) δ 185.9, 158.4, 154.8, 153.5, 137.5, 129.6, 128.5, 123.4, 122.6, 118.6, 111.3, 110.5, 53.3, 47.7, 46.2, 45.3, 29.6, 24.5, 16.9; HRMS (EI): mass calcd for C 23H 29N 5O 3S [M+H] +, 455.1991; found, 455.1990. 1 H NMR (600 MHz, CDCl 3 ) δ 7.48 (t, 1H, J = 7.7 Hz), 7.28 (m, 2H), 7.20 (m, 2H), 7.06 (d, 1H, J = 7.6 Hz), 6.90 (d, 1H, J = 7.8 Hz), 5.44 (s, 2H), 3.80 (m, 2H), 3.17 (m, 1H), 3.00 (m, 2H), 2.56 (s, 4H), 2.05 (m, 2H), 1.85 (m, 2H), 1.33 (d, 6H, J = 6.8 Hz). 13 C NMR (150 MHz, CDCl 3 ) δ 185.9, 158.4, 154.8, 153.5, 137.5, 129.6, 128.5, 123.4, 122.6, 118.6, 111.3, 110.5, 53.3, 47.7, 46.2, 45.3, 29.6, 24.5, 16.9; HRMS (EI): mass calcd for C 23 H 29 N 5 O 3 S [M+H] + , 455.1991; found, 455.1990.
[실시예 45][Example 45]
terttert -부틸 4-((1-(2-(4-페닐피페라진-1-일)에틸)-1-Butyl 4-((1-(2-(4-phenylpiperazin-1-yl)ethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000055
Figure PCTKR2020016038-appb-img-000055
1-(2-(4-페닐피페라진-1-일)에틸)-1 H-벤조[ d]이미다졸-2-아민(0.02 g, 0.07 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.02 g, 0.07 mmol), EDCI (0.07 g, 0.37 mmol), HOBt (0.01 g, 0.07 mmol), 및 DMAP (0.002 g, 0.02 mmol)를 첨가하였다. DIPEA (0.18 mL, 1.02 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(23 mg, 59%).1-(2-(4-phenylpiperazin-1-yl)ethyl)-1 H -benzo[ d ]imidazol-2-amine (0.02 g, 0.07 mmol) in CH 2 Cl 2 solution (2 mL) 1-( tert -butoxycarbonyl)piperidine-4-carboxylic acid (0.02 g, 0.07 mmol), EDCI (0.07 g, 0.37 mmol), HOBt (0.01 g, 0.07 mmol), and DMAP (0.002 g , 0.02 mmol) was added. DIPEA (0.18 mL, 1.02 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (23 mg, 59%).
1H NMR (600 MHz, CDCl 3) δ 7.25 (m, 6H), 6.91 (d, 2H, J = 8.2 Hz), 6.88 (t, 1H, J = 7.2 Hz), 4.39 (s, 2H), 4.10 (s, 2H), 3.24 (s, 4H), 2.85 (s, 8H), 2.51 (s, 1H), 1.96 (d, 2H, J = 13.2 Hz), 1.71 (d, 2H, J = 10.7 Hz), 1.47 (s, 9H). 1 H NMR (600 MHz, CDCl 3 ) δ 7.25 (m, 6H), 6.91 (d, 2H, J = 8.2 Hz), 6.88 (t, 1H, J = 7.2 Hz), 4.39 (s, 2H), 4.10 (s, 2H), 3.24 (s, 4H), 2.85 (s, 8H), 2.51 (s, 1H), 1.96 (d, 2H, J = 13.2 Hz), 1.71 (d, 2H, J = 10.7 Hz) , 1.47 (s, 9H).
[실시예 46][Example 46]
1-(이소프로필설포닐)-1-(isopropylsulfonyl)- NN -(1-(2-(4-페닐피페라진-1-일)에틸)-1-(1-(2-(4-phenylpiperazin-1-yl)ethyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000056
Figure PCTKR2020016038-appb-img-000056
tert-부틸 4-((1-(2-(4-페닐피페라진-1-일)에틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트 (0.02 g, 0.04 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드 (0.01 mL, 0.06 mmol)과 DIPEA (0.02 mL, 0.08 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(10 mg, 44%). tert -Butyl 4-((1-(2-(4-phenylpiperazin-1-yl)ethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1- TFA (excess) was added to a CH 2 Cl 2 solution (2 mL) of carboxylate (0.02 g, 0.04 mmol). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.01 mL, 0.06 mmol) and DIPEA (0.02 mL, 0.08 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (10 mg, 44%).
1H NMR (600 MHz, CDCl 3) δ 7.26 (m, 6H), 6.92 (m, 2H), 6.86 (m, 1H), 4.30 (m, 2H), 3.83 (m, 2H), 3.18 (m, 5H), 3.03 (m, 2H), 2.82 (t, 2H, J = 6.8 Hz), 2.73 (t, 3H, J = 5.0 Hz), 2.67 (m, 1H), 2.50 (m, 1H), 2.07 (m, 2H), 1.88 (m, 2H), 1.36 (d, 6H, J = 6.8 Hz). 13C NMR (150 MHz, CDCl 3) δ 151.3, 129.3, 123.2, 123.1, 120.0, 116.2, 109.5, 62.0, 60.5, 56.8, 55.9, 53.5, 53.3, 49.2, 46.3, 45.7, 40.5, 39.8, 29.7, 28.5, 21.2, 17.0, 14.3. 1 H NMR (600 MHz, CDCl 3 ) δ 7.26 (m, 6H), 6.92 (m, 2H), 6.86 (m, 1H), 4.30 (m, 2H), 3.83 (m, 2H), 3.18 (m, 5H), 3.03 (m, 2H), 2.82 (t, 2H, J = 6.8 Hz), 2.73 (t, 3H, J = 5.0 Hz), 2.67 (m, 1H), 2.50 (m, 1H), 2.07 ( m, 2H), 1.88 (m, 2H), 1.36 (d, 6H, J = 6.8 Hz). 13 C NMR (150 MHz, CDCl 3 ) δ 151.3, 129.3, 123.2, 123.1, 120.0, 116.2, 109.5, 62.0, 60.5, 56.8, 55.9, 53.5, 53.3, 49.2, 46.3, 45.7, 40.5, 39.8, 29.7, 28.5 , 21.2, 17.0, 14.3.
[실시예 47][Example 47]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1-(6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000057
Figure PCTKR2020016038-appb-img-000057
5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민과 6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민 (0.03 g, 0.09 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.03 g, 0.14 mmol), EDCI (0.09 g, 0.45 mmol), HOBt (0.01 g, 0.09 mmol), 및 DMAP (2 mg, 0.02 mmol)를 첨가하였다. DIPEA (0.09 mL, 0.54 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(7.6 mg, 16%).5-Fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-amine and 6-fluoro-1-(3-(trifluoromethoxy)benzyl )-1 H -benzo[ d ]imidazol-2-amine (0.03 g, 0.09 mmol) in a CH 2 Cl 2 solution (2 mL) of 1-( N , N -dimethylsulfamoyl) piperidine-4- Carboxylic acid (0.03 g, 0.14 mmol), EDCI (0.09 g, 0.45 mmol), HOBt (0.01 g, 0.09 mmol), and DMAP (2 mg, 0.02 mmol) were added. DIPEA (0.09 mL, 0.54 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (7.6 mg, 16%).
1H NMR (400 MHz, CDCl 3) δ 7.38 (t, 1H, J = 7.9 Hz), 7.20 (m, 4H), 6.95 (m, 1H), 6.83 (m, 1H), 5.30 (s, 2H), 3.70 (d, 2H, J = 12.4 Hz), 2.92 (m, 2H), 2.82 (s, 6H), 2.51 (m, 1H), 2.06 (m, 2H), 1.85 (m, 2H); HRMS (EI): mass calcd for C 23H 25F 4N 5O 4S [M+H] +, 543.1563; found, 543.1563. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (t, 1H, J = 7.9 Hz), 7.20 (m, 4H), 6.95 (m, 1H), 6.83 (m, 1H), 5.30 (s, 2H) , 3.70 (d, 2H, J = 12.4 Hz), 2.92 (m, 2H), 2.82 (s, 6H), 2.51 (m, 1H), 2.06 (m, 2H), 1.85 (m, 2H); HRMS (EI): mass calcd for C 23 H 25 F 4 N 5 O 4 S [M+H] + , 543.1563; found, 543.1563.
[실시예 48][Example 48]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1-(5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000058
Figure PCTKR2020016038-appb-img-000058
5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민과 6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민 (0.03 g, 0.09 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.03 g, 0.14 mmol), EDCI (0.09 g, 0.45 mmol), HOBt (0.01 g, 0.09 mmol), 및 DMAP (2 mg, 0.02 mmol)를 첨가하였다. DIPEA (0.09 mL, 0.54 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다( mg, %).5-Fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-amine and 6-fluoro-1-(3-(trifluoromethoxy)benzyl )-1 H -benzo[ d ]imidazol-2-amine (0.03 g, 0.09 mmol) in a CH 2 Cl 2 solution (2 mL) of 1-( N , N -dimethylsulfamoyl) piperidine-4- Carboxylic acid (0.03 g, 0.14 mmol), EDCI (0.09 g, 0.45 mmol), HOBt (0.01 g, 0.09 mmol), and DMAP (2 mg, 0.02 mmol) were added. DIPEA (0.09 mL, 0.54 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (mg, %).
1H NMR (400 MHz, CDCl 3) δ 7.37 (t, 1H, J = 7.9 Hz), 7.22 (m, 2H), 7.16 (d, 1H, J = 8.3 Hz), 7.04 (m, 2H), 6.94 (m, 1H), 5.36 (s, 2H), 3.69 (m, 2H), 2.92 (m, 2H), 2.82 (d, 6H, J = 1.1 Hz), 2.56 (s, 1H), 2.06 (m, 2H), 1.85 (m, 2H) ); HRMS (EI): mass calcd for C 23H 25F 4N 5O 4S [M+H] +, 543.1563; found, 543.1563. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (t, 1H, J = 7.9 Hz), 7.22 (m, 2H), 7.16 (d, 1H, J = 8.3 Hz), 7.04 (m, 2H), 6.94 (m, 1H), 5.36 (s, 2H), 3.69 (m, 2H), 2.92 (m, 2H), 2.82 (d, 6H, J = 1.1 Hz), 2.56 (s, 1H), 2.06 (m, 2H), 1.85 (m, 2H) ); HRMS (EI): mass calcd for C 23 H 25 F 4 N 5 O 4 S [M+H] + , 543.1563; found, 543.1563.
[실시예 49][Example 49]
terttert -부틸 4-((6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1-Butyl 4-((6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000059
Figure PCTKR2020016038-appb-img-000059
5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민과 6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민(0.05 g, 0.14 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.05 g, 0.21 mmol), EDCI (0.13 g, 0.70 mmol), HOBt (0.02 g, 0.14 mmol), 및 DMAP (0.004 g, 0.03 mmol)를 첨가하였다. DIPEA (0.15 mL, 0.84 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(5 mg, 7%).5-Fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-amine and 6-fluoro-1-(3-(trifluoromethoxy)benzyl )-1 H -benzo[ d ]imidazol-2-amine (0.05 g, 0.14 mmol) in a CH 2 Cl 2 solution (2 mL) of 1-( tert -butoxycarbonyl) piperidine-4-car Acid (0.05 g, 0.21 mmol), EDCI (0.13 g, 0.70 mmol), HOBt (0.02 g, 0.14 mmol), and DMAP (0.004 g, 0.03 mmol) were added. DIPEA (0.15 mL, 0.84 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (5 mg, 7%).
1H NMR (600 MHz, CDCl 3) δ 7.37 (t, 1H, J = 8.1 Hz), 7.19 (m, 4H), 6.93 (m, 1H), 6.82 (m, 1H), 5.28 (s, 2H), 4.12 (m, 2H), 2.83 (s, 2H), 2.52 (m, 1H), 1.96 (d, 2H, J = 13.2 Hz), 1.70 (m, 2H), 1.46 (s, 9H) ; HRMS (EI): mass calcd for C 26H 28F 4N 4O 4 [M+H] +, 536.2047; found, 536.2046. 1 H NMR (600 MHz, CDCl 3 ) δ 7.37 (t, 1H, J = 8.1 Hz), 7.19 (m, 4H), 6.93 (m, 1H), 6.82 (m, 1H), 5.28 (s, 2H) , 4.12 (m, 2H), 2.83 (s, 2H), 2.52 (m, 1H), 1.96 (d, 2H, J = 13.2 Hz), 1.70 (m, 2H), 1.46 (s, 9H); HRMS (EI): mass calcd for C 26 H 28 F 4 N 4 O 4 [M+H] + , 536.2047; found, 536.2046.
[실시예 50][Example 50]
terttert -부틸 4-((5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1-Butyl 4-((5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000060
Figure PCTKR2020016038-appb-img-000060
5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민과 6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민(0.05 g, 0.14 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.05 g, 0.21 mmol), EDCI (0.13 g, 0.70 mmol), HOBt (0.02 g, 0.14 mmol), 및 DMAP (4 mg, 0.03 mmol)를 첨가하였다. DIPEA (0.15 mL, 0.84 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(6.4 mg, 9%).5-Fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-amine and 6-fluoro-1-(3-(trifluoromethoxy)benzyl )-1 H -benzo[ d ]imidazol-2-amine (0.05 g, 0.14 mmol) in a CH 2 Cl 2 solution (2 mL) of 1-( tert -butoxycarbonyl) piperidine-4-car Acid (0.05 g, 0.21 mmol), EDCI (0.13 g, 0.70 mmol), HOBt (0.02 g, 0.14 mmol), and DMAP (4 mg, 0.03 mmol) were added. DIPEA (0.15 mL, 0.84 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (6.4 mg, 9%).
1H NMR (600 MHz, CDCl 3) δ 7.36 (m, 1H), 7.23 (m, 2H), 7.16 (m, 1H), 7.03 (m, 2H), 6.93 (m, 1H), 5.36 (m, 2H), 4.09 (s, 2H), 2.84 (s, 2H), 2.60 (m, 1H), 1.96 (d, 2H, J = 13.4 Hz), 1.70 (m, 2H), 1.46 (d, 9H, J = 1.0 Hz) ); HRMS (EI): mass calcd for C 26H 28F 4N 4O 4 [M+H] +, 536.2047; found, 536.2046. 1 H NMR (600 MHz, CDCl 3 ) δ 7.36 (m, 1H), 7.23 (m, 2H), 7.16 (m, 1H), 7.03 (m, 2H), 6.93 (m, 1H), 5.36 (m, 2H), 4.09 (s, 2H), 2.84 (s, 2H), 2.60 (m, 1H), 1.96 (d, 2H, J = 13.4 Hz), 1.70 (m, 2H), 1.46 (d, 9H, J = 1.0 Hz)); HRMS (EI): mass calcd for C 26 H 28 F 4 N 4 O 4 [M+H] + , 536.2047; found, 536.2046.
[실시예 51][Example 51]
NN -(6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1-(6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(이소프로필술포닐)피페리딘-4-카르복스아미드]Imidazol-2-yl)-1-(isopropylsulfonyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000061
Figure PCTKR2020016038-appb-img-000061
tert-부틸 4-((6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트(0.02 g, 0.03 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.01 mL, 0.04 mmol)과 DIPEA (0.01 mL, 0.06 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2.5 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(2 mg, 11%). tert -Butyl 4-((6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1- TFA (excess) was added to a CH 2 Cl 2 solution (2 mL) of carboxylate (0.02 g, 0.03 mmol). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.01 mL, 0.04 mmol) and DIPEA (0.01 mL, 0.06 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2.5: 0.1) to obtain a compound (2 mg, 11%).
1H NMR (400 MHz, CDCl 3) δ 7.38 (t, 1H, J = 7.9 Hz), 7.23 (m, 3H), 7.17 (d, 1H, J = 8.1 Hz), 6.96 (m, 1H), 6.84 (m, 1H), 5.33 (s, 2H), 3.81 (m, 2H), 3.18 (m, 1H), 3.01 (m, 2H), 2.57 (s, 1H), 2.05 (m, 2H), 1.86 (m, 2H), 1.34 (d, 6H, J = 6.8 Hz) ; HRMS (EI): mass calcd for C 24H 26F 4N 4O 4S [M+H] +, 542.1611; found, 542.1607. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (t, 1H, J = 7.9 Hz), 7.23 (m, 3H), 7.17 (d, 1H, J = 8.1 Hz), 6.96 (m, 1H), 6.84 (m, 1H), 5.33 (s, 2H), 3.81 (m, 2H), 3.18 (m, 1H), 3.01 (m, 2H), 2.57 (s, 1H), 2.05 (m, 2H), 1.86 ( m, 2H), 1.34 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 24 H 26 F 4 N 4 O 4 S [M+H] + , 542.1611; found, 542.1607.
[실시예 52][Example 52]
NN -(5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1-(5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-1-(이소프로필술포닐)피페리딘-4-카르복스아미드]Imidazol-2-yl)-1-(isopropylsulfonyl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000062
Figure PCTKR2020016038-appb-img-000062
tert-부틸 4-((5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트(0.01 g, 0.03 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.01 mL, 0.04 mmol)과 DIPEA (0.01 mL, 0.05 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2.5 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(3 mg, 22%). tert -Butyl 4-((5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1- TFA (excess) was added to a CH 2 Cl 2 solution (2 mL) of carboxylate (0.01 g, 0.03 mmol). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.01 mL, 0.04 mmol) and DIPEA (0.01 mL, 0.05 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2.5: 0.1) to give a compound (3 mg, 22%).
1H NMR (400 MHz, CDCl 3) δ 7.38 (m, 1H), 7.19 (m, 3H), 7.00 (m, 3H), 5.37 (d, 2H, J = 11.6 Hz), 3.81 (m, 2H), 3.18 (m, 1H), 3.00 (m, 2H), 2.58 (s, 1H), 2.06 (m, 2H), 1.87 (m, 2H), 1.34 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 24H 26F 4N 4O 4S [M+H] +, 542.1611; found, 542.1607. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (m, 1H), 7.19 (m, 3H), 7.00 (m, 3H), 5.37 (d, 2H, J = 11.6 Hz), 3.81 (m, 2H) , 3.18 (m, 1H), 3.00 (m, 2H), 2.58 (s, 1H), 2.06 (m, 2H), 1.87 (m, 2H), 1.34 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 24 H 26 F 4 N 4 O 4 S [M+H] + , 542.1611; found, 542.1607.
[실시예 53][Example 53]
1-(One-( NN ,, NN -디메틸설파모일)--Dimethylsulfamoyl)- NN -(5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1-(5-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000063
Figure PCTKR2020016038-appb-img-000063
6-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민과 5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민(0.03 g, 0.09 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( N, N-디메틸설파모일)피페리딘-4-카르복실산(0.03 g, 0.14 mmol), EDCI (0.09 g, 0.45 mmol), HOBt (0.01 g, 0.09 mmol), 및 DMAP (0.002 g, 0.02 mmol)를 첨가하였다. DIPEA (0.09 mL, 0.54 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(10 mg, 20%).6-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-amine and 5-methoxy-1-(3-(trifluoromethoxy)benzyl )-1 H -benzo[ d ]imidazol-2-amine (0.03 g, 0.09 mmol) in CH 2 Cl 2 solution (2 mL) 1-( N , N -dimethylsulfamoyl) piperidine-4- Carboxylic acid (0.03 g, 0.14 mmol), EDCI (0.09 g, 0.45 mmol), HOBt (0.01 g, 0.09 mmol), and DMAP (0.002 g, 0.02 mmol) were added. DIPEA (0.09 mL, 0.54 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (10 mg, 20%).
1H NMR (400 MHz, CDCl 3) δ 7.36 (m, 1H), 7.18 (m, 3H), 6.83 (m, 2H), 6.65 (d, 1H, J = 2.2 Hz), 5.39 (s, 2H), 3.82 (s, 1.3H) and 3.76 (S, 1.7H) , 3.70 (d, 2H, J = 12.2 Hz), 2.93 (t, 3H, J = 11.9 Hz), 2.82 (s, 6H), 1.86 (m, 4H); HRMS (EI): mass calcd for C 24H 28F 3N 5O 5S [M+H] +, 555.1763; found, 555.1765. 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (m, 1H), 7.18 (m, 3H), 6.83 (m, 2H), 6.65 (d, 1H, J = 2.2 Hz), 5.39 (s, 2H) , 3.82 (s, 1.3H) and 3.76 (S, 1.7H), 3.70 (d, 2H, J = 12.2 Hz), 2.93 (t, 3H, J = 11.9 Hz), 2.82 (s, 6H), 1.86 ( m, 4H); HRMS (EI): mass calcd for C 24 H 28 F 3 N 5 O 5 S [M+H] + , 555.1763; found, 555.1765.
[실시예 54][Example 54]
terttert -부틸 4-((5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1-Butyl 4-((5-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트]Imidazol-2-yl)carbamoyl)piperidine-1-carboxylate
Figure PCTKR2020016038-appb-img-000064
Figure PCTKR2020016038-appb-img-000064
5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민과 6-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-아민(0.03 g, 0.08 mmol)의 CH 2Cl 2 용액(2 mL)에 1-( tert-부톡시카르보닐)피페리딘-4-카르복실산(0.03 g, 0.12 mmol), EDCI (0.08 g, 0.40 mmol), HOBt (0.01 g, 0.08 mmol), 및 DMAP (2 mg, 0.02 mmol)를 첨가하였다. DIPEA (0.08 mL, 0.48 mmol)를 0 ℃에서 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 CH 2Cl 2로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(7.6 mg, 17%).5-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-amine and 6-methoxy-1-(3-(trifluoromethoxy)benzyl )-1 H -benzo[ d ]imidazol-2-amine (0.03 g, 0.08 mmol) in a CH 2 Cl 2 solution (2 mL) of 1-( tert -butoxycarbonyl) piperidine-4-car Acid (0.03 g, 0.12 mmol), EDCI (0.08 g, 0.40 mmol), HOBt (0.01 g, 0.08 mmol), and DMAP (2 mg, 0.02 mmol) were added. DIPEA (0.08 mL, 0.48 mmol) was added to the reaction mixture at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with CH 2 Cl 2 , and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2: 0.1) to obtain a compound (7.6 mg, 17%).
1H NMR (600 MHz, CDCl 3) δ 7.35 (m, 1H), 7.23 (m, 2H), 7.07 (m, 2H), 6.73 (m, 2H), 5.31 (s, 2H), 4.09 (s, 2H), 3.80 (m, 3H), 2.84 (s, 2H), 2.53 (s, 1H), 1.96 (d, 2 H, J = 13.0 Hz), 1.70 (d, 2H, J = 11.1 Hz), 1.46 (d, 9H, J = 1.9 Hz); HRMS (EI): mass calcd for C 27H 31F 3N 4O 5 [M+H] +, 548.2247; found, 548.2248. 1 H NMR (600 MHz, CDCl 3 ) δ 7.35 (m, 1H), 7.23 (m, 2H), 7.07 (m, 2H), 6.73 (m, 2H), 5.31 (s, 2H), 4.09 (s, 2H), 3.80 (m, 3H), 2.84 (s, 2H), 2.53 (s, 1H), 1.96 (d, 2H, J = 13.0 Hz), 1.70 (d, 2H, J = 11.1 Hz), 1.46 (d, 9H, J = 1.9 Hz); HRMS (EI): mass calcd for C 27 H 31 F 3 N 4 O 5 [M+H] + , 548.2247; found, 548.2248.
[실시예 55][Example 55]
1-(이소프로필설포닐)-1-(isopropylsulfonyl)- NN -(5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1-(5-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-4-카르복스아미드]Imidazol-2-yl)piperidine-4-carboxamide
Figure PCTKR2020016038-appb-img-000065
Figure PCTKR2020016038-appb-img-000065
tert-부틸 4-((5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트와 tert-부틸 4-((6-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트 (0.02 g, 0.04 mmol)의 CH 2Cl 2 용액(2 mL)에 TFA (excess)를 첨가하였다. 10분간 교반하고 혼합물을 농축시켰다. 반응 혼합물을 ACN (1 mL)에 녹이고 프로판-2-설포닐 클로라이드(0.01 mL, 0.06 mmol)과 DIPEA (0.01 mL, 0.08 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 EtOAc로 희석하고, 유기층을 증류수 및 brine으로 세척하였다. 그 후, 무수 Na 2SO 4로 물 분자를 제거한 후 감압농축하였다. 잔여물을 실리카겔(EtOAc/Hexane/CH 3OH = 1 : 2.5 : 0.1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(11 mg, 50%). tert -Butyl 4-((5-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1- Carboxylate and tert -butyl 4-((6-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperi TFA (excess) was added to a CH 2 Cl 2 solution (2 mL) of din-1-carboxylate (0.02 g, 0.04 mmol). Stir for 10 minutes and the mixture was concentrated. The reaction mixture was dissolved in ACN (1 mL), and propane-2-sulfonyl chloride (0.01 mL, 0.06 mmol) and DIPEA (0.01 mL, 0.08 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the organic layer was washed with distilled water and brine. Then, water molecules were removed with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 3 OH = 1: 2.5: 0.1) to give a compound (11 mg, 50%).
1H NMR (400 MHz, CDCl 3) δ 7.35 (m, 1H), 7.22 (m, 2H), 7.15 (m, 1H), 6.81 (m, 3H), 5.30 (s, 2H), 3.80 (d, 5H, J = 13.3 Hz), 3.18 (m, 1H), 3.00 (t, 2H, J = 11.9 Hz), 2.53 (s, 1H), 2.06 (m, 2H), 1.87 (m, 2H), 1.34 (d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 25H 29F 3N 4O 5S [M+H] +, 554.1811; found, 554.1810. 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (m, 1H), 7.22 (m, 2H), 7.15 (m, 1H), 6.81 (m, 3H), 5.30 (s, 2H), 3.80 (d, 5H, J = 13.3 Hz), 3.18 (m, 1H), 3.00 (t, 2H, J = 11.9 Hz), 2.53 (s, 1H), 2.06 (m, 2H), 1.87 (m, 2H), 1.34 ( d, 6H, J = 6.8 Hz); HRMS (EI): mass calcd for C 25 H 29 F 3 N 4 O 5 S [M+H] + , 554.1811; found, 554.1810.
본 발명에 따른 벤즈이미다졸계 화합물은 하기 반응식 2의 합성 프로토콜 또는 이의 변형을 이용해서 합성될 수 있다.The benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 2 below or a modification thereof.
[반응식 2][Scheme 2]
Figure PCTKR2020016038-appb-img-000066
Figure PCTKR2020016038-appb-img-000066
Conditions: a) LiAlH 4 (3 eq.), THF, overnight.Conditions: a) LiAlH 4 (3 eq.), THF, overnight.
[실시예 56][Example 56]
4-(((1-(3-아미노벤질)-14-(((1-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)아미노)메틸)-]Imidazol-2-yl)amino)methyl)- NN ,, NN -디메틸피페리딘-1-설폰아미드-Dimethylpiperidine-1-sulfonamide
Figure PCTKR2020016038-appb-img-000067
Figure PCTKR2020016038-appb-img-000067
N-(1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-일)-1-( N, N-디메틸술파모일)피페리딘-4-카르복스아미드 (0.03 g, 0.07 mmol)의 THF (1 mL) 혼합 용액에 LiAlH4 (0.01 g, 0.21 mmol)을 첨가하였다. 밤새 교반한 후, 혼합물에 메탄올을 넣어 반응을 종결시켰다. 상기 혼합물에서 타타르산 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(EtOAc/Hexane = 2 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(6 mg, 20%). N- (1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-( N , N -dimethylsulfamoyl)piperidine-4-carboxamide (0.03 g , 0.07 mmol) of THF (1 mL) was added LiAlH4 (0.01 g, 0.21 mmol). After stirring overnight, methanol was added to the mixture to terminate the reaction. In the mixture, the organic layer was washed with a saturated aqueous solution of tartaric acid and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (EtOAc/Hexane = 2: 1) to obtain a compound (6 mg, 20%).
1H NMR (600 MHz, CDCl 3) δ 7.51 (t, 2H, J = 8.4 Hz), 7.14 (m, 3H), 7.08 (m, 1H), 6.60 (m, 2H), 6.39 (t, 1H, J = 2.1 Hz), 5.00 (s, 2H), 3.67 (m, 5H), 3.38 (t, 2H, J = 6.3 Hz), 2.83 (s, 1H), 2.78 (s, 6H), 2.71 (m, 2H), 2.61 (s, 2H). 13C NMR (150 MHz, CDCl 3) δ 162.6, 147.7, 136.6, 130.4, 121.6, 120.0, 116.6, 115.0, 112.7, 107.3, 81.1, 48.4, 46.4, 45.9, 41.1, 38.3, 35.6, 31.1, 29.9, 29.4. 1 H NMR (600 MHz, CDCl 3 ) δ 7.51 (t, 2H, J = 8.4 Hz), 7.14 (m, 3H), 7.08 (m, 1H), 6.60 (m, 2H), 6.39 (t, 1H, J = 2.1 Hz), 5.00 (s, 2H), 3.67 (m, 5H), 3.38 (t, 2H, J = 6.3 Hz), 2.83 (s, 1H), 2.78 (s, 6H), 2.71 (m, 2H), 2.61 (s, 2H). 13 C NMR (150 MHz, CDCl 3 ) δ 162.6, 147.7, 136.6, 130.4, 121.6, 120.0, 116.6, 115.0, 112.7, 107.3, 81.1, 48.4, 46.4, 45.9, 41.1, 38.3, 35.6, 31.1, 29.9, 29.4 .
[실시예 57][Example 57]
NN ,, NN -디메틸-4-(((1-(3-메틸벤질)-1-Dimethyl-4-(((1-(3-methylbenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)아미노)메틸)피페리딘-1-설폰아미드]Imidazol-2-yl)amino)methyl)piperidine-1-sulfonamide
Figure PCTKR2020016038-appb-img-000068
Figure PCTKR2020016038-appb-img-000068
1- ( N, N-디메틸설파모일)- N-(1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드 (0.05 g, 0.10 mmol)의 ether (1 mL) 혼합 용액에 LiAlH4 (0.01 g, 0.30 mmol)을 첨가하였다. 밤새 교반한 후, 혼합물에 메탄올을 넣어 반응을 종결시켰다. 상기 혼합물에서 타타르산 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(EtOAc/Hexane = 2 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(5 mg, 11%).1- ( N , N -dimethylsulfamoyl)- N -(1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)piperidine-4-carboxamide (0.05 g , 0.10 mmol) of ether (1 mL) was added LiAlH4 (0.01 g, 0.30 mmol). After stirring overnight, methanol was added to the mixture to terminate the reaction. In the mixture, the organic layer was washed with a saturated aqueous solution of tartaric acid and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (EtOAc/Hexane = 2: 1) to obtain a compound (5 mg, 11%).
1H NMR (400 MHz, CDCl 3) δ 7.53 (d, 1H, J = 7.8 Hz), 7.22 (d, 1H, J = 7.7 Hz), 7.13 (m, 4H), 6.97 (d, 2H, J = 6.9 Hz), 5.08 (s, 2H), 4.39 (s, 1H), 3.62 (d, 2H, J = 11.6 Hz), 3.39 (d, 2H, J = 6.8 Hz), 2.78 (d, 6H, J = 1.2 Hz), 2.68 (m, 2H), 2.30 (s, 3H), 1.72 (m, 1H), 1.59 (d, 2H, J = 13.1 Hz), 1.16 (m, 2H); HRMS (EI): mass calcd for C 23H 31N 5O 2S [M+H] +, 441.2198; found, 441.2197. 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, 1H, J = 7.8 Hz), 7.22 (d, 1H, J = 7.7 Hz), 7.13 (m, 4H), 6.97 (d, 2H, J = 6.9 Hz), 5.08 (s, 2H), 4.39 (s, 1H), 3.62 (d, 2H, J = 11.6 Hz), 3.39 (d, 2H, J = 6.8 Hz), 2.78 (d, 6H, J = 1.2 Hz), 2.68 (m, 2H), 2.30 (s, 3H), 1.72 (m, 1H), 1.59 (d, 2H, J = 13.1 Hz), 1.16 (m, 2H); HRMS (EI): mass calcd for C 23 H 31 N 5 O 2 S [M+H] + , 441.2198; found, 441.2197.
[실시예 58][Example 58]
NN ,, NN -디메틸-4-(((1-(3-(트리플루오로메톡시)벤질)-1-Dimethyl-4-(((1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)아미노)메틸)피페리딘-1-설폰아미드]Imidazol-2-yl)amino)methyl)piperidine-1-sulfonamide
Figure PCTKR2020016038-appb-img-000069
Figure PCTKR2020016038-appb-img-000069
1-( N, N-디메틸설파모일)- N-(1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드 (0.05 g, 0.10 mmol)의 ether (1 mL) 혼합 용액에 LiAlH4 (0.01 g, 0.30 mmol)을 첨가하였다. 밤새 교반한 후, 혼합물에 메탄올을 넣어 반응을 종결시켰다. 상기 혼합물에서 타타르산 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(EtOAc/Hexane = 2 : 1) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(7 mg, 14%).1- (N, N - dimethyl sulfamoyl) - N - (1- (3- ( trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxylic LiAlH4 (0.01 g, 0.30 mmol) was added to a mixed solution of voxamide (0.05 g, 0.10 mmol) in ether (1 mL). After stirring overnight, methanol was added to the mixture to terminate the reaction. In the mixture, the organic layer was washed with a saturated aqueous solution of tartaric acid and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (EtOAc/Hexane = 2: 1) to obtain a compound (7 mg, 14%).
1H NMR (400 MHz, CDCl 3) δ 7.53 (d, 1H, J = 7.9 Hz), 7.37 (t, 1H, J = 7.9 Hz), 7.18 (m, 2H), 7.06 (t, 4H, J = 7.8 Hz), 5.15 (s, 2H), 3.64 (m, 2H), 3.42 (d, 2H, J = 7.0 Hz), 2.77 (s, 6H), 2.72 (m, 2H), 1.78 (m, 1H), 1.62 (m, 2H), 1.21 (m, 2H); HRMS (EI): mass calcd for C 23H 28F 3N 5O 3S [M+H] +, 511.1865; found, 511.1864. 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, 1H, J = 7.9 Hz), 7.37 (t, 1H, J = 7.9 Hz), 7.18 (m, 2H), 7.06 (t, 4H, J = 7.8 Hz), 5.15 (s, 2H), 3.64 (m, 2H), 3.42 (d, 2H, J = 7.0 Hz), 2.77 (s, 6H), 2.72 (m, 2H), 1.78 (m, 1H) , 1.62 (m, 2H), 1.21 (m, 2H); HRMS (EI): mass calcd for C 23 H 28 F 3 N 5 O 3 S [M+H] + , 511.1865; found, 511.1864.
본 발명에 따른 벤즈이미다졸계 화합물은 하기 반응식 3의 합성 프로토콜 또는 이의 변형을 이용해서 합성될 수 있다.The benzimidazole-based compound according to the present invention can be synthesized using the synthesis protocol of Scheme 3 below or a modification thereof.
[반응식 3][Scheme 3]
Figure PCTKR2020016038-appb-img-000070
Figure PCTKR2020016038-appb-img-000070
Conditions: a) acid (0.9 eq.), CDI (1 eq.), phenylenediamine (1 eq.), 60 oC, overnight, b) AcOH, microwave, c) substituted-benzyl bromide, K 2CO 3, actone.Conditions: a) acid (0.9 eq.), CDI (1 eq.), phenylenediamine (1 eq.), 60 o C, overnight, b) AcOH, microwave, c) substituted-benzyl bromide, K 2 CO 3 , actone .
[실시예 59][Example 59]
4-(14-(1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-]Imidazol-2-yl)- NN ,, NN -디메틸피페리딘-1-설폰아미드-Dimethylpiperidine-1-sulfonamide
Figure PCTKR2020016038-appb-img-000071
Figure PCTKR2020016038-appb-img-000071
1-( N,N-디메틸설파모일)피페리딘-4-카르복실산(588 mg, 2.49 mmol)과 카보닐디이미다졸(449 mg, 2.77 mmol)를 THF로 용해시켰다. 30 min 동안 상온에서 교반한 후에 o-페닐렌다이아민(300 mg, 2.77 mmol)을 첨가하였다. 60 °C에서 밤새 교반한 후, 용매를 감압 하에 제거하고 아세트산을 첨가하였다. 상기 혼합물을 마이크로웨이브 장비를 통해 120 °C에서 30분 동안 반응을 진행한 후, 실리카겔(EtOAc/CH2Cl2/NH4OH = 3:1:0.01) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(510mg, 60%).1-( N,N -dimethylsulfamoyl)piperidine-4-carboxylic acid (588 mg, 2.49 mmol) and carbonyldiimidazole (449 mg, 2.77 mmol) were dissolved in THF. After stirring at room temperature for 30 min, o-phenylenediamine (300 mg, 2.77 mmol) was added. After stirring at 60 °C overnight, the solvent was removed under reduced pressure and acetic acid was added. The mixture was reacted through a microwave equipment at 120 °C for 30 minutes, and then purified by flash column chromatography on silica gel (EtOAc/CH2Cl2/NH4OH = 3:1:0.01) to obtain a compound (510mg, 60%).
1H NMR (600 MHz, DMSO- d 6) δ 12.25 (s, 2H), 7.48 (s, 2H), 7.12 (m, 2H), 3.63 (m, 2H), 3.32 (m, 1H), 3.03 (m, 2H), 2.77 (s, 6H), 2.06 (m, 2H), 1.83 (m, 3H). 13C NMR (150 MHz, DMSO- d 6) δ 157.0, 121.3, 120.4, 45.8, 37.9, 35.0, 30.0. 1 H NMR (600 MHz, DMSO- d 6 ) δ 12.25 (s, 2H), 7.48 (s, 2H), 7.12 (m, 2H), 3.63 (m, 2H), 3.32 (m, 1H), 3.03 ( m, 2H), 2.77 (s, 6H), 2.06 (m, 2H), 1.83 (m, 3H). 13 C NMR (150 MHz, DMSO- d 6 ) δ 157.0, 121.3, 120.4, 45.8, 37.9, 35.0, 30.0.
[실시예 60][Example 60]
4-(1-(3-아미노벤질)-14-(1-(3-aminobenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)-]Imidazol-2-yl)- NN ,, NN -디메틸피페리딘-1-설폰아미드-Dimethylpiperidine-1-sulfonamide
Figure PCTKR2020016038-appb-img-000072
Figure PCTKR2020016038-appb-img-000072
N, N-디메틸-4-(1-(3-니트로벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-1-설폰아미드 (0.02 g, 0.05 mmol)의 메틸 알코올 용액 및 10% wet Pd/C (3 mg, 0.03 mmol)를 수소 대기하에 두었다. 10분 동안 교반한 후, 반응 혼합물을 메틸 알코올로 희석시키고, celite pad로 여과한 후 갑압농축하였다. 잔여물을 실리카겔(CH 3OH/CH 2Cl 2 = 1 : 30) 상에서 플래시 컬럼 크로마토그래피로 정제하여 아민 화합물을 수득하였다.(11.8 mg, 53%). N , N -dimethyl-4-(1-(3-nitrobenzyl)-1 H -benzo[ d ]imidazol-2-yl)piperidine-1-sulfonamide (0.02 g, 0.05 mmol) methyl alcohol The solution and 10% wet Pd/C (3 mg, 0.03 mmol) were placed under a hydrogen atmosphere. After stirring for 10 minutes, the reaction mixture was diluted with methyl alcohol, filtered through a celite pad, and concentrated under pressure. The residue was purified by flash column chromatography on silica gel (CH 3 OH/CH 2 Cl 2 = 1:30) to give an amine compound (11.8 mg, 53%).
1H NMR (600 MHz, MeOD) δ 7.63 (m, 1H), 7.43 (m, 1H), 7.25 (m, 2H), 7.04 (t, 1H, J = 7.8 Hz), 6.61 (d, 1H, J = 7.9 Hz), 6.43 (d, 1H, J = 7.6 Hz), 6.39 (s, 1H), 5.43 (s, 2H), 3.73 (d, 2H, J = 12.5 Hz), 3.13 (m, 1H), 2.90 (m, 2H), 2.82 (s, 6H), 1.98 (m, 2H), 1.83 (d, 2H, J = 12.9 Hz). 13C NMR (150 MHz, MeOD) δ 158.9, 149.7, 142.7, 138.9, 136.4, 130.7, 124.0, 123.6, 119.2, 116.8, 115.9, 113.9, 111.6, 49.0, 47.7, 47.4, 38.4, 35.2, 31.7. 1 H NMR (600 MHz, MeOD) δ 7.63 (m, 1H), 7.43 (m, 1H), 7.25 (m, 2H), 7.04 (t, 1H, J = 7.8 Hz), 6.61 (d, 1H, J = 7.9 Hz), 6.43 (d, 1H, J = 7.6 Hz), 6.39 (s, 1H), 5.43 (s, 2H), 3.73 (d, 2H, J = 12.5 Hz), 3.13 (m, 1H), 2.90 (m, 2H), 2.82 (s, 6H), 1.98 (m, 2H), 1.83 (d, 2H, J = 12.9 Hz). 13 C NMR (150 MHz, MeOD) δ 158.9, 149.7, 142.7, 138.9, 136.4, 130.7, 124.0, 123.6, 119.2, 116.8, 115.9, 113.9, 111.6, 49.0, 47.7, 47.4, 38.4, 35.2, 31.7.
[실시예 61][Example 61]
NN ,, NN -디메틸-4-(1-(3-메틸벤질)-1-Dimethyl-4-(1-(3-methylbenzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-1-설포나미드]Imidazol-2-yl)piperidine-1-sulfonamide
Figure PCTKR2020016038-appb-img-000073
Figure PCTKR2020016038-appb-img-000073
4-(1 H-벤조[ d]이미다졸-2-일)- N, N-디메틸피페리딘-1-설폰아미드 (0.04 g, 0.1 mmol)의 아세톤 (2 mL) 혼합 용액에 K 2CO 3 (0.04 g, 0.30 mmol) 및 1-(브로모메틸)-3-메틸벤젠(0.02 mL, 0.10 mmol)을 첨가하였다. 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH 4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(EtOAc/Hexane/CH 2Cl 2 = 1 : 1 : 0.2) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(27 mg, 50%).In a mixture solution of 4-(1 H -benzo[ d ]imidazol-2-yl) -N , N -dimethylpiperidine-1-sulfonamide (0.04 g, 0.1 mmol) in acetone (2 mL), K 2 CO 3 (0.04 g, 0.30 mmol) and 1-(bromomethyl)-3-methylbenzene (0.02 mL, 0.10 mmol) were added. After stirring overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with a saturated aqueous NH 4 Cl solution and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 2 Cl 2 = 1: 1: 0.2) to obtain a compound (27 mg, 50%).
1H NMR (600 MHz, MeOD) δ 7.64 (m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.17 (t, 1H, J = 7.6 Hz), 7.08 (d, 1H, J = 7.6 Hz), 6.93 (s, 1H), 6.83 (d, 1H, J = 7.6 Hz), 5.49 (s, 2H), 3.71 (d, 2H, J = 12.6 Hz), 3.12 (m, 1H), 2.88 (m, 2H), 2.81 (s, 6H), 2.25 (s, 3H), 1.98 (m, 2H), 1.79 (d, 2H, J = 12.7 Hz). 13C NMR (150 MHz, MeOD) δ 158.9, 143.0, 140.0, 138.1, 136.4, 130.0, 129.6, 128.1, 124.5, 124.0, 123.5, 119.4, 111.5, 47.5, 47.4, 38.4, 35.1, 31.8, 21.4. 1 H NMR (600 MHz, MeOD) δ 7.64 (m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.17 (t, 1H, J = 7.6 Hz), 7.08 (d, 1H, J = 7.6 Hz), 6.93 (s, 1H), 6.83 (d, 1H, J = 7.6 Hz), 5.49 (s, 2H), 3.71 (d, 2H, J = 12.6 Hz), 3.12 (m, 1H), 2.88 (m, 2H), 2.81 (s, 6H), 2.25 (s, 3H), 1.98 (m, 2H), 1.79 (d, 2H, J = 12.7 Hz). 13 C NMR (150 MHz, MeOD) δ 158.9, 143.0, 140.0, 138.1, 136.4, 130.0, 129.6, 128.1, 124.5, 124.0, 123.5, 119.4, 111.5, 47.5, 47.4, 38.4, 35.1, 31.8, 21.4.
[실시예 62][Example 62]
NN ,, NN -디메틸-4-(1-(3-(트리플루오로메톡시)벤질)-1-Dimethyl-4-(1-(3-(trifluoromethoxy)benzyl)-1 HH -벤조[-Benzo[ dd ]이미다졸-2-일)피페리딘-1-설폰아미드]Imidazol-2-yl)piperidine-1-sulfonamide
Figure PCTKR2020016038-appb-img-000074
Figure PCTKR2020016038-appb-img-000074
4-(1 H-벤조[ d]이미다졸-2-일)- N, N-디메틸피페리딘-1-설폰아미드 (0.04 g, 0.10 mmol)의 아세톤 (2 mL) 혼합 용액에 K 2CO 3 (0.04 g, 0.30 mmol) 및 1-(브로모메틸)-3-(트리플루오로메톡시)벤젠 (0.02 mL, 0.10 mmol)을 첨가하였다. 밤새 교반한 후, 혼합물을 에틸 아세테이트로 희석시켰다. 상기 혼합물에서 NH 4Cl 포화수용액 및 증류수를 이용하여 유기층을 세척한 후 무수 Na 2SO 4로 물 분자를 제거하였다. 용매를 감압 하에 제거하고 실리카겔(EtOAc/Hexane/CH 2Cl 2 = 1 : 1 : 0.2) 상에서 플래시 컬럼 크로마토그래피로 정제하여 화합물을 수득하였다(5.4 mg, 9%).In a mixture solution of 4-(1 H -benzo[ d ]imidazol-2-yl) -N , N -dimethylpiperidine-1-sulfonamide (0.04 g, 0.10 mmol) in acetone (2 mL), K 2 CO 3 (0.04 g, 0.30 mmol) and 1-(bromomethyl)-3-(trifluoromethoxy)benzene (0.02 mL, 0.10 mmol) were added. After stirring overnight, the mixture was diluted with ethyl acetate. In the mixture, the organic layer was washed with a saturated aqueous NH 4 Cl solution and distilled water, and then water molecules were removed with anhydrous Na 2 SO 4. The solvent was removed under reduced pressure and purified by flash column chromatography on silica gel (EtOAc/Hexane/CH 2 Cl 2 = 1: 1: 0.2) to obtain a compound (5.4 mg, 9%).
1H NMR (600 MHz, MeOD) δ 7.67 (m, 1H), 7.40 (m, 2H), 7.27 (m, 2H), 7.21 (d, 1H, J = 8.3 Hz), 7.02 (d, 2H, J = 7.0 Hz), 5.63 (s, 2H), 3.74 (d, 2H, J = 12.5 Hz), 3.14 (m, 1H), 2.92 (m, 2H), 2.83 (s, 6H), 2.01 (m, 2H), 1.83 (d, 2H, J = 11.8 Hz). 13C NMR (150 MHz, MeOD) δ 158.9, 150.9, 143.1, 141.0, 136.1, 131.9, 126.1, 124.2, 123.8, 121.4, 120.1, 119.5, 111.3, 47.3, 46.8, 38.4, 35.0, 31.8. 1 H NMR (600 MHz, MeOD) δ 7.67 (m, 1H), 7.40 (m, 2H), 7.27 (m, 2H), 7.21 (d, 1H, J = 8.3 Hz), 7.02 (d, 2H, J = 7.0 Hz), 5.63 (s, 2H), 3.74 (d, 2H, J = 12.5 Hz), 3.14 (m, 1H), 2.92 (m, 2H), 2.83 (s, 6H), 2.01 (m, 2H ), 1.83 (d, 2H, J = 11.8 Hz). 13 C NMR (150 MHz, MeOD) δ 158.9, 150.9, 143.1, 141.0, 136.1, 131.9, 126.1, 124.2, 123.8, 121.4, 120.1, 119.5, 111.3, 47.3, 46.8, 38.4, 35.0, 31.8.
[실험예 1] [Experimental Example 1]
최종당화산물 (Advanced glycation end products, AGEs) 분해 효과 확인Confirmation of decomposition effect of advanced glycation end products (AGEs)
최종당화산물은 단백질의 유리 아민 말단이 반응성 글루코스 또는 기타 카르보닐 함유 분자에 의해 공유적 개질이 일어나는 비효소적 반응을 통해 생성된다. 따라서 본 실험예에서는 TNBSA(2,4,6-트리니트로벤젠 설폰산) 어세이를 이용하여 최종당화산물의 분해물인 유리 아민의 양을 측정함으로써, 본 발명의 실시예 화합물이 나타내는 최종당화산물 (AGEs) 분해 효과를 평가하였다.The final glycated product is produced through a non-enzymatic reaction in which the free amine end of the protein is covalently modified by reactive glucose or other carbonyl-containing molecules. Therefore, in this experimental example, by measuring the amount of free amine, which is a decomposition product of the final saccharified product, using a TNBSA (2,4,6-trinitrobenzene sulfonic acid) assay, the final saccharified product (AGEs ) The decomposition effect was evaluated.
[실험예 1-1][Experimental Example 1-1]
메틸글리옥살 (methylglyoxal, MGO) 또는 글리옥살 (glyoxal, GO)을 소 혈청 알부민 (BSA) 및 아지드화 나트륨 (sodium azide)과 혼합한 후 7일 동안 37 ℃에 보관하여 최종당화산물 (AGEs)을 제조하였다. 메틸글리옥살 (MGO)로부터 유도된 최종당화산물을 MGO-AGEs, 글리옥살 (GO)로부터 유도된 최종당화산물을 GO-AGEs로 지칭하였다.Methylglyoxal (MGO) or glyoxal (GO) is mixed with bovine serum albumin (BSA) and sodium azide, and then stored at 37°C for 7 days to produce final glycation products (AGEs). Was prepared. The final glycated products derived from methylglyoxal (MGO) were referred to as MGO-AGEs, and the final glycated products derived from glyoxal (GO) were referred to as GO-AGEs.
MGO-AGEs 또는 GO-AGEs 1 mg/ml의 최종당화산물에 본 발명의 화합물을 0.4 mM의 농도로 24시간 동안 처리하였다. 양성대조군으로는 최종당화산물 (AGEs) 억제제로 알려진 아미노구아니딘(AG)을 사용하였다. TNBSA (2,4,6-트리니트로벤젠 설폰산), 4% 소듐바이카보네이트(sodium bicarbonate) 시약을 넣어 반응시킨 후, 10% 소듐 도데실 설페이트(sodium dedecyl sulfate) 및 1N 염산 용액을 첨가하여 반응을 정지시켰다. 마이크로플레이트 리더기를 이용하여 최종당화산물의 분해물인 유리 아민의 양을 335 nm에서 측정하여, 최종당화산물(AGEs)의 분해 정도를 확인하였다. 본 발명의 화합물을 MGO-AGEs에 처리하였을 때의 결과는 표 1 및 표 2에, GO-AGEs에 처리하였을 때의 결과는 표 3 및 표 4에 나타내었다. MGO-AGEs or GO-AGEs 1 mg/ml of the final glycosylated product was treated with the compound of the present invention at a concentration of 0.4 mM for 24 hours. As a positive control, aminoguanidine (AG), known as an inhibitor of final glycosylated products (AGEs), was used. TNBSA (2,4,6-trinitrobenzene sulfonic acid) and 4% sodium bicarbonate reagent were added to react, followed by 10% sodium dedecyl sulfate and 1N hydrochloric acid solution. Stopped. Using a microplate reader, the amount of free amine, which is a decomposition product of the final saccharified product, was measured at 335 nm, and the degree of decomposition of the final saccharified product (AGEs) was confirmed. The results of the treatment of the compound of the present invention with MGO-AGEs are shown in Tables 1 and 2, and the results of treatment with GO-AGEs are shown in Tables 3 and 4.
구분division 농도density 유리 아민 (%)Free amine (%)
BSA (Control)BSA (Control) 1mg/ml1mg/ml 100.00±1.51100.00±1.51
MGO-AGEsMGO-AGEs 1mg/ml1mg/ml 75.15±1.1975.15±1.19
실시예 8의 화합물Compound of Example 8 0.4 mM0.4 mM 88.23±1.4988.23±1.49
실시예 9의 화합물Compound of Example 9 0.4 mM0.4 mM 90.85±1.9190.85±1.91
실시예 11의 화합물(SA)Compound of Example 11 (SA) 0.4 mM0.4 mM 97.28±1.3297.28±1.32
실시예 12의 화합물Compound of Example 12 0.4 mM0.4 mM 86.40±0.8286.40±0.82
아미노구아니딘Aminoguanidine 1 mM1 mM 101.75±1.62101.75±1.62
구분division 농도density 유리 아민 (%)Free amine (%)
BSA (Control)BSA (Control) 1mg/ml1mg/ml 100.00±2.28100.00±2.28
MGO-AGEsMGO-AGEs 1mg/ml1mg/ml 57.54±1.1957.54±1.19
실시예 11의 화합물(SA)Compound of Example 11 (SA) 0.4 mM0.4 mM 70.80±1.4970.80±1.49
아미노구아니딘Aminoguanidine 1 mM1 mM 70.92±1.6270.92±1.62
구분division 농도density 유리 아민 (%)Free amine (%)
BSA (Control)BSA (Control) 1mg/ml1mg/ml 100.00±3.09100.00±3.09
GO-AGEsGO-AGEs 1mg/ml1mg/ml 77.43±0.7977.43±0.79
실시예 8의 화합물Compound of Example 8 0.4 mM0.4 mM 88.71±1.4188.71±1.41
실시예 9의 화합물Compound of Example 9 0.4 mM0.4 mM 89.37±2.3889.37±2.38
실시예 10의 화합물Compound of Example 10 0.4 mM0.4 mM 83.44±3.5283.44±3.52
실시예 11의 화합물(SA)Compound of Example 11 (SA) 0.4 mM0.4 mM 96.04±1.6796.04±1.67
실시예 12의 화합물 Compound of Example 12 0.4 mM0.4 mM 87.85±2.9387.85±2.93
실시예 1의 화합물Compound of Example 1 0.4 mM0.4 mM 80.45±0.9180.45±0.91
아미노구아니딘Aminoguanidine 1 mM1 mM 97.42±2.7397.42±2.73
구분division 농도density 유리 아민 (%)Free amine (%)
BSA (Control)BSA (Control) 1mg/ml1mg/ml 100.00±3.09100.00±3.09
GO-AGEsGO-AGEs 1mg/ml1mg/ml 77.43±0.7977.43±0.79
실시예 11의 화합물(SA)Compound of Example 11 (SA) 0.4 mM0.4 mM 88.71±1.4188.71±1.41
실시예 20의 화합물The compound of Example 20 0.4 mM0.4 mM 89.37±2.3889.37±2.38
실시예 21의 화합물The compound of Example 21 0.4 mM0.4 mM 83.44±3.5283.44±3.52
실시예 22의 화합물The compound of Example 22 0.4 mM0.4 mM 96.04±1.6796.04±1.67
아미노구아니딘Aminoguanidine 1 mM1 mM 97.42±2.7397.42±2.73
표 1 내지 4에 나타낸 바와 같이, 본 발명의 화합물은 최종당화산물만을 처리한 음성 대조군(MGO-AGEs 또는 GO-AGEs)과 비교하여 유리 아민의 양을 증가시켰다. 특히 실시예 11의 화합물(SA) 0.4 mM은 양성 대조군(아미노구아니딘 1 nM)과 비교시 낮은 농도에서 최종당화산물 MGO-AGEs 또는 GO-AGEs의 분해 정도가 매우 우수함을 확인하였다.As shown in Tables 1 to 4, the compound of the present invention increased the amount of free amine compared to the negative control (MGO-AGEs or GO-AGEs) treated with only the final glycosylated product. Particularly, it was confirmed that 0.4 mM of the compound (SA) of Example 11 had a very good degree of decomposition of the final glycosylated products MGO-AGEs or GO-AGEs at a low concentration compared to the positive control (aminoguanidine 1 nM).
[실험예 1-2][Experimental Example 1-2]
실험예 1-1과 동일한 방법으로 추가의 화합물(실시예 11, 44, 56 및 60)에 대하여 실험을 수해하였고, 그 결과를 하기 표 5에 나타내었다.Experiments were carried out for additional compounds (Examples 11, 44, 56, and 60) in the same manner as in Experimental Example 1-1, and the results are shown in Table 5 below.
구분division 농도density 유리 아민 (%)Free amine (%)
BSA (Control)BSA (Control) 1mg/ml1mg/ml 100.00±2.43100.00±2.43
MGO-AGEsMGO-AGEs 1mg/ml1mg/ml 46.97±4.2646.97±4.26
실시예 11의 화합물(SA)Compound of Example 11 (SA) 0.4 mM0.4 mM 72.38±1.9172.38±1.91
실시예 60의 화합물The compound of Example 60 0.4 mM0.4 mM 65.53±1.1865.53±1.18
실시예 56의 화합물The compound of Example 56 0.4 mM0.4 mM 60.86±2.1260.86±2.12
실시예 44의 화합물The compound of Example 44 0.4 mM0.4 mM 53.35±0.9253.35±0.92
아미노구아니딘Aminoguanidine 1 mM1 mM 66.74±1.1466.74±1.14
상기 표 5에 나타낸 바와 같이, 본 발명의 화합물은 최종당화산물만을 처리한 음성 대조군 (MGO-AGEs)과 비교하여 유리 아민의 양을 증가시켰다. 실시예 56 및 60의 화합물은 양성 대조군(아미노구아니딘 1 nM)과 비교시 유사한 수치를 나타내었고, 실시예 11의 화합물(SA) 0.4 mM은 양성 대조군(아미노구아니딘 1 nM)과 비교시 낮은 농도에서 최종당화산물 MGO-AGEs의 분해 정도가 매우 우수한 것을 재확인하였다.As shown in Table 5, the compound of the present invention increased the amount of free amine compared to the negative control group (MGO-AGEs) treated with only the final glycosylated product. The compounds of Examples 56 and 60 exhibited similar values when compared to the positive control (aminoguanidine 1 nM), and the compound (SA) of Example 11 was 0.4 mM at a lower concentration when compared to the positive control (aminoguanidine 1 nM). It was reconfirmed that the degree of decomposition of the final glycation product MGO-AGEs was very good.
[실험예 1-3][Experimental Example 1-3]
실험예 1-1과 동일한 방법으로 실험하되, 최종당화산물로서 MGO-AGEs 또는 GO-AGEs 1 mg/ml을 사용하였고, 실험군으로 실시예 11의 화합물(SA)을 0.1 mM 또는 0.4 mM 사용하였으며, 양성 대조군으로는 아미노구아니딘 1 mM 이외에, 알라게브리움(Alagebrium)을 0.1 mM 또는 0.4 mM 사용하였다. Experimented in the same manner as in Experimental Example 1-1, but 1 mg/ml of MGO-AGEs or GO-AGEs was used as the final glycation product, and 0.1 mM or 0.4 mM of the compound (SA) of Example 11 was used as the experimental group, In addition to 1 mM aminoguanidine, 0.1 mM or 0.4 mM Alagebrium was used as a positive control.
그 결과는 도 1a 및 1b에 나타낸 바와 같이, 본 발명의 벤즈이미다졸 화합물은 음성 대조군과 비교하여 유리 아민의 양을 증가시켰고, 특히 본 발명의 화합물과 동일한 농도를 사용한 양성 대조군인 Alagebrium과 비교하여 보다 높은 유리 아민의 양을 나타내었다. 이로부터 본 발명의 화합물(SA)은 최종당화산물의 분해능이 우수한 것을 확인하였다.The results are as shown in Figures 1a and 1b, the benzimidazole compound of the present invention increased the amount of free amine compared to the negative control, in particular compared to the positive control Alagebrium using the same concentration as the compound of the present invention. It indicated a higher amount of free amine. From this, it was confirmed that the compound (SA) of the present invention has excellent resolution of the final saccharified product.
[실험예 1-4][Experimental Example 1-4]
실험예 1-1과 동일한 방법으로 실험하되, 최종당화산물로서 GA-AGEs 또는 GC-AGEs 1 mg/ml을 사용하였고, 실험군으로 실시예 11의 화합물(SA)을 0.1 mM 또는 0.4 mM 사용하였으며, 양성 대조군으로는 아미노구아니딘 1 mM을 사용하였다. Experimented in the same manner as in Experimental Example 1-1, but GA-AGEs or GC-AGEs 1 mg/ml was used as the final glycation product, and 0.1 mM or 0.4 mM of the compound (SA) of Example 11 was used as the experimental group, As a positive control, 1 mM aminoguanidine was used.
글리세라알데하이드 (glyceraldehyde, GA) 또는 글리코알데하이드 (glycoaldehyde, GC)를 소 혈청 알부민 (BSA) 및 아지드화 나트륨 (sodium azide)과 혼합한 후 7일 동안 37 ℃에 보관하여 최종당화산물 (AGEs)을 제조하였다. 글리세라알데하이드 (GA)로부터 유도된 최종당화산물을 GA-AGEs, 글리코알데하이드 (GC)로부터 유도된 최종당화산물을 GC-AGEs로 지칭하였다.Glyceraldehyde (GA) or glycoaldehyde (GC) is mixed with bovine serum albumin (BSA) and sodium azide, and then stored at 37°C for 7 days to final glycated product (AGEs). Was prepared. The final glycated product derived from glyceraaldehyde (GA) was referred to as GA-AGEs, and the final glycated product derived from glycoaldehyde (GC) was referred to as GC-AGEs.
그 결과는 도 2a 및 2b에 나타낸 바와 같이, 본 발명의 벤즈이미다졸 화합물(SA)는 음성 대조군과 비교하여 유리 아민의 양을 증가시켰고, 특히 GA-AGEs 분해 정도를 양성 대조군과 비교하면, 본 발명의 화합물(SA)을 처리하였을 때 더 낮은 농도에서도 더 높은 유리 아민의 양을 나타내었다. 이로부터 본 발명의 벤즈이미다졸 화합물은 최종당화산물의 분해능이 우수함을 확인하였다.The results are as shown in Figs. 2a and 2b, the benzimidazole compound (SA) of the present invention increased the amount of free amine compared to the negative control, and in particular, when comparing the degree of decomposition of GA-AGEs with the positive control, the present Treatment with the inventive compound (SA) showed a higher amount of free amine even at a lower concentration. From this, it was confirmed that the benzimidazole compound of the present invention has excellent resolution of the final saccharified product.
[실험예 2] [Experimental Example 2]
HepG2 cell에서의 지질 축적 평가Assessment of lipid accumulation in HepG2 cells
HepG2 cell의 중성지방 생성량을 확인하기 위해, 세포질 내 지방 (intracytoplasmic lipids)을 측정하는데 적합한 Oil red O (J Korean Med. 2016;37(1): 62-76)를 활용하여 염색을 하였다. 40 φ dish에 1X10 6 cells/dish만큼 시딩하였다. 24시간 배양 후, 실시예 11의 화합물(SA) 1 μM 또는 10 μM을 1시간 동안 전처리한 후, 팔미틱 산 0.5 mM + LPS 1 μg/ml를 처리하여 지질 축적을 유도하였다. 24시간 후, Oil red O로 염색하여 microplate reader로 560 nm에서 세포 내 지질방울을 측정하였다. To confirm the amount of triglyceride produced by HepG2 cells, staining was performed using Oil red O (J Korean Med. 2016;37(1): 62-76) suitable for measuring intracytoplasmic lipids. It was seeded as much as 1X10 6 cells/dish on a 40 φ dish. After 24 hours incubation, 1 μM or 10 μM of the compound (SA) of Example 11 was pretreated for 1 hour, followed by treatment with 0.5 mM palmitic acid + 1 μg/ml LPS to induce lipid accumulation. After 24 hours, it was stained with Oil red O and the lipid droplets in the cells were measured at 560 nm with a microplate reader.
그 결과, 도 3에 나타낸 바와 같이, 본 발명의 벤즈이미다졸 화합물(SA)은 음성 대조군과 비교하여 지질 축적의 양을 감소시켰고, 특히 10 μM를 처리하였을 경우 정상군 수준으로 지질 축적의 양이 감소하였다.As a result, as shown in FIG. 3, the benzimidazole compound (SA) of the present invention reduced the amount of lipid accumulation compared to the negative control, and in particular, when 10 μM was treated, the amount of lipid accumulation was at the level of the normal group. Decreased.
이로써 본 발명의 화합물은 지질 축적을 억제하는 것을 확인하였다.Thus, it was confirmed that the compound of the present invention inhibits lipid accumulation.
[실험예 3][Experimental Example 3]
항염증 효과 확인Confirmation of anti-inflammatory effect
비알코올성 지방간염, 당뇨합병증 등에서는 염증 반응이 동반된다. 본 실험예에서는 본 발명의 화합물이 항염증 효과를 나타내는지를 확인하기 위해, NO 생성 억제, iNOS 또는 COX2 발현 감소 여부를 평가하였다.Inflammatory reactions accompany non-alcoholic steatohepatitis and diabetes complications. In this experimental example, in order to confirm whether the compound of the present invention exhibits an anti-inflammatory effect, it was evaluated whether NO production was suppressed or iNOS or COX2 expression decreased.
[실험예 3-1] [Experimental Example 3-1]
대식세포인 Raw 264.7 세포를 96 웰 플레이트에 각각 5X10 4 로 시딩하여 37 ℃, 5% CO 2 인큐베이터에서 24 시간 배양한 후, 실시예 11의 화합물(SA) 10 μM를 30분 동안 전처리한 후 100 ng/ml의 LPS으로 24시간 동안 자극하였다. 24 시간 후, 상등액을 50 μl씩 취해 96 웰 플레이트에 옮겨준 후, Griess reagent (50 μl, % sulfanilamide in 5% phosphoric acid and 50 μl 0.1% N-1-napthylethylenediamine dihydrochloride in water)를 각각 1:1 로 섞어준 후에 50 μl 상층액이 들어있는 플레이트에 처리하였다. 반응 후, microplate reader의 파장의 범위는 540 nm로 측정을 하였으며, NO 측정을 위하여 조정배지(conditioned medium)을 사용하였다. 이 때, 양성 대조군으로는 20 μM의 L-NMMA를 사용하였다.Raw 264.7 cells, which are macrophages, were seeded in a 96-well plate at 5×10 4 each and incubated in an incubator at 37° C. and 5% CO 2 for 24 hours, followed by pretreatment with 10 μM of the compound (SA) of Example 11 for 30 minutes, and then 100 It was stimulated with ng/ml LPS for 24 hours. After 24 hours, 50 μl of the supernatant was taken and transferred to a 96-well plate, and then Griess reagent (50 μl,% sulfanilamide in 5% phosphoric acid and 50 μl 0.1% N-1-napthylethylenediamine dihydrochloride in water) was added 1:1. After mixing with, it was treated on a plate containing 50 μl supernatant. After the reaction, the wavelength range of the microplate reader was measured to be 540 nm, and a conditioned medium was used for NO measurement. At this time, 20 μM of L-NMMA was used as a positive control.
그 결과, 도 4a 내지 도 4c에 나타낸 바와 같이, 실시예 11, 12 및 18의 화합물(SA)은 NO 생성을 억제하였다. As a result, as shown in FIGS. 4A to 4C, the compounds (SA) of Examples 11, 12 and 18 suppressed NO generation.
[실험예 3-2] [Experimental Example 3-2]
상시 실험예 3-1과 동일한 방법으로 실시예 11, 44, 56 및 60의 화합물에 대하여 추가의 실험을 수행하였고, 그 결과를 도 4d에 나타내었다.Further experiments were performed on the compounds of Examples 11, 44, 56 and 60 in the same manner as in Experimental Example 3-1, and the results are shown in FIG. 4D.
도 4d에 나타낸 바와 같이, 실시예 11, 44, 56 및 60의 화합물은 우수한 NO 생성 억제 효과를 나타내었다.As shown in Figure 4d, the compounds of Examples 11, 44, 56 and 60 showed excellent NO production inhibitory effect.
[실험예 3-3][Experimental Example 3-3]
Raw 264.7 세포를 60 φ 디쉬에 각각 1Х10 6 로 시딩하여 37 ℃, 5% CO 2 인큐베이터에서 24 시간 배양한 후, 실시예 11의 화합물(SA)을 농도별로 전처리하여 30 분 동안 배양하고, LPS를 100 ng/ml의 농도로 처리하여 24 시간 동안 배양하였다. 배양한 세포를 모은 후, 원심분리기 (5,000 rpm, 5 min, 4℃)로 세포 pellet을 spin down 시키고 lysis buffer를 첨가, 1일 동안 용해시킨 후 원심분리기 (12,000 rpm, 25 min, 4℃)하여 세포막 성분 등을 제거하였다. SDS-PAGE로 변성 분리하여, 이를 PVDF membrane에 transfer하였다. 그 후, 1차 항체를 하룻밤 동안 반응시킨 후, 2차 항체를 결합시키고 ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA)을 이용해서 iNOS, COX2의 발현을 측정하였다.Raw 264.7 cells were seeded in a 60 φ dish with 1Х10 6 each and incubated for 24 hours in a 37° C., 5% CO 2 incubator, and then the compound (SA) of Example 11 was pretreated for each concentration and incubated for 30 minutes, and LPS was It was treated at a concentration of 100 ng/ml and incubated for 24 hours. After collecting the cultured cells, spin down the cell pellet with a centrifuge (5,000 rpm, 5 min, 4℃), add lysis buffer, dissolve for 1 day, and then centrifuge (12,000 rpm, 25 min, 4℃) Cell membrane components and the like were removed. After denatured separation by SDS-PAGE, it was transferred to a PVDF membrane. Thereafter, after reacting with the primary antibody overnight, the secondary antibody was bound and the expression of iNOS and COX2 was measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
그 결과, 도 4e 및 4f에 나타낸 바와 같이, 실시예 11의 화합물(SA)은 음성 대조군 대비 iNOS, 및 COX2의 발현을 감소시켰다. As a result, as shown in Figures 4e and 4f, the compound (SA) of Example 11 decreased the expression of iNOS and COX2 compared to the negative control.
따라서, 본 발명의 화합물은 항염증 효과가 우수한 것을 알 수 있다.Therefore, it can be seen that the compound of the present invention has an excellent anti-inflammatory effect.
[실험예 4][Experimental Example 4]
세포 독성 평가Cytotoxicity assessment
본 실험예에서는 본 발명의 화합물을 사용시 세포 독성 발현 여부를 확인하였다. 이를 위해 세포에 본 발명의 화합물을 처리한 후 세포 생존율을 확인하였다.In this experimental example, it was confirmed whether or not cytotoxicity was expressed when the compound of the present invention was used. To this end, cells were treated with the compound of the present invention, and then cell viability was confirmed.
[실험예 4-1] [Experimental Example 4-1]
대식세포인 Raw 264.7 세포를 96 웰 플레이트에 각각 5X10 4 로 시딩하여 37 ℃, 5% CO 2 인큐베이터에서 24 시간 배양한 후, 실시예 11의 화합물(SA) 0.1, 1, 10 μM 및 양성 대조군 L-NMMA (20 μM)를 30분 동안 전처리한 후 100 ng/ml의 LPS으로 24시간 동안 자극하였다. 24 시간 배양한 후, 0.5 mg/ml MTT 용액 (3-[4,5-dimethylthiazol-2-yl]-2,5-bromide)을 1시간 동안 처리하였다. 이 후, DMSO 100 μl를 이용하여 세포를 용해시킨 뒤 570 nm 파장 값을 microplated reader기로 측정하여 세포 독성 여부를 평가하였다. Raw 264.7 cells, which are macrophages, were seeded in a 96-well plate at 5×10 4 each and incubated in an incubator at 37° C. and 5% CO 2 for 24 hours, and then compound (SA) of Example 11 0.1, 1, 10 μM and positive control L -NMMA (20 μM) was pretreated for 30 minutes and then stimulated with 100 ng/ml LPS for 24 hours. After incubation for 24 hours, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 μl of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
그 결과, 도 5a 내지 도 5c에 각각 나타낸 바와 같이, 실시예 11(SA), 12 및 18의 화합물은 세포 생존율을 거의 100%로 유지하여 세포 독성이 없이 안전하게 사용할 수 있음을 확인하였다. As a result, as shown in FIGS. 5A to 5C, respectively, it was confirmed that the compounds of Examples 11 (SA), 12, and 18 maintained cell viability at almost 100%, so that they could be safely used without cytotoxicity.
[실험예 4-2] [Experimental Example 4-2]
상기 실험예 4-1과 동일한 방법으로, 실시예 11, 44, 56 및 60의 화합물에 대하여 추가의 실험을 수행하여, 그 결과를 도 5d에 나타내었다.In the same manner as in Experimental Example 4-1, additional experiments were performed on the compounds of Examples 11, 44, 56, and 60, and the results are shown in FIG. 5D.
도 5d에 나타낸 바와 같이, 실시예 11, 44, 56 및 60의 화합물은 세포 생존율을 거의 100%로 유지하여 세포 독성 없이 안전하게 사용할 수 있는 것을 확인하였다.As shown in FIG. 5D, it was confirmed that the compounds of Examples 11, 44, 56 and 60 maintained cell viability at almost 100% and could be safely used without cytotoxicity.
또한, 실시예 11, 44, 56 및 60의 화합물에 대하여 세포 보호 효과를 평가하여, 그 결과를 도 5e에 나타내었다. In addition, the cell protective effect was evaluated for the compounds of Examples 11, 44, 56 and 60, and the results are shown in FIG. 5E.
도 5e에 나타낸 바와 같이, LPS 100 ng/ml 유도 그룹은 세포독성을 나타내었고, 실시예 11, 44, 56 및 60의 화합물은 세포 보호 효과를 나타내었다.As shown in Figure 5e, the LPS 100 ng / ml inducing group exhibited cytotoxicity, and the compounds of Examples 11, 44, 56 and 60 exhibited a cytoprotective effect.
[실험예 5][Experimental Example 5]
항섬유증 효과 확인Confirmation of antifibrotic effect
본 실험예에서는 본 발명의 화합물의 α-SMA의 발현 정도에 미치는 영향을 측정하여 본 발명의 화합물의 항섬유증 활성을 확인하고자 하였다.In this experimental example, the effect of the compound of the present invention on the expression level of α-SMA was measured to confirm the antifibrotic activity of the compound of the present invention.
LX2 세포 (Human stellate cells)를 60 φ 디쉬에 각각 1Х10 6 로 시딩하여 37 ℃, 5% CO 2 인큐베이터에서 24 시간 배양한 후, 실시예 11의 화합물(SA) 1, 5, 10 μM을 농도별로 전처리하여 1시간 동안 배양하고, TGF-β를 2 ng/ml의 농도로 처리하여 24 시간 동안 배양하였다. 배양한 세포를 모은 후, 원심분리기 (5,000 rpm, 5 min, 4℃)로 세포 pellet을 spin down 시킨 후 lysis buffer를 첨가, 1일 동안 용해시킨 후 원심분리기 (12,000 rpm, 25 min, 4℃)하여 세포막 성분 등을 제거하였다. SDS-PAGE로 변성 분리하여, 이를 PVDF membrane에 transfer하였다. 그 후, 1차 항체를 하룻밤 동안 반응시킨 후, 2차 항체를 결합시키고 ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA)을 이용해서 α-SMA의 발현을 측정하였다.LX2 cells (Human stellate cells) were seeded in a 60 φ dish with 1Х10 6 each and incubated in an incubator at 37° C. and 5% CO 2 for 24 hours, and then compound (SA) 1, 5, and 10 μM of Example 11 were added by concentration. Pretreatment was performed and incubated for 1 hour, and TGF-β was treated at a concentration of 2 ng/ml and incubated for 24 hours. After collecting the cultured cells, spin down the cell pellet with a centrifuge (5,000 rpm, 5 min, 4℃), add lysis buffer, dissolve for 1 day, and then centrifuge (12,000 rpm, 25 min, 4℃) Thus, cell membrane components and the like were removed. After denatured separation by SDS-PAGE, it was transferred to a PVDF membrane. Thereafter, after reacting the primary antibody overnight, the secondary antibody was bound and the expression of α-SMA was measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
그 결과, 도 6a 및 6b에 나타낸 바와 같이, 실시예 11의 화합물(SA)로 전처리한 경우에는 정상군 대비 α-SMA의 양이 농도의존적으로 감소하였다. As a result, as shown in FIGS. 6A and 6B, when pretreatment with the compound (SA) of Example 11 was performed, the amount of α-SMA decreased in a concentration-dependent manner compared to the normal group.
이로써, 본 발명의 화합물이 항섬유증 활성을 나타내어, 간섬유증, 피부섬유증, 폐섬유증, 신장섬유증, 또는 심장섬유증 등의 치료에 사용될 수 있음을 확인하였다.Accordingly, it was confirmed that the compound of the present invention exhibits anti-fibrotic activity and can be used for the treatment of liver fibrosis, skin fibrosis, pulmonary fibrosis, renal fibrosis, or cardiac fibrosis.
[실험예 6][Experimental Example 6]
경구내당능 검사(oral glucose tolerance test; OGTT) 및 인슐린내성 검사(insulin tolerance test; ITT) (Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) ( in vivoin vivo test) test)
본 발명의 화합물의 혈중 포도당 수치 감소 효능을 확인하기 위하여 C57BL/6J 마우스 수컷을 사용하여 도 7에 나타낸 바와 같이 in vivo 실험을 수행하였다. 음성 대조군(DMC; Diabetes mellitus control) 및 실험군은 60 % kcal의 지방이 함유된 고지방 식이를 하도록 하였고, 정상군(CON 또는 C)은 설취류의 정상 식이를 하도록 하였다. 실험 시작 후 5주, 8주째 STZ(streptozotocin) 60 mg/kg을 투여하였고, 정상군의 경우 citrate buffer 만을 투여하였다. 실험군의 경우 실험 시작후 11주 째부터 실시예 11 화합물(SA) 10 mg/kg을 투여하였다. In order to confirm the effect of the compound of the present invention on reducing blood glucose levels, an in vivo experiment was performed as shown in FIG. 7 using a male C57BL/6J mouse. The negative control group (DMC; Diabetes mellitus control) and the experimental group were fed a high-fat diet containing 60% kcal of fat, and the normal group (CON or C) was fed a normal diet of tongue odors. At 5 and 8 weeks after the start of the experiment, STZ (streptozotocin) 60 mg/kg was administered, and in the case of the normal group, only citrate buffer was administered. In the case of the experimental group, 10 mg/kg of the compound of Example 11 (SA) was administered from the 11th week after the start of the experiment.
고지방 식이 섭취 23주째 (T12) 마우스를 대상으로 경구내당능 검사(OGTT) 및 인슐린내성 검사(ITT)을 수행하여 혈중 포도당 수치를 측정하였다. 경구내당능 검사(OGTT)는 23주째 12시간 금식 시킨 후 포도당 용액을 체중 kg당 1g씩 경구투여 한 다음 0, 15, 30, 60, 90 및 120분 후 마우스 꼬리 정맥에서 혈액을 채취하여 혈당을 측정하였다. 인슐린내성 검사(ITT)는 23주째 12시간 금식 시킨 후 인슐린 용액을 체중 kg당 1 unit씩 복강투여 한 다음 0, 15, 30, 60, 90 및 120분 후 마우스 꼬리 정맥에서 혈액을 채취하여 혈당을 측정하였다.At 23 weeks after ingestion of a high fat diet (T12), mice were subjected to an oral glucose tolerance test (OGTT) and an insulin resistance test (ITT) to measure blood glucose levels. In the oral glucose tolerance test (OGTT), after fasting for 12 hours at 23 weeks, 1g of glucose solution per kg of body weight is administered orally, and blood is collected from the tail vein of the mouse after 0, 15, 30, 60, 90 and 120 minutes to measure blood sugar. I did. Insulin tolerance test (ITT) is performed at 23 weeks after fasting for 12 hours, intraperitoneally administering 1 unit of insulin solution per kg of body weight, and then collecting blood from the tail vein of the mouse after 0, 15, 30, 60, 90 and 120 minutes to measure blood sugar. It was measured.
그 결과, 도 8a 내지 8d에 나타낸 바와 같이, 음성 대조군(DMC)와 비교하여, 본 발명의 실시예 11의 화합물(SA)을 처리한 군에서 혈중 포도당 농도가 감소하였다. 이로부터 본 발명의 화합물은 당뇨 또는 당뇨 합병증 등의 치료에 효과적으로 사용될 수 있음이 확인되었다.As a result, as shown in FIGS. 8A to 8D, compared to the negative control (DMC), the blood glucose concentration in the group treated with the compound (SA) of Example 11 of the present invention was decreased. From this, it was confirmed that the compound of the present invention can be effectively used in the treatment of diabetes or diabetic complications.
[실험예 7][Experimental Example 7]
GO level 감소 효과 확인 (Check the GO level reduction effect ( in vivoin vivo test) test)
글리옥살 (GO)은 당뇨 합병증을 유발하는 물질 중 하나로 알려져 있다. 이에 본 실험예에서는 본 발명의 화합물의 GO level 감소 효과를 평가하여 본 발명의 화합물이 당뇨 합병증 치료에 활용가능한지 확인하고자 하였다.Glyoxal (GO) is known to be one of the substances that cause diabetes complications. Accordingly, in this experimental example, the effect of reducing the GO level of the compound of the present invention was evaluated to determine whether the compound of the present invention can be used in the treatment of diabetic complications.
Dhar et al. 논문을 참고로 글리옥살 (GO)의 양을 실험예 6의 고지방 식이 섭취 23주 째 마우스의 간 조직에서 측정하였다 (PMID: 19299210). 마우스의 간 조직을 균질화한(homogenized) 후 24시간 동안 10 mM o-phenlyenediamine (o-PD) 및 0.45N perchloric acid 용매와 각각 반응시켰다. 반응 후, 여과하고 HPLC vial에 옮겨 20% ACN 용매 조건으로 분석하였다. 글리옥살 (GO)은 o-PD와 반응하여 Quinoxaline의 유도체가 생성되어 HPLC에 검출되며 internal standard로 5-methylauinoxlaine (5-MQ)을 처리 후 HPLC를 통해서 분석하였다.Dhar et al. Referring to the paper, the amount of glyoxal (GO) was measured in the liver tissue of mice 23 weeks after ingestion of the high fat diet of Experimental Example 6 (PMID: 19299210). The liver tissues of mice were homogenized and then reacted with 10 mM o-phenlyenediamine (o-PD) and 0.45N perchloric acid solvents for 24 hours, respectively. After the reaction, it was filtered, transferred to an HPLC vial, and analyzed under 20% ACN solvent conditions. Glyoxal (GO) reacts with o-PD to produce a derivative of quinoxaline and is detected by HPLC. 5-methylauinoxlaine (5-MQ) was treated as an internal standard and analyzed through HPLC.
그 결과, 도 9에 나타낸 바와 같이, 음성 대조군(DMC)와 비교하여, 본 발명의 실시예 11의 화합물(SA)을 처리한 군에서 GO level이 감소하였다. 특히 본 발명의 화합물을 처리시 GO level은 정상군과 거의 유사한 정도까지 감소하였다. 이로써 본 발명의 화합물이 당뇨 합병증의 치료에 효과적으로 사용될 수 있음을 확인하였다.As a result, as shown in FIG. 9, compared to the negative control (DMC), the GO level was decreased in the group treated with the compound (SA) of Example 11 of the present invention. In particular, when the compound of the present invention was treated, the GO level was reduced to a degree similar to that of the normal group. Accordingly, it was confirmed that the compound of the present invention can be effectively used in the treatment of diabetic complications.
[실험예 8][Experimental Example 8]
간장 지질 대사(hepatic lipid metabolism) 관련 간장 단백질(hepatic protein) level 측정 (Hepatic lipid metabolism related hepatic protein level measurement ( in vivoin vivo test) test)
본 실험예에서는 간장 지질 대사와 관련된 간장 단백질의 level을 측정였다. 구체적으로, 지방생성 또는 지방분해과 관련된 단백질 발현의 감소 여부를 측정하여, 본 발명의 화합물이 지방간, 특히 비알코올성 지방간염의 치료에 효과적으로 사용될 수 있는지 여부를 확인하고자 하였다.In this experimental example, the level of liver protein related to liver lipid metabolism was measured. Specifically, it was attempted to determine whether the compound of the present invention can be effectively used in the treatment of fatty liver, especially non-alcoholic steatohepatitis, by measuring whether or not the protein expression related to adipogenesis or lipolysis is decreased.
[실험예 8-1] 지방생성(Lipogenesis)-관련 마커[Experimental Example 8-1] Lipogenesis-related marker
Acetyl-CoA carboxylase (ACC)의 경우는 지방산을 산화시키는 인자로써 지방생성시 감소되고, FAS, SREBP1c, C/EBP α의 경우는 지방생성 인자로써 지방생성시 많이 발현되는 것으로 알려져 있다.Acetyl-CoA carboxylase (ACC) is known to be a factor that oxidizes fatty acids and is reduced during adipogenesis, and FAS, SREBP1c, and C/EBP α are known to be highly expressed during adipogenesis as adipogenesis factors.
실험예 6의 고지방 식이 섭취 23주째 마우스의 간 조직을 균질화한(homogenized) 후 24시간 동안 lysis buffer를 넣고 단백질을 추출하였다. 단백질 추출 후, 브래드 퍼드 (Bradford assay) 단백질 정량법을 통해서 정량한 후 샘플을 제작하였다. 그 후, SDS-PAGE로 변성 분리하여, 이를 PVDF membrane에 transfer하였다. 그 후, 1차 항체를 하룻밤 동안 반응시킨 후, 2차 항체를 결합시키고 ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA)을 이용해서 Acetyl-CoA carboxylase (ACC), FAS, SREBP1c, C/EBP α 단백질의 발현을 측정하였다.After the 23 weeks of ingestion of the high-fat diet of Experimental Example 6, the liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins. After protein extraction, a sample was prepared after quantification through the Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Thereafter, after reacting the primary antibody overnight, the secondary antibody is bound and Acetyl-CoA carboxylase (ACC), FAS, SREBP1c, C/EBP is used using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA). The expression of the α protein was measured.
그 결과, 도 10 및 11에 나타낸 바와 같이, 본 발명의 실시예 11의 화합물(SA)을 처리한 군에서 ACC 대비 p-ACC의 비율이 증가하였고(도 10a 및 10b), FAS, SREBP1c, C/EBP α 단백질 발현이 감소하였다(도 11a 및 11b).As a result, as shown in Figs. 10 and 11, the ratio of p-ACC to ACC was increased in the group treated with the compound (SA) of Example 11 of the present invention (Figs. 10a and 10b), FAS, SREBP1c, C /EBP α protein expression was decreased (Figs. 11A and 11B).
[실험예 8-2] 지방분해(Lipolysis)-관련 마커[Experimental Example 8-2] Lipolysis-related marker
PPAR-α 단백질은 지방분해시 많이 발현되는 것으로 알려져 있다. It is known that PPAR-α protein is highly expressed during lipolysis.
상기 실험예 8-1과 동일한 방법으로 실험예 6의 고지방 식이 섭취 23주째 마우스의 간 조직에서 PPAR-α 단백질 발현을 측정하였다. In the same manner as in Experimental Example 8-1, expression of PPAR-α protein was measured in liver tissues of mice at 23 weeks after ingestion of the high-fat diet of Experimental Example 6.
그 결과, 도 12a 및 도 12b에 나타낸 바와 같이, 본 발명의 실시예 11의 화합물(SA)을 처리한 군에서 PPAR-α 단백질 발현이 감소되었다.As a result, as shown in FIGS. 12A and 12B, the expression of PPAR-α protein was decreased in the group treated with the compound (SA) of Example 11 of the present invention.
이로부터, 본 발명의 화합물은 지방생성 또는 지방분해과 관련된 단백질 발현의 감소시켜, 지방간, 특히 비알코올성 지방간염의 치료에 효과적으로 사용될 수 있음을 확인하였다.From this, it was confirmed that the compounds of the present invention can be effectively used in the treatment of fatty liver, particularly non-alcoholic steatohepatitis, by reducing the expression of proteins associated with adipogenesis or lipolysis.
[실험예 9][Experimental Example 9]
에너지 대사 관련 간장 단백질(hepatic protein) level 측정 (Measurement of hepatic protein level related to energy metabolism ( in vivoin vivo test) test)
Sirt1 단백질의 발현량이 감소될 경우 비알코올성 지방간(NAFLD)이 유도되고 내피세포 기능장애(Endothelial dysfunction), 죽상동맥경화, 고혈압 등의 질병이 야기될 수 있다고 보고된 바 있다. 이에 본 실험예에서는 본 발명의 화합물이 Sirt1 단백질의 발현량에 미치는 영향을 확인하여 본 발명의 화합물의 비알코올성 지방간 등 치료에 대한 활용가능성을 평가하고자 하였다.It has been reported that when the expression level of Sirt1 protein is decreased, non-alcoholic fatty liver (NAFLD) is induced and diseases such as endothelial dysfunction, atherosclerosis, and hypertension can be caused. Accordingly, in this experimental example, the effect of the compound of the present invention on the expression level of the Sirt1 protein was checked to evaluate the applicability of the compound of the present invention for treatment such as non-alcoholic fatty liver.
실험예 6의 고지방 식이 섭취 23주째 마우스의 간 조직을 균질화한(homogenized) 후 24시간 동안 lysis buffer를 넣고 단백질을 추출하였다. 단백질 추출 후, 브래드 퍼드 (Bradford assay) 단백질 정량법을 통해서 정량 후 샘플을 제작하였다. 그 후, SDS-PAGE로 변성 분리하여, 이를 PVDF membrane에 transfer하였다. 그 후, 1차 항체를 하룻밤 동안 반응시킨 후, 2차 항체를 결합시키고 ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA)을 이용해서 간 조직의 Sirt1 단백질의 발현량을 측정하였다.After the 23 weeks of ingestion of the high-fat diet of Experimental Example 6, the liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins. After protein extraction, a sample was prepared after quantification through a Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Thereafter, after reacting with the primary antibody overnight, the secondary antibody was combined and the expression level of Sirt1 protein in liver tissue was measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
그 결과, 도 13a 및 13b에 나타낸 바와 같이, 본 발명의 실시예 11의 화합물(SA)을 처리한 군에서 Sirt1 단백질의 발현량이 증가하였다. 이로써 본 발명의 화합물의 비알코올성 지방간염 치료에 대한 활용가능성을 확인하였다.As a result, as shown in Figs. 13A and 13B, the expression level of the Sirt1 protein was increased in the group treated with the compound (SA) of Example 11 of the present invention. This confirmed the applicability of the compound of the present invention for the treatment of non-alcoholic steatohepatitis.
[실험예 10][Experimental Example 10]
염증 관련 간장 단백질(hepatic protein) level 측정 (Inflammation-related hepatic protein level measurement ( in vivoin vivo test) test)
본 실험예에서는 본 발명의 화합물의 비알코올성 지방간염, 당뇨, 당뇨 합병증 등에서 동반되는 염증반응 억제 효능을 평가하여, 본 발명의 화합물이 비알코올성 지방간염, 당뇨, 당뇨 합병증 치료에 사용될 수 있는지 확인하고자 하였다. In this experimental example, by evaluating the efficacy of the compound of the present invention to inhibit the inflammatory response accompanying non-alcoholic steatohepatitis, diabetes, and complications of diabetes, etc. I did.
실험예 6의 고지방 식이 섭취 23주째 마우스의 간 조직을 균질화한(homogenized) 후 24시간 동안 lysis buffer를 넣고 단백질을 추출하였다. 단백질 추출 후, 브래드 퍼드 (Bradford assay) 단백질 정량법을 통해서 정량 후 샘플을 제작하였다. 그 후, SDS-PAGE로 변성 분리하여, 이를 PVDF membrane에 transfer하였다. 그 후, 1차 항체를 하룻밤 동안 반응시킨 후, 2차 항체를 결합시키고 ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA)을 이용해서 마우스의 간 조직의 iNOS 및 COX2의 발현량을 측정하였다.After the 23 weeks of ingestion of the high-fat diet of Experimental Example 6, the liver tissues of the mice were homogenized, and the lysis buffer was added thereto for 24 hours to extract proteins. After protein extraction, a sample was prepared after quantification through a Bradford assay protein quantification method. Then, it was denatured and separated by SDS-PAGE, and it was transferred to the PVDF membrane. Then, after reacting with the primary antibody overnight, the secondary antibody was combined and the expression levels of iNOS and COX2 in the liver tissue of mice were measured using a ChmiDoc XRS+ imaging system (Bio-Rad, CA, USA).
그 결과, 도 14에 나타낸 바와 같이, 본 발명의 실시예 11의 화합물(SA)을 처리한 군에서 iNOS의 발현량이 감소하였다. 이로써 본 발명의 화합물이 비알코올성 지방간염, 당뇨, 당뇨 합병증 치료에 효과적으로 활용될 수 있음을 확인하였다.As a result, as shown in Fig. 14, the expression level of iNOS decreased in the group treated with the compound (SA) of Example 11 of the present invention. Accordingly, it was confirmed that the compound of the present invention can be effectively used in the treatment of non-alcoholic steatohepatitis, diabetes, and diabetic complications.
[실험예 11][Experimental Example 11]
간 지방증(hepatic steatosis)에의 효과 확인 (Confirmation of the effect on hepatic steatosis ( in vivoin vivo test) test)
간 지방증의 대표적인 특징은 간 조직에서의 지질방울이 관찰되고, 지질 축적이 확인되며, 콜라겐이 발현된다는 점이다. 이에 본 실험예에서는 간 조직에서의 지질방울, 지질 축적, 콜라겐 발현 정도를 확인하여, 본 발명의 화합물이 간 지방증, 특히 비알코올성 지방간 또는 비알코올성 지방간염의 치료에 사용될 수 있는지를 확인하고자 하였다.Representative features of hepatic steatosis are that lipid droplets are observed in liver tissue, lipid accumulation is confirmed, and collagen is expressed. Accordingly, in this experimental example, the degree of lipid droplets, accumulation of lipids, and collagen expression in liver tissues were checked to determine whether the compound of the present invention can be used for the treatment of hepatic steatosis, particularly non-alcoholic fatty liver or non-alcoholic steatohepatitis.
실험예 6의 고지방 식이 섭취 23주째 마우스의 간 조직을 hematoxylin eosin (H&E) 또는 PAS로 염색하여 지질방울(lipid droplet)을 확인하였고, Oil Red O로 염색하여 지질 축적을 확인하였으며, Masson's trichrome로 염색하여 콜라겐 발현을 확인하였다. The liver tissue of the mouse at 23 weeks of ingestion of the high fat diet of Experimental Example 6 was stained with hematoxylin eosin (H&E) or PAS to identify lipid droplets, stained with Oil Red O to confirm lipid accumulation, and stained with Masson's trichrome. Thus, collagen expression was confirmed.
그 결과, 도 15a 내지 15d에 나타낸 바와 같이, 본 발명의 실시예 11의 화합물(SA)을 투여한 군에서 지질방울, 지질 축적, 및 콜라겐 발현이 음성 대조군 대비 감소하였다. 이로부터 본 발명의 화합물은 간 지방증, 특히 비알코올성 지방간 또는 비알코올성 지방간염의 치료에 효과적으로 사용될 수 있음을 확인하였다. As a result, as shown in FIGS. 15A to 15D, lipid droplets, lipid accumulation, and collagen expression were decreased in the group administered with the compound (SA) of Example 11 of the present invention compared to the negative control group. From this, it was confirmed that the compound of the present invention can be effectively used in the treatment of hepatic steatosis, in particular, non-alcoholic fatty liver or non-alcoholic steatohepatitis.
[실험예 12][Experimental Example 12]
당뇨병성 신장병증(diabetic nephropathy)에의 효과 확인 (Confirmation of effect on diabetic nephropathy ( in vivoin vivo test) test)
당뇨병성 신장병증의 대표적인 특징은 사구체 모양이 변형되며, 혈관사이바탕질(mesangial matrix)의 수 및 콜라겐 발현이 증가된다는 점이다. 이에 본 실험예에서는 신장 조직에서의 사구체 모양을 관찰하고, 혈관사이바탕질(mesangial matrix)의 수 및 콜라겐 발현 정도를 확인하여, 본 발명의 화합물이 당뇨병성 신장병증의 치료에 사용될 수 있는지를 확인하고자 하였다.A typical characteristic of diabetic nephropathy is that the shape of the glomerulus is deformed, and the number of mesangial matrix and the expression of collagen are increased. Therefore, in this experimental example, the shape of the glomerulus in the kidney tissue was observed, the number of mesangial matrices and the degree of collagen expression were checked to determine whether the compound of the present invention can be used in the treatment of diabetic nephropathy. I wanted to.
실험예 6의 고지방 식이 섭취 23주째 마우스의 신장 조직을 hematoxylin eosin(H&E)로 염색하여 사구체(glomerulus)를 확인하였고, PAS로 염색하여 혈관사이바탕질(mesangial matrix)을 확인하였으며, Masso' trichrome로 염색하여 신장의 콜라겐 발현을 확인하였다.The kidney tissue of the mouse at 23 weeks after ingestion of the high fat diet of Experimental Example 6 was stained with hematoxylin eosin (H&E) to confirm the glomerulus, stained with PAS to confirm the mesangial matrix, and with Masso' trichrome. By staining, collagen expression in the kidneys was confirmed.
그 결과, 도 16a 내지 도 16c에 나타낸 바와 같이, 본 발명의 실시예 11의 화합물(SA)을 투여한 군에서는 변형된 사구체(glomerulus)의 모양이 회복하며, 혈관사이바탕질(mesangial matrix)의 수, 신장의 콜라겐 발현이 감소하였다. 이로부터 본 발명의 화합물은 당뇨병성 신장병증의 치료에 효과적으로 사용될 수 있음을 확인하였다. As a result, as shown in FIGS. 16A to 16C, in the group to which the compound (SA) of Example 11 of the present invention was administered, the shape of the modified glomerulus was restored, and the mesangial matrix The number and the expression of collagen in the kidney were decreased. From this, it was confirmed that the compound of the present invention can be effectively used in the treatment of diabetic nephropathy.
[실험예 13][Experimental Example 13]
항근감소증 효과 확인Confirmation of antimyelopathy effect
당뇨합병증에서는 근감소증이 동반된다. 본 실험예에서는 본 발명의 화합물이 항근감소중 효과를 나타내는지를 확인하기 위해, 당독소 물질 중에서 독성이 강력한 메틸글리옥살 (MGO) 처리로 인한 세포 보호효과를 나타내는지를 확인하기 위해 세포생존률 및 세포형태를 관찰하였다.Diabetic complications are accompanied by sarcopenia. In this experimental example, in order to confirm whether the compound of the present invention exhibits an effect during anti-muscular reduction, cell viability and cell morphology are observed to confirm whether the compound of the present invention exhibits a cell protective effect due to treatment with methylglyoxal (MGO), which is highly toxic among glycotoxin substances. Was observed.
근육세포인 C2C12 세포를 6 웰 플레이트에 각각 2.5X10 5 로 시딩하여 37 ℃, 5% CO 2 인큐베이터에서 24 시간 배양한 후, 2% horse serum 배지로 교체 후 4일 동안 분화하였다. 4일 후, 실시예 11(SA), 44, 56 및 60의 화합물 10 μM를 각각 1시간 동안 전처리한 후 1.5 mM의 MGO로 24시간 동안 자극하였다. 24시간 후, IncuCyte imaging 프로그램을 이용하여 세포형태를 관찰한 후 0.5 mg/ml MTT 용액 (3-[4,5-dimethylthiazol-2-yl]-2,5- bromide)을 1시간 동안 처리하였다. 이 후, DMSO 100 μl를 이용하여 세포를 용해시킨 뒤 570 nm 파장 값을 microplated reader기로 측정하여 세포 독성 여부를 평가하였다. C2C12 cells, which are muscle cells, were seeded in a 6-well plate at 2.5×10 5 each, incubated in a 37° C., 5% CO 2 incubator for 24 hours, and then differentiated for 4 days after replacement with 2% horse serum medium. After 4 days, 10 μM of the compounds of Examples 11 (SA), 44, 56, and 60 were each pretreated for 1 hour, followed by stimulation with 1.5 mM MGO for 24 hours. After 24 hours, after observing the cell morphology using IncuCyte imaging program, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 μl of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
실시예 11(SA), 44, 56 및 60의 화합물은 모두 MGO에 대한 보호효과가 우수한 것을 확인하였고, 특히 도 17에 나타낸 바와 같이 실시예 60 화합물은 MGO에 대한 보호효과가 매우 우수한 것을 확인하였다.It was confirmed that the compounds of Examples 11 (SA), 44, 56, and 60 all have excellent protective effects against MGO, and in particular, as shown in FIG. 17, it was confirmed that the compound of Example 60 has very excellent protective effects against MGO. .
따라서, 실시예 11(SA), 44, 56 및 60의 화합물은 모두 당뇨병성 근감소증 치료에 효과적으로 사용될 수 있는 것을 알 수 있다.Therefore, it can be seen that the compounds of Examples 11 (SA), 44, 56 and 60 can be effectively used in the treatment of diabetic sarcopenia.
[실험예 14][Experimental Example 14]
항궤양성 대장염 효과 확인Confirmation of anti-ulcerative colitis effect
당뇨합병증에서는 궤양성 대장염 및 염증성 장질환이 동반된다. 본 실험예에서는 항궤양성 대장염 및 염증성 장질환 효과를 나타내는지를 확인하기 위해, 당독소 물질 중에서 독성이 강력한 메틸글리옥살 (MGO) 처리로 인한 세포 보호효과를 나타내는지를 확인하기 위해 세포생존율 및 세포이동성을 관찰하였다.Diabetic complications are accompanied by ulcerative colitis and inflammatory bowel disease. In this experimental example, in order to confirm whether it exhibits anti-ulcerative colitis and inflammatory bowel disease effects, cell viability and cell mobility were observed to confirm whether it exhibits a cell protective effect due to treatment with methylglyoxal (MGO), which is highly toxic among glycotoxin substances. Was observed.
인간 소장 상피세포인 HIEC-6 세포를 96 웰 플레이트에 각각 2.0X10 4 및 8.0X10 4 로 시딩하여 37 ℃, 5% CO 2 인큐베이터에서 24 시간 배양한 후, 세포생존률의 경우는 실시예 11(SA), 44, 56 및 60의 화합물 10 μM를 1시간 동안 전처리한 후 1.0 mM의 MGO로 24시간 동안 자극하였다. 24시간 후, 0.5 mg/ml MTT 용액 (3-[4,5-dimethylthiazol-2-yl]-2,5- bromide)을 1시간 동안 처리하였다. 이 후, DMSO 100 μl를 이용하여 세포를 용해시킨 후 570 nm 파장 값을 microplated reader기로 측정하여 세포 독성 여부를 평가하였다. HIEC-6 cells, which are human small intestine epithelial cells, were seeded in a 96-well plate at 2.0X10 4 and 8.0X10 4 , respectively, and cultured in an incubator at 37°C and 5% CO 2 for 24 hours. ), 10 μM of compounds of 44, 56 and 60 were pretreated for 1 hour and then stimulated with 1.0 mM MGO for 24 hours. After 24 hours, 0.5 mg/ml MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5- bromide) was treated for 1 hour. Thereafter, cells were lysed using 100 μl of DMSO, and then the 570 nm wavelength value was measured with a microplated reader to evaluate the cytotoxicity.
세포이동성의 경우 24시간 배양한 후, wound maker를 통해서 세포에 상처를 낸 후, 세포생존률과 동일하게 처리한 후, 0시간부터 24시간까지 2시간 간격으로 IncuCyte imaing 프로그램을 이용하여 세포이동성 형태학적 관찰 및 세포이동성 관련 요소 (relative wound density, wound confluence, 및 wound width)를 측정하였다.In the case of cell mobility, after culturing for 24 hours, wound the cells through a wound maker, treated in the same manner as the cell viability, and then used the IncuCyte imaing program at intervals of 2 hours from 0 to 24 hours. Observation and cell mobility related factors (relative wound density, wound confluence, and wound width) were measured.
그 결과, 실시예 11(SA), 44, 56 및 60의 화합물은 MGO에 대한 보호 효과를 나타내는 것을 확인하였고, 특히 도 18a 및 18b에 나타낸 바와 같이, 실시예 11 및 60의 화합물은 MGO에 대한 우수한 보호 효과를 나타내는 것을 확인하였다.As a result, it was confirmed that the compounds of Examples 11 (SA), 44, 56 and 60 exhibit a protective effect against MGO, and in particular, as shown in FIGS. 18A and 18B, the compounds of Examples 11 and 60 were It was confirmed that an excellent protective effect was exhibited.
또한, 세포이동성 효과는 MGO 처리에 의해서 세포이동 억제를 회복하는 효과로 평가하였으며, 실시예 11, 44, 56 및 60의 화합물은 MGO에 대해 억제된 세포이동을 회복하는 효과를 나타내는 것을 확인하였고, 특히 도 19a 내지 19d에 나타낸 바와 같이 실시예 56 및 60의 화합물은 우수한 세포이동 회복 효과를 갖는 것을 확인하였다. In addition, the effect of cell migration was evaluated as the effect of restoring the inhibition of cell migration by treatment with MGO, and it was confirmed that the compounds of Examples 11, 44, 56 and 60 exhibit the effect of restoring the suppressed cell migration to MGO, In particular, as shown in Figs. 19A to 19D, it was confirmed that the compounds of Examples 56 and 60 have excellent cell migration recovery effects.
따라서, 본 발명의 화합물은 궤양성 대장염 및 염증성 장질환 치료에 효과적으로 사용될 수 있는 것을 알 수 있다.Therefore, it can be seen that the compound of the present invention can be effectively used for the treatment of ulcerative colitis and inflammatory bowel disease.

Claims (17)

  1. 하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염:A compound of formula (I) or a pharmaceutically acceptable salt thereof:
    [화학식 I][Formula I]
    Figure PCTKR2020016038-appb-img-000075
    Figure PCTKR2020016038-appb-img-000075
    상기 식에서,In the above formula,
    고리 A는 시클로알킬, 헤테로시클로알킬, 아릴, 헤테로아릴, 또는 바이시클로알킬이고;Ring A is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
    고리 B는 시클로알킬, 헤테로시클로알킬, 아릴, 헤테로아릴, 또는 바이시클로알킬이고;Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or bicycloalkyl;
    W는 단일결합이거나, -NR 4C(=O)-, 또는 -NR 4알킬-이고;W is a single bond, -NR 4 C(=O)-, or -NR 4 alkyl-;
    R 1, R 2, R 3, 또는 R 4는 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O) 2Rb, -NO 2, -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2Ra, -S(=O) 2N(Ra)(Rb), 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고;R 1 , R 2 , R 3, or R 4 are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Ra, -C(=O)N(Ra)( Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S (=O) 2 Rb, -NO 2 , -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S( =O) 2 Ra, -S(=O) 2 N(Ra)(Rb), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    R 1, R 2, 및 R 3는 각각 독립적으로 하나 이상일 수 있으며;R 1 , R 2 , and R 3 may each independently be one or more;
    Ra 또는 Rb는 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -N(Rc) 2, -ORc, -SRc, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고, 이 때 Rc는 각각 독립적으로 수소, 할로, 알킬, 알케닐, 알키닐, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고;Ra or Rb are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -N(Rc) 2 , -ORc, -SRc, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and Each Rc is independently hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    n은 0 내지 4이며;n is 0 to 4;
    여기서 상기 알킬, 알케닐, 알키닐, 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴은 각각 독립적으로 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Rd, -C(=O)N(Rd)(Re), -C(=O)ORd, -N(Rd)(Re), -N(Rd)C(=O)Re, -N(Rd)S(=O)Re, -N(Rd)S(=O) 2Re, -NO 2, -ORd, -OC(=O)Rd, -SRd, -S(=O)Rd, -S(=O)N(Rd)(Re), -S(=O) 2Rd, -S(=O) 2N(Rd)(Re), 시클로알킬, 헤테로시클로알킬, 아릴, 및 헤테로아릴로 이루어진 군으로부터 선택된 하나 이상의 기로 치환되거나 치환되지 않으며, 이 때 Rd 또는 Re는 각각 독립적으로 수소, 할로, 또는 알킬이다.Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are each independently halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Rd, -C( =O)N(Rd)(Re), -C(=O)ORd, -N(Rd)(Re), -N(Rd)C(=O)Re, -N(Rd)S(=O) Re, -N(Rd)S(=O) 2 Re, -NO 2 , -ORd, -OC(=O)Rd, -SRd, -S(=O)Rd, -S(=O)N(Rd )(Re), -S(=O) 2 Rd, -S(=O) 2 N(Rd)(Re), cycloalkyl, heterocycloalkyl, aryl, and substituted with one or more groups selected from the group consisting of heteroaryl Or not substituted, wherein Rd or Re is each independently hydrogen, halo, or alkyl.
  2. 제1항에 있어서, The method of claim 1,
    W는 단일결합이거나, -NHC(=O)-, 또는 -NH알킬-이고,W is a single bond, -NHC(=O)-, or -NHalkyl-,
    R 1, R 2, 또는 R 3은 각각 독립적으로 수소, 할로, 시아노, 알킬, 알케닐, 알키닐, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O) 2Rb, -NO 2, -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2Ra, -S(=O) 2N(Ra)(Rb), 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴인, 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염.R 1 , R 2 , or R 3 are each independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C(=O)ORa, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O)Rb, -N(Ra)S(=O ) 2 Rb, -NO 2 , -ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)N(Ra)(Rb), -S(=O) 2 Ra, -S(=O) 2 N(Ra)(Rb), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, a compound of formula I, or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서, The method of claim 1,
    고리 A는 5- 또는 6-원 헤테로시클로알킬이고;Ring A is 5- or 6-membered heterocycloalkyl;
    고리 B는
    Figure PCTKR2020016038-appb-img-000076
    또는
    Figure PCTKR2020016038-appb-img-000077
    이고;    Ring B is
    Figure PCTKR2020016038-appb-img-000076
    or
    Figure PCTKR2020016038-appb-img-000077
    ego;
    X는 C 또는 N이며;X is C or N;
    W는 단일결합이거나, -NHC(=O)-, 또는 -NH알킬-이고;W is a single bond, -NHC(=O)-, or -NHalkyl-;
    R 1은 -C(=O)Ra, -C(=O)ORa, -S(=O) 2Ra, 또는 -S(=O) 2N(Ra)(Rb)이고;R 1 is -C(=O)Ra, -C(=O)ORa, -S(=O) 2 Ra, or -S(=O) 2 N(Ra)(Rb);
    R 2는 수소, 할로, 알킬, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O) 2Rb, -NO 2, -ORa, 또는 아릴이고; R 2 is hydrogen, halo, alkyl, -N(Ra)(Rb), -N(Ra)C(=O)Rb, -N(Ra)S(=O) 2 Rb, -NO 2 , -ORa, Or aryl;
    R 3는 수소, 할로, -N(Ra)(Rb), -NO 2, 또는 -ORa이고;R 3 is hydrogen, halo, -N(Ra)(Rb), -NO 2 , or -ORa;
    Ra 또는 Rb는 각각 독립적으로 수소; 할로기로 치환되거나 비치환된 C 1-6알킬; 또는 -S(=O) 2N(Rd)(Re)로 치환되거나 비치환된 5- 또는 6-원 헤테로시클로알킬이며, 이 때 Rd 또는 Re는 각각 독립적으로 수소 또는 C 1-6알킬인Ra or Rb are each independently hydrogen; C 1-6 alkyl unsubstituted or substituted with halo group; Or -S(=O) 2 N(Rd)(Re) substituted or unsubstituted 5- or 6-membered heterocycloalkyl, wherein Rd or Re is each independently hydrogen or C 1-6 alkyl
    화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염.A compound of formula I or a pharmaceutically acceptable salt thereof.
  4. 하기 화학식 II의 화합물 또는 이의 약학적으로 허용가능한 염:A compound of formula II or a pharmaceutically acceptable salt thereof:
    [화학식 II][Formula II]
    Figure PCTKR2020016038-appb-img-000078
    Figure PCTKR2020016038-appb-img-000078
    상기 식에서,In the above formula,
    고리 B는
    Figure PCTKR2020016038-appb-img-000079
    또는
    Figure PCTKR2020016038-appb-img-000080
    이고;    Ring B is
    Figure PCTKR2020016038-appb-img-000079
    or
    Figure PCTKR2020016038-appb-img-000080
    ego;
    X는 C 또는 N이고;X is C or N;
    Y 및 Z 중 하나는 N, 나머지는 C이고;One of Y and Z is N and the other is C;
    W는 단일결합이거나, -NHC(=O)-, 또는 -NHC 1-6알킬-이고;W is a single bond, -NHC(=O)-, or -NHC 1-6 alkyl-;
    R 1는 -C(=O)C 1-6알킬, -C(=O)OC 1-6알킬, -S(=O) 2C 1-6알킬, 또는 -S(=O) 2N(C 1-6알킬) 2이고;R 1 is -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -S(=O) 2 C 1-6 alkyl, or -S(=O) 2 N( C 1-6 alkyl) 2 ;
    R 2는 수소, C 1-6알킬, -NH(Rb), -NHC(=O)Rb, -NHS(=O) 2Rb, -NO 2, -ORa, 또는 페닐이고;R 2 is hydrogen, C 1-6 alkyl, -NH(Rb), -NHC(=O)Rb, -NHS(=O) 2 Rb, -NO 2 , -ORa, or phenyl;
    R 3는 수소, 할로 또는 -ORa이고;R 3 is hydrogen, halo or -ORa;
    R 1, R 2, 및 R 3는 각각 독립적으로 하나 이상일 수 있으며;R 1 , R 2 , and R 3 may each independently be one or more;
    Ra는 각각 독립적으로 할로기로 치환되거나 비치환된 C 1-6알킬이고; Each Ra is independently C 1-6 alkyl unsubstituted or substituted with a halo group;
    Rb는 각각 독립적으로 수소; C 1-6알킬; 또는 -S(=O) 2N-(C 1-6알킬) 2로 치환되거나 비치환된 피페리딘이며;Each Rb is independently hydrogen; C 1-6 alkyl; Or piperidine unsubstituted or substituted with -S(=O) 2 N-(C 1-6 alkyl) 2;
    n은 1 또는 2이다.n is 1 or 2.
  5. 제4항에 있어서, The method of claim 4,
    W는 단일결합이거나, -NHC(=O)-, 또는 -NHCH 2-이고;W is a single bond, -NHC(=O)-, or -NHCH 2 -;
    R 1은 -C(=O)CH 3, -C(=O)OC(CH 3) 3, -S(=O) 2CH 3, -S(=O) 2CH(CH 3) 2 또는 -S(=O) 2N(CH 3) 2이고;R 1 is -C(=O)CH 3 , -C(=O)OC(CH 3 ) 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH(CH 3 ) 2 or- S(=O) 2 N(CH 3 ) 2 ;
    R2는 수소, -CH 3, -NH 2, -NHC(=O)CH 3,
    Figure PCTKR2020016038-appb-img-000081
    , -NHS(=O) 2CH 3, -NO 2, -OCH 3, -OCF 3, 또는 페닐이고;     R2 is hydrogen, -CH 3 , -NH 2 , -NHC(=O)CH 3 ,
    Figure PCTKR2020016038-appb-img-000081
    , -NHS (= O) 2 CH 3, -NO 2, -OCH 3, -OCF 3, or phenyl;
    R3는 수소, 할로 또는 -OCH 3인 R3 is hydrogen, halo or -OCH 3
    화학식 II의 화합물 또는 이의 약학적으로 허용가능한 염.A compound of formula II or a pharmaceutically acceptable salt thereof.
  6. 하기 화합물로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용가능한 염:A compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
    1) 1-아세틸-N-(1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;1) 1-acetyl-N-(1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
    2) tert-부틸 4-((1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;2) tert-butyl 4-((1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
    3) tert-부틸 3-((1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;3) tert-butyl 3-((1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
    4) N-(1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)-1-(메틸설포닐)피페리딘-4-카르복스아미드;4) N-(1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;
    5) N-(1-(3-아미노벤질)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드;5) N-(1-(3-aminobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide;
    6) tert-부틸 4-((1-(4-아미노페네틸)-1H-벤조[d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;6) tert-butyl 4-((1-(4-aminophenethyl)-1H-benzo[d]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
    7) N-(1-(4-아미노페네틸)-1H-벤조[d]이미다졸-2-일)-1-(메틸설포닐)피페리딘-4-카르복스아미드;7) N-(1-(4-aminophenethyl)-1H-benzo[d]imidazol-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;
    8) 1-(N,N-디메틸설파모일)-N-(3-((2-(1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미도)-1H-벤조[d]이미다졸-1-일)메틸)페닐)피페리딘-4-카르복스아미드;8) 1-(N,N-dimethylsulfamoyl)-N-(3-((2-(1-(N,N-dimethylsulfamoyl) piperidine-4-carboxamido)-1H-benzo [d]imidazol-1-yl)methyl)phenyl)piperidine-4-carboxamide;
    9) N-(1-(3-아세트아미도벤질)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드;9) N-(1-(3-acetamidobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide ;
    10) 1-(N,N-디메틸설파모일)-N-(1-(3-(메틸설폰아미도)벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;10) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-(methylsulfonamido)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4- Carboxamide;
    11) 1-(N,N-디메틸설파모일)-N-(1-(3-니트로벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;11) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-nitrobenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
    12) 1-(N,N-디메틸설파모일)-N-(1-(4-니트로벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;12) 1-(N,N-dimethylsulfamoyl)-N-(1-(4-nitrobenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
    13) 1-(N,N-디메틸설파모일)-N-(1-(3-니트로페네틸)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;13) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-nitrophenethyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
    14) N-(1-(4-아미노벤질)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드;14) N-(1-(4-aminobenzyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide;
    15) N-(1-(3-아미노페네틸)-1H-벤조[d]이미다졸-2-일)-1-(N,N-디메틸설파모일)피페리딘-4-카르복스아미드;15) N-(1-(3-aminophenethyl)-1H-benzo[d]imidazol-2-yl)-1-(N,N-dimethylsulfamoyl)piperidine-4-carboxamide;
    16) 1-(N,N-디메틸설파모일)-N-(1-(4-니트로페네틸)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;16) 1-(N,N-dimethylsulfamoyl)-N-(1-(4-nitrophenethyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
    17) 1-(N,N-디메틸설파모일)-N-(1-(피리딘-3-일메틸)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;17) 1-(N,N-dimethylsulfamoyl)-N-(1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide ;
    18) 1-(N,N-디메틸설파모일)-N-(1-(3-메틸벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;18) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-methylbenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
    19) 1-(N,N-디메틸설파모일)-N-(1-(3-(트리플루오로메톡시)벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드; 19) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-(trifluoromethoxy)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-4- Carboxamide;
    20) 1-(N,N-디메틸설파모일)-N-(1-(3-메톡시벤질)-1H-벤조[d]이미다졸-2-일)피페리딘-4-카르복스아미드;20) 1-(N,N-dimethylsulfamoyl)-N-(1-(3-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
    21) N-(1-(3-아미노-4-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)-1-( N, N-디메틸술파모일)피페리딘-4-카르복스아미드;21) N- (1-(3-amino-4-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-( N , N -dimethylsulfamoyl)piperidin-4- Carboxamide;
    22) tert-부틸 4-((1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;22) tert -butyl 4-((1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate ;
    23) 1-(이소프로필설포닐)- N-(1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;23) 1- (isopropylsulfonyl) - N - (1- (3- ( trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide, amides;
    24) tert-부틸 4-((1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;24) tert -butyl 4-((1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
    25) 1-(이소프로필설포닐)- N-(1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카복스아미드;25) 1- (isopropylsulfonyl) - N - (1- (3- methyl-benzyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide;
    26) tert-부틸 4-((1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;26) tert -butyl 4-((1-(pyridin-3-ylmethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
    27) 1-(이소프로필설포닐)- N-(1-(피리딘-3-일메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;27) 1- (isopropylsulfonyl) - N - (1- (pyridin-3-ylmethyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide;
    28) tert-부틸 4-((1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;28) tert -butyl 4-((1-(thiazol-4-ylmethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine-1-carboxylate;
    29) 1-(이소프로필설포닐)- N-(1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카복스아미드;29) 1- (isopropylsulfonyl) - N - (1- (4-ylmethyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxamide;
    30) 1-( N, N-디메틸술파모일)- N-(1-(티아졸-4-일메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;30) 1- (N, N - dimethyl sulfamoyl) - N - (1- (4-ylmethyl) -1 H - benzo [d] imidazol-2-yl) piperidine-4-carboxylic Boxamide;
    31) tert-부틸 4-((1-((6-메틸피리딘-2-일)메틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;31) tert -butyl 4-((1-((6-methylpyridin-2-yl)methyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidin-1-car Boxylate;
    32) 1-(이소프로필설포닐)- N-(1-((6-메틸피리딘-2-일)메틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;32) 1- (isopropylsulfonyl) - N - (1 - ( (6- methylpyridin-2-yl) methyl) -1 H - benzo [d] imidazol-2-yl) piperidin-4 Carboxamide;
    33) tert-부틸 4-((1-(2-(4-페닐피페라진-1-일)에틸)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;33) tert -Butyl 4-((1-(2-(4-phenylpiperazin-1-yl)ethyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
    34) 1-(이소프로필설포닐)- N-(1-(2-(4-페닐피페라진-1-일)에틸)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카복스아미드;34) 1- (isopropylsulfonyl) - N - (1- (2- (4- phenyl-piperazin-1-yl) ethyl) -1 H - benzo [d] imidazol-2-yl) piperidine -4-carboxamide;
    35) 1-( N, N-디메틸설파모일)- N-(6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;35) 1- (N, N - dimethyl sulfamoyl) - N - (6- fluoro-1 - (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) Piperidine-4-carboxamide;
    36) 1-( N, N-디메틸설파모일)- N-(5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;36) 1- (N, N - dimethyl sulfamoyl) - N - (5-fluoro-1- (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) Piperidine-4-carboxamide;
    37) tert-부틸 4-((6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;37) tert -Butyl 4-((6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
    38) tert-부틸 4-((5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;38) tert -Butyl 4-((5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
    39) N-(6-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)-1-(이소프로필술포닐)피페리딘-4-카르복스아미드;39) N- (6-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-(isopropylsulfonyl)piperidine -4-carboxamide;
    40) N-(5-플루오로-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)-1-(이소프로필술포닐)피페리딘-4-카르복스아미드;40) N- (5-fluoro-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)-1-(isopropylsulfonyl)piperidine -4-carboxamide;
    41) 1-( N, N-디메틸설파모일)- N-(5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;41) 1- (N, N - dimethyl sulfamoyl) - N - (5- methoxy-1- (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) Piperidine-4-carboxamide;
    42) tert-부틸 4-((5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)카르바모일)피페리딘-1-카르복실레이트;42) tert -Butyl 4-((5-methoxy-1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)carbamoyl)piperidine- 1-carboxylate;
    43) 1-(이소프로필설포닐)- N-(5-메톡시-1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-4-카르복스아미드;43) 1- (isopropylsulfonyl) - N - (5- methoxy-1- (3- (trifluoromethoxy) benzyl) -1 H - benzo [d] imidazol-2-yl) piperidine -4-carboxamide;
    44) 4-(((1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-일)아미노)메틸)- N, N-디메틸피페리딘-1-설폰아미드;44) 4-(((1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-yl)amino)methyl) -N , N -dimethylpiperidine-1-sulfonamide;
    45) N, N-디메틸-4-(((1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)아미노)메틸)피페리딘-1-설폰아미드;45) N , N -dimethyl-4-(((1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)amino)methyl)piperidine-1-sulfonamide;
    46) N, N-디메틸-4-(((1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)아미노)메틸)피페리딘-1-설폰아미드;46) N , N -dimethyl-4-(((1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)amino)methyl)piperidine-1 -Sulfonamide;
    47) 4-(1-(3-아미노벤질)-1 H-벤조[ d]이미다졸-2-일)- N, N-디메틸피페리딘-1-설폰아미드;47) 4-(1-(3-aminobenzyl)-1 H -benzo[ d ]imidazol-2-yl) -N , N -dimethylpiperidine-1-sulfonamide;
    48) N, N-디메틸-4-(1-(3-메틸벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-1-설포나미드; 및48) N , N -dimethyl-4-(1-(3-methylbenzyl)-1 H -benzo[ d ]imidazol-2-yl)piperidine-1-sulfonamide; And
    49) N, N-디메틸-4-(1-(3-(트리플루오로메톡시)벤질)-1 H-벤조[ d]이미다졸-2-일)피페리딘-1-설폰아미드.49) N , N -dimethyl-4-(1-(3-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazol-2-yl)piperidine-1-sulfonamide.
  7. 제1항 내지 제6항 중 어느 한 항에 따른 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for the prevention or treatment of diseases related to final glycation products, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
  8. 제7항에 있어서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 퇴행성 뇌질환, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물.8. A pharmaceutical composition for preventing or treating diseases related to final glycosylated products, characterized in that it is selected from the group.
  9. 제7항에 있어서, 상기 최종당화산물 관련 질환은 당뇨 합병증 또는 비알코올성 지방간염인 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물.[8] The pharmaceutical composition of claim 7, wherein the final glycated product-related disease is a diabetic complication or non-alcoholic steatohepatitis.
  10. 제8항에 있어서, 상기 당뇨 합병증은 궤양성 대장염, 염증성 장질환, 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 및 근감소증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물.The method of claim 8, wherein the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis. , Diabetic osteoporosis, and sarcopenia, characterized in that selected from the group consisting of, the final glycation product-related diseases for the prevention or treatment of pharmaceutical composition.
  11. 제8항에 있어서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 치료용 약학 조성물.The method of claim 8, wherein the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia. , Progressive nuclear paralysis, cognitive dysfunction, senile dementia, lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early dementia, temporal lobe epilepsy, and stroke. Pharmaceutical composition for the prophylaxis or treatment of.
  12. 제1항 내지 제6항 중 어느 한 항에 따른 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 식품 조성물.A food composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
  13. 제1항 내지 제6항 중 어느 한 항에 따른 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.A food composition for the prevention or improvement of diseases related to final glycation products, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
  14. 제13항에 있어서, 상기 최종당화산물 관련 질환은 노화, 당뇨병, 당뇨 합병증, 퇴행성 뇌질환, 동맥경화, 비알코올성 지방간, 비알코올성 지방간염, 피부섬유증, 폐섬유증, 신장섬유증, 및 심장섬유증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.The method of claim 13, wherein the final glycated product-related diseases are aging, diabetes, complications of diabetes, degenerative brain disease, arteriosclerosis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, skin fibrosis, pulmonary fibrosis, renal fibrosis, and heart fibrosis. Food composition for preventing or improving the disease related to the final glycation product, characterized in that selected from the group.
  15. 제13항에 있어서, 상기 최종당화산물 관련 질환은 당뇨 합병증 또는 비알코올성 지방간염인 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.[14] The food composition of claim 13, wherein the final glycated product-related disease is a diabetes complication or non-alcoholic steatohepatitis.
  16. 제14항에 있어서, 상기 당뇨 합병증은 궤양성 대장염, 염증성 장질환, 당뇨병성 신장병증, 당뇨병성 망막증, 당뇨병성 백내장, 당뇨병성 신경병증, 당뇨병성 족부궤양, 당뇨병성 심혈관 질환, 당뇨병성 동맥경화, 당뇨병성 골다공증, 및 근감소증으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.The method of claim 14, wherein the diabetic complication is ulcerative colitis, inflammatory bowel disease, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy, diabetic foot ulcer, diabetic cardiovascular disease, diabetic arteriosclerosis. , Diabetic osteoporosis, and sarcopenia, characterized in that selected from the group consisting of, the final glycation product-related disease prevention or improvement food composition.
  17. 제14항에 있어서, 상기 퇴행성 뇌질환은 알츠하이머, 파킨슨병, 헌팅턴병, 피크병, 크로이츠펠트-야콥병, 루게릭병, 척수소뇌변성증, 프리드리히 운동실조증, 척수소뇌 실조증, 마카도-조셉병, 근육긴장이상, 진행성 핵상 마비, 인지기능장애, 노인성 치매, 루이소체 치매, 전두측두엽 치매, 혈관성 치매, 알코올성 치매, 초로기 치매, 측두엽 간질, 및 뇌졸중으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 최종당화산물 관련 질환의 예방 또는 개선용 식품 조성물.The method of claim 14, wherein the degenerative brain disease is Alzheimer's, Parkinson's disease, Huntington's disease, Peak's disease, Creutzfeldt-Jakob's disease, Lou Gehrig's disease, spinal cerebellar degeneration, Friedrich's ataxia, spinal cerebellar ataxia, Macado-Joseph's disease, dystonia. , Progressive nuclear paralysis, cognitive dysfunction, senile dementia, lewy body dementia, frontotemporal dementia, vascular dementia, alcoholic dementia, early dementia, temporal lobe epilepsy, and stroke. Food composition for the prevention or improvement of.
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