WO2017135786A1 - Novel amide compound and use thereof - Google Patents

Novel amide compound and use thereof Download PDF

Info

Publication number
WO2017135786A1
WO2017135786A1 PCT/KR2017/001288 KR2017001288W WO2017135786A1 WO 2017135786 A1 WO2017135786 A1 WO 2017135786A1 KR 2017001288 W KR2017001288 W KR 2017001288W WO 2017135786 A1 WO2017135786 A1 WO 2017135786A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
pyrazole
methyl
carboxamido
carbamoyl
Prior art date
Application number
PCT/KR2017/001288
Other languages
French (fr)
Korean (ko)
Inventor
장성연
이혁
김성환
김범태
김성수
허정녕
임환정
임승길
강명모
노경태
이경로
최지원
Original Assignee
연세대학교 산학협력단
한국화학연구원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 연세대학교 산학협력단, 한국화학연구원 filed Critical 연세대학교 산학협력단
Publication of WO2017135786A1 publication Critical patent/WO2017135786A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds that can be usefully used for the prevention or treatment of bone diseases and uses thereof.
  • Bone formation and bone resorption are largely caused by the interaction of three cells: chondrocytes, osteoblasts and osteoclasts. .
  • osteoclasts are derived from hematopoietic stem cells and are responsible for uptake of aged bone.
  • Osteoblasts are cells derived from bone marrow stromal cells and play a major role in bone formation.
  • Osteoclasts differentiate RAW264.7 monocytes from mice into multinucleated osteoclasts by the receptor activator of nuclear factor ⁇ B (RANK) ligand (RANKL).
  • RANK nuclear factor ⁇ B
  • MAPK mitogen-activated protein kinase
  • NF- ⁇ B transcription factor NF- ⁇ B
  • RANKL when RANKL binds to RANK, it promotes the activity of TRAF6 (tumor necrosis factor receptor-associated factor 6), thereby promoting the activity of transcription factors such as MAPK or NF- ⁇ B, AP-1, NFATc1 (Lee ZH, Kim).
  • TRAF6 tumor necrosis factor receptor-associated factor 6
  • HH. Signal trasduction by receptor activator of nuclear factor kappa B in osteoclasts.Biochem Biophys Res Commun. 2003 May 30, 305, 211-4). Therefore, blocking of signaling pathways activated by RANKL has been recognized as one of the therapeutic approaches for the treatment of bone diseases including osteoporosis.
  • osteoblasts originate from mesenchymal stem cells, and mineralization such as calcium formation by osteoblast differentiation not only maintains bone strength, but also plays an important role in the homeostasis of calcium and hormone metabolism throughout the body.
  • Calcium formation by osteoblast differentiation is regulated by vitamin D and parathyroid hormone
  • bone formation by osteoblast differentiation is bone morphogenetic protein (BMP), Wnt MAP kinase in cells.
  • BMP bone morphogenetic protein
  • Wnt MAP kinase Wnt MAP kinase in cells.
  • Alkaline phosphatase associated with differentiation of osteoblasts by cross-talk of various signaling systems such as calcineurin-caldomulin kinase, NF- ⁇ B, and AP-1.
  • osteopontin, osteocalcin, type I collagen and the like related to mineralization are synthesized (Pittenger, MF; Mackay, AM; Beck, S. C; Craig, S .; Marshak, DR, Multilineage potential of Adult Human Mesenchymal Stem Cells.Science 1999, 284, 143-147). That is, compounds that promote the activity of alkaline phosphatase may promote the differentiation of osteocytes and may be a target of therapeutic agents for bone diseases.
  • bone formation is continuously controlled by bone resorption by osteoclasts and bone remodeling by an equal action of bone formation by osteoblasts. maintain.
  • excessive activity of osteoclasts or deactivation of osteoblasts may cause imbalances in the remodeling process of bone formation, which may cause bone disease by breaking the balance between osteoclasts and osteoblasts in vivo.
  • Osteoporosis a representative example of bone disease
  • Osteoporosis is a condition in which bone balance decreases due to a loss in the balance between bone formation and bone absorption, and the risk of fracture is continuously increased due to the degeneration of the microstructure of bone tissue. This is a reduced state and the balance of aggregate formation is broken so that osteoclasts occur in an increased state than osteoblasts.
  • Normal bone inside has a dense structure like a mesh, but in the case of osteoporosis, the gap between bone microstructures becomes thinner and the microstructure becomes thinner and weaker, which increases the risk of bone fractures even after a small impact. It is classified as elderly osteoporosis, which occurs gradually in men and women over 70 years of age and causes progressive bone loss of the pelvis and vertebra, and secondary osteoporosis due to diseases, drugs, alcohol, smoking, or accidents, regardless of age.
  • Osteoporosis is currently one of the most important social problems in the United States, causing about 260,000 women every year, with about 12% to 20% of deaths. Aging and postmenopausal women's osteoporosis and osteoporosis fractures cause serious problems in an aging society and women's social participation.
  • Materials currently used for the treatment of osteoporosis include estrogen, androtic anagolic ateroids, calcium preparations, phosphates, fluorides, ipriflavones, and vitamin D3.
  • Estrogens inhibit osteoblastic cell death, increase cell survival, and promote osteoclast cell death to decrease cell survival, which is somewhat effective in treating menopausal symptoms and maintaining bone mineral density. There are side effects that cause back.
  • as a drug for inhibiting the activity of osteoclasts to inhibit bone destruction or to increase the activity of bone regeneration units through the proliferation of osteoblasts calcitonin, para-acid hormone, bisphosphonate preparations, and the like.
  • existing osteoporosis therapeutic agents cause many side effects when administered for a long time. Therefore, there is a need for the development of safe prophylactic and therapeutic agents that have a long-term effect of increasing bone mineral density and have fewer side effects.
  • the present inventors have diligently researched to find novel substances that can effectively treat bone diseases while reducing side effects of conventional bone diseases such as the use of therapeutic agents for osteoporosis. It was confirmed that the prophylactic and therapeutic effect was completed the present invention.
  • One object of the present invention is to provide a series of novel amide compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of bone diseases comprising the compound, its stereoisomers, or pharmaceutically acceptable salts thereof as an active ingredient.
  • a pharmaceutical composition comprising a compound represented by Formulas 1 to 3, stereoisomers thereof, or a pharmaceutically acceptable salt thereof according to the present invention
  • FIGS. 1 to 18 are diagrams showing examples of the compound represented by Formula 1 according to an embodiment of the present invention.
  • 19 to 24 are diagrams showing examples of the compound represented by Formula 2 according to an embodiment of the present invention.
  • 25 to 32 are diagrams showing examples of the compound represented by Formula 3 according to an embodiment of the present invention.
  • 33 is a view showing the results of mineralization assay of the compounds according to the embodiment of the present invention.
  • 34A and 34B show mineralization assay results of compounds according to an embodiment of the present invention.
  • ALP alkaline phosphatase
  • 36 is a diagram showing a numerical comparison of ALP assay results of the compounds according to the embodiment of the present invention. Compounds that are 120% or more of KY-06003 are marked in red.
  • FIG. 37 is a diagram showing a numerical comparison of the results of mineralization assay of the compounds according to the embodiment of the present invention. Compounds that are 120% or more of KY-06003 are marked in red.
  • 38A to 38D illustrate ALP assay results of OVX-injected compounds of compounds according to an embodiment of the present invention.
  • 39 is a view showing the results of mineralization assay of the compound injected OVX of the compound according to the embodiment of the present invention.
  • FIG. 40 is a diagram showing an example of a method for preparing a compound represented by Formula 1 of the present invention.
  • 41 is a diagram showing an example of a method for preparing a compound represented by Formula 2 of the present invention.
  • FIG. 42 is a diagram showing an example of a method for preparing a compound represented by Formula 3 of the present invention.
  • 43 is a diagram showing the recovery effect on the Wnt signaling system by the compound of the present invention.
  • 44A to 44J show ELISA binding assay results for the compounds of the present invention.
  • 45 is a diagram showing a result of SPR binding assay of a compound of the present invention.
  • 46 is a diagram showing the effect on the bone density of the compound of the present invention.
  • FIG. 47 is a diagram showing the effect on the bone area and the bone circumference of the compound of the present invention.
  • 48 is a diagram showing the effect on the bone cross-sectional thickness and bone surface area of the compound of the present invention.
  • the present invention is a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 to R 3 are each independently hydrogen, halogen, —SO 3 H, C 1-4 alkyl, C 6-10 aryl, or two adjacent substituents connected to each other and fused together with a thiophene ring to which they are bonded; Form hetero aryl,
  • the aryl is unsubstituted or from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluorinated alkyl, C 1-4 fluorinated alkoxy, cyano, carboxamido and acetamino May be substituted with any one or more substituents selected;
  • R 4 is hydrogen, halogen, —CO 2 (C 0-4 alkyl), —CO 2 (C 6-10 aryl), or —CONHW, wherein W is a protected or unprotected amino acid;
  • R 5 is C 1-4 alkyl, or unsubstituted or substituted C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, or C 3-10 cycloalkyl,
  • W ' is a protected or unprotected amino acid
  • n is an integer of 0-3.
  • R 1 to R 3 are each independently hydrogen, chloro, bromo, -SO 3 H, cyano, methyl, phenyl, or R 1 and R 2 are linked to each other to form benzothiophene together with the thiophene ring to which they are bonded.
  • the phenyl may be unsubstituted or substituted with any one or more substituents selected from the group consisting of fluoro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, aminoformyl and acetamino;
  • R 4 is hydrogen, fluoro, —CO 2 H, —CO 2 CH 3 , —CO 2 C 2 H 5 , or —CONHW, wherein W is isoleucine, protected or unprotected with methyl;
  • R 5 is propyl, cyclopropyl, benzodioxolyl, or unsubstituted or substituted phenyl, pyridinyl, piperidinyl or cyclohexyl,
  • the phenyl, pyridinyl, piperidinyl and cyclohexyl may be unsubstituted or benzyl, benzyloxy, morpholinyl, -CONH (CH 2 ) 2 morpholinyl, -CONH (CHCH 3 ) CONH (CH 2 ) 2 morpholi Nyl, fluoro, chloro, bromo, methyl, trifluoromethyl, thiophenyl, -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -SO 2 NH 2 , -CH 2 CO 2 H, -CH 2 CO 2 CH 3 , -COCH 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 C 2 H 5 , -CO 2 (tert-butyl), -SO 3 H, phenoxy, sulfofenoxy, and -CONHW 'may be substituted with any one or more substituents selected from the
  • W is tryptophan, alanine, aspartic acid, phenylalanine, tyrosine, valine, isoleucine, leucine or methionine, protected or unprotected with methyl or tert-butyl;
  • n can be zero or one.
  • the present invention provides a compound represented by the following formula (2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 6 is C 6-10 aryl, 3 to 10 membered heterocycloalkyl, or (3 to 10 membered heterocycloalkyl) (C 1-4 alkyl),
  • the aryl and heterocycloalkyl are unsubstituted or C 1-4 halogenated alkyl, -CO (C 6-10 aryl), -CO ( 1-4 alkyl), -CONH (C 6-10 aryl), -SO 2 (C 6-10 aryl unsubstituted or substituted with C 1-4 alkyl), (C 6-10 aryl) (C 1-4 alkyl), -CO 2 (C 0-4 alkyl), halogen, C 1- 4 alkoxy, C 6-10 aryloxy, 5-10 membered heteroaryl, or -CONHW '', which may be substituted with any one or more substituents selected from the group consisting of:
  • R 7 is hydrogen, C 6-10 aryloxy, -CONH (C 1-4 alkylene) (3 to 10 membered heterocycloalkyl), -CO 2 (C 0-4 alkyl), or -CONHW '',
  • Each of W ′′ is an independently protected or unprotected amino acid.
  • R 6 is phenyl, piperidinyl, or piperidinylmethyl
  • phenyl and piperidinyl are unsubstituted or trifluoromethyl, trifluoromethoxy, -CO 2 H, -CO 2 CH 3 , -CO 2 (phenyl), -CONH (phenyl), halogen, C 1- 4 may be substituted with any one or more substituents selected from the group consisting of alkoxy, benzyl, imidazolyl, tosyl, or phenoxy;
  • R 7 is hydrogen, phenoxy, -CONH (CH 2 ) 2 (morpholinyl), -CO 2 H, -CO 2 CH 3 or -CONHW '',
  • the W ′′ may be tryptophan, protected with or without methyl, but is not limited thereto.
  • the present invention provides a compound represented by the following formula (3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • Z is -CO 2 H, -CO 2 (C 1-4 alkyl), -CONH (C 1-4 alkyl), hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 3-8 cycloalkyl , 3 to 10 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl,
  • the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted, hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 6-10 aryloxy, (C 6-10 aryl) (C 1 -4 alkyl), (C 6-10 aryl) (C 1-4 alkyl) oxy, -CONH (C 0-4 alkyl), 3 to 10 membered heterocycloalkyl, and - (C 0-4 alkylene) CO Can be substituted with any one or more substituents selected from the group consisting of 2 (C 0-4 alkyl);
  • R 8 and R 9 are each independently hydrogen, — (C 0-4 alkylene) CO 2 (C 0-4 alkyl), —CONH (C 0-4 alkyl), or halogen;
  • R 10 and R 11 are each independently hydrogen or halogen.
  • Z is -CO 2 H, -CO 2 C 2 H 5 , -CONH 2 , -CONHCH 3 , hydroxy, methyl, propyl, trifluoroalkyl, or hydroxy, bromo, trifluoroalkyl, phenoxy, Unsubstituted or substituted with any one or more substituents selected from the group consisting of phenylethyl, benzyl, benzyloxy, morpholinyl, -CONHCH 3 , -CO 2 H, -CO 2 CH 3 , and -CO 2 C 2 H 5 Cyclopropyl, piperidinyl, morpholinyl, indolyl, indazolyl, phenyl or pyridinyl;
  • R 8 and R 9 are each independently hydrogen, —CO 2 H, —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —CO 2 CH 3 , —CO 2 C 2 H 5 , chloro, bromo, -CONHCH 3 , -CH 2 CONH 2 , or -CONH 2 ;
  • R 10 and R 11 may each independently be hydrogen or fluoro.
  • the compounds represented by Formulas 1 to 3 of the present invention may be used in the form of a pharmaceutically acceptable salt.
  • salts are acid addition salts formed with pharmaceutically acceptable free acids.
  • pharmaceutically acceptable salt of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, and the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (I). Means any organic or inorganic addition salt.
  • the compounds of the present invention may be used alone or in combination or in combination with other pharmaceutically active compounds.
  • Pharmaceutically acceptable salts of the compounds represented by Formulas 1 to 3 of the present invention refer to salts prepared according to methods conventional in the art, and such preparation methods are known to those skilled in the art.
  • the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • organic acids and inorganic acids may be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid
  • methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid may be used as the organic acid.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium, or calcium salt, but is not limited thereto.
  • Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds represented by formulas (1) to (3) include salts of acidic or basic groups which may be present in the compound of formula (I), unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfates, hydrogen sulphates, phosphates, hydrogen phosphates , Dihydrogenphosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts; It can be prepared through the method.
  • any salts of the compounds represented by the formulas (1) to (3) of the present invention any salts of the compounds that exhibit biological activities equivalent to those of the compounds may be used without limitation.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases comprising a compound represented by the formula (1) to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a method for preventing or treating bone disease, comprising administering the pharmaceutical composition to a subject in need thereof.
  • bone disease refers to a condition or disease that results from excessive production and / or migration of osteoclasts or a condition or disease in which bone mass is required or required by promoting osteoblast activity.
  • Bone loss disorders refers to a condition or a disease in which a decrease in bone mass accompanied by symptoms such as a decrease in bone density and deterioration of bone tissue occurs. Rheumatoid arthritis, but is not limited thereto.
  • the composition of the present invention can be used for the prophylactic treatment of osteoporosis or osteopenia.
  • osteoporosis used in the present invention refers to a state in which bone fracture may occur due to a decrease in bone mass and qualitative change
  • osteoporosis refers to an initial symptom of osteoporosis.
  • it is classified as osteopenia in case of -1.0 to -2.5 and osteoporosis in case of -2.5 or more based on bone density (T).
  • the term "prophylaxis or treatment of bone disease” includes the prevention and complete or partial treatment of said bone disease achieved by administering a composition according to the invention to a subject. It also includes reducing or improving symptoms of bone disease, alleviating the pain of the symptoms, reducing the incidence of bone disease, or any other change in the patient that increases the outcome of treatment.
  • the term "individual" means any animal, including humans, who may or may have a bone disease.
  • the composition of the present invention can be administered to an individual to effectively prevent or treat the bone disease.
  • the composition of the present invention can be administered in parallel with existing therapeutic agents for bone disease.
  • the term "administration" means introducing a predetermined substance into a patient in an appropriate manner, and the route of administration of the composition of the present invention may be administered via any general route as long as it can reach the target tissue. Can be. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment and not causing side effects, wherein the effective dose level is the sex, age and weight of the patient. , Factors such as health status, type of disease, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration, and rate of release, duration of treatment, combination or drug used, and other medical fields. It can be easily determined by those skilled in the art according to known factors.
  • the active substance can be administered at a dose of about 0.01 mg / kg / day to 1000 mg / kg / day. In the case of oral administration, a range of 50 to 500 mg / kg may be suitable and may be administered at least once a day.
  • the pharmaceutical composition of the present invention may contain 0.001 to 1% by weight of the compound represented by Formula 1 to 3, stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition for preventing or treating bone diseases according to the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient described above.
  • a pharmaceutically acceptable carrier means to exhibit properties that are not toxic to an individual such as a cell or human being exposed to the composition.
  • the carrier can be used without limitation so long as it is known in the art such as buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, bases, excipients, lubricants.
  • Carriers, excipients and diluents that may be included in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • composition of the present invention when formulating the composition of the present invention, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
  • a solid preparation such as tablets, pills, powders, granules, capsules and the like.
  • Such solid preparations are prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, or lactose, gelatin and the like in addition to the composition.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups.In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, flavoring agents, preservatives, etc. Can be.
  • the oral composition may be formulated to coat the active agent or to protect it from degradation in the stomach.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • As the base of the suppository utopsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • carbohydrates such as glucose, sucrose, dextran, antioxidants such as ascorbic acid, glutathione, chelating substances, small molecule proteins or other stabilizers can be used.
  • compositions of the present invention may be administered by any device in which the active substance may migrate to target cells.
  • Preferred modes of administration and preparations are intravenous, subcutaneous, intradermal, intramuscular, injectable and the like.
  • Injections include non-aqueous solvents such as aqueous solvents such as physiological saline solution and ring gel solution, vegetable oils, higher fatty acid esters (e.g., oleic acid, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.).
  • Stabilizers e.g.
  • Preservatives eg, mercury nitrate, chimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc. may be included.
  • compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • Wnt signaling is required for skeletal development, adult skeletal homeostasis, and bone aggregate formation.
  • Wnt proteins are involved in various signaling pathways (Box1), but it is believed that most of the Wnt signaling system's action on the skeletal system is explained by the canonical wnt-beta-catenin signaling pathway.
  • betacatenin is released from the complex and is not subject to proteolysis.
  • Stabilization of betacatenin induces the transfer of betacatenin into the nucleus and induces osteoblast differentiation by controlling transcription of genes such as WISP1 and RUNX2 in conjunction with transcription factors (TCF-4 or LEF-1).
  • Adipogenesis is inhibited by inhibiting adipogenic factors such as C / EBP ⁇ (CCAAT / enhancer binding protein ⁇ ) and PPAR- ⁇ (peroxisome proliferator activated receptor ⁇ ).
  • Wnt signaling systems are also important in the inhibition of osteoclast formation and bone resorption. Inhibition of osteoclast formation by Wnt is reported to be due to the induction of the expression of osteoprotegerin (also known as TNF receptor superfamily member 11B), which binds to RANKL and inhibits osteoclast formation. .
  • the mechanical load activates the Wnt signaling system in cells of the osteoblast lineage, suggesting that the action of Wnt may be involved in linking mechanical forces to assimilation of the skeletal system.
  • This mechanism is associated with the inhibition of sclerostin, a Wnt antagonist preferentially expressed by epidemiological osteoblasts. Inhibition of sclerostin is particularly present in sites that are subject to high loads in bone, which promotes Wnt signaling and bone formation. In contrast, sclerostin is increased by no-load of the skeletal system, which causes bone loss due to increased bone resorption and reduced bone formation. This mechanism is thought to be related to the development of osteoporosis of disuse, which results in decreased bone mass due to continued bed rest and nerve damage. Insoluble
  • Antagonists that interact with Wnt and LRP-5-LRP-6 co-receptors include sclerostin and Dickkopf-related protein 1 (Dkk-1).
  • Sclerostine encoded by SOST is mainly expressed by osteoblasts, which binds to the LRP5-LRP6 co-receptor and interferes with Wnt signaling.
  • sclerostin inhibits osteoblast formation and bone formation in vitro and in vivo.
  • Sclerostine expression is inhibited by mechanical compression and parathyroid hormone (PTH) in osteoblasts and osteocytes. In patients with hyperparathyroidism, lower levels of sclerostin than those with normal parathyroid function can be observed. .
  • PTH parathyroid hormone
  • Osteopenia is caused by decreased osteoblast count and bone formation.
  • recently developed antibodies against sclerostin have demonstrated that sclerostin is prevented from binding to the Lrp-5-Lrp-6 co-receptor, thereby enhancing the Wnt signal and increasing bone density and bone mass.
  • Monoclonal Anti-body (Ab) against sclerostin is the main competitor.
  • the problems of Monoclonal Ab are as follows.
  • Carboxylic acid compound (40 mg, 0.1 mmol), methylamine (3.0 equiv), EDCI (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide; 3.0 equiv), HOBt (N-hydroxybenzotriaxole; 3.0 equiv) in 7 mL vials, DIPEA (N, N-diisopropylethylamine; 3.0 equivalents) was dissolved in dimethylformamide (DMF; 0.3 M) and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (36 mg, 89%).
  • DIPEA N, N-diisopropylethylamine; 3.0 equivalents
  • the ester compound (200 mg, 0.43 mmol) in a 7 mL vial was dissolved in LiOH (5.0 equiv), THF / H 2 O / MeOH mixed solvent, and then stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).
  • Example 14 3- (3- (N- Profile Sulpa Mole ) Benzamido ) Benzoic acid (3- (3- (N-propylsulfamoyl) benzamido) benzoic acid); KY-06430
  • the ester compound (100 mg, 0.4 mmol) was dissolved in a THF / H 2 O / MeOH mixed solvent in a 7 mL round bottom flask, and LiOH (30 mg, 0.8 mmol) was added thereto and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, 15 mL of water was added, 1N HCl was added, and extracted three times with EA (30 mL) at pH 2. The organic layer was dried over MgSO 4 to afford the title compound (133 mg, 95%).
  • Example 21 N- (3- (2- (methylamino) -2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide (N- (3- (2- (methylamino) -2-oxoethyl ) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06437
  • Example 24 3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06440
  • Example 25 3- (3- (N- (1- Benzylpiperidine -4- days) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoic acid); KY-06442
  • Example 26 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1-benzylpiperidin-4- yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06443
  • Example 27 3- (3- (N- (4- Morpholinophenyl ) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoic acid); KY-06445
  • Example 30 3- (N- (1H-indol-5-yl) Sulfa Mole ) -N- (3- ( Methylcarbamoyl ) Phenyl) benzamide (3- (N- (1H-indol-5-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06448
  • Example 31 3- (3- (N- (1H-indol-6-yl) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoic acid); KY-06449
  • Example 32 3- (N- (1H-indol-6-yl) Sulfa Mole ) -N- (3- ( Methylcarbamoyl ) Phenyl) benzamide (3- (N- (1H-indol-6-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06450
  • Example 33 3- (3- (N- (3,5- Bis (trifluoromethyl) phenyl ) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoic acid); KY-06451
  • Example 34 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (3,5- bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06452
  • Example 35 3-((3-((3- Carboxyphenyl ) Cabamo ) Phenyl) Sulfonamido ) Benzoic acid (3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid); KY-06453
  • the ester compound (200 mg, 0.43 mmol) in a 7 mL vial was dissolved in LiOH (5.0 equiv), THF / H 2 O / MeOH mixed solvent, and stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).
  • Example 36 Ethyl 3-((2,4- Difluoro -5- ( Phenylcarbamoyl ) Phenyl) Sulfonamido ) Benzoate (ethyl 3-((2,4- difluoro -5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate); KY-06454
  • sulfonyl chloride compound (2.59 mmol, 860 mg) was dissolved in methylene chloride (MC, 9 mL), followed by ethyl 3-aminobenzoate (1.0 equiv., 0.38 mL), DIPEA (1.5 equiv., 0.68 mL) was added and stirred at room temperature for 2 days. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was dried over MgSO 4 . After silica gel column was concentrated under reduced pressure, solidified with MC / ether / hexane and filtered through a sinter to give the title compound (128 mg, 11%) as a yellow solid compound.
  • MC methylene chloride
  • DIPEA 1.5 equiv., 0.68 mL
  • Example 37 3-((2,4- Difluoro -5- ( Phenylcarbamoyl ) Phenyl) Sulfonamido ) Benzoic acid (3-((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06455
  • Example 38 Ethyl 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido ) Benzoate (ethyl 3- (4- fluoro -3- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06456
  • acyl chloride compound (1.3 mmol, 346 mg) was dissolved in MC (1.5 mL) in a 25 mL round bottom flask, ethyl 3-aminobenzoate (0.95 equiv., 209 mg, 1.24 mmol), DIPEA (0.95) in a 7 mL vial. Equivalent weight, 0.218 mL, 1.24 mmol) and MC (1.5 mL) were stirred together. The mixture contained in a 7 mL vial was slowly added to a 25 mL round bottom flask, and the 7 mL vial was further added with MC (0.5 mL), followed by stirring at 0 ° C. for 30 minutes.
  • Example 39 3- (4- Fluoro -3- (N- Phenylsulfamoyl ) Benzamido ) Benzoic acid (3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06457
  • Example 40 Ethyl 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido ) Benzoate (ethyl 3- (2,4- difluoro -5- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06458
  • acyl chloride compound (1.4 mmol, 392.5 mg) was dissolved in MC (1.5 mL) in a 25 mL round bottom flask, ethyl 3-aminobenzoate (0.95 equiv., 224 mg, 1.33 mmol), DIPEA (0.95) in a 7 mL vial. Equivalent, 0.234 mL, 1.33 mmol) and MC (1.5 mL) were stirred together. The mixture contained in a 7 mL vial was slowly added to a 25 mL round bottom flask, and the 7 mL vial was further added with MC (0.5 mL), followed by stirring at 0 ° C. for 30 minutes.
  • Example 41 3- (2,4- Difluoro -5- (N- Phenylsulfamoyl ) Benzamido ) Benzoic acid (3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06459
  • the ester compound (230 mg, 0.49 mmol) was dissolved in THF (1.5 mL) in a 7 mL vial and stirred.
  • H 2 O (1.5 mL) and MeOH (1.0 mL) were added by syringe, and LiOH (12.6 mg, 2.0 equiv., 0.30 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours.
  • Example 42 methyl 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (2- phenoxyphenyl ) sulfamoyl ) benzamido ) benzoate); KY-06462
  • Example 43 methyl 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (3- phenoxyphenyl ) sulfamoyl ) benzamido ) benzoate); KY-06463
  • Example 44 methyl 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (4- phenoxyphenyl ) sulfamoyl ) benzamido ) benzoate); KY-06464
  • Example 45 methyl 3- (3- (N- (4- ( Benzyloxy ) Phenyl) Sulfa Mole ) Benzamido ) Benzoate (methyl 3- (3- (N- (4- ( benzyloxy ) phenyl) sulfamoyl ) benzamido ) benzoate); KY-06465
  • Example 46 methyl 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- ( pyridin -2- yl ) sulfamoyl ) benzamido ) benzoate); KY-06466
  • Example 47 methyl 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- ( pyridin -3- yl ) sulfamoyl ) benzamido ) benzoate); KY-06467
  • Example 48 methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate); KY-06468
  • Example 49 methyl 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N- cyclopropylsulfamoyl ) benzamido ) benzoate); KY-06469
  • Example 50 methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate); KY-06470
  • Example 51 methyl 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (4- morpholinophenyl ) sulfamoyl ) benzamido ) benzoate); KY-06471
  • Example 52 methyl 3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (1H- indol -5- yl ) sulfamoyl ) benzamido ) benzoate); KY-06472
  • Example 53 methyl 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (1H- indol -6- yl ) sulfamoyl ) benzamido ) benzoate); KY-06473
  • Example 54 methyl 3- (3- (N- (3,5- Bis (trifluoromethyl) phenyl ) Sulfa Mole ) Benzamido ) Benzoate (methyl 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate); KY-06474
  • Example 55 methyl 3- (3- (N- (1- Benzylpiperidine -4- days) Sulfa Mole ) Benzamido ) Benzoate (methyl 3- (3- (N- (1- benzylpiperidin -4- yl ) sulfamoyl ) benzamido ) benzoate); KY-06475
  • Example 56 methyl 3-((3-((3- ( Methoxycarbonyl ) Phenyl) Cabamo ) Phenyl) Sulfonamido ) Benzoate (methyl 3-((3-((3- (methoxycarbonyl) phenyl) carbamoyl) phenyl) sulfonamido) benzoate); KY-06476
  • a carboxylic acid compound (2.2 g, 10 mmol) was added to thionyl chloride (20 mL) and refluxed for 16 hours. After completion of the reaction, thionyl chloride was removed, aminobenzoate (1.69 g, 9 mmol, 0.9 sugar) and DIPEA (1.6 mL) were dissolved in MC (8 mL), followed by stirring at 0 ° C. 3-chlorosulfonyl benzoyl chloride was dissolved in MC (8 mL) and added slowly. After stirring for 30 minutes at 0 ° C., the mixture was extracted with distilled water and MC, dried over MgSO 4 , and separated by silica gel column to obtain the title compound.
  • Example 58 methyl 3- Bromo -5- (3- (N-phenylsulfamoyl) benzamido) benzoate (methyl 3- bromo -5- (3- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06478
  • Example 59 methyl 3- Bromo -5- ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoate (methyl 3- bromo -5-((3- ( phenylcarbamoyl ) phenyl) sulfonamido ) benzoate); KY-06479
  • Example 60 3- Bromo -5- (3- (N- Phenylsulfamoyl ) Benzamido ) Benzoic acid (3- bromo -5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06480
  • the ester compound (100 mg, 0.2 mol) was added to a 7 mL vial with LiOH (20 equivalents) and THF / H 2 O / MeOH mixed solution as a solvent and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (95 mg, 98%).
  • Example 61 3- Bromo -5-((3- ( Phenylcarbamoyl ) Phenyl) Sulfonamido ) Benzoic acid (3- bromo -5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06481
  • the ester compound (100 mg, 0.2 mol) was added to a 7 mL vial with LiOH (20 equivalents) and THF / H 2 O / MeOH mixed solution as a solvent and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (85 mg, 83%).
  • Example 64 methyl 3-((1-oxo-1,2,3,4- Tetrahydroisoquinoline ) -7- Sulfonamido ) Benzoate (methyl 3-((1- oxo -1,2,3,4- tetrahydroisoquinoline ) -7-sulfonamido) benzoate); KY-06484
  • Example 65 3- (N- (2- ( Phenylamino ) Phenyl) Sulfa Mole ) Benzoic acid (3- (N- (2- (phenylamino) phenyl) sulfamoyl) benzoic acid); KY-06486
  • the amine compound (300 mg, 1.6 mmol) was dissolved in pyridine (4.0 mL) in a 7 mL vial and stirred for 30 minutes.
  • 3- (chlorosulfonyl) benzoic acid (379 mg, 1.0 equiv) was added slowly.
  • the pyridine was removed under reduced pressure, extracted three times with 1N HCl / EA mixed solution, the organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and a silica gel column was performed to obtain the title compound (167 mg, 28%). Obtained.
  • Example 66 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1-benzylpiperidin-4- yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06489
  • Example 67 1- (4-Fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- ( 4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06490
  • Example 68 1- (4-fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- (4-fluorophenyl ) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06491
  • Example 69 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid (3- (1- (4- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06492
  • Example 70 methyl 3- (1- (4- Fluorophenyl ) -3- (thiophen-2-yl) -1H- Pyrazole -4- Carcassamido ) Benzoate (methyl 3- (1- (4- fluorophenyl ) -3- ( thiophen -2- yl ) -1H-pyrazole-4-carboxamido) benzoate); KY-06493
  • Example 71 N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (3-carbamoylphenyl ) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06494
  • Example 72 1- (4-Fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- ( 4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06496
  • Example 74 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamido) benzoic acid); KY-06498
  • Example 78 3- (N- (1- Benzylpiperidine -4- days) Sulfa Mole ) -N- (3- Carbamoylphenyl ) Benzamide (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06504
  • Example 80 3- (N- (1H- Indazole -5 days) Sulfa Mole ) -N- (3- Carbamoylphenyl ) Benzamide (3- (N- (1H-indazol-5-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06506
  • Example 81 3- (N- (1H- Indazole -6- days) Sulfa Mole ) -N- (3- Carbamoylphenyl ) Benzamide (3- (N- (1H-indazol-6-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06507
  • Example 83 2,4-difluoro-N- (3- (methylcarbamoyl) phenyl) -5- (N-phenylsulfamoyl) benzamide (2,4-difluoro-N- (3- (methylcarbamoyl) phenyl ) -5- (N-phenylsulfamoyl) benzamide); KY-06509
  • Example 84 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide (3- (N- (3,5-bis (trifluoromethyl ) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06510
  • Example 85 4- Fluoro -N- (3- ( Methylcarbamoyl ) Phenyl) -3- (N- Phenylsulfamoyl ) Benzamide (4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06511
  • Example 87 Ethyl 3-((5-((3- ( Ethoxycarbonyl ) Phenyl) Cabamo )-2- Fluorophenyl Sulfonamido) benzoate (ethyl 3-((5-((3- ( ethoxycarbonyl ) phenyl) carbamoyl ) -2-fluorophenyl) sulfonamido) benzoate); KY-06513
  • Example 88 3-((5-((3- Carboxyphenyl ) Cabamo )-2- Fluorophenyl ) Sulfonamido ) Benzoic acid (3-((5-((3-carboxyphenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoic acid); KY-06514
  • Example 89 4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide (4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide); KY-06515
  • Example 90 Ethyl 3- ((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido ) Benzoate (ethyl 3-((2- fluoro -5- ( phenylcarbamoyl ) phenyl) sulfonamido ) benzoate); KY-06516
  • Example 98 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamido) benzoic acid); KY-06524
  • Example 99 4- (5-((3- Phenoxyphenyl ) Cabamo ) Thiazol-2-yl) benzoic acid (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06525
  • Example 100 methyl (4- (5-((3- Phenoxyphenyl ) Cabamo ) Thiazol-2-yl) Benzoyl ) -D- Tryptophanate (methyl (4- (5-((3- phenoxyphenyl ) carbamoyl ) thiazol -2- yl ) benzoyl ) -D-tryptophanate); KY-06527
  • Example 101 (4- (5-((3- Phenoxyphenyl ) Cabamo ) Thiazol-2-yl) Benzoyl ) -D-tryptophan (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophan; KY-06528
  • Example 102 methyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) -L-tryptophanate (methyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate); KY-06529
  • Example 103 (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan ((3- (3- ( 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan); KY-06530
  • Example 104 methyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) -D-alanine (methyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alaninate); KY-06531
  • Example 105 (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine ((3- (3- ( 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine); KY-06532
  • Example 106 Dimethyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) -L-aspartate (dimethyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate); KY-06533
  • Example 107 (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid ((3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid); KY-06534
  • Example 108 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid (4- (1- (4- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06535
  • Example 109 Ethyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) glycinate (ethyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate); KY-06536

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a novel amide compound usefully available for the prevention or treatment of a bone disease and the use thereof.

Description

신규 아미드 화합물 및 이의 용도Novel Amide Compounds and Uses thereof
본 발명은 골질환의 예방 또는 치료에 유용하게 사용될 수 있는 신규한 화합물 및 이의 용도에 관한 것이다.The present invention relates to novel compounds that can be usefully used for the prevention or treatment of bone diseases and uses thereof.
정상적인 뼈의 재형성과정은 뼈 형성과 뼈 흡수의 균형으로 이루어지며, 이러한 뼈 형성과 뼈 흡수는 크게 세 가지 세포, 연골세포, 조골세포(osteoblast) 및 파골세포(osteoclast)의 상호작용에 의해 이루어진다. 이들 중 파골세포는 조혈모세포로부터 유래한 세포로서 노화된 골의 흡수를 담당하며, 조골세포는 골수 내 간질세포(bone marrow stromal cell)로부터 유래한 세포로서 골 형성에 주된 역할을 담당한다.Normal bone remodeling is a balance between bone formation and bone resorption, and bone formation and bone resorption are largely caused by the interaction of three cells: chondrocytes, osteoblasts and osteoclasts. . Of these, osteoclasts are derived from hematopoietic stem cells and are responsible for uptake of aged bone. Osteoblasts are cells derived from bone marrow stromal cells and play a major role in bone formation.
파골세포는 예컨대, 마우스의 RAW264.7 단핵구 세포가 RANKL(receptor activator of nuclear factor κB(RANK) ligand)에 의해 다핵 파골세포(multinucleated osteoclasts)로 분화된다. 이러한 분화 과정은 세포 외부의 RANKL이 RANK에 결합하여 미토겐 활성 단백질 키나아제(mitogen-activated protein kinase, MAPK)의 활성을 촉진하고, 이는 NF-κB라는 전사 인자가 핵 내로 들어가서 파골세포 분화와 관련된 TRAP(tartrate-resistant acid phosphatase), MMP-9(matrix metalloproteinase-9), c-Src 티로신 키아나제(tyrosine kinase) 등의 발현을 증가시킴으로써 가능한데, 이러한 과정으로 형성된 다핵 파골세포는 무기질골(mineralized bone)을 흡수하는 역할을 한다. 또한, RANKL이 RANK에 결합하면 TRAF6(tumor necrosis factor receptor-associated factor 6)의 활성을 촉진시켜 MAPK, 또는 NF-κB, AP-1, NFATc1과 같은 전사인자들의 활성을 촉진시킨다(Lee ZH, Kim HH., Signal trasduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun. 2003 May 30, 305, 211-4). 따라서 RANKL에 의해 활성화되는 신호전달 경로의 차단은 골다공증을 비롯한 골 질환의 치료를 위한 치료적 접근 방법 중의 하나로 인지되고 있다.Osteoclasts, for example, differentiate RAW264.7 monocytes from mice into multinucleated osteoclasts by the receptor activator of nuclear factor κB (RANK) ligand (RANKL). This differentiation process promotes the activity of mitogen-activated protein kinase (MAPK) by RANKL binding to RANK, which is involved in osteoclast differentiation by the transcription factor NF-κB. It is possible by increasing the expression of tartrate-resistant acid phosphatase, matrix metalloproteinase-9, and c-Src tyrosine kinase, and the multinucleated osteoclasts formed by this process result in mineralized bone. ) Absorbs. In addition, when RANKL binds to RANK, it promotes the activity of TRAF6 (tumor necrosis factor receptor-associated factor 6), thereby promoting the activity of transcription factors such as MAPK or NF-κB, AP-1, NFATc1 (Lee ZH, Kim). HH., Signal trasduction by receptor activator of nuclear factor kappa B in osteoclasts.Biochem Biophys Res Commun. 2003 May 30, 305, 211-4). Therefore, blocking of signaling pathways activated by RANKL has been recognized as one of the therapeutic approaches for the treatment of bone diseases including osteoporosis.
한편, 조골세포는 간엽 줄기세포에서 기원하여 형성되는데 조골세포의 분화에 의한 칼슘 형성과 같은 무기질화는 뼈의 세기를 유지시켜 줄 뿐만 아니라, 신체 전체의 칼슘 및 호르몬 대사의 항상성에도 매우 중요한 기능을 하고 있다. 조골세포의 분화에 의한 칼슘 형성은 비타민 D 및 부갑상선 호르몬(parathyroid hormone) 등에 의해 조절되며, 조골세포의 분화에 의한 골 형성은 세포 내에서 뼈 형태형성 단백질(bone morphogenetic protein, BMP), Wnt MAP 키나아제, 칼시뉴린-칼모듈린 키나아제(calcineurin-caldomulin kinase), NF-κB, AP-1 등의 다양한 신호전달 체계의 상호작용(cross-talk)에 의해 조골세포의 분화와 관련된 알칼리성 포스파타제(alkaline phosphatase, ALP)가 초기 분화단계에서 합성된 후, 무기질화와 관련된 오스테오폰틴(osteopontin), 오스테오칼신(osteocalcin), 타입 I 콜라겐 등이 합성됨으로써 이루어진다고 알려져 있다(Pittenger, M. F.; Mackay, A. M.; Beck, S. C; Craig, S.; Marshak, D. R., Multilineage potential of Adult Human Mesenchymal Stem Cells. Science 1999, 284, 143-147). 즉, 알칼리성 포스포타제의 활성을 촉진하는 화합물들은 골세포의 분화를 촉진하게 되어 골 질환의 치료제의 타겟이 될 수 있다.On the other hand, osteoblasts originate from mesenchymal stem cells, and mineralization such as calcium formation by osteoblast differentiation not only maintains bone strength, but also plays an important role in the homeostasis of calcium and hormone metabolism throughout the body. have. Calcium formation by osteoblast differentiation is regulated by vitamin D and parathyroid hormone, and bone formation by osteoblast differentiation is bone morphogenetic protein (BMP), Wnt MAP kinase in cells. Alkaline phosphatase associated with differentiation of osteoblasts by cross-talk of various signaling systems such as calcineurin-caldomulin kinase, NF-κB, and AP-1. After ALP) is synthesized in the early differentiation stage, it is known that osteopontin, osteocalcin, type I collagen and the like related to mineralization are synthesized (Pittenger, MF; Mackay, AM; Beck, S. C; Craig, S .; Marshak, DR, Multilineage potential of Adult Human Mesenchymal Stem Cells.Science 1999, 284, 143-147). That is, compounds that promote the activity of alkaline phosphatase may promote the differentiation of osteocytes and may be a target of therapeutic agents for bone diseases.
상기와 같이 골 형성은 파골세포(osteoclast)에 의한 골 흡수(bone resorption)와 조골세포(osteoblast)에 의한 골 형성(bone formation)의 대등한 작용에 의한 리모델링 과정(bone remodeling)이 지속적으로 조절됨으로써 유지된다. 그러나, 파골세포의 과도한 활성이나 조골세포의 활성 저하는 골 형성의 리모델링 과정에서 불균형을 초래하여, 생체 내에서 파골세포와 조골세포와의 평형을 깨뜨려 골 질환을 유발할 수 있다.As described above, bone formation is continuously controlled by bone resorption by osteoclasts and bone remodeling by an equal action of bone formation by osteoblasts. maintain. However, excessive activity of osteoclasts or deactivation of osteoblasts may cause imbalances in the remodeling process of bone formation, which may cause bone disease by breaking the balance between osteoclasts and osteoblasts in vivo.
골 질환의 대표적인 예인 골다공증은 골 형성과 골 흡수의 평형이 깨져 뼈의 질량이 감소하고 뼈 조직의 미세구조의 퇴화로 골절 위험이 지속적으로 증가하는 질환으로 뼈를 구성하는 미네랄(특히 칼슘)과 기질이 감소한 상태이며, 골재형성의 균형이 깨져서 파골작용이 조골작용 보다 증가된 상태에서 발생한다. 정상적인 뼈 내부는 그물망처럼 치밀한 구조를 이루고 있으나, 골다공증의 경우에는 골미세구조 사이의 간격이 넓어지고 미세구조가 얇아져 약해짐으로써 조그만 충격에도 뼈가 쉽게 골절될 위험이 증가하는 질환으로 폐경기 이후 골다공증, 70세 이상의 남녀 노인에게 서서히 발생하며 골반골과 척추뼈의 점진적인 골 손실을 가져오는 노년기 골다공증 및 연령에 상관없이 질병이나 약물, 알코올, 흡연, 사고로 인해 발생하는 2차 골다공증으로 분류된다.Osteoporosis, a representative example of bone disease, is a condition in which bone balance decreases due to a loss in the balance between bone formation and bone absorption, and the risk of fracture is continuously increased due to the degeneration of the microstructure of bone tissue. This is a reduced state and the balance of aggregate formation is broken so that osteoclasts occur in an increased state than osteoblasts. Normal bone inside has a dense structure like a mesh, but in the case of osteoporosis, the gap between bone microstructures becomes thinner and the microstructure becomes thinner and weaker, which increases the risk of bone fractures even after a small impact. It is classified as elderly osteoporosis, which occurs gradually in men and women over 70 years of age and causes progressive bone loss of the pelvis and vertebra, and secondary osteoporosis due to diseases, drugs, alcohol, smoking, or accidents, regardless of age.
골다공증은 현재 가장 중요한 사회적 문제 중 하나로, 미국의 경우 매년 약 26 만명의 여성들에게 유발되고 있으며, 이중 약 12% 내지 20% 정도는 사망에 이르고 있다. 사회가 노령화되고 여성들의 사회참여가 활발해지고 있는 상황에서 노인들이나 폐경 후 여성들의 골다공증 및 골다공증으로 인한 골절은 심각한 문제를 야기한다.Osteoporosis is currently one of the most important social problems in the United States, causing about 260,000 women every year, with about 12% to 20% of deaths. Aging and postmenopausal women's osteoporosis and osteoporosis fractures cause serious problems in an aging society and women's social participation.
상기와 같은 골 질환을 치료하기 위해서는 파골세포와 조골세포의 균형을 조절하는 것이 필요하며, 따라서 이에 대한 치료제로 크게 골 흡수 억제제와 골 형성자극제가 있다.In order to treat such bone diseases, it is necessary to control the balance of osteoclasts and osteoblasts, and thus there are largely bone absorption inhibitors and bone formation stimulants.
현재 골다공증 치료제로 사용되고 있는 물질로는 에스트로겐(estrogen), 남성화 스테로이드 호르몬(androgenic anagolic ateroid), 칼슘 제제, 인산염, 불소제제, 이프리플라본(Ipriflavone), 비타민 D3 등이 있다. 에스트로겐은 조골세포의 세포고사를 억제하여 세포의 생존기간을 증가시키고 파골세포의 세포고사를 촉진하여 세포의 생존기간을 감소시켜 폐경증상의 치료와 골밀도 유지에 어느 정도 효과적인 방법이나 유방암, 자궁내막증식증 등을 유발하는 부작용이 있다. 이외에도 파골세포의 활성을 억제하여 골 파괴를 억제시키거나 조골세포의 증식을 통해 골 재생 단위의 활성을 증가시키는 약물로 칼시토닌, 부갑산성호르몬, 비스포스포네이트 제제 등이 있다. 그러나, 기존 골다공증 치료약제들은 장기간 투여시 많은 부작용을 유발하고 있다. 따라서 장기간 투여에도 지속적인 골밀도 증가 효과를 나타내고 부작용이 적은 안전한 예방 및 치료제 개발이 요구되고 있다.Materials currently used for the treatment of osteoporosis include estrogen, androtic anagolic ateroids, calcium preparations, phosphates, fluorides, ipriflavones, and vitamin D3. Estrogens inhibit osteoblastic cell death, increase cell survival, and promote osteoclast cell death to decrease cell survival, which is somewhat effective in treating menopausal symptoms and maintaining bone mineral density. There are side effects that cause back. In addition, as a drug for inhibiting the activity of osteoclasts to inhibit bone destruction or to increase the activity of bone regeneration units through the proliferation of osteoblasts, calcitonin, para-acid hormone, bisphosphonate preparations, and the like. However, existing osteoporosis therapeutic agents cause many side effects when administered for a long time. Therefore, there is a need for the development of safe prophylactic and therapeutic agents that have a long-term effect of increasing bone mineral density and have fewer side effects.
본 발명자들은 종래 골질환 예컨대, 골다공증 치료제의 사용에서 나타나는 부작용은 감소시키면서 효과적으로 골질환 치료 효과를 나타낼 수 있는 신규한 물질을 발굴하기 위하여 예의 연구노력한 결과, 일련의 신규한 아마드 화합물들이 우수한 골질환의 예방 및 치료 효과를 갖는 것을 확인하고 본 발명을 완성하였다.The present inventors have diligently researched to find novel substances that can effectively treat bone diseases while reducing side effects of conventional bone diseases such as the use of therapeutic agents for osteoporosis. It was confirmed that the prophylactic and therapeutic effect was completed the present invention.
본 발명의 하나의 목적은 일련의 신규 아미드 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.One object of the present invention is to provide a series of novel amide compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof.
본 발명의 다른 목적은 상기 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 골질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of bone diseases comprising the compound, its stereoisomers, or pharmaceutically acceptable salts thereof as an active ingredient.
본 발명에 따른 화학식 1 내지 3으로 표시되는 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염을 포함하는 약학적 조성물은 A pharmaceutical composition comprising a compound represented by Formulas 1 to 3, stereoisomers thereof, or a pharmaceutically acceptable salt thereof according to the present invention
SOST 또는 LRP5/6에 결합하여 이 둘의 결합을 저해함으로써 SOST에 의한 Wnt 신호전달 저해를 감소시킴으로써 이와 관련된 다양한 골질환의 예방 또는 치료에 유용하게 이용될 수 있다.By binding to SOST or LRP5 / 6 and inhibiting the binding of the two, it can be usefully used for the prevention or treatment of various bone diseases related thereto by reducing Wnt signaling inhibition by SOST.
도 1 내지 18는 본 발명의 실시예에 따른 화학식 1로 표시되는 화합물의 예를 나타낸 도이다.1 to 18 are diagrams showing examples of the compound represented by Formula 1 according to an embodiment of the present invention.
도 19 내지 24는 본 발명의 실시예에 따른 화학식 2로 표시되는 화합물의 예를 나타낸 도이다.19 to 24 are diagrams showing examples of the compound represented by Formula 2 according to an embodiment of the present invention.
도 25 내지 32는 본 발명의 실시예에 따른 화학식 3으로 표시되는 화합물의 예를 나타낸 도이다.25 to 32 are diagrams showing examples of the compound represented by Formula 3 according to an embodiment of the present invention.
도 33은 본 발명의 실시예에 따른 화합물들의 무기질화(mineralization) 어세이 결과를 나타낸 도이다.33 is a view showing the results of mineralization assay of the compounds according to the embodiment of the present invention.
도 34a 및 34b는 본 발명의 실시예에 따른 화합물들의 무기질화(mineralization) 어세이 결과를 나타낸 도이다.34A and 34B show mineralization assay results of compounds according to an embodiment of the present invention.
도 35는 본 발명의 실시예에 따른 화합물들의 ALP(alkaline phosphatase) 어세이 결과를 나타낸 도이다.35 is a diagram showing the results of an alkaline phosphatase (ALP) assay of compounds according to an embodiment of the present invention.
도 36은 본 발명의 실시예에 따른 화합물들의 ALP 어세이 결과를 수치로 비교하여 나타낸 도이다. KY-06003 대비 120% 이상인 화합물을 붉은 색으로 표시하였다.36 is a diagram showing a numerical comparison of ALP assay results of the compounds according to the embodiment of the present invention. Compounds that are 120% or more of KY-06003 are marked in red.
도 37은 본 발명의 실시예에 따른 화합물들의 무기질화 어세이 결과를 수치로 비교하여 나타낸 도이다. KY-06003 대비 120% 이상인 화합물을 붉은 색으로 표시하였다.37 is a diagram showing a numerical comparison of the results of mineralization assay of the compounds according to the embodiment of the present invention. Compounds that are 120% or more of KY-06003 are marked in red.
도 38a 내지 38d는 본 발명의 실시예에 따른 화합물들의 OVX 투입된 화합물의 ALP 어세이 결과를 나타낸 도이다.38A to 38D illustrate ALP assay results of OVX-injected compounds of compounds according to an embodiment of the present invention.
도 39는 본 발명의 실시예에 따른 화합물들의 OVX 투입된 화합물의 무기질화 어세이 결과를 나타낸 도이다.39 is a view showing the results of mineralization assay of the compound injected OVX of the compound according to the embodiment of the present invention.
도 40은 본 발명의 화학식 1로 표시되는 화합물의 제조방법의 예를 나타낸 도이다.40 is a diagram showing an example of a method for preparing a compound represented by Formula 1 of the present invention.
도 41은 본 발명의 화학식 2로 표시되는 화합물의 제조방법의 예를 나타낸 도이다.41 is a diagram showing an example of a method for preparing a compound represented by Formula 2 of the present invention.
도 42는 본 발명의 화학식 3으로 표시되는 화합물의 제조방법의 예를 나타낸 도이다.42 is a diagram showing an example of a method for preparing a compound represented by Formula 3 of the present invention.
도 43은 본 발명의 화합물에 의한 Wnt 신호 체계에 대한 회복효과를 나타낸 도이다.43 is a diagram showing the recovery effect on the Wnt signaling system by the compound of the present invention.
도 44a 내지 44j는 본 발명의 화합물의 ELISA 결합 어세이 결과를 나타낸 도이다.44A to 44J show ELISA binding assay results for the compounds of the present invention.
도 45는 본 발명의 화합물의 SPR 결합 어세이 결과를 나타낸 도이다.45 is a diagram showing a result of SPR binding assay of a compound of the present invention.
도 46은 본 발명의 화합물의 골밀도에 대한 효과를 나타낸 도이다.46 is a diagram showing the effect on the bone density of the compound of the present invention.
도 47은 본 발명의 화합물의 골단면적 및 골둘레 길이에 대한 효과를 나타낸 도이다.FIG. 47 is a diagram showing the effect on the bone area and the bone circumference of the compound of the present invention.
도 48은 본 발명의 화합물의 골 단면두께 및 골 표면적에 대한 효과를 나타낸 도이다.48 is a diagram showing the effect on the bone cross-sectional thickness and bone surface area of the compound of the present invention.
상기 과제를 해결하기 위한 하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 또는 이들의 약학적으로 허용 가능한 염:As one embodiment for solving the above problems, the present invention is a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2017001288-appb-I000001
Figure PCTKR2017001288-appb-I000001
상기 식에서,Where
R1 내지 R3은 각각 독립적으로 수소, 할로겐, -SO3H, C1-4 알킬, C6-10 아릴, 또는 서로 이웃한 두개의 치환기가 서로 연결되어 이들이 결합된 티오펜 고리와 함께 융합된 헤테로 아릴을 형성하며,R 1 to R 3 are each independently hydrogen, halogen, —SO 3 H, C 1-4 alkyl, C 6-10 aryl, or two adjacent substituents connected to each other and fused together with a thiophene ring to which they are bonded; Form hetero aryl,
상기 아릴은 비치환 또는 할로겐, C1-4 알킬, C1-4 알콕시, C1-4 플루오르화 알킬, C1-4 플루오르화 알콕시, 시아노, 카르복스아미도 및 아세트아미노로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The aryl is unsubstituted or from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluorinated alkyl, C 1-4 fluorinated alkoxy, cyano, carboxamido and acetamino May be substituted with any one or more substituents selected;
R4는 수소, 할로겐, -CO2(C0-4 알킬), -CO2(C6-10 아릴), 또는 -CONHW이며, 상기 W는 보호되거나 보호되지 않은 아미노산;R 4 is hydrogen, halogen, —CO 2 (C 0-4 alkyl), —CO 2 (C 6-10 aryl), or —CONHW, wherein W is a protected or unprotected amino acid;
R5는 C1-4 알킬, 또는 비치환 또는 치환된 C6-10 아릴, 5 내지 10원 헤테로아릴, 3 내지 10원 헤테로사이클로알킬, 또는 C3-10 사이클로알킬로서,R 5 is C 1-4 alkyl, or unsubstituted or substituted C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, or C 3-10 cycloalkyl,
상기 아릴, 헤테로아릴, 헤테로사이클로알킬 및 사이클로알킬은 비치환 또는 C1-4 알킬, C1-4 알콕시, C1-4 플루오르화 알킬, C1-4 플루오르화 알콕시, C6-10 아릴, (C6-10 아릴)-(C0-4 알킬)옥시, 할로겐, 3 내지 10원 헤테로사이클로알킬, 5 내지 10원 헤테로아릴, -CO(C0- 4알킬), -CONH(C0- 4알킬), -CONH(C1- 4알킬렌)(C=O)-O-(C1- 4알킬), -SO2NH2, -CO2(C1- 4알킬), -SO3H, (설폰페닐)옥시, 및 -CONHW'로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 직접 또는 C1-4 알킬렌을 통해 치환될 수 있으며,The aryl, heteroaryl, heterocycloalkyl and cycloalkyl may be unsubstituted or C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluorinated alkyl, C 1-4 fluorinated alkoxy, C 6-10 aryl, (C 6-10 aryl), - (C 0-4 alkyl) oxy, halogen, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -CO (C 0- 4 alkyl), -CONH (C 0- 4 alkyl), -CONH (C 1- 4 alkylene) (C = O) -O- ( C 1- 4 alkyl), -SO 2 NH 2, -CO 2 (C 1- 4 alkyl), -SO 3 May be substituted directly or via C 1-4 alkylene with any one or more substituents selected from the group consisting of H, (sulfonphenyl) oxy, and -CONHW ',
상기 W'은 보호되거나 보호되지 않은 아미노산;W 'is a protected or unprotected amino acid;
n은 0 내지 3의 정수이다.n is an integer of 0-3.
바람직하게, 상기 화학식 1에서,Preferably, in Formula 1,
R1 내지 R3은 각각 독립적으로 수소, 클로로, 브로모, -SO3H, 시아노, 메틸, 페닐, 또는 R1과 R2가 서로 연결되어 이들이 결합된 티오펜 고리와 함께 벤조티오펜을 형성하며,R 1 to R 3 are each independently hydrogen, chloro, bromo, -SO 3 H, cyano, methyl, phenyl, or R 1 and R 2 are linked to each other to form benzothiophene together with the thiophene ring to which they are bonded. Forming,
상기 페닐은 비치환 또는 플루오로, 메틸, 메톡시, 트리플루오로메틸, 트리플루오로메톡시, 시아노, 아미노포르밀 및 아세트아미노로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The phenyl may be unsubstituted or substituted with any one or more substituents selected from the group consisting of fluoro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, aminoformyl and acetamino;
R4는 수소, 플루오로, -CO2H, -CO2CH3, -CO2C2H5, 또는 -CONHW이며, 상기 W는 메틸로 보호되거나 보호되지 않은 이소루신;R 4 is hydrogen, fluoro, —CO 2 H, —CO 2 CH 3 , —CO 2 C 2 H 5 , or —CONHW, wherein W is isoleucine, protected or unprotected with methyl;
R5는 프로필, 사이클로프로필, 벤조디옥솔릴, 또는 비치환 또는 치환된 페닐, 피리디닐, 피페리디닐 또는 사이클로헥실로서,R 5 is propyl, cyclopropyl, benzodioxolyl, or unsubstituted or substituted phenyl, pyridinyl, piperidinyl or cyclohexyl,
상기 페닐, 피리디닐, 피페리디닐 및 사이클로헥실은 비치환 또는 벤질, 벤질옥시, 몰포리닐, -CONH(CH2)2몰포리닐, -CONH(CHCH3)CONH(CH2)2몰포리닐, 플루오로, 클로로, 브로모, 메틸, 트리플루오로메틸, 티오페닐, -CONH2, -CONHCH3, -CONHC2H5, -SO2NH2, -CH2CO2H, -CH2CO2CH3, -COCH3, -CO2H, -CO2CH3, -CO2C2H5, -CO2(tert-부틸), -SO3H, 페녹시, 설포페녹시, 및 -CONHW'로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있으며,The phenyl, pyridinyl, piperidinyl and cyclohexyl may be unsubstituted or benzyl, benzyloxy, morpholinyl, -CONH (CH 2 ) 2 morpholinyl, -CONH (CHCH 3 ) CONH (CH 2 ) 2 morpholi Nyl, fluoro, chloro, bromo, methyl, trifluoromethyl, thiophenyl, -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -SO 2 NH 2 , -CH 2 CO 2 H, -CH 2 CO 2 CH 3 , -COCH 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 C 2 H 5 , -CO 2 (tert-butyl), -SO 3 H, phenoxy, sulfofenoxy, and -CONHW 'may be substituted with any one or more substituents selected from the group consisting of
상기 W'은 메틸 또는 tert-부틸로 보호되거나 보호되지 않은 트립토판, 알라닌, 아스파르트산, 페닐알라닌, 티로신, 발린, 이소루신, 루신 또는 메티오닌;W 'is tryptophan, alanine, aspartic acid, phenylalanine, tyrosine, valine, isoleucine, leucine or methionine, protected or unprotected with methyl or tert-butyl;
n은 0 또는 1인일 수 있다.n can be zero or one.
예컨대, 상기 화학식 1로 표시되는 화합물은For example, the compound represented by Formula 1 is
1. 1-(4-플루오로페닐)-N-(3-(메틸카바모일)페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,1.1- (4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
2. 1-(4-플루오로페닐)-N-(3-설파모일페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,2. 1- (4-fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
3. 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤젠설폰산,3. 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid,
4. 메틸 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트,4. methyl 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
5. N-(3-카바모일페닐)-1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,5. N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
6. 1-(4-플루오로페닐)-N-(4-(메틸카바모일)페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,6. 1- (4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
7. N-(4-카바모일페닐)-1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,7.N- (4-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
8. 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,8. 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
9. 4-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,9. 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
10. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-트립토파네이트,10. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate,
11. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-트립토판,11. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan,
12. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-D-알라니네이트,12. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanineate,
13. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-D-알라닌,13. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine,
14. 디메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-아스파테이트,14. Dimethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate,
15. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-아스파르트산,15. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid,
16. 4-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤젠설폰산,16. 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid,
17. 에틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)글리시네이트,17. ethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate,
18. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)글리신,18. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine,
19. 3-(5-클로로티오펜-2-일)-N-(3-((2-몰포리노에틸)카바모일)페닐)-1-페닐-1H-피라졸-4-카르복스아미드,19. 3- (5-chlorothiophen-2-yl) -N- (3-((2-morpholinoethyl) carbamoyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
20. 메틸 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조에이트,20. Methyl 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoate,
21. 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조산,21. 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoic acid,
22. 메틸 (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조일)-D-알라니네이트,22. Methyl (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alanineate,
23. (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조일)-D-알라닌,23. (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alanine,
24. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조에이트,24. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,
25. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조산,25. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid,
26. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-트립토파네이트,26. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophanate ,
27. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-트립토판,27. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophan,
28. (S)-3-(5-클로로티오펜-2-일)-N-(3-((1-((2-몰포리노에틸)아미노)-1-옥소프로판-2-일)카바모일)페닐)-1-페닐-1H-피라졸-4-카르복스아미드,28. (S) -3- (5-chlorothiophen-2-yl) -N- (3-((1-((2-morpholinoethyl) amino) -1-oxopropan-2-yl) carba Moyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
29. 에틸 3-(3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트,29. ethyl 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
30. 3-(3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,30. 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
31. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-(트리플루오로메틸)벤조에이트,31.Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoate,
32. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-(트리플루오로메틸)벤조산,32. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoic acid,
33. 메틸 3-클로로-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,33. Methyl 3-chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
34. 3-클로로-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,34. 3-chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
35. 메틸 3-브로모-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,35. Methyl 3-bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
36. 3-브로모-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,36. 3-bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
37. 메틸 2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세테이트,37. Methyl 2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetate,
38. 2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세트산,38. 2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetic acid,
39. 메틸 (2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세틸)-L-트립토파네이트,39. Methyl (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophanate ,
40. (2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세틸)-L-트립토판,40. (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophan,
41. 에틸 3-(3-(5-클로로티오펜-2-일)-4-(페닐카바모일)-1H-피라졸-1-일)벤조에이트,41. ethyl 3- (3- (5-chlorothiophen-2-yl) -4- (phenylcarbamoyl) -1H-pyrazol-1-yl) benzoate,
42. 3-(3-(5-클로로티오펜-2-일)-4-(페닐카바모일)-1H-피라졸-1-일)벤조산,42. 3- (3- (5-chlorothiophen-2-yl) -4- (phenylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid,
43. 에틸 3-(4-((3-클로로페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조에이트,43. ethyl 3- (4-((3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate,
44. 3-(4-((3-클로로페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,44. 3- (4-((3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
45. 에틸 3-(3-(5-클로로티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조에이트,45. ethyl 3- (3- (5-chlorothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate,
46. 3-(3-(5-클로로티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조산,46. 3- (3- (5-chlorothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
47. tert-부틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-페닐알라니네이트,47. tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-phenyl Alanine,
48. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-페닐알라닌,48. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-phenylalanine,
49. 메틸 (S)-3-(4-(tert-부톡시)페닐)-2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤즈아미도)프로파네이트,49.Methyl (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1 H-pyrazole- 4-carboxamido) -5-fluorobenzamido) propane,
50. (S)-3-(4-(tert-부톡시)페닐)-2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤즈아미도)프로판산,50. (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4 -Carboxamido) -5-fluorobenzamido) propanoic acid,
51. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-티로신,51. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tyrosine,
52. tert-부틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-발리네이트,52. tert-Butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-vari Nate,
53. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-발린,53. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-valine,
54. tert-부틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-이소루시네이트,54. tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-iso Lucinate,
55. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-이소루신,55. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-isoleucine,
56. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-루시네이트,56. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-lucinate,
57. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-루신,57. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-leucine,
58. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-메티오네이트,58. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methionate ,
59. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-메티오닌,59. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methionine,
60. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-플루오로벤조에이트,60. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoate,
61. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-플루오로벤조산,61. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoic acid,
62. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-(트리플루오로메틸)벤조에이트,62. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoate,
63. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-(트리플루오로메틸)벤조산,63. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoic acid,
64. tert-부틸 3-(3-(5-클로로티오펜-2-일)-1-(4-(메톡시카보닐)페닐)-1H-피라졸-4-카르복스아미도)벤조에이트,64. tert-Butyl 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoate ,
65. 4-(4-((3-(tert-부톡시카보닐)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,65. 4- (4-((3- (tert-butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
66. 3-(3-(5-클로로티오펜-2-일)-1-(4-(메톡시카보닐)페닐)-1H-피라졸-4-카르복스아미도)벤조산,66. 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoic acid,
67. 3-(1-(4-카르복시페닐)-3-(5-클로로티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,67. 3- (1- (4-carboxyphenyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
68. 메틸 4-(4-((3-(((2R,3R)-1-(tert-부톡시)-3-메틸-1-옥소펜탄-2-일)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조에이트,68.Methyl 4- (4-((3-(((2R, 3R) -1- (tert-butoxy) -3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1 H-pyrazol-1-yl) benzoate,
69. 4-(4-((3-(((2S,3S)-1-(tert-부톡시)-3-메틸-1-옥소펜탄-2-일)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,69. 4- (4-((3-(((2S, 3S) -1- (tert-butoxy) -3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl)- 3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
70. 4-(4-((3-(((1R,2R)-1-카르복시-2-메틸부틸)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,70. 4- (4-((3-(((1R, 2R) -1-carboxy-2-methylbutyl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
71. 메틸 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조에이트,71. Methyl 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoate,
72. 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조산,72. 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoic acid,
73. tert-부틸 (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조일)-L-이소루시네이트,73.tert-butyl (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl)- L-isorushinate,
74. (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조일)-L-이소루신,74. (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-iso Leucine,
75. 메틸 3-(3-(5-시아노티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조에이트,75. Methyl 3- (3- (5-cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,
76. 3-(3-(5-시아노티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조산,76. 3- (3- (5-cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid,
77. 메틸 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,77. Methyl 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate,
78. 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,78. 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
79. 메틸 (1S,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,79. Methyl (1S, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
80. (1S,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,80. (1S, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
81. 메틸 (1R,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,81. Methyl (1R, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
82. (1R,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,82. (1R, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
83. tert-부틸 ((1S,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트,83. tert-Butyl ((1S, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1- Carbonyl) -L-isorushinate,
84. ((1S,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신,84. ((1S, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,
85. tert-부틸 ((1R,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트,85. tert-butyl ((1R, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1- Carbonyl) -L-isorushinate,
86. ((1R,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신,86. ((1R, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,
87. 에틸 4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조에이트,87. ethyl 4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate,
88. 4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조산,88. 4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
89. 메틸 (4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조일)-L-알로이소루시네이트,89. Methyl (4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoyl) -L-alloy Sorcinate,
90. 2-(4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤즈아미도)-3-메틸펜탄산,90. 2- (4- (3- (5-Bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzamido)- 3-methylpentanoic acid,
91. 메틸 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤조에이트,91. Methyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoate,
92. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤조산,92. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoic acid,
93. 메틸 (3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤조일)-L-이소루시네이트,93. Methyl (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoyl) -L-isorushinate ,
94. 2-(3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤즈아미도)-3-메틸펜탄산,94. 2- (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzamido) -3- Methylpentanoic acid,
95. 메틸 (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,95. Methyl (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
96. (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,96. (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
97. 메틸 ((1R,3S)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-D-이소루시네이트,97. Methyl ((1R, 3S) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl ) -D-isorushinate,
98. 2-((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복스아미도)-3-메틸펜탄산,98. 2-((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-car Voxamido) -3-methylpentanoic acid,
99. 메틸 4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복실레이트,99. Methyl 4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylate,
100. 4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복시산,100. 4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylic acid,
101. 메틸 (4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카보닐)-D-이소루시네이트,101.Methyl (4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carbonyl) -D Isorushinate,
102. 2-(4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복스아미도)-3-메틸펜탄산,102. 2- (4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxamido ) -3-methylpentanoic acid,
103. 메틸 (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,103. Methyl (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
104. (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,104. (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
105. 메틸 ((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트,105. Methyl ((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl ) -L-isorushinate,
106. ((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신,106. ((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,
107. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3S)-3-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,107. Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3S) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
108. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3S)-3-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,108. 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3S) -3-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
109. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3R)-3-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,109. Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3R) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
110. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3R)-3-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,110. 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3R) -3-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
111. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1S,4S)-4-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,111.Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1S, 4S) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
112. 4-(3-(5-브로모티오펜-2-일)-4-(((1S,4S)-4-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,112. 4- (3- (5-bromothiophen-2-yl) -4-(((1S, 4S) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
113. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1R,4R)-4-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,113. Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 4R) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
114. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,4R)-4-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,114. 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 4R) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
115. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤젠설폰산,115. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid,
116. 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤젠설폰산,116. 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid,
117. 3-(1-페닐-3-(5-설포티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,117. 3- (1-phenyl-3- (5-sulfothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
118. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,118. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
119. 페닐-N-(3-설파모일페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,119. Phenyl-N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamide,
120. 1-페닐-3-(티오펜-2-일)-N-(m-톨릴)-1H-피라졸-4-카르복스아미드,120. 1-phenyl-3- (thiophen-2-yl) -N- (m-tolyl) -1H-pyrazole-4-carboxamide,
121. N-(3-아세틸페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,121.N- (3-acetylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
122. N-(4-카바모일페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,122. N- (4-carbamoylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
123. 메틸 (4-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조일)글리시네이트,123. Methyl (4- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate,
124. 3-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,124. 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
125. 에틸 3-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트,125. ethyl 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
126. N,1-디페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,126. N, 1-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
127. N-(3-페녹시페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,127.N- (3-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
128. N-(4-페녹시페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,128.N- (4-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
129. N-(3-클로로페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,129.N- (3-chlorophenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
130. N-(벤조[d][1,3]디옥솔-5-일)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,130. N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
131. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,131. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
132. 3-(5-클로로티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,132. 3- (5-chlorothiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
133. 에틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,133. ethyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
134. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,134. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
135. N-(3-클로로페닐)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,135. N- (3-chlorophenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
136. 3-(5-클로로티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,136. 3- (5-chlorothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
137. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,137.N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide ,
138. 3-(5-클로로티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,138. 3- (5-chlorothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
139. 3-(5-클로로티오펜-2-일)-1-페닐-N-프로필-1H-피라졸-4-카르복스아미드,139. 3- (5-chlorothiophen-2-yl) -1-phenyl-N-propyl-1H-pyrazole-4-carboxamide,
140. 3-(5-클로로티오펜-2-일)-N-사이클로프로필-1-페닐-1H-피라졸-4-카르복스아미드,140. 3- (5-chlorothiophen-2-yl) -N-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxamide,
141. N-(1-벤질피페리딘-4-일)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,141.N- (1-benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
142. 3-(5-클로로티오펜-2-일)-1-페닐-N-(피리딘-3-일)-1H-피라졸-4-카르복스아미드,142. 3- (5-chlorothiophen-2-yl) -1-phenyl-N- (pyridin-3-yl) -1H-pyrazole-4-carboxamide,
143. 3-(5-클로로티오펜-2-일)-1-페닐-N-(4-(티오펜-2-일)페닐)-1H-피라졸-4-카르복스아미드,143. 3- (5-chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen-2-yl) phenyl) -1H-pyrazole-4-carboxamide,
144. 3-(5-클로로티오펜-2-일)-N-(4-몰포리노페닐)-1-페닐-1H-피라졸-4-카르복스아미드,144. 3- (5-chlorothiophen-2-yl) -N- (4-morpholinophenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
145. N-(4-(벤질옥시)페닐)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,145.N- (4- (benzyloxy) phenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
146. 에틸 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,146. ethyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
147. 3-(5-브로모티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,147. 3- (5-Bromothiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
148. 3-(5-브로모티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,148. 3- (5-Bromothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
149. 3-(5-브로모티오펜-2-일)-N-(3-클로로페닐)-1-페닐-1H-피라졸-4-카르복스아미드,149. 3- (5-Bromothiophen-2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
150. 3-(5-브로모티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,150. 3- (5-bromothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
151. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,151.N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide ,
152. 3-(5-메틸티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,152. 3- (5-methylthiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
153. 에틸 3-(3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,153. ethyl 3- (3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
154. 3-(3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,154. 3- (3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
155. N-(3-클로로페닐)-3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,155.N- (3-chlorophenyl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
156. 3-(5-메틸티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,156. 3- (5-methylthiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
157. 3-(5-메틸티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,157. 3- (5-methylthiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
158. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,158. N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide ,
159. 에틸 3-(3-(벤조[b]티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,159. ethyl 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
160. 3-(벤조[b]티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,160. 3- (benzo [b] thiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
161. 3-(벤조[b]티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,161. 3- (benzo [b] thiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
162. 3-(벤조[b]티오펜-2-일)-N-(3-클로로페닐)-1-페닐-1H-피라졸-4-카르복스아미드,162. 3- (benzo [b] thiophen-2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
163. 3-(3-(벤조[b]티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,163. 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
164. 3-(벤조[b]티오펜-2-일)-N-(벤조[d][1,3]디옥솔-5-일)-1-페닐-1H-피라졸-4-카르복스아미드,164. 3- (benzo [b] thiophen-2-yl) -N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-1H-pyrazole-4-carbox amides,
165. 3-(벤조[b]티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,165. 3- (benzo [b] thiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
166. 3-(벤조[b]티오펜-3-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,166. 3- (benzo [b] thiophen-3-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
167. 에틸 3-(3-(벤조[b]티오펜-3-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,167. ethyl 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
168. 3-(3-(벤조[b]티오펜-3-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,168. 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
169. 3-(1-페닐-3-(5-(4-(트리플루오로메톡시)페닐)티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,169. 3- (1-phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
170. 3-(3-(5-(3-아세트아미도페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,170. 3- (3- (5- (3-acetamidophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
171. 3-(3-(5-(2-플루오로-4-(트리플루오로메틸)페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,171. 3- (3- (5- (2-fluoro-4- (trifluoromethyl) phenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) Benzoic Acid,
172. 3-(3-(5-(3-시아노-4-플루오로페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,172. 3- (3- (5- (3-cyano-4-fluorophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
173. 3-(1-페닐-3-(5-(4-(트리플루오로메틸)페닐)티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,173. 3- (1-phenyl-3- (5- (4- (trifluoromethyl) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
174. 3-(3-(5-(3-플루오로-4-메톡시페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산, 또는174. 3- (3- (5- (3-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid, or
175. 3-(3-(5-(4-카바모일페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산일 수 있다.175. It may be 3- (3- (5- (4-carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid.
다른 하나의 양태로서, 본 발명은 하기 화학식 2로 표시되는 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용가능한 염을 제공한다:In another aspect, the present invention provides a compound represented by the following formula (2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 2][Formula 2]
Figure PCTKR2017001288-appb-I000002
Figure PCTKR2017001288-appb-I000002
상기 식에서,Where
R6은 C6-10 아릴, 3 내지 10원 헤테로사이클로알킬, 또는 (3 내지 10원 헤테로사이클로알킬)(C1-4 알킬)로서,R 6 is C 6-10 aryl, 3 to 10 membered heterocycloalkyl, or (3 to 10 membered heterocycloalkyl) (C 1-4 alkyl),
상기 아릴 및 헤테로사이클로알킬은 비치환되거나, C1-4 할로겐화 알킬, -CO(C6-10 아릴), -CO(1-4 알킬), -CONH(C6-10 아릴), -SO2(비치환 또는 C1-4 알킬로 치환된 C6-10 아릴), (C6-10 아릴)(C1-4 알킬), -CO2(C0-4 알킬), 할로겐, C1-4 알콕시, C6-10 아릴옥시, 5 내지 10원 헤테로아릴 또는 -CONHW''로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The aryl and heterocycloalkyl are unsubstituted or C 1-4 halogenated alkyl, -CO (C 6-10 aryl), -CO ( 1-4 alkyl), -CONH (C 6-10 aryl), -SO 2 (C 6-10 aryl unsubstituted or substituted with C 1-4 alkyl), (C 6-10 aryl) (C 1-4 alkyl), -CO 2 (C 0-4 alkyl), halogen, C 1- 4 alkoxy, C 6-10 aryloxy, 5-10 membered heteroaryl, or -CONHW '', which may be substituted with any one or more substituents selected from the group consisting of:
R7은 수소, C6-10 아릴옥시, -CONH(C1-4 알킬렌)(3 내지 10원 헤테로사이클로알킬), -CO2(C0-4 알킬), 또는 -CONHW''로서,R 7 is hydrogen, C 6-10 aryloxy, -CONH (C 1-4 alkylene) (3 to 10 membered heterocycloalkyl), -CO 2 (C 0-4 alkyl), or -CONHW '',
상기 W''은 각각 독립적으로 보호되거나 보호되지 않은 아미노산임.Each of W ″ is an independently protected or unprotected amino acid.
바람직하게, 상기 화학식 2에서,Preferably, in Formula 2,
R6은 페닐, 피페리디닐, 또는 피페리디닐메틸로서,R 6 is phenyl, piperidinyl, or piperidinylmethyl,
상기 페닐 및 피페리디닐은 비치환되거나, 트리플루오로메틸, 트리플루오로메톡시, -CO2H, -CO2CH3, -CO2(페닐), -CONH(페닐), 할로겐, C1-4 알콕시, 벤질, 이미다졸릴, 토실, 또는 페녹시로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The phenyl and piperidinyl are unsubstituted or trifluoromethyl, trifluoromethoxy, -CO 2 H, -CO 2 CH 3 , -CO 2 (phenyl), -CONH (phenyl), halogen, C 1- 4 may be substituted with any one or more substituents selected from the group consisting of alkoxy, benzyl, imidazolyl, tosyl, or phenoxy;
R7은 수소, 페녹시, -CONH(CH2)2(몰포리닐), -CO2H, -CO2CH3 또는 -CONHW''로서,R 7 is hydrogen, phenoxy, -CONH (CH 2 ) 2 (morpholinyl), -CO 2 H, -CO 2 CH 3 or -CONHW '',
상기 W''은 메틸로 보호되거나 보호되지 않은 트립토판일 수 있으나, 이에 제한되지 않는다.The W ″ may be tryptophan, protected with or without methyl, but is not limited thereto.
예컨대, 상기 화학식 2로 표시되는 화합물은For example, the compound represented by Formula 2 is
1. 4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조산,1. 4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid,
2. 메틸 (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-D-트립토파네이트,2. methyl (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophanate,
3. 메틸 (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-D-트립토판,3. Methyl (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophan,
4. 2-(4-((2-몰포리노에틸)카바모일)페닐)-N-(3-페녹시페닐)티아졸-5-카르복스아미드,4. 2- (4-((2-morpholinoethyl) carbamoyl) phenyl) -N- (3-phenoxyphenyl) thiazole-5-carboxamide,
5. 3-(5-((4-페녹시페닐)카바모일)티아졸-2-일)벤조산,5. 3- (5-((4-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid,
6. 메틸 3-(2-(4-페녹시페닐)티아졸-5-카르복스아미도)벤조에이트,6. Methyl 3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoate,
7. 3-(2-(4-페녹시페닐)티아졸-5-카르복스아미도)벤조산,7. 3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoic acid,
8. 메틸 (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토파네이트,8. Methyl (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophanate,
9. (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토판,9. (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan,
10. 메틸 4-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조에이트,10. methyl 4- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,
11. 메틸 4-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조에이트,11.Methyl 4- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,
12. 메틸 4-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,12. Methyl 4- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
13. 4-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,13. 4- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
14. 메틸 4-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,14. Methyl 4- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
15. 4-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,15. 4- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
16. 메틸 4-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,16. Methyl 4- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
17. 4-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,17. 4- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
18. 메틸 3-(5-((1-벤질피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,18. Methyl 3- (5-((1-benzylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
19. 3-(5-((1-벤질피페리딘-4-일)카바모일)티아졸-2-일)벤조산,19. 3- (5-((1-benzylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
20. 메틸 3-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조에이트,20. Methyl 3- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,
21. 3-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조산,21. 3- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoic acid,
22. 메틸 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,22. Methyl 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
23. 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,23. 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
24. 메틸 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,24. Methyl 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
25. 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,25. 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
26. 메틸 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,26. Methyl 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
27. 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,27. 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
28. 메틸 (3-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토파네이트,28. Methyl (3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophanate,
29. (3-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토판,29. (3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan,
30. 메틸 3-(5-(((1-아세틸피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,30. Methyl 3- (5-(((1-acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
31. 메틸 3-(5-(((1-아세틸피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,31. Methyl 3- (5-(((1-acetylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
32. 메틸 3-(5-((1-아세틸피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,32. Methyl 3- (5-((1-acetylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
33. 메틸 3-(5-((1-아세틸피페리딘-3-일)카바모일)티아졸-2-일)벤조에이트,33. Methyl 3- (5-((1-acetylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoate,
34. 3-(5-(((1-아세틸피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,34. 3- (5-(((1-acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
35. 3-(5-(((1-아세틸피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,35. 3- (5-(((1-acetylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
36. 3-(5-((1-아세틸피페리딘-4-일)카바모일)티아졸-2-일)벤조산,36. 3- (5-((1-acetylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
37. 3-(5-((1-아세틸피페리딘-3-일)카바모일)티아졸-2-일)벤조산,37. 3- (5-((1-acetylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid,
38. 메틸 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,38. Methyl 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
39. 메틸 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,39. Methyl 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
40. 메틸 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,40. Methyl 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
41. 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,41. 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
42. 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,42. 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
43. 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,43. 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
44. 메틸 3-(5-(((1-벤조일피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,44. Methyl 3- (5-(((1-benzoylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
45. 메틸 3-(5-(((1-(페닐카바모일)피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,45. Methyl 3- (5-(((1- (phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
46. 메틸 3-(5-(((1-토실피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,46. Methyl 3- (5-(((1-tosylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
47. 3-(5-(((1-벤조일피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,47. 3- (5-(((1-benzoylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
48. 3-(5-(((1-(페닐카바모일)피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,48. 3- (5-(((1- (phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
49. 3-(5-(((1-토실피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,49. 3- (5-(((1-tosylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
50. 메틸 3-(5-((1-벤조일피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,50. methyl 3- (5-((1-benzoylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
51. 메틸 3-(5-((1-토실피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,51. methyl 3- (5-((1-tosylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
52. 메틸 3-(5-((1-벤조일피페리딘-3-일)카바모일)티아졸-2-일)벤조에이트,52. Methyl 3- (5-((1-benzoylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoate,
53. 메틸 3-(5-((1-토실피페리딘-3-일)카바모일)티아졸-2-일)벤조에이트,53. methyl 3- (5-((1-tosylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoate,
54. 3-(5-((1-벤조일피페리딘-4-일)카바모일)티아졸-2-일)벤조산,54. 3- (5-((1-benzoylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
55. 3-(5-((1-토실피페리딘-4-일)카바모일)티아졸-2-일)벤조산,55. 3- (5-((1-tosylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
56. 3-(5-((1-벤조일피페리딘-3-일)카바모일)티아졸-2-일)벤조산,56. 3- (5-((1-benzoylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid,
57. 3-(5-((1-토실피페리딘-3-일)카바모일)티아졸-2-일)벤조산,57. 3- (5-((1-tosylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid,
58. N,2-디페닐티아졸-5-카르복스아마이드,58. N, 2-diphenylthiazole-5-carboxamide,
59. 메틸 4-(5-(페닐카바모일)티아졸-2-일)벤조에이트,59. Methyl 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoate,
60. 4-(5-(페닐카바모일)티아졸-2-일)벤조산,60. 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoic acid,
61. 메틸 4-(5-((3,5-비스(트리플루오로메틸)페닐)카바모일)티아졸-2-일)벤조에이트,61. Methyl 4- (5-((3,5-bis (trifluoromethyl) phenyl) carbamoyl) thiazol-2-yl) benzoate,
62. N-(3-페녹시페닐)-2-페닐티아졸-5-카르복스아마이드,62. N- (3-phenoxyphenyl) -2-phenylthiazole-5-carboxamide,
63. N-(4-(1H-이미다졸-1-일)페닐)-2-페닐티아졸-5-카르복스아마이드,63. N- (4- (1H-imidazol-1-yl) phenyl) -2-phenylthiazole-5-carboxamide,
64. 메틸 4-(5-((3-페녹시페닐)카바모일)티아졸-2-일l)벤조에이트,64. Methyl 4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yll) benzoate,
65. 3-(5-((3- 페녹시페닐)카바모일)티아졸-2-일)벤조산, 또는65. 3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid, or
66. N-(4-페녹시페닐)-2-페닐티아졸-5-카르복스아마이드일 수 있다.66. N- (4-phenoxyphenyl) -2-phenylthiazole-5-carboxamide.
또 하나의 양태로서, 본 발명은 하기 화학식 3으로 표시되는 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용가능한 염을 제공한다:In another aspect, the present invention provides a compound represented by the following formula (3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 3][Formula 3]
Figure PCTKR2017001288-appb-I000003
Figure PCTKR2017001288-appb-I000003
상기 식에서,Where
Z는 -CO2H, -CO2(C1-4 알킬), -CONH(C1-4 알킬), 히드록시, C1-4 알킬, C1-4 할로겐화 알킬, C3-8 사이클로알킬, 3 내지 10원 헤테로사이클로알킬, C6-10 아릴 또는 5 내지 10원 헤테로아릴로서,Z is -CO 2 H, -CO 2 (C 1-4 alkyl), -CONH (C 1-4 alkyl), hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 3-8 cycloalkyl , 3 to 10 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl,
상기 사이클로알킬, 헤테로사이클로알킬, 아릴 및 헤테로아릴은 비치환되거나, 히드록시, C1-4 알킬, C1-4 할로겐화 알킬, C6-10 아릴옥시, (C6-10 아릴)(C1-4 알킬), (C6-10 아릴)(C1-4 알킬)옥시, -CONH(C0-4 알킬), 3 내지 10원 헤테로사이클로알킬, 및 -(C0-4 알킬렌)CO2(C0-4 알킬)로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted, hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 6-10 aryloxy, (C 6-10 aryl) (C 1 -4 alkyl), (C 6-10 aryl) (C 1-4 alkyl) oxy, -CONH (C 0-4 alkyl), 3 to 10 membered heterocycloalkyl, and - (C 0-4 alkylene) CO Can be substituted with any one or more substituents selected from the group consisting of 2 (C 0-4 alkyl);
R8 및 R9는 각각 독립적으로 수소, -(C0-4 알킬렌)CO2(C0-4 알킬), -CONH(C0-4 알킬), 또는 할로겐;R 8 and R 9 are each independently hydrogen, — (C 0-4 alkylene) CO 2 (C 0-4 alkyl), —CONH (C 0-4 alkyl), or halogen;
R10 및 R11은 각각 독립적으로 수소 또는 할로겐이다.R 10 and R 11 are each independently hydrogen or halogen.
바람직하게, 상기 화학식 3에서,Preferably, in Chemical Formula 3,
Z는 -CO2H, -CO2C2H5, -CONH2, -CONHCH3, 히드록시, 메틸, 프로필, 트리플루오로알킬, 또는 히드록시, 브로모, 트리플루오로알킬, 페녹시, 페닐에틸, 벤질, 벤질옥시, 몰포리닐, -CONHCH3, -CO2H, -CO2CH3, 및 -CO2C2H5로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환 또는 비치환된 사이클로프로필, 피페리디닐, 몰포리닐, 인돌릴, 인다졸릴, 페닐 또는 피리디닐;Z is -CO 2 H, -CO 2 C 2 H 5 , -CONH 2 , -CONHCH 3 , hydroxy, methyl, propyl, trifluoroalkyl, or hydroxy, bromo, trifluoroalkyl, phenoxy, Unsubstituted or substituted with any one or more substituents selected from the group consisting of phenylethyl, benzyl, benzyloxy, morpholinyl, -CONHCH 3 , -CO 2 H, -CO 2 CH 3 , and -CO 2 C 2 H 5 Cyclopropyl, piperidinyl, morpholinyl, indolyl, indazolyl, phenyl or pyridinyl;
R8 및 R9는 각각 독립적으로 수소, -CO2H, -CH2CO2H, -CH2CO2CH3, -CO2CH3, -CO2C2H5, 클로로, 브로모, -CONHCH3, -CH2CONH2, 또는 -CONH2;R 8 and R 9 are each independently hydrogen, —CO 2 H, —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —CO 2 CH 3 , —CO 2 C 2 H 5 , chloro, bromo, -CONHCH 3 , -CH 2 CONH 2 , or -CONH 2 ;
R10 및 R11은 각각 독립적으로 수소 또는 플루오로일 수 있다.R 10 and R 11 may each independently be hydrogen or fluoro.
예컨대, 상기 화학식 3으로 표시되는 화합물은For example, the compound represented by Formula 3 is
1. 3-((3-(페닐카바모일)페닐)설폰아미도)벤조산,1. 3-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
2. N-메틸-3-((3-(페닐카바모일)페닐)설폰아미도)벤즈아미드,2.N-methyl-3-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide,
3. 3-((3-((3-카르복시페닐)카바모일)페닐)설폰아미도)벤조산,3. 3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid,
4. 3-(3-(N-(2-페녹시페닐)설파모일)벤즈아미도)벤조산,4. 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,
5. N-메틸-3-(3-(N-(2-페녹시페닐)설파모일)벤즈아미도)벤즈아미드,5.N-methyl-3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzamide,
6. 3-(3-(N-(3-페녹시페닐)설파모일)벤즈아미도)벤조산,6. 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,
7. N-메틸-3-(3-(N-(3-페녹시페닐)설파모일)벤즈아미도)벤즈아미드,7.N-methyl-3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzamide,
8. 3-(3-(N-(4-페녹시페닐)설파모일)벤즈아미도)벤조산,8. 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,
9. N-메틸-3-(3-(N-(4-페녹시페닐)설파모일)벤즈아미도)벤즈아미드,9.N-methyl-3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzamide,
10. 3-(3-(N-(피리딘-2-일)설파모일)벤즈아미도)벤조산,10. 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoic acid,
11. N-메틸-3-(3-(N-(피리딘-2-일)설파모일)벤즈아미도)벤즈아미드,11.N-methyl-3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzamide,
12. 3-(3-(N-(피리딘-3-일)설파모일)벤즈아미도)벤조산,12. 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoic acid,
13. N-메틸-3-(3-(N-(피리딘-3-일)설파모일)벤즈아미도)벤즈아미드,13.N-methyl-3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzamide,
14. 3-(3-(N-프로필설파모일)벤즈아미도)벤조산,14. 3- (3- (N-propylsulfamoyl) benzamido) benzoic acid,
15. N-메틸-3-(3-(N-프로필설파모일)벤즈아미도)벤즈아미드,15.N-methyl-3- (3- (N-propylsulfamoyl) benzamido) benzamide,
16. 3-(3-(N-사이클로프로필설파모일)벤즈아미도)벤조산,16. 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoic acid,
17. 3-(N-사이클로프로필설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,17. 3- (N-cyclopropylsulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
18. 3-(3-(N-메틸설파모일)벤즈아미도)벤조산,18. 3- (3- (N-methylsulfamoyl) benzamido) benzoic acid,
19. N-메틸-3-(3-(N-메틸설파모일)벤즈아미도)벤즈아미드,19.N-methyl-3- (3- (N-methylsulfamoyl) benzamido) benzamide,
20. 2-(3-(3-(N-페닐설파모일)벤즈아미도)페닐)아세트산,20. 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetic acid,
21. N-(3-(2-(메틸아미노)-2-옥소에틸)페닐)-3-(N-페닐설파모일)벤즈아미드,21.N- (3- (2- (methylamino) -2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide,
22. N-(3-(2-아미노-2-옥소에틸)페닐)-3-(N-페닐설파모일)벤즈아미드,22.N- (3- (2-amino-2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide,
23. 3-(3-(N-(4-(벤질옥시)페닐)설파모일)벤즈아미도)벤조산,23. 3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoic acid,
24. 3-(N-(4-(벤질옥시)페닐)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,24. 3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
25. 3-(3-(N-(1-벤질피페리딘-4-일)설파모일)벤즈아미도)벤조산,25. 3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoic acid,
26. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,26. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
27. 3-(3-(N-(4-몰포리노페닐)설파모일)벤즈아미도)벤조산,27. 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoic acid,
28. N-메틸-3-(3-(N-(4-몰포리노페닐)설파모일)벤즈아미도)벤즈아미드,28.N-methyl-3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzamide,
29. 3-(3-(N-(1H-인돌-5-일)설파모일)벤즈아미도)벤조산,29. 3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido) benzoic acid,
30. 3-(N-(1H-인돌-5-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,30. 3- (N- (1H-indol-5-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
31. 3-(3-(N-(1H-인돌-6-일)설파모일)벤즈아미도)벤조산,31. 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoic acid,
32. 3-(N-(1H-인돌-6-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,32. 3- (N- (1H-indol-6-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
33. 3-(3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)벤즈아미도)벤조산,33. 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoic acid,
34. 3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,34. 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
35. 3-((3-((3-카르복시페닐)카바모일)페닐)설폰아미도)벤조산,35. 3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid,
36. 에틸 3-((2,4-디플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조에이트,36. ethyl 3-((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,
37. 3-((2,4-디플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조산,37. 3-((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
38. 에틸 3-(4-플루오로-3-(N-페닐설파모일)벤즈아미도)벤조에이트,38. ethyl 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoate,
39. 3-(4-플루오로-3-(N-페닐설파모일)벤즈아미도)벤조산,39. 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoic acid,
40. 에틸 3-(2,4-디플루오로-5-(N-페닐설파모일)벤즈아미도)벤조에이트,40. ethyl 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoate,
41. 3-(2,4-디플루오로-5-(N-페닐설파모일)벤즈아미도)벤조산,41. 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoic acid,
42. 메틸 3-(3-(N-(2-페녹시페닐)설파모일)벤즈아미도)벤조에이트,42. Methyl 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoate,
43. 메틸 3-(3-(N-(3-페녹시페닐)설파모일)벤즈아미도)벤조에이트,43. Methyl 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoate,
44. 메틸 3-(3-(N-(4-페녹시페닐)설파모일)벤즈아미도)벤조에이트,44. Methyl 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoate,
45. 메틸 3-(3-(N-(4-(벤질옥시)페닐)설파모일)벤즈아미도)벤조에이트,45. Methyl 3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoate,
46. 메틸 3-(3-(N-(피리딘-2-일)설파모일)벤즈아미도)벤조에이트,46. Methyl 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoate,
47. 메틸 3-(3-(N-(피리딘-3-일)설파모일)벤즈아미도)벤조에이트,47. Methyl 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoate,
48. 메틸 3-(3-(N-프로필설파모일)벤즈아미도)벤조에이트,48. Methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate,
49. 메틸 3-(3-(N-사이클로프로필설파모일)벤즈아미도)벤조에이트,49. Methyl 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoate,
50. 메틸 3-(3-(N-메틸설파모일)벤즈아미도)벤조에이트,50. Methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate,
51. 메틸 3-(3-(N-(4-몰포리노페닐)설파모일)벤즈아미도)벤조에이트,51. Methyl 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoate,
52. 메틸 3-(3-(N-(1H-인돌-5-일)설파모일)벤즈아미도)벤조에이트,52. Methyl 3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido) benzoate,
53. 메틸 3-(3-(N-(1H-인돌-6-일)설파모일)벤즈아미도)벤조에이트,53. Methyl 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoate,
54. 메틸 3-(3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)벤즈아미도)벤조에이트,54. Methyl 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate,
55. 메틸 3-(3-(N-(1-벤질피페리딘-4-일)설파모일)벤즈아미도)벤조에이트,55. Methyl 3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoate,
56. 메틸 3-((3-((3-(메톡시카보닐)페닐)카바모일)페닐)설폰아미도)벤조에이트,56. Methyl 3-((3-((3- (methoxycarbonyl) phenyl) carbamoyl) phenyl) sulfonamido) benzoate,
57. 메틸 2-(3-(3-(N-페닐설파모일)벤즈아미도)페닐)아세테이트,57. Methyl 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetate,
58. 메틸 3-브로모-5-(3-(N-페닐설파모일)벤즈아미도)벤조에이트,58. Methyl 3-bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoate,
59. 메틸 3-브로모-5-((3-(페닐카바모일)페닐)설폰아미도)벤조에이트,59. Methyl 3-bromo-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,
60. 3-브로모-5-(3-(N-페닐설파모일)벤즈아미도)벤조산,60. 3-bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid,
61. 3-브로모-5-((3-(페닐카바모일)페닐)설폰아미도)벤조산,61. 3-bromo-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
62. 3-브로모-N-메틸-5-(3-(N-페닐설파모일)벤즈아미도)벤즈아미드,62. 3-bromo-N-methyl-5- (3- (N-phenylsulfamoyl) benzamido) benzamide,
63. 3-브로모-N-메틸-5-((3-(페닐카바모일)페닐)설폰아미도)벤즈아미드,63. 3-bromo-N-methyl-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide,
64. 메틸 3-((1-옥소-1,2,3,4-테트라하이드로이소퀴놀린)-7-설폰아미도)벤조에이트,64. Methyl 3-((1-oxo-1,2,3,4-tetrahydroisoquinoline) -7-sulfonamido) benzoate,
65. 3-(N-(2-(페닐아미노)페닐)설파모일)벤조산,65. 3- (N- (2- (phenylamino) phenyl) sulfamoyl) benzoic acid,
66. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,66. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
67. N-(3-카바모일페닐)-3-(N-펜에틸설파모일)벤즈아미드,67.N- (3-carbamoylphenyl) -3- (N-phenethylsulfamoyl) benzamide,
68. N-(3-카바모일페닐)-3-(N-(4-페녹시페닐)설파모일)벤즈아미드,68. N- (3-carbamoylphenyl) -3- (N- (4-phenoxyphenyl) sulfamoyl) benzamide,
69. N-(3-카바모일페닐)-3-(N-(피리딘-2-일)설파모일)벤즈아미드,69.N- (3-carbamoylphenyl) -3- (N- (pyridin-2-yl) sulfamoyl) benzamide,
70. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-카바모일페닐)벤즈아미드,70. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
71. N-(3-카바모일페닐)-3-(N-(3-페녹시페닐)설파모일)벤즈아미드,71.N- (3-carbamoylphenyl) -3- (N- (3-phenoxyphenyl) sulfamoyl) benzamide,
72. 3-(N-(1H-인다졸-5-일)설파모일)-N-(3-카바모일페닐)벤즈아미드,72. 3- (N- (1H-indazol-5-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
73. 3-(N-(1H-인다졸-6-일)설파모일)-N-(3-카바모일페닐)벤즈아미드,73. 3- (N- (1H-indazol-6-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
74. N-(3-카바모일페닐)-3-(N-(피리딘-3-일)설파모일)벤즈아미드,74.N- (3-carbamoylphenyl) -3- (N- (pyridin-3-yl) sulfamoyl) benzamide,
75. 2,4-디플루오로-N-(3-(메틸카바모일)페닐)-5-(N-페닐설파모일)벤즈아미드,75. 2,4-difluoro-N- (3- (methylcarbamoyl) phenyl) -5- (N-phenylsulfamoyl) benzamide,
76. 3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)-N-(3-카바모일페닐)벤즈아미드,76. 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
77. 4-플루오로-N-(3-(메틸카바모일)페닐)-3-(N-페닐설파모일)벤즈아미드,77. 4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N-phenylsulfamoyl) benzamide,
78. N-(3-카바모일페닐)-4-플루오로-3-(N-페닐설파모일)벤즈아미드,78. N- (3-carbamoylphenyl) -4-fluoro-3- (N-phenylsulfamoyl) benzamide,
79. 에틸 3-((5-((3-(에톡시카보닐)페닐)카바모일)-2-플루오로페닐)설폰아미도)벤조에이트,79. Ethyl 3-((5-((3- (ethoxycarbonyl) phenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoate,
80. 3-((5-((3-카르복시페닐)카바모일)-2-플루오로페닐)설폰아미도)벤조산,80. 3-((5-((3-carboxyphenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoic acid,
81. 4-플루오로-N-(3-(메틸카바모일)페닐)-3-(N-(3-(메틸카바모일)페닐)설파모일)벤즈아미드,81. 4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide,
82. 에틸 3-((2-플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조에이트,82. ethyl 3-((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,
83. 3-((2-플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조산,83. 3-((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
84. N-(4-클로로페닐)-3-(N-페닐설파모일)벤즈아미드,84. N- (4-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide,
85. N-(4-브로모페닐)-3-(N-페닐설파모일)벤즈아미드,85.N- (4-bromophenyl) -3- (N-phenylsulfamoyl) benzamide,
86. N-(3-클로로페닐)-3-(N-페닐설파모일)벤즈아미드,86. N- (3-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide,
87. N-(3,4-디클로로페닐)-3-(N-페닐설파모일)벤즈아미드,87.N- (3,4-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide,
88. N-(3,5-디클로로페닐)-3-(N-페닐설파모일)벤즈아미드, 또는88. N- (3,5-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide, or
89. N-(2,4-디브로모페닐)-3-(N-페닐설파모일)벤즈아미드일 수 있다.89. N- (2,4-dibromophenyl) -3- (N-phenylsulfamoyl) benzamide.
본 발명의 화학식 1 내지 3으로 표시되는 화합물은 약학적으로 허용되는 염의 형태로 사용될 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 I로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다. 또한, 본 발명의 화합물은 단독으로 또는 다른 약학적 활성 화합물과 결합하거나 집합으로 사용될 수 있다.The compounds represented by Formulas 1 to 3 of the present invention may be used in the form of a pharmaceutically acceptable salt. As salts are acid addition salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, and the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (I). Means any organic or inorganic addition salt. In addition, the compounds of the present invention may be used alone or in combination or in combination with other pharmaceutically active compounds.
상기 본 발명의 화학식 1 내지 3으로 표시되는 화합물의 약학적으로 허용가능한 염은 당해 기술분야에서 통상적인 방법에 따라 제조된 염을 의미하며, 이러한 제조방법은 당업자에게 공지되어 있다. 구체적으로, 상기 약학적으로 허용 가능한 염은 약리학적 또는 생리학적으로 허용되는 하기 무기산과 유기산 및 염기로부터 유도된 염을 포함하지만 이에 제한되지 않는다.Pharmaceutically acceptable salts of the compounds represented by Formulas 1 to 3 of the present invention refer to salts prepared according to methods conventional in the art, and such preparation methods are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다. 이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄설폰산, p-톨루엔설폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으며, 이들에 제한되지 않는다.Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered. In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid may be used as the organic acid. , Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, etc. Can be, and not limited to these.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한, 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium, or calcium salt, but is not limited thereto. Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
상기 화학식 1 내지 3으로 표시되는 화합물의 약학적으로 허용가능한 염은, 달리 지시하지 않는 한, 화학식 I의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the compounds represented by formulas (1) to (3) include salts of acidic or basic groups which may be present in the compound of formula (I), unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfates, hydrogen sulphates, phosphates, hydrogen phosphates , Dihydrogenphosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts; It can be prepared through the method.
본 발명의 화학식 1 내지 3으로 표시되는 화합물의 염으로는 약학적으로 허용가능한 염으로서, 상기 화합물들과 동등한 생물학적 활성을 나타내는 상기 화합물의 염이면 제한없이 모두 사용 가능하다.As salts of the compounds represented by the formulas (1) to (3) of the present invention, any salts of the compounds that exhibit biological activities equivalent to those of the compounds may be used without limitation.
또 다른 양태로서, 본 발명은 화학식 1 내지 3으로 표시되는 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 골질환의 예방 또는 치료용 약학적 조성물을 제공한다.As another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases comprising a compound represented by the formula (1) to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 상기 약학적 조성물을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 골질환의 예방 또는 치료방법을 제공한다.The present invention also provides a method for preventing or treating bone disease, comprising administering the pharmaceutical composition to a subject in need thereof.
본 발명에서 사용된 용어, "골 질환"이란, 조골세포의 활성 촉진으로 골량증가가 필요 또는 요구되는, 상태 또는 질병 또는 파골세포의 과다한 생성 및/또는 이동으로 인해 나타나는 상태 또는 질병을 의미하는 것으로 골량 저하 질환을 포함한다. 상기 골량 저하 질환이란 골밀도의 저하, 골조직의 열화 등의 증상을 수반하는 골량의 저하가 발생되는 상태 또는 질환을 의미하는 것으로, 예컨대 골다공증, 파제트병, 치주질환, 골 성장 장애, 골 전이암 및 류마티스 관절염일 수 있으나, 이에 제한되지 않는다.As used herein, the term "bone disease" refers to a condition or disease that results from excessive production and / or migration of osteoclasts or a condition or disease in which bone mass is required or required by promoting osteoblast activity. Bone loss disorders. The bone loss lowering disease refers to a condition or a disease in which a decrease in bone mass accompanied by symptoms such as a decrease in bone density and deterioration of bone tissue occurs. Rheumatoid arthritis, but is not limited thereto.
바람직하게 본 발명의 조성물은 골다공증 또는 골감소증의 예방 치료용으로 사용될 수 있다. 구체적으로 본 발명에서 사용된 용어, "골다공증"이란 골량이 감소하고 질적인 변화로 인해 골절이 일어날 가능성이 있는 상태를 의미하며, "골감소증"이란 골다공증의 초기 증세를 의미한다. 일반적으로 골밀도 수치(T 수치)를 기준으로 -1.0 내지 -2.5인 경우 골감소증, -2.5 이상인 경우 골다공증으로 분류한다.Preferably the composition of the present invention can be used for the prophylactic treatment of osteoporosis or osteopenia. Specifically, the term "osteoporosis" used in the present invention refers to a state in which bone fracture may occur due to a decrease in bone mass and qualitative change, and "osteoporosis" refers to an initial symptom of osteoporosis. Generally, it is classified as osteopenia in case of -1.0 to -2.5 and osteoporosis in case of -2.5 or more based on bone density (T).
본 발명에서 사용된 용어, "골질환의 예방 또는 치료"는 본 발명에 따른 조성물을 개체에 투여하여 달성되는 상기 골질환의 예방 및 완전한 또는 부분적인 치료를 포함한다. 이는 또한 골질환 증상의 감소, 개선, 그 증상의 고통 경감, 골질환 발생율 감소 또는 치료결과를 증가시키는 환자의 어떠한 다른 변화를 포함한다.As used herein, the term "prophylaxis or treatment of bone disease" includes the prevention and complete or partial treatment of said bone disease achieved by administering a composition according to the invention to a subject. It also includes reducing or improving symptoms of bone disease, alleviating the pain of the symptoms, reducing the incidence of bone disease, or any other change in the patient that increases the outcome of treatment.
본 발명에서 사용된 용어, "개체"는 골질환이 발병하였거나 발병할 수 있는 인간을 포함한 모든 동물을 의미한다. 본 발명의 조성물을 개체에게 투여하여 상기 골질환을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 조성물은 기존의 골질환 치료제와 병행하여 투여될 수 있다.As used herein, the term "individual" means any animal, including humans, who may or may have a bone disease. The composition of the present invention can be administered to an individual to effectively prevent or treat the bone disease. The composition of the present invention can be administered in parallel with existing therapeutic agents for bone disease.
본 발명에서 사용된 용어, "투여"란, 적절한 방법으로 환자에게 소정의 물질을 도입하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있으나, 이에 제한되지는 않는다.As used herein, the term "administration" means introducing a predetermined substance into a patient in an appropriate manner, and the route of administration of the composition of the present invention may be administered via any general route as long as it can reach the target tissue. Can be. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 상기 용어 "약학적으로 유효한 양"이란 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다. 일반적으로, 활성물질을 약 0.01 mg/kg/일 내지 1000 mg/kg/일의 용량으로 투여할 수 있다. 경구 투여하는 경우, 50 내지 500 mg/kg의 범위가 적합할 수 있으며, 1일 1회 이상 투여할 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term “pharmaceutically effective amount” means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment and not causing side effects, wherein the effective dose level is the sex, age and weight of the patient. , Factors such as health status, type of disease, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration, and rate of release, duration of treatment, combination or drug used, and other medical fields. It can be easily determined by those skilled in the art according to known factors. Generally, the active substance can be administered at a dose of about 0.01 mg / kg / day to 1000 mg / kg / day. In the case of oral administration, a range of 50 to 500 mg / kg may be suitable and may be administered at least once a day.
바람직하게, 본 발명의 약학적 조성물은 상기 화학식 1 내지 3으로 표시되는 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용가능한 염을 0.001 내지 1 중량% 함유할 수 있다.Preferably, the pharmaceutical composition of the present invention may contain 0.001 to 1% by weight of the compound represented by Formula 1 to 3, stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
또한, 상기 본 발명에 따른 골질환의 예방 또는 치료용 약학적 조성물은 상기 기재한 유효성분 이외에 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 본 발명에서 사용된 용어, "약학적으로 허용가능한"은 상기 조성물에 노출되는 세포나 인간 등의 개체에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제, 기제, 부형제, 윤활제 등 당업계에 공지된 것이라면 제한없이 사용할 수 있다. 본 발명의 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질셀룰로스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.In addition, the pharmaceutical composition for preventing or treating bone diseases according to the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient described above. As used herein, the term "pharmaceutically acceptable" means to exhibit properties that are not toxic to an individual such as a cell or human being exposed to the composition. The carrier can be used without limitation so long as it is known in the art such as buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, bases, excipients, lubricants. Carriers, excipients and diluents that may be included in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
또한, 본 발명의 조성물을 제제화 할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있다.In addition, when formulating the composition of the present invention, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
경구 투여를 위하여 정제, 환제, 산제, 과립제, 캡슐제 등의 고형 제제로 제조할 수 있다. 이러한 고형제제는 상기 조성물 이외에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트, 수크로스, 또는 락토즈, 젤라틴 등을 섞어 조제한다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면, 습윤제 감미제, 방향제, 보존제 등이 포함될 수 있다. 활성 성분이 산에 의해 분해되기 쉬운 경우, 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 활성 성분의 안정성이나 흡수성을 증가시키기 위하여 글루코스, 수크로스, 덱스트란 등의 카보하이드레이트, 아스코르빅산, 글루타치온 등의 항산화제, 킬레이팅 물질, 저분자 단백질 또는 다른 안정화제들을 사용할 수 있다.For oral administration, it may be prepared as a solid preparation such as tablets, pills, powders, granules, capsules and the like. Such solid preparations are prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, or lactose, gelatin and the like in addition to the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups.In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, flavoring agents, preservatives, etc. Can be. If the active ingredient is susceptible to degradation by acid, the oral composition may be formulated to coat the active agent or to protect it from degradation in the stomach. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, utopsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used. To increase the stability or absorption of the active ingredient, carbohydrates such as glucose, sucrose, dextran, antioxidants such as ascorbic acid, glutathione, chelating substances, small molecule proteins or other stabilizers can be used.
또한, 본 발명의 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하주사제, 피내 주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제(예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.In addition, the compositions of the present invention may be administered by any device in which the active substance may migrate to target cells. Preferred modes of administration and preparations are intravenous, subcutaneous, intradermal, intramuscular, injectable and the like. Injections include non-aqueous solvents such as aqueous solvents such as physiological saline solution and ring gel solution, vegetable oils, higher fatty acid esters (e.g., oleic acid, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). Stabilizers (e.g. ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, to prevent microbial growth Preservatives (eg, mercury nitrate, chimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
1. 골다공증 개선을 위한 새로운 약제의 작용 기전 (Mode of Action) 1.Mode of Action of New Drugs to Improve Osteoporosis
가. Wnt signaling과 Boneend. Wnt signaling and bone
19개의 당단백으로 구성된 Wnt계(Wnt family)는 발생 단계 및 생애 전반에 걸쳐 중요한 역할을 수행한다. 특히 Wnt 신호체계는 골격계 발생과 성인기 골격계 항상성 및 골 골재형성에 필요하다. Wnt 단백질은 다양한 신호 경로(Box1)에 관여하지만, 캐노니칼 Wnt-베타카테닌 신호 경로(Canonical wnt-β-catenin signalling pathway)를 통해 골격계에 대한 Wnt 신호체계 작용의 대부분이 설명되는 것으로 여겨진다. Wnt 단백질이 frizzled transmembrane receptor와 LRP-5 및 LRP-6에 결합하게 되면, 베타카테닌은 복합체로부터 분리되어 나오고, 단백 분해 과정을 거치지 않게 된다. 베타카테닌의 안정화는 핵 내로의 베타카테닌의 이동을 유발하고, 전사인자(TCF-4 or LEF-1)와의 연계하에 WISP1과 RUNX2와 같은 유전자의 전사를 조절하게 됨으로써 조골세포의 분화를 유도하고 동시에 C/EBPα (CCAAT/enhancer binding protein α) 와 PPAR-γ (peroxisome proliferator activated receptor γ) 와 같은 지방세포화 인자들을 억제함으로써 지방생성을 억제한다. Wnt 신호 체계는 파골세포 형성 및 골 흡수의 억제에 있어서도 중요하다. Wnt에 의한 파골세포 형성 억제는 RANKL에 결합하여 파골세포 형성을 억제하는 오스테오프로테게린(Osteoprotegerin, 종양괴사인자 수용체 계통(TNF receptor superfamily member 11B)로도 알려져 있음)의 발현 유도에 의한 것으로 보고되고 있다.The Wnt family of 19 glycoproteins plays an important role throughout the developmental stage and throughout life. In particular, Wnt signaling is required for skeletal development, adult skeletal homeostasis, and bone aggregate formation. Wnt proteins are involved in various signaling pathways (Box1), but it is believed that most of the Wnt signaling system's action on the skeletal system is explained by the canonical wnt-beta-catenin signaling pathway. When the Wnt protein binds to the frizzled transmembrane receptor and LRP-5 and LRP-6, betacatenin is released from the complex and is not subject to proteolysis. Stabilization of betacatenin induces the transfer of betacatenin into the nucleus and induces osteoblast differentiation by controlling transcription of genes such as WISP1 and RUNX2 in conjunction with transcription factors (TCF-4 or LEF-1). Adipogenesis is inhibited by inhibiting adipogenic factors such as C / EBPα (CCAAT / enhancer binding protein α) and PPAR-γ (peroxisome proliferator activated receptor γ). Wnt signaling systems are also important in the inhibition of osteoclast formation and bone resorption. Inhibition of osteoclast formation by Wnt is reported to be due to the induction of the expression of osteoprotegerin (also known as TNF receptor superfamily member 11B), which binds to RANKL and inhibits osteoclast formation. .
나. Sclerostin과 BoneI. Sclerostin and Bone
기계적 부하는 조골세포 계통의 세포에 있어서의 Wnt 신호 체계를 활성화시키는데, 이는 Wnt의 작용이 기계적인 힘을 골격계의 동화 작용으로 연계하는데에 연루되었을 가능성을 시사하고 있다. 이 기전은 역학감지 골세포에 의해 우선적으로 발현되는 Wnt 길항제인 스클레로스틴(sclerostin)의 억제와 관련이 있다. 스클레로스틴의 억제는 특히 뼈 중에서도 많은 부하를 받는 부위에서 나타나는데, 이는 Wnt 신호 체계와 골 형성을 촉진시킨다. 이와 반대로, 스클레로스틴은 골격계의 무부하에 의해서 증가되는데, 이는 골 흡수의 증가와 골 형성의 감소로 인해 골 감소를 유발한다. 이러한 기전은 지속된 침상 안정 및 신경 손상으로 인해 골량 감소가 초래되는 불용성 골다공증(osteoporosis of disuse)의 발병과 관련이 있을 것으로 생각된다. 불용성The mechanical load activates the Wnt signaling system in cells of the osteoblast lineage, suggesting that the action of Wnt may be involved in linking mechanical forces to assimilation of the skeletal system. This mechanism is associated with the inhibition of sclerostin, a Wnt antagonist preferentially expressed by epidemiological osteoblasts. Inhibition of sclerostin is particularly present in sites that are subject to high loads in bone, which promotes Wnt signaling and bone formation. In contrast, sclerostin is increased by no-load of the skeletal system, which causes bone loss due to increased bone resorption and reduced bone formation. This mechanism is thought to be related to the development of osteoporosis of disuse, which results in decreased bone mass due to continued bed rest and nerve damage. Insoluble
골다공증은 골절 발생 위험을 현저히 증가시키며, 골 감소의 방지 또는 교정은 이러한 환자 군에 있어서 유익할 것으로 여겨진다.Osteoporosis significantly increases the risk of fractures, and the prevention or correction of bone reduction is believed to be beneficial in this group of patients.
다. Sclerostin의 작용 기전 및 Sclerostin inhibitorAll. Mechanism of action of sclerostin and sclerostin inhibitor
Wnt 와 LRP-5-LRP-6 공동수용체와 상호작용을 하는 길항제에는 스클레로스틴 및 Dickkopf-related protein 1 (Dkk-1) 이 있다. SOST로 코딩되는 스클레로스틴은 주로 골세포에 의해 발현이 되며, LRP5-LRP6 공동 수용체에 붙어서 Wnt 신호를 방해하는 역할을 한다. 결과적으로 스클레로스틴은 조골세포형성과 골형성을 in vitro 와 in vivo 에서 억제한다. 스클레로스틴의 발현은 조골세포와 골세포에서 기계적 압박과 부갑상선호르몬(PTH) 에 의해서 억제되는데, 부갑상선기능 항진증 환자에서는 정상부갑상선기능을 가진 사람보다 스클레로스틴 레벨이 낮은 것을 관찰 할 수 있다. Antagonists that interact with Wnt and LRP-5-LRP-6 co-receptors include sclerostin and Dickkopf-related protein 1 (Dkk-1). Sclerostine encoded by SOST is mainly expressed by osteoblasts, which binds to the LRP5-LRP6 co-receptor and interferes with Wnt signaling. As a result, sclerostin inhibits osteoblast formation and bone formation in vitro and in vivo. Sclerostine expression is inhibited by mechanical compression and parathyroid hormone (PTH) in osteoblasts and osteocytes. In patients with hyperparathyroidism, lower levels of sclerostin than those with normal parathyroid function can be observed. .
Wnt신호의 상향조절이 부갑상선호르몬에 대한 반응으로 골 동화작용을 나타내는데 필수적인 것은 아니지만, 부갑상선호르몬에 의한 스클레로스틴의 발현 억제는 부갑상선호르몬의 선택적 골 동화작용을 설명할 수 있으며, Lrp5 유전자가 불활성화 된 마우스에서도 부갑상선호르몬에 대한 골 동화작용효과가 나타남. 마우스에서 선택적으로 Sost 유전자를 없애면 조골세포수, 뼈 형성 및 피질골과 해면골의 생체 역학특성이 증가하게 된다. 반대로 Sost 를 과발현시키면Although upregulation of Wnt signaling is not essential for indicating bone assimilation in response to parathyroid hormone, inhibition of expression of sclerostin by parathyroid hormone may explain the selective bone assimilation of parathyroid hormone, and the Lrp5 gene is incomplete. Bone assimilation effect on parathyroid hormone is also shown in activated mice. Selective elimination of Sost genes in mice increases osteoblast counts, bone formation, and biomechanical properties of cortical and cavernous bones. Conversely, overexpressing Sost
조골세포수와 뼈 형성 감소로 인해 골감소증이 생기게 된다. 한편 최근에 개발된 스클레로스틴에 대한 항체는 스클레로스틴이 Lrp-5- Lrp-6 공동수용체에 결합하는 것을 막아 Wnt 신호가 강화되고 골밀도 및 골량을 증가시키는 것을 입증시켰다. 본 연구에서는 항체가 아닌 PPI 제제로 Wnt 신호를 강화시켜 골밀도 및 골량을 증가시키고자 하였다.Osteopenia is caused by decreased osteoblast count and bone formation. On the other hand, recently developed antibodies against sclerostin have demonstrated that sclerostin is prevented from binding to the Lrp-5-Lrp-6 co-receptor, thereby enhancing the Wnt signal and increasing bone density and bone mass. In this study, we tried to increase bone mineral density and bone mineral density by enhancing Wnt signal with PPI instead of antibody.
2. 동일 MOA 경쟁 물질 대비 차별점 2. Differentiation from comparable MOA
Sclerostin에 대한 monoclonal Anti-body (Ab)가 주요 경쟁 물질이다. Monoclonal Ab의 문제점은 다음과 같다.Monoclonal Anti-body (Ab) against sclerostin is the main competitor. The problems of Monoclonal Ab are as follows.
● 2nd Ab가 생길 수 있다. 일부는 Neutralizing Ab인 것으로 이미 AMG785 phase I study에서 보고된 바 있다● 2nd Ab may occur. Some are Neutralizing Abs and have already been reported in the AMG785 phase I study
● 현재 monthly 제제로 개발되고 있어 고가일 것으로 예상된다.● As it is being developed as a monthly formulation, it is expected to be expensive.
● Phase II study에서 치료 초기에만 골형성 지표가 증가되었다. Local factor 인 Sclerostin에 대한 항체이기 때문에 counter regulatory factor들의 생성이 증가될 것으로 예측된다. 그러나 high spot approach에 결합하는 PPI로 개발되는 본 연구에서 개발되는 제제는 Sclerostin 및 DKK1,4 에 대한 작용도 억제하여 지속적인 약효를 얻을 수도 있을 것으로 예상된다.In the Phase II study, bone formation index increased only at the beginning of treatment. Since it is an antibody against Sclerostin, a local factor, the production of counter regulatory factors is expected to be increased. However, the formulation developed in this study, which is developed as a PPI that binds to the high spot approach, is also expected to be able to obtain long-acting effects by inhibiting the action of Sclerostin and DKK1,4.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.
실시예Example 1. 3-((3-( 1. 3-((3- ( 페닐카바모일Phenylcarbamoyl )페닐)) Phenyl) 설폰아미도Sulfonamido )벤조산(3-((3-(phenylcarbamoyl)phenyl)sulfonamido)benzoic acid); KY-06417) Benzoic acid (3-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06417
25 mL 둥근바닥플라스크에 에스테르 화합물(100 mg, 0.25 mmol)을 테트라하이드로퓨란(THF)/H2O/메탄올(MeOH) 혼합 용매에 용해시킨 후, LiOH(21 mg, 0.5 mmol)을 넣고 상온에서 16시간 동안 교반하였다. 반응종료 후, 용매를 감압하에서 제거한 후, 물 15 mL을 넣고 1N HCl을 가하여 pH 2에서 에틸아세테이트(EA; 30 mL)로 3회 추출하였다. 유기층을 MgSO4로 건조시켜 표제 화합물(80 mg, 81%)을 수득하였다.In a 25 mL round bottom flask, an ester compound (100 mg, 0.25 mmol) was dissolved in a tetrahydrofuran (THF) / H 2 O / methanol (MeOH) mixed solvent, and LiOH (21 mg, 0.5 mmol) was added thereto at room temperature. Stir for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, 15 mL of water was added, 1N HCl was added, and extracted three times with ethyl acetate (EA; 30 mL) at pH 2. The organic layer was dried over MgSO 4 to afford the title compound (80 mg, 81%).
1H NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 10.64 (s, 1H), 10.48 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 8.19 (dt, J = 7.7, 1.4 Hz, 1H), 7.93 (dt, J = 7.8, 1.4 Hz, 1H), 7.78-7.68 (m, 4H), 7.61 (dq, J = 5.0, 1.7 Hz, 1H), 7.42-7.32 (m, 4H), 7.18-7.09 (m, 1H). 1 H NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 10.64 (s, 1H), 10.48 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 8.19 (dt, J = 7.7 , 1.4 Hz, 1H), 7.93 (dt, J = 7.8, 1.4 Hz, 1H), 7.78-7.68 (m, 4H), 7.61 (dq, J = 5.0, 1.7 Hz, 1H), 7.42-7.32 (m, 4H), 7.18-7.09 (m, 1H).
실시예Example 2. N- 2. N- 메틸methyl -3-((3-(-3-((3- ( 페닐카바모일Phenylcarbamoyl )페닐)) Phenyl) 설폰아미도Sulfonamido )벤즈아미드(N-methyl-3-((3-(phenylcarbamoyl)phenyl)sulfonamido)benzamide); KY-06418 ) Benzamide (N-methyl-3-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide); KY-06418
7 mL 바이알에 카르복시산 화합물(40 mg, 0.1 mmol), 메틸아민(3.0 당량), EDCI(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; 3.0 당량), HOBt(N-hydroxybenzotriaxole; 3.0 당량), DIPEA(N,N-diisopropylethylamine; 3.0 당량)를 디메틸포름아미드(DMF; 0.3 M)에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 포화 탄산나트륨으로 세척하였다. 유기층을 MgSO4로 건조한 후 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(36 mg, 89%)을 수득하였다.Carboxylic acid compound (40 mg, 0.1 mmol), methylamine (3.0 equiv), EDCI (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide; 3.0 equiv), HOBt (N-hydroxybenzotriaxole; 3.0 equiv) in 7 mL vials, DIPEA (N, N-diisopropylethylamine; 3.0 equivalents) was dissolved in dimethylformamide (DMF; 0.3 M) and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (36 mg, 89%).
1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.38 (t, J = 7.8 Hz, 3H), 7.30 (d, J = 5.2 Hz, 3H), 7.19 (d, J = 7.2 Hz, 1H), 2.95 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.36 (s, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.7 Hz , 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.38 (t, J = 7.8 Hz, 3H), 7.30 (d, J = 5.2 Hz, 3H), 7.19 (d , J = 7.2 Hz, 1H), 2.95 (s, 3H).
실시예Example 3. 3-((3-((3- 3. 3-((3-((3- 카르복시페닐Carboxyphenyl )) 카바모일Cabamo )페닐)) Phenyl) 설폰아미도Sulfonamido )벤조산(3-((3-((3-carboxyphenyl)carbamoyl)phenyl)sulfonamido)benzoic acid); KY-06419) Benzoic acid (3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid); KY-06419
7 mL 바이알에 에스테르 화합물(200 mg, 0.43 mmol)을 LiOH(5.0 당량), THF/H2O/MeOH 혼합 용매에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, 용매를 감압하에서 제거하고, 산-염기 추출을 수행하였다. 물층을 에테르로 세척한 후 1N HCl을 가하여 pH 3으로 맞춘 후 EA로 추출하였다. 유기층을 MgSO4로 건조시켜 표제 화합물(178 mg, 94%)을 수득하였다.The ester compound (200 mg, 0.43 mmol) in a 7 mL vial was dissolved in LiOH (5.0 equiv), THF / H 2 O / MeOH mixed solvent, and then stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).
1H NMR (300 MHz, DMSO) δ 13.04 (s, 1H), 10.66 (s, 2H), 8.37 (s, 2H), 8.21 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.77-7.65 (m, 3H), 7.60 (dt, J = 5.6, 2.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42-7.33 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 13.04 (s, 1H), 10.66 (s, 2H), 8.37 (s, 2H), 8.21 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.77-7.65 (m, 3H), 7.60 (dt, J = 5.6, 2.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H ), 7.42-7.33 (m, 2 H).
실시예Example 4. 3-(3-(N-(2- 4. 3- (3- (N- (2- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(2-phenoxyphenyl)sulfamoyl)benzamido)benzoic acid); KY-06420) Benzoic acid (3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid); KY-06420
7 mL 바이알에 카르복시산 화합물(1 당량), 메틸아민(3.0 당량), EDCI(3.0 당량), HOBt(3.0 당량), DIPEA(3.0 당량)를 DMF(0.3 M)에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 포화 탄산나트륨으로 세척하였다. 유기층을 MgSO4로 건조한 후 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(66%)을 수득하였다.In a 7 mL vial, a carboxylic acid compound (1 equivalent), methylamine (3.0 equivalent), EDCI (3.0 equivalent), HOBt (3.0 equivalent), and DIPEA (3.0 equivalent) were dissolved in DMF (0.3 M), followed by 16 hours at room temperature. Was stirred. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (66%).
1H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 10.23-9.98 (m, 1H), 8.36 (d, J = 9.5 Hz, 2H), 8.19 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.75-7.60 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 7.7, 2.5 Hz, 1H), 7.26 (t, J = 7.9 Hz, 2H), 7.09 (dt, J = 12.8, 9.1 Hz, 3H), 6.68 (dd, J = 13.5, 8.2 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 10.23-9.98 (m, 1H), 8.36 (d, J = 9.5 Hz, 2H), 8.19 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.75-7.60 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 7.7, 2.5 Hz, 1H), 7.26 (t, J = 7.9 Hz, 2H), 7.09 (dt, J = 12.8, 9.1 Hz, 3H), 6.68 (dd, J = 13.5, 8.2 Hz, 3H).
실시예Example 5. N- 5. N- 메틸methyl -3-(3-(N-(2--3- (3- (N- (2- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-(2-phenoxyphenyl)sulfamoyl)benzamido)benzamide); KY-06421) Benzamide (N-methyl-3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzamide); KY-06421
KY-06420과 동일한 방법으로 합성하여 표제 화합물(86%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (86%).
1H NMR (300 MHz, MeOD) δ 8.33 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 2H), 7.88 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.64-7.41 (m, 4H), 6.61-6.52 (m, 2H), 7.18 (t, J = 7.7 Hz, 2H), 7.06 (dd, J = 5.9, 3.5 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.63 (dd, J = 5.9, 3.6 Hz, 2H), 2.92 (s, 3H). 1 H NMR (300 MHz, MeOD) δ 8.33 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 2H), 7.88 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.64-7.41 (m, 4H), 6.61-6.52 (m, 2H), 7.18 (t, J = 7.7 Hz, 2H), 7.06 (dd, J = 5.9, 3.5 Hz, 1H ), 7.00 (t, J = 7.4 Hz, 1H), 6.63 (dd, J = 5.9, 3.6 Hz, 2H), 2.92 (s, 3H).
실시예Example 6. 3-(3-(N-(3- 6. 3- (3- (N- (3- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(3-phenoxyphenyl)sulfamoyl)benzamido)benzoic acid); KY-06422) Benzoic acid (3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid); KY-06422
KY-06420과 동일한 방법으로 합성하여 표제 화합물(96%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (96%).
1H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 10.67 (s, 1H), 10.50 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 15.1, 7.6 Hz, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.3 Hz, 2H), 7.24 (t, J = 8.1 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.97-6.82 (m, 3H), 6.75-6.62 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 10.67 (s, 1H), 10.50 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 15.1, 7.6 Hz, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.3 Hz, 2H), 7.24 (t, J = 8.1 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.97-6.82 (m, 3H ), 6.75-6.62 (m, 2 H).
실시예Example 7. N- 7. N- 메틸methyl -3-(3-(N-(3--3- (3- (N- (3- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-(3-phenoxyphenyl)sulfamoyl)benzamido)benzamide); KY-06423) Benzamide (N-methyl-3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzamide); KY-06423
KY-06420과 동일한 방법으로 합성하여 표제 화합물(90%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (90%).
1H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 10.50 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 8.21 (s, 2H), 7.91 (dd, J = 12.5, 8.4 Hz, 2H), 7.74 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 6.89 (d, J = 8.0 Hz, 3H), 6.69 (s, 2H), 3.16 (d, J = 5.3 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 10.50 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 8.21 (s, 2H), 7.91 (dd, J = 12.5, 8.4 Hz, 2H), 7.74 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.11 (s, 1H) , 6.89 (d, J = 8.0 Hz, 3H), 6.69 (s, 2H), 3.16 (d, J = 5.3 Hz, 3H).
실시예Example 8. 3-(3-(N-(4- 8. 3- (3- (N- (4- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(4-phenoxyphenyl)sulfamoyl)benzamido)benzoic acid); KY-06424) Benzoic acid (3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid); KY-06424
KY-06420과 동일한 방법으로 합성하여 표제 화합물(98%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (98%).
1H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 10.66 (s, 1H), 10.27 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 14.9, 7.1 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.20-7.02 (m, 3H), 6.91 (ddd, J = 8.0, 4.8, 2.7 Hz, 4H). 1 H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 10.66 (s, 1H), 10.27 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 14.9, 7.1 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.20-7.02 (m, 3H), 6.91 (ddd, J = 8.0, 4.8, 2.7 Hz, 4H).
실시예Example 9. N- 9. N- 메틸methyl -3-(3-(N-(4--3- (3- (N- (4- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-(4-phenoxyphenyl)sulfamoyl)benzamido)benzamide); KY-06425) Benzamide (N-methyl-3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzamide); KY-06425
KY-06420과 동일한 방법으로 합성하여 표제 화합물(89%)을 수득하였다.Synthesis was performed in the same manner as KY-06420 to obtain the title compound (89%).
1H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 10.28 (s, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.35-8.27 (m, 1H), 8.27-8.17 (m, 2H), 7.98-7.86 (m, 2H), 7.73 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.50-7.40 (m, 1H), 7.37-7.26 (m, 2H), 7.15-7.02 (m, 3H), 6.98-6.85 (m, 4H), 2.79 (dd, J = 4.1, 2.2 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 10.28 (s, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.35-8.27 (m, 1H), 8.27-8.17 (m , 2H), 7.98-7.86 (m, 2H), 7.73 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.50-7.40 (m, 1H), 7.37-7.26 ( m, 2H), 7.15-7.02 (m, 3H), 6.98-6.85 (m, 4H), 2.79 (dd, J = 4.1, 2.2 Hz, 3H).
실시예Example 10. 3-(3-(N-(피리딘-2-일) 10. 3- (3- (N- (pyridin-2-yl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(pyridin-2-yl)sulfamoyl)benzamido)benzoic acid); KY-06426) Benzoic acid (3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoic acid); KY-06426
KY-06420과 동일한 방법으로 합성하여 표제 화합물(39%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (39%).
1H NMR (300 MHz, DMSO) δ 12.73 (s, 1H), 10.66 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.05 (t, J = 7.3 Hz, 2H), 7.96 (s, 1H), 7.82-7.64 (m, 3H), 7.49 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.85 (t, J = 6.7 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.73 (s, 1H), 10.66 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.05 (t, J = 7.3 Hz, 2H), 7.96 (s, 1H), 7.82-7.64 (m, 3H), 7.49 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H ), 6.85 (t, J = 6.7 Hz, 1H).
실시예Example 11. N- 11.N- 메틸methyl -3-(3-(N-(피리딘-2-일)-3- (3- (N- (pyridin-2-yl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-(pyridin-2-yl)sulfamoyl)benzamido)benzamide); KY-06427) Benzamide (N-methyl-3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzamide); KY-06427
KY-06420과 동일한 방법으로 합성하여 표제 화합물(60%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (60%).
1H NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 8.48 (s, 2H), 8.25 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.98 (t, J = 7.7 Hz, 2H), 7.75 (dt, J = 15.1, 7.9 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.87 (t, J = 6.6 Hz, 1H), 2.82 (d, J = 4.4 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 8.48 (s, 2H), 8.25 (s, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.98 (t, J = 7.7 Hz, 2H), 7.75 (dt, J = 15.1, 7.9 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.87 (t, J = 6.6 Hz, 1H), 2.82 (d, J = 4.4 Hz, 3H).
실시예Example 12. 3-(3-(N-(피리딘-3-일) 12. 3- (3- (N- (pyridin-3-yl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(pyridin-3-yl)sulfamoyl)benzamido)benzoic acid); KY-06428) Benzoic acid (3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoic acid); KY-06428
KY-06420과 동일한 방법으로 합성하여 표제 화합물(93%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (93%).
1H NMR (300 MHz, DMSO) δ 12.57 (s, 1H), 10.69 (d, J = 13.2 Hz, 2H), 8.42-8.18 (m, 5H), 8.02 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.73 (dd, J = 15.7, 7.8 Hz, 2H), 7.51 (q, J = 7.9 Hz, 2H), 7.30 (dd, J = 8.1, 4.6 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.57 (s, 1H), 10.69 (d, J = 13.2 Hz, 2H), 8.42-8.18 (m, 5H), 8.02 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.73 (dd, J = 15.7, 7.8 Hz, 2H), 7.51 (q, J = 7.9 Hz, 2H), 7.30 (dd, J = 8.1, 4.6 Hz, 1H ).
실시예Example 13. N- 13.N- 메틸methyl -3-(3-(N-(피리딘-3-일)-3- (3- (N- (pyridin-3-yl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-(pyridin-3-yl)sulfamoyl)benzamido)benzamide); KY-06429) Benzamide (N-methyl-3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzamide); KY-06429
KY-06420과 동일한 방법으로 합성하여 표제 화합물(35%)을 수득하였다.Synthesis was performed in the same manner as KY-06420 to obtain the title compound (35%).
1H NMR (300 MHz, DMSO) δ 10.74 (s, 1H), 10.66 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 8.35-8.18 (m, 4H), 7.96 (t, J = 8.7 Hz, 2H), 7.77 (t, J = 7.8 Hz, 1H), 7.67-7.52 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.33 (dd, J = 8.2, 4.6 Hz, 1H), 2.81 (d, J = 4.6 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.74 (s, 1H), 10.66 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 8.35-8.18 (m, 4H ), 7.96 (t, J = 8.7 Hz, 2H), 7.77 (t, J = 7.8 Hz, 1H), 7.67-7.52 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.33 (dd , J = 8.2, 4.6 Hz, 1H), 2.81 (d, J = 4.6 Hz, 3H).
실시예Example 14. 3-(3-(N- 14. 3- (3- (N- 프로필설파모일Profile Sulpa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-propylsulfamoyl)benzamido)benzoic acid); KY-06430) Benzoic acid (3- (3- (N-propylsulfamoyl) benzamido) benzoic acid); KY-06430
KY-06420과 동일한 방법으로 합성하여 표제 화합물(70%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (70%).
1H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.35 (d, J = 8.6 Hz, 2H), 8.20 (d, J = 7.9 Hz, 1H), 7.99 (dd, J = 17.2, 7.7 Hz, 2H), 7.71 (dt, J = 19.7, 7.8 Hz, 3H), 7.47 (t, J = 7.8 Hz, 1H), 2.70 (q, J = 6.5 Hz, 2H), 1.35 (q, J = 7.3 Hz, 2H), 0.82-0.71 (m, 3H). 1 H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.35 (d, J = 8.6 Hz, 2H), 8.20 (d, J = 7.9 Hz, 1H), 7.99 (dd, J = 17.2, 7.7 Hz, 2H), 7.71 (dt, J = 19.7, 7.8 Hz, 3H), 7.47 (t, J = 7.8 Hz, 1H), 2.70 (q, J = 6.5 Hz, 2H), 1.35 (q, J = 7.3 Hz, 2H), 0.82-0.71 (m, 3H).
실시예Example 15. N- 15.N- 메틸methyl -3-(3-(N--3- (3- (N- 프로필설파모일Profile Sulpa Mole )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-propylsulfamoyl)benzamido)benzamide); KY-06431) Benzamide (N-methyl-3- (3- (N-propylsulfamoyl) benzamido) benzamide); KY-06431
KY-06420과 동일한 방법으로 합성하여 표제 화합물(96%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (96%).
1H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.24 (d, J = 8.9 Hz, 2H), 7.98 (dd, J = 13.8, 7.9 Hz, 2H), 7.85-7.65 (m, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 2.80 (d, J = 4.2 Hz, 3H), 2.78-2.69 (m, 2H), 1.39 (h, J = 7.4 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.24 (d, J = 8.9 Hz, 2H), 7.98 (dd, J = 13.8 , 7.9 Hz, 2H), 7.85-7.65 (m, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 2.80 (d, J = 4.2 Hz, 3H ), 2.78-2.69 (m, 2H), 1.39 (h, J = 7.4 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H).
LC Mass m/z = 376.1 (MH+), 377.2, 112.4.LC Mass m / z = 376.1 (MH + ), 377.2, 112.4.
실시예Example 16. 3-(3-(N- 16. 3- (3- (N- 사이클로프로필설파모일Cyclopropyl sulfamoyl )) 벤즈아미도Benzamido )벤조산(3-(3-(N-cyclopropylsulfamoyl)benzamido)benzoic acid); KY-06432) Benzoic acid (3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoic acid); KY-06432
KY-06420과 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was performed in the same manner as KY-06420 to obtain the title compound (99%).
1H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.70 (s, 1H), 8.40 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.14-7.97 (m, 3H), 7.80 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 2.13 (ddd, J = 9.9, 5.1, 2.5 Hz, 1H), 0.50 (d, J = 6.6 Hz, 2H), 0.43-0.33 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.70 (s, 1H), 8.40 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.14-7.97 (m, 3H ), 7.80 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 2.13 (ddd, J = 9.9, 5.1, 2.5 Hz , 1H), 0.50 (d, J = 6.6 Hz, 2H), 0.43-0.33 (m, 2H).
실시예Example 17. 3-(N- 17. 3- (N- 사이클로프로필설파모일Cyclopropyl sulfamoyl )-N-(3-() -N- (3- ( 메틸카바모일Methylcarbamoyl )페닐)벤즈아미드(3-(N-cyclopropylsulfamoyl)-N-(3-(methylcarbamoyl)phenyl)benzamide); KY-06433) Phenyl) benzamide (3- (N-cyclopropylsulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06433
KY-06420과 동일한 방법으로 합성하여 표제 화합물(96%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (96%).
1H NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 8.42 (d, J = 7.9 Hz, 2H), 8.28 (d, J = 7.7 Hz, 1H), 8.23 (s, 1H), 8.03 (d, J = 9.4 Hz, 2H), 7.96 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 2.80 (d, J = 4.3 Hz, 3H), 2.16 (tt, J = 7.1, 3.6 Hz, 1H), 0.49 (dd, J = 6.9, 4.6 Hz, 2H), 0.39 (t, J = 3.7 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 8.42 (d, J = 7.9 Hz, 2H), 8.28 (d, J = 7.7 Hz, 1H), 8.23 (s, 1H), 8.03 ( d, J = 9.4 Hz, 2H), 7.96 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 2.80 (d, J = 4.3 Hz, 3H), 2.16 (tt, J = 7.1, 3.6 Hz, 1H), 0.49 (dd, J = 6.9, 4.6 Hz, 2H), 0.39 ( t, J = 3.7 Hz, 2H).
실시예Example 18. 3-(3-(N- 18. 3- (3- (N- 메틸설파모일Methylsulfamoyl )) 벤즈아미도Benzamido )벤조산(3-(3-(N-methylsulfamoyl)benzamido)benzoic acid); KY-06434) Benzoic acid (3- (3- (N-methylsulfamoyl) benzamido) benzoic acid); KY-06434
KY-06420과 동일한 방법으로 합성하여 표제 화합물(88%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (88%).
1H NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 10.69 (s, 1H), 8.38 (d, J = 11.0 Hz, 2H), 8.25 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 6.5 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 2.45 (d, J = 5.4 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 10.69 (s, 1H), 8.38 (d, J = 11.0 Hz, 2H), 8.25 (d, J = 7.6 Hz, 1H), 8.06 ( d, J = 6.5 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 2.45 (d, J = 5.4 Hz, 3H).
실시예Example 19. N- 19.N- 메틸methyl -3-(3-(N--3- (3- (N- 메틸설파모일Methylsulfamoyl )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-methylsulfamoyl)benzamido)benzamide); KY-06435) Benzamide (N-methyl-3- (3- (N-methylsulfamoyl) benzamido) benzamide); KY-06435
KY-06420과 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was performed in the same manner as KY-06420 to obtain the title compound (99%).
1H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.37 (s, 1H), 8.29-8.19 (m, 2H), 8.03-7.92 (m, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.66-7.54 (m, 2H), 7.46 (t, J = 7.9 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H), 2.46 (d, J = 4.6 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.37 (s, 1H), 8.29-8.19 (m, 2H), 8.03-7.92 (m , 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.66-7.54 (m, 2H), 7.46 (t, J = 7.9 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H), 2.46 (d, J = 4.6 Hz, 3H).
실시예Example 20. 2-(3-(3-(N- 20. 2- (3- (3- (N- 페닐설파모일Phenylsulfamoyl )) 벤즈아미도Benzamido )페닐)아세트산(2-(3-(3-(N-phenylsulfamoyl)benzamido)phenyl)acetic acid); KY-06436) Phenyl) acetic acid (2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetic acid); KY-06436
7 mL 둥근바닥플라스크에 에스테르 화합물(100 mg, 0.4 mmol)을 THF/H2O/MeOH 혼합 용매에 용해시킨 후, LiOH(30 mg, 0.8 mmol)을 넣고 상온에서 16시간 동안 교반하였다. 반응종료 후, 용매를 감압하에서 제거한 후, 물 15 mL을 넣고 1N HCl을 가하여 pH 2에서 EA(30 mL)로 3회 추출하였다. 유기층을 MgSO4로 건조시켜 표제 화합물(133 mg, 95%)을 수득하였다.The ester compound (100 mg, 0.4 mmol) was dissolved in a THF / H 2 O / MeOH mixed solvent in a 7 mL round bottom flask, and LiOH (30 mg, 0.8 mmol) was added thereto and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, 15 mL of water was added, 1N HCl was added, and extracted three times with EA (30 mL) at pH 2. The organic layer was dried over MgSO 4 to afford the title compound (133 mg, 95%).
1H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 8.32 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.95-7.85 (m, 1H), 7.73-7.59 (m, 3H), 7.25 (dt, J = 20.4, 7.8 Hz, 3H), 7.09 (d, J = 7.7 Hz, 2H), 7.01 (s, 2H), 3.55 (s, 2H). 1 H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 8.32 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.95-7.85 (m, 1H), 7.73-7.59 (m , 3H), 7.25 (dt, J = 20.4, 7.8 Hz, 3H), 7.09 (d, J = 7.7 Hz, 2H), 7.01 (s, 2H), 3.55 (s, 2H).
실시예Example 21. N-(3-(2-(메틸아미노)-2-옥소에틸)페닐)-3-(N-페닐설파모일)벤즈아미드(N-(3-(2-(methylamino)-2-oxoethyl)phenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06437 21.N- (3- (2- (methylamino) -2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide (N- (3- (2- (methylamino) -2-oxoethyl ) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06437
7 mL 바이알에 카르복시산 화합물(50 mg, 0.1 mmol), 메틸아민(3.0 당량), EDCI(3.0 당량), HOBt(3.0 당량), DIPEA(3.0 당량)를 DMF(0.3 M)에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 포화 탄산나트륨으로 세척하였다. 유기층을 MgSO4로 건조한 후 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(39.6 mg, 78%)을 수득하였다.In a 7 mL vial, the carboxylic acid compound (50 mg, 0.1 mmol), methylamine (3.0 equiv), EDCI (3.0 equiv), HOBt (3.0 equiv), DIPEA (3.0 equiv) were dissolved in DMF (0.3 M), then room temperature Stirred for 16 h. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (39.6 mg, 78%).
1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.19 (ddt, J = 24.8, 16.7, 8.0 Hz, 6H), 7.00 (d, J = 7.8 Hz, 1H), 5.78 (s, 1H), 3.55 (s, 2H), 2.76 (d, J = 4.7 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.68 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.19 (ddt, J = 24.8, 16.7, 8.0 Hz, 6H), 7.00 ( d, J = 7.8 Hz, 1H), 5.78 (s, 1H), 3.55 (s, 2H), 2.76 (d, J = 4.7 Hz, 3H).
실시예Example 22. N-(3-(2-아미노-2- 22.N- (3- (2-amino-2- 옥소에틸Oxoethyl )페닐)-3-(N-) Phenyl) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(3-(2-amino-2-oxoethyl)phenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06438) Benzamide (N- (3- (2-amino-2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06438
25 mL 둥근바닥플라스크에 에스테르 화합물(100 mg, 0.23 mmol)을 MeOH(1 mL)에 용해시킨 후, 암모니아 수용액(3 mL)을 넣고 상온에서 12시간 동안 교반하였다. 반응종료 후, 감압하에서 용매를 모두 제거하여 흰색 고체의 표제 화합물(90 mg, 94%)을 수득하였다.In a 25 mL round bottom flask, an ester compound (100 mg, 0.23 mmol) was dissolved in MeOH (1 mL), an aqueous ammonia solution (3 mL) was added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed under reduced pressure to give the title compound (90 mg, 94%) as a white solid.
1H NMR (300 MHz, MeOD) δ 7.04 (s, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.36-6.25 (m, 3H), 6.02 (t, J = 7.6 Hz, 1H), 5.92 (t, J = 7.4 Hz, 2H), 5.79 (dd, J = 20.3, 7.4 Hz, 4H), 2.25 (s, 2H), 2.02 (s, 2H). 1 H NMR (300 MHz, MeOD) δ 7.04 (s, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.36-6.25 (m, 3H), 6.02 (t, J = 7.6 Hz, 1H), 5.92 (t, J = 7.4 Hz, 2H), 5.79 (dd, J = 20.3, 7.4 Hz, 4H), 2.25 (s, 2H), 2.02 (s, 2H ).
실시예Example 23. 3-(3-(N-(4-( 23. 3- (3- (N- (4- ( 벤질옥시Benzyloxy )페닐)) Phenyl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(4-(benzyloxy)phenyl)sulfamoyl)benzamido)benzoic acid); KY-06439) Benzoic acid (3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoic acid); KY-06439
KY-06420과 동일한 방법으로 합성하여 표제 화합물(86%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (86%).
1H NMR (300 MHz, DMSO) δ 13.21-12.74 (m, 1H), 10.67 (s, 1H), 10.45 (s, 1H), 8.46-8.33 (m, 2H), 8.21 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.42-7.24 (m, 5H), 7.13 (t, J = 8.3 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.68 (d, J = 8.0 Hz, 2H), 5.00 (s, 2H). 1 H NMR (300 MHz, DMSO) δ 13.21-12.74 (m, 1H), 10.67 (s, 1H), 10.45 (s, 1H), 8.46-8.33 (m, 2H), 8.21 (d, J = 7.9 Hz , 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H ), 7.42-7.24 (m, 5H), 7.13 (t, J = 8.3 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.68 (d, J = 8.0 Hz, 2H), 5.00 (s , 2H).
실시예Example 24. 3-(N-(4-(벤질옥시)페닐)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드(3-(N-(4-(benzyloxy)phenyl)sulfamoyl)-N-(3-(methylcarbamoyl)phenyl)benzamide); KY-06440 24. 3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06440
KY-06420과 동일한 방법으로 합성하여 표제 화합물(78%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (78%).
1H NMR (300 MHz, DMSO) δ 10.83 (d, J = 3.8 Hz, 1H), 10.65 (s, 1H), 8.71-8.52 (m, 2H), 8.40 (d, J = 5.0 Hz, 2H), 8.13 (d, J = 7.9 Hz, 2H), 7.92 (t, J = 7.1 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.57 (td, J = 19.3, 16.8, 7.4 Hz, 5H), 7.32 (q, J = 7.0 Hz, 1H), 6.96 (d, J = 4.7 Hz, 1H), 6.87 (d, J = 7.7 Hz, 2H), 5.19 (d, J = 4.6 Hz, 2H), 2.99 (d, J = 4.7 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.83 (d, J = 3.8 Hz, 1H), 10.65 (s, 1H), 8.71-8.52 (m, 2H), 8.40 (d, J = 5.0 Hz, 2H), 8.13 (d, J = 7.9 Hz, 2H), 7.92 (t, J = 7.1 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.57 (td, J = 19.3, 16.8, 7.4 Hz, 5H ), 7.32 (q, J = 7.0 Hz, 1H), 6.96 (d, J = 4.7 Hz, 1H), 6.87 (d, J = 7.7 Hz, 2H), 5.19 (d, J = 4.6 Hz, 2H), 2.99 (d, J = 4.7 Hz, 3H).
실시예Example 25. 3-(3-(N-(1- 25. 3- (3- (N- (1- 벤질피페리딘Benzylpiperidine -4-일)-4- days) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(1-benzylpiperidin-4-yl)sulfamoyl)benzamido)benzoic acid); KY-06442) Benzoic acid (3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoic acid); KY-06442
KY-06420과 동일한 방법으로 합성하여 표제 화합물(86%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (86%).
1H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.74 (s, 1H), 10.43 (s, 1H), 8.43 (s, 2H), 8.27 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.05 (t, J = 9.7 Hz, 2H), 7.83-7.64 (m, 2H), 7.61-7.36 (m, 5H), 4.33 (s, 1H), 4.15 (s, 2H), 3.21-3.07 (m, 2H), 1.77 (s, 4H). 1 H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.74 (s, 1H), 10.43 (s, 1H), 8.43 (s, 2H), 8.27 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.05 (t, J = 9.7 Hz, 2H), 7.83-7.64 (m, 2H), 7.61-7.36 (m, 5H), 4.33 (s, 1H), 4.15 (s, 2H) , 3.21-3.07 (m, 2 H), 1.77 (s, 4 H).
실시예Example 26. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드(3-(N-(1-benzylpiperidin-4-yl)sulfamoyl)-N-(3-(methylcarbamoyl)phenyl)benzamide); KY-06443 26. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1-benzylpiperidin-4- yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06443
KY-06420과 동일한 방법으로 합성하여 표제 화합물(59%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (59%).
1H NMR (500 MHz, DMSO) δ 10.64 (s, 1H), 8.44 (q, J = 4.5 Hz, 1H), 8.40 (t, J = 1.8 Hz, 1H), 8.23 (ddt, J = 4.1, 2.9, 1.3 Hz, 2H), 8.05-8.01 (m, 1H), 7.95 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.58 (dt, J = 7.9, 1.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.32-7.26 (m, 2H), 7.23 (dt, J = 7.9, 1.9 Hz, 3H), 3.38 (s, 2H), 3.00 (dh, J = 15.2, 4.5 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.64 (d, J = 11.7 Hz, 2H), 1.89 (t, J = 10.7 Hz, 2H), 1.54 (dd, J = 13.1, 3.9 Hz, 2H), 1.44-1.33 (m, 2H). 1 H NMR (500 MHz, DMSO) δ 10.64 (s, 1H), 8.44 (q, J = 4.5 Hz, 1H), 8.40 (t, J = 1.8 Hz, 1H), 8.23 (ddt, J = 4.1, 2.9 , 1.3 Hz, 2H), 8.05-8.01 (m, 1H), 7.95 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.58 (dt, J = 7.9, 1.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.32-7.26 (m, 2H), 7.23 (dt, J = 7.9, 1.9 Hz, 3H), 3.38 (s, 2H), 3.00 (dh, J = 15.2, 4.5 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.64 (d, J = 11.7 Hz, 2H), 1.89 (t, J = 10.7 Hz, 2H), 1.54 (dd, J = 13.1, 3.9 Hz, 2H), 1.44-1.33 (m, 2H).
실시예Example 27. 3-(3-(N-(4- 27. 3- (3- (N- (4- 몰포리노페닐Morpholinophenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(4-morpholinophenyl)sulfamoyl)benzamido)benzoic acid); KY-06445) Benzoic acid (3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoic acid); KY-06445
KY-06420과 동일한 방법으로 합성하여 표제 화합물(70%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (70%).
1H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 10.62 (s, 1H), 9.94 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.67 (t, J = 6.4 Hz, 2H), 7.46 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 3.63 (s, 4H), 2.95 (s, 4H). 1 H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 10.62 (s, 1H), 9.94 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.67 (t, J = 6.4 Hz, 2H), 7.46 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 3.63 (s, 4H), 2.95 (s, 4H).
실시예Example 28. N- 28.N- 메틸methyl -3-(3-(N-(4--3- (3- (N- (4- 몰포리노페닐Morpholinophenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤즈아미드(N-methyl-3-(3-(N-(4-morpholinophenyl)sulfamoyl)benzamido)benzamide); KY-06446) Benzamide (N-methyl-3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzamide); KY-06446
KY-06420과 동일한 방법으로 합성하여 표제 화합물(84%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (84%).
1H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 9.96 (s, 1H), 8.42 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 3.67 (t, J = 4.5 Hz, 4H), 2.99 (t, J = 4.6 Hz, 4H), 2.80 (d, J = 4.2 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 9.96 (s, 1H), 8.42 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.45 ( t, J = 7.9 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 3.67 (t, J = 4.5 Hz, 4H), 2.99 (t, J = 4.6 Hz, 4H), 2.80 (d, J = 4.2 Hz, 3H).
실시예Example 29. 3-(3-(N-(1H-인돌-5-일) 29. 3- (3- (N- (1H-indol-5-yl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(1H-indol-5-yl)sulfamoyl)benzamido)benzoic acid); KY-06447) Benzoic acid (3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido) benzoic acid); KY-06447
KY-06420과 동일한 방법으로 합성하여 표제 화합물(90%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (90%).
1H NMR (300 MHz, DMSO) δ 12.96 (s, 1H), 10.63 (s, 1H), 10.21 (s, 1H), 8.36 (d, J = 6.6 Hz, 2H), 8.19 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 9.6 Hz, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.68 (q, J = 7.9, 7.4 Hz, 2H), 7.53-7.38 (m, 3H), 7.10 (dd, J = 8.9, 2.0 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.96 (s, 1H), 10.63 (s, 1H), 10.21 (s, 1H), 8.36 (d, J = 6.6 Hz, 2H), 8.19 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 9.6 Hz, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.68 (q, J = 7.9, 7.4 Hz, 2H), 7.53-7.38 (m, 3H ), 7.10 (dd, J = 8.9, 2.0 Hz, 1H).
실시예Example 30. 3-(N-(1H-인돌-5-일) 30. 3- (N- (1H-indol-5-yl) 설파모일Sulfa Mole )-N-(3-() -N- (3- ( 메틸카바모일Methylcarbamoyl )페닐)벤즈아미드(3-(N-(1H-indol-5-yl)sulfamoyl)-N-(3-(methylcarbamoyl)phenyl)benzamide); KY-06448) Phenyl) benzamide (3- (N- (1H-indol-5-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06448
KY-06420과 동일한 방법으로 합성하여 표제 화합물(89%)을 수득하였다.Synthesis was performed in the same manner as KY-06420 to obtain the title compound (89%).
1H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.60 (s, 1H), 10.22 (s, 1H), 8.43 (q, J = 4.5 Hz, 1H), 8.35 (t, J = 1.8 Hz, 1H), 8.19 (dt, J = 5.6, 1.6 Hz, 2H), 8.00 (s, 1H), 7.92-7.89 (m, 1H), 7.85 (dt, J = 7.8, 1.4 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.57 (dt, J = 7.7, 1.4 Hz, 1H), 7.48-7.40 (m, 3H), 7.10 (dd, J = 8.7, 2.0 Hz, 1H), 3.18 (d, J = 5.0 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.60 (s, 1H), 10.22 (s, 1H), 8.43 (q, J = 4.5 Hz, 1H), 8.35 (t, J = 1.8 Hz, 1H), 8.19 (dt, J = 5.6, 1.6 Hz, 2H), 8.00 (s, 1H), 7.92-7.89 (m, 1H), 7.85 (dt, J = 7.8, 1.4 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.57 (dt, J = 7.7, 1.4 Hz, 1H), 7.48-7.40 (m, 3H), 7.10 (dd, J = 8.7, 2.0 Hz, 1H), 3.18 ( d, J = 5.0 Hz, 3H).
실시예Example 31. 3-(3-(N-(1H-인돌-6-일) 31. 3- (3- (N- (1H-indol-6-yl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(1H-indol-6-yl)sulfamoyl)benzamido)benzoic acid); KY-06449) Benzoic acid (3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoic acid); KY-06449
KY-06420과 동일한 방법으로 합성하여 표제 화합물(94%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (94%).
1H NMR (300 MHz, DMSO) δ 12.91 (s, 1H), 10.65 (s, 1H), 10.56 (s, 1H), 8.39 (d, J = 9.5 Hz, 2H), 8.19 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 6.1 Hz, 2H), 7.70 (dt, J = 7.7, 4.0 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 6.90 (dd, J = 8.4, 2.1 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.91 (s, 1H), 10.65 (s, 1H), 10.56 (s, 1H), 8.39 (d, J = 9.5 Hz, 2H), 8.19 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 6.1 Hz, 2H), 7.70 (dt, J = 7.7, 4.0 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 6.90 (dd, J = 8.4, 2.1 Hz, 1H).
실시예Example 32. 3-(N-(1H-인돌-6-일) 32. 3- (N- (1H-indol-6-yl) 설파모일Sulfa Mole )-N-(3-() -N- (3- ( 메틸카바모일Methylcarbamoyl )페닐)벤즈아미드(3-(N-(1H-indol-6-yl)sulfamoyl)-N-(3-(methylcarbamoyl)phenyl)benzamide); KY-06450) Phenyl) benzamide (3- (N- (1H-indol-6-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06450
KY-06420과 동일한 방법으로 합성하여 표제 화합물(85%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (85%).
1H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 10.61 (s, 1H), 10.55 (s, 1H), 8.41 (s, 2H), 8.26-8.15 (m, 2H), 7.93 (dd, J = 12.1, 7.0 Hz, 3H), 7.70 (t, J = 7.9 Hz, 1H), 7.59 (dd, J = 13.4, 8.2 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 6.91 (dd, J = 8.6, 1.8 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 10.61 (s, 1H), 10.55 (s, 1H), 8.41 (s, 2H), 8.26-8.15 (m, 2H), 7.93 (dd , J = 12.1, 7.0 Hz, 3H), 7.70 (t, J = 7.9 Hz, 1H), 7.59 (dd, J = 13.4, 8.2 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.28 (s, 1 H), 6.91 (dd, J = 8.6, 1.8 Hz, 1 H), 2.79 (d, J = 4.4 Hz, 3H).
실시예Example 33. 3-(3-(N-(3,5- 33. 3- (3- (N- (3,5- 비스(트리플루오로메틸)페닐Bis (trifluoromethyl) phenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조산(3-(3-(N-(3,5-bis(trifluoromethyl)phenyl)sulfamoyl)benzamido)benzoic acid); KY-06451) Benzoic acid (3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoic acid); KY-06451
KY-06420과 동일한 방법으로 합성하여 표제 화합물(83%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (83%).
1H NMR (300 MHz, DMSO) δ 13.31 (s, 1H), 11.69 (s, 1H), 11.03 (s, 1H), 8.78 (s, 1H), 8.72 (s, 1H), 8.62 (d, J = 7.7 Hz, 1H), 8.37 (d, J = 7.9 Hz, 2H), 8.21-7.98 (m, 5H), 7.85 (t, J = 7.8 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.31 (s, 1H), 11.69 (s, 1H), 11.03 (s, 1H), 8.78 (s, 1H), 8.72 (s, 1H), 8.62 (d, J = 7.7 Hz, 1H), 8.37 (d, J = 7.9 Hz, 2H), 8.21-7.98 (m, 5H), 7.85 (t, J = 7.8 Hz, 1H).
실시예Example 34. 3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드(3-(N-(3,5-bis(trifluoromethyl)phenyl)sulfamoyl)-N-(3-(methylcarbamoyl)phenyl)benzamide); KY-06452 34. 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (3,5- bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06452
KY-06420과 동일한 방법으로 합성하여 표제 화합물(88%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (88%).
1H NMR (300 MHz, DMSO) δ 11.33 (s, 1H), 10.64 (s, 1H), 8.43 (s, 2H), 8.28 (d, J = 7.8 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.69 (s, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 2.80 (d, J = 4.3 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 11.33 (s, 1H), 10.64 (s, 1H), 8.43 (s, 2H), 8.28 (d, J = 7.8 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.69 (s, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 2.80 (d, J = 4.3 Hz, 3H).
실시예Example 35. 3-((3-((3- 35. 3-((3-((3- 카르복시페닐Carboxyphenyl )) 카바모일Cabamo )페닐)) Phenyl) 설폰아미도Sulfonamido )벤조산(3-((3-((3-carboxyphenyl)carbamoyl)phenyl)sulfonamido)benzoic acid); KY-06453) Benzoic acid (3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid); KY-06453
7 mL 바이알에 에스테르 화합물(200 mg, 0.43 mmol)을 LiOH(5.0 당량), THF/H2O/MeOH 혼합 용매에 용해시킨 후, 상온에서 6시간 동안 교반하였다. 반응종료 후, 용매를 제거하고, 산-염기 추출을 수행하였다. 물층을 에테르로 세척한 후 1N HCl을 가하여 pH 3으로 맞춘 후 EA로 추출하였다. 유기층을 MgSO4로 건조시켜 표제 화합물(178 mg, 94%)을 수득하였다.The ester compound (200 mg, 0.43 mmol) in a 7 mL vial was dissolved in LiOH (5.0 equiv), THF / H 2 O / MeOH mixed solvent, and stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).
1H NMR (300 MHz, DMSO) δ 13.04 (s, 1H), 10.66 (s, 2H), 8.37 (s, 2H), 8.21 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.77-7.65 (m, 3H), 7.60 (dt, J = 5.6, 2.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42-7.33 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 13.04 (s, 1H), 10.66 (s, 2H), 8.37 (s, 2H), 8.21 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.77-7.65 (m, 3H), 7.60 (dt, J = 5.6, 2.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H ), 7.42-7.33 (m, 2 H).
실시예Example 36. 에틸 3-((2,4- 36. Ethyl 3-((2,4- 디플루오로Difluoro -5-(-5- ( 페닐카바모일Phenylcarbamoyl )페닐)) Phenyl) 설폰아미도Sulfonamido )) 벤조에이트Benzoate (ethyl 3-((2,4-(ethyl 3-((2,4- difluorodifluoro -5-(phenylcarbamoyl)phenyl)sulfonamido)benzoate); KY-06454-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate); KY-06454
100 mL 둥근바닥플라스크에 염화설포닐 화합물(2.59 mmol, 860 mg)을 메틸렌클로라이드(MC, 9 mL)에 용해시킨 후, 에틸 3-아미노벤조에이트(1.0 당량, 0.38 mL), DIPEA(1.5 당량, 0.68 mL)를 첨가하고, 상온에서 2일 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 MgSO4로 건조하였다. 실리카겔컬럼을 수행한 후 감압농축하고, MC/에테르/헥산으로 고체화한 후 신터로 여과하여 노란색 고체 화합물로 표제 화합물(128 mg, 11%)을 수득하였다.In a 100 mL round bottom flask, sulfonyl chloride compound (2.59 mmol, 860 mg) was dissolved in methylene chloride (MC, 9 mL), followed by ethyl 3-aminobenzoate (1.0 equiv., 0.38 mL), DIPEA (1.5 equiv., 0.68 mL) was added and stirred at room temperature for 2 days. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was dried over MgSO 4 . After silica gel column was concentrated under reduced pressure, solidified with MC / ether / hexane and filtered through a sinter to give the title compound (128 mg, 11%) as a yellow solid compound.
1H NMR (300 MHz, CDCl3) δ 8.70 (t, J = 8.1 Hz, 1H), 8.18 (d, J = 10.0 Hz, 1H), 7.81 (d, J = 7.6, 1H), 7.69 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.44-7.36 (m, 4H), 7.19 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 10.1 Hz, 1H), 6.97 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.70 (t, J = 8.1 Hz, 1H), 8.18 (d, J = 10.0 Hz, 1H), 7.81 (d, J = 7.6, 1H), 7.69 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.44-7.36 (m, 4H), 7.19 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 10.1 Hz, 1H), 6.97 ( s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).
실시예Example 37. 3-((2,4- 37. 3-((2,4- 디플루오로Difluoro -5-(-5- ( 페닐카바모일Phenylcarbamoyl )페닐)) Phenyl) 설폰아미도Sulfonamido )벤조산(3-((2,4-difluoro-5-(phenylcarbamoyl)phenyl)sulfonamido)benzoic acid); KY-06455) Benzoic acid (3-((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06455
7 mL 바이알에 에스테르 화합물(128 mg, 0.28 mmol), LiOH(2.0 당량, 24 mg), 아세토니트릴(ACN, 1.4 mL), H2O(1.4 mL)을 넣고 상온에서 20시간 동안 교반하였다. 반응종료 후, 50 mL 둥근바닥플라스크에 옮겨 회전증발기(rotavapor)로 ACN을 제거하였다. 잔여물은 에테르:H2O=1:2 혼합용매로 세척하였다. pH 페이퍼를 이용하여 물층이 pH 8인 것을 확인한 후, 1N HCl을 첨가하면서 pH를 2 내지 3으로 맞추었다. 1N HCl 혼합물을 EA로 추출한 후 감압농축하였다. 마지막으로 EA/헥산 혼합용매로 고체화한 후 신터로 여과하여 흰색 고체 화합물로 표제 화합물(40%)을 수득하였다.Ester compound (128 mg, 0.28 mmol), LiOH (2.0 equiv, 24 mg), acetonitrile (ACN, 1.4 mL) and H 2 O (1.4 mL) were added to a 7 mL vial and stirred at room temperature for 20 hours. After the reaction was completed, the reaction mixture was transferred to a 50 mL round bottom flask to remove ACN using a rotavapor. The residue was washed with ether: H 2 O = 1: 2 mixed solvent. After confirming that the water layer was pH 8 using pH paper, the pH was adjusted to 2-3 while adding 1N HCl. The 1N HCl mixture was extracted with EA and concentrated under reduced pressure. Finally solidified with EA / hexane mixed solvent and filtered through sinter to give the title compound (40%) as a white solid compound.
1H NMR (300 MHz, DMSO) δ 13.08 (s,1H), 11.01 (S, 1H), 10.54 (s, 1H), 8.13 (t, J = 7.6 Hz, 1H), 7.78-7.64 (m , 5H), 7.44-7.34 (m, 4H), 7.14 (d, J = 7.0, 1H). 1 H NMR (300 MHz, DMSO) δ 13.08 (s, 1H), 11.01 (S, 1H), 10.54 (s, 1H), 8.13 (t, J = 7.6 Hz, 1H), 7.78-7.64 (m, 5H ), 7.44-7.34 (m, 4H), 7.14 (d, J = 7.0, 1H).
실시예Example 38. 에틸 3- 38. Ethyl 3- (4-플루오로-3-(N-페닐설파모일)벤즈아미도(4-fluoro-3- (N-phenylsulfamoyl) benzamido )) 벤조에이트Benzoate (ethyl 3-(4-(ethyl 3- (4- fluorofluoro -3-(N--3- (N- phenylsulfamoylphenylsulfamoyl )) benzamidobenzamido )benzoate); KY-06456) benzoate); KY-06456
25 mL 둥근바닥플라스크에 염화아실 화합물(1.3 mmol, 346 mg)을 MC(1.5 mL)에 용해시키고, 7 mL 바이알에 에틸 3-아미노벤조에이트(0.95 당량, 209 mg, 1.24 mmol), DIPEA(0.95 당량, 0.218 mL, 1.24 mmol), MC(1.5 mL)를 함께 교반하였다. 7 mL 바이알에 담긴 혼합물을 25 mL 둥근바닥플라스크에 천천히 넣고 MC(0.5 mL)로 7 mL 바이알을 세척하여 더 첨가한 후, 0℃에서 30분 동안 교반하였다.The acyl chloride compound (1.3 mmol, 346 mg) was dissolved in MC (1.5 mL) in a 25 mL round bottom flask, ethyl 3-aminobenzoate (0.95 equiv., 209 mg, 1.24 mmol), DIPEA (0.95) in a 7 mL vial. Equivalent weight, 0.218 mL, 1.24 mmol) and MC (1.5 mL) were stirred together. The mixture contained in a 7 mL vial was slowly added to a 25 mL round bottom flask, and the 7 mL vial was further added with MC (0.5 mL), followed by stirring at 0 ° C. for 30 minutes.
상기 반응물에 아닐린(0.118 mL, 1.0 당량, 1.3 mmol), DIPEA(1.0 당량, 0.23 mL, 1.3 mmol), DMAP(4-dimethylaminopyridine, 15.9 mg, 1.0 당량, 0.13 mmol)을 넣어 상온에서 3시간 동안 교반하였다. 반응종료 후, H2O:MC=1:3 혼합용매로 MC를 추출하고, MC:1N HCl=1:1 혼합용액으로 MC를 추출하여 MgSO4로 건조한 후 감압 농축하였다. 실리카겔컬럼 크로마토그래피(EA:MC=1:19)로 분리하여 노란색 액체 화합물로 표제 화합물(71.7 mg, 12%)을 수득하였다.Aniline (0.118 mL, 1.0 equiv, 1.3 mmol), DIPEA (1.0 equiv, 0.23 mL, 1.3 mmol) and DMAP (4-dimethylaminopyridine, 15.9 mg, 1.0 equiv, 0.13 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours. It was. After completion of the reaction, MC was extracted with a mixed solvent of H 2 O: MC = 1: 3, MC was extracted with a MC: 1N HCl = 1: 1 mixed solution, dried over MgSO 4, and concentrated under reduced pressure. Separation by silica gel column chromatography (EA: MC = 1: 19) afforded the title compound (71.7 mg, 12%) as a yellow liquid compound.
1H NMR (500 MHz, CDCl3) δ 8.32 (dd, J = 2.5, 6.5 Hz, 1H), 8.22 (ddd, J = 2.5, 5.0, 8.5 Hz, 1H), 8.16 (t, J = 1.8 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 9.0 Hz, 1H), 7.07 (dd, J = 2.0, 4.5 Hz, 2H), 7.14 (d, J = 29.0 Hz, 2H), 4.41 (q, J = 7.3, 14.3 Hz, 2H), 1.43 (t, J = 7.3 Hz, 3H). 1 H NMR (500 MHz, CDCl 3 ) δ 8.32 (dd, J = 2.5, 6.5 Hz, 1H), 8.22 (ddd, J = 2.5, 5.0, 8.5 Hz, 1H), 8.16 (t, J = 1.8 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 9.0 Hz, 1H) , 7.07 (dd, J = 2.0, 4.5 Hz, 2H), 7.14 (d, J = 29.0 Hz, 2H), 4.41 (q, J = 7.3, 14.3 Hz, 2H), 1.43 (t, J = 7.3 Hz, 3H).
실시예Example 39. 3-(4- 39. 3- (4- 플루오로Fluoro -3-(N--3- (N- 페닐설파모일Phenylsulfamoyl )) 벤즈아미도Benzamido )벤조산(3-(4-fluoro-3-(N-phenylsulfamoyl)benzamido)benzoic acid); KY-06457) Benzoic acid (3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06457
7 mL 바이알에 에스테르 화합물(65 mg, 0.15 mmol)을 THF(1 mL)에 용해시켜 교반하였다. H2O(1 mL)과 MeOH(0.5 mL)을 실린지로 첨가한 후 LiOH(12.6 mg, 2.0 당량, 0.30 mmol)을 넣어 26시간 동안 상온에서 교반하였다. 반응종료 후, 50 mL 둥근바닥플라스크에 옮겨 회전증발기로 MeOH와 THF를 제거하였다. 잔여물은 에테르:H2O=1:2 혼합용매(에테르 25 mL, H2O 45 mL)로 세척하였다. pH 페이퍼를 이용하여 물층이 pH 8인 것을 확인한 후, 1N HCl을 첨가하면서 pH를 2 내지 3으로 맞추었다. 고체가 관찰되었으나 여과되지 않아 EA:H2O=2:1(EA 100mL, H2O 50 mL) 혼합용매로 EA를 추출하였다. MgSO4로 건조한 후 감압 농축하여 흰색 고체 화합물로 표제 화합물(56.4 mg, 93%)을 수득하였다.The ester compound (65 mg, 0.15 mmol) was dissolved in THF (1 mL) in a 7 mL vial and stirred. After adding H 2 O (1 mL) and MeOH (0.5 mL) with a syringe, LiOH (12.6 mg, 2.0 equiv, 0.30 mmol) was added thereto, followed by stirring at room temperature for 26 hours. After the reaction was completed, the resultant was transferred to a 50 mL round bottom flask to remove MeOH and THF using a rotary evaporator. The residue was washed with ether: H 2 O = 1: 2 mixed solvent (25 mL ether, 45 mL H 2 O). After confirming that the water layer was pH 8 using pH paper, the pH was adjusted to 2-3 while adding 1N HCl. Solids were observed but not filtered, so EA was extracted with EA: H 2 O = 2: 1 (EA 100 mL, H 2 O 50 mL) mixed solvent. After drying over MgSO 4 and concentration under reduced pressure, the title compound (56.4 mg, 93%) was obtained as a white solid compound.
1H NMR (300 MHz, DMSO) δ 10.64 (s, 1H), 8.45 (d, J = 5.4 Hz, 1H), 8.36 (s, 1H), 8.31 - 8.264 (m, 1H), 8.02 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 9.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.24 (t, J = 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 7.02 (t, J = 7.1 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 10.64 (s, 1H), 8.45 (d, J = 5.4 Hz, 1H), 8.36 (s, 1H), 8.31-8.264 (m, 1H), 8.02 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 9.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.24 (t, J = 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 7.02 (t, J = 7.1 Hz, 2H).
실시예Example 40. 에틸 3- 40. Ethyl 3- (2,4-디플루오로-5-(N-페닐설파모일)벤즈아미도(2,4-difluoro-5- (N-phenylsulfamoyl) benzamido )) 벤조에이트Benzoate (ethyl 3-(2,4-(ethyl 3- (2,4- difluorodifluoro -5-(N--5- (N- phenylsulfamoylphenylsulfamoyl )) benzamidobenzamido )benzoate); KY-06458) benzoate); KY-06458
25 mL 둥근바닥플라스크에 염화아실 화합물(1.4 mmol, 392.5 mg)을 MC(1.5 mL)에 용해시키고, 7 mL 바이알에 에틸 3-아미노벤조에이트(0.95 당량, 224 mg, 1.33 mmol), DIPEA(0.95 당량, 0.234 mL, 1.33 mmol), MC(1.5 mL)를 함께 교반하였다. 7 mL 바이알에 담긴 혼합물을 25 mL 둥근바닥플라스크에 천천히 넣고 MC(0.5 mL)로 7 mL 바이알을 세척하여 더 첨가한 후, 0℃에서 30분 동안 교반하였다.The acyl chloride compound (1.4 mmol, 392.5 mg) was dissolved in MC (1.5 mL) in a 25 mL round bottom flask, ethyl 3-aminobenzoate (0.95 equiv., 224 mg, 1.33 mmol), DIPEA (0.95) in a 7 mL vial. Equivalent, 0.234 mL, 1.33 mmol) and MC (1.5 mL) were stirred together. The mixture contained in a 7 mL vial was slowly added to a 25 mL round bottom flask, and the 7 mL vial was further added with MC (0.5 mL), followed by stirring at 0 ° C. for 30 minutes.
상기 반응물에 아닐린(0.128 mL, 1.0 당량, 1.4 mmol), DIPEA(1.0 당량, 0.25 mL, 1.4 mmol), DMAP(4-dimethylaminopyridine, 15.9 mg, 1.0 당량, 0.13 mmol)을 넣어 상온에서 3시간 동안 교반하였다. 반응종료 후, H2O:MC=1:3 혼합용매로 MC를 추출하고, MC:1N HCl=1:1 혼합용액으로 MC를 추출하여 MgSO4로 건조한 후 감압 농축하였다. 실리카겔컬럼 크로마토그래피(EA:MC=1:19)로 분리하여 흰색 고체 화합물로 표제 화합물(281.8 mg, 43%)을 수득하였다.Aniline (0.128 mL, 1.0 equiv, 1.4 mmol), DIPEA (1.0 equiv, 0.25 mL, 1.4 mmol) and DMAP (4-dimethylaminopyridine, 15.9 mg, 1.0 equiv, 0.13 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours. It was. After completion of the reaction, MC was extracted with a mixed solvent of H 2 O: MC = 1: 3, MC was extracted with a MC: 1N HCl = 1: 1 mixed solution, dried over MgSO 4, and concentrated under reduced pressure. Silica gel column chromatography (EA: MC = 1: 19) gave the title compound (281.8 mg, 43%) as a white solid compound.
1H NMR (500 MHz, CDCl3) δ 10.78 (s, 2NH), 8.32 (s, 1H), 8.15 (t, J = 7.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.89 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H), 7.07 (dd, J = 1.2, 2.7 Hz, 2H), 7.14 (d, J = 17.4 Hz, 2H), 4.33 (q, J = 6.5, 13,5 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). 1 H NMR (500 MHz, CDCl 3 ) δ 10.78 (s, 2NH), 8.32 (s, 1H), 8.15 (t, J = 7.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.89 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H), 7.07 (dd , J = 1.2, 2.7 Hz, 2H), 7.14 (d, J = 17.4 Hz, 2H), 4.33 (q, J = 6.5, 13,5 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H) .
실시예Example 41. 3-(2,4- 41. 3- (2,4- 디플루오로Difluoro -5-(N--5- (N- 페닐설파모일Phenylsulfamoyl )) 벤즈아미도Benzamido )벤조산(3-(2,4-difluoro-5-(N-phenylsulfamoyl)benzamido)benzoic acid); KY-06459) Benzoic acid (3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06459
7 mL 바이알에 에스테르 화합물(230 mg, 0.49 mmol)을 THF(1.5 mL)에 용해시켜 교반하였다. H2O(1.5 mL)과 MeOH(1.0 mL)을 실린지로 첨가한 후 LiOH(12.6 mg, 2.0 당량, 0.30 mmol)을 넣어 24시간 동안 상온에서 교반하였다. 반응종료 후, 50 mL 둥근바닥플라스크에 옮겨 회전증발기로 MeOH와 THF를 제거하였다. 잔여물은 에테르:H2O=1:2 혼합용매(에테르 20 mL, H2O 40 mL)로 세척하였다. pH 페이퍼를 이용하여 물층이 pH 8 내지 9인 것을 확인한 후, 1N HCl을 첨가하면서 pH를 2 내지 3으로 맞추었다. 관찰되는 고체를 여과지로 여과하여 흰색 고체로 혼합 화합물(101.1 mg)을 획득하였다. 실리카겔컬럼 크로마토그래피(EA:헥산=1:2 -> MC:MeOH=19:1)로 분리하여 흰색 고체 혼합물로 표제 화합물(41.4 mg, 19%)을 수득하였다.The ester compound (230 mg, 0.49 mmol) was dissolved in THF (1.5 mL) in a 7 mL vial and stirred. H 2 O (1.5 mL) and MeOH (1.0 mL) were added by syringe, and LiOH (12.6 mg, 2.0 equiv., 0.30 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the resultant was transferred to a 50 mL round bottom flask to remove MeOH and THF using a rotary evaporator. The residue was washed with ether: H 2 O = 1: 2 mixed solvent (20 mL ether, 40 mL H 2 O). After confirming that the water layer was pH 8-9 using pH paper, pH was adjusted to 2-3, adding 1N HCl. The observed solid was filtered through filter paper to obtain a mixed compound (101.1 mg) as a white solid. Silica gel column chromatography (EA: hexane = 1: 2-> MC: MeOH = 19: 1) gave the title compound (41.4 mg, 19%) as a white solid mixture.
1H NMR (300 MHz, DMSO) δ 10.69 (s, 1OH), 8.29 (s, 1H), 8.13 (t, J = 7.8 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.69 (t, J = 6.3 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.69 (s, 1OH), 8.29 (s, 1H), 8.13 (t, J = 7.8 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.69 ( t, J = 6.3 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1 H).
실시예Example 42.  42. 메틸methyl 3- 3- (3-(N-(2-페녹시페닐)설파모일)벤즈아미도(3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(2-(methyl 3- (3- (N- (2- phenoxyphenylphenoxyphenyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06462) benzoate); KY-06462
KY-06420과 동일한 방법으로 합성하여 표제 화합물(22%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (22%).
1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 8.13 (s, 2H), 8.06 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.76-7.66 (m, 1H), 7.47 (dt, J = 21.0, 7.9 Hz, 2H), 7.32 (s, 1H), 7.19 (t, J = 7.5 Hz, 2H), 7.14-6.97 (m, 3H), 6.70 (d, J = 7.4 Hz, 1H), 6.58 (d, J = 8.6 Hz, 2H), 3.90 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.20 (s, 1H), 8.13 (s, 2H), 8.06 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.76-7.66 (m, 1H), 7.47 (dt, J = 21.0, 7.9 Hz, 2H), 7.32 (s, 1H), 7.19 ( t, J = 7.5 Hz, 2H), 7.14-6.97 (m, 3H), 6.70 (d, J = 7.4 Hz, 1H), 6.58 (d, J = 8.6 Hz, 2H), 3.90 (s, 3H).
실시예Example 43.  43. 메틸methyl 3- 3- (3-(N-(3-페녹시페닐)설파모일)벤즈아미도(3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(3-(methyl 3- (3- (N- (3- phenoxyphenylphenoxyphenyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06463) benzoate); KY-06463
KY-06420과 동일한 방법으로 합성하여 표제 화합물(69%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (69%).
1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.78 (dt, J = 13.3, 8.2 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.47-7.28 (m, 3H), 7.11 (dt, J = 27.0, 8.0 Hz, 3H), 6.98-6.69 (m, 5H), 3.85 (d, J = 2.5 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.78 (dt, J = 13.3, 8.2 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.47-7.28 (m, 3H), 7.11 (dt, J = 27.0, 8.0 Hz, 3H), 6.98-6.69 (m, 5H), 3.85 (d, J = 2.5 Hz, 3H).
실시예Example 44.  44. 메틸methyl 3- 3- (3-(N-(4-페녹시페닐)설파모일)벤즈아미도(3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(4-(methyl 3- (3- (N- (4- phenoxyphenylphenoxyphenyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06464) benzoate); KY-06464
KY-06420과 동일한 방법으로 합성하여 표제 화합물(82%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (82%).
1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.73 (t, J = 7.2 Hz, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.33 (dt, J = 14.0, 7.0 Hz, 3H), 7.14-7.00 (m, 3H), 6.92 (d, J = 7.8 Hz, 2H), 6.87-6.75 (m, 2H), 3.83 (d, J = 3.6 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.73 (t, J = 7.2 Hz, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.33 (dt, J = 14.0, 7.0 Hz, 3H) , 7.14-7.00 (m, 3H), 6.92 (d, J = 7.8 Hz, 2H), 6.87-6.75 (m, 2H), 3.83 (d, J = 3.6 Hz, 3H).
실시예Example 45.  45. 메틸methyl 3- 3- (3-(3- (N-(4-((N- (4- ( 벤질옥시Benzyloxy )페닐)) Phenyl) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(4-((methyl 3- (3- (N- (4- ( benzyloxybenzyloxy )phenyl)) phenyl) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06465) benzoate); KY-06465
KY-06420과 동일한 방법으로 합성하여 표제 화합물(69%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (69%).
1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 8.19 (s, 1H), 8.15-8.04 (m, 2H), 7.83 (d, J = 7.7 Hz, 2H), 7.55-7.27 (m, 9H), 7.12 (t, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.69 (dd, J = 13.3, 8.3 Hz, 2H), 5.00 (s, 2H), 3.93 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.35 (s, 1H), 8.19 (s, 1H), 8.15-8.04 (m, 2H), 7.83 (d, J = 7.7 Hz, 2H), 7.55-7.27 ( m, 9H), 7.12 (t, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.69 (dd, J = 13.3, 8.3 Hz, 2H), 5.00 (s, 2H), 3.93 (s, 3H ).
실시예Example 46.  46. 메틸methyl 3- 3- (3-(N-(피리딘-2-일)설파모일)벤즈아미도(3- (N- (pyridin-2-yl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-((methyl 3- (3- (N- ( pyridinpyridin -2--2- ylyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06466) benzoate); KY-06466
KY-06420과 동일한 방법으로 합성하여 표제 화합물(52%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (52%).
1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.26 (s, 1H), 8.18-8.03 (m, 3H), 7.96 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.65 (dt, J = 26.6, 7.3 Hz, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 5.9 Hz, 1H), 6.83 (t, J = 6.7 Hz, 1H), 3.94 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.49 (s, 1H), 8.26 (s, 1H), 8.18-8.03 (m, 3H), 7.96 (d, J = 5.1 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.65 (dt, J = 26.6, 7.3 Hz, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 5.9 Hz, 1H), 6.83 (t, J = 6.7 Hz, 1H), 3.94 (s, 3H).
실시예Example 47.  47. 메틸methyl 3- 3- (3-(N-(피리딘-3-일)설파모일)벤즈아미도(3- (N- (pyridin-3-yl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-((methyl 3- (3- (N- ( pyridinpyridin -3--3- ylyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06467) benzoate); KY-06467
KY-06420과 동일한 방법으로 합성하여 표제 화합물(81%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (81%).
1H NMR (300 MHz, CDCl3) δ 8.42-8.37 (m, 1H), 8.27 (dd, J = 4.9, 1.8 Hz, 1H), 8.21 (d, J = 2.9 Hz, 2H), 8.14 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.4 Hz, 1H), 7.86 (dd, J = 15.1, 7.8 Hz, 2H), 7.67 (d, J = 7.3 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.4, 4.8 Hz, 1H), 3.94 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.42-8.37 (m, 1H), 8.27 (dd, J = 4.9, 1.8 Hz, 1H), 8.21 (d, J = 2.9 Hz, 2H), 8.14 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.4 Hz, 1H), 7.86 (dd, J = 15.1, 7.8 Hz, 2H), 7.67 (d, J = 7.3 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.4, 4.8 Hz, 1H), 3.94 (s, 3H).
실시예Example 48.  48. 메틸methyl 3- 3- (3-(N-프로필설파모일)벤즈아미도)벤조에이트(3- (N-propylsulfamoyl) benzamido) benzoate (methyl 3-(3-(N-propylsulfamoyl)benzamido)benzoate); KY-06468(methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate); KY-06468
KY-06420과 동일한 방법으로 합성하여 표제 화합물(93%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (93%).
1H NMR (300 MHz, CDCl3) δ 8.43 (d, J = 10.8 Hz, 2H), 8.24 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.06 (t, J = 10.3 Hz, 2H), 7.86-7.80 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 5.03 (t, J = 6.1 Hz, 1H), 3.92 (d, J = 2.4 Hz, 3H), 2.96 (q, J = 7.0, 6.5 Hz, 2H), 1.54-1.47 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (d, J = 10.8 Hz, 2H), 8.24 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.06 (t, J = 10.3 Hz , 2H), 7.86-7.80 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 5.03 (t, J = 6.1 Hz, 1H), 3.92 (d, J = 2.4 Hz, 3H), 2.96 (q, J = 7.0, 6.5 Hz, 2H), 1.54-1.47 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).
실시예Example 49.  49. 메틸methyl 3- 3- (3-(N-사이클로프로필설파모일)벤즈아미도)벤조에이트(3- (N-cyclopropylsulfamoyl) benzamido) benzoate (methyl 3-(3-(N-(methyl 3- (3- (N- cyclopropylsulfamoylcyclopropylsulfamoyl )) benzamidobenzamido )benzoate); KY-06469) benzoate); KY-06469
KY-06420과 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was performed in the same manner as KY-06420 to obtain the title compound (99%).
1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 8.18 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 6.9 Hz, 2H), 7.76 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 3.87 (s, 3H), 2.23-2.07 (m, 1H), 0.53 (d, J = 5.0 Hz, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.36 (s, 1H), 8.18 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 6.9 Hz, 2H), 7.76 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 3.87 (s, 3H), 2.23-2.07 (m, 1H) , 0.53 (d, J = 5.0 Hz, 4H).
실시예Example 50.  50. 메틸methyl 3- 3- (3-(N-메틸설파모일)벤즈아미도)벤조에이트(3- (N-methylsulfamoyl) benzamido) benzoate (methyl 3-(3-(N-methylsulfamoyl)benzamido)benzoate); KY-06470(methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate); KY-06470
KY-06420과 동일한 방법으로 합성하여 표제 화합물(78%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (78%).
1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 5.26 (q, J = 5.2 Hz, 1H), 3.89 (s, 3H), 2.68 (d, J = 5.0 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.68 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 8.0 Hz , 1H), 5.26 (q, J = 5.2 Hz, 1H), 3.89 (s, 3H), 2.68 (d, J = 5.0 Hz, 3H).
실시예Example 51.  51. 메틸methyl 3- 3- (3-(N-(4-몰포리노페닐)설파모일)벤즈아미도(3- (N- (4-morpholinophenyl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(4-(methyl 3- (3- (N- (4- morpholinophenylmorpholinophenyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06471) benzoate); KY-06471
KY-06420과 동일한 방법으로 합성하여 표제 화합물(66%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (66%).
1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 6.9 Hz, 2H), 8.22 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 5.5 Hz, 2H), 7.58-7.50 (m, 1H), 7.44 (t, J = 8.1 Hz, 1H), 6.99 (d, J = 7.2 Hz, 3H), 6.76 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 4H), 3.08 (s, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.30 (d, J = 6.9 Hz, 2H), 8.22 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.1 Hz , 1H), 7.80 (d, J = 5.5 Hz, 2H), 7.58-7.50 (m, 1H), 7.44 (t, J = 8.1 Hz, 1H), 6.99 (d, J = 7.2 Hz, 3H), 6.76 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 4H), 3.08 (s, 4H).
실시예Example 52.  52. 메틸methyl 3- 3- (3-(N-(1H-인돌-5-일)설파모일)벤즈아미도(3- (N- (1H-indol-5-yl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(1H-(methyl 3- (3- (N- (1H- indolindol -5--5- ylyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06472) benzoate); KY-06472
KY-06420과 동일한 방법으로 합성하여 표제 화합물(66%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (66%).
1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.40 (m, 4H), 7.31 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.28 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.40 (m, 4H), 7.31 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1 H), 3.87 (s, 3 H).
실시예Example 53.  53. 메틸methyl 3- 3- (3-(N-(1H-인돌-6-일)설파모일)벤즈아미도(3- (N- (1H-indol-6-yl) sulfamoyl) benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(1H-(methyl 3- (3- (N- (1H- indolindol -6--6- ylyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06473) benzoate); KY-06473
KY-06420과 동일한 방법으로 합성하여 표제 화합물(86%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (86%).
1H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 10.68 (s, 1H), 10.56 (s, 1H), 8.42 (s, 2H), 8.20 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 6.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 3H), 7.62 (d, J = 8.7 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H). 1 H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 10.68 (s, 1H), 10.56 (s, 1H), 8.42 (s, 2H), 8.20 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 6.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 3H), 7.62 (d, J = 8.7 Hz, 1H), 7.53 ( t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H).
실시예Example 54.  54. 메틸methyl 3-(3-(N-(3,5- 3- (3- (N- (3,5- 비스(트리플루오로메틸)페닐Bis (trifluoromethyl) phenyl )) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )벤조에이트(methyl 3-(3-(N-(3,5-bis(trifluoromethyl)phenyl)sulfamoyl)benzamido)benzoate); KY-06474) Benzoate (methyl 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate); KY-06474
KY-06420과 동일한 방법으로 합성하여 표제 화합물(25%)을 수득하였다.Synthesis was carried out in the same manner as KY-06420 to obtain the title compound (25%).
1H NMR (300 MHz, DMSO) δ 11.33 (s, 1H), 10.71 (s, 1H), 8.42 (d, J = 10.2 Hz, 2H), 8.28 (d, J = 7.9 Hz, 1H), 8.11-7.97 (m, 2H), 7.83-7.66 (m, 5H), 7.53 (t, J = 7.9 Hz, 1H), 3.88 (s, 3H). 1 H NMR (300 MHz, DMSO ) δ 11.33 (s, 1H), 10.71 (s, 1H), 8.42 (d, J = 10.2 Hz, 2H), 8.28 (d, J = 7.9 Hz, 1H), 8.11- 7.97 (m, 2H), 7.83-7.66 (m, 5H), 7.53 (t, J = 7.9 Hz, 1H), 3.88 (s, 3H).
실시예Example 55.  55. 메틸methyl 3- 3- (3-(3- (N-(1-(N- (1- 벤질피페리딘Benzylpiperidine -4-일)-4- days) 설파모일Sulfa Mole )) 벤즈아미도Benzamido )) 벤조에이트Benzoate (methyl 3-(3-(N-(1-(methyl 3- (3- (N- (1- benzylpiperidinbenzylpiperidin -4--4- ylyl )) sulfamoylsulfamoyl )) benzamidobenzamido )benzoate); KY-06475) benzoate); KY-06475
KY-06420과 동일한 방법으로 합성하여 표제 화합물(68%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (68%).
1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.05 (dd, J = 16.6, 8.0 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 10.9 Hz, 6H), 3.92 (s, 3H), 3.44 (s, 2H), 3.19 (d, J = 7.6 Hz, 1H), 2.72 (d, J = 11.5 Hz, 2H), 2.08-1.93 (m, 2H), 1.74 (d, J = 12.6 Hz, 2H), 1.51 (dd, J = 34.9, 3.4 Hz, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.53 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.05 (dd, J = 16.6, 8.0 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 10.9 Hz, 6H), 3.92 (s, 3H), 3.44 (s, 2H), 3.19 (d, J = 7.6 Hz, 1H), 2.72 (d, J = 11.5 Hz, 2H), 2.08-1.93 (m, 2H), 1.74 (d, J = 12.6 Hz, 2H), 1.51 (dd, J = 34.9, 3.4 Hz, 2H).
실시예Example 56.  56. 메틸methyl 3-((3-((3-( 3-((3-((3- ( 메톡시카보닐Methoxycarbonyl )페닐)) Phenyl) 카바모일Cabamo )페닐)) Phenyl) 설폰아미도Sulfonamido )벤조에이트(methyl 3-((3-((3-(methoxycarbonyl)phenyl)carbamoyl)phenyl)sulfonamido)benzoate); KY-06476) Benzoate (methyl 3-((3-((3- (methoxycarbonyl) phenyl) carbamoyl) phenyl) sulfonamido) benzoate); KY-06476
카르복시산 화합물(2.2 g, 10 mmol)을 염화티오닐(20 mL)에 넣고 16시간 동안 환류시켰다. 반응 종료 후, 염화티오닐을 제거하고 아미노벤조에이트(1.69 g, 9 mmol, 0.9 당랑)와 DIPEA(1.6 mL)를 MC(8 mL)에 용해시킨 후, 0℃에서 교반하였다. 3-클로로설포닐 벤조일 클로라이드를 MC(8 mL)에 용해시켜 천천히 첨가하였다. 0℃에서 30분 더 교반한 후 증류수와 MC로 추출하고, MgSO4로 건조한 후 실리카겔 컬럼으로 분리하여 표제 화합물을 수득하였다.A carboxylic acid compound (2.2 g, 10 mmol) was added to thionyl chloride (20 mL) and refluxed for 16 hours. After completion of the reaction, thionyl chloride was removed, aminobenzoate (1.69 g, 9 mmol, 0.9 sugar) and DIPEA (1.6 mL) were dissolved in MC (8 mL), followed by stirring at 0 ° C. 3-chlorosulfonyl benzoyl chloride was dissolved in MC (8 mL) and added slowly. After stirring for 30 minutes at 0 ° C., the mixture was extracted with distilled water and MC, dried over MgSO 4 , and separated by silica gel column to obtain the title compound.
1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.36 (s, 1H), 8.08-8.01 (m, 2H), 7.83 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.68-7.67 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.34-7.23 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.65 (s, 1H), 8.36 (s, 1H), 8.08-8.01 (m, 2H), 7.83 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.68-7.67 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.34-7.23 (m, 2H), 3.87 (s, 3 H), 3.82 (s, 3 H).
실시예Example 57.  57. 메틸methyl 2-(3-(3-(N- 2- (3- (3- (N- 페닐설파모일Phenylsulfamoyl )) 벤즈아미도Benzamido )페닐)아세테이트(methyl 2-(3-(3-(N-) Phenyl) acetate (methyl 2- (3- (3- (N-) phenylsulfamoylphenylsulfamoyl )) benzamidobenzamido )phenyl)acetate); KY-06477) phenyl) acetate); KY-06477
KY-06420의 step 3과 동일한 방법으로 합성하여 표제 화합물(76%)을 수득하였다.Synthesis was performed in the same manner as in step 3 of KY-06420, to obtain the title compound (76%).
1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.41 (s, 1H), 8.07 (d, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J = 4.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.44 (t, J = 4.7 Hz, 1H), 7.29-7.20 (m, 3H), 7.13-7.12 (m, 3H), 7.00 (d, J = 4.5 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.41 (s, 1H), 8.07 (d, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J = 4.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.44 (t, J = 4.7 Hz, 1H), 7.29-7.20 (m, 3H), 7.13-7.12 ( m, 3H), 7.00 (d, J = 4.5 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 2H).
실시예Example 58.  58. 메틸methyl 3- 3- 브로모Bromo -5--5- (3-(N-페닐설파모일)벤즈아미도)벤조에이트(3- (N-phenylsulfamoyl) benzamido) benzoate (methyl 3-(methyl 3- bromobromo -5-(3-(N--5- (3- (N- phenylsulfamoylphenylsulfamoyl )) benzamidobenzamido )benzoate); KY-06478) benzoate); KY-06478
7 mL 바이알에 카르복시산 화합물(332 mg, 1.2 mmol), 메틸 3-아미노-5-브로모벤조에이트(270 mg, 1.2 당량), EDCI(3.0 당량), HOBt(3.0 당량), DIPEA(3.0 당량)를 DMF(0.3 M)에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 포화 탄산나트륨으로 세척하였다. 유기층을 MgSO4로 건조한 후 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(475 mg, 83%)을 수득하였다.In a 7 mL vial carboxylic acid compound (332 mg, 1.2 mmol), methyl 3-amino-5-bromobenzoate (270 mg, 1.2 equiv), EDCI (3.0 equiv), HOBt (3.0 equiv), DIPEA (3.0 equiv) Was dissolved in DMF (0.3 M), and then stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (475 mg, 83%).
1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.28-7.05 (m, 5H), 3.84 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.91 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 9.0 Hz, 2H) , 7.77 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.28-7.05 (m, 5H), 3.84 (s, 3H).
실시예Example 59.  59. 메틸methyl 3- 3- 브로모Bromo -5--5- ((3-(페닐카바모일)페닐)설폰아미도)벤조에이트((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoate (methyl 3-(methyl 3- bromobromo -5-((3-(-5-((3- ( phenylcarbamoylphenylcarbamoyl )phenyl)) phenyl) sulfonamidosulfonamido )benzoate); KY-06479) benzoate); KY-06479
7 mL 바이알에 카르복시산 화합물(330 mg, 1.2 mmol), 아닐린(0.147 mL, 2.0 당량), EDCI(3.0 당량), HOBt(3.0 당량), DIPEA(3.0 당량)를 DMF(0.3 M)에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 포화 탄산나트륨으로 세척하였다. 유기층을 MgSO4로 건조한 후 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(348 mg, 89%)을 수득하였다.In a 7 mL vial, carboxylic acid compound (330 mg, 1.2 mmol), aniline (0.147 mL, 2.0 equiv), EDCI (3.0 equiv), HOBt (3.0 equiv), DIPEA (3.0 equiv) were dissolved in DMF (0.3 M) And stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (348 mg, 89%).
1H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 8.13 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.84 (s, 1H), 7.68 (d, J = 7.1 Hz, 4H), 7.63-7.51 (m, 2H), 7.37 (dd, J = 14.3, 6.4 Hz, 3H), 7.18 (t, J = 7.2 Hz, 1H), 3.88 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.13 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.84 (s, 1H), 7.68 (d, J = 7.1 Hz, 4H), 7.63-7.51 (m, 2H), 7.37 (dd, J = 14.3, 6.4 Hz, 3H), 7.18 (t, J = 7.2 Hz, 1H), 3.88 (s, 3H).
실시예Example 60. 3- 60. 3- 브로모Bromo -5-(3-(N--5- (3- (N- 페닐설파모일Phenylsulfamoyl )) 벤즈아미도Benzamido )벤조산(3-) Benzoic acid (3- bromobromo -5-(3-(N-phenylsulfamoyl)benzamido)benzoic acid); KY-06480-5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06480
7 mL 바이알에 에스테르 화합물(100 mg, 0.2 mol)을 LiOH(20 당량), THF/H2O/MeOH 혼합 용액을 용매로 하여 상온에서 1시간 동안 교반하였다. 반응종료 후, 용매를 감압하에서 제거하고, 산-염기 추출을 수행하였다. 물층을 에테르로 세척한 후 1N HCl을 가하여 pH 3으로 맞춘 후 EA로 추출하였다. 유기층을 MgSO4로 건조시켜 표제 화합물(95 mg, 98%)을 수득하였다.The ester compound (100 mg, 0.2 mol) was added to a 7 mL vial with LiOH (20 equivalents) and THF / H 2 O / MeOH mixed solution as a solvent and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (95 mg, 98%).
1H NMR (300 MHz, DMSO) δ 10.79 (s, 1H), 10.45 (s, 1H), 8.35 (d, J = 12.7 Hz, 3H), 8.22 (s, 1H), 7.95 (s, 1H), 7.77 (d, J = 17.5 Hz, 2H), 7.24 (s, 2H), 7.08 (d, J = 21.9 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.79 (s, 1H), 10.45 (s, 1H), 8.35 (d, J = 12.7 Hz, 3H), 8.22 (s, 1H), 7.95 (s, 1H), 7.77 (d, J = 17.5 Hz, 2H), 7.24 (s, 2H), 7.08 (d, J = 21.9 Hz, 3H).
실시예Example 61. 3- 61. 3- 브로모Bromo -5-((3-(-5-((3- ( 페닐카바모일Phenylcarbamoyl )페닐)) Phenyl) 설폰아미도Sulfonamido )벤조산(3-) Benzoic acid (3- bromobromo -5-((3-(phenylcarbamoyl)phenyl)sulfonamido)benzoic acid); KY-06481-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06481
7 mL 바이알에 에스테르 화합물(100 mg, 0.2 mol)을 LiOH(20 당량), THF/H2O/MeOH 혼합 용액을 용매로 하여 상온에서 1시간 동안 교반하였다. 반응종료 후, 용매를 감압하에서 제거하고, 산-염기 추출을 수행하였다. 물층을 에테르로 세척한 후 1N HCl을 가하여 pH 3으로 맞춘 후 EA로 추출하였다. 유기층을 MgSO4로 건조시켜 표제 화합물(85 mg, 83%)을 수득하였다.The ester compound (100 mg, 0.2 mol) was added to a 7 mL vial with LiOH (20 equivalents) and THF / H 2 O / MeOH mixed solution as a solvent and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (85 mg, 83%).
1H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.82-7.63 (m, 5H), 7.50 (s, 1H), 7.37 (s, 2H), 7.13 (s, 1H). 1 H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.82-7.63 (m, 5H), 7.50 (s , 1H), 7.37 (s, 2H), 7.13 (s, 1H).
실시예Example 62. 3- 62. 3- 브로모Bromo -N--N- 메틸methyl -5-(3-(N--5- (3- (N- 페닐설파모일Phenylsulfamoyl )) 벤즈아미도Benzamido )벤즈아미드(3-bromo-N-methyl-5-(3-(N-phenylsulfamoyl)benzamido)benzamide); KY-06482) Benzamide (3-bromo-N-methyl-5- (3- (N-phenylsulfamoyl) benzamido) benzamide); KY-06482
7 mL 바이알에 산 화합물(50 mg, 0.1 mmol), 메틸 메틸 아민(3.0 당량), EDCI(3.0 당량), HOBt(3.0 당량), DIPEA(3.0 당량)를 DMF(0.3 M)에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 포화 탄산나트륨으로 세척하였다. 유기층을 MgSO4로 건조한 후 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(38 mg, 72%)을 수득하였다.In a 7 mL vial acid compound (50 mg, 0.1 mmol), methyl methyl amine (3.0 equiv), EDCI (3.0 equiv), HOBt (3.0 equiv), DIPEA (3.0 equiv) were dissolved in DMF (0.3 M), Stir at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (38 mg, 72%).
1H NMR (300 MHz, DMSO) δ 10.76 (s, 1H), 8.58 (q, J = 3.9 Hz, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.19 (d, J = 6.8 Hz, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.76 (s, 1H), 8.58 (q, J = 3.9 Hz, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.19 (d, J = 6.8 Hz, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.09 ( d, J = 7.8 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H).
실시예Example 63. 3- 63. 3- 브로모Bromo -N--N- 메틸methyl -5-((3-(-5-((3- ( 페닐카바모일Phenylcarbamoyl )페닐)) Phenyl) 설폰아미도Sulfonamido )벤즈아미드(3-bromo-N-methyl-5-((3-(phenylcarbamoyl)phenyl)sulfonamido)benzamide); KY-06483) Benzamide (3-bromo-N-methyl-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide); KY-06483
7 mL 바이알에 산 화합물(50 mg, 0.1 mmol), 메틸 메틸 아민(3.0 당량), EDCI(3.0 당량), HOBt(3.0 당량), DIPEA(3.0 당량)를 DMF(0.3 M)에 용해시킨 후, 상온에서 16시간 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 포화 탄산나트륨으로 세척하였다. 유기층을 MgSO4로 건조한 후 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(17 mg, 31%)을 수득하였다.In a 7 mL vial acid compound (50 mg, 0.1 mmol), methyl methyl amine (3.0 equiv), EDCI (3.0 equiv), HOBt (3.0 equiv), DIPEA (3.0 equiv) were dissolved in DMF (0.3 M), Stir at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (17 mg, 31%).
1H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 10.49 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.73 (s, 3H), 7.64 (s, 1H), 7.57 (s, 1H), 7.37 (s, 3H), 7.12 (s, 2H), 2.76-2.66 (m, 3H). 1 H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 10.49 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.94 (s, 1H ), 7.73 (s, 3H), 7.64 (s, 1H), 7.57 (s, 1H), 7.37 (s, 3H), 7.12 (s, 2H), 2.76-2.66 (m, 3H).
실시예Example 64.  64. 메틸methyl 3-((1-옥소-1,2,3,4- 3-((1-oxo-1,2,3,4- 테트라하이드로이소퀴놀린Tetrahydroisoquinoline )-7-) -7- 설폰아미도Sulfonamido )벤조에이트(methyl 3-((1-) Benzoate (methyl 3-((1- oxooxo -1,2,3,4--1,2,3,4- tetrahydroisoquinolinetetrahydroisoquinoline )-7-sulfonamido)benzoate); KY-06484) -7-sulfonamido) benzoate); KY-06484
100 mL 둥근바닥플라스크에 염화설포닐 화합물(1.2 mmol, 300 mg), 메틸 3-아미노벤조에이트(2.0 당량, 252 mg)를 THF(5.0 mL)에 넣고, 상온에서 2일 동안 교반하였다. 반응종료 후, H2O/EA 혼합용매로 3회 추출한 후 유기층을 MgSO4로 건조하고, 용매는 감압 농축하였다. 반응물을 MeOH로 여과하여 흰색 고체 화합물로 표제 화합물(293 mg, 67%)을 수득하였다.In a 100 mL round bottom flask, sulfonyl chloride compound (1.2 mmol, 300 mg) and methyl 3-aminobenzoate (2.0 equiv, 252 mg) were added to THF (5.0 mL) and stirred at room temperature for 2 days. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent, the organic layer was dried over MgSO 4 , and the solvent was concentrated under reduced pressure. The reaction was filtered through MeOH to give the title compound (293 mg, 67%) as a white solid compound.
1H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.14 (t, J = 3.0 Hz, 1H), 7.82 (dd, J = 8.0, 2.1 Hz, 1H), 7.73 (q, J = 1.4 Hz, 1H), 7.66-7.57 (m, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 4.9, 2.4 Hz, 2H), 3.82 (s, 3H), 3.37 (dd, J = 10.0, 3.4 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.14 (t, J = 3.0 Hz, 1H), 7.82 (dd, J = 8.0, 2.1 Hz, 1H), 7.73 (q, J = 1.4 Hz, 1H), 7.66-7.57 (m, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 4.9, 2.4 Hz, 2H ), 3.82 (s, 3H), 3.37 (dd, J = 10.0, 3.4 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H).
실시예Example 65. 3-(N-(2-( 65. 3- (N- (2- ( 페닐아미노Phenylamino )페닐)) Phenyl) 설파모일Sulfa Mole )벤조산(3-(N-(2-(phenylamino)phenyl)sulfamoyl)benzoic acid); KY-06486) Benzoic acid (3- (N- (2- (phenylamino) phenyl) sulfamoyl) benzoic acid); KY-06486
7 mL 바이알에 아민 화합물(300 mg, 1.6 mmol)을 피리딘(4.0 mL)에 용해시킨 후, 30분 동안 교반하였다. 3-(클로로설포닐)벤조산(379 mg, 1.0 당량)을 천천히 첨가하였다. 반응종료 후, 감압하에서 피리딘을 제거한 후 1N HCl/EA 혼합용액으로 3회 추출한 후 유기층을 MgSO4로 건조한 후, 용매를 감압농축시키고, 실리카겔컬럼을 수행하여 표제 화합물(167 mg, 28%)을 수득하였다.The amine compound (300 mg, 1.6 mmol) was dissolved in pyridine (4.0 mL) in a 7 mL vial and stirred for 30 minutes. 3- (chlorosulfonyl) benzoic acid (379 mg, 1.0 equiv) was added slowly. After completion of the reaction, the pyridine was removed under reduced pressure, extracted three times with 1N HCl / EA mixed solution, the organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and a silica gel column was performed to obtain the title compound (167 mg, 28%). Obtained.
1H NMR (500 MHz, DMSO) δ 13.27 (s, 1H), 9.57 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.15-7.03 (m, 5H), 6.87 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 7.8 Hz, 2H). 1 H NMR (500 MHz, DMSO) δ 13.27 (s, 1H), 9.57 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.15-7.03 (m, 5H), 6.87 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 7.8 Hz, 2H).
실시예Example 66. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드(3-(N-(1-benzylpiperidin-4-yl)sulfamoyl)-N-(3-(methylcarbamoyl)phenyl)benzamide); KY-06489 66. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1-benzylpiperidin-4- yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06489
KY-06420과 동일한 방법으로 합성하여 표제 화합물(59%)을 수득하였다.Synthesis in the same manner as KY-06420 gave the title compound (59%).
1H NMR (500 MHz, DMSO) δ 10.64 (s, 1H), 8.44 (q, J = 4.5 Hz, 1H), 8.40 (t, J = 1.8 Hz, 1H), 8.23 (ddt, J = 4.1, 2.9, 1.3 Hz, 2H), 8.05-8.01 (m, 1H), 7.95 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.58 (dt, J = 7.9, 1.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.32-7.26 (m, 2H), 7.23 (dt, J = 7.9, 1.9 Hz, 3H), 3.38 (s, 2H), 3.00 (dh, J = 15.2, 4.5 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.64 (d, J = 11.7 Hz, 2H), 1.89 (t, J = 10.7 Hz, 2H), 1.54 (dd, J = 13.1, 3.9 Hz, 2H), 1.44-1.33 (m, 2H). 1 H NMR (500 MHz, DMSO) δ 10.64 (s, 1H), 8.44 (q, J = 4.5 Hz, 1H), 8.40 (t, J = 1.8 Hz, 1H), 8.23 (ddt, J = 4.1, 2.9 , 1.3 Hz, 2H), 8.05-8.01 (m, 1H), 7.95 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.58 (dt, J = 7.9, 1.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.32-7.26 (m, 2H), 7.23 (dt, J = 7.9, 1.9 Hz, 3H), 3.38 (s, 2H), 3.00 (dh, J = 15.2, 4.5 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.64 (d, J = 11.7 Hz, 2H), 1.89 (t, J = 10.7 Hz, 2H), 1.54 (dd, J = 13.1, 3.9 Hz, 2H), 1.44-1.33 (m, 2H).
실시예Example 67. 1-(4-플루오로페닐)-N-(3-(메틸카바모일)페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(1-(4-fluorophenyl)-N-(3-(methylcarbamoyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide); KY-06490 67. 1- (4-Fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- ( 4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06490
KY-06531과 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was carried out in the same manner as KY-06531 to obtain the title compound (99%).
1H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.14 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.19 (s. 1H), 7.97-7.88 (m, 4H), 7.60 (dd, J = 1.2, 5.4 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 7.49-7.42 (m, 3H), 7.13 (dd, J = 3.6, 5.1 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.14 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.19 (s. 1H), 7.97-7.88 (m, 4H ), 7.60 (dd, J = 1.2, 5.4 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 7.49-7.42 (m, 3H), 7.13 (dd, J = 3.6, 5.1 Hz, 1H) , 2.80 (d, J = 4.5 Hz, 3H).
실시예Example 68. 1-(4-플루오로페닐)-N-(3-설파모일페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(1-(4-fluorophenyl)-N-(3-sulfamoylphenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide); KY-06491 68. 1- (4-fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- (4-fluorophenyl ) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06491
KY-06531과 동일한 방법으로 합성하여 표제 화합물(30%)을 수득하였다.Synthesis in the same manner as KY-06531 gave the title compound (30%).
1H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 9.14 (s, 1H), 8.32 (s. 1H), 7.97-7.86 (m, 4H), 7.61-7.56 (m, 3H), 7.49-7.40 (m, 4H), 7.14 (dd, J = 3.4, 5.3 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 9.14 (s, 1H), 8.32 (s. 1H), 7.97-7.86 (m, 4H), 7.61-7.56 (m, 3H), 7.49 -7.40 (m, 4H), 7.14 (dd, J = 3.4, 5.3 Hz, 1H).
실시예Example 69. 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤젠설폰산(3-(1-(4-fluorophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzenesulfonic acid); KY-06492 69. 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid (3- (1- (4- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06492
KY-06531과 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was carried out in the same manner as KY-06531 to obtain the title compound (99%).
1H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 9.14 (s, 1H), 8.32 (s. 1H), 7.97-7.86 (m, 4H), 7.61-7.56 (m, 3H), 7.49-7.40 (m, 4H), 7.14 (dd, J = 3.4, 5.3 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 9.14 (s, 1H), 8.32 (s. 1H), 7.97-7.86 (m, 4H), 7.61-7.56 (m, 3H), 7.49 -7.40 (m, 4H), 7.14 (dd, J = 3.4, 5.3 Hz, 1H).
실시예Example 70.  70. 메틸methyl 3-(1-(4- 3- (1- (4- 플루오로페닐Fluorophenyl )-3-(티오펜-2-일)-1H-) -3- (thiophen-2-yl) -1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )벤조에이트(methyl 3-(1-(4-) Benzoate (methyl 3- (1- (4- fluorophenylfluorophenyl )-3-() -3- ( thiophenthiophen -2--2- ylyl )-1H-pyrazole-4-carboxamido)benzoate); KY-06493) -1H-pyrazole-4-carboxamido) benzoate); KY-06493
KY-06531과 동일한 방법으로 합성하여 표제 화합물(85%)을 수득하였다.Synthesis was performed in the same manner as KY-06531 to obtain the title compound (85%).
1H NMR (300 MHz, DMSO) δ 10.42 (s, 1H), 9.15 (s, 1H), 8.40 (s, 1H), 8.04-8.00 (m, 1H), 7.97-7.92 (m, 3H), 7.71 (td, J = 0.8, 8.1 Hz, 1H), 7.60 (dd, J = 1.2, 5.2 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.47 (t, J = 8.7 Hz, 2H), 7.14 (dd, J = 3.6, 5.1 Hz, 1H), 3.89 (s, 3H). 1 H NMR (300 MHz, DMSO) δ 10.42 (s, 1H), 9.15 (s, 1H), 8.40 (s, 1H), 8.04-8.00 (m, 1H), 7.97-7.92 (m, 3H), 7.71 (td, J = 0.8, 8.1 Hz, 1H), 7.60 (dd, J = 1.2, 5.2 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.47 (t, J = 8.7 Hz, 2H) , 7.14 (dd, J = 3.6, 5.1 Hz, 1H), 3.89 (s, 3H).
실시예Example 71. N-(3-카바모일페닐)-1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(3-carbamoylphenyl)-1-(4-fluorophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide); KY-06494 71.N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (3-carbamoylphenyl ) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06494
KY-06531과 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was carried out in the same manner as KY-06531 to obtain the title compound (99%).
1H NMR (300 MHz, DMSO) δ 10.32 (s, 1H), 9.14 (s, 1H), 8.21 (s, 1H), 7.97-7.89 (m, 5H), 7.62-7.59 (m, 2H), 7.49-7.41 (m, 3H), 7.36 (s, 1H), 7.13 (dd, J = 3.6, 5.1 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.32 (s, 1H), 9.14 (s, 1H), 8.21 (s, 1H), 7.97-7.89 (m, 5H), 7.62-7.59 (m, 2H), 7.49 -7.41 (m, 3H), 7.36 (s, 1H), 7.13 (dd, J = 3.6, 5.1 Hz, 1H).
실시예Example 72. 1-(4-플루오로페닐)-N-(4-(메틸카바모일)페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(1-(4-fluorophenyl)-N-(4-(methylcarbamoyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide); KY-06496 72. 1- (4-Fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- ( 4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06496
KY-06531과 동일한 방법으로 합성하여 표제 화합물(10%)을 수득하였다.Synthesis was performed in the same manner as KY-06531 to obtain the title compound (10%).
1H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.13 (s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 7.99-7.92 (m, 3H), 7.87-7.78 (m, 4H), 7.60 (dd, J = 1.2, 5.1 Hz, 1H), 7.46 (t, J = 8.7 Hz, 2H), 7.14 (dd, J = 3.6, 5.1 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.13 (s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 7.99-7.92 (m, 3H), 7.87-7.78 (m , 4H), 7.60 (dd, J = 1.2, 5.1 Hz, 1H), 7.46 (t, J = 8.7 Hz, 2H), 7.14 (dd, J = 3.6, 5.1 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H).
실시예Example 73. N-(4-카바모일페닐)-1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(4-carbamoylphenyl)-1-(4-fluorophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide); KY-06497 73.N- (4-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (4-carbamoylphenyl ) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06497
KY-06531과 동일한 방법으로 합성하여 표제 화합물(35%)을 수득하였다.Synthesis was performed in the same manner as KY-06531 to obtain the title compound (35%).
1H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.13 (s, 1H), 7.97-7.88 (m, 5H), 7.79 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 6.9 Hz, 1H) 7.60 (dd, J = 1.2, 5.1 Hz, 1H), 7.46 (t, J = 8.7 Hz, 2H), 7.26 (s, 1H), 7.14 (dd, J = 3.6, 5.1 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.13 (s, 1H), 7.97-7.88 (m, 5H), 7.79 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 6.9 Hz, 1H) 7.60 (dd, J = 1.2, 5.1 Hz, 1H), 7.46 (t, J = 8.7 Hz, 2H), 7.26 (s, 1H), 7.14 (dd, J = 3.6, 5.1 Hz, 1H).
실시예Example 74. 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산(3-(1-(4-fluorophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid); KY-06498 74. 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamido) benzoic acid); KY-06498
KY-06455와 동일한 방법으로 합성하여 표제 화합물(98%)을 수득하였다.Synthesis in the same manner as KY-06455 gave the title compound (98%).
1H NMR (300 MHz, DMSO) δ 12.95 (s, 1H), 10.39 (s, 1H), 9.15 (s, 1H), 8.37 (s, 1H), 8.00-7.92 (m, 4H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 1.1, 5.1 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.14 (dd, J = 3.7, 5.1 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.95 (s, 1H), 10.39 (s, 1H), 9.15 (s, 1H), 8.37 (s, 1H), 8.00-7.92 (m, 4H), 7.69 (d , J = 7.8 Hz, 1H), 7.60 (dd, J = 1.1, 5.1 Hz, 1H), 7.52-7.43 (m, 3H), 7.14 (dd, J = 3.7, 5.1 Hz, 1H).
실시예Example 75. N-(3- 75.N- (3- 카바모일페닐Carbamoylphenyl )-3-(N-) -3- (N- 펜에틸설파모일Phenethylsulfamoyl )벤즈아미드(N-(3-carbamoylphenyl)-3-(N-phenethylsulfamoyl)benzamide); KY-06500) Benzamide (N- (3-carbamoylphenyl) -3- (N-phenethylsulfamoyl) benzamide); KY-06500
염화설포닐 화합물(150 mg, 0.44 mmol)을 THF(3 mL)에 용해시키고, 펜에틸아민(phenethylamine, 54 mg, 0.44 mmol, 1 당량)을 첨가하고, 트리에틸아민(Et3N, TEA, 60 μL)을 첨가한 후, 실온에서 24시간 동안 교반하였다. 용매를 제거하고 실리카겔 컬럼으로 분리하여 표제 화합물(61%)을 수득하였다.Sulfonyl chloride compound (150 mg, 0.44 mmol) was dissolved in THF (3 mL), phenethylamine (54 mg, 0.44 mmol, 1 equiv) was added, triethylamine (Et 3 N, TEA, 60 μL) was added and then stirred at room temperature for 24 hours. The solvent was removed and separated by silica gel column to give the title compound (61%).
1H NMR (500 MHz, DMSO) δ 10.66 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 8.02-7.98 (m, 3H), 7.90 (t, J = 5.8 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.41 (s, 1H), 7.29 (t, J = 7.2 Hz, 2H), 7.22-7.18 (m, 3H), 3.05(q, J = 6.8 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H). 1 H NMR (500 MHz, DMSO) δ 10.66 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 8.02-7.98 (m, 3H), 7.90 (t , J = 5.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.41 (s, 1H ), 7.29 (t, J = 7.2 Hz, 2H), 7.22-7.18 (m, 3H), 3.05 (q, J = 6.8 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H).
실시예Example 76. N-(3- 76.N- (3- 카바모일페닐Carbamoylphenyl )-3-(N-(4-) -3- (N- (4- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )벤즈아미드(N-(3-carbamoylphenyl)-3-(N-(4-phenoxyphenyl)sulfamoyl)benzamide); KY-06501) Benzamide (N- (3-carbamoylphenyl) -3- (N- (4-phenoxyphenyl) sulfamoyl) benzamide); KY-06501
KY-06500과 동일한 방법으로 합성하여 표제 화합물(98%)을 수득하였다.Synthesis was performed in the same manner as KY-06500 to obtain the title compound (98%).
1H NMR (500 MHz, DMSO) δ 9.75 (s, 1H), 9.47-9.43 (m, 2H), 9.30 (d, J = 8.0 Hz, 1H), 9.14 (d, J = 7.1 Hz, 1H), 8.88-8.79 (m, 4H), 8.65 (t, J = 7.8 Hz. 2H), 8.52 (t, J = 7.0 Hz, 2H), 8.36-8.28 (m, 3H), 8.13 (d, J = 8.5 Hz, 2H), 8.0o1 (d, J = 9.0 Hz, 2H), 7.66 (s, 1H). 1 H NMR (500 MHz, DMSO) δ 9.75 (s, 1H), 9.47-9.43 (m, 2H), 9.30 (d, J = 8.0 Hz, 1H), 9.14 (d, J = 7.1 Hz, 1H), 8.88-8.79 (m, 4H), 8.65 (t, J = 7.8 Hz. 2H), 8.52 (t, J = 7.0 Hz, 2H), 8.36-8.28 (m, 3H), 8.13 (d, J = 8.5 Hz , 2H), 8.0o1 (d, J = 9.0 Hz, 2H), 7.66 (s, 1H).
실시예Example 77. N-(3- 77.N- (3- 카바모일페닐Carbamoylphenyl )-3-(N-(피리딘-2-일)) -3- (N- (pyridin-2-yl) 설파모일Sulfa Mole )벤즈아미드(N-(3-carbamoylphenyl)-3-(N-(pyridin-2-yl)sulfamoyl)benzamide); KY-06503) Benzamide (N- (3-carbamoylphenyl) -3- (N- (pyridin-2-yl) sulfamoyl) benzamide); KY-06503
염화설포닐 화합물(150 mg)을 THF(2.2 mL)에 넣어 교반하고, 아닐린 화합물(41 mg), Et3N(0.06 mL)를 넣어 50℃에서 교반하였다. MC를 더하고 증류수로 세척한 후 MgSO4로 건조하였다. MC:MeOH=19:1 혼합용매로 컬럼을 수행하여 표제 화합물(35%)을 수득하였다.Sulfonyl chloride (150 mg) was added to THF (2.2 mL) and stirred, and aniline compound (41 mg) and Et 3 N (0.06 mL) were added and stirred at 50 ° C. MC was added, washed with distilled water and dried over MgSO 4 . Column column with MC: MeOH = 19: 1 mixed solvent afforded the title compound (35%).
1H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.96 - 7.93 (m, 3H), 7.79 - 7.68 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.22 (s, 1H), 6.86 (s, 1H). 1 H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.96-7.93 (m, 3H), 7.79-7.68 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.37 (s , 1H), 7.22 (s, 1 H), 6.86 (s, 1 H).
실시예Example 78. 3-(N-(1- 78. 3- (N- (1- 벤질피페리딘Benzylpiperidine -4-일)-4- days) 설파모일Sulfa Mole )-N-(3-) -N- (3- 카바모일페닐Carbamoylphenyl )벤즈아미드(3-(N-(1-benzylpiperidin-4-yl)sulfamoyl)-N-(3-carbamoylphenyl)benzamide); KY-06504) Benzamide (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06504
KY-06503과 동일한 방법으로 합성하여 표제 화합물(80%)을 수득하였다.Synthesis was carried out in the same manner as KY-06503 to obtain the title compound (80%).
1H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 8.39 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.31 - 7.21 (m, 6H), 3.37 (s, 2H), 3.06 - 2.94 (m, 1H), 2.63 (d, J = 13.5 Hz, 2H), 1.89 (t, J = 10.7 Hz, 2H), 1.54 (d, J = 12.9 Hz, 2H), 1.37 (q, J = 10.2 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 8.39 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.95 ( d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.31-7.21 (m, 6H), 3.37 (s, 2H), 3.06-2.94 (m, 1H), 2.63 (d, J = 13.5 Hz, 2H ), 1.89 (t, J = 10.7 Hz, 2H), 1.54 (d, J = 12.9 Hz, 2H), 1.37 (q, J = 10.2 Hz, 2H).
실시예Example 79. N-(3- 79.N- (3- 카바모일페닐Carbamoylphenyl )-3-(N-(3-) -3- (N- (3- 페녹시페닐Phenoxyphenyl )) 설파모일Sulfa Mole )벤즈아미드(N-(3-carbamoylphenyl)-3-(N-(3-phenoxyphenyl)sulfamoyl)benzamide); KY-06505) Benzamide (N- (3-carbamoylphenyl) -3- (N- (3-phenoxyphenyl) sulfamoyl) benzamide); KY-06505
KY-06503과 동일한 방법으로 합성하여 표제 화합물(3%)을 수득하였다.Synthesis in the same manner as KY-06503 afforded the title compound (3%).
1H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 8.21 (s, 1H), 8.17 (dd, J = 1.2 Hz, 7.8 Hz, 1H), 7.96 - 7.87 (m, 5H), 7.69 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.46 - 7.41 (m, 4H), 7.37 (s, 1H), 7.30 (s, 1H), 7.26 - 7.19 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 8.21 (s, 1H), 8.17 (dd, J = 1.2 Hz, 7.8 Hz, 1H), 7.96-7.87 (m, 5H), 7.69 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.46-7.41 (m, 4H ), 7.37 (s, 1 H), 7.30 (s, 1 H), 7.26-7.19 (m, 2 H).
실시예Example 80. 3-(N-(1H- 80. 3- (N- (1H- 인다졸Indazole -5-일)-5 days) 설파모일Sulfa Mole )-N-(3-) -N- (3- 카바모일페닐Carbamoylphenyl )벤즈아미드(3-(N-(1H-indazol-5-yl)sulfamoyl)-N-(3-carbamoylphenyl)benzamide); KY-06506) Benzamide (3- (N- (1H-indazol-5-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06506
KY-06503과 동일한 방법으로 합성하여 표제 화합물(39%)을 수득하였다.Synthesis was carried out in the same manner as KY-06503 to obtain the title compound (39%).
1H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.59 (s, 1H), 10.21 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 9.9 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.46 - 7.37 (m, 4H), 7.10 (dd, J = 1.7 Hz, 8.9 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.59 (s, 1H), 10.21 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 9.9 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.62 ( d, J = 7.8 Hz, 1H), 7.46-7.37 (m, 4H), 7.10 (dd, J = 1.7 Hz, 8.9 Hz, 1H).
실시예Example 81. 3-(N-(1H- 81. 3- (N- (1H- 인다졸Indazole -6-일)-6- days) 설파모일Sulfa Mole )-N-(3-) -N- (3- 카바모일페닐Carbamoylphenyl )벤즈아미드(3-(N-(1H-indazol-6-yl)sulfamoyl)-N-(3-carbamoylphenyl)benzamide); KY-06507) Benzamide (3- (N- (1H-indazol-6-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06507
KY-06503과 동일한 방법으로 합성하여 표제 화합물(61%)을 수득하였다.Synthesis was carried out in the same manner as KY-06503 to obtain the title compound (61%).
1H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 10.60 (s, 1H), 10.55 (s, 1H), 8.41 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.96 - 7.89 (m, 4H), 7.70 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.27 (s, 1H), 6.91 (dd, J = 1.4 Hz, 8.6 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 10.60 (s, 1H), 10.55 (s, 1H), 8.41 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.96-7.89 (m, 4H), 7.70 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H ), 7.27 (s, 1 H), 6.91 (dd, J = 1.4 Hz, 8.6 Hz, 1H).
실시예Example 82. N-(3- 82.N- (3- 카바모일페닐Carbamoylphenyl )-3-(N-(피리딘-3-일)) -3- (N- (pyridin-3-yl) 설파모일Sulfa Mole )벤즈아미드(N-(3-carbamoylphenyl)-3-(N-(pyridin-3-yl)sulfamoyl)benzamide); KY-06508) Benzamide (N- (3-carbamoylphenyl) -3- (N- (pyridin-3-yl) sulfamoyl) benzamide); KY-06508
KY-06503과 동일한 방법으로 합성하여 표제 화합물(68%)을 수득하였다.Synthesis was performed in the same manner as KY-06503 to obtain the title compound (68%).
1H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.39 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.27 - 8.22 (m, 3H), 7.96 - 7.91 (m, 3H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.44 (qd, J = 1.2 Hz, 8.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.30 (dd, J = 4.6 Hz, 8.2 Hz, 1H) 1 H NMR (300 MHz, DMSO) δ 10.65 (s, 1H), 8.39 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.27-8.22 (m, 3H), 7.96-7.91 (m , 3H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.44 (qd, J = 1.2 Hz, 8.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.30 (dd, J = 4.6 Hz, 8.2 Hz, 1H)
실시예Example 83. 2,4-디플루오로-N-(3-(메틸카바모일)페닐)-5-(N-페닐설파모일)벤즈아미드(2,4-difluoro-N-(3-(methylcarbamoyl)phenyl)-5-(N-phenylsulfamoyl)benzamide); KY-06509 83. 2,4-difluoro-N- (3- (methylcarbamoyl) phenyl) -5- (N-phenylsulfamoyl) benzamide (2,4-difluoro-N- (3- (methylcarbamoyl) phenyl ) -5- (N-phenylsulfamoyl) benzamide); KY-06509
KY-06531과 동일한 방법으로 합성하여 표제 화합물(31%)을 수득하였다.Synthesis was performed in the same manner as KY-06531 to obtain the title compound (31%).
1H NMR (300 MHz, DMSO) δ 10.78 (s, 1H), 10.68 (s, 1H), 8.43(d, J = 4.5 Hz, 1H), 8.16-8.11 (m, 2H), 7.73 (m, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.27(t, J = 7.5 Hz, 2H), 7.15-7.04(m 3H), 2.79 (d, J = 4.2 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.78 (s, 1H), 10.68 (s, 1H), 8.43 (d, J = 4.5 Hz, 1H), 8.16-8.11 (m, 2H), 7.73 (m, 1H ), 7.57 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.15-7.04 (m 3H), 2.79 (d, J = 4.2 Hz, 3H).
실시예Example 84. 3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)-N-(3-카바모일페닐)벤즈아미드(3-(N-(3,5-bis(trifluoromethyl)phenyl)sulfamoyl)-N-(3-carbamoylphenyl)benzamide); KY-06510 84. 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide (3- (N- (3,5-bis (trifluoromethyl ) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06510
KY-06500과 동일한 방법으로 합성하여 표제 화합물(26%)을 수득하였다.Synthesis was carried out in the same manner as KY-06500 to obtain the title compound (26%).
1H NMR (500 MHz, DMSO) δ 11.35 (s, 1H), 10.62 (s, 1H), 841 (s, 1H), 8.24 (d, J = 4.8 Hz, 1H), 8.22 (s, 1H), 8.00-7.98 (m, 2H), 7.90 (d, J = 1.8 Hz, 1H), 7.75 (t, J = 4.7 Hz, 1H), 7.71 (s, 1H), 7.63-7.61 (m, 3H), 7.43 (t, J = 4.8 Hz, 1H), 7.37 (s, 1H). 1 H NMR (500 MHz, DMSO) δ 11.35 (s, 1H), 10.62 (s, 1H), 841 (s, 1H), 8.24 (d, J = 4.8 Hz, 1H), 8.22 (s, 1H), 8.00-7.98 (m, 2H), 7.90 (d, J = 1.8 Hz, 1H), 7.75 (t, J = 4.7 Hz, 1H), 7.71 (s, 1H), 7.63-7.61 (m, 3H), 7.43 (t, J = 4.8 Hz, 1H), 7.37 (s, 1H).
실시예Example 85. 4- 85. 4- 플루오로Fluoro -N-(3-(-N- (3- ( 메틸카바모일Methylcarbamoyl )페닐)-3-(N-) Phenyl) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(4-fluoro-N-(3-(methylcarbamoyl)phenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06511) Benzamide (4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06511
KY-06478과 동일한 방법으로 합성하여 표제 화합물(66%)을 수득하였다.Synthesis was performed in the same manner as KY-06478 to give the title compound (66%).
1H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 10.63 (s, 1H), 8.47-8.42 (m, 2H), 8.32-8.27 (m, 1H), 8.18 (s, 1H), 7.92 (d, J = 13.5 Hz, 1H), 7.64 (s, 1H), 7.61-7.56 (m, 1H), 7.45 (t, J = 13.0 Hz, 1H), 7.24 (t, J = 13.0 Hz, 2H), 7.13 (d, J = 13.0 Hz, 2H), 7.04 (t, J = 12.3 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H). 1 H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 10.63 (s, 1H), 8.47-8.42 (m, 2H), 8.32-8.27 (m, 1H), 8.18 (s, 1H), 7.92 (d, J = 13.5 Hz, 1H), 7.64 (s, 1H), 7.61-7.56 (m, 1H), 7.45 (t, J = 13.0 Hz, 1H), 7.24 (t, J = 13.0 Hz, 2H) , 7.13 (d, J = 13.0 Hz, 2H), 7.04 (t, J = 12.3 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H).
실시예Example 86. N-(3- 86.N- (3- 카바모일페닐Carbamoylphenyl )-4-)-4- 플루오로Fluoro -3-(N--3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(3-carbamoylphenyl)-4-fluoro-3-(N-phenylsulfamoyl)benzamide); KY-06512) Benzamide (N- (3-carbamoylphenyl) -4-fluoro-3- (N-phenylsulfamoyl) benzamide); KY-06512
KY-06478과 동일한 방법으로 합성하여 표제 화합물(56%)을 수득하였다.Synthesis in the same manner as KY-06478 gave the title compound (56%).
1H NMR (300 MHz, DMSO) δ 10.77 (s, 1H), 10.63 (s, 1H), 8.46 (dd, J = 1.2, 4.2 Hz, 1H), 8.30-8.29 (m, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.93 (dd, J = 0.9, 4.8 Hz, 1H), 7.64-7.59 (m, 2H), 7.45 (t, J = 4.8 Hz, 1H), 7.84 (s, 1H), 7.25 (t, J = 4.78 Hz, 2H), 7.13 (d, J =4.8Hz, 2H), 7.04 (t, J = 4.2Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.77 (s, 1H), 10.63 (s, 1H), 8.46 (dd, J = 1.2, 4.2 Hz, 1H), 8.30-8.29 (m, 1H), 8.20 (s , 1H), 7.98 (s, 1H), 7.93 (dd, J = 0.9, 4.8 Hz, 1H), 7.64-7.59 (m, 2H), 7.45 (t, J = 4.8 Hz, 1H), 7.84 (s, 1H), 7.25 (t, J = 4.78 Hz, 2H), 7.13 (d, J = 4.8 Hz, 2H), 7.04 (t, J = 4.2 Hz, 1H).
실시예Example 87. 에틸 3-((5-((3-( 87. Ethyl 3-((5-((3- ( 에톡시카보닐Ethoxycarbonyl )페닐)) Phenyl) 카바모일Cabamo )-2-)-2- 플루오로페닐Fluorophenyl )설폰아미도)벤조에이트(ethyl 3-((5-((3-(Sulfonamido) benzoate (ethyl 3-((5-((3- ( ethoxycarbonylethoxycarbonyl )phenyl)) phenyl) carbamoylcarbamoyl )-2-fluorophenyl)sulfonamido)benzoate); KY-06513) -2-fluorophenyl) sulfonamido) benzoate); KY-06513
KY-06633과 동일한 방법으로 합성하여 표제 화합물(12%)을 수득하였다.Synthesis in the same manner as KY-06633 gave the title compound (12%).
1H NMR (300 MHz, DMSO) δ 8.30 (dd, J = 2.3, 6.5 Hz, 1H), 8.21-8.13 (m, 3H), 8.04 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.34-7.28 (m, 2H), 7.24 (s, 1H), 7.16-7.14 (m, 4H), 4.38 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 8.30 (dd, J = 2.3, 6.5 Hz, 1H), 8.21-8.13 (m, 3H), 8.04 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.34-7.28 (m, 2H), 7.24 (s, 1H), 7.16-7.14 (m, 4H), 4.38 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).
실시예Example 88. 3-((5-((3- 88. 3-((5-((3- 카르복시페닐Carboxyphenyl )) 카바모일Cabamo )-2-)-2- 플루오로페닐Fluorophenyl )) 설폰아미도Sulfonamido )벤조산(3-((5-((3-carboxyphenyl)carbamoyl)-2-fluorophenyl)sulfonamido)benzoic acid); KY-06514) Benzoic acid (3-((5-((3-carboxyphenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoic acid); KY-06514
KY-06455과 동일한 방법으로 정량적으로 합성하여 표제 화합물을 수득하였다.Quantitative synthesis in the same manner as KY-06455 gave the title compound.
1H NMR (300 MHz, DMSO) δ 13.10 (s, 2H), 11.07 (s, 1H), 10.74 (s, 1H), 8.55 (dd, J = 2.1, 6.9 Hz, 1H), 8.44 (s, 1H), 8.42-8.37 (m, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.81-7.68 (m ,4H), 7.58 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 5.1 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 13.10 (s, 2H), 11.07 (s, 1H), 10.74 (s, 1H), 8.55 (dd, J = 2.1, 6.9 Hz, 1H), 8.44 (s, 1H ), 8.42-8.37 (m, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.81-7.68 (m, 4H), 7.58 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 5.1 Hz, 2H).
실시예Example 89. 4-플루오로-N-(3-(메틸카바모일)페닐)-3-(N-(3-(메틸카바모일)페닐)설파모일)벤즈아미드(4-fluoro-N-(3-(methylcarbamoyl)phenyl)-3-(N-(3-(methylcarbamoyl)phenyl)sulfamoyl)benzamide); KY-06515 89. 4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide (4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide); KY-06515
KY-06531과 동일한 방법으로 합성하여 표제 화합물(53%)을 수득하였다.Synthesis was performed in the same manner as KY-06531 to obtain the title compound (53%).
1H NMR (500 MHz, DMSO) δ 10.92 (s, 1H), 10.63 (s, 1H), 8.47-8.44 (m, 2H), 8.40 (q, J = 4.3 Hz, 1H), 8.32-8.29 (m, 1H), 8.19 (s, 1H), 7.93 (dd, J = 7.7, 1.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.50-7.44 (m, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.28 (dd, J = 1.3, 8.2 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.74 (t, J = 5.0 Hz, 3H). 1 H NMR (500 MHz, DMSO) δ 10.92 (s, 1H), 10.63 (s, 1H), 8.47-8.44 (m, 2H), 8.40 (q, J = 4.3 Hz, 1H), 8.32-8.29 (m , 1H), 8.19 (s, 1H), 7.93 (dd, J = 7.7, 1.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.50-7.44 ( m, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.28 (dd, J = 1.3, 8.2 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.74 (t, J = 5.0 Hz, 3H).
실시예Example 90. 에틸 3- 90. Ethyl 3- ((2-플루오로-5-(페닐카바모일)페닐)설폰아미도((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido )) 벤조에이트Benzoate (ethyl 3-((2-(ethyl 3-((2- fluorofluoro -5-(-5- ( phenylcarbamoylphenylcarbamoyl )phenyl)) phenyl) sulfonamidosulfonamido )benzoate); KY-06516) benzoate); KY-06516
KY-06454와 동일한 방법으로 합성하여 표제 화합물(11%)을 수득하였다.Synthesis in the same manner as KY-06454 afforded the title compound (11%).
1H NMR (300 MHz, CDCl3) δ 8.33 (dd, J = 2.4, 6.6 Hz, 1H), 8.20-8.15 (m, 1H), 8.00 (s, 1H), 7.81-7.76 (m, 2H), 7.68 (d, J =8.1 Hz, 2H), 7.41-7.29 (m, 5H), 7.18 (t, J =6.9 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.33 (dd, J = 2.4, 6.6 Hz, 1H), 8.20-8.15 (m, 1H), 8.00 (s, 1H), 7.81-7.76 (m, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.41-7.29 (m, 5H), 7.18 (t, J = 6.9 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).
실시예Example 91. 3-((2- 91. 3-((2- 플루오로Fluoro -5-(-5- ( 페닐카바모일Phenylcarbamoyl )페닐)) Phenyl) 설폰아미도Sulfonamido )벤조산(3-((2-fluoro-5-(phenylcarbamoyl)phenyl)sulfonamido)benzoic acid); KY-06517) Benzoic acid (3-((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06517
KY-06455와 동일한 방법으로 합성하여 표제 화합물(85%)을 수득하였다.Synthesis in the same manner as KY-06455 gave the title compound (85%).
1H NMR (300 MHz, DMSO) δ 13.0 (s, 1H), 11.00 (s, 1H), 10.49 (s, 1H), 8.43 (dd, J = 2.3, 6.8 Hz, 1H), 8.30-8.26 (m, 1H), 7.74-7.72 (m, 3H), 7.64-7.58 (m, 2H), 7.42-7.34 (m, 4H), 7.13 (t, J = 7.2 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.0 (s, 1H), 11.00 (s, 1H), 10.49 (s, 1H), 8.43 (dd, J = 2.3, 6.8 Hz, 1H), 8.30-8.26 (m , 1H), 7.74-7.72 (m, 3H), 7.64-7.58 (m, 2H), 7.42-7.34 (m, 4H), 7.13 (t, J = 7.2 Hz, 1H).
실시예Example 92. N-(4- 92.N- (4- 클로로페닐Chlorophenyl )-3-(N-) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(4-chlorophenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06518) Benzamide (N- (4-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06518
KY-06478과 동일한 방법으로 합성하여 표제 화합물(75%)을 수득하였다.Synthesis in the same manner as KY-06478 gave the title compound (75%).
1H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 10.41 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 7.7 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 10.41 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 7.7 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H).
실시예Example 93. N-(4- 93.N- (4- 브로모페닐Bromophenyl )-3-(N-) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(4-bromophenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06519) Benzamide (N- (4-bromophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06519
KY-06478과 동일한 방법으로 합성하여 표제 화합물(69%)을 수득하였다.Synthesis in the same manner as KY-06478 gave the title compound (69%).
1H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 10.41 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75-7.68 (m, 3H), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 10.41 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75-7.68 (m, 3H), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H).
실시예Example 94. N-(3- 94.N- (3- 클로로페닐Chlorophenyl )-3-(N-) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(3-chlorophenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06520) Benzamide (N- (3-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06520
KY-06478과 동일한 방법으로 합성하여 표제 화합물(50%)을 수득하였다.Synthesis in the same manner as KY-06478 gave the title compound (50%).
1H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 10.43 (s, 1H), 8.33 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.94-7.93 (m, 2H), 7.74-7.67 (m, 2H), 7.40 (t, J = 8.1 Hz, 1H), 7.21 (q, J = 7.2 Hz, 3H), 7.09 (d, J = 7.7 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 10.43 (s, 1H), 8.33 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.94-7.93 (m, 2H ), 7.74-7.67 (m, 2H), 7.40 (t, J = 8.1 Hz, 1H), 7.21 (q, J = 7.2 Hz, 3H), 7.09 (d, J = 7.7 Hz, 2H), 7.01 (t , J = 7.4 Hz, 1H).
실시예Example 95. N-(3,4- 95.N- (3,4- 디클로로페닐Dichlorophenyl )-3-(N-) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(3,4-dichlorophenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06521) Benzamide (N- (3,4-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06521
KY-06478과 동일한 방법으로 합성하여 표제 화합물(67%)을 수득하였다.Synthesis was performed in the same manner as KY-06478 to give the title compound (67%).
1H NMR (300 MHz, DMSO) δ 10.72 (s, 1H), 10.42 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.75-7.71 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.72 (s, 1H), 10.42 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.75-7.71 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H).
실시예Example 96. N-(3,5- 96.N- (3,5- 디클로로페닐Dichlorophenyl )-3-(N-) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(3,5-dichlorophenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06522) Benzamide (N- (3,5-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06522
KY-06478과 동일한 방법으로 합성하여 표제 화합물(56%)을 수득하였다.Synthesis in the same manner as KY-06478 gave the title compound (56%).
1H NMR (300 MHz, DMSO) δ 10.74 (s, 1H), 10.43 (s, 1H), 8.34 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 1.8 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 1.8 hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.11 (s, 1H), 7.09 (s, 1H), 7.03 (t, J = 7.3 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.74 (s, 1H), 10.43 (s, 1H), 8.34 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 1.8 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 1.8 hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.11 (s, 1H), 7.09 (s, 1H), 7.03 (t, J = 7.3 Hz, 1H).
실시예Example 97. N-(2,4- 97. N- (2,4- 디브로모페닐Dibromophenyl )-3-(N-) -3- (N- 페닐설파모일Phenylsulfamoyl )벤즈아미드(N-(2,4-dibromophenyl)-3-(N-phenylsulfamoyl)benzamide); KY-06523) Benzamide (N- (2,4-dibromophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06523
KY-06478과 동일한 방법으로 합성하여 표제 화합물(30%)을 수득하였다.Synthesis in the same manner as KY-06478 gave the title compound (30%).
1H NMR (300 MHz, DMSO) δ 10.42 (s, 1H), 10.39 (s, 1H), 8.36 (s, 1H), 8.20 (d, J = 7.7. Hz, 1H), 7.99 (d, J =2.1 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.67 (dd, J = 8.5, 2.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.42 (s, 1H), 10.39 (s, 1H), 8.36 (s, 1H), 8.20 (d, J = 7.7.Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.67 (dd, J = 8.5, 2.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H).
실시예Example 98. 4-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산(4-(1-(4-fluorophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid); KY-06524 98. 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamido) benzoic acid); KY-06524
KY-06455와 동일한 방법으로 합성하여 표제 화합물(89%)을 수득하였다.Synthesis in the same manner as KY-06455 gave the title compound (89%).
1H NMR (300 MHz, DMSO) δ 9.06 (s, 1H), 8.16 (d, J = 3.5 Hz, 1H), 8.02-7.97 (m, 3H), 7.72 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.54 (t, J = 7.5 hz, 1H), 7.43-7.37 (m, 3H), 7.16 (dd, J = 3.8, 5.0 hz, 1H). 1 H NMR (300 MHz, DMSO) δ 9.06 (s, 1H), 8.16 (d, J = 3.5 Hz, 1H), 8.02-7.97 (m, 3H), 7.72 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.54 (t, J = 7.5 hz, 1H), 7.43-7.37 (m, 3H), 7.16 (dd, J = 3.8, 5.0 hz, 1H).
실시예Example 99. 4-(5-((3- 99. 4- (5-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)벤조산(4-(5-((3-phenoxyphenyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06525) Thiazol-2-yl) benzoic acid (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06525
7 mL 바이알에 에스테르 화합물(32 mg, 0.074 mmol), THF/H2O/MeOH 혼합 용매를 넣고 교반하였다. LiOH(15.6 mg, 0.37 mmol)을 넣고 상온에서 17시간 동안 교반하였다. 반응종료 후, 1N HCl을 가하여 pH 2 내지 3에 맞추고 EA와 H2O로 추출하였다. 유기층을 MgSO4로 건조시킨 후 농축하고, 고체를 여과하여 표제 화합물(72%)을 수득하였다.Ester compound (32 mg, 0.074 mmol) and THF / H 2 O / MeOH mixed solvent were added and stirred in a 7 mL vial. LiOH (15.6 mg, 0.37 mmol) was added thereto and stirred at room temperature for 17 hours. After completion of the reaction, 1N HCl was added, adjusted to pH 2-3 and extracted with EA and H 2 O. The organic layer was dried over MgSO 4 , concentrated and the solid was filtered to give the title compound (72%).
1H NMR (300 MHz, DMSO) δ 13.23 (s, 1H), 10.56 (s, 1H), 8.71 (s, 1H), 8.18-7.97 (m, 4H), 7.54 (d, 1H, J = 8.3 Hz), 7.48-7.34 (m, 4H), 7.18 (t, 1H, J = 7.4 Hz), 7.07 (d, 2H, J = 8.0 Hz), 6.86-6.76 (m, 1H). 1 H NMR (300 MHz, DMSO) δ 13.23 (s, 1H), 10.56 (s, 1H), 8.71 (s, 1H), 8.18-7.97 (m, 4H), 7.54 (d, 1H, J = 8.3 Hz ), 7.48-7.34 (m, 4H), 7.18 (t, 1H, J = 7.4 Hz), 7.07 (d, 2H, J = 8.0 Hz), 6.86-6.76 (m, 1H).
실시예Example 100.  100. 메틸methyl (4-(5-((3- (4- (5-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조일Benzoyl )-D-) -D- 트립토파네이트Tryptophanate (methyl (4-(5-((3-(methyl (4- (5-((3- phenoxyphenylphenoxyphenyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )) benzoylbenzoyl )-D-tryptophanate); KY-06527) -D-tryptophanate); KY-06527
20 mL 바이알에 카르복시산 화합물(50 mg, 0.12 mmol), L-트립토판 메틸 에스테르 하이드로클로라이드(37.4 mg, 0.14 mmol), HBTU(54.6 mg, 0.14 mmol), DIPEA(0.14 mmol, 25 μL), DMF(1 mL)를 넣고 상온에서 16시간 동안 반응시켰다. 반응종료 후, EA와 H2O로 추출하고 MgSO4로 건조시켰다. 실리카겔컬럼 크로마토그래피로 분리 정제하여 표제 화합물(50 mg, 62%)을 수득하였다.In 20 mL vials carboxylic acid compound (50 mg, 0.12 mmol), L-tryptophan methyl ester hydrochloride (37.4 mg, 0.14 mmol), HBTU (54.6 mg, 0.14 mmol), DIPEA (0.14 mmol, 25 μL), DMF (1 mL) was added and reacted at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with EA and H 2 O and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (50 mg, 62%).
1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.74-7.64 (m, 2H), 7.53 (t, 3H, J = 2.3 Hz), 7.49-7.37 (m, 2H), 7.36-7.21 (m, 4H), 7.20-6.94 (m, 6H), 6.85 (d, 1H, J = 7.7 Hz), 6.81-6.71 (m, 1H), 5.08 (t, 1H, J = 6.3 Hz), 3.70 (s, 3H), 3.49-3.32 (m, 2H), 2.34-2.15 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.85 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.74-7.64 (m, 2H), 7.53 (t, 3H, J = 2.3 Hz), 7.49-7.37 (m, 2H), 7.36-7.21 (m, 4H), 7.20-6.94 (m, 6H), 6.85 (d, 1H, J = 7.7 Hz), 6.81-6.71 (m, 1H) , 5.08 (t, 1H, J = 6.3 Hz), 3.70 (s, 3H), 3.49-3.32 (m, 2H), 2.34-2.15 (m, 2H).
실시예Example 101. (4-(5-((3- 101. (4- (5-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조일Benzoyl )-D-트립토판(4-(5-((3-phenoxyphenyl)carbamoyl)thiazol-2-yl)benzoyl)-D-tryptophan; KY-06528) -D-tryptophan (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophan; KY-06528
20 mL 바이알에 에스테르 화합물(45 mg, 0.1 mmol), THF/H2O/MeOH 혼합 용매를 넣고 교반하였다. LiOH(21 mg, 0.5 mmol)을 넣고 상온에서 15시간 동안 교반하였다. 반응종료 후, 1N HCl을 가하여 pH 2 내지 3에 맞추고 EA와 H2O로 추출하였다. 유기층을 MgSO4로 건조시킨 후 농축하고, 고체를 여과하여 표제 화합물(31.8 mg, 75%)을 수득하였다.Ester compound (45 mg, 0.1 mmol) and THF / H 2 O / MeOH mixed solvent were added and stirred in a 20 mL vial. LiOH (21 mg, 0.5 mmol) was added thereto and stirred at room temperature for 15 hours. After completion of the reaction, 1N HCl was added, adjusted to pH 2-3 and extracted with EA and H 2 O. The organic layer was dried over MgSO 4 , concentrated and the solid was filtered to give the title compound (31.8 mg, 75%).
1H NMR (300 MHz, DMSO) δ 12.77 (s, 1H), 10.83 (s, 1H), 10.55 (s, 1H), 8.86 (d, 1H, J = 7.8 Hz), 8.70 (s, 1H), 8.10 (d, 2H, J = 8.0 Hz), 7.97 (d, 2H, J = 8.0 Hz), 7.57 (d, 2H, J = 7.9 Hz), 7.49-7.27 (m, 4H), 7.27-7.12 (m, 1H), 7.03 (d, 3H, J = 7.6 Hz), 6.81 (d, 1H, J = 7.9 Hz), 4.68 (q, 1H, J = 7.2 Hz), 3.32-3.08 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 12.77 (s, 1H), 10.83 (s, 1H), 10.55 (s, 1H), 8.86 (d, 1H, J = 7.8 Hz), 8.70 (s, 1H), 8.10 (d, 2H, J = 8.0 Hz), 7.97 (d, 2H, J = 8.0 Hz), 7.57 (d, 2H, J = 7.9 Hz), 7.49-7.27 (m, 4H), 7.27-7.12 (m , 1H), 7.03 (d, 3H, J = 7.6 Hz), 6.81 (d, 1H, J = 7.9 Hz), 4.68 (q, 1H, J = 7.2 Hz), 3.32-3.08 (m, 2H).
실시예Example 102.  102. 메틸methyl (3-(3-(5- (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )벤조일)-L-트립토파네이트(methyl (3-(3-(5-) Benzoyl) -L-tryptophanate (methyl (3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)-L-tryptophanate); KY-06529) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate); KY-06529
20 mL 바이알에 카르복시산 화합물(200 mg, 0.47 mmol), L-트립토판 메틸 에스테르 하이드로클로라이드(184 mg, 0.71 mmol), HBTU(534.7 mg, 1.14 mmol), DIPEA(0.41 mmol, 0.25 mL), DMF(1.6 mL)를 넣고 상온에서 16시간 동안 반응시켰다. 반응종료 후, EA와 H2O로 추출하고 MgSO4로 건조시켰다. 실리카겔컬럼 크로마토그래피로 분리 정제하여 표제 화합물(243 mg, 83%)을 수득하였다.In a 20 mL vial carboxylic acid compound (200 mg, 0.47 mmol), L-tryptophan methyl ester hydrochloride (184 mg, 0.71 mmol), HBTU (534.7 mg, 1.14 mmol), DIPEA (0.41 mmol, 0.25 mL), DMF (1.6 mL) was added and reacted at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with EA and H 2 O and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (243 mg, 83%).
1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.83-7.69 (m, 4H), 7.60-7.41 (m, 4H), 7.37-7.29 (m, 4H), 7.21-7.03 (m, 3H), 6.93 (d, 1H, J = 3.9 Hz), 6.75 (d, 1H, J = 7.5 Hz), 5.06-5.04 (m, 1H), 3.69 (s, 3H), 3.42 (d, 2H, J = 5.3 Hz, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.83-7.69 (m, 4H), 7.60-7.41 (m, 4H), 7.37-7.29 (m, 4H), 7.21-7.03 (m, 3H), 6.93 (d, 1H, J = 3.9 Hz), 6.75 (d, 1H, J = 7.5 Hz), 5.06-5.04 (m, 1H) , 3.69 (s, 3H), 3.42 (d, 2H, J = 5.3 Hz, 2H).
실시예Example 103. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-트립토판((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)-L-tryptophan); KY-06530 103. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan ((3- (3- ( 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan); KY-06530
20 mL 바이알에 에스테르 화합물(240 mg, 0.39 mmol), THF/H2O 혼합 용매를 넣고 교반하였다. LiOH(80.7 mg, 1.91 mmol)을 넣고 상온에서 15시간 동안 교반하였다. 반응종료 후, 1N HCl을 가하여 pH 2 내지 3에 맞추고 EA와 H2O로 추출하였다. 유기층을 MgSO4로 건조시킨 후 농축하고, 고체를 여과하여 표제 화합물(175.9 mg, 74%)을 수득하였다.An ester compound (240 mg, 0.39 mmol) and a THF / H 2 O mixed solvent were added and stirred in a 20 mL vial. LiOH (80.7 mg, 1.91 mmol) was added thereto and stirred at room temperature for 15 hours. After completion of the reaction, 1N HCl was added, adjusted to pH 2-3 and extracted with EA and H 2 O. The organic layer was dried over MgSO 4 and concentrated and the solid was filtered to give the title compound (175.9 mg, 74%).
1H NMR (300 MHz, DMSO) δ 12.74 (s, 1H), 10.83 (s, 1H), 10.33 (s, 1H), 9.21 (s, 1H), 8.66 (d, 1H, J = 7.7 Hz), 8.11 (s, 1H), 7.98-7.83 (m, 4H), 7.59 (d, 4H, J = 4.9 Hz), 7.44 (q, 2H, J = 7.7 Hz), 7.33 (d, 1H, J = 7.9 Hz), 7.21 (d, 1H, J = 2.3 Hz), 7.18-7.12 (m, 1H), 7.06-6.99 (m, 2H), 4.67 (t, 1H, J = 9.0 Hz), 3.29-3.23 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 12.74 (s, 1H), 10.83 (s, 1H), 10.33 (s, 1H), 9.21 (s, 1H), 8.66 (d, 1H, J = 7.7 Hz), 8.11 (s, 1H), 7.98-7.83 (m, 4H), 7.59 (d, 4H, J = 4.9 Hz), 7.44 (q, 2H, J = 7.7 Hz), 7.33 (d, 1H, J = 7.9 Hz ), 7.21 (d, 1H, J = 2.3 Hz), 7.18-7.12 (m, 1H), 7.06-6.99 (m, 2H), 4.67 (t, 1H, J = 9.0 Hz), 3.29-3.23 (m, 2H).
실시예Example 104.  104. 메틸methyl (3-(3-(5- (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )벤조일)-D-알라니네이트(methyl (3-(3-(5-) Benzoyl) -D-alanine (methyl (3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)-D-alaninate); KY-06531) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alaninate); KY-06531
20 mL 바이알에 산 화합물(200 mg, 0.47 mmol), L-알라닌 메틸 에스테르 하이드로클로라이드(2.0 당량, 131 mg), HBTU(3.0 당량, 535 mg), DIPEA(3.0 당량, 0.25 mL), DMF(1.5 mL)를 넣고 40℃에서 16시간 동안 반응시켰다. 반응종료 후, EA와 H2O로 3회 추출하고 유기층을 포화 탄산나트륨 수용액으로 세척한 후, MgSO4로 건조시켰다. 실리카겔컬럼을 수행한 후 감압 농축하고, MC/에테르/헥산으로 고체화한 후 신터로 여과하여 흰색 고체로 표제 화합물(131 mg, 55%)을 수득하였다.20 mL vials with acid compound (200 mg, 0.47 mmol), L-alanine methyl ester hydrochloride (2.0 equiv, 131 mg), HBTU (3.0 equiv, 535 mg), DIPEA (3.0 equiv, 0.25 mL), DMF (1.5 mL) was added and reacted at 40 ° C. for 16 hours. After completion of the reaction, the mixture was extracted three times with EA and H 2 O, and the organic layer was washed with a saturated aqueous sodium carbonate solution and dried over MgSO 4 . The silica gel column was then concentrated under reduced pressure, solidified with MC / ether / hexane, filtered through sinter to give the title compound (131 mg, 55%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 7.93 (s, 1H), 7.85 7.74 (m, 4H), 7.53-7.49 (m, 4H), 7.44-7.35 (m, 2H), 6.99 (d, J = 3.9 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H) 4.78 (q, J = 7.2, 1H), 1.53 (d, J = 7.1 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.52 (s, 1H), 7.93 (s, 1H), 7.85 7.74 (m, 4H), 7.53-7.49 (m, 4H), 7.44-7.35 (m, 2H) , 6.99 (d, J = 3.9 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H) 4.78 (q, J = 7.2, 1H), 1.53 (d, J = 7.1 Hz, 3H).
실시예Example 105. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-D-알라닌((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)-D-alanine); KY-06532 105. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine ((3- (3- ( 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine); KY-06532
7 mL 바이알에 에스테르 화합물(100 mg, 0.19 mmol), LiOH(2.0 당량, 16 mg), THF(1 mL), H2O(1 mL)을 넣고 상온에서 20시간 동안 교반하였다. 반응종료 후, 50 mL 둥근바닥플라스크에 옮겨 회전증발기로 THF를 제거하였다. 잔여물은 에테르:H2O=1:2 혼합용매로 세척하였다. pH 페이퍼를 이용하여 물층이 pH 8인 것을 확인한 후, 1N HCl을 첨가하면서 pH를 2 내지 3으로 맞추었다. 1N HCl 혼합물을 EA로 추출한 후 감압농축하였다. MC/헥산 혼합용매로 고체화한 후 신터로 여과하고, 실리카겔 컬럼을 수행한 후 감압 농축하여 흰색 고체 화합물로 표제 화합물(70 mg, 74%)을 수득하였다.Ester compound (100 mg, 0.19 mmol), LiOH (2.0 equiv, 16 mg), THF (1 mL), H 2 O (1 mL) were added to a 7 mL vial and stirred at room temperature for 20 hours. After completion of the reaction, transfer to a 50 mL round bottom flask to remove THF by rotary evaporator. The residue was washed with ether: H 2 O = 1: 2 mixed solvent. After confirming that the water layer was pH 8 using pH paper, the pH was adjusted to 2-3 while adding 1N HCl. The 1N HCl mixture was extracted with EA and concentrated under reduced pressure. Solidified with MC / hexane mixed solvent, filtered through sinter, silica gel column and concentrated under reduced pressure to give the title compound (70 mg, 74%) as a white solid compound.
1H NMR (300 MHz, DMSO) δ 12.54 (s, 1OH), 10.34 (s, 1NH), 9.22 (s, 1H), 8.68 (d, J = 7.3 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J = 7.9, 1H), 7.66-7.58 (m, 3H), 7.48 (t, J = 7.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 4.44 (q, J = 7.3 Hz, 1H), 1.41 (d, J = 7.3 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 12.54 (s, 1OH), 10.34 (s, 1NH), 9.22 (s, 1H), 8.68 (d, J = 7.3 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J = 7.9, 1H), 7.66-7.58 (m, 3H), 7.48 (t, J = 7.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 4.44 (q, J = 7.3 Hz, 1H), 1.41 (d, J = 7.3 Hz, 3H).
실시예Example 106. 디메틸 (3-(3-(5- 106. Dimethyl (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )벤조일)-L-아스파테이트(dimethyl (3-(3-(5-) Benzoyl) -L-aspartate (dimethyl (3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)-L-aspartate); KY-06533) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate); KY-06533
7 mL 바이알에 산 화합물(200 mg, 0.47 mmol), L-아스파르트산 디메틸 에스테르 하이드로클로라이드(2.0 당량, 140 mg), HBTU(3.0 당량, 535 mg), DIPEA(3.0 당량, 0.25 mL), DMF(1.5 mL)를 넣고 40℃에서 16시간 동안 반응시켰다. 반응종료 후, EA와 H2O로 3회 추출하고 유기층을 포화 탄산나트륨 수용액으로 세척한 후, MgSO4로 건조시켰다. 실리카겔컬럼을 수행한 후 감압 농축하고, MC/에테르/헥산으로 고체화한 후 신터로 여과하여 흰색 고체로 표제 화합물(126 mg, 47%)을 수득하였다.In a 7 mL vial acid compound (200 mg, 0.47 mmol), L-aspartic acid dimethyl ester hydrochloride (2.0 equiv, 140 mg), HBTU (3.0 equiv, 535 mg), DIPEA (3.0 equiv, 0.25 mL), DMF ( 1.5 mL) was added and reacted at 40 ° C. for 16 hours. After completion of the reaction, the mixture was extracted three times with EA and H 2 O, and the organic layer was washed with a saturated aqueous sodium carbonate solution and dried over MgSO 4 . After silica gel column was concentrated under reduced pressure, solidified with MC / ether / hexane and filtered through sinter to obtain the title compound (126 mg, 47%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.92-7.86 (m, 1H), 7.79-7.74 (m, 3H), 7.55-7.38 (m, 6H), 7.00 (d, J = 3.9 Hz, 1H), 5.05 (q, J = 4.2 Hz, 1H) 3.79 (s, 3H), 3.72 (s, 3H), 3.05 (ddd, J = 4.5, 17.1, 48.8, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.49 (s, 1H), 7.92-7.86 (m, 1H), 7.79-7.74 (m, 3H), 7.55-7.38 (m, 6H), 7.00 (d, J = 3.9 Hz, 1H), 5.05 (q, J = 4.2 Hz, 1H) 3.79 (s, 3H), 3.72 (s, 3H), 3.05 (ddd, J = 4.5, 17.1, 48.8, 2H).
실시예Example 107. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-아스파르트산((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)-L-aspartic acid); KY-06534 107. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid ((3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid); KY-06534
7 mL 바이알에 디에스테르 화합물(100 mg, 0.18 mmol), LiOH(2.0 당량, 15 mg), THF(1 mL), H2O(1 mL)을 넣고 상온에서 20시간 동안 교반하였다. 반응종료 후, 50 mL 둥근바닥플라스크에 옮겨 회전증발기(rotavapor)로 THF를 제거하였다. 잔여물은 에테르:H2O=1:2 혼합용매로 세척하였다. pH 페이퍼를 이용하여 물층이 pH 8인 것을 확인한 후, 1N HCl을 첨가하면서 pH를 3 내지 4로 맞추었다. 1N HCl 혼합물을 EA로 추출한 후 감압농축하였다. MC/헥산 혼합용매로 고체화한 후 에테르로 세척하며 신터로 여과하고, 실리카겔 컬럼을 수행한 후 감압 농축하여 흰색 고체 화합물로 표제 화합물(42 mg, 45%)을 수득하였다.The diester compound (100 mg, 0.18 mmol), LiOH (2.0 equiv, 15 mg), THF (1 mL), H 2 O (1 mL) were added to a 7 mL vial, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the THF was removed by a rotavapor by transferring to a 50 mL round bottom flask. The residue was washed with ether: H 2 O = 1: 2 mixed solvent. After confirming that the water layer was pH 8 by using pH paper, the pH was adjusted to 3 to 4 while adding 1N HCl. The 1N HCl mixture was extracted with EA and concentrated under reduced pressure. Solidified with MC / hexane mixed solvent, washed with ether, filtered with sinter, silica gel column and concentrated under reduced pressure to give the title compound (42 mg, 45%) as a white solid compound.
1H NMR (300 MHz, DMSO) δ 12.65 (s, 2OH), 10.36 (s, 1NH), 9.22 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.97-7.89 (m, 4H), 7.63-7.59 (m, 3H), 7.51-7.41 (m, 2H), 7.16 (d, J = 3.8 Hz, 1H), 4.77 (q, J = 6.6 Hz, 1H), 2.80 (ddd, J = 7.2, 16.3, 40.9 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 12.65 (s, 2OH), 10.36 (s, 1NH), 9.22 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.97-7.89 (m, 4H), 7.63-7.59 (m, 3H), 7.51-7.41 (m, 2H), 7.16 (d, J = 3.8 Hz, 1H), 4.77 (q, J = 6.6 Hz, 1H) , 2.80 (ddd, J = 7.2, 16.3, 40.9 Hz, 2H).
실시예Example 108. 4-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤젠설폰산(4-(1-(4-fluorophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzenesulfonic acid); KY-06535 108. 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid (4- (1- (4- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06535
KY-06531과 동일한 방법으로 합성하여 표제 화합물(58%)을 수득하였다.Synthesis in the same manner as KY-06531 gave the title compound (58%).
1H NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 9.13 (s, 1H), 9.79-7.92 (m, 3H), 7.68 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 7.8 Hz, 3H), 7.45 (t, J = 8.8 Hz, 2H), 7.13 (t, J = 4.4 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 9.13 (s, 1H), 9.79-7.92 (m, 3H), 7.68 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 7.8 Hz, 3H), 7.45 (t, J = 8.8 Hz, 2H), 7.13 (t, J = 4.4 Hz, 1H).
실시예Example 109. 에틸 (3-(3-(5- 109. Ethyl (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )벤조일)글리시네이트(ethyl (3-(3-(5-) Benzoyl) glycinate (ethyl (3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)glycinate); KY-06536) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate); KY-06536
7 mL 바이알에 산 화합물(200 mg, 0.47 mmol), 글리신 에틸 에스테르 하이드로클로라이드(2.0 당량, 140 mg), HBTU(3.0 당량, 535 mg), DIPEA(3.0 당량, 0.25 mL), DMF(1.5 mL)를 넣고 40℃에서 16시간 동안 반응시켰다. 반응종료 후, EA와 H2O로 3회 추출하고 유기층을 포화 탄산나트륨 수용액으로 세척한 후, MgSO4로 건조시켰다. 실리카겔컬럼을 수행한 후 감압 농축하고, MC/에테르/헥산으로 고체화한 후 신터로 여과하여 흰색 고체로 표제 화합물(92 mg, 38%)을 수득하였다.Acid compounds (200 mg, 0.47 mmol), glycine ethyl ester hydrochloride (2.0 equiv, 140 mg), HBTU (3.0 equiv, 535 mg), DIPEA (3.0 equiv, 0.25 mL), DMF (1.5 mL) in 7 mL vials Was added and reacted at 40 ° C. for 16 hours. After completion of the reaction, the mixture was extracted three times with EA and H 2 O, and the organic layer was washed with a saturated aqueous sodium carbonate solution and dried over MgSO 4 . The silica gel column was then concentrated under reduced pressure, solidified with MC / ether / hexane and filtered through sinter to give the title compound (92 mg, 38%) as a white solid.
1H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.22 (s, 1H), 8.93 (t, J = 5.5 Hz, 1H), 8.23 (s, 1H), 7.94-7.89 (m, 4H), 7.63-7.58 (m, 3H), 7.52-7.41 (m, 2H), 7.16 (d, J = 3.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.01 (d, J = 5.5 Hz, 2H), 1.22 (t, J = 7.1, 3H). 1 H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.22 (s, 1H), 8.93 (t, J = 5.5 Hz, 1H), 8.23 (s, 1H), 7.94-7.89 (m, 4H ), 7.63-7.58 (m, 3H), 7.52-7.41 (m, 2H), 7.16 (d, J = 3.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.01 (d, J = 5.5 Hz, 2H), 1.22 (t, J = 7.1, 3H).
실시예Example 110. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)글리신((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoyl)glycine); KY-06537 110. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine ((3- (3- (5-chlorothiophen -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine); KY-06537
7 mL 바이알에 디에스테르 화합물(60 mg, 0.12 mmol), LiOH(2.0 당량, 10 mg), THF(1 mL), H2O(1 mL)을 넣고 상온에서 20시간 동안 교반하였다. 반응종료 후, 50 mL 둥근바닥플라스크에 옮겨 회전증발기(rotavapor)로 THF를 제거하였다. 잔여물은 에테르:H2O=1:2 혼합용매로 세척하였다. pH 페이퍼를 이용하여 물층이 pH 8인 것을 확인한 후, 1N HCl을 첨가하면서 pH를 3으로 맞추었다. 1N HCl 혼합물을 EA로 추출한 후 감압농축하였다. MC/헥산 혼합용매로 고체화한 후 신터로 여과하여 흰색 고체 화합물로 표제 화합물(26 mg, 45%)을 수득하였다.A diester compound (60 mg, 0.12 mmol), LiOH (2.0 equiv, 10 mg), THF (1 mL), H 2 O (1 mL) were added to a 7 mL vial, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the THF was removed by a rotavapor by transferring to a 50 mL round bottom flask. The residue was washed with ether: H 2 O = 1: 2 mixed solvent. After confirming that the water layer was pH 8 using pH paper, the pH was adjusted to 3 while adding 1N HCl. The 1N HCl mixture was extracted with EA and concentrated under reduced pressure. Solidified with MC / hexane mixed solvent and filtered through sinter to give the title compound (26 mg, 45%) as a white solid compound.
1H NMR (300 MHz, DMSO) δ 12.59 (s, 1OH), 10.35 (s, 1NH), 9.23 (s, 1H), (s, 1H), 8.82 (s, 1H), 8.22 (s, 1H), 7.89 (s, 4H), 7.61 (s, 3H), 7.51-7.44 (m, 2H), 7.16 (s, 1H), 3.94 (s, 2H). 1 H NMR (300 MHz, DMSO) δ 12.59 (s, 1OH), 10.35 (s, 1NH), 9.23 (s, 1H), (s, 1H), 8.82 (s, 1H), 8.22 (s, 1H) , 7.89 (s, 4H), 7.61 (s, 3H), 7.51-7.44 (m, 2H), 7.16 (s, 1H), 3.94 (s, 2H).
실시예Example 111. 2-(4-((2-몰포리노에틸)카바모일)페닐)-N-(3-페녹시페닐)티아졸-5-카르복스아미드(2-(4-((2-morpholinoethyl)carbamoyl)phenyl)-N-(3-phenoxyphenyl)thiazole-5-carboxamide); KY-06538 111. 2- (4-((2-morpholinoethyl) carbamoyl) phenyl) -N- (3-phenoxyphenyl) thiazole-5-carboxamide (2- (4-((2-morpholinoethyl) carbamoyl) phenyl) -N- (3-phenoxyphenyl) thiazole-5-carboxamide); KY-06538
20 mL 바이알에 산 화합물(50 mg, 0.12 mmol), MC, TEA(0.12 mmol, 17 μL) DPPA(diphenylphosphorylazide, 0.11 mmol, 24 μL)를 넣고 30분 동안 교반한 후, 아민(0.18 mmol, 24 μL)를 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, 생성된 고체를 여과하고 헥산으로 세척한 후 건조시켜 표제 화합물(30 mg, 47%)을 수득하였다.Acid compound (50 mg, 0.12 mmol), MC, TEA (0.12 mmol, 17 μL) DPPA (diphenylphosphorylazide, 0.11 mmol, 24 μL) was added to a 20 mL vial and stirred for 30 minutes, followed by amine (0.18 mmol, 24 μL). ) And allowed to react overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed with hexane and dried to give the title compound (30 mg, 47%).
1H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 8.70 (s, 1H), 8.59 (t, 1H, J = 5.7 Hz), 8.11 (d, 2H, J = 8.1 Hz), 7.98 (d, 2H, J = 8.1 Hz), 7.59-7.50 (m, 1H), 7.48-7.33 (m, 4H), 7.18 (t, 1H, J = 7.4 Hz), 7.07 (d, 2H, J = 8.0 Hz), 6.87-6.74 (m, 1H), 3.57 (t, 4H, J = 4.5 Hz), 3.41 (q, 2H, J = 6.6 Hz), 2.48-2.27 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 8.70 (s, 1H), 8.59 (t, 1H, J = 5.7 Hz), 8.11 (d, 2H, J = 8.1 Hz), 7.98 ( d, 2H, J = 8.1 Hz), 7.59-7.50 (m, 1H), 7.48-7.33 (m, 4H), 7.18 (t, 1H, J = 7.4 Hz), 7.07 (d, 2H, J = 8.0 Hz ), 6.87-6.74 (m, 1H), 3.57 (t, 4H, J = 4.5 Hz), 3.41 (q, 2H, J = 6.6 Hz), 2.48-2.27 (m, 6H).
실시예Example 112. 3-(5-((4- 112. 3- (5-((4- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((4-phenoxyphenyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06539) Thiazol-2-yl) benzoic acid (3- (5-((4-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06539
20 mL 바이알에 에스테르 화합물(43 mg, 0.1 mmol), THF/H2O/MeOH 혼합 용매를 넣고 교반하였다. LiOH(21 mg, 0.5 mmol)을 넣고 상온에서 15시간 동안 교반하였다. 반응종료 후, 1N HCl을 가하여 pH 2 내지 3에 맞추고 EA와 H2O로 추출하였다. 유기층을 MgSO4로 건조시킨 후 농축하고, 고체를 여과하여 표제 화합물(23.1 mg, 56%)을 수득하였다.Ester compound (43 mg, 0.1 mmol) and THF / H 2 O / MeOH mixed solvent were added and stirred in a 20 mL vial. LiOH (21 mg, 0.5 mmol) was added thereto and stirred at room temperature for 15 hours. After completion of the reaction, 1N HCl was added, adjusted to pH 2-3 and extracted with EA and H 2 O. The organic layer was dried over MgSO 4 , concentrated and the solid was filtered to give the title compound (23.1 mg, 56%).
1H NMR (300 MHz, DMSO) δ 13.33 (s, 1H), 10.54 (s, 1H), 8.71 (s, 1H), 8.55 (t, 1H, J = 1.7 Hz), 8.25 (t, 1H, J = 7.8 Hz), 8.09 (t, 1H, J = 7.7 Hz), 7.83-7.60 (m, 3H), 7.48-7.28 (m, 2H), 7.25-6.90 (m, 5H). 1 H NMR (300 MHz, DMSO) δ 13.33 (s, 1H), 10.54 (s, 1H), 8.71 (s, 1H), 8.55 (t, 1H, J = 1.7 Hz), 8.25 (t, 1H, J = 7.8 Hz), 8.09 (t, 1H, J = 7.7 Hz), 7.83-7.60 (m, 3H), 7.48-7.28 (m, 2H), 7.25-6.90 (m, 5H).
실시예Example 113.  113. 메틸methyl 3- 3- (2-(2- (4-(4- 페녹시페닐Phenoxyphenyl )티아졸-5-Thiazole-5- 카르복스아미도Carcassamido )) 벤조에이트Benzoate (methyl 3-(2-(4-phenoxyphenyl)thiazole-5-carboxamido)benzoate); KY-06540(methyl 3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoate); KY-06540
5 mL 마이크로웨이브용 바이알에 브롬화 화합물(100 mg, 0.27 mmol), 브롬산(bronic acid, 72.8 mg, 0.34 mmol), K3PO4(101.0 mg, 0.46 mmol), Pd2(dba)3(25.6 mg, 0.028 mmol), PCy3HBF4(30.9 mg, 0.084 mmol)를 글러브박스에서 넣고, 질소를 바늘로 꽂아 디옥산과 H2O를 넣은 뒤, 100℃에서 밤새도록 반응시켰다. 반응종료 후, 셀라이트 여과하여 농축하고, EA와 H2O로 추출하였다. 유기층을 MgSO4로 건조시킨 후 다시 농축하였다. 실리카겔 컬럼크로마토그래피를 통해 분리 정제하여 표제 화합물(43.8 mg, 18%, 100 mg 2회 반응)을 수득하였다.Bromine compounds (100 mg, 0.27 mmol), bromic acid (72.8 mg, 0.34 mmol), K 3 PO 4 (101.0 mg, 0.46 mmol), Pd 2 (dba) 3 (25.6) in 5 mL microwave vials mg, 0.028 mmol) and PCy 3 HBF 4 (30.9 mg, 0.084 mmol) were put in a glovebox, nitrogen was inserted through a needle, dioxane and H 2 O were added, and reacted at 100 ° C. overnight. After completion of the reaction, the mixture was filtered through celite, concentrated, and extracted with EA and H 2 O. The organic layer was dried over MgSO 4 and concentrated again. Separation and purification through silica gel column chromatography gave the title compound (43.8 mg, 18%, 100 mg twice).
1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.0 (s, 1H), 8.06-8.00 (m, 1H), 7.98-7.91 (m, 2H), 7.90-7.80 (m, 2H), 7.43 (t, 3H, J = 7.9 Hz), 7.19 (t, 1H, J = 7.4 Hz), 7.07-7.03 (m, 4H), 4.39 (q, 2H, J = 7.1 Hz), 1.40 (t, 3H, J = 7.1 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 8.29 (s, 1H), 8.0 (s, 1H), 8.06-8.00 (m, 1H), 7.98-7.91 (m, 2H), 7.90-7.80 (m, 2H ), 7.43 (t, 3H, J = 7.9 Hz), 7.19 (t, 1H, J = 7.4 Hz), 7.07-7.03 (m, 4H), 4.39 (q, 2H, J = 7.1 Hz), 1.40 (t , 3H, J = 7.1 Hz).
실시예Example 114. 3-(2-(4- 114. 3- (2- (4- 페녹시페닐Phenoxyphenyl )티아졸-5-Thiazole-5- 카르복스아미도Carcassamido )벤조산(3-(2-(4-phenoxyphenyl)thiazole-5-carboxamido)benzoic acid); KY-06541) Benzoic acid (3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoic acid); KY-06541
KY-06539와 동일한 방법으로 합성하여 표제 화합물(58%)을 수득하였다.Synthesis in the same manner as KY-06539 afforded the title compound (58%).
1H NMR (300 MHz, DMSO) δ 13.03 (s, 2H), 10.62 (s, 1H), 9.32 (s, 1H), 8.72 (s, 1H), 8.33-8.28 (m, 2H), 8.02-7.97 (m, 2H), 7.70 (d, 2H, J = 7.7 Hz), 7.50 (t, 2H, J = 7.9 Hz). 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 2H), 10.62 (s, 1H), 9.32 (s, 1H), 8.72 (s, 1H), 8.33-8.28 (m, 2H), 8.02-7.97 (m, 2H), 7.70 (d, 2H, J = 7.7 Hz), 7.50 (t, 2H, J = 7.9 Hz).
실시예Example 115.  115. 메틸methyl (4-(5-((3- (4- (5-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조일Benzoyl )-L-) -L- 트립토파네이트Tryptophanate (methyl (4-(5-((3-(methyl (4- (5-((3- phenoxyphenylphenoxyphenyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )) benzoylbenzoyl )-L-tryptophanate); KY-06542) -L-tryptophanate); KY-06542
L-트립토판 메틸 에스테르 하이드로클로라이드 대신에 D-트립토판 메틸 에스테르 하이드로클로라이드를 사용하는 것을 제외하고는 실시예 104와 동일한 방법으로 반응시켜 표제 화합물(70 mg, 95%)을 수득하였다.The reaction was carried out in the same manner as in Example 104, except that D-tryptophan methyl ester hydrochloride was used instead of L-tryptophan methyl ester hydrochloride to give the title compound (70 mg, 95%).
1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 8.54 (d, 1H, J = 2.5 Hz), 8.18 (s, 1H), 7.75-7.63 (m, 2H), 7.58-7.50 (m, 3H), 7.48-7.40 (m, 2H), 7.36-7.25 (m, 4H), 7.21-6.97 (m, 6H), 6.90 (d, 1H, J = 7.6 Hz), 6.80 (d, 1H, J = 2.4 Hz), 5.10 (t, 1H, J = 7.6 Hz), 3.73 (s, 3H), 3.53-3.29 (m, 2H), 2.81 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.54 (d, 1H, J = 2.5 Hz), 8.18 (s, 1H), 7.75-7.63 (m, 2H), 7.58-7.50 ( m, 3H), 7.48-7.40 (m, 2H), 7.36-7.25 (m, 4H), 7.21-6.97 (m, 6H), 6.90 (d, 1H, J = 7.6 Hz), 6.80 (d, 1H, J = 2.4 Hz), 5.10 (t, 1H, J = 7.6 Hz), 3.73 (s, 3H), 3.53-3.29 (m, 2H), 2.81 (s, 2H).
실시예Example 116. (4-(5-((3- 116. (4- (5-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조일Benzoyl )-L-트립토판((4-(5-((3-phenoxyphenyl)carbamoyl)thiazol-2-yl)benzoyl)-L-tryptophan); KY-06543 ) -L-tryptophan ((4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan); KY-06543
KY-06539와 동일한 방법으로 합성하여 표제 화합물(58%)을 수득하였다.Synthesis in the same manner as KY-06539 afforded the title compound (58%).
1H NMR (300 MHz, DMSO) δ 12.76 (s, 1H), 10.82 (s, 1H), 10.55 (s, 1H), 8.86 (d, 1H, J = 7.8 Hz), 8.70 (s, 1H), 8.19-8.07 (m, 2H), 8.04-7.91 (m, 2H), 7.59-7.44 (m, 2H), 7.43-7.31 (m, 5H), 7.21-7.18 (m, 2H), 7.09-6.99 (m, 4H), 6.81 (d, 1H, J = 8.0 Hz), 4.67 (d, 1H, J = 10.6 Hz), 3.31-3.27 (m, 3H). 1 H NMR (300 MHz, DMSO) δ 12.76 (s, 1H), 10.82 (s, 1H), 10.55 (s, 1H), 8.86 (d, 1H, J = 7.8 Hz), 8.70 (s, 1H), 8.19-8.07 (m, 2H), 8.04-7.91 (m, 2H), 7.59-7.44 (m, 2H), 7.43-7.31 (m, 5H), 7.21-7.18 (m, 2H), 7.09-6.99 (m , 4H), 6.81 (d, 1H, J = 8.0 Hz), 4.67 (d, 1H, J = 10.6 Hz), 3.31-3.27 (m, 3H).
실시예Example 117. 3-(5-클로로티오펜-2-일)-N-(3-((2-몰포리노에틸)카바모일)페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-N-(3-((2-morpholinoethyl)carbamoyl)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide); KY-06544 117. 3- (5-chlorothiophen-2-yl) -N- (3-((2-morpholinoethyl) carbamoyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide ( 3- (5-chlorothiophen-2-yl) -N- (3-((2-morpholinoethyl) carbamoyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide); KY-06544
L-알라닌 메틸 에스테르 하이드로클로라이드 대신 2-모폴리노에탄올-1-아민(2-morpholinoethan-1-amine)을 사용한 것을 제외하고는 실시예 104와 동일한 방법으로 반응시켜 표제 화합물(250 mg, 99%)을 수득하였다.The title compound (250 mg, 99%) was reacted in the same manner as in Example 104, except that 2-morpholinoethan-1-amine was used instead of L-alanine methyl ester hydrochloride. ) Was obtained.
1H NMR (300 MHz, DMSO) δ 10.34 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 7.91-7.88 (m, 4H), 7.64-7.57 (m, 3H), 7.51-7.41 (m, 2H), 7.16 (d, J = 4.0 Hz, 1H), 3.66-3.49 (m, 4H), 1.28-1.22 (m, 8H). 1 H NMR (300 MHz, DMSO) δ 10.34 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 7.91-7.88 (m, 4H), 7.64-7.57 (m, 3H), 7.51-7.41 (m, 2H), 7.16 (d, J = 4.0 Hz, 1H), 3.66-3.49 (m, 4H), 1.28-1.22 (m, 8H).
실시예Example 118.  118. 메틸methyl 3-((3-(5- 3-((3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )메틸)벤조에이트(methyl 3-((3-(5-Methyl) benzoate (methyl 3-((3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)methyl)benzoate; KY-06545) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoate; KY-06545
50 mL 둥근바닥플라스크에 산 화합물(400 mg, 1.31 mmol), 3-아미노메틸 벤조산 메틸 에스테르(1.5 당량, 397 mg), HBTU(3.0 당량, 1.49 mg), DIPEA(3.0 당량, 0.69 mL), DMF(4 mL)를 넣고 40℃에서 교반하였다. 반응종료 후, EA와 H2O(2:1)로 추출하고 유기층을 포화 탄산나트륨 수용액으로 세척한 후, MgSO4로 건조시켰다. 감압 농축하여 실리카겔컬럼을 수행한 후 에테르로 초음파처리하여 고체화하여 흰색 고체로 표제 화합물(531 mg, 89%)을 수득하였다.Acid compound (400 mg, 1.31 mmol), 3-aminomethyl benzoic acid methyl ester (1.5 equiv, 397 mg), HBTU (3.0 equiv, 1.49 mg), DIPEA (3.0 equiv, 0.69 mL), DMF in a 50 mL round bottom flask (4 mL) was added and stirred at 40 ° C. After completion of the reaction, the mixture was extracted with EA and H 2 O (2: 1), and the organic layer was washed with a saturated aqueous sodium carbonate solution and dried over MgSO 4 . Concentration under reduced pressure was carried out to perform a silica gel column, followed by ultrasonication with ether to solidify to obtain the title compound (531 mg, 89%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.97 (s, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.51-7.42 (m, 5H), 7.36 (d, J = 3.9 Hz, 1H), 6.86 (d, J = 3.9 Hz, 1H), 6.36 (t, J = 5.5 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 3.93 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.39 (s, 1H), 7.97 (s, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.51-7.42 (m, 5H), 7.36 (d, J = 3.9 Hz, 1H), 6.86 (d, J = 3.9 Hz, 1H), 6.36 (t, J = 5.5 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 3.93 (s, 3H) .
실시예Example 119. 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조산(3-((3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)methyl)benzoic acid); KY-06546 119. 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoic acid (3-((3- (5-chlorothiophen -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoic acid); KY-06546
20 mL 바이알에 에스테르 화합물(461 mg, 1.09 mmol)을 THF(2 mL)에 용해시켜 교반하였다. H2O(2 mL)와 LiOH(5.0 당량, 228 mg)를 넣고 상온에서 20시간 동안 교반하였다. 반응종료 후, 50 mL 둥근바닥플라스크에 옮겨 회전증발기로 THF를 제거하였다. 잔여물은 에테르:H2O=1:2 혼합용매로 세척하였다. pH 페이퍼를 이용하여 물층이 pH 8인 것을 확인한 후, 1N HCl을 첨가하면서 pH를 2 내지 3으로 맞추었다. EA:1N HCl=2:1 혼합 용액으로 EA로 3회 추출한 후 MgSO4로 건조시켜 감압 농축하여 흰색 고체 화합물로 표제 화합물(396 mg, 81%)을 수득하였다.The ester compound (461 mg, 1.09 mmol) was dissolved in THF (2 mL) in a 20 mL vial and stirred. H 2 O (2 mL) and LiOH (5.0 equiv, 228 mg) were added and stirred at room temperature for 20 hours. After completion of the reaction, transfer to a 50 mL round bottom flask to remove THF by rotary evaporator. The residue was washed with ether: H 2 O = 1: 2 mixed solvent. After confirming that the water layer was pH 8 using pH paper, the pH was adjusted to 2-3 while adding 1N HCl. Extracted with EA three times with EA: 1N HCl = 2: 1 mixed solution, dried over MgSO 4 , and concentrated under reduced pressure to obtain the title compound (396 mg, 81%) as a white solid compound.
1H NMR (300 MHz, DMSO) δ 12.97 (s, 1OH), 9.04 (s, 1H), 8.90 (t, J = 5.4 Hz, 1H), 7.96-7.92 (m, 2H), 7.86-7.83 (m, 3H), 7.64-7.55 (m, 3H) 7.49 (t, J = 7.6, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.11 (s, 1), 4.54 (d, J = 5.1 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 12.97 (s, 1OH), 9.04 (s, 1H), 8.90 (t, J = 5.4 Hz, 1H), 7.96-7.92 (m, 2H), 7.86-7.83 (m , 3H), 7.64-7.55 (m, 3H) 7.49 (t, J = 7.6, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.11 (s, 1), 4.54 (d, J = 5.1 Hz , 2H).
실시예Example 120.  120. 메틸methyl (3-((3-(5- (3-((3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )메틸)벤조일)-D-알라니네이트(methyl (3-((3-(5-Methyl) benzoyl) -D-alanine (methyl (3-((3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)methyl)benzoyl)-D-alaninate); KY-06547) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alaninate); KY-06547
50 mL 둥근바닥플라스크에 산 화합물(350 mg, 0.80 mmol), L-알라닌 메틸 에스테르 하이드로클로라이드(1.6 당량, 223 mg), HBTU(3.0 당량, 910 mg), DIPEA(3.0 당량, 0.42 mL), DMF(2.5 mL)를 넣고 40℃에서 교반하였다. 반응종료 후, EA와 H2O(2:1)로 추출하고 유기층을 포화 탄산나트륨 수용액으로 세척한 후, MgSO4로 건조시켰다. 감압 농축하여 실리카겔컬럼을 수행한 후 에테르로 초음파처리하여 고체화하여 흰색 고체로 표제 화합물(335 mg, 80%)을 수득하였다.Acid compound (350 mg, 0.80 mmol), L-alanine methyl ester hydrochloride (1.6 equiv, 223 mg), HBTU (3.0 equiv, 910 mg), DIPEA (3.0 equiv, 0.42 mL), DMF in a 50 mL round bottom flask (2.5 mL) was added and stirred at 40 ° C. After completion of the reaction, the mixture was extracted with EA and H 2 O (2: 1), and the organic layer was washed with a saturated aqueous sodium carbonate solution and dried over MgSO 4 . After concentration under reduced pressure, silica gel column was subjected to sonication with ether to solidify to obtain the title compound (335 mg, 80%) as a white solid.
1H NMR (300 MHz, DMSO) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.81 (d, J = 6.1 Hz, 1H), 7.93-7.79 (m, 6H), 7.58-7.55 (m, 3H), 7.49-7.38 (m, 2H), 7.11 (s, 1H), 4.55-4.47 (m, 3H), 3.64 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.81 (d, J = 6.1 Hz, 1H), 7.93-7.79 (m, 6H), 7.58-7.55 (m , 3H), 7.49-7.38 (m, 2H), 7.11 (s, 1H), 4.55-4.47 (m, 3H), 3.64 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H).
실시예Example 121. (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조일)-D-알라닌((3-((3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)methyl)benzoyl)-D-alanine); KY-06548 121. (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alanine ((3- ( (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alanine); KY-06548
20 mL 바이알에 에스테르 화합물(250 mg)을 THF(2 mL), H2O(2 mL)을 넣고 교반한 후, LiOH(40 mg)를 넣고 상온에서 교반하였다. 반응종료 후, THF를 제거하고 에테르를 더하여 증류수로 세척하였다. pH를 3으로 맞추어 EtOAc로 추출한 후 MgSO4로 건조한 후 용매를 제거하여 흰색 고체 화합물로 표제 화합물(171 mg, 70%)을 수득하였다.In a 20 mL vial, an ester compound (250 mg) was added with THF (2 mL) and H 2 O (2 mL), followed by stirring. Then, LiOH (40 mg) was added thereto and stirred at room temperature. After completion of the reaction, THF was removed, ether was added, and the mixture was washed with distilled water. The pH was adjusted to 3, extracted with EtOAc, dried over MgSO 4 and the solvent removed to give the title compound (171 mg, 70%) as a white solid compound.
1H NMR (300 MHz, DMSO) δ 12.49 (s, 1H), 9.05 (s, 1H), 8.86 (s, 1H), 8.66 (d, J = 5.8 Hz, 1H), 7.93-7.79 (m, 5H), 7.60-7.39 (m, 5H), 7.12 (d, J = 2.5 Hz, 1H), 4.54 (d, J = 4.3 Hz, 2H), 4.42 (t, J = 7.3 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 12.49 (s, 1H), 9.05 (s, 1H), 8.86 (s, 1H), 8.66 (d, J = 5.8 Hz, 1H), 7.93-7.79 (m, 5H ), 7.60-7.39 (m, 5H), 7.12 (d, J = 2.5 Hz, 1H), 4.54 (d, J = 4.3 Hz, 2H), 4.42 (t, J = 7.3 Hz, 1H), 1.40 (d , J = 6.8 Hz, 3H).
실시예Example 122.  122. 메틸methyl 3-(3-(5- 3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조에이트(methyl 3-(3-(5-) -5-fluorobenzoate (methyl 3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoate); KY-06549) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate); KY-06549
KY-06545와 동일한 방법으로 합성하여 표제 화합물(26%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (26%).
1H NMR (300 MHz, CDCl3) δ 8.49(s, 1H),7.89(d, J = 8.1 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.63 (s, 1H), 7.54-7.37 (m, 5H), 7.26 (s, 1H), 7.01 (d, J = 0.3 Hz, 1H), 3.93 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.49 (s, 1 H), 7.89 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.63 (s, 1H), 7.54 -7.37 (m, 5H), 7.26 (s, 1H), 7.01 (d, J = 0.3 Hz, 1H), 3.93 (s, 3H).
실시예Example 123. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조산(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoic acid); KY-06550 123. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid (3- (3- (5- chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid); KY-06550
KY-06546과 동일한 방법으로 합성하여 표제 화합물(53%)을 수득하였다.Synthesis in the same manner as KY-06546 gave the title compound (53%).
1H NMR (300 MHz, DMSO) δ 13.36 (s, 1H), 10.55 (s, 1H), 9.24 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 10.8 Hz, 1H), 7.91-7.88 (m, 3H), 7.61 (t, J = 7.2 Hz, 2H), 7.47-7.40 (m, 2H), 7.17 (d, J = 2.6 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.36 (s, 1H), 10.55 (s, 1H), 9.24 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 10.8 Hz, 1H), 7.91-7.88 (m, 3H), 7.61 (t, J = 7.2 Hz, 2H), 7.47-7.40 (m, 2H), 7.17 (d, J = 2.6 Hz, 1H).
실시예Example 124.  124. 메틸methyl (3-(3-(5- (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조일)-L-트립토파네이트(methyl (3-(3-(5-) -5-fluorobenzoyl) -L-tryptophanate (methyl (3- (3- (5- chlorothiophenchlorothiophen -2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-tryptophanate); KY-06551-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophanate); KY-06551
KY-06545와 동일한 방법으로 합성하여 표제 화합물(69%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (69%).
1H NMR (300 MHz, DMSO) δ 10.85 (s. 1H), 10.51 (s, 1H), 9.22 (s, 1H), 8.93 (d, J = 7.5 Hz, 1H), 7.91-7.87 (m, 5H), 7.63-7.56 (m, 3H), 7.46-7.44 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 7.07 (t, J = 6.6 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 4.71 (q, J = 7.4 Hz, 1H), 3.65 (s, 3H), 3.26 (d, J = 10.4 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 10.85 (s. 1H), 10.51 (s, 1H), 9.22 (s, 1H), 8.93 (d, J = 7.5 Hz, 1H), 7.91-7.87 (m, 5H ), 7.63-7.56 (m, 3H), 7.46-7.44 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 7.07 (t, J = 6.6 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 4.71 (q, J = 7.4 Hz, 1H), 3.65 (s, 3H), 3.26 (d, J = 10.4 Hz, 2H) .
실시예Example 125. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-트립토판((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-tryptophan); KY-06552 125. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophan ((3 -(3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophan); KY-06552
KY-06546과 동일한 방법으로 합성하여 표제 화합물(93%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (93%).
1H NMR (300 MHz, DMSO) δ 10.82 (s. 1H), 10.53 (s, 1H), 9.23 (s, 1H), 8.73 (d, J = 3.8 Hz, 1H), 7.93 (d, J = 6.7 Hz, 1H), 7.90-7.88 (m, 4H), 7.61-7.60 (m, 3H), 7.45-7.42 (m, 2H), 7.33 (d, J = 4.8 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 1.7 Hz, 1H), 7.07 (t, J = 4.5 Hz, 1H), 6.99 (t, J = 4.5 Hz, 1H), 4.66 (s, 1H), 3.22 (q, J = 4.9 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 10.82 (s. 1H), 10.53 (s, 1H), 9.23 (s, 1H), 8.73 (d, J = 3.8 Hz, 1H), 7.93 (d, J = 6.7 Hz, 1H), 7.90-7.88 (m, 4H), 7.61-7.60 (m, 3H), 7.45-7.42 (m, 2H), 7.33 (d, J = 4.8 Hz, 1H), 7.21 (s, 1H) , 7.16 (d, J = 1.7 Hz, 1H), 7.07 (t, J = 4.5 Hz, 1H), 6.99 (t, J = 4.5 Hz, 1H), 4.66 (s, 1H), 3.22 (q, J = 4.9 Hz, 2H).
실시예Example 126. (S)-3-(5-클로로티오펜-2-일)-N-(3-((1-((2-몰포리노에틸)아미노)-1-옥소프로판-2-일)카바모일)페닐)-1-페닐-1H-피라졸-4-카르복스아미드((S)-3-(5-chlorothiophen-2-yl)-N-(3-((1-((2-morpholinoethyl)amino)-1-oxopropan-2-yl)carbamoyl)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide); KY-06553 126. (S) -3- (5-chlorothiophen-2-yl) -N- (3-((1-((2-morpholinoethyl) amino) -1-oxopropan-2-yl) carba Moyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide ((S) -3- (5-chlorothiophen-2-yl) -N- (3-((1-((2-morpholinoethyl ) amino) -1-oxopropan-2-yl) carbamoyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide); KY-06553
KY-06545와 동일한 방법으로 합성하여 표제 화합물(47%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (47%).
1H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.22 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 7.94-7.89 (m, 5H), 7.68 (d, J = 7.3 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.50-7.41 (m, 2H), 7.15 (d, J = 2.2 Hz, 1H), 4.45 (qui, J = 8.0 Hz, 1H), 3.56 (s, 4H), 3.23 (s, 2H), 2.92 (s, 2H), 2.38 (d, J = 16.4 Hz, 4H), 1.35 (d, J = 6.9 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.22 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 7.94-7.89 (m, 5H ), 7.68 (d, J = 7.3 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.50-7.41 (m, 2H), 7.15 (d, J = 2.2 Hz, 1H), 4.45 (qui , J = 8.0 Hz, 1H), 3.56 (s, 4H), 3.23 (s, 2H), 2.92 (s, 2H), 2.38 (d, J = 16.4 Hz, 4H), 1.35 (d, J = 6.9 Hz , 3H).
실시예Example 127. 에틸 3-(3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트(ethyl 3-(3-( 127. Ethyl 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate thiophenthiophen -2--2- ylyl )-1H-) -1H- pyrazolepyrazole -4--4- carboxamidocarboxamido )benzoate); KY-06554) benzoate); KY-06554
KY-06545와 동일한 방법으로 합성하여 표제 화합물(47%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (47%).
1H NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 13.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.52-7.49 (m, 2H), 7.08 (s, 1H), 4.34 (q, J = 7.3 Hz, 2H), 1.34 (t, J = 6.8 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 13.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.52-7.49 (m, 2H), 7.08 (s, 1H), 4.34 (q, J = 7.3 Hz, 2H), 1.34 (t, J = 6.8 Hz, 3H).
실시예Example 128. 3-(3-(티오펜-2-일)-1H- 128. 3- (3- (thiophen-2-yl) -1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )벤조산(3-(3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid); KY-06555) Benzoic acid (3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid); KY-06555
KY-06546과 동일한 방법으로 합성하여 표제 화합물(80%)을 수득하였다.Synthesis in the same manner as KY-06546 gave the title compound (80%).
1H NMR (300 MHz, DMSO) δ 13.30 (s. 1H), 10.14 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.10 (s, 1H). 1 H NMR (300 MHz, DMSO) δ 13.30 (s. 1H), 10.14 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.91 (s, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 2 H), 7.10 (s, 1 H).
실시예Example 129.  129. 메틸methyl 4- 4- (5-((피페리딘-4-일메틸)카바모일)(5-((piperidin-4-ylmethyl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 4-(5-(((methyl 4- (5-(( piperidinpiperidin -4--4- ylmethylylmethyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06556) benzoate); KY-06556
100 mL 둥근바닥플라스크에 N-Boc 화합물(329 mg, 0.72 mmol)을 MC(16 mL)에 용해시켰다. 상기 용액에 TFA(trifluoroacetic acid, 3.57 mmol, 0.27 mL)를 천천히 적가하여 상온에서 16시간 동안 반응시켰다. 반응종료 후, 용매를 제거하여 정량적으로 표제 화합물을 수득하였다.N-Boc compound (329 mg, 0.72 mmol) was dissolved in MC (16 mL) in a 100 mL round bottom flask. To the solution was slowly added dropwise TFA (trifluoroacetic acid, 3.57 mmol, 0.27 mL) was reacted for 16 hours at room temperature. After completion of the reaction, the solvent was removed to yield the title compound quantitatively.
1H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 8.23 (d, 2H, J = 8.3 Hz), 8.03-8.00 (m, 2H), 3.98 (s, 3H), 3.59 (d, 2H, J = 12.7 Hz), 3.47 (t, 2H, J = 6.1 Hz), 3.02 (d, 2H, J = 12.2 Hz), 2.05 (d, 3H, J = 14.1 Hz), 1.76-1.67 (m, 2H), 1.34 (s, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.82 (s, 1H), 8.23 (d, 2H, J = 8.3 Hz), 8.03-8.00 (m, 2H), 3.98 (s, 3H), 3.59 (d, 2H, J = 12.7 Hz), 3.47 (t, 2H, J = 6.1 Hz), 3.02 (d, 2H, J = 12.2 Hz), 2.05 (d, 3H, J = 14.1 Hz), 1.76-1.67 (m, 2H), 1.34 (s, 1 H).
실시예Example 130.  130. 메틸methyl 4- 4- (5-((피페리딘-4-일메틸)카바모일)(5-((piperidin-4-ylmethyl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 4-(5-(((methyl 4- (5-(( piperidinpiperidin -4--4- ylmethylylmethyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06557) benzoate); KY-06557
KY-06539와 동일한 방법으로 합성하여 표제 화합물(91%)을 수득하였다.Synthesis was carried out in the same manner as KY-06539 to give the title compound (91%).
1H NMR (300 MHz, DMSO) δ 8.57 (s, 1H), 8.09 (s, 4H), 3.22 (d, 4H, J = 14.9 Hz), 2.84-2.81 (m, 2H), 1.92-1.77 (m, 3H), 1.37 (d, 2H, J = 10.8 Hz). 1 H NMR (300 MHz, DMSO) δ 8.57 (s, 1H), 8.09 (s, 4H), 3.22 (d, 4H, J = 14.9 Hz), 2.84-2.81 (m, 2H), 1.92-1.77 (m , 3H), 1.37 (d, 2H, J = 10.8 Hz).
실시예Example 131.  131. 메틸methyl 4-(5-(((1- 4- (5-(((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 4-(5-(((1-) Thiazol-2-yl) benzoate (methyl 4- (5-(((1- benzoylpiperidinbenzoylpiperidin -4-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06558-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06558
100 mL 둥근바닥플라스크에 피페리딘 화합물(100 mg, 0.17 mmol), TEA(triethylamine, 2.04 mmol, 0.3 mL), DMA(2.6 mL)을 넣고 교반하였다. 상기 반응용액에 벤조일 클로라이드(benzoyl chloride, 0.2 mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, EA/H2O 혼합용매를 사용하여 추출하고 MgSO4로 건조하였다. 실리카겔 컬럼크로마토그래피로 분리 정제하여 표제 화합물(80%)을 수득하였다.Piperidine compound (100 mg, 0.17 mmol), TEA (triethylamine, 2.04 mmol, 0.3 mL) and DMA (2.6 mL) were added to a 100 mL round bottom flask and stirred. Benzoyl chloride (0.2 mmol) was added to the reaction solution and reacted at room temperature overnight. After completion of the reaction, the mixture was extracted using EA / H 2 O mixed solvent and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (80%).
1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 8.10 (d, 2H, J = 8.5 Hz), 7.99 (d, 2H, J = 8.3 Hz), 7.39-7.34 (m, 5H), 7.02 (t, 1H, J = 6.1 Hz), 4.71 (s, 1H), 3.94 (s, 3H), 3.72 (d, 1H, J = 20.7 Hz), 3.38-3.24 (m, 2H), 2.97-2.77 (m, 2H), 1.94-1.67 (m, 3H), 1.23 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.25 (s, 1H), 8.10 (d, 2H, J = 8.5 Hz), 7.99 (d, 2H, J = 8.3 Hz), 7.39-7.34 (m, 5H) , 7.02 (t, 1H, J = 6.1 Hz), 4.71 (s, 1H), 3.94 (s, 3H), 3.72 (d, 1H, J = 20.7 Hz), 3.38-3.24 (m, 2H), 2.97- 2.77 (m, 2H), 1.94-1.67 (m, 3H), 1.23 (s, 2H).
실시예Example 132. 4-(5-(((1- 132. 4- (5-(((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(4-(5-(((1-benzoylpiperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06559) Thiazol-2-yl) benzoic acid (4- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06559
KY-06539와 동일한 방법으로 합성하여 표제 화합물(76%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (76%).
1H NMR (300 MHz, DMSO) δ 8.84 (t, 1H, J = 5.8 Hz), 8.51 (s, 1H), 8.08 (q, 4H, J = 8.3 Hz), 7.45-7.35 (m, 5H), 4.47 (s, 1H), 3.20 (t, 3H, J = 6.3 Hz), 3.00 (s, 1H), 2.78 (s, 1H), 1.91-1.67 (m, 3H), 1.221.13 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 8.84 (t, 1H, J = 5.8 Hz), 8.51 (s, 1H), 8.08 (q, 4H, J = 8.3 Hz), 7.45-7.35 (m, 5H), 4.47 (s, 1H), 3.20 (t, 3H, J = 6.3 Hz), 3.00 (s, 1H), 2.78 (s, 1H), 1.91-1.67 (m, 3H), 1.221.13 (m, 2H) .
실시예Example 133.  133. 메틸methyl 4-(5-(((1-( 4- (5-(((1- ( 페닐카바모일Phenylcarbamoyl )피페리딘-4-일)Piperidin-4-yl) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 4-(5-(((1-() Thiazol-2-yl) benzoate (methyl 4- (5-(((1- ( phenylcarbamoylphenylcarbamoyl )) piperidinpiperidin -4-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06560-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06560
KY-06538과 동일한 방법으로 합성하여 표제 화합물(80%)을 수득하였다.Synthesis in the same manner as KY-06538 gave the title compound (80%).
1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 8.14 (d, 2H, J = 8.3 Hz), 8.04 (d, 2H, J = 8.3 Hz), 7.39-7.28 (m, 4H), 7.03 (t, 1H, J = 7.2 Hz), 6.34 (s, 1H), 6.17 (d, 1H, J = 6.3 Hz), 5.30 (s, 2H), 4.12 (d, 2H, J = 13.4 Hz), 3.96 (s, 3H), 3.40 (t, 2H, J = 6.3 Hz), 3.01-2.87 (m, 2H), 1.88 (t, 3H, J = 14.0 Hz), 1.36-1.25 (m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.21 (s, 1H), 8.14 (d, 2H, J = 8.3 Hz), 8.04 (d, 2H, J = 8.3 Hz), 7.39-7.28 (m, 4H) , 7.03 (t, 1H, J = 7.2 Hz), 6.34 (s, 1H), 6.17 (d, 1H, J = 6.3 Hz), 5.30 (s, 2H), 4.12 (d, 2H, J = 13.4 Hz) , 3.96 (s, 3H), 3.40 (t, 2H, J = 6.3 Hz), 3.01-2.87 (m, 2H), 1.88 (t, 3H, J = 14.0 Hz), 1.36-1.25 (m, 4H).
실시예Example 134. 4-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산(4-(5-(((1-(phenylcarbamoyl)piperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06561 134. 4- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid (4- (5-(((1- ( phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06561
KY-06539와 동일한 방법으로 합성하여 표제 화합물(20%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (20%).
1H NMR (300 MHz, DMSO) δ 8.85 (t, 1H, J = 5.8 Hz), 8.52 (d, 1H, J = 4.4 Hz), 8.45 (s, 1H), 8.12-8.04 (m, 4H), 7.44 (d, 2H, J = 7.7 Hz), 7.21 (t, 2H, J = 7.8 Hz), 6.91 (t, 1H, J = 7.3 Hz), 4.13 (d, 2H, J = 13.1 Hz), 3.19 (d, 2H, J = 6.2 Hz), 2.77 (t, 2H, J = 12.5 Hz), 1.78-1.70 (m, 3H), 1.23-1.07 (m, 3H). 1 H NMR (300 MHz, DMSO) δ 8.85 (t, 1H, J = 5.8 Hz), 8.52 (d, 1H, J = 4.4 Hz), 8.45 (s, 1H), 8.12-8.04 (m, 4H), 7.44 (d, 2H, J = 7.7 Hz), 7.21 (t, 2H, J = 7.8 Hz), 6.91 (t, 1H, J = 7.3 Hz), 4.13 (d, 2H, J = 13.1 Hz), 3.19 ( d, 2H, J = 6.2 Hz), 2.77 (t, 2H, J = 12.5 Hz), 1.78-1.70 (m, 3H), 1.23-1.07 (m, 3H).
실시예Example 135.  135. 메틸methyl 4-(5-(((1- 4- (5-(((1- 토실피페리딘Tosylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 4-(5-(((1-) Thiazol-2-yl) benzoate (methyl 4- (5-(((1- tosylpiperidintosylpiperidin -4--4- ylyl )methyl)methyl) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06562-2-yl) benzoate); KY-06562
KY-06538과 동일한 방법으로 합성하여 표제 화합물(78%)을 수득하였다.Synthesis in the same manner as KY-06538 gave the title compound (78%).
1H NMR (300 MHz, CDCl3) δ 8.35 (d, 2H, J = 8.2 Hz), 8.02 (d, 2H, J = 8.2 Hz), 7.63 (d, 2H, J = 7.9 Hz), 7.32 (d, 2H, J = 7.9 Hz), 6.11 (d, 1H, J = 6.8 Hz), 3.95 (s, 3H), 3.81 (d, 2H, J = 11.7 Hz), 3.32 (t, 2H, J = 6.4 Hz), 2.43 (s, 3H), 2.27 (t, 2H, J = 11.7 Hz), 1.81 (d, 2H, J = 12.8 Hz), 1.63 (s, 1H), 1.46-1.37 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.35 (d, 2H, J = 8.2 Hz), 8.02 (d, 2H, J = 8.2 Hz), 7.63 (d, 2H, J = 7.9 Hz), 7.32 (d , 2H, J = 7.9 Hz), 6.11 (d, 1H, J = 6.8 Hz), 3.95 (s, 3H), 3.81 (d, 2H, J = 11.7 Hz), 3.32 (t, 2H, J = 6.4 Hz ), 2.43 (s, 3H), 2.27 (t, 2H, J = 11.7 Hz), 1.81 (d, 2H, J = 12.8 Hz), 1.63 (s, 1H), 1.46-1.37 (m, 2H).
실시예Example 136. 4-(5-(((1- 136. 4- (5-(((1- 토실피페리딘Tosylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(4-(5-(((1-tosylpiperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06563) Thiazol-2-yl) benzoic acid (4- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06563
KY-06539와 동일한 방법으로 합성하여 표제 화합물(20%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (20%).
1H NMR (300 MHz, DMSO) δ 8.77 (t, 1H, J = 5.8 Hz), 8.49 (d, 1H, J = 11.8 Hz), 8.07 (q, 4H, J = 7.7 Hz), 7.61 (d, 2H, J = 7.9 Hz), 7.43 (d, 2H, J = 8.2 Hz), 3.61 (d, 3H, J = 11.6 Hz), 3.13 (q, 2H, J = 6.0 Hz), 2.40 (d, 3H, J = 7.2 Hz), 2.21 (t, 2H, J = 11.2 Hz), 1.73 (d, 2H, J = 13.0 Hz), 1.51 (s, 1H), 1.20 (q, 2H, J = 11.4 Hz). 1 H NMR (300 MHz, DMSO) δ 8.77 (t, 1H, J = 5.8 Hz), 8.49 (d, 1H, J = 11.8 Hz), 8.07 (q, 4H, J = 7.7 Hz), 7.61 (d, 2H, J = 7.9 Hz), 7.43 (d, 2H, J = 8.2 Hz), 3.61 (d, 3H, J = 11.6 Hz), 3.13 (q, 2H, J = 6.0 Hz), 2.40 (d, 3H, J = 7.2 Hz), 2.21 (t, 2H, J = 11.2 Hz), 1.73 (d, 2H, J = 13.0 Hz), 1.51 (s, 1H), 1.20 (q, 2H, J = 11.4 Hz).
실시예Example 137.  137. 메틸methyl 3- 3- (5-((1-벤질피페리딘-4-일)카바모일)(5-((1-benzylpiperidin-4-yl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-((1-(methyl 3- (5-((1- benzylpiperidinbenzylpiperidin -4--4- ylyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06564) benzoate); KY-06564
5 mL 마이크로웨이브용 바이알에 브롬화 화합물(100 mg, 0.26 mmol), 브롬산(56.8 mg, 0.32 mmol), K3PO4(93.8 mg, 0.44 mmol), Pd2(dba)3(23.8 mg, 0.026 mmol), PCy3HBF4(23 mg, 0.062 mmol)를 글러브박스에서 넣고, 질소를 바늘로 꽂아 디옥산과 H2O를 넣은 뒤, 100℃에서 밤새도록 반응시켰다(3회 반복). 반응종료 후, 셀라이트 여과하여 농축하고, EA와 H2O로 추출하였다. 유기층을 MgSO4로 건조시킨 후 다시 농축하였다. 실리카겔 컬럼크로마토그래피를 통해 분리 정제하여 표제 화합물(170.3 mg, 50%)을 수득하였다.Bromination compound (100 mg, 0.26 mmol), bromic acid (56.8 mg, 0.32 mmol), K 3 PO 4 (93.8 mg, 0.44 mmol), Pd 2 (dba) 3 (23.8 mg, 0.026) in a 5 mL microwave vial mmol) and PCy 3 HBF 4 (23 mg, 0.062 mmol) were added in a glovebox, nitrogen was inserted into the needle, dioxane and H 2 O were added, and the reaction was continued at 100 ° C. overnight (repeated three times). After completion of the reaction, the mixture was filtered through celite, concentrated, and extracted with EA and H 2 O. The organic layer was dried over MgSO 4 and concentrated again. Separation and purification through silica gel column chromatography gave the title compound (170.3 mg, 50%).
1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (t, 3H, J = 7.8 Hz), 7.50 (t, 1H, J = 7.8 Hz), 7.27 (s, 3H), 7.20 (s, 2H), 5.78 (d, 1H, J = 7.9 Hz), 3.90 (s, 3H), 3.47 (s, 2H), 2.82 (d, 2H, J = 11.3 Hz), 2.12 (t, 2H, J = 11.6 Hz), 2.00-1.95 (m, 2H), 1.59-1.51 (m, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.54 (s, 1H), 8.09 (t, 3H, J = 7.8 Hz), 7.50 (t, 1H, J = 7.8 Hz), 7.27 (s, 3H), 7.20 (s, 2H), 5.78 (d, 1H, J = 7.9 Hz), 3.90 (s, 3H), 3.47 (s, 2H), 2.82 (d, 2H, J = 11.3 Hz), 2.12 (t, 2H, J = 11.6 Hz), 2.00-1.95 (m, 2H), 1.59-1.51 (m, 3H).
실시예Example 138. 3-(5-((1- 138. 3- (5-((1- 벤질피페리딘Benzylpiperidine -4-일)-4- days) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((1-benzylpiperidin-4-yl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06565) Thiazol-2-yl) benzoic acid (3- (5-((1-benzylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06565
KY-06539와 동일한 방법으로 합성하여 표제 화합물(20%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (20%).
1H NMR (300 MHz, DMSO) δ 8.80 (s, 1H), 8.52 (d, 2H, J = 8.0 Hz), 8.21 (d, 1H, J = 7.9 Hz), 8.08 (d, 1H, J = 7.7 Hz), 7.67 (t, 1H, J = 7.8 Hz), 7.50 (d, 5H, J = 14.1 Hz), 4.26 (s, 2H), 3.97 (s, 1H), 3.07 (s, 2H), 2.04 (s, 3H), 1.82 (s, 2H), 1.25 (s, 1H). 1 H NMR (300 MHz, DMSO) δ 8.80 (s, 1H), 8.52 (d, 2H, J = 8.0 Hz), 8.21 (d, 1H, J = 7.9 Hz), 8.08 (d, 1H, J = 7.7 Hz), 7.67 (t, 1H, J = 7.8 Hz), 7.50 (d, 5H, J = 14.1 Hz), 4.26 (s, 2H), 3.97 (s, 1H), 3.07 (s, 2H), 2.04 ( s, 3H), 1.82 (s, 2H), 1.25 (s, 1H).
실시예Example 139.  139. 메틸methyl 3- 3- (5-((피페리딘-4-일메틸)카바모일)(5-((piperidin-4-ylmethyl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-(((methyl 3- (5-(( piperidinpiperidin -4--4- ylmethylylmethyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06566) benzoate); KY-06566
100 mL 둥근바닥플라스크에 N-Boc 화합물(396 mg, 0.84 mmol)을 MC(16 mL)에 용해시켰다. 상기 용액에 TFA(4.2 mmol, 0.32 mL)를 천천히 적가하여 상온에서 16시간 동안 반응시켰다. 반응종료 후, 용매를 농축하고 고진공으로 잔여 용매를 제거하여 정량적으로 표제 화합물을 수득하였다.N-Boc compound (396 mg, 0.84 mmol) was dissolved in MC (16 mL) in a 100 mL round bottom flask. TFA (4.2 mmol, 0.32 mL) was slowly added dropwise to the solution and reacted at room temperature for 16 hours. After completion of the reaction, the solvent was concentrated and the residual solvent was removed by high vacuum to quantitatively obtain the title compound.
1H NMR (300 MHz, CDCl3) δ 8.60 (d, 2H, J = 8.3 Hz), 8.23-8.10 (m, 2H) 7.68 (s, 1H), 3.96 (s, 3H), 3.56-3.44 (m, 4H), 3.00 (s, 2H), 2.03 (s, 3H), 1.66-1.56 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.60 (d, 2H, J = 8.3 Hz), 8.23-8.10 (m, 2H) 7.68 (s, 1H), 3.96 (s, 3H), 3.56-3.44 (m , 4H), 3.00 (s, 2H), 2.03 (s, 3H), 1.66-1.56 (m, 2H).
실시예Example 140. 3-(5-((피페리딘-4- 140. 3- (5-((piperidine-4- 일메틸Methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((piperidin-4-ylmethyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06567) Thiazol-2-yl) benzoic acid (3- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06567
20 mL 바이알에 에스테르 화합물(150 mg, 0.26 mmol), THF/H2O/MeOH 혼합 용매를 넣고 교반하였다. LiOH·H2O(109.1 mg, 2.6 mmol)을 넣고 상온에서 18시간 동안 반응시켰다. 반응종료 후, 1N HCl을 가하여 pH 2 내지 3에 맞추고 IPA(isopropyl alcohol)/CHCl3을 사용하여 물층에서 추출하였다. 유기층을 MgSO4로 건조시킨 후 농축하여 표제 화합물(163 mg)을 수득하였다.Ester compound (150 mg, 0.26 mmol) and THF / H 2 O / MeOH mixed solvent were added and stirred in a 20 mL vial. LiOH.H 2 O (109.1 mg, 2.6 mmol) was added and reacted at room temperature for 18 hours. After completion of the reaction, 1N HCl was added, adjusted to pH 2-3, and extracted from the water layer using IPA (isopropyl alcohol) / CHCl 3 . The organic layer was dried over MgSO 4 and concentrated to give the title compound (163 mg).
1H NMR (300 MHz, DMSO) δ 8.98 (t, 1H, J = 5.8 Hz), 8.53 (d, 2H, J = 14.1 Hz), 8.20 (d, 1H, J = 7.9 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 3.20 (d, 4H, J =7.5 Hz), 2.91-2.75 (m, 2H), 1.82 (d, 3H, J = 11.4 Hz), 1.38 (d, 2H, J = 11.1 Hz). 1 H NMR (300 MHz, DMSO) δ 8.98 (t, 1H, J = 5.8 Hz), 8.53 (d, 2H, J = 14.1 Hz), 8.20 (d, 1H, J = 7.9 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 3.20 (d, 4H, J = 7.5 Hz), 2.91-2.75 (m, 2H), 1.82 (d, 3H, J = 11.4 Hz), 1.38 (d, 2H, J = 11.1 Hz).
실시예Example 141.  141. 메틸methyl 3-(5-(((1- 3- (5-(((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- benzoylpiperidinbenzoylpiperidin -4-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06568-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06568
100 mL 둥근바닥플라스크에 피페리딘 화합물(100 mg, 0.17 mmol), TEA(2.04 mmol, 0.3 mL), DMA(2.6 mL)을 넣고 교반하였다. 상기 반응용액에 벤조일클로라이드(0.2 mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, EA/H2O 혼합용매를 사용하여 추출하고 MgSO4로 건조하였다. 실리카겔 컬럼크로마토그래피로 분리 정제하여 표제 화합물(84%)을 수득하였다.Piperidine compound (100 mg, 0.17 mmol), TEA (2.04 mmol, 0.3 mL) and DMA (2.6 mL) were added to a 100 mL round bottom flask and stirred. Benzoyl chloride (0.2 mmol) was added to the reaction solution and reacted at room temperature overnight. After completion of the reaction, the mixture was extracted using EA / H 2 O mixed solvent and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (84%).
1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.20-8.14 (m, 3H), 7.56 (t, 1H, J = 7.8 Hz), 7.39 (s, 5H), 6.31 (d, 1H, J = 6.0 Hz), 3.96 (d, 3H, J = 2.6 Hz), 3.37 (s, 2H), 2.97 (d, 4H, J = 2.5 Hz), 2.81 (s, 1H), 1.92-1.74 (m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.60 (s, 1H), 8.20-8.14 (m, 3H), 7.56 (t, 1H, J = 7.8 Hz), 7.39 (s, 5H), 6.31 (d, 1H, J = 6.0 Hz), 3.96 (d, 3H, J = 2.6 Hz), 3.37 (s, 2H), 2.97 (d, 4H, J = 2.5 Hz), 2.81 (s, 1H), 1.92-1.74 ( m, 4H).
실시예Example 142. 3-(5-(((1- 142. 3- (5-(((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-benzoylpiperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06569) Thiazol-2-yl) benzoic acid (3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06569
7 mL 바이알에 메틸 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트(63 mg, 0.14 mmol), THF/H2O/MeOH 혼합 용매를 넣고 교반하였다. LiOH·H2O(28.5 mg, 0.68 mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, 1N HCl을 가하여 pH 2 내지 3에 맞추고 EA와 H2O를 사용하여 추출하였다. 유기층을 MgSO4로 건조시킨 후 농축하고 고체를 여과하여 표제 화합물(87%)을 수득하였다.In a 7 mL vial methyl 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate (63 mg, 0.14 mmol), THF / H 2 O / MeOH mixed solvent was added and stirred. LiOH.H 2 O (28.5 mg, 0.68 mmol) was added and allowed to react overnight at room temperature. After completion of the reaction, 1N HCl was added to adjust the pH to 2-3 and extracted using EA and H 2 O. The organic layer was dried over MgSO 4 , concentrated and the solid was filtered to give the title compound (87%).
1H NMR (300 MHz, DMSO) δ 8.83 (t, 1H, J = 5.8 Hz), 8.50 (d, 2H, J = 3.5 Hz), 8.21-8.18 (m, 1H), 8.07 (d, 1H, J = 7.7 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.50-7.35 (m, 5H), 3.19 (t, 3H, J = 6.4 Hz), 2.84-2.73 (m, 2H), 1.91-1.65 (m, 3H), 1.22-1.14 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 8.83 (t, 1H, J = 5.8 Hz), 8.50 (d, 2H, J = 3.5 Hz), 8.21-8.18 (m, 1H), 8.07 (d, 1H, J = 7.7 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.50-7.35 (m, 5H), 3.19 (t, 3H, J = 6.4 Hz), 2.84-2.73 (m, 2H), 1.91-1.65 (m, 3 H), 1.22-1.14 (m, 2 H).
실시예Example 143.  143. 메틸methyl 3-(5-(((1-( 3- (5-(((1- ( 페닐카바모일Phenylcarbamoyl )피페리딘-4-일)Piperidin-4-yl) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-() Thiazol-2-yl) benzoate (methyl 3- (5-(((1- ( phenylcarbamoylphenylcarbamoyl )) piperidinpiperidin -4-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06570-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06570
KY-06568과 동일한 방법으로 합성하여 표제 화합물(98%)을 수득하였다.Synthesis in the same manner as KY-06568 gave the title compound (98%).
1H NMR (300 MHz, CDCl3) δ 8.60 (d, 1H, J = 2.2 Hz), 8.22 (d, 1H, J = 1.1 Hz), 8.15 (t, 2H, J = 6.0 Hz), 7.55 (t, 2H, J = 7.0 Hz), 7.35-7.29 (m, 4H), 7.02 (t, 1H, J = 7.1 Hz), 6.50-6.44 (m, 2H), 3.96 (s, 3H), 3.39-3.35 (m, 2H), 3.01 (s, 2H), 2.92 (d, 3H, J = 11.9 Hz), 1.86 (t, 3H, J = 13.2 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 8.60 (d, 1H, J = 2.2 Hz), 8.22 (d, 1H, J = 1.1 Hz), 8.15 (t, 2H, J = 6.0 Hz), 7.55 (t , 2H, J = 7.0 Hz), 7.35-7.29 (m, 4H), 7.02 (t, 1H, J = 7.1 Hz), 6.50-6.44 (m, 2H), 3.96 (s, 3H), 3.39-3.35 ( m, 2H), 3.01 (s, 2H), 2.92 (d, 3H, J = 11.9 Hz), 1.86 (t, 3H, J = 13.2 Hz).
실시예Example 144. 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산(3-(5-(((1-(phenylcarbamoyl)piperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06571 144. 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid (3- (5-(((1- ( phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06571
KY-06569와 동일한 방법으로 합성하여 표제 화합물(75%)을 수득하였다.Synthesis was performed in the same manner as KY-06569 to give the title compound (75%).
1H NMR (300 MHz, DMSO) δ 8.84 (t, 1H, J = 5.8 Hz), 8.48 (d, 3H, J = 15.9 Hz), 8.23-8.20 (m, 2H), 8.06 (d, 1H, J = 5.8 Hz), 7.67 (t, 1H, J = 7.8 Hz), 7.45 (d, 2H, J = 8.0 Hz), 7.21 (t, 2H, J = 7.8 Hz), 6.91 (t, 1H, J = 7.3 Hz), 4.15-3.99 (m, 2H), 3.20 (t, 3H, J = 6.1 Hz), 2.78 (t, 2H, J = 11.1 Hz), 1.82-1.70 (m, 3H), 1.23-1.07 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 8.84 (t, 1H, J = 5.8 Hz), 8.48 (d, 3H, J = 15.9 Hz), 8.23-8.20 (m, 2H), 8.06 (d, 1H, J = 5.8 Hz), 7.67 (t, 1H, J = 7.8 Hz), 7.45 (d, 2H, J = 8.0 Hz), 7.21 (t, 2H, J = 7.8 Hz), 6.91 (t, 1H, J = 7.3 Hz), 4.15-3.99 (m, 2H), 3.20 (t, 3H, J = 6.1 Hz), 2.78 (t, 2H, J = 11.1 Hz), 1.82-1.70 (m, 3H), 1.23-1.07 (m , 2H).
실시예Example 145.  145. 메틸methyl 3-(5-(((1- 3- (5-(((1- 토실피페리딘Tosylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- tosylpiperidintosylpiperidin -4--4- ylyl )methyl)methyl) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06572-2-yl) benzoate); KY-06572
KY-06568과 동일한 방법으로 합성하여 표제 화합물(92%)을 수득하였다.Synthesis was performed in the same manner as KY-06568 to give the title compound (92%).
1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.17-8.13 (m, 3H), 7.64-7.53 (m, 3H), 7.31 (d, 2H, J = 7.9 Hz), 6.25-6.20 (m, 1H), 3.96 (s, 3H), 3.80 (d, 2H, J = 11.6 Hz), 3.31 (t, 2H, J = 6.4 Hz), 2.43 (s, 3H), 2.24 (t, 2H, J = 11.6 Hz), 1.81 (d, 2H, J = 12.6 Hz), 1.65 (d, 1H, J = 12.4 Hz), 1.45-1.33 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.59 (s, 1H), 8.17-8.13 (m, 3H), 7.64-7.53 (m, 3H), 7.31 (d, 2H, J = 7.9 Hz), 6.25- 6.20 (m, 1H), 3.96 (s, 3H), 3.80 (d, 2H, J = 11.6 Hz), 3.31 (t, 2H, J = 6.4 Hz), 2.43 (s, 3H), 2.24 (t, 2H , J = 11.6 Hz), 1.81 (d, 2H, J = 12.6 Hz), 1.65 (d, 1H, J = 12.4 Hz), 1.45-1.33 (m, 2H).
실시예Example 146. 3-(5-(((1- 146. 3- (5-(((1- 토실피페리딘Tosylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-tosylpiperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06573) Thiazol-2-yl) benzoic acid (3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06573
KY-06569와 동일한 방법으로 합성하여 표제 화합물(97%)을 수득하였다.Synthesis in the same manner as KY-06569 gave the title compound (97%).
1H NMR (300 MHz, DMSO) δ 8.75 (t, 1H, J = 5.8 Hz), 8.50 (d, 1H, J = 1.9 Hz), 8.46 (s, 1H), 8.21-8.18 (m, 1H), 8.07 (d, 1H, J = 7.7 Hz), 7.68-7.60 (m, 3H), 7.43 (d, 2H, J = 8.0 Hz), 3.65-3.58 (m, 3H), 3.12 (t, 2H, J = 6.2 Hz), 2.39 (s, 3H), 2.26-2.17 (t, 2H, J = 2.6 Hz), 1.73 (d, 2H, J = 3.8 Hz), 1.54-1.46 (m, 1H), 1.27-1.14 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 8.75 (t, 1H, J = 5.8 Hz), 8.50 (d, 1H, J = 1.9 Hz), 8.46 (s, 1H), 8.21-8.18 (m, 1H), 8.07 (d, 1H, J = 7.7 Hz), 7.68-7.60 (m, 3H), 7.43 (d, 2H, J = 8.0 Hz), 3.65-3.58 (m, 3H), 3.12 (t, 2H, J = 6.2 Hz), 2.39 (s, 3H), 2.26-2.17 (t, 2H, J = 2.6 Hz), 1.73 (d, 2H, J = 3.8 Hz), 1.54-1.46 (m, 1H), 1.27-1.14 ( m, 2H).
실시예Example 147.  147. 메틸methyl 3-(3-(5- 3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-(트리플루오로메틸)벤조에이트(methyl 3-(3-(5-) -5- (trifluoromethyl) benzoate (methyl 3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)-5-(trifluoromethyl)benzoate); KY-06574) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoate); KY-06574
KY-06545와 동일한 방법으로 합성하여 표제 화합물(21%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (21%).
1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.54-7.37 (m, 4H), 7.01 (s, 1H), 3.97 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.54-7.37 (m, 4H), 7.01 (s, 1H), 3.97 (s, 3H).
실시예Example 148. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-(트리플루오로메틸)벤조산(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-(trifluoromethyl)benzoic acid); KY-06575 148. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoic acid (3- (3 -(5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoic acid); KY-06575
KY-06546과 동일한 방법으로 합성하여 표제 화합물(98%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (98%).
1H NMR (300 MHz, DMSO) δ 13.60 (s, 1H), 10.65 (s, 1H), 9.27 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 7.91-7.87 (m, 4H), 7.62 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.17 (s, 1H). 1 H NMR (300 MHz, DMSO) δ 13.60 (s, 1H), 10.65 (s, 1H), 9.27 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 7.91-7.87 (m , 4H), 7.62 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.17 (s, 1H).
실시예Example 149.  149. 메틸methyl 3- 3- 클로로Chloro -5-(3-(5--5- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)벤조에이트(methyl 3-4-carboxamido) benzoate (methyl 3- chlorochloro -5-(3-(5--5- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)benzoate); KY-06576) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate); KY-06576
KY-06545와 동일한 방법으로 합성하여 표제 화합물(32%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (32%).
1H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 9.25 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.91-7.88 (m, 3H), 7.67 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.17 (d, J = 3.9 Hz, 1H), 3.90 (s, 1H). 1 H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 9.25 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.91-7.88 (m, 3H), 7.67 (s , 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.17 (d, J = 3.9 Hz, 1H), 3.90 (s, 1H).
실시예Example 150. 3-클로로-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-chloro-5-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid); KY-06577 150. 3-Chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3-chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid); KY-06577
KY-06546과 동일한 방법으로 합성하여 표제 화합물(97%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (97%).
1H NMR (300 MHz, DMSO) δ 13.41 (s, 1H), 10.51 (s, 1H), 9.24 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 7.90-7.88 (m, 3H), 7.64-7.59 (m, 3H), 7.44 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 3.2 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.41 (s, 1H), 10.51 (s, 1H), 9.24 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 7.90-7.88 (m , 3H), 7.64-7.59 (m, 3H), 7.44 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 3.2 Hz, 1H).
실시예Example 151.  151. 메틸methyl 3- 3- 브로모Bromo -5-(3-(5--5- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)벤조에이트(methyl 3-4-carboxamido) benzoate (methyl 3- bromobromo -5-(3-(5--5- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)benzoate); KY-06578) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate); KY-06578
KY-06545와 동일한 방법으로 합성하여 표제 화합물(33%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (33%).
1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.89 (s, 2H), 7.75 (d, J = 7.9 Hz, 2H), 7.53 (t, J = 7.8 Hz, 2H), 7.48 (d, J = 3.8 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 3.9 Hz, 1H), 3.94 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.49 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.89 (s, 2H), 7.75 (d, J = 7.9 Hz, 2H) , 7.53 (t, J = 7.8 Hz, 2H), 7.48 (d, J = 3.8 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 3.9 Hz, 1H), 3.94 (s, 3 H).
실시예Example 152. 3-브로모-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-bromo-5-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid); KY-06579 152. 3-Bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3-bromo-5- (3 -(5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid); KY-06579
KY-06546과 동일한 방법으로 합성하여 표제 화합물(98%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (98%).
1H NMR (300 MHz, DMSO) δ 13.44 (s, 1H), 10.49 (s, 1H), 9.24 (s, 1H), 8.31 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 6.0 Hz, 3H), 7.78 (s, 1H), 7.61 (t, J = 7.8 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 2.9 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.44 (s, 1H), 10.49 (s, 1H), 9.24 (s, 1H), 8.31 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 6.0 Hz, 3H), 7.78 (s, 1H), 7.61 (t, J = 7.8 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 2.9 Hz, 1H).
실시예Example 153.  153. 메틸methyl 2-(3-(3-(5- 2- (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )페닐)아세테이트(methyl 2-(3-(3-(5-) Phenyl) acetate (methyl 2- (3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)phenyl)acetate); KY-06580) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetate); KY-06580
KY-06545와 동일한 방법으로 합성하여 표제 화합물(79%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (79%).
1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.76 (d, J = 7.7 Hz, 3H), 7.55-7.47 (m, 4H), 7.40 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 3.8 Hz, 1H), 3.73 (s, 3H), 3.66 (s, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.47 (s, 1H), 7.76 (d, J = 7.7 Hz, 3H), 7.55-7.47 (m, 4H), 7.40 (t, J = 7.5 Hz, 2H) , 7.32 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 3.8 Hz, 1H), 3.73 (s, 3H), 3.66 (s, 2H) .
실시예Example 154. 2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세트산(2-(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)phenyl)acetic acid); KY-06581 154. 2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetic acid (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetic acid); KY-06581
KY-06546과 동일한 방법으로 합성하여 표제 화합물(96%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (96%).
1H NMR (300 MHz, DMSO) δ 12.34 (s, 1H), 10.19 (s, 1H), 9.18 (s, 1H), 7.91-7.88 (m, 3H), 7.64-7.58 (m, 4H), 7.43 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.16 (s, 1H), 7.02 (d, J = 7.3 Hz, 1H), 3.58 (s, 2H). 1 H NMR (300 MHz, DMSO) δ 12.34 (s, 1H), 10.19 (s, 1H), 9.18 (s, 1H), 7.91-7.88 (m, 3H), 7.64-7.58 (m, 4H), 7.43 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.16 (s, 1H), 7.02 (d, J = 7.3 Hz, 1H), 3.58 (s, 2H).
실시예Example 155.  155. 메틸methyl (2-(3-(3-(5- (2- (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )페닐)아세틸)-L-트립토파네이트(methyl (2-(3-(3-(5-(Phenyl) acetyl) -L-tryptophanate (methyl (2- (3- (3- (5- chlorothiophenchlorothiophen -2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)phenyl)acetyl)-L-tryptophanate); KY-06582-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophanate); KY-06582
KY-06545와 동일한 방법으로 합성하여 표제 화합물(70%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (70%).
1H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 10.16 (s, 1H), 9.17 (s, 1H), 8.55 (d, J = 7.2 Hz, 1H), 7.90-7.87 (m, 3H), 7.62 -7.57 (m, 4H), 7.49 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.13 (s, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.01-6.92 (m, 2H), 4.54 (q, J = 7.3 Hz, 1H), 3.57 (s, 3H), 3.48 (s, 2H), 3.13 (qd, J = 7.3, 29.3 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 10.16 (s, 1H), 9.17 (s, 1H), 8.55 (d, J = 7.2 Hz, 1H), 7.90-7.87 (m, 3H ), 7.62 -7.57 (m, 4H), 7.49 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.26 (t , J = 7.7 Hz, 1H), 7.13 (s, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.01-6.92 (m, 2H), 4.54 (q, J = 7.3 Hz, 1H), 3.57 (s, 3H), 3.48 (s, 2H), 3.13 (qd, J = 7.3, 29.3 Hz, 2H).
실시예Example 156. (2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세틸)-L-트립토판((2-(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)phenyl)acetyl)-L-tryptophan); KY-06583 156. (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophan ((2 -(3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophan); KY-06583
KY-06546과 동일한 방법으로 합성하여 표제 화합물(21%)을 수득하였다.Synthesis in the same manner as KY-06546 gave the title compound (21%).
1H NMR (300 MHz, DMSO) δ 10.82 (s, 1H), 10.16 (s, 1H), 9.17 (s, 1H), 8.35 (d, J = 7.5 Hz, 1H), 7.90-7.87 (m, 3H), 7.62 -7.57 (m, 4H), 7.53 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.12 (s, 2H), 7.05 (t, J = 7.3 Hz, 1H), 7.00-6.91 (m, 2H), 4.49 (q, J = 8.0 Hz, 1H), 3.47 (s, 2H), 3.22-3.01 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 10.82 (s, 1H), 10.16 (s, 1H), 9.17 (s, 1H), 8.35 (d, J = 7.5 Hz, 1H), 7.90-7.87 (m, 3H ), 7.62 -7.57 (m, 4H), 7.53 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.24 (t , J = 7.7 Hz, 1H), 7.12 (s, 2H), 7.05 (t, J = 7.3 Hz, 1H), 7.00-6.91 (m, 2H), 4.49 (q, J = 8.0 Hz, 1H), 3.47 (s, 2H), 3.22-3.01 (m, 2H).
실시예Example 157. 에틸 3-(3-(5- 157. Ethyl 3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-4-(-2-yl) -4- ( 페닐카바모일Phenylcarbamoyl )-1H-) -1H- 피라졸Pyrazole -1-일)벤조에이트(ethyl 3-(3-(5--1-yl) benzoate (ethyl 3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-4-()-4-( phenylcarbamoylphenylcarbamoyl )-1H-pyrazol-1-yl)benzoate); KY-06584) -1H-pyrazol-1-yl) benzoate); KY-06584
KY-06545와 동일한 방법으로 합성하여 표제 화합물(70%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (70%).
1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.38 (s, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.05-8.02 (m, 1H), 7.75 (s, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 4.1 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.18 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 3.9 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.58 (s, 1H), 8.38 (s, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.05-8.02 (m, 1H), 7.75 (s, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 4.1 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H) , 7.18 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 3.9 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H).
실시예Example 158. 3-(3-(5-클로로티오펜-2-일)-4-(페닐카바모일)-1H-피라졸-1-일)벤조산(3-(3-(5-chlorothiophen-2-yl)-4-(phenylcarbamoyl)-1H-pyrazol-1-yl)benzoic acid); KY-06585 158. 3- (3- (5-chlorothiophen-2-yl) -4- (phenylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid (3- (3- (5-chlorothiophen-2- yl) -4- (phenylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid); KY-06585
KY-06546과 동일한 방법으로 합성하여 표제 화합물(96%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (96%).
1H NMR (300 MHz, DMSO) δ 13.43 (s, 1H), 10.22 (s, 1H), 9.32 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.76-7.72 (m, 3H), 7.38 (t, J = 7.7 Hz, 2H), 7.17 (d, J = 3.9 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.43 (s, 1H), 10.22 (s, 1H), 9.32 (s, 1H), 8.42 (s, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.76-7.72 (m, 3H), 7.38 (t, J = 7.7 Hz, 2H), 7.17 (d, J = 3.9 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H).
실시예Example 159. 에틸 3-(4-((3- 159. Ethyl 3- (4-((3- 클로로페닐Chlorophenyl )) 카바모일Cabamo )-3-(5-) -3- (5- 클로로티오펜Chlorothiophene -2-일)-1H-피라졸-1-일)벤조에이트(ethyl 3-(4-((3--2-yl) -1H-pyrazol-1-yl) benzoate (ethyl 3- (4-((3- chlorophenylchlorophenyl )) carbamoylcarbamoyl )-3-(5-chlorothiophen-2-yl)-1H-pyrazol-1-yl)benzoate); KY-06586) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate); KY-06586
KY-06545와 동일한 방법으로 합성하여 표제 화합물을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound.
1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.35 (s, 1H), 8.05-7.97 (m, 2H), 7.75-7.57 (m, 3H), 7.47 (s, 1H), 7.30 (s, 1H), 7.14 (s, 1H), 7.01 (s, 1H), 4.44 (q, J = 7.3 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (s, 1H), 8.35 (s, 1H), 8.05-7.97 (m, 2H), 7.75-7.57 (m, 3H), 7.47 (s, 1H), 7.30 (s, 1 H), 7.14 (s, 1 H), 7.01 (s, 1 H), 4.44 (q, J = 7.3 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H).
실시예Example 160. 3-(4-((3-클로로페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산(3-(4-((3-chlorophenyl)carbamoyl)-3-(5-chlorothiophen-2-yl)-1H-pyrazol-1-yl)benzoic acid); KY-06587 160. 3- (4-((3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid (3- (4-(( 3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid); KY-06587
KY-06546과 동일한 방법으로 합성하여 표제 화합물(87%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (87%).
1H NMR (300 MHz, DMSO) δ 13.42 (s, 1H), 10.37 (s, 1H), 9.34 (s, 1H), 8.42 (s, 1H), 8.16 (dd, J = 1.5, 8.1 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.21-7.16 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 13.42 (s, 1H), 10.37 (s, 1H), 9.34 (s, 1H), 8.42 (s, 1H), 8.16 (dd, J = 1.5, 8.1 Hz, 1H ), 7.98 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.21-7.16 (m, 2H).
실시예Example 161. 에틸 3-(3-(5- 161.Ethyl 3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-4-((3--2-yl) -4-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )-1H-피라졸-1-일)벤조에이트(ethyl 3-(3-(5-) -1H-pyrazol-1-yl) benzoate (ethyl 3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-4-((3-phenoxyphenyl)carbamoyl)-1H-pyrazol-1-yl)benzoate); KY-06588) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate); KY-06588
KY-06545와 동일한 방법으로 합성하여 표제 화합물(78%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (78%).
1H NMR (300 MHz, DMSO) δ 10.31 (s, 1H), 9.35 (s, 1H), 8.48 (s, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 4.1 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.45-7.36 (m, 3H), 7.22-7.12 (m, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.79 (dd, J = 2.2, 7.9 Hz, 1H) 4.40 (q, J = 7.0 Hz, 2H), 1.37 (d, J = 7.1 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 10.31 (s, 1H), 9.35 (s, 1H), 8.48 (s, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 4.1 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.45-7.36 (m, 3H), 7.22-7.12 (m, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.79 (dd, J = 2.2, 7.9 Hz, 1H) 4.40 (q, J = 7.0 Hz, 2H), 1.37 (d, J = 7.1 Hz, 3H).
실시예Example 162. 3-(3-(5-클로로티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조산(3-(3-(5-chlorothiophen-2-yl)-4-((3-phenoxyphenyl)carbamoyl)-1H-pyrazol-1-yl)benzoic acid); KY-06589 162. 3- (3- (5-chlorothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid (3- (3- ( 5-chlorothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid); KY-06589
KY-06546과 동일한 방법으로 합성하여 표제 화합물(53%)을 수득하였다.Synthesis in the same manner as KY-06546 gave the title compound (53%).
1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 9.29 (s,1H), 8.40 (s, 1H), 8.10 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.69 (t, J = 7.3 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.43-7.35 (m, 4H), 7.15 (m, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.78 (d, J = 9.2 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 9.29 (s, 1H), 8.40 (s, 1H), 8.10 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.69 (t, J = 7.3 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.43-7.35 (m, 4H), 7.15 (m, 2H ), 7.07 (d, J = 7.8 Hz, 2H), 6.78 (d, J = 9.2 Hz, 1H).
실시예Example 163.  163. 메틸methyl (3-(5-((3- (3- (5-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조일Benzoyl )-L-) -L- 트립토파네이트Tryptophanate (methyl (3-(5-((3-(methyl (3- (5-((3- phenoxyphenylphenoxyphenyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )) benzoylbenzoyl )-L-tryptophanate); KY-06590) -L-tryptophanate); KY-06590
KY-06542와 동일한 방법으로 합성하여 표제 화합물(95%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (95%).
1H NMR (300 MHz, CDCl3) δ 8.76 (d, 1H, J = 1.9 Hz), 8.56 (s, 1H), 8.19 (s, 1H), 8.11 (t, 1H, J = 1.8 Hz), 7.87 (d, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 7.8 Hz), 7.54-7.46 (m, 2H), 7.42 (d, 1H, J = 2.4 Hz), 7.34-7.30 (m, 5H), 7.13-7.02 (m, 7H), 6.83-6.79 (m, 1H), 5.15 (q, 1H, J = 6.1 Hz), 3.52-3.37 (m, 2H), 2.79 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.76 (d, 1H, J = 1.9 Hz), 8.56 (s, 1H), 8.19 (s, 1H), 8.11 (t, 1H, J = 1.8 Hz), 7.87 (d, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 7.8 Hz), 7.54-7.46 (m, 2H), 7.42 (d, 1H, J = 2.4 Hz), 7.34-7.30 (m, 5H), 7.13-7.02 (m, 7H), 6.83-6.79 (m, 1H), 5.15 (q, 1H, J = 6.1 Hz), 3.52-3.37 (m, 2H), 2.79 (s, 3H).
실시예Example 164. (3-(5-((3- 164. (3- (5-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조일Benzoyl )-L-트립토판((3-(5-((3-phenoxyphenyl)carbamoyl)thiazol-2-yl)benzoyl)-L-tryptophan); KY-06591) -L-tryptophan ((3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan); KY-06591
KY-06539와 동일한 방법으로 합성하여 표제 화합물(62%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (62%).
1H NMR (300 MHz, DMSO) δ 10.83 (s, 1H), 10.55 (s, 1H), 8.99 (d, 1H, J = 7.8 Hz), 8.70 (s, 1H), 8.45 (s, 1H), 8.17 (d, 1H, J = 7.7 Hz), 7.98 (d, 1H, J = 7.8 Hz), 7.62 (t, 2H, J = 7.3 Hz), 7.54 (d, 1H, J = 8.3 Hz), 7.45-7.37 (m, 4H), 7.32 (d, 1H, J = 8.0 Hz), 7.21-7.15 (m, 2H), 7.08-6.98 (m, 4H), 6.83-6.80 (m, 1H), 4.71 (q, 1H, J = 5.1 Hz), 3.37-3.20 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 10.83 (s, 1H), 10.55 (s, 1H), 8.99 (d, 1H, J = 7.8 Hz), 8.70 (s, 1H), 8.45 (s, 1H), 8.17 (d, 1H, J = 7.7 Hz), 7.98 (d, 1H, J = 7.8 Hz), 7.62 (t, 2H, J = 7.3 Hz), 7.54 (d, 1H, J = 8.3 Hz), 7.45- 7.37 (m, 4H), 7.32 (d, 1H, J = 8.0 Hz), 7.21-7.15 (m, 2H), 7.08-6.98 (m, 4H), 6.83-6.80 (m, 1H), 4.71 (q, 1H, J = 5.1 Hz), 3.37-3.20 (m, 2H).
실시예Example 165.  165. 메틸methyl 3-(5-(((1- 3- (5-(((1- 아세틸피페리딘Acetylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- acetylpiperidinacetylpiperidin -4--4- ylyl )methyl)methyl) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06592-2-yl) benzoate); KY-06592
20 mL 바이알에 피페리딘 화합물(100 mg, 0.18 mmol), TFA(2.17 mmol, 0.3 mL), DMA(2.8 mL)을 넣고 교반하였다. 상기 반응용액에 아세틸클로라이드(0.22 mmol, 15 μL)를 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, EA/H2O 혼합용매를 사용하여 추출하고 MgSO4로 건조하였다. 실리카겔 컬럼크로마토그래피로 분리 정제하여 표제 화합물(54 mg, 75%)을 수득하였다.Piperidine compound (100 mg, 0.18 mmol), TFA (2.17 mmol, 0.3 mL) and DMA (2.8 mL) were added to a 20 mL vial and stirred. Acetyl chloride (0.22 mmol, 15 μL) was added to the reaction solution and reacted at room temperature overnight. After completion of the reaction, the mixture was extracted using EA / H 2 O mixed solvent and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (54 mg, 75%).
1H NMR (300 MHz, CDCl3) δ 8.55 (d, 1H, J = 6.7 Hz), 8.19-8.11 (m, 3H), 7.49 (t, 1H, J = 8.2 Hz), 4.96 (s, 1H), 4.07 (t, 1H, J = 6.1 Hz), 3.93 (s, 3H), 3.68-3.58 (m, 2H), 3.25-3.22 (m, 2H), 2.99 (d, 2H, J = 3.7 Hz), 2.91 (s, 3H), 2.08-2.01 (m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (d, 1H, J = 6.7 Hz), 8.19-8.11 (m, 3H), 7.49 (t, 1H, J = 8.2 Hz), 4.96 (s, 1H) , 4.07 (t, 1H, J = 6.1 Hz), 3.93 (s, 3H), 3.68-3.58 (m, 2H), 3.25-3.22 (m, 2H), 2.99 (d, 2H, J = 3.7 Hz), 2.91 (s, 3 H), 2.08-2.01 (m, 4 H).
실시예Example 166.  166. 메틸methyl 3-(5-(((1- 3- (5-(((1- 아세틸피페리딘Acetylpiperidine -2-일)-2 days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- acetylpiperidinacetylpiperidin -2--2- ylyl )methyl)methyl) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06593-2-yl) benzoate); KY-06593
KY-06592와 동일한 방법으로 합성하여 표제 화합물(71%)을 수득하였다.Synthesis in the same manner as KY-06592 afforded the title compound (71%).
1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.31 (d, 1H, J = 13.0 Hz), 8.13-8.07 (m, 2H), 7.53-7.48 (m, 2H), 3.94 (s, 3H), 3.72-3.33 (m, 4H), 2.97 (s, 3H), 2.90 (s, 2H), 2.07-2.68 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.31 (d, 1H, J = 13.0 Hz), 8.13-8.07 (m, 2H), 7.53-7.48 (m, 2H), 3.94 ( s, 3H), 3.72-3.33 (m, 4H), 2.97 (s, 3H), 2.90 (s, 2H), 2.07-2.68 (m, 5H).
실시예Example 167.  167. 메틸methyl 3- 3- (5-((1-아세틸피페리딘-4-일)카바모일)(5-((1-acetylpiperidin-4-yl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-((1-(methyl 3- (5-((1- acetylpiperidinacetylpiperidin -4--4- ylyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06594) benzoate); KY-06594
KY-06592와 동일한 방법으로 합성하여 표제 화합물(80%)을 수득하였다.Synthesis was carried out in the same manner as KY-06592 to obtain the title compound (80%).
1H NMR (300 MHz, CDCl3) δ 8.60 (d, 1H, J = 11.5 Hz), 8.27-8.05 (m, 3H), 7.54 (q, 1H, J = 9.8 Hz), 6.37 (d, 1H, J = 9.0 Hz), 4.66 (d, 1H, J = 14.2 Hz), 4.21 (d, 1H, J = 11.3 Hz), 3.95 (s, 3H), 3.22 (t, 1H, J = 12.6 Hz), 2.73 (d, 1H, J = 12.9 Hz), 2.21-1.97 (m, 5H), 1.47-1.24 (m, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.60 (d, 1H, J = 11.5 Hz), 8.27-8.05 (m, 3H), 7.54 (q, 1H, J = 9.8 Hz), 6.37 (d, 1H, J = 9.0 Hz), 4.66 (d, 1H, J = 14.2 Hz), 4.21 (d, 1H, J = 11.3 Hz), 3.95 (s, 3H), 3.22 (t, 1H, J = 12.6 Hz), 2.73 (d, 1H, J = 12.9 Hz), 2.21-1.97 (m, 5H), 1.47-1.24 (m, 3H).
실시예Example 168.  168. 메틸methyl 3- 3- (5-((1-아세틸피페리딘-3-일)카바모일)(5-((1-acetylpiperidin-3-yl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-((1-(methyl 3- (5-((1- acetylpiperidinacetylpiperidin -3--3- ylyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06595) benzoate); KY-06595
KY-06592와 동일한 방법으로 합성하여 표제 화합물(79%)을 수득하였다.Synthesis was carried out in the same manner as KY-06592 to obtain the title compound (79%).
1H NMR (300 MHz, CDCl3) δ 8.54 (d, 1H, J = 18.5 Hz), 8.26-8.10 (m, 3H), 7.52-7.39 (m, 1H), 6.80 (d, 1H, J = 7.6 Hz), 4.09-4.06 (m, 1H), 3.93 (s, 3H), 3.78-3.67 (m, 2H), 3.46-3.15 (m, 2H), 2.99 (d, 1H, J = 6.0 Hz), 2.92 (s, 3H), 2.15-1.88 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.54 (d, 1H, J = 18.5 Hz), 8.26-8.10 (m, 3H), 7.52-7.39 (m, 1H), 6.80 (d, 1H, J = 7.6 Hz), 4.09-4.06 (m, 1H), 3.93 (s, 3H), 3.78-3.67 (m, 2H), 3.46-3.15 (m, 2H), 2.99 (d, 1H, J = 6.0 Hz), 2.92 (s, 3 H), 2.15-1.88 (m, 5 H).
실시예Example 169. 3-(5-(((1- 169. 3- (5-(((1- 아세틸피페리딘Acetylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-acetylpiperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06596) Thiazol-2-yl) benzoic acid (3- (5-(((1-acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06596
KY-06592와 동일한 방법으로 합성하여 표제 화합물(47%)을 수득하였다.Synthesis was carried out in the same manner as KY-06592 to obtain the title compound (47%).
1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.40 (s, 1H), 8.03 (t, 1H, J = 5.9 Hz), 7.41 (t, 2H, J = 6.2 Hz), 3.80-3.38 (m, 4H), 2.21 (s, 3H), 1.45-1.21 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.60 (s, 1H), 8.40 (s, 1H), 8.03 (t, 1H, J = 5.9 Hz), 7.41 (t, 2H, J = 6.2 Hz), 3.80 -3.38 (m, 4H), 2.21 (s, 3H), 1.45-1.21 (m, 5H).
실시예Example 179. 3-(5-(((1- 179. 3- (5-(((1- 아세틸피페리딘Acetylpiperidine -2-일)-2 days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-acetylpiperidin-2-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06597) Thiazol-2-yl) benzoic acid (3- (5-(((1-acetylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06597
KY-06539와 동일한 방법으로 합성하여 표제 화합물(29%)을 수득하였다.Synthesis was carried out in the same manner as KY-06539 to obtain the title compound (29%).
1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.38 (s, 1H), 8.07 (t, 1H, J = 5.8 Hz), 7.48 (t, 2H, J = 6.4 Hz), 3.84-3.35 (m, 4H), 2.19 (s, 3H), 1.40-1.18 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.59 (s, 1H), 8.38 (s, 1H), 8.07 (t, 1H, J = 5.8 Hz), 7.48 (t, 2H, J = 6.4 Hz), 3.84 -3.35 (m, 4H), 2.19 (s, 3H), 1.40-1.18 (m, 5H).
실시예Example 171. 3-(5-((1- 171. 3- (5-((1- 아세틸피페리딘Acetylpiperidine -4-일)-4- days) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((1-acetylpiperidin-4-yl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06598) Thiazol-2-yl) benzoic acid (3- (5-((1-acetylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06598
KY-06539와 동일한 방법으로 합성하여 표제 화합물(36%)을 수득하였다.Synthesis was carried out in the same manner as KY-06539 to obtain the title compound (36%).
1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.41 (s, 1H), 8.03 (t, 1H, J = 6.0 Hz), 7.41 (t, 2H, J = 5.9 Hz), 3.80-3.21 (m, 4H), 2.22 (s, 3H), 1.38-1.10 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.41 (s, 1H), 8.03 (t, 1H, J = 6.0 Hz), 7.41 (t, 2H, J = 5.9 Hz), 3.80 -3.21 (m, 4H), 2.22 (s, 3H), 1.38-1.10 (m, 5H).
실시예Example 172. 3-(5-((1- 172. 3- (5-((1- 아세틸피페리딘Acetylpiperidine -3-일)-3 days) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((1-acetylpiperidin-3-yl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06599) Thiazol-2-yl) benzoic acid (3- (5-((1-acetylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06599
KY-06539와 동일한 방법으로 합성하여 표제 화합물(68%)을 수득하였다.Synthesis in the same manner as KY-06539 afforded the title compound (68%).
1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.27 (s, 1H), 8.11 (t, 1H, J = 5.5 Hz), 7.30 (t, 2H, J = 5.7 Hz), 3.71-3.28 (m, 4H), 2.25 (s, 3H), 1.38-1.25 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.65 (s, 1H), 8.27 (s, 1H), 8.11 (t, 1H, J = 5.5 Hz), 7.30 (t, 2H, J = 5.7 Hz), 3.71 -3.28 (m, 4H), 2.25 (s, 3H), 1.38-1.25 (m, 5H).
실시예Example 173.  173. 메틸methyl 3-(5-(((1- 3- (5-(((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- benzoylpiperidinbenzoylpiperidin -4-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06600-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06600
20 mL 바이알에 메틸 3-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조에이트(methyl 3-(5-((piperidin-4-ylmethyl)carbamoyl)thiazol-2-yl)benzoate TFA salt, 100 mg, 0.18 mmol), TEA(2.17 mmol, 0.3 mL), DMA(2.8 mL)을 넣고 교반하였다. 상기 반응용액에 벤조일 클로라이드(0.22 mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, EA/H2O 혼합용매를 사용하여 추출하고 MgSO4로 건조하였다. 실리카겔 컬럼크로마토그래피로 분리 정제하여 표제 화합물(66%)을 수득하였다.In a 20 mL vial methyl 3- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate (methyl 3- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate TFA salt, 100 mg, 0.18 mmol), TEA (2.17 mmol, 0.3 mL) and DMA (2.8 mL) were added and stirred. Benzoyl chloride (0.22 mmol) was added to the reaction solution and reacted at room temperature overnight. After completion of the reaction, the mixture was extracted using EA / H 2 O mixed solvent and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (66%).
1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.19 (s, 1H), 8.10-7.93 (m, 2H), 7.48 (q, 2H, J = 5.6 Hz), 7.32-7.10 (m, 4H), 5.02 (s, 1H), 4.28 (d, 1H, J = 13.5 Hz), 3.89 (s, 3H), 3.56 (d, 1H, J = 13.9 Hz), 3.22 (d, 2H, J = 14.6 Hz), 1.90-1.46 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.51 (s, 1H), 8.19 (s, 1H), 8.10-7.93 (m, 2H), 7.48 (q, 2H, J = 5.6 Hz), 7.32-7.10 ( m, 4H), 5.02 (s, 1H), 4.28 (d, 1H, J = 13.5 Hz), 3.89 (s, 3H), 3.56 (d, 1H, J = 13.9 Hz), 3.22 (d, 2H, J = 14.6 Hz), 1.90-1.46 (m, 6H).
실시예Example 174.  174. 메틸methyl 3-(5-(((1-( 3- (5-(((1- ( 페닐카바모일Phenylcarbamoyl )피페리딘-4-일)Piperidin-4-yl) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-() Thiazol-2-yl) benzoate (methyl 3- (5-(((1- ( phenylcarbamoylphenylcarbamoyl )) piperidinpiperidin -4-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06601-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06601
KY-06600과 동일한 방법으로 합성하여 표제 화합물(45%)을 수득하였다.Synthesis in the same manner as KY-06600 afforded the title compound (45%).
1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.12 (s, 1H), 8.02 (t, 2H, J = 7.7 Hz), 7.44 (t, 2H, J = 7.9 Hz), 7.29 (s, 1H), 7.17-7.11 (m, 3H), 6.88 (t, 1H, J = 7.3 Hz), 4.53 (d, 1H, J = 8.8 Hz), 3.89-3.79 (m, 6H), 3.22 (t, 1H, J = 9.6 Hz), 2.96-2.92 (m, 1H), 1.48-1.45 (m, 3H), 1.18 (d, 1H, J = 8.3 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (s, 1H), 8.12 (s, 1H), 8.02 (t, 2H, J = 7.7 Hz), 7.44 (t, 2H, J = 7.9 Hz), 7.29 (s, 1H), 7.17-7.11 (m, 3H), 6.88 (t, 1H, J = 7.3 Hz), 4.53 (d, 1H, J = 8.8 Hz), 3.89-3.79 (m, 6H), 3.22 ( t, 1H, J = 9.6 Hz), 2.96-2.92 (m, 1H), 1.48-1.45 (m, 3H), 1.18 (d, 1H, J = 8.3 Hz).
실시예Example 175.  175. 메틸methyl 3-(5-(((1- 3- (5-(((1- 토실피페리딘Tosylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- tosylpiperidintosylpiperidin -4--4- ylyl )methyl)methyl) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06602-2-yl) benzoate); KY-06602
KY-06600과 동일한 방법으로 합성하여 표제 화합물(54%)을 수득하였다.Synthesis in the same manner as KY-06600 gave the title compound (54%).
1H NMR (300 MHz, CDCl3) δ 8.59 (t, 1H, J = 1.8 Hz), 8.30 (s, 1H), 8.13 (t, 3H, J = 7.9 Hz), 7.77-7.66 (m, 3H), 7.53 (t, 2H, J = 7.8 Hz), 7.28 (d, 3H, J = 4.7 Hz), 7.15-7.05 (m, 1H), 4.15 (t, 1H, J = 4.9 Hz), 3.94 (s, 3H), 3.87-3.77 (m, 2H), 3.48-3.38 (m, 1H), 3.15 (d, 2H, J = 12.7 Hz), 1.39-1.07 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.59 (t, 1H, J = 1.8 Hz), 8.30 (s, 1H), 8.13 (t, 3H, J = 7.9 Hz), 7.77-7.66 (m, 3H) , 7.53 (t, 2H, J = 7.8 Hz), 7.28 (d, 3H, J = 4.7 Hz), 7.15-7.05 (m, 1H), 4.15 (t, 1H, J = 4.9 Hz), 3.94 (s, 3H), 3.87-3.77 (m, 2H), 3.48-3.38 (m, 1H), 3.15 (d, 2H, J = 12.7 Hz), 1.39-1.07 (m, 5H).
실시예Example 176. 3-(5-(((1- 176. 3- (5-(((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-benzoylpiperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06603) Thiazol-2-yl) benzoic acid (3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06603
20 mL 바이알에 피페리딘 화합물(100 mg, 0.18 mmol), TEA(2.17 mmol, 0.3 mL), DMA(2.8 mL)을 넣고 교반하였다. 상기 반응용액에 염화아실 화합물(0.22 mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, EA/H2O 혼합용매를 사용하여 추출하고 MgSO4로 건조하였다. 실리카겔 컬럼크로마토그래피로 분리 정제하여 표제 화합물(24%)을 수득하였다.Piperidine compound (100 mg, 0.18 mmol), TEA (2.17 mmol, 0.3 mL) and DMA (2.8 mL) were added to a 20 mL vial and stirred. An acyl chloride compound (0.22 mmol) was added to the reaction solution and reacted at room temperature overnight. After completion of the reaction, the mixture was extracted using EA / H 2 O mixed solvent and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (24%).
1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.43-8.27 (m, 1H), 8.16-8.05 (m, 3H), 7.55 (q, 5H, J = 7.6 Hz), 7.59-7.49 (m, 3H), 3.95 (s, 3H), 3.74 (q, 3H, J = 12.2 Hz), 3.50-3.41 (m, 2H), 3.18-3.03 (m, 2H), 3.03-2.89 (m, 2H), 2.23-2.05 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.58 (s, 1H), 8.43-8.27 (m, 1H), 8.16-8.05 (m, 3H), 7.55 (q, 5H, J = 7.6 Hz), 7.59- 7.49 (m, 3H), 3.95 (s, 3H), 3.74 (q, 3H, J = 12.2 Hz), 3.50-3.41 (m, 2H), 3.18-3.03 (m, 2H), 3.03-2.89 (m, 2H), 2.23-2.05 (m, 2H).
실시예Example 177. 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산(3-(5-(((1-(phenylcarbamoyl)piperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06604 177. 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid (3- (5-(((1- ( phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06604
KY-06603과 동일한 방법으로 합성하여 표제 화합물(21%)을 수득하였다.Synthesis was carried out in the same manner as KY-06603 to obtain the title compound (21%).
1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.31 (s, 1H), 8.16-8.07 (m, 2H), 7.53 (q, 2H, J = 7.3 Hz), 7.37 (d, 2H, J = 8.1 Hz), 7.33-7.19 (m, 3H), 7.09-6.92 (m, 2H), 3.94 (s, 3H), 3.65-3.54 (m, 1H), 3.45-3.28 (m, 5H), 1.84-1.32 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.31 (s, 1H), 8.16-8.07 (m, 2H), 7.53 (q, 2H, J = 7.3 Hz), 7.37 (d, 2H, J = 8.1 Hz), 7.33-7.19 (m, 3H), 7.09-6.92 (m, 2H), 3.94 (s, 3H), 3.65-3.54 (m, 1H), 3.45-3.28 (m, 5H) , 1.84-1.32 (m, 5 H).
실시예Example 178. 3-(5-(((1- 178. 3- (5-(((1- 토실피페리딘Tosylpiperidine -4-일)-4- days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-tosylpiperidin-4-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06605) Thiazol-2-yl) benzoic acid (3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06605
KY-06603과 동일한 방법으로 합성하여 표제 화합물(49%)을 수득하였다.Synthesis was carried out in the same manner as KY-06603 to obtain the title compound (49%).
1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.23 (s, 1H), 8.06 (t, 2H, J = 6.1 Hz), 7.62-7.52 (m, 3H), 7.47 (t, 1H, J = 7.8 Hz), 7.23 (s, 3H), 6.94-6.81 (m, 1H), 3.88 (s, 3H), 3.43 (t, 2H, J = 6.2 Hz), 3.32-3.14 (m, 4H), 2.75-2.58 (m, 2H), 2.52-2.45 (m, 1H), 1.83-1.51 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.52 (s, 1H), 8.23 (s, 1H), 8.06 (t, 2H, J = 6.1 Hz), 7.62-7.52 (m, 3H), 7.47 (t, 1H, J = 7.8 Hz), 7.23 (s, 3H), 6.94-6.81 (m, 1H), 3.88 (s, 3H), 3.43 (t, 2H, J = 6.2 Hz), 3.32-3.14 (m, 4H ), 2.75-2.58 (m, 2H), 2.52-2.45 (m, 1H), 1.83-1.51 (m, 5H).
실시예Example 179.  179. 메틸methyl 3-(5-(((1- 3- (5-(((1- 벤조일피페리딘Benzoylpiperidine -2-일)-2 days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- benzoylpiperidinbenzoylpiperidin -2-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06606-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06606
KY-06539와 동일한 방법으로 합성하여 표제 화합물(73%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (73%).
1H NMR (300 MHz, DMSO) δ 13.33 (s, 1H), 8.92 (s, 1H), 8.44 (s, 1H), 8.33-8.17 (m, 1H), 8.11-7.97 (m, 1H), 7.67 (t, 1H, J = 7.8 Hz), 7.37-7.27 (m, 5H), 4.94 (s, 1H), 4.18-3.66 (m, 1H), 1.63-1.54 (m, 6H), 1.54-1.17 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 13.33 (s, 1H), 8.92 (s, 1H), 8.44 (s, 1H), 8.33-8.17 (m, 1H), 8.11-7.97 (m, 1H), 7.67 (t, 1H, J = 7.8 Hz), 7.37-7.27 (m, 5H), 4.94 (s, 1H), 4.18-3.66 (m, 1H), 1.63-1.54 (m, 6H), 1.54-1.17 (m , 2H).
실시예Example 180.  180. 메틸methyl 3-(5-(((1-( 3- (5-(((1- ( 페닐카바모일Phenylcarbamoyl )피페리딘-2-일)Piperidin-2-yl) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-() Thiazol-2-yl) benzoate (methyl 3- (5-(((1- ( phenylcarbamoylphenylcarbamoyl )) piperidinpiperidin -2-yl)methyl)carbamoyl)thiazol-2-yl)benzoate); KY-06607-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate); KY-06607
KY-06539와 동일한 방법으로 합성하여 표제 화합물(44%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (44%).
1H NMR (300 MHz, DMSO) δ 13.2 (s, 1H), 8.96 (t, 1H, J = 5.9 Hz), 8.53-8.35 (m, 3H), 8.16 (d, 1H, J = 8.0 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.65 (t, 1H, J = 7.8 Hz), 7.37 (d, 2H, J = 8.0 Hz), 7.14 (t, 2H, J = 7.8 Hz), 6.83 (t, 1H, J = 7.3 Hz), 4.43 (d, 1H, J = 8.1 Hz), 4.00 (d, 1H, J = 13.3 Hz), 3.51 (q, 2H, J = 6.7 Hz), 2.95 (t, 1H, J = 13.5 Hz), 1.80-1.52 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 13.2 (s, 1H), 8.96 (t, 1H, J = 5.9 Hz), 8.53-8.35 (m, 3H), 8.16 (d, 1H, J = 8.0 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.65 (t, 1H, J = 7.8 Hz), 7.37 (d, 2H, J = 8.0 Hz), 7.14 (t, 2H, J = 7.8 Hz), 6.83 ( t, 1H, J = 7.3 Hz, 4.43 (d, 1H, J = 8.1 Hz), 4.00 (d, 1H, J = 13.3 Hz), 3.51 (q, 2H, J = 6.7 Hz), 2.95 (t, 1H, J = 13.5 Hz), 1.80-1.52 (m, 6H).
실시예Example 181.  181. 메틸methyl 3-(5-(((1- 3- (5-(((1- 토실피페리딘Tosylpiperidine -2-일)-2 days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조에이트(methyl 3-(5-(((1-) Thiazol-2-yl) benzoate (methyl 3- (5-(((1- tosylpiperidintosylpiperidin -2--2- ylyl )methyl)methyl) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06608-2-yl) benzoate); KY-06608
KY-06539와 동일한 방법으로 합성하여 표제 화합물(59%)을 수득하였다.Synthesis was carried out in the same manner as KY-06539 to give the title compound (59%).
1H NMR (300 MHz, DMSO) δ 13.32 (s, 1H), 8.77 (t, 1H, J = 6.0 Hz), 8.52 (t, 1H, J = 1.8 Hz), 8.37 (s, 1H), 8.21 (t, 1H, J = 7.9 Hz, 1H), 8.08 (t, 1H, J = 1.4 Hz), 7.67 (t, 3H, J = 7.8 Hz), 7.28 (d, 2H, J = 8.1 Hz), 4.14 (q, 1H, J = 7.2 Hz), 3.70 (d, 1H, J = 13.7 Hz), 3.46 (q, 2H, J = 7.0 Hz), 3.14 (d, 1H, J = 13.3 Hz), 2.27 (s, 3H), 1.67-1.48 (m, 2H), 1.38-1.22 (m, 1H), 1.19-1.01 (m, 1H). 1 H NMR (300 MHz, DMSO) δ 13.32 (s, 1H), 8.77 (t, 1H, J = 6.0 Hz), 8.52 (t, 1H, J = 1.8 Hz), 8.37 (s, 1H), 8.21 ( t, 1H, J = 7.9 Hz, 1H), 8.08 (t, 1H, J = 1.4 Hz), 7.67 (t, 3H, J = 7.8 Hz), 7.28 (d, 2H, J = 8.1 Hz), 4.14 ( q, 1H, J = 7.2 Hz), 3.70 (d, 1H, J = 13.7 Hz), 3.46 (q, 2H, J = 7.0 Hz), 3.14 (d, 1H, J = 13.3 Hz), 2.27 (s, 3H), 1.67-1.48 (m, 2H), 1.38-1.22 (m, 1H), 1.19-1.01 (m, 1H).
실시예Example 182. 3-(5-(((1- 182. 3- (5-(((1- 벤조일피페리딘Benzoylpiperidine -2-일)-2 days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-benzoylpiperidin-2-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06609) Thiazol-2-yl) benzoic acid (3- (5-(((1-benzoylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06609
KY-06539와 동일한 방법으로 합성하여 표제 화합물(51%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (51%).
1H NMR (300 MHz, DMSO) δ 13.32 (s, 1H), 8.89 (s, 1H), 8.22 (d, 1H, J = 7.8 Hz), 8.08 (d, 1H, J = 8.2 Hz), 7.67 (t, 1H, J = 7.9 Hz), 7.42-7.32 (m, 5H), 4.04 (s, 1H), 3.00-2.75 (m, 3H), 1.85-1.81 (m, 2H), 1.29-1.24 (m, 5H). 1 H NMR (300 MHz, DMSO) δ 13.32 (s, 1H), 8.89 (s, 1H), 8.22 (d, 1H, J = 7.8 Hz), 8.08 (d, 1H, J = 8.2 Hz), 7.67 ( t, 1H, J = 7.9 Hz), 7.42-7.32 (m, 5H), 4.04 (s, 1H), 3.00-2.75 (m, 3H), 1.85-1.81 (m, 2H), 1.29-1.24 (m, 5H).
실시예Example 183. 3-(5-(((1-(페닐카바모일)피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산(3-(5-(((1-(phenylcarbamoyl)piperidin-2-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06610 183. 3- (5-(((1- (phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid (3- (5-(((1- ( phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06610
KY-06539와 동일한 방법으로 합성하여 표제 화합물(34%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (34%).
1H NMR (300 MHz, DMSO) δ 13.45 (s, 1H), 8.82 (s, 1H), 8.49 (d, 3H, J = 8.4 Hz), 8.21 (d, 1H, J = 8.0 Hz), 8.07 (d, 1H, J = 7.7 Hz), 7.67 (t, 1H, J = 7.9 Hz), 7.43 (d, 2H, J = 8.1 Hz), 7.21 (t, 2H, J = 7.7 Hz), 6.92 (d, 1H, J = 7.5 Hz), 4.04-3.92 (m, 2H), 2.87-2.75 (m, 2H), 1.78-1.54 (m, 4H), 1.50-1.10 (m, 3H). 1 H NMR (300 MHz, DMSO) δ 13.45 (s, 1H), 8.82 (s, 1H), 8.49 (d, 3H, J = 8.4 Hz), 8.21 (d, 1H, J = 8.0 Hz), 8.07 ( d, 1H, J = 7.7 Hz, 7.67 (t, 1H, J = 7.9 Hz), 7.43 (d, 2H, J = 8.1 Hz), 7.21 (t, 2H, J = 7.7 Hz), 6.92 (d, 1H, J = 7.5 Hz), 4.04-3.92 (m, 2H), 2.87-2.75 (m, 2H), 1.78-1.54 (m, 4H), 1.50-1.10 (m, 3H).
실시예Example 184. 3-(5-(((1- 184. 3- (5-(((1- 토실피페리딘Tosylpiperidine -2-일)-2 days) 메틸methyl )) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-(((1-tosylpiperidin-2-yl)methyl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06611) Thiazol-2-yl) benzoic acid (3- (5-(((1-tosylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06611
KY-06539와 동일한 방법으로 합성하여 표제 화합물(72%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (72%).
1H NMR (300 MHz, DMSO) δ 13.28 (s, 1H), 8.83 (d, 1H, J = 6.0 Hz), 8.54-8.43 (m, 2H), 8.22 (d, 1H, J = 8.0 Hz), 8.08 (d, 1H, J = 7.8 Hz), 7.69-7.56 (m, 3H), 7.45 (d, 2H, J = 7.9 Hz), 3.50 (q, 2H, J = 11.3 Hz), 3.16 (q, 3H, J = 6.6 Hz), 2.40 (s, 3H), 2.25 (t, 1H, J = 11.2 Hz), 2.16-1.96 (m, 1H), 1.84 (s, 1H), 1.79-1.64 (m, 2H), 1.46 (d, 1H, J = 12.6 Hz). 1 H NMR (300 MHz, DMSO) δ 13.28 (s, 1H), 8.83 (d, 1H, J = 6.0 Hz), 8.54-8.43 (m, 2H), 8.22 (d, 1H, J = 8.0 Hz), 8.08 (d, 1H, J = 7.8 Hz), 7.69-7.56 (m, 3H), 7.45 (d, 2H, J = 7.9 Hz), 3.50 (q, 2H, J = 11.3 Hz), 3.16 (q, 3H , J = 6.6 Hz), 2.40 (s, 3H), 2.25 (t, 1H, J = 11.2 Hz), 2.16-1.96 (m, 1H), 1.84 (s, 1H), 1.79-1.64 (m, 2H) , 1.46 (d, 1H, J = 12.6 Hz).
실시예Example 185.  185. terttert -부틸 (3-(3-(5--Butyl (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조일)-L-페닐알라니네이트(tert-butyl (3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-phenylalaninate); KY-06612Tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L-phenylalaninate); KY-06612
KY-06545와 동일한 방법으로 합성하여 표제 화합물(72%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (72%).
1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.05 (s, 1H), 7.85 (d, J = 9.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.53-7.48 (m, 3H), 7.39 (d, J = 9.4 Hz, 2H), 7.32-7.29 (m, 2H), 7.18 (d, J = 6.3 Hz, 2H), 7.11 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 3.9 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.89 (q, J = 6.8 Hz, 1H), 3.21 (d, J = 3.1 Hz, 1H), 1.43 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.53 (s, 1H), 8.05 (s, 1H), 7.85 (d, J = 9.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.53 -7.48 (m, 3H), 7.39 (d, J = 9.4 Hz, 2H), 7.32-7.29 (m, 2H), 7.18 (d, J = 6.3 Hz, 2H), 7.11 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 3.9 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.89 (q, J = 6.8 Hz, 1H), 3.21 (d, J = 3.1 Hz, 1H) , 1.43 (s, 9 H).
실시예Example 186. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-페닐알라닌((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-phenylalanine); KY-06613 186. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-phenylalanine ((3 -(3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-phenylalanine); KY-06613
25 mL 둥근바닥플라스크에 tert-부틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-페닐알라니네이트(100 mg)와 MC(2 mL), TFA(0.5 mL)을 넣고 실온에서 3시간 동안 교반하였다. TFA와 용매를 제거하고 표제 화합물(98 mg, 88%)을 수득하였다.Tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) in a 25 mL round bottom flask -L-phenylalanine (100 mg), MC (2 mL) and TFA (0.5 mL) were added thereto and stirred at room temperature for 3 hours. TFA and solvent were removed to afford the title compound (98 mg, 88%).
1H NMR (300 MHz, DMSO) δ 12.84 (s, 1H), 10.51 (s, 1H), 9.22 (s, 1H), 8.82 (d, J = 8.2 Hz, 1H), 7.93-7.88 (m, 5H), 7.61 (t, J = 7.9 Hz, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 9.7 Hz, 1H), 7.35-7.26 (m, 4H), 7.21 (d, J = 6.7 Hz, 1H), 4.68-4.60 (m, 1H), 3.21 (dd, J = 4.4, 13.9 Hz, 1H), 3.07 (dd, J = 10.5, 13.8 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.84 (s, 1H), 10.51 (s, 1H), 9.22 (s, 1H), 8.82 (d, J = 8.2 Hz, 1H), 7.93-7.88 (m, 5H ), 7.61 (t, J = 7.9 Hz, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 9.7 Hz, 1H), 7.35-7.26 (m, 4H), 7.21 (d , J = 6.7 Hz, 1H), 4.68-4.60 (m, 1H), 3.21 (dd, J = 4.4, 13.9 Hz, 1H), 3.07 (dd, J = 10.5, 13.8 Hz, 1H).
실시예Example 187.  187. 메틸methyl (S)-3-(4-(tert-부톡시)페닐)-2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤즈아미도)프로파네이트(methyl (S)-3-(4-( (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-car Voxamido) -5-fluorobenzamido) propane (methyl (S) -3- (4- ( terttert -- butoxybutoxy )phenyl)-2-(3-(3-(5-) phenyl) -2- (3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzamido)propanoate); KY-06614) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzamido) propanoate); KY-06614
KY-06545와 동일한 방법으로 합성하여 표제 화합물(59%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (59%).
1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 10.3 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.55-7.50 (m, 3H), 7.43-7.39 (m, 2H), 7.10 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 3.9 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 7.7 Hz, 1H), 5.00 (q, J = 6.5 Hz, 1H), 3.75 (s, 3H), 3.21 (qd, J = 6.7, 21.6 Hz, 2H), 1.34 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.54 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 10.3 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.55 -7.50 (m, 3H), 7.43-7.39 (m, 2H), 7.10 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 3.9 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 7.7 Hz, 1H), 5.00 (q, J = 6.5 Hz, 1H), 3.75 (s, 3H), 3.21 (qd, J = 6.7, 21.6 Hz, 2H), 1.34 (s, 9H).
실시예Example 188. (S)-3-(4-(tert-부톡시)페닐)-2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤즈아미도)프로판산((S)-3-(4-(tert-butoxy)phenyl)-2-(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzamido)propanoic acid); KY-06615 188. (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4 -Carboxamido) -5-fluorobenzamido) propanoic acid ((S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5-chlorothiophen-2- yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzamido) propanoic acid); KY-06615
KY-06614 화합물(180 mg, 0.27 mmol)과 NaOH(54 mg, 1.35 mmol, 5.0 당량)에 아세토니트릴(3 mL)과 H2O(1 mL)를 더하고 실온에서 3시간 동안 교반하였다. 1N HCl을 더하여 pH를 3으로 맞추고, 증류수를 더한 뒤 EtOAc로 추출하였다. 유기용매를 MgSO4로 건조하고 용매를 제거하여 표제 화합물(99%)을 수득하였다.Acetonitrile (3 mL) and H 2 O (1 mL) were added to KY-06614 compound (180 mg, 0.27 mmol) and NaOH (54 mg, 1.35 mmol, 5.0 equiv) and stirred at room temperature for 3 hours. 1N HCl was added to adjust the pH to 3, distilled water was added and extracted with EtOAc. The organic solvent was dried over MgSO 4 and the solvent was removed to give the title compound (99%).
1H NMR (300 MHz, DMSO) δ 10.91 (s, 1H), 9.39 (s, 1H), 8.55 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.93-7.88 (m, 3H), 7.60 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.17-7.15 (m, 3H), 6.80 (d, J = 8.3 Hz, 2H), 4.50 (d, J = 6.9 Hz, 1H), 3.20 (dd, J = 4.1, 13.5 Hz, 1H), 3.02 (dd, J = 9.2, 13.5 Hz, 1H), 1.20 (s, 9H). 1 H NMR (300 MHz, DMSO) δ 10.91 (s, 1H), 9.39 (s, 1H), 8.55 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.93- 7.88 (m, 3H), 7.60 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.17-7.15 (m, 3H ), 6.80 (d, J = 8.3 Hz, 2H), 4.50 (d, J = 6.9 Hz, 1H), 3.20 (dd, J = 4.1, 13.5 Hz, 1H), 3.02 (dd, J = 9.2, 13.5 Hz , 1H), 1.20 (s, 9H).
실시예Example 189. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-티로신((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-tyrosine); KY-06616 189. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tyrosine ((3 -(3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tyrosine); KY-06616
KY-06613과 동일한 방법으로 합성하여 표제 화합물(96%)을 수득하였다.Synthesis in the same manner as KY-06613 gave the title compound (96%).
1H NMR (300 MHz, DMSO) δ 12.76 (s, 1H), 10.52 (s, 1H), 9.23 (s, 1H), 9.20 (s, 1H), 8.75 (d, J = 8.1 Hz, 1H), 7.93- 7.89 (m, 5H), 7.61 (t, J = 8.0 Hz, 2H), 7.46-7.40 (m, 2H), 7.17 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.57-4.52 (m, 1H), 3.08 (dd, J = 4.4, 13.8 Hz, 1H), 2.95 (dd, J = 10.5, 13.8 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 12.76 (s, 1H), 10.52 (s, 1H), 9.23 (s, 1H), 9.20 (s, 1H), 8.75 (d, J = 8.1 Hz, 1H), 7.93-7.89 (m, 5H), 7.61 (t, J = 8.0 Hz, 2H), 7.46-7.40 (m, 2H), 7.17 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 8.4 Hz , 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.57-4.52 (m, 1H), 3.08 (dd, J = 4.4, 13.8 Hz, 1H), 2.95 (dd, J = 10.5, 13.8 Hz, 1H).
실시예Example 190.  190. terttert -부틸 (3-(3-(5--Butyl (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조일)-L-발리네이트(tert-butyl (3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-valinate); KY-06617Tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -5-fluorobenzoyl) -L-valinate -L-valinate); KY-06617
KY-06545와 동일한 방법으로 합성하여 표제 화합물(71%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (71%).
1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.03 (s, 1H), 7.89 (d, J = 10.4 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.56-7.49 (m, 3H), 7.44-7.39 (m, 2H), 7.25-7.24 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.63 (dd, J = 4.4, 8.3 Hz, 1H), 2.30 (q, J = 5.9 Hz, 1H), 1.52 (s, 9H), 1.02 (dd, J = 4.4, 6.8 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (s, 1H), 8.03 (s, 1H), 7.89 (d, J = 10.4 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.56 -7.49 (m, 3H), 7.44-7.39 (m, 2H), 7.25-7.24 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.63 (dd, J = 4.4, 8.3 Hz, 1H), 2.30 (q, J = 5.9 Hz, 1H), 1.52 (s, 9H), 1.02 (dd, J = 4.4, 6.8 Hz, 6H).
실시예Example 191. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-발린((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-valine); KY-06618 191. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-valine ((3 -(3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-valine); KY-06618
KY-06613과 동일한 방법으로 합성하여 표제 화합물(87%)을 수득하였다.Synthesis was performed in the same manner as KY-06613 to give the title compound (87%).
1H NMR (300 MHz, DMSO) δ 12.66 (s, 1H), 10.54 (s, 1H), 9.24 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 10.9 Hz, 1H), 7.92-7.88 (m, 4H), 7.61 (t, J = 7.9 Hz, 2H), 7.54 (d, J = 9.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 4.30 (t, J = 7.5 Hz, 1H), 2.26-2.14 (m, 1H), 0.98 (dd, J = 5.0, 6.6 Hz, 6H). 1 H NMR (300 MHz, DMSO) δ 12.66 (s, 1H), 10.54 (s, 1H), 9.24 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 10.9 Hz, 1H), 7.92-7.88 (m, 4H), 7.61 (t, J = 7.9 Hz, 2H), 7.54 (d, J = 9.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 4.30 (t, J = 7.5 Hz, 1H), 2.26-2.14 (m, 1H), 0.98 (dd, J = 5.0, 6.6 Hz, 6H).
실시예Example 192.  192. terttert -부틸 (3-(3-(5--Butyl (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조일)-L-이소루시네이트(tert-butyl (3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-isoleucinate); KY-06619) -5-fluorobenzoyl) -L-isorushinate (tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl ) -L-isoleucinate); KY-06619
KY-06545와 동일한 방법으로 합성하여 표제 화합물(74%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (74%).
1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.18 (s, 1H), 7.89 (d, J = 10.3 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.54-7.49 (m, 3H), 7.43-7.37 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 3.8 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 4.65 (dd, J = 4.6, 8.0 Hz, 1H), 2.05-1.94 (m, 1H), 1.49 (s, 9H), 1.34-1.21 (m, 2H), 1.01-0.97 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.18 (s, 1H), 7.89 (d, J = 10.3 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.54 -7.49 (m, 3H), 7.43-7.37 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 3.8 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 4.65 (dd, J = 4.6, 8.0 Hz, 1H), 2.05-1.94 (m, 1H), 1.49 (s, 9H), 1.34-1.21 (m, 2H), 1.01-0.97 (m, 6H) .
실시예Example 193. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-이소루신((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-isoleucine); KY-06620 193. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-isoleucine (( 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-isoleucine); KY-06620
KY-06613과 동일한 방법으로 합성하여 표제 화합물(88%)을 수득하였다.Synthesis was performed in the same manner as KY-06613 to obtain the title compound (88%).
1H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 10.54 (s, 1H), 9.23 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 11.0 Hz, 1H), 7.91-7.88 (m, 4H), 7.61 (t, J = 7.9 Hz, 2H), 7.53 (d, J = 9.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 4.34 (t, J = 7.3 Hz, 1H), 2.00-1.92 (m, 1H), 1.52-1.44 (m, 1H), 1.34-1.24 (m, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 10.54 (s, 1H), 9.23 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 11.0 Hz, 1H), 7.91-7.88 (m, 4H), 7.61 (t, J = 7.9 Hz, 2H), 7.53 (d, J = 9.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 4.34 (t, J = 7.3 Hz, 1H), 2.00-1.92 (m, 1H), 1.52-1.44 (m, 1H), 1.34-1.24 (m, 1H) , 0.95 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H).
실시예Example 194.  194. 메틸methyl (3-(3-(5- (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조일)-L-루시네이트(methyl (3-(3-(5-) -5-fluorobenzoyl) -L-rushin (methyl (3- (3- (5- chlorothiophenchlorothiophen -2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-leucinate); KY-06621-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-leucinate); KY-06621
KY-06545와 동일한 방법으로 합성하여 표제 화합물(70%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (70%).
1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.05 (s, 1H), 7.80-7.75 (m, 3H), 7.53-7.47 (m, 4H), 7.39 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 3.8 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.84-4.77 (m, 1H), 3.75 (s, 3H), 1.78-1.66 (m, 3H), 0.99 (d, J = 3.6 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.56 (s, 1H), 8.05 (s, 1H), 7.80-7.75 (m, 3H), 7.53-7.47 (m, 4H), 7.39 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 3.8 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.84-4.77 (m, 1H), 3.75 (s, 3H), 1.78-1.66 (m, 3H), 0.99 (d, J = 3.6 Hz, 6H).
실시예Example 195. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-루신((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-leucine); KY-06622 195. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-leucine ((3 -(3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-leucine); KY-06622
KY-06615와 동일한 방법으로 합성하여 표제 화합물(78%)을 수득하였다.Synthesis in the same manner as KY-06615 gave the title compound (78%).
1H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 9.23 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.94-7.88 (m, 5H), 7.61 (t, J = 7.9 Hz, 2H), 7.50 (d, J = 9.2 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 4.47-4.39 (m, 1H), 1.18-1.57 (m, 3H), 0.91 (dd, J = 6.1, 12.3 Hz, 6H). 1 H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 9.23 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.94-7.88 (m, 5H), 7.61 (t, J = 7.9 Hz, 2H), 7.50 (d, J = 9.2 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 4.47-4.39 (m, 1H ), 1.18-1.57 (m, 3H), 0.91 (dd, J = 6.1, 12.3 Hz, 6H).
실시예Example 196.  196. 메틸methyl (3-(3-(5- (3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조일)-L-메티오네이트(methyl (3-(3-(5-) -5-fluorobenzoyl) -L-methionate (methyl (3- (3- (5- chlorothiophenchlorothiophen -2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-methioninate); KY-06623-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methioninate); KY-06623
KY-06545와 동일한 방법으로 합성하여 표제 화합물(74%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (74%).
1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.11 (s, 1H), 7.81-7.74 (m, 3H), 7.53-7.48 (m, 4H), 7.38 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 3.9 Hz, 1H), 4.88 (q, J = 6.6 Hz, 1H), 3.77 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.33-2.21 (m, 1H), 2.18-2.07 (m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.53 (s, 1H), 8.11 (s, 1H), 7.81-7.74 (m, 3H), 7.53-7.48 (m, 4H), 7.38 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 3.9 Hz, 1H), 4.88 (q, J = 6.6 Hz, 1H), 3.77 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.33-2.21 (m, 1H), 2.18-2.07 (m, 4H).
실시예Example 197. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-메티오닌((3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoyl)-L-methionine); KY-06624 197. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methionine ((3 -(3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methionine); KY-06624
KY-06615와 동일한 방법으로 합성하여 표제 화합물(97%)을 수득하였다.Synthesis in the same manner as KY-06615 gave the title compound (97%).
1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 9.23 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 7.96-7.88 (m, 5H), 7.61 (t, J = 7.9 Hz, 2H), 7.50 (d, J = 9.4 Hz, 1H), 7.44 (t, J = 9.4 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 4.52 (q, J = 7.2 Hz, 1H), 2.63-2.50 (m, 4H), 2.06 (s, 3H). 1 H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 9.23 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 7.96-7.88 (m, 5H), 7.61 (t, J = 7.9 Hz, 2H), 7.50 (d, J = 9.4 Hz, 1H), 7.44 (t, J = 9.4 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 4.52 (q, J = 7.2 Hz, 1H), 2.63-2.50 (m, 4H), 2.06 (s, 3H).
실시예Example 198.  198. 메틸methyl 3-(5-((1- 3- (5-((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-((1-(methyl 3- (5-((1- benzoylpiperidinbenzoylpiperidin -4--4- ylyl )) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06625-2-yl) benzoate); KY-06625
20 mL 바이알에 피페리딘 화합물(100 mg, 0.18 mmol), TEA(2.2 mmol, 0.3 mL), DMA(2.6 mL)을 넣고 교반하였다. 상기 반응용액에 벤조일클로라이드(0.21 mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, EA/H2O 혼합용매를 사용하여 추출하고 MgSO4로 건조하였다. 실리카겔 컬럼크로마토그래피로 분리 정제하여 표제 화합물(56%)을 수득하였다.Piperidine compound (100 mg, 0.18 mmol), TEA (2.2 mmol, 0.3 mL) and DMA (2.6 mL) were added to a 20 mL vial and stirred. Benzoyl chloride (0.21 mmol) was added to the reaction solution and reacted at room temperature overnight. After completion of the reaction, the mixture was extracted using EA / H 2 O mixed solvent and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (56%).
1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.12 (s, 2H), 8.00 (d, 3H, J = 7.5 Hz), 7.40 (t, 2H, J = 8.0 Hz), 7.12 (s, 1H), 6.54 (d, 1H, J = 7.6 Hz), 4.63 (s, 1H), 4.11 (s, 2H), 3.82 (s, 3H), 3.69 (s, 1H), 3.16-2.65 (m, 5H), 1.11 (s, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (s, 1H), 8.12 (s, 2H), 8.00 (d, 3H, J = 7.5 Hz), 7.40 (t, 2H, J = 8.0 Hz), 7.12 (s, 1H), 6.54 (d, 1H, J = 7.6 Hz), 4.63 (s, 1H), 4.11 (s, 2H), 3.82 (s, 3H), 3.69 (s, 1H), 3.16-2.65 ( m, 5H), 1.11 (s, 1H).
실시예Example 199.  199. 메틸methyl 3- 3- (5-((1-토실피페리딘-4-일)카바모일)(5-((1-Tosylpiperidin-4-yl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-((1-(methyl 3- (5-((1- tosylpiperidintosylpiperidin -4--4- ylyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06626) benzoate); KY-06626
KY-06625와 동일한 방법으로 합성하여 표제 화합물(22%)을 수득하였다.Synthesis in the same manner as KY-06625 gave the title compound (22%).
1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.24 (s, 1H), 8.12 (d, 2H, J = 7.6 Hz), 7.64 (d, 2H, J = 8.1 Hz), 7.60-7.48 (m, 1H), 7.34 (t, 2H, J = 8.4 Hz), 4.16-4.08 (m, 1H), 3.95 (s, 3H), 3.88 (d, 2H, J = 8.1 Hz), 2.68 (s, 1H), 2.45 (s, 3H), 2.37 (d, 1H, J = 11.4 Hz), 2.15-1.96 (m, 2H), 1.86-1.67 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.58 (s, 1H), 8.24 (s, 1H), 8.12 (d, 2H, J = 7.6 Hz), 7.64 (d, 2H, J = 8.1 Hz), 7.60 -7.48 (m, 1H), 7.34 (t, 2H, J = 8.4 Hz), 4.16-4.08 (m, 1H), 3.95 (s, 3H), 3.88 (d, 2H, J = 8.1 Hz), 2.68 ( s, 1H), 2.45 (s, 3H), 2.37 (d, 1H, J = 11.4 Hz), 2.15-1.96 (m, 2H), 1.86-1.67 (m, 2H).
실시예Example 200.  200. 메틸methyl 3-(5-((1- 3- (5-((1- 벤조일피페리딘Benzoylpiperidine -3-일)-3 days) 카바모일Cabamo )티아졸-2-일)) Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-((1-(methyl 3- (5-((1- benzoylpiperidinbenzoylpiperidin -3--3- ylyl )) carbamoylcarbamoyl )) thiazolthiazol -2-yl)benzoate); KY-06627-2-yl) benzoate); KY-06627
20 mL 바이알에 피페리딘 화합물(100 mg, 0.18 mmol), TEA(2.2 mmol, 0.3 mL), DMA(2.6 mL)을 넣고 교반하였다. 상기 반응용액에 벤조일클로라이드(0.21 mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응종료 후, EA/H2O 혼합용매를 사용하여 추출하고 MgSO4로 건조하였다. 실리카겔 컬럼크로마토그래피로 분리 정제하여 표제 화합물(53%)을 수득하였다.Piperidine compound (100 mg, 0.18 mmol), TEA (2.2 mmol, 0.3 mL) and DMA (2.6 mL) were added to a 20 mL vial and stirred. Benzoyl chloride (0.21 mmol) was added to the reaction solution and reacted at room temperature overnight. After completion of the reaction, the mixture was extracted using EA / H 2 O mixed solvent and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (53%).
1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 8.13 (s, 1H), 7.97 (d, 2H, J = 7.8 Hz), 7.38 (t, 2H, J = 7.8 Hz), 7.35-7.19 (m, 4H), 4.13-3.92 (m, 1H), 3.80 (s, 3H), 3.74-3.54 (m, 1H), 3.28 (s, 1H), 2.86 (s, 1H), 2.79 (s, 3H), 2.00-1.74 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (s, 1H), 8.13 (s, 1H), 7.97 (d, 2H, J = 7.8 Hz), 7.38 (t, 2H, J = 7.8 Hz), 7.35 -7.19 (m, 4H), 4.13-3.92 (m, 1H), 3.80 (s, 3H), 3.74-3.54 (m, 1H), 3.28 (s, 1H), 2.86 (s, 1H), 2.79 (s , 3H), 2.00-1.74 (m, 2H).
실시예Example 201.  201. 메틸methyl 3- 3- (5-((1-토실피페리딘-3-일)카바모일)(5-((1-Tosylpiperidin-3-yl) carbamoyl) 티아졸-2-일)Thiazol-2-yl) 벤조에이트Benzoate (methyl 3-(5-((1-(methyl 3- (5-((1- tosylpiperidintosylpiperidin -3--3- ylyl )) carbamoylcarbamoyl )) thiazolthiazol -2--2- ylyl )benzoate); KY-06628) benzoate); KY-06628
KY-06627과 동일한 방법으로 합성하여 표제 화합물(33%)을 수득하였다.Synthesis in the same manner as KY-06627 gave the title compound (33%).
1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.25 (s, 2H), 8.19-8.06 (m, 1H), 7.66 (d, 2H, J = 7.9 Hz), 7.57 (t, 1H, J = 7.8 Hz), 7.35 (d, 2H, J = 7.9 Hz), 6.56 (d, 1H, J = 7.8 Hz), 4.33 (s, 1H), 3.97 (s, 3H), 3.57 (d, 1H, J = 11.9 Hz), 3.44-3.28 (m, 1H), 2.93-2.83 (m, 1H), 2.67 (t, 1H, J = 10.8 Hz), 2.45 (s, 3H), 1.95-1.77 (m, 2H), 1.72 (d, 2H, J = 4.8 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.25 (s, 2H), 8.19-8.06 (m, 1H), 7.66 (d, 2H, J = 7.9 Hz), 7.57 (t, 1H, J = 7.8 Hz), 7.35 (d, 2H, J = 7.9 Hz), 6.56 (d, 1H, J = 7.8 Hz), 4.33 (s, 1H), 3.97 (s, 3H), 3.57 (d, 1H, J = 11.9 Hz), 3.44-3.28 (m, 1H), 2.93-2.83 (m, 1H), 2.67 (t, 1H, J = 10.8 Hz), 2.45 (s, 3H), 1.95-1.77 (m , 2H), 1.72 (d, 2H, J = 4.8 Hz).
실시예Example 202. 3-(5-((1- 202. 3- (5-((1- 벤조일피페리딘Benzoylpiperidine -4-일)-4- days) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((1-benzoylpiperidin-4-yl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06629) Thiazol-2-yl) benzoic acid (3- (5-((1-benzoylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06629
KY-06539와 동일한 방법으로 합성하여 표제 화합물(95%)을 수득하였다.Synthesis was carried out in the same manner as KY-06539 to give the title compound (95%).
1H NMR (300 MHz, DMSO) δ 13.28 (s, 1H), 8.64 (d, 1H, J = 7.6 Hz), 8.51 (d, 2H, J = 2.4 Hz), 8.21 (d, 1H, J = 7.9 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.51-7.34 (m, 4H), 4.46 (s, 1H), 4.08-4.01 (m, 1H), 3.61 (s, 1H), 3.18 (s, 1H), 2.98 (s, 1H), 1.99 (s, 2H), 1.50 (s, 2H). 1 H NMR (300 MHz, DMSO) δ 13.28 (s, 1H), 8.64 (d, 1H, J = 7.6 Hz), 8.51 (d, 2H, J = 2.4 Hz), 8.21 (d, 1H, J = 7.9 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.51-7.34 (m, 4H), 4.46 (s, 1H), 4.08-4.01 (m, 1H ), 3.61 (s, 1H), 3.18 (s, 1H), 2.98 (s, 1H), 1.99 (s, 2H), 1.50 (s, 2H).
실시예Example 203. 3-(5-((1- 203. 3- (5-((1- 토실피페리딘Tosylpiperidine -4-일)-4- days) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((1-tosylpiperidin-4-yl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06630) Thiazol-2-yl) benzoic acid (3- (5-((1-tosylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06630
KY-06539와 동일한 방법으로 합성하여 표제 화합물(43%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (43%).
1H NMR (300 MHz, DMSO) δ 13.65 (s, 1H), 9.02 (d, 1H, J = 7.3 Hz), 8.90 (d, 2H, J = 7.3 Hz), 8.61 (d, 1H, J = 7.9 Hz), 8.48 (d, 1H, J = 7.7 Hz), 8.06 (d, 2H, J = 7.7 Hz), 7.88 (d, 2H, J = 7.8 Hz), 4.24-3.97 (m, 3H), 2.92 (s, 3H), 2.83 (d, 2H, J = 6.8 Hz), 2.31 (t, 2H, J = 9.1 Hz), 1.99 (q, 2H, J = 13.0 Hz). 1 H NMR (300 MHz, DMSO) δ 13.65 (s, 1H), 9.02 (d, 1H, J = 7.3 Hz), 8.90 (d, 2H, J = 7.3 Hz), 8.61 (d, 1H, J = 7.9 Hz), 8.48 (d, 1H, J = 7.7 Hz), 8.06 (d, 2H, J = 7.7 Hz), 7.88 (d, 2H, J = 7.8 Hz), 4.24-3.97 (m, 3H), 2.92 ( s, 3H), 2.83 (d, 2H, J = 6.8 Hz), 2.31 (t, 2H, J = 9.1 Hz), 1.99 (q, 2H, J = 13.0 Hz).
실시예Example 204. 3-(5-((1- 204. 3- (5-((1- 벤조일피페리딘Benzoylpiperidine -3-일)-3 days) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((1-benzoylpiperidin-3-yl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06631) Thiazol-2-yl) benzoic acid (3- (5-((1-benzoylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06631
KY-06539와 동일한 방법으로 합성하여 표제 화합물(80%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (80%).
1H NMR (300 MHz, DMSO) δ 13.32 (s, 1H), 8.60 (d, 3H, J = 10.2 Hz), 8.21 (d, 1H, J = 7.8 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.67 (t, 1H, J = 7.5 Hz), 7.49-7.33 (m, 4H), 4.51 (s, 1H), 3.89 (s, 1H), 3.67 (s, 1H), 3.06 (s, 1H), 2.91-2.64 (m, 1H), 2.00 (d, 1H, J = 11.0 Hz), 1.84-1.45 (m, 3H). 1 H NMR (300 MHz, DMSO) δ 13.32 (s, 1H), 8.60 (d, 3H, J = 10.2 Hz), 8.21 (d, 1H, J = 7.8 Hz), 8.07 (d, 1H, J = 7.8 Hz), 7.67 (t, 1H, J = 7.5 Hz), 7.49-7.33 (m, 4H), 4.51 (s, 1H), 3.89 (s, 1H), 3.67 (s, 1H), 3.06 (s, 1H ), 2.91-2.64 (m, 1H), 2.00 (d, 1H, J = 11.0 Hz), 1.84-1.45 (m, 3H).
실시예Example 205. 3-(5-((1- 205. 3- (5-((1- 토실피페리딘Tosylpiperidine -3-일)-3 days) 카바모일Cabamo )티아졸-2-일)벤조산(3-(5-((1-tosylpiperidin-3-yl)carbamoyl)thiazol-2-yl)benzoic acid); KY-06632) Thiazol-2-yl) benzoic acid (3- (5-((1-tosylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06632
KY-06539와 동일한 방법으로 합성하여 표제 화합물(69%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (69%).
1H NMR (300 MHz, DMSO) δ 13.30 (s, 1H), 8.67-8.59 (m, 3H), 8.32 (d, 1H, J = 7.8 Hz), 8.19 (d, 1H, J = 7.7 Hz), 7.76 (d, 3H, J = 7.4 Hz), 7.56 (d, 1H, J = 7.9 Hz), 4.03 (s, 1H), 3.76 (d, 1H, J = 13.5 Hz), 2.61 (s, 3H), 3.68-3.54 (m, 3H), 1.94 (d, 2H, J = 11.9 Hz), 1.67 (d, 1H, J = 11.2 Hz), 1.44-1.35 (m, 1H). 1 H NMR (300 MHz, DMSO) δ 13.30 (s, 1H), 8.67-8.59 (m, 3H), 8.32 (d, 1H, J = 7.8 Hz), 8.19 (d, 1H, J = 7.7 Hz), 7.76 (d, 3H, J = 7.4 Hz), 7.56 (d, 1H, J = 7.9 Hz), 4.03 (s, 1H), 3.76 (d, 1H, J = 13.5 Hz), 2.61 (s, 3H), 3.68-3.54 (m, 3H), 1.94 (d, 2H, J = 11.9 Hz), 1.67 (d, 1H, J = 11.2 Hz), 1.44-1.35 (m, 1H).
실시예Example 206.  206. 메틸methyl 3-(3-(5- 3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-4-플루오로벤조에이트(methyl 3-(3-(5-) -4-fluorobenzoate (methyl 3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)-4-fluorobenzoate); KY-06633) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoate); KY-06633
25 mL 둥근바닥플라스크에 염화아실 화합물(213 mg)을 넣고 MC(1 mL)에 용해시킨 뒤, 0℃에서 30분 동안 교반하였다. 7 mL 바이알에 메틸 3-아미노-4-플루오로벤조에이트(134 mg)을 MC(2 mL)에 용해시키고, DIPEA(0.17 mL)을 첨가하여 교반하였다. 0℃의 얼음수조에서 7 mL 바이알에 담긴 혼합물을 25 mL 둥근바닥플라스크에 20분에 걸쳐 적가하였다. 이후 실온에서 14시간 동안 교반하고, 2일 동안 환류 교반하였다. 반응물에 EtOAc를 가하고 증류수로 세척한 뒤 MgSO4로 건조하고 용매를 제거하였다. 실리카겔컬럼 크로마토그래피(EA:헥산=1:2->EA)로 분리하여 노란색 rh체 화합물로 표제 화합물(81 mg, 27%)을 수득하였다.Acyl chloride compound (213 mg) was added to a 25 mL round bottom flask, dissolved in MC (1 mL), and stirred at 0 ° C. for 30 minutes. Methyl 3-amino-4-fluorobenzoate (134 mg) was dissolved in MC (2 mL) in a 7 mL vial and DIPEA (0.17 mL) was added and stirred. In a 0 mL ice bath, the mixture in 7 mL vials was added dropwise to a 25 mL round bottom flask over 20 minutes. It was then stirred for 14 hours at room temperature and refluxed for 2 days. EtOAc was added to the reaction, washed with distilled water, dried over MgSO 4 and the solvent was removed. Separation by silica gel column chromatography (EA: hexane = 1: 2-> EA) gave the title compound (81 mg, 27%) as a yellow rh compound.
1H NMR (300 MHz, CDCl3) δ 9.07 (dd, J = 2.1, 7.6 Hz, 1H), 8.52 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.82 (ddd, J = 2.2, 5.1, 8.6 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.54-7.48 (m, 3H), 7.39 (t, J = 7.4 Hz, 1H), 7.15 (dd, J = 8.7, 10.4 Hz, 1H), 7.00 (d, J = 3.9 Hz, 1H), 3.93 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.07 (dd, J = 2.1, 7.6 Hz, 1H), 8.52 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.82 (ddd, J = 2.2, 5.1, 8.6 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.54-7.48 (m, 3H), 7.39 (t, J = 7.4 Hz, 1H), 7.15 (dd, J = 8.7 , 10.4 Hz, 1H), 7.00 (d, J = 3.9 Hz, 1H), 3.93 (s, 3H).
실시예Example 207. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-플루오로벤조산(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-4-fluorobenzoic acid); KY-06634 207. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoic acid (3- (3- (5- chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoic acid); KY-06634
KY-06615와 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was carried out in the same manner as KY-06615 to obtain the title compound (99%).
1H NMR (500 MHz, DMSO) δ 10.17 (s, 1H), 9.24 (s, 1H), 8.38 (dd, J = 1.7, 7.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.84 (ddd, J = 2.2, 4.8, 8.6 Hz, 2H), 7.61 (t, J = 8.0 Hz, 2H), 7.46-7.42 (m, 2H), 7.16 (d, J = 4.0 Hz, 1H). 1 H NMR (500 MHz, DMSO) δ 10.17 (s, 1H), 9.24 (s, 1H), 8.38 (dd, J = 1.7, 7.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.84 (ddd , J = 2.2, 4.8, 8.6 Hz, 2H), 7.61 (t, J = 8.0 Hz, 2H), 7.46-7.42 (m, 2H), 7.16 (d, J = 4.0 Hz, 1H).
실시예Example 208.  208. 메틸methyl 3-(3-(5- 3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-4-(트리플루오로메틸)벤조에이트(methyl 3-(3-(5-) -4- (trifluoromethyl) benzoate (methyl 3- (3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)-4-(trifluoromethyl)benzoate); KY-06635) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoate); KY-06635
25 mL 둥근바닥플라스크에 염화아실 화합물(213 mg)을 넣고 톨루엔(1 mL)을 첨가하여 0℃에서 30분 동안 교반하였다. 7 mL 바이알에 메틸 3-아미노-4-(트리플루오로메틸)벤조에이트(134 mg)과 톨루엔(2 mL), Et3N(0.14 mL)을 넣고 교반하였다. 0℃에서 7 mL 바이알에 담긴 혼합물을 25 mL 둥근바닥플라스크에 20분에 걸쳐 적가하였다. 이후 실온에서 1시간 동안 교반하고, 다음 1일 동안 환류 교반하였다. 반응물에 EtOAc를 가하고 증류수로 세척한 뒤 MgSO4로 건조하고 용매를 제거하였다. 실리카겔컬럼 크로마토그래피(EA:헥산=1:4)로 분리하여 노란색 rh체 화합물로 표제 화합물(16 mg, 5%)을 수득하였다.An acyl chloride compound (213 mg) was added to a 25 mL round bottom flask, and toluene (1 mL) was added thereto, followed by stirring at 0 ° C. for 30 minutes. Methyl 3-amino-4- (trifluoromethyl) benzoate (134 mg), toluene (2 mL) and Et 3 N (0.14 mL) were added to a 7 mL vial and stirred. The mixture contained in a 7 mL vial at 0 ° C. was added dropwise to a 25 mL round bottom flask over 20 minutes. It was then stirred at room temperature for 1 hour and then at reflux for 1 day. EtOAc was added to the reaction, washed with distilled water, dried over MgSO 4 and the solvent was removed. Silica gel column chromatography (EA: hexane = 1: 4) to give the title compound (16 mg, 5%) as a yellow rh compound.
1H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.82-7.77 (m, 3H), 7.62-7.51 (m, 4H), 3.99 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.31 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.82-7.77 (m, 3H) , 7.62-7.51 (m, 4H), 3.99 (s, 3H).
실시예Example 209. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-(트리플루오로메틸)벤조산(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-4-(trifluoromethyl)benzoic acid); KY-06636 209. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoic acid (3- (3 -(5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoic acid); KY-06636
KY-06615와 동일한 방법으로 합성하여 표제 화합물(88%)을 수득하였다.Synthesis in the same manner as KY-06615 gave the title compound (88%).
1H NMR (300 MHz, DMSO) δ 13.57 (s, 1H), 9.26 (s, 1H), 8.42 (s, 1H), 8.08-7.92 (m, 6H), 7.59 (t, J = 1.7, 2H), 7.47 (t, J = 7.6 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.57 (s, 1H), 9.26 (s, 1H), 8.42 (s, 1H), 8.08-7.92 (m, 6H), 7.59 (t, J = 1.7, 2H) , 7.47 (t, J = 7.6 Hz, 1H).
실시예Example 210.  210. terttert -부틸 3-(3-(5--Butyl 3- (3- (5- 클로로티오펜Chlorothiophene -2-일)-1-(4-(-2-yl) -1- (4- ( 메톡시카보닐Methoxycarbonyl )페닐)-1H-피라졸-4-카르복스아미도)벤조에이트(tert-butyl 3-(3-(5-) Phenyl) -1H-pyrazole-4-carboxamido) benzoate (tert-butyl 3- (3- (5- chlorothiophenchlorothiophen -2-yl)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxamido)benzoate); KY-06637-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoate); KY-06637
KY-06542와 동일한 방법으로 합성하여 표제 화합물(69%)을 수득하였다.Synthesis in the same manner as KY-06542 gave the title compound (69%).
1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.18 (d, 2H, J = 8.5 Hz), 7.97-7.90 (m, 1H), 7.89-7.80 (m, 4H), 7.77 (d, 1H, J = 7.9 Hz), 7.50-7.38 (m, 2H), 7.00 (d, 1H, J = 4.1 Hz), 3.96 (s, 3H), 1.60 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.18 (d, 2H, J = 8.5 Hz), 7.97-7.90 (m, 1H), 7.89-7.80 (m, 4H), 7.77 ( d, 1H, J = 7.9 Hz), 7.50-7.38 (m, 2H), 7.00 (d, 1H, J = 4.1 Hz), 3.96 (s, 3H), 1.60 (s, 9H).
실시예Example 211. 4-(4-((3-(tert-부톡시카보닐)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산(4-(4-((3-(tert-butoxycarbonyl)phenyl)carbamoyl)-3-(5-chlorothiophen-2-yl)-1H-pyrazol-1-yl)benzoic acid); KY-06638 211. 4- (4-((3- (tert-butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid ( 4- (4-((3- (tert-butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid); KY-06638
KY-06539와 동일한 방법으로 합성하여 표제 화합물(86%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (86%).
1H NMR (300 MHz, DMSO) δ 13.14 (s, 1H), 10.47 (s, 1H), 9.33 (s, 1H), 8.25 (s, 1H), 8.15 (d, 2H, J = 8.5 Hz), 8.09 (s, 1H), 8.03 (d, 3H, J = 8.3 Hz), 7.87 (d, 1H, J = 4.0 Hz), 7.66 (d, 1H, J = 7.6 Hz), 7.50 (t, 1H, J = 7.9 Hz), 7.18 (t, 1H, J = 5.6 Hz), 1.56 (s, 9H). 1 H NMR (300 MHz, DMSO) δ 13.14 (s, 1H), 10.47 (s, 1H), 9.33 (s, 1H), 8.25 (s, 1H), 8.15 (d, 2H, J = 8.5 Hz), 8.09 (s, 1H), 8.03 (d, 3H, J = 8.3 Hz), 7.87 (d, 1H, J = 4.0 Hz), 7.66 (d, 1H, J = 7.6 Hz), 7.50 (t, 1H, J = 7.9 Hz), 7.18 (t, 1H, J = 5.6 Hz), 1.56 (s, 9H).
실시예Example 212. 3-(3-(5-클로로티오펜-2-일)-1-(4-(메톡시카보닐)페닐)-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-chlorothiophen-2-yl)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxamido)benzoic acid); KY-06639 212. 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoic acid (3- ( 3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoic acid); KY-06639
50 mL 둥근바닥플라스크에 t-부틸 에스테르 화합물(200 mg, 0.37 mmol)을 MC에 용해시켜 교반하였다. 상기 혼합물에 TFA(1.85 mmol, 0.15 mL)를 첨가하여 상온에서 반응시켰다. 24시간 후, TLC를 이용하여 출발물질이 남아있는 것을 확인하여 동량의 TFA를 더 첨가하여 상온에서 24시간 더 반응시켰다. 반응종료 후, 용매를 농축하고 고진공으로 건조하여 표제 화합물(196.7 mg, 89%)을 수득하였다.A t-butyl ester compound (200 mg, 0.37 mmol) was dissolved in MC and stirred in a 50 mL round bottom flask. TFA (1.85 mmol, 0.15 mL) was added to the mixture, followed by reaction at room temperature. After 24 hours, it was confirmed that the starting material remained by using TLC, the same amount of TFA was further added and reacted at room temperature for 24 hours. After completion of the reaction, the solvent was concentrated and dried in high vacuum to give the title compound (196.7 mg, 89%).
1H NMR (300 MHz, DMSO) δ 13.00 (s, 1H), 10.45 (s, 1H), 9.35 (s, 1H), 8.36 (d, 1H, J = 2.8 Hz), 8.24-7.92 (m, 5H), 7.90 (t, 1H, J = 3.4 Hz), 7.51 (t, 1H, J = 7.8 Hz), 7.18 (t, 1H, J = 3.6 Hz), 3.90 (s, 3H). 1 H NMR (300 MHz, DMSO) δ 13.00 (s, 1H), 10.45 (s, 1H), 9.35 (s, 1H), 8.36 (d, 1H, J = 2.8 Hz), 8.24-7.92 (m, 5H ), 7.90 (t, 1H, J = 3.4 Hz), 7.51 (t, 1H, J = 7.8 Hz), 7.18 (t, 1H, J = 3.6 Hz), 3.90 (s, 3H).
실시예Example 213. 3-(1-(4-카르복시페닐)-3-(5-클로로티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산(3-(1-(4-carboxyphenyl)-3-(5-chlorothiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid); KY-06640 213. 3- (1- (4-carboxyphenyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (3- (1- (4- carboxyphenyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid); KY-06640
KY-06539와 동일한 방법으로 합성하여 표제 화합물(80%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (80%).
1H NMR (300 MHz, DMSO) δ 13.09 (s, 1H), 10.45 (s, 1H), 9.34 (s, 1H), 8.36 (s, 1H), 8.15 (d, 2H, J = 8.6 Hz), 8.07-7.97 (m, 3H), 7.90 (d, 1H, J = 4.0 Hz), 7.70 (d, 1H, J = 7.7 Hz), 7.51 (t, 1H, J = 7.9 Hz), 7.17 (d, 1H, J = 4.0 Hz). 1 H NMR (300 MHz, DMSO) δ 13.09 (s, 1H), 10.45 (s, 1H), 9.34 (s, 1H), 8.36 (s, 1H), 8.15 (d, 2H, J = 8.6 Hz), 8.07-7.97 (m, 3H), 7.90 (d, 1H, J = 4.0 Hz), 7.70 (d, 1H, J = 7.7 Hz), 7.51 (t, 1H, J = 7.9 Hz), 7.17 (d, 1H , J = 4.0 Hz).
실시예Example 214.  214. 메틸methyl 4-(4-((3-(((2R,3R)-1-(tert-부톡시)-3-메틸-1-옥소펜탄-2-일)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조에이트(methyl 4-(4-((3-(((2R,3R)-1-(tert-butoxy)-3-methyl-1-oxopentan-2-yl)carbamoyl)phenyl)carbamoyl)-3-(5-chlorothiophen-2-yl)-1H-pyrazol-1-yl)benzoate); KY-06641 4- (4-((3-(((2R, 3R) -1- (tert-butoxy) -3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate (methyl 4- (4-((3-(((2R, 3R) -1- (tert-butoxy)- 3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate); KY-06641
7 mL 바이알에 산 화합물(100 mg, 0.2 mmol), L-이소루신 tert-부틸 에스테르 하이드로클로라이드(45 mg, 0.2 mmol), HBTU(193.4 mg, 0.51 mmol), DIPEA(0.51 mmol, 89.6 μL), DMF를 넣고 상온에서 24시간 동안 반응시켰다. TLC로 반응을 확인하여 출발물질이 남아있는 경우 24시간 더 반응을 진행하였다. 반응종료 후, EA와 H2O로 추출하고 MgSO4로 건조시켰다. 실리카겔컬럼 크로마토그래피로 분리 정제하여 표제 화합물(104.4 mg, 93%)을 수득하였다.In a 7 mL vial acid compound (100 mg, 0.2 mmol), L-isoleucine tert-butyl ester hydrochloride (45 mg, 0.2 mmol), HBTU (193.4 mg, 0.51 mmol), DIPEA (0.51 mmol, 89.6 μL), DMF was added and reacted at room temperature for 24 hours. The reaction was confirmed by TLC and the reaction proceeded further for 24 hours when the starting material remained. After completion of the reaction, the mixture was extracted with EA and H 2 O and dried over MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (104.4 mg, 93%).
1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.18 (d, 2H, J = 8.5 Hz), 7.98 (s, 1H), 7.87 (t, 3H, J = 10.9 Hz), 7.78 (s, 1H), 7.54 (t, 2H, J = 4.8 Hz), 7.43 (t, 1H, J = 7.8 Hz), 6.99 (d, 1H, J = 3.9 Hz), 6.82 (d, 1H, J = 8.0 Hz), 4.68 (d, 1H, J = 7.9 Hz), 3.96 (s, 3H), 1.99 (s, 1H), 1.49 (s, 9H), 1.36-1.18 (m, 2H), 0.98 (d, 6H, J = 6.9 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.18 (d, 2H, J = 8.5 Hz), 7.98 (s, 1H), 7.87 (t, 3H, J = 10.9 Hz), 7.78 (s, 1H), 7.54 (t, 2H, J = 4.8 Hz), 7.43 (t, 1H, J = 7.8 Hz), 6.99 (d, 1H, J = 3.9 Hz), 6.82 (d, 1H, J = 8.0 Hz), 4.68 (d, 1H, J = 7.9 Hz), 3.96 (s, 3H), 1.99 (s, 1H), 1.49 (s, 9H), 1.36-1.18 (m, 2H), 0.98 (d, 6H, J = 6.9 Hz).
실시예Example 215. 4-(4-((3-(((2S,3S)-1-(tert-부톡시)-3-메틸-1-옥소펜탄-2-일)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산(4-(4-((3-(((2S,3S)-1-(tert-butoxy)-3-methyl-1-oxopentan-2-yl)carbamoyl)phenyl)carbamoyl)-3-(5-chlorothiophen-2-yl)-1H-pyrazol-1-yl)benzoic acid); KY-06642 215. 4- (4-((3-(((2S, 3S) -1- (tert-butoxy) -3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl)- 3- (5-Chlorothiophen-2-yl) -1 H-pyrazol-1-yl) benzoic acid 4- (4-((3-(((2S, 3S) -1- (tert-butoxy)- 3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid); KY-06642
KY-06539와 동일한 방법으로 합성하여 표제 화합물(94%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (94%).
1H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.33 (s, 1H), 8.45 (d, 1H, J = 7.7 Hz), 8.15 (d, 3H, J = 8.8 Hz), 8.02 (d, 2H, J = 8.7 Hz), 7.92 (d, 2H, J = 15.8 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.47 (t, 1H, J = 7.9 Hz), 7.17 (d, 1H, J = 4.0 Hz), 4.27 (d, 1H, J = 15.8 Hz), 1.96 (d, 1H, J = 15.5 Hz), 1.43 (s, 9H), 1.34-1.24 (m, 2H), 1.02-0.81 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.33 (s, 1H), 8.45 (d, 1H, J = 7.7 Hz), 8.15 (d, 3H, J = 8.8 Hz), 8.02 ( d, 2H, J = 8.7 Hz), 7.92 (d, 2H, J = 15.8 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.47 (t, 1H, J = 7.9 Hz), 7.17 (d, 1H, J = 4.0 Hz), 4.27 (d, 1H, J = 15.8 Hz), 1.96 (d, 1H, J = 15.5 Hz), 1.43 (s, 9H), 1.34-1.24 (m, 2H), 1.02- 0.81 (m, 6 H).
실시예Example 216. 4-(4-((3-(((1R,2R)-1-카르복시-2-메틸부틸)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산(4-(4-((3-(((1R,2R)-1-carboxy-2-methylbutyl)carbamoyl)phenyl)carbamoyl)-3-(5-chlorothiophen-2-yl)-1H-pyrazol-1-yl)benzoic acid); KY-06643 216. 4- (4-((3-(((1R, 2R) -1-carboxy-2-methylbutyl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid (4- (4-((3-(((1R, 2R) -1-carboxy-2-methylbutyl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen -2-yl) -1H-pyrazol-1-yl) benzoic acid); KY-06643
50 mL 둥근바닥플라스크에 t-부틸 에스테르 화합물(70 mg, 0.11 mmol)을 MC에 용해시켜 10분 동안 교반하였다. 상기 혼합물에 TFA(0.55 mmol, 42 μL)를 적가하고 상온에서 12시간 동안 반응시켰다. 반응종료 후, 용매를 농축하고 고진공으로 건조하고 고체화한 후 생성된 고체를 여과하여 표제 화합물(65.2 mg, 87%)을 수득하였다.The t-butyl ester compound (70 mg, 0.11 mmol) was dissolved in MC in a 50 mL round bottom flask and stirred for 10 minutes. TFA (0.55 mmol, 42 μL) was added dropwise to the mixture and reacted at room temperature for 12 hours. After completion of the reaction, the solvent was concentrated, dried in high vacuum and solidified, and the resulting solid was filtered to give the title compound (65.2 mg, 87%).
1H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.33 (s, 1H), 8.44 (d, 1H, J = 7.9 Hz), 8.23-7.84 (m, 7H), 7.65 (d, 1H, J = 7.8 Hz), 7.47 (t, 1H, J = 7.8 Hz), 7.16 (s, 1H), 4.34 (t, 1H, J = 7.1 Hz), 1.96 (s, 1H), 1.52-1.29 (m, 2H), 1.10-0.71 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.33 (s, 1H), 8.44 (d, 1H, J = 7.9 Hz), 8.23-7.84 (m, 7H), 7.65 (d, 1H , J = 7.8 Hz), 7.47 (t, 1H, J = 7.8 Hz), 7.16 (s, 1H), 4.34 (t, 1H, J = 7.1 Hz), 1.96 (s, 1H), 1.52-1.29 (m , 2H), 1.10-0.71 (m, 6H).
실시예Example 217.  217. 메틸methyl 3-((3-(5- 3-((3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )메틸)-4-플루오로벤조에이트(methyl 3-((3-(5-Methyl) -4-fluorobenzoate (methyl 3-((3- (5- chlorothiophenchlorothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)methyl)-4-fluorobenzoate); KY-06644) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoate); KY-06644
KY-06545와 동일한 방법으로 합성하여 표제 화합물(77%)을 수득하였다.Synthesis in the same manner as KY-06545 gave the title compound (77%).
1H NMR (300 MHz, DMSO) δ 9.03 (s, 1H), 8.91 (t, J = 5.7 Hz, 1H), 8.07 (dd, J = 2.2, 7.3 Hz, 1H), 7.95 (ddd, J = 2.4, 5.2, 8.5 Hz, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.9 Hz, 2H), 7.44-7.35 (m, 2H), 7.12 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H). 1 H NMR (300 MHz, DMSO) δ 9.03 (s, 1H), 8.91 (t, J = 5.7 Hz, 1H), 8.07 (dd, J = 2.2, 7.3 Hz, 1H), 7.95 (ddd, J = 2.4 , 5.2, 8.5 Hz, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.9 Hz, 2H), 7.44-7.35 (m , 2H), 7.12 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H).
실시예Example 218. 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조산(3-((3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)methyl)-4-fluorobenzoic acid); KY-06645 218. 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoic acid (3-((3 -(5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoic acid); KY-06645
KY-06615와 동일한 방법으로 합성하여 표제 화합물(92%)을 수득하였다.Synthesis in the same manner as KY-06615 gave the title compound (92%).
1H NMR (300 MHz, DMSO) δ 9.03 (s, 1H), 8.88 (t, J = 5.5 Hz, 1H), 8.04 (dd, J = 2.1, 7.3 Hz, 1H), 7.94 -7.89 (m, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H). 1 H NMR (300 MHz, DMSO) δ 9.03 (s, 1H), 8.88 (t, J = 5.5 Hz, 1H), 8.04 (dd, J = 2.1, 7.3 Hz, 1H), 7.94 -7.89 (m, 1H ), 7.90 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H).
실시예Example 219.  219. terttert -부틸 (3-((3-(5--Butyl (3-((3- (5- 클로로티오펜Chlorothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)메틸)-4-플루오로벤조일)-L-이소루시네이트(tert-butyl (3-((3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)methyl)-4-fluorobenzoyl)-L-isoleucinate); KY-066464-carboxamido) methyl) -4-fluorobenzoyl) -L-isorushinate (tert-butyl (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H- pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-isoleucinate); KY-06646
KY-06545와 동일한 방법으로 합성하여 표제 화합물(85%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (85%).
1H NMR (300 MHz, DMSO) δ 9.05 (s, 1H), 8.83 (t, J = 5.7 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H), 7.97 (dd, J = 1.9, 7.3 Hz, 1H), 7.92 -7.86 (m, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.24 (t, J = 7.4 Hz, 1H), 1.95-1.86 (m, 1H), 1.51-1.43 (m, 1H), 1.39 (s, 1H), 1.30-1.18 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 9.05 (s, 1H), 8.83 (t, J = 5.7 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H), 7.97 (dd, J = 1.9, 7.3 Hz, 1H), 7.92 -7.86 (m, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.24 ( t, J = 7.4 Hz, 1H), 1.95-1.86 (m, 1H), 1.51-1.43 (m, 1H), 1.39 (s, 1H), 1.30-1.18 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).
실시예Example 220. (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조일)-L-이소루신((3-((3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)methyl)-4-fluorobenzoyl)-L-isoleucine); KY-06647 220. (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-iso Leucine ((3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-isoleucine); KY-06647
KY-06613과 동일한 방법으로 합성하여 표제 화합물(93%)을 수득하였다.Synthesis was performed in the same manner as KY-06613 to give the title compound (93%).
1H NMR (300 MHz, DMSO) δ 12.58 (s, 1H), 9.05 (s, 1H), 8.82 (t, J = 5.4 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.99 (dd, J = 1.9, 7.2 Hz, 1H), 7.93 -7.88 (m, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 4.24 (t, J = 7.5 Hz, 1H), 1.98-1.86 (m, 1H), 1.55-1.42 (m, 1H), 1.33-1.18 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 1 H NMR (300 MHz, DMSO) δ 12.58 (s, 1H), 9.05 (s, 1H), 8.82 (t, J = 5.4 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.99 ( dd, J = 1.9, 7.2 Hz, 1H), 7.93 -7.88 (m, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 4.24 (t, J = 7.5 Hz, 1H), 1.98-1.86 (m, 1H), 1.55-1.42 (m, 1H), 1.33-1.18 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).
실시예Example 221.  221. 메틸methyl 3-(3-(5- 3- (3- (5- 시아노티오펜Cyanothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-5-플루오로벤조에이트(methyl 3-(3-(5-) -5-fluorobenzoate (methyl 3- (3- (5- cyanothiophencyanothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoate); KY-06648) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate); KY-06648
KY-06545와 동일한 방법으로 합성하여 표제 화합물(34%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (34%).
1H NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 9.32 (s, 1H), 8.15 (t, J = 1.5 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 8.05 (t, J = 2.2 Hz, 1H), 8.01 (t, J = 2.2 Hz, 1H), 7.99 (d, J = 4.1 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.50-7.44 (m, 2H), 3.90 (s, 3H). 1 H NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 9.32 (s, 1H), 8.15 (t, J = 1.5 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 8.05 ( t, J = 2.2 Hz, 1H), 8.01 (t, J = 2.2 Hz, 1H), 7.99 (d, J = 4.1 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.50-7.44 (m, 2H), 3.90 (s, 3H).
실시예Example 222. 3-(3-(5-시아노티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조산(3-(3-(5-cyanothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-5-fluorobenzoic acid); KY-06649 222. 3- (3- (5-cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid (3- (3- (5- cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid); KY-06649
KY-06615와 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was carried out in the same manner as KY-06615 to obtain the title compound (99%).
1H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 9.33 (s, 1H), 8.10 (d, J = 4.0 Hz, 2H), 8.00-7.92 (m, 4H), 7.64 (d, J = 7.9 Hz, 2H), 7.50-7.40 (m, 2H). 1 H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 9.33 (s, 1H), 8.10 (d, J = 4.0 Hz, 2H), 8.00-7.92 (m, 4H), 7.64 (d, J 7.9 Hz, 2H), 7.50-7.40 (m, 2H).
실시예Example 223.  223. 메틸methyl 4-(3-(5- 4- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )사이클로헥산-1-카르복실레이트(methyl 4-(3-(5-Cyclohexane-1-carboxylate (methyl 4- (3- (5- bromothiophenbromothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylate); KY-06650) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate); KY-06650
KY-06545와 동일한 방법으로 합성하여 표제 화합물(59%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (59%).
1H NMR (300 MHz, DMSO) δ 8.97 (d, J = 6.2 Hz, 1H), 8.09 (dd, J = 7.5, 20.6 Hz, 1H), 7.86-7.84 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.91-3.86 (m, 1H), 3.62 (d, J = 5.9 Hz, 3H), 2.61-2.58 (m, 1H), 2.02-1.96 (m, 2H), 1.76-1.25 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 8.97 (d, J = 6.2 Hz, 1H), 8.09 (dd, J = 7.5, 20.6 Hz, 1H), 7.86-7.84 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.91-3.86 (m, 1H), 3.62 (d, J = 5.9 Hz, 3H ), 2.61-2.58 (m, 1H), 2.02-1.96 (m, 2H), 1.76-1.25 (m, 6H).
실시예Example 224. 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산(4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylic acid); KY-06651 224. 4- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid (4- (3- (5- bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid); KY-06651
KY-06546과 동일한 방법으로 합성하여 표제 화합물(94%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (94%).
1H NMR (300 MHz, DMSO) δ 12.16 (s, 1H), 8.97 (d, J = 6.4 Hz, 1H), 8.10 (dd, J = 7.7, 17.3 Hz, 1H), 7.86-7.84 (m, 3H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.87 (s, 1H), 2.05-1.91 (m, 2H), 1.72-1.29 (m, 7H). 1 H NMR (300 MHz, DMSO) δ 12.16 (s, 1H), 8.97 (d, J = 6.4 Hz, 1H), 8.10 (dd, J = 7.7, 17.3 Hz, 1H), 7.86-7.84 (m, 3H ), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.87 (s, 1H), 2.05-1.91 (m , 2H), 1.72-1.29 (m, 7H).
실시예Example 225.  225. 메틸methyl ( ( 1S,4S1S, 4S )-4-(3-(5-) -4- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카르복실레이트(methyl (1S,4S)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylate); KY-066524-carboxamido) cyclohexane-1-carboxylate (methyl (1S, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido ) cyclohexane-1-carboxylate); KY-06652
KY-06545와 동일한 방법으로 합성하여 표제 화합물(95%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (95%).
1H NMR (300 MHz, DMSO) δ 8.98 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.86-7.84 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.92-3.86 (m, 1H), 3.63 (s, 3H), 2.63-2.57 (m, 1H), 2.02-1.94 (m. 2H), 1.75-1.48 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 8.98 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.86-7.84 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.92-3.86 (m, 1H), 3.63 (s, 3H), 2.63-2.57 (m, 1H), 2.02 -1.94 (m. 2H), 1.75-1.48 (m, 6H).
실시예Example 226. (1S,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산((1S,4S)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylic acid); KY-06653 226. (1S, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid ((1S , 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid); KY-06653
KY-06546과 동일한 방법으로 합성하여 표제 화합물(98%)을 수득하였다.Synthesis was performed in the same manner as KY-06546 to give the title compound (98%).
1H NMR (300 MHz, DMSO) δ 8.98 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.86-7.84 (m, 3H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.87 (s, 1H), 2.47 (s, 1H), 2.02-1.98 (m, 2H), 1.07-1.54 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 8.98 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.86-7.84 (m, 3H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.87 (s, 1H), 2.47 (s, 1H), 2.02-1.98 (m, 2H), 1.07-1.54 (m, 6 H).
실시예Example 227.  227. 메틸methyl ( ( 1R,4R1R, 4R )-4-(3-(5-) -4- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카르복실레이트(methyl (1R,4R)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylate); KY-066544-carboxamido) cyclohexane-1-carboxylate (methyl (1R, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido ) cyclohexane-1-carboxylate); KY-06654
KY-06545와 동일한 방법으로 합성하여 표제 화합물(93%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (93%).
1H NMR (300 MHz, DMSO) δ 8.96 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.86-7.83 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.78-3.67 (m, 1H), 3.61 (s, 3H), 2.36-2.28 (m, 1H), 1.97 (d, J = 10.0 Hz, 4H), 1.52-1.26 (m, 4H). 1 H NMR (300 MHz, DMSO) δ 8.96 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.86-7.83 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.78-3.67 (m, 1H), 3.61 (s, 3H), 2.36-2.28 (m, 1H), 1.97 (d, J = 10.0 Hz, 4H), 1.52-1.26 (m, 4H).
실시예Example 228. (1R,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산((1R,4R)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylic acid); KY-06655 228. (1R, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid ((1R , 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid); KY-06655
KY-06546과 동일한 방법으로 합성하여 표제 화합물(90%)을 수득하였다.Synthesis in the same manner as KY-06546 gave the title compound (90%).
1H NMR (300 MHz, DMSO) δ 12.11 (s, 1H), 8.96 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.86-7.84 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 4.0 Hz, 1H), 3.76-3.67 (m, 1H), 2.23-2.16 (m, 1H), 1.96 (d, J = 10.0 Hz, 4H), 1.49-1.24 (m, 4H). 1 H NMR (300 MHz, DMSO) δ 12.11 (s, 1H), 8.96 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.86-7.84 (m, 3H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 4.0 Hz, 1H), 3.76-3.67 (m, 1H), 2.23-2.16 (m, 1H), 1.96 (d, J = 10.0 Hz, 4H), 1.49-1.24 (m, 4H).
실시예Example 229.  229. terttert -부틸 ((-Butyl (( 1S,4R1S, 4R )-4-(3-(5-) -4- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트(tert-butyl ((1S,4R)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carbonyl)-L-isoleucinate); KY-066564-carboxamido) cyclohexane-1-carbonyl) -L-isorushinate (tert-butyl ((1S, 4R) -4- (3- (5-bromothiophen-2-yl) -1- phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucinate); KY-06656
KY-06545와 동일한 방법으로 합성하여 표제 화합물(93%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to give the title compound (93%).
1H NMR (300 MHz, DMSO) δ 8.99 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.87-7.82 (m, 4H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 4.14-4.09 (m, 1H), 3.97 (s, 1H), 2.43 (s, 1H), 1.90-1.80 (m, 5H), 1.65-1.54 (m, 4H), 1.40 (s, 9H), 1.24-1.16 (m, 2H), 0.87-0.82 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 8.99 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.87-7.82 (m, 4H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 4.14-4.09 (m, 1H), 3.97 (s, 1H), 2.43 (s, 1H), 1.90-1.80 (m, 5H), 1.65-1.54 (m, 4H), 1.40 (s, 9H), 1.24-1.16 (m, 2H), 0.87-0.82 (m, 6H).
실시예Example 230. ((1S,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신(((1S,4R)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carbonyl)-L-isoleucine); KY-06657 230. ((1S, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-Isoleucine (((1S, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine ); KY-06657
KY-06613과 동일한 방법으로 합성하여 표제 화합물(75%)을 수득하였다.Synthesis in the same manner as KY-06613 gave the title compound (75%).
1H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 9.00 (s, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.87-7.82 (m, 4H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 4.19 (dd, J = 6.3, 8.3 Hz, 1H), 3.96 (s, 1H), 2.43 (s, 1H), 1.91-1.72 (m, 5H), 1.64-1.54 (m, 4H), 1.21-1.13 (m, 2H), 0.87-0.82 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 9.00 (s, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.87-7.82 (m, 4H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 4.19 (dd, J = 6.3, 8.3 Hz, 1H), 3.96 (s, 1H ), 2.43 (s, 1H), 1.91-1.72 (m, 5H), 1.64-1.54 (m, 4H), 1.21-1.13 (m, 2H), 0.87-0.82 (m, 6H).
실시예Example 231.  231. terttert -부틸 ((-Butyl (( 1R,4S1R, 4S )-4-(3-(5-) -4- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트(tert-butyl ((1R,4S)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carbonyl)-L-isoleucinate); KY-066584-carboxamido) cyclohexane-1-carbonyl) -L-isorushinate (tert-butyl ((1R, 4S) -4- (3- (5-bromothiophen-2-yl) -1- phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucinate); KY-06658
KY-06545와 동일한 방법으로 합성하여 표제 화합물(67%)을 수득하였다.Synthesis was performed in the same manner as KY-06545 to obtain the title compound (67%).
1H NMR (300 MHz, DMSO) δ 8.96 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.89-7.84 (m, 4H), 7.58 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 4.0 Hz, 1H), 4.10 (dd, J = 6.2, 8.2 Hz, 1H), 3.79-3.65 (m, 1H), 2.32-2.25 (m, 1H), 1.96 (d, J = 12.4 Hz, 2H), 1.80-1.77 (m, 3H), 1.62-1.18 (m, 15H), 0.88-0.83 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 8.96 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.89-7.84 (m, 4H), 7.58 (t, J = 7.9 Hz, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 4.0 Hz, 1H), 4.10 (dd, J = 6.2, 8.2 Hz, 1H), 3.79-3.65 (m, 1H), 2.32-2.25 (m, 1 H), 1.96 (d, J = 12.4 Hz, 2H), 1.80-1.77 (m, 3H), 1.62-1.18 (m, 15H), 0.88-0.83 (m, 6H).
실시예Example 232. ((1R,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신(((1R,4S)-4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carbonyl)-L-isoleucine); KY-06659 232. ((1R, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-Isoleucine (((1R, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine ); KY-06659
KY-06613과 동일한 방법으로 합성하여 표제 화합물(91%)을 수득하였다.Synthesis in the same manner as KY-06613 gave the title compound (91%).
1H NMR (300 MHz, DMSO) δ 12.53 (s, 1H), 8.96 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.87-7.84 (m, 4H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 4.0 Hz, 1H), 4.19 (dd, J = 6.2, 8.6 Hz, 1H), 3.78 - 3.65 (m, 1H), 2.34-2.25 (s, 1H), 1.97-1.93 (m, 2H), 1.80-1.77 (m, 3H), 1.52-1.18 (m, 6H), 0.87-0.83 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 12.53 (s, 1H), 8.96 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.87-7.84 (m, 4H), 7.58 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 4.0 Hz, 1H), 4.19 (dd, J = 6.2, 8.6 Hz, 1H), 3.78-3.65 (m , 1H), 2.34-2.25 (s, 1H), 1.97-1.93 (m, 2H), 1.80-1.77 (m, 3H), 1.52-1.18 (m, 6H), 0.87-0.83 (m, 6H).
실시예Example 233. 에틸 4-(3-(5- 233. ethyl 4- (3- (5- 브로모티오펜Bromothiophene -2-일)-4-((3--2-yl) -4-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )-1H-피라졸-1-일)벤조에이트(ethyl 4-(3-(5-) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5- bromothiophenbromothiophen -2--2- ylyl )-4-((3-phenoxyphenyl)carbamoyl)-1H-pyrazol-1-yl)benzoate); KY-06660) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate); KY-06660
KY-06542와 동일한 방법으로 합성하여 표제 화합물(63%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (63%).
1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J = 3.3 Hz), 8.15 (dd, 2H, J = 8.6, 3.2 Hz), 7.84-7.71 (m, 3H), 7.46-6.97 (m, 10H), 6.78 (d, 1H, J = 7.9 Hz), 4.40 (q, 2H, J = 7.1 Hz), 1.42 (t, 3H, J = 7.0 Hz). 1 H NMR (300 MHz, CDCl 3 ) δ 8.51 (d, 1H, J = 3.3 Hz), 8.15 (dd, 2H, J = 8.6, 3.2 Hz), 7.84-7.71 (m, 3H), 7.46-6.97 ( m, 10H), 6.78 (d, 1H, J = 7.9 Hz), 4.40 (q, 2H, J = 7.1 Hz), 1.42 (t, 3H, J = 7.0 Hz).
실시예Example 234. 4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조산(4-(3-(5-bromothiophen-2-yl)-4-((3-phenoxyphenyl)carbamoyl)-1H-pyrazol-1-yl)benzoic acid); KY-06661 234. 4- (3- (5-Bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid (4- (3- ( 5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid); KY-06661
KY-06539와 동일한 방법으로 합성하여 표제 화합물(78%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (78%).
1H NMR (300 MHz, DMSO) δ 13.16 (s, 1H), 10.35 (s, 1H), 9.27 (s, 1H), 8.14 (d, 2H, J = 8.7 Hz), 8.06-7.97 (m, 2H), 7.78 (d, 1H, J = 4.0 Hz), 7.60-7.48 (m, 1H), 7.47-7.34 (m, 4H), 7.26 (d, 1H, J = 4.0 Hz), 7.17 (t, 1H, J = 7.3 Hz), 7.10-7.01 (m, 2H), 6.78 (dd, 1H, J = 8.1, 2.4 Hz). 1 H NMR (300 MHz, DMSO) δ 13.16 (s, 1H), 10.35 (s, 1H), 9.27 (s, 1H), 8.14 (d, 2H, J = 8.7 Hz), 8.06-7.97 (m, 2H ), 7.78 (d, 1H, J = 4.0 Hz), 7.60-7.48 (m, 1H), 7.47-7.34 (m, 4H), 7.26 (d, 1H, J = 4.0 Hz), 7.17 (t, 1H, J = 7.3 Hz), 7.10-7.01 (m, 2H), 6.78 (dd, 1H, J = 8.1, 2.4 Hz).
실시예Example 235.  235. 메틸methyl (4-(3-(5- (4- (3- (5- 브로모티오펜Bromothiophene -2-일)-4-((3--2-yl) -4-((3- 페녹시페닐Phenoxyphenyl )) 카바모일Cabamo )-1H-피라졸-1-일)벤조일)-L-알로이소루시네이트(methyl (4-(3-(5-bromothiophen-2-yl)-4-((3-phenoxyphenyl)carbamoyl)-1H-pyrazol-1-yl)benzoyl)-L-alloisoleucinate); KY-06662) -1H-pyrazol-1-yl) benzoyl) -L-alloisorushate (methyl (4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H -pyrazol-1-yl) benzoyl) -L-alloisoleucinate); KY-06662
KY-06542와 동일한 방법으로 합성하여 표제 화합물(57%)을 수득하였다.Synthesis in the same manner as KY-06542 gave the title compound (57%).
1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 8.00 (s, 1H), 7.87 (d, 2H, J = 8.7 Hz), 7.76 (d, 2H, J = 8.6 Hz), 7.53-7.31 (m, 3H), 7.18-6.97 (m, 4H), 6.74 (d, 2H, J = 7.8 Hz), 4.79 (d, 1H, J = 8.5 Hz), 3.78 (s, 3H), 1.72-1.46 (m, 3H), 0.99-0.97 (m, 6H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.47 (s, 1H), 8.00 (s, 1H), 7.87 (d, 2H, J = 8.7 Hz), 7.76 (d, 2H, J = 8.6 Hz), 7.53 -7.31 (m, 3H), 7.18-6.97 (m, 4H), 6.74 (d, 2H, J = 7.8 Hz), 4.79 (d, 1H, J = 8.5 Hz), 3.78 (s, 3H), 1.72- 1.46 (m, 3H), 0.99-0.97 (m, 6H)
실시예Example 236. 2-(4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤즈아미도)-3-메틸펜탄산(2-(4-(3-(5-bromothiophen-2-yl)-4-((3-phenoxyphenyl)carbamoyl)-1H-pyrazol-1-yl)benzamido)-3-methylpentanoic acid); KY-06663 236. 2- (4- (3- (5-Bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzamido)- 3-methylpentanoic acid (2- (4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzamido) -3-methylpentanoic acid ); KY-06663
KY-06539와 동일한 방법으로 합성하여 표제 화합물(79%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (79%).
1H NMR (300 MHz, DMSO) δ 12.63 (s, 1H), 10.34 (s, 1H), 9.24 (s, 1H), 8.55 (d, 1H, J = 7.9 Hz), 8.11 (d, 2H, J = 8.3 Hz), 7.98 (d, 2H, J = 7.8 Hz), 7.77 (s, 1H), 7.54 (d, 1H, J = 7.9 Hz), 7.48-7.35 (m, 3H), 7.26 (s, 1H), 7.17 (t, 1H, J = 6.9 Hz), 7.06 (d, 2H, J = 7.8 Hz), 6.78 (d, 1H, J = 7.8 Hz), 4.36 (t, 1H, J = 7.2 Hz), 1.99 (s, 1H), 1.54 (s, 1H), 1.25 (s, 2H), 1.04-0.81 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 12.63 (s, 1H), 10.34 (s, 1H), 9.24 (s, 1H), 8.55 (d, 1H, J = 7.9 Hz), 8.11 (d, 2H, J = 8.3 Hz), 7.98 (d, 2H, J = 7.8 Hz), 7.77 (s, 1H), 7.54 (d, 1H, J = 7.9 Hz), 7.48-7.35 (m, 3H), 7.26 (s, 1H ), 7.17 (t, 1H, J = 6.9 Hz), 7.06 (d, 2H, J = 7.8 Hz), 6.78 (d, 1H, J = 7.8 Hz), 4.36 (t, 1H, J = 7.2 Hz), 1.99 (s, 1 H), 1.54 (s, 1 H), 1.25 (s, 2 H), 1.04-0.81 (m, 6 H).
실시예Example 237.  237. 메틸methyl 3-(3-(5- 3- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-4-메톡시벤조에이트(methyl 3-(3-(5-) -4-methoxybenzoate (methyl 3- (3- (5- bromothiophenbromothiophen -2--2- ylyl )-1-phenyl-1H-pyrazole-4-carboxamido)-4-methoxybenzoate); KY-06664) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoate); KY-06664
KY-06542와 동일한 방법으로 합성하여 표제 화합물(30%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to obtain the title compound (30%).
1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 7.86-7.71 (m, 3H), 7.52 (d, 2H, J = 7.7 Hz), 7.40 (t, 2H, J = 4.2 Hz), 7.13 (d, 1H, J = 4.1 Hz), 6.89 (d, 1H, J = 8.4 Hz), 3.90 (s, 3H), 3.82 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 9.13 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 7.86-7.71 (m, 3H), 7.52 (d, 2H, J = 7.7 Hz), 7.40 (t, 2H, J = 4.2 Hz), 7.13 (d, 1H, J = 4.1 Hz), 6.89 (d, 1H, J = 8.4 Hz), 3.90 (s, 3H), 3.82 (s, 3H).
실시예Example 238. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤조산(3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-4-methoxybenzoic acid); KY-06665 238. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoic acid (3- (3- (5- bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoic acid); KY-06665
KY-06539와 동일한 방법으로 합성하여 표제 화합물(94%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (94%).
1H NMR (300 MHz, DMSO) δ 12.76 (s, 1H), 9.47 (s, 1H), 9.22 (s, 1H), 8.46 (s, 1H), 7.90 (d, 2H, J = 8.2 Hz), 7.83-7.76 (m, 2H), 7.59 (t, 2H, J = 7.8 Hz), 7.43 (t, 1H, J = 7.5 Hz), 7.30-7.15 (m, 2H), 3.91 (s, 3H). 1 H NMR (300 MHz, DMSO) δ 12.76 (s, 1H), 9.47 (s, 1H), 9.22 (s, 1H), 8.46 (s, 1H), 7.90 (d, 2H, J = 8.2 Hz), 7.83-7.76 (m, 2H), 7.59 (t, 2H, J = 7.8 Hz), 7.43 (t, 1H, J = 7.5 Hz), 7.30-7.15 (m, 2H), 3.91 (s, 3H).
실시예Example 239.  239. 메틸methyl (3-(3-(5- (3- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )-4-메톡시벤조일)-L-이소루시네이트(methyl (3-(3-(5-) -4-methoxybenzoyl) -L-isorushinate (methyl (3- (3- (5- bromothiophenbromothiophen -2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-4-methoxybenzoyl)-L-isoleucinate); KY-06666-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoyl) -L-isoleucinate); KY-06666
KY-06542와 동일한 방법으로 합성하여 표제 화합물(96%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (96%).
1H NMR (300 MHz, CDCl3) δ 8.94 (t, 1H, J = 2.2 Hz), 8.54 (s, 1H), 8.40 (s, 1H), 7.76 (d, 2H, J = 8.4 Hz), 7.66 (t, 1H, J = 8.6 Hz), 7.51 (t, 2H, J = 7.0 Hz), 7.38 (t, 2H, J = 5.5 Hz), 7.13 (d, 1H, J = 3.8 Hz), 6.91-6.84 (m, 1H), 6.69 (d, 1H, J = 13.6 Hz), 4.82-4.77 (m, 1H), 3.78 (d, 6H, J = 8.6 Hz), 1.58-1.50 (m, 1H), 1.36-1.22 (m, 2H), 0.99-0.81 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.94 (t, 1H, J = 2.2 Hz), 8.54 (s, 1H), 8.40 (s, 1H), 7.76 (d, 2H, J = 8.4 Hz), 7.66 (t, 1H, J = 8.6 Hz), 7.51 (t, 2H, J = 7.0 Hz), 7.38 (t, 2H, J = 5.5 Hz), 7.13 (d, 1H, J = 3.8 Hz), 6.91-6.84 (m, 1H), 6.69 (d, 1H, J = 13.6 Hz), 4.82-4.77 (m, 1H), 3.78 (d, 6H, J = 8.6 Hz), 1.58-1.50 (m, 1H), 1.36- 1.22 (m, 2 H), 0.99-0.81 (m, 6 H).
실시예Example 240. 2-(3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤즈아미도)-3-메틸펜탄산(2-(3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)-4-methoxybenzamido)-3-methylpentanoic acid); KY-06667 240. 2- (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzamido) -3- Methylpentanoic acid (2- (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzamido) -3-methylpentanoic acid); KY-06667
KY-06539와 동일한 방법으로 합성하여 표제 화합물(75%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (75%).
1H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 9.48 (s, 1H), 9.21 (s, 1H), 8.30 (s, 1H), 7.98-7.74 (m, 4H), 7.59 (t, 2H, J = 7.9 Hz), 7.43 (t, 1H, J = 7.7 Hz), 7.24-7.10 (m, 2H), 4.33 (t, 1H, J = 7.7 Hz), 3.89 (s, 3H), 1.93 (d, 1H, J = 14.7 Hz), 1.51 (d, 1H, J = 11.5 Hz), 1.37-1.17 (m, 2H), 0.96-0.78 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 9.48 (s, 1H), 9.21 (s, 1H), 8.30 (s, 1H), 7.98-7.74 (m, 4H), 7.59 (t , 2H, J = 7.9 Hz), 7.43 (t, 1H, J = 7.7 Hz), 7.24-7.10 (m, 2H), 4.33 (t, 1H, J = 7.7 Hz), 3.89 (s, 3H), 1.93 (d, 1H, J = 14.7 Hz), 1.51 (d, 1H, J = 11.5 Hz), 1.37-1.17 (m, 2H), 0.96-0.78 (m, 6H).
실시예Example 241.  241. 메틸methyl ( ( 1S,3R1S, 3R )-3-(3-(5-) -3- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카르복실레이트(methyl (1S,3R)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylate); KY-066684-carboxamido) cyclohexane-1-carboxylate (methyl (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido ) cyclohexane-1-carboxylate); KY-06668
KY-06542와 동일한 방법으로 합성하여 표제 화합물(50%)을 수득하였다.Synthesis in the same manner as KY-06542 gave the title compound (50%).
1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.71 (d, 2H, J = 8.1 Hz), 7.58-7.30 (m, 4H), 7.17-7.04 (m, 1H), 5.95 (d, 1H, J = 8.0 Hz), 4.00 (d, 1H, J = 10.7 Hz), 3.68 (s, 3H), 2.50 (t, 1H, J = 11.4 Hz), 2.29 (d, 1H, J = 12.6 Hz), 2.01-1.85 (m, 2H), 1.48-1.09 (m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.33 (s, 1H), 7.71 (d, 2H, J = 8.1 Hz), 7.58-7.30 (m, 4H), 7.17-7.04 (m, 1H), 5.95 ( d, 1H, J = 8.0 Hz), 4.00 (d, 1H, J = 10.7 Hz), 3.68 (s, 3H), 2.50 (t, 1H, J = 11.4 Hz), 2.29 (d, 1H, J = 12.6 Hz), 2.01-1.85 (m, 2H), 1.48-1.09 (m, 4H).
실시예Example 242. (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산((1S,3R)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylic acid); KY-06669 242. (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid ((1S , 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid); KY-06669
KY-06539와 동일한 방법으로 합성하여 표제 화합물(74%)을 수득하였다.Synthesis was carried out in the same manner as KY-06539 to give the title compound (74%).
1H NMR (300 MHz, DMSO) δ 12.01 (s, 1H), 8.95 (s, 1H), 7.93-7.76 (m, 3H), 7.57 (t, 2H, J = 7.8 Hz), 7.41 (d, 1H, J = 7.3 Hz), 7.22 (d, 1H, J = 4.0 Hz), 3.75-3.71 (m, 1H), 2.11-1.98 (m, 3H), 1.92-1.80 (m, 5H). 1 H NMR (300 MHz, DMSO) δ 12.01 (s, 1H), 8.95 (s, 1H), 7.93-7.76 (m, 3H), 7.57 (t, 2H, J = 7.8 Hz), 7.41 (d, 1H , J = 7.3 Hz), 7.22 (d, 1H, J = 4.0 Hz), 3.75-3.71 (m, 1H), 2.11-1.98 (m, 3H), 1.92-1.80 (m, 5H).
실시예Example 243.  243. 메틸methyl 2-(( 2-(( 1S,3R1S, 3R )-3-(3-(5-) -3- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카르복스아미도)-3-메틸펜타네이트(methyl 2-((1S,3R)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxamido)-3-methylpentanate); KY-066704-carboxamido) cyclohexane-1-carboxamido) -3-methylpentanate (methyl 2-((1S, 3R) -3- (3- (5-bromothiophen-2-yl)- 1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxamido) -3-methylpentanate); KY-06670
KY-06542와 동일한 방법으로 합성하여 표제 화합물(22%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (22%).
1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.72 (d, 2H, J = 7.9 Hz), 7.48 (d, 3H, J = 9.8 Hz), 7.36 (d, 1H, J = 7.4 Hz), 7.08 (t, 1H, J = 5.6 Hz), 6.24 (s, 1H), 5.97 (d, 1H, J = 9.0 Hz), 4.59 (t, 1H, J = 8.6 Hz), 4.06 (s, 1H), 3.73 (s, 3H), 2.37 (s, 1H), 2.20 (s, 1H), 2.02-1.79 (m, 4H), 1.4-1.42 (m, 2H), 1.30-1.14 (m, 3H), 1.03-0.85 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.35 (s, 1H), 7.72 (d, 2H, J = 7.9 Hz), 7.48 (d, 3H, J = 9.8 Hz), 7.36 (d, 1H, J = 7.4 Hz), 7.08 (t, 1H, J = 5.6 Hz), 6.24 (s, 1H), 5.97 (d, 1H, J = 9.0 Hz), 4.59 (t, 1H, J = 8.6 Hz), 4.06 (s , 1H), 3.73 (s, 3H), 2.37 (s, 1H), 2.20 (s, 1H), 2.02-1.79 (m, 4H), 1.4-1.42 (m, 2H), 1.30-1.14 (m, 3H ), 1.03-0.85 (m, 6H).
실시예Example 244. 2-((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복스아미도)-3-메틸펜탄산(2-((1S,3R)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxamido)-3-methylpentanoic acid); KY-06671 244. 2-((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-car Voxamido) -3-methylpentanoic acid (2-((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1 -carboxamido) -3-methylpentanoic acid); KY-06671
KY-06539와 동일한 방법으로 합성하여 표제 화합물(67%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (67%).
1H NMR (300 MHz, DMSO) δ 12.47 (s, 1H), 8.96 (s, 1H), 8.13 (d, 1H, J = 7.9 Hz), 7.93 (d, 1H, J = 8.4 Hz), 7.84 (q, 3H, J = 3.7 Hz), 7.57 (t, 2H, J = 7.6 Hz), 7.40 (t, 1H, J = 7.3 Hz), 7.22 (t, 1H, J = 3.9 Hz), 4.18 (d, 1H, J = 7.0 Hz), 3.81 (s, 1H), 2.03-1.59 (m, 5H), 1.50-1.08 (m, 7H), 0.91-0.76 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 12.47 (s, 1H), 8.96 (s, 1H), 8.13 (d, 1H, J = 7.9 Hz), 7.93 (d, 1H, J = 8.4 Hz), 7.84 ( q, 3H, J = 3.7 Hz), 7.57 (t, 2H, J = 7.6 Hz), 7.40 (t, 1H, J = 7.3 Hz), 7.22 (t, 1H, J = 3.9 Hz), 4.18 (d, 1H, J = 7.0 Hz), 3.81 (s, 1H), 2.03-1.59 (m, 5H), 1.50-1.08 (m, 7H), 0.91-0.76 (m, 6H).
실시예Example 245.  245. 메틸methyl 4-((3-(5- 4-((3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )메틸)사이클로헥산-1-카르복실레이트(methyl 4-((3-(5-Methyl) cyclohexane-1-carboxylate (methyl 4-((3- (5- bromothiophenbromothiophen -2-yl)-1-phenyl-1H-pyrazole-4-카르복스아미도)methyl)cyclohexane-1-carboxylate); KY-06672-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylate); KY-06672
KY-06542와 동일한 방법으로 합성하여 표제 화합물(55%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (55%).
1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.71 (d, 2H, J = 7.9 Hz), 7.49 (d, 2H, J = 7.6 Hz), 7.43-7.32 (m, 2H), 7.09 (t, 1H, J = 5.7 Hz), 6.00 (d, 1H, J = 7.4 Hz), 3.67 (s, 3H), 3.27 (q, 2H, J = 8.0 Hz), 2.26-2.23 (m, 1H), 2.08-1.94 (m, 2H), 1.80 (d, 2H, J = 13.0 Hz), 1.51-1.70 (m, 2H), 1.11-0.88 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.35 (s, 1H), 7.71 (d, 2H, J = 7.9 Hz), 7.49 (d, 2H, J = 7.6 Hz), 7.43-7.32 (m, 2H) , 7.09 (t, 1H, J = 5.7 Hz), 6.00 (d, 1H, J = 7.4 Hz), 3.67 (s, 3H), 3.27 (q, 2H, J = 8.0 Hz), 2.26-2.23 (m, 1H), 2.08-1.94 (m, 2H), 1.80 (d, 2H, J = 13.0 Hz), 1.51-1.70 (m, 2H), 1.11-0.88 (m, 2H).
실시예Example 246. 4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복시산(4-((3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)methyl)cyclohexane-1-carboxylic acid); KY-06673 246. 4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylic acid (4-((3 -(5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylic acid); KY-06673
KY-06539와 동일한 방법으로 합성하여 표제 화합물(40%)을 수득하였다.Synthesis was carried out in the same manner as KY-06539 to obtain the title compound (40%).
1H NMR (300 MHz, DMSO) δ 11.99 (s, 1H), 8.96 (s, 1H, J = 3.3 Hz), 8.24 (t, 1H, J = 5.7 Hz), 7.84 (d, 3H, J = 8.3 Hz), 7.57 (t, 2H, J = 7.8 Hz), 7.44-7.35 (m, 1H), 7.22 (d, 1H, J = 3.9 Hz), 3.11 (t, 2H, J = 6.3 Hz), 2.21-2.08 (m, 1H), 1.98-1.80 (m, 4H), 1.49 (s, 1H), 1.39-1.21 (m, 2H), 1.11-0.89 (m, 2H) 1 H NMR (300 MHz, DMSO) δ 11.99 (s, 1H), 8.96 (s, 1H, J = 3.3 Hz), 8.24 (t, 1H, J = 5.7 Hz), 7.84 (d, 3H, J = 8.3 Hz), 7.57 (t, 2H, J = 7.8 Hz), 7.44-7.35 (m, 1H), 7.22 (d, 1H, J = 3.9 Hz), 3.11 (t, 2H, J = 6.3 Hz), 2.21- 2.08 (m, 1H), 1.98-1.80 (m, 4H), 1.49 (s, 1H), 1.39-1.21 (m, 2H), 1.11-0.89 (m, 2H)
실시예Example 247.  247. 메틸methyl (4-((3-(5- (4-((3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )메틸)사이클로헥산-1-카보닐)-D-이소루시네이트(methyl (4-((3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-카르복스아미도)methyl)cyclohexane-1-carbonyl)-D-isoleucinate); KY-06674Methyl) cyclohexane-1-carbonyl) -D-isorushinate (methyl (4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido ) methyl) cyclohexane-1-carbonyl) -D-isoleucinate); KY-06674
KY-06542와 동일한 방법으로 합성하여 표제 화합물(85%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (85%).
1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.78-7.66 (m, 2H), 7.57-7.45 (m, 2H), 7.42-7.30 (m, 2H), 7.10 (t, 1H, J = 2.9 Hz), 5.96 (q, 2H, J = 7.9 Hz), 4.62 (t, 1H, J = 8.5 Hz), 3.74 (s, 3H), 3.27 (q, 2H, J = 5.8 Hz), 2.19-2.03 (m, 1H), 1.99-1.74 (m, 6H), 1.50-1.45 (m, 3H), 1.31-1.12 (m, 3H), 1.04-0.87 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.37 (s, 1H), 7.78-7.66 (m, 2H), 7.57-7.45 (m, 2H), 7.42-7.30 (m, 2H), 7.10 (t, 1H , J = 2.9 Hz), 5.96 (q, 2H, J = 7.9 Hz), 4.62 (t, 1H, J = 8.5 Hz), 3.74 (s, 3H), 3.27 (q, 2H, J = 5.8 Hz), 2.19-2.03 (m, 1H), 1.99-1.74 (m, 6H), 1.50-1.45 (m, 3H), 1.31-1.12 (m, 3H), 1.04-0.87 (m, 6H).
실시예Example 248. 2-(4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복스아미도)-3-메틸펜탄산(2-(4-((3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)methyl)cyclohexane-1-carboxamido)-3-methylpentanoic acid); KY-06675 248. 2- (4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxamido ) -3-methylpentanoic acid (2- (4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxamido) -3- methylpentanoic acid); KY-06675
KY-06539와 동일한 방법으로 합성하여 표제 화합물(99%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (99%).
1H NMR (300 MHz, DMSO) δ 8.99 (s, 1H), 8.25 (d, 1H, J = 5.9 Hz), 7.89-7.81 (m, 3H), 7.75 (d, 1H, J = 7.5 Hz), 7.57 (q, 2H, J = 7.3 Hz), 7.40 (q, 1H, J = 7.0 Hz), 7.28-7.17 (m, 1H), 4.12 (q, 1H, J = 6.8 Hz), 3.09 (d, 2H, J = 6.3 Hz), 2.23 (t, 1H, J = 12.2 Hz), 1.84-1.71 (m, 5H), 1.53-1.09 (m, 5H), 0.95 (d, 1H, J = 12.9 Hz), 0.85-0.79 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 8.99 (s, 1H), 8.25 (d, 1H, J = 5.9 Hz), 7.89-7.81 (m, 3H), 7.75 (d, 1H, J = 7.5 Hz), 7.57 (q, 2H, J = 7.3 Hz), 7.40 (q, 1H, J = 7.0 Hz), 7.28-7.17 (m, 1H), 4.12 (q, 1H, J = 6.8 Hz), 3.09 (d, 2H , J = 6.3 Hz), 2.23 (t, 1H, J = 12.2 Hz), 1.84-1.71 (m, 5H), 1.53-1.09 (m, 5H), 0.95 (d, 1H, J = 12.9 Hz), 0.85 -0.79 (m, 6 H).
실시예Example 249.  249. 메틸methyl ( ( 1S,3R1S, 3R )-3-(3-(5-) -3- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카르복실레이트(methyl (1S,3R)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylate); KY-066764-carboxamido) cyclohexane-1-carboxylate (methyl (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido ) cyclohexane-1-carboxylate); KY-06676
KY-06542와 동일한 방법으로 합성하여 표제 화합물(83%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (83%).
1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.78-7.66 (m, 2H), 7.49 (t, 2H, J = 7.7 Hz), 7.43-7.30 (m, 2H), 7.11 (d, 1H, J = 3.8 Hz), 5.97 (d, 1H, J = 7.7 Hz), 4.32 (s, 1H), 3.70 (s, 3H), 2.37 (d, 1H, J = 12.0 Hz), 2.00-1.84 (m, 2H), 1.76-1.61 (m, 4H), 1.30-1.26 (m, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.39 (s, 1H), 7.78-7.66 (m, 2H), 7.49 (t, 2H, J = 7.7 Hz), 7.43-7.30 (m, 2H), 7.11 ( d, 1H, J = 3.8 Hz), 5.97 (d, 1H, J = 7.7 Hz), 4.32 (s, 1H), 3.70 (s, 3H), 2.37 (d, 1H, J = 12.0 Hz), 2.00- 1.84 (m, 2H), 1.76-1.61 (m, 4H), 1.30-1.26 (m, 1H).
실시예Example 250. (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산((1S,3R)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carboxylic acid); KY-06677 250. (1S, 3R) -3- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid ((1S , 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid); KY-06677
KY-06539와 동일한 방법으로 합성하여 표제 화합물(94%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (94%).
1H NMR (300 MHz, DMSO) δ 12.18 (s, 1H), 9.08-8.90 (m, 1H), 8.14-7.77 (m, 4H), 7.59 (t, 2H, J = 10.9 Hz), 7.41 (s, 1H), 7.24 (d, 1H, J = 10.0 Hz), 4.09 (s, 1H), 1.98-1.37 (m, 8H). 1 H NMR (300 MHz, DMSO) δ 12.18 (s, 1H), 9.08-8.90 (m, 1H), 8.14-7.77 (m, 4H), 7.59 (t, 2H, J = 10.9 Hz), 7.41 (s , 1H), 7.24 (d, 1H, J = 10.0 Hz), 4.09 (s, 1H), 1.98-1.37 (m, 8H).
실시예Example 251.  251. 메틸methyl (( (( 1R,3S1R, 3S )-3-(3-(5-) -3- (3- (5- 브로모티오펜Bromothiophene -2-일)-1-페닐-1H--2-yl) -1-phenyl-1H- 피라졸Pyrazole -4-카르복스아미도)사이클로헥산-1-카보닐)-D-이소루시네이트(methyl ((1R,3S)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carbonyl)-D-isoleucinate); KY-066784-carboxamido) cyclohexane-1-carbonyl) -D-isorushinate (methyl ((1R, 3S) -3- (3- (5-bromothiophen-2-yl) -1-phenyl- 1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -D-isoleucinate); KY-06678
KY-06542와 동일한 방법으로 합성하여 표제 화합물(81%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (81%).
1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.73 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 7.6 Hz), 7.37 (d, 2H, J = 9.0 Hz), 7.17 (d, 1H, J = 2.9 Hz), 6.05 (s, 2H), 4.61 (d, 1H, J = 9.2 Hz), 4.39 (s, 1H), 3.75 (s, 3H), 2.15 (d, 2H, J = 3.0 Hz), 1.98-1.72 (m, 6H), 1.45 (d, 1H, J = 11.4 Hz), 1.25 (d, 3H, J = 3.8 Hz), 0.95-0.91 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (s, 1H), 7.73 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 7.6 Hz), 7.37 (d, 2H, J = 9.0 Hz), 7.17 (d, 1H, J = 2.9 Hz), 6.05 (s, 2H), 4.61 (d, 1H, J = 9.2 Hz), 4.39 (s, 1H), 3.75 (s, 3H), 2.15 (d, 2H, J = 3.0 Hz), 1.98-1.72 (m, 6H), 1.45 (d, 1H, J = 11.4 Hz), 1.25 (d, 3H, J = 3.8 Hz), 0.95-0.91 (m, 6H).
실시예Example 252. ((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신(((1S,3R)-3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)cyclohexane-1-carbonyl)-L-isoleucine); KY-06679 252. ((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-Isoleucine (((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine ); KY-06679
KY-06539와 동일한 방법으로 합성하여 표제 화합물(78%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (78%).
1H NMR (300 MHz, DMSO) δ 12.53 (s, 1H), 9.00 (s, 1H), 7.89-7.80 (m, 4H), 7.75-7.49 (m, 3H), 7.41 (t, 1H, J = 7.3 Hz), 7.22 (t, 1H, J = 3.6 Hz), 4.24-4.18 (m, 3H), 2.68 (s, 1H), 1.85-1.52 (m, 8H), 1.45-1.26 (m, 1H), 1.18 (t, 1H, J = 13.2 Hz, 1H), 0.99-0.69 (m, 6H). 1 H NMR (300 MHz, DMSO) δ 12.53 (s, 1H), 9.00 (s, 1H), 7.89-7.80 (m, 4H), 7.75-7.49 (m, 3H), 7.41 (t, 1H, J = 7.3 Hz), 7.22 (t, 1H, J = 3.6 Hz), 4.24-4.18 (m, 3H), 2.68 (s, 1H), 1.85-1.52 (m, 8H), 1.45-1.26 (m, 1H), 1.18 (t, 1 H, J = 13.2 Hz, 1 H), 0.99-0.69 (m, 6H).
실시예Example 253. 에틸 4-(3-(5- 253. Ethyl 4- (3- (5- 브로모티오펜Bromothiophene -2-일)-4-(((-2-yl) -4-((( 1R,3S1R, 3S )-3-() -3- ( 메톡시카보닐Methoxycarbonyl )사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트(ethyl 4-(3-(5-bromothiophen-2-yl)-4-(((1R,3S)-3-(methoxycarbonyl)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoate); KY-06680) Cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3S) -3- (methoxycarbonyl) ) cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate); KY-06680
KY-06542와 동일한 방법으로 합성하여 표제 화합물(94%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to obtain the title compound (94%).
1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 8.26-8.10 (m, 2H), 7.87-7.75 (m, 2H), 7.52 (s, 1H), 7.15 (s, 1H), 6.00 (d, 1H, J = 8.5 Hz), 4.41 (q, 2H, J = 8.1 Hz), 4.11-3.95 (m, 1H), 3.78 (s, 3H), 2.60-2.45 (m, 1H), 2.29 (d, 1H, J = 12.6 Hz), 2.14-1.94 (m, 3H), 1.89-1.80 (m, 1H), 1.48-1.22 (m, 4H), 1.19-1.03 (m, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.47 (s, 1H), 8.26-8.10 (m, 2H), 7.87-7.75 (m, 2H), 7.52 (s, 1H), 7.15 (s, 1H), 6.00 (d, 1H, J = 8.5 Hz), 4.41 (q, 2H, J = 8.1 Hz), 4.11-3.95 (m, 1H), 3.78 (s, 3H), 2.60-2.45 (m, 1H), 2.29 (d, 1H, J = 12.6 Hz), 2.14-1.94 (m, 3H), 1.89-1.80 (m, 1H), 1.48-1.22 (m, 4H), 1.19-1.03 (m, 1H).
실시예Example 254. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3S)-3-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산(4-(3-(5-bromothiophen-2-yl)-4-(((1R,3S)-3-carboxycyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoic acid); KY-06681 254. 4- (3- (5-Bromothiophen-2-yl) -4-(((1R, 3S) -3-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid ( 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3S) -3-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid); KY-06681
KY-06539와 동일한 방법으로 합성하여 표제 화합물(90%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (90%).
1H NMR (300 MHz, DMSO) δ 12.87 (s, 2H), 9.19 (s, 1H), 8.29-8.10 (m, 3H), 7.97 (d, 2H, J = 8.6 Hz), 7.86 (q, 1H, J = 4.3 Hz), 7.24 (q, 1H, J = 4.2 Hz), 3.94 (s, 1H), 2.35 (d, 1H, J = 12.5 Hz), 2.11 (d, 1H, J = 12.5 Hz), 1.84 (d, 3H, J = 33.4 Hz), 1.50-1.06 (m, 5H). 1 H NMR (300 MHz, DMSO) δ 12.87 (s, 2H), 9.19 (s, 1H), 8.29-8.10 (m, 3H), 7.97 (d, 2H, J = 8.6 Hz), 7.86 (q, 1H , J = 4.3 Hz), 7.24 (q, 1H, J = 4.2 Hz), 3.94 (s, 1H), 2.35 (d, 1H, J = 12.5 Hz), 2.11 (d, 1H, J = 12.5 Hz), 1.84 (d, 3H, J = 33.4 Hz), 1.50-1.06 (m, 5H).
실시예Example 255. 에틸 4-(3-(5- 255. Ethyl 4- (3- (5- 브로모티오펜Bromothiophene -2-일)-4-(((-2-yl) -4-((( 1R,3R1R, 3R )-3-() -3- ( 메톡시카보닐Methoxycarbonyl )사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트(ethyl 4-(3-(5-bromothiophen-2-yl)-4-(((1R,3R)-3-(methoxycarbonyl)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoate); KY-06682) Cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3R) -3- (methoxycarbonyl) ) cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate); KY-06682
KY-06542와 동일한 방법으로 합성하여 표제 화합물(88%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (88%).
1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.17 (d, 2H, J = 8.6 Hz), 7.81 (d, 2H, J = 8.8 Hz), 7.46-7.32 (m, 1H), 7.21-7.06 (m, 1H), 5.98 (d, 1H, J = 7.9 Hz), 4.55-4.37 (m, 2H), 4.32 (s, 1H), 3.81 (s, 3H), 2.40 (s, 1H), 1.98-1.61 (m, 6H), 1.42 (t, 3H, J = 7.5 Hz), 1.35-1.22 (m, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (s, 1H), 8.17 (d, 2H, J = 8.6 Hz), 7.81 (d, 2H, J = 8.8 Hz), 7.46-7.32 (m, 1H) , 7.21-7.06 (m, 1H), 5.98 (d, 1H, J = 7.9 Hz), 4.55-4.37 (m, 2H), 4.32 (s, 1H), 3.81 (s, 3H), 2.40 (s, 1H ), 1.98-1.61 (m, 6H), 1.42 (t, 3H, J = 7.5 Hz), 1.35-1.22 (m, 1H).
실시예Example 256. 4-(3-(5- 256. 4- (3- (5- 브로모티오펜Bromothiophene -2-일)-4-(((-2-yl) -4-((( 1R,3R1R, 3R )-3-) -3- 카르복시사이클로헥실Carboxycyclohexyl )카바모일)-1H-피라졸-1-일)벤조산(4-(3-(5-bromothiophen-2-yl)-4-(((1R, 3R)-3-carboxycyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoic acid); KY-06683) Carbamoyl) -1H-pyrazol-1-yl) benzoic acid (4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3R) -3-carboxycyclohexyl) carbamoyl) -1H- pyrazol-1-yl) benzoic acid); KY-06683
KY-06539와 동일한 방법으로 합성하여 표제 화합물(79%)을 수득하였다.Synthesis was performed in the same manner as KY-06539 to give the title compound (79%).
1H NMR (300 MHz, DMSO) δ 13.05 (s, 2H), 9.10 (s, 1H), 8.18-7.94 (m, 4H), 7.83 (s, 1H), 7.24 (s, 1H), 4.05 (s, 1H), 2.74 (s, 1H), 1.93-1.81 (m, 1H), 1.77-1.57 (m, 5H), 1.48 (t, 3H, J = 7.2 Hz). 1 H NMR (300 MHz, DMSO) δ 13.05 (s, 2H), 9.10 (s, 1H), 8.18-7.94 (m, 4H), 7.83 (s, 1H), 7.24 (s, 1H), 4.05 (s , 1H), 2.74 (s, 1H), 1.93-1.81 (m, 1H), 1.77-1.57 (m, 5H), 1.48 (t, 3H, J = 7.2 Hz).
실시예Example 257. 에틸 4-(3-(5- 257. ethyl 4- (3- (5- 브로모티오펜Bromothiophene -2-일)-4-(((-2-yl) -4-((( 1S,4S1S, 4S )-4-()-4-( 메톡시카보닐Methoxycarbonyl )사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트(ethyl 4-(3-(5-bromothiophen-2-yl)-4-(((1s,4s)-4-(methoxycarbonyl)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoate); KY-06684) Cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1s, 4s) -4- (methoxycarbonyl) ) cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate); KY-06684
KY-06542와 동일한 방법으로 합성하여 표제 화합물(87%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (87%).
1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 8.16 (d, 2H, J = 8.0 Hz), 7.89-7.75 (m, 2H), 7.45-7.35 (m, 1H), 7.16-7.04 (m, 1H), 5.99 (d, 1H, J = 7.1 Hz), 4.51-4.33 (m, 2H), 4.12 (d, 1H, J = 9.0 Hz), 3.77 (s, 3H), 2.57 (s, 1H), 1.84-1.69 (m, 5H), 1.61 (d, 3H, J = 24.3 Hz), 1.49-1.36 (m, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.42 (s, 1H), 8.16 (d, 2H, J = 8.0 Hz), 7.89-7.75 (m, 2H), 7.45-7.35 (m, 1H), 7.16- 7.04 (m, 1H), 5.99 (d, 1H, J = 7.1 Hz), 4.51-4.33 (m, 2H), 4.12 (d, 1H, J = 9.0 Hz), 3.77 (s, 3H), 2.57 (s , 1H), 1.84-1.69 (m, 5H), 1.61 (d, 3H, J = 24.3 Hz), 1.49-1.36 (m, 3H).
실시예Example 258. 4-(3-(5-브로모티오펜-2-일)-4-(((1S,4S)-4-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산(4-(3-(5-bromothiophen-2-yl)-4-(((1s,4s)-4-carboxycyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoic acid); KY-06685 258. 4- (3- (5-Bromothiophen-2-yl) -4-(((1S, 4S) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid ( 4- (3- (5-bromothiophen-2-yl) -4-(((1s, 4s) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid); KY-06685
KY-06542와 동일한 방법으로 합성하여 표제 화합물(77%)을 수득하였다.Synthesis was performed in the same manner as KY-06542 to give the title compound (77%).
1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 8.16 (d, 2H, J = 8.6 Hz), 7.80 (d, 2H, J = 8.7 Hz), 7.40 (d, 1H, J = 3.8 Hz), 7.09 (d, 1H, J = 3.9 Hz), 5.78 (d, 1H, J = 8.0 Hz), 4.48-4.33 (m, 2H), 3.94 (q, 1H, J = 10.9 Hz), 3.68 (s, 3H), 2.34-2.18 (m, 1H), 2.18-1.95 (m, 3H), 1.63 (d, 2H, J = 14.2 Hz), 1.42 (t, 3H, J = 7.1 Hz), 1.32-1.04 (m, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.39 (s, 1H), 8.16 (d, 2H, J = 8.6 Hz), 7.80 (d, 2H, J = 8.7 Hz), 7.40 (d, 1H, J = 3.8 Hz), 7.09 (d, 1H, J = 3.9 Hz), 5.78 (d, 1H, J = 8.0 Hz), 4.48-4.33 (m, 2H), 3.94 (q, 1H, J = 10.9 Hz), 3.68 (s, 3H), 2.34-2.18 (m, 1H), 2.18-1.95 (m, 3H), 1.63 (d, 2H, J = 14.2 Hz), 1.42 (t, 3H, J = 7.1 Hz), 1.32- 1.04 (m, 3 H).
실시예Example 259. 에틸 4-(3-(5- 259. Ethyl 4- (3- (5- 브로모티오펜Bromothiophene -2-일)-4-(((-2-yl) -4-((( 1R,4R1R, 4R )-4-()-4-( 메톡시카보닐Methoxycarbonyl )사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트(ethyl 4-(3-(5-bromothiophen-2-yl)-4-(((1R,4R)-4-(methoxycarbonyl)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoate); KY-06686) Cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 4R) -4- (methoxycarbonyl) ) cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate); KY-06686
KY-06539와 동일한 방법으로 합성하여 표제 화합물(63%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (63%).
1H NMR (300 MHz, DMSO) δ 12.56 (s, 2H), 9.18-9.02 (m, 1H), 8.18-8.05 (m, 3H), 7.98 (dd, 2H, J = 8.4, 5.1 Hz), 7.89-7.81 (m, 1H), 7.36-7.18 (m, 1H), 4.01-3.73 (m, 1H), 1.97 (d, 2H, J = 9.9 Hz), 1.65 (d, 6H, J = 34.7 Hz). 1 H NMR (300 MHz, DMSO) δ 12.56 (s, 2H), 9.18-9.02 (m, 1H), 8.18-8.05 (m, 3H), 7.98 (dd, 2H, J = 8.4, 5.1 Hz), 7.89 -7.81 (m, 1H), 7.36-7.18 (m, 1H), 4.01-3.73 (m, 1H), 1.97 (d, 2H, J = 9.9 Hz), 1.65 (d, 6H, J = 34.7 Hz).
실시예Example 260. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,4R)-4-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산(4-(3-(5-bromothiophen-2-yl)-4-(((1R,4R)-4-carboxycyclohexyl)carbamoyl)-1H-pyrazol-1-yl)benzoic acid); KY-06687 260. 4- (3- (5-Bromothiophen-2-yl) -4-(((1R, 4R) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid ( 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 4R) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid); KY-06687
KY-06539와 동일한 방법으로 합성하여 표제 화합물(63%)을 수득하였다.Synthesis in the same manner as KY-06539 gave the title compound (63%).
1H NMR (300 MHz, DMSO) δ 12.55 (s, 2H), 9.18-8.98 (m, 1H), 8.18-8.06 (m, 3H), 8.02-7.93 (m, 2H), 7.86 (q, 1H, J = 3.4 Hz), 7.34-7.19 (m, 1H), 3.88-3.60 (m, 1H), 2.36-2.11 (m, 1H), 1.96 (d, 3H, J = 11.4 Hz), 1.36 (q, 5H, J = 12.5 Hz). 1 H NMR (300 MHz, DMSO) δ 12.55 (s, 2H), 9.18-8.98 (m, 1H), 8.18-8.06 (m, 3H), 8.02-7.93 (m, 2H), 7.86 (q, 1H, J = 3.4 Hz), 7.34-7.19 (m, 1H), 3.88-3.60 (m, 1H), 2.36-2.11 (m, 1H), 1.96 (d, 3H, J = 11.4 Hz), 1.36 (q, 5H , J = 12.5 Hz).
실시예Example 261. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤젠설폰산(3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzenesulfonic acid); KY-06688 261. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid (3- (3- (5-bromothiophen-2 -yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06688
KY-06533과 동일한 방법으로 합성하여 표제 화합물(93%)을 수득하였다.Synthesis in the same manner as KY-06533 gave the title compound (93%).
Column (MC packing, MC Loading)) MC → MC:MeOH = 19:1 → MC:MeOH = 10:1 93%Column (MC packing, MC Loading)) MC → MC: MeOH = 19: 1 → MC: MeOH = 10: 1 93%
1H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 9.23 (s, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 4.0 Hz, 1H), 7.80 (td, J = 1.1, 7.2 Hz, 1H), 7.61 (t, J = 7.9 Hz, 2H), 7.43 (d, J = 7.4 Hz, 1H), 7.37-7.32 (m, 2H), 7.26 (d, J = 4.0 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 9.23 (s, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 4.0 Hz, 1H), 7.80 (td, J = 1.1, 7.2 Hz, 1H), 7.61 (t, J = 7.9 Hz, 2H), 7.43 (d, J = 7.4 Hz, 1H), 7.37-7.32 (m, 2H ), 7.26 (d, J = 4.0 Hz, 1H).
실시예Example 262. 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤젠설폰산(4-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzenesulfonic acid); KY-06689 262. 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid (4- (3- (5-bromothiophen-2 -yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06689
KY-06533과 동일한 방법으로 합성하여 표제 화합물(72%)을 수득하였다.Synthesis in the same manner as KY-06533 gave the title compound (72%).
1H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 9.21 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 4.0 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.63-7.58 (m, 4H), 7.43 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 9.21 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 4.0 Hz, 1H), 7.68 ( d, J = 8.7 Hz, 2H), 7.63-7.58 (m, 4H), 7.43 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H).
실시예Example 263. 3-(1-페닐-3-(5- 263. 3- (1-phenyl-3- (5- 설포티오펜Sulfothiophene -2-일)-1H-2-yl) -1H- 피라졸Pyrazole -4--4- 카르복스아미도Carcassamido )벤조산(3-(1-phenyl-3-(5-sulfothiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid); KY-06690) Benzoic acid (3- (1-phenyl-3- (5-sulfothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid); KY-06690
7 mL 바이알에 염화설포닐 화합물(50 mg), THF(1 mL), H2O(5 mL)을 넣고 교반한 후, LiOH(15 mg)을 넣고 상온에서 16시간 동안 교반하였다. 이후 증류수를 더하고 에테르로 세척하였다. 1N HCl을 이용하여 물층의 pH를 1로 맞추고, IPA:CHCl3=1:3 혼합용매로 추출하였다. 유기층을 MgSO4로 건조시켜 표제 화합물(64%)을 수득하였다.Into a 7 mL vial, sulfonyl chloride compound (50 mg), THF (1 mL), H 2 O (5 mL) was added thereto, followed by stirring. Then, LiOH (15 mg) was added thereto and stirred at room temperature for 16 hours. Then distilled water was added and washed with ether. The pH of the water layer was adjusted to 1 using 1N HCl, and extracted with IPA: CHCl 3 = 1: 3 mixed solvent. The organic layer was dried over MgSO 4 to afford the title compound (64%).
1H NMR (300 MHz, DMSO) δ 10.39 (s, 1H), 9.18 (s, 1H), 8.37 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.7 Hz, 2H), 7.74 (d, J = 3.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 2H), 7.53 ? 7.47 (m, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 3.8 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 10.39 (s, 1H), 9.18 (s, 1H), 8.37 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.7 Hz, 2H), 7.74 (d, J = 3.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 2H), 7.53? 7.47 (m, 1 H), 7.42 (t, J = 7.4 Hz, 1 H), 7.09 (d, J = 3.8 Hz, 1 H).
실시예Example 264. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid); KY-06277 264. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (5-bromothiophen-2-yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid); KY-06277
20 mL 바이알에 에스테르 화합물(4.31 mmol, 1.95 g)을 THF(6 mL)에 용해시켜 교반하였다. H2O(6 mL)과 MeOH(3 mL)을 넣은 후, LiOH(5.0 eq. 904 mg)을 넣고 상온에서 18시간 동안 교반하였다. 반응 종료 후, 100 mL 둥근바닥플라스크에 옮겨 회전증발기(rotavapor)로 MeOH과 THF를 제거하고, 에테르:H2O=1:2 혼합 용매로 세척하였다. 물층의 pH가 8인 것을 리트머스지로 확인한 후, 1N HCl을 가하면서 pH를 2 내지 3으로 맞추었다. 1N HCl 혼합물을 신터를 사용하여 헥산으로 세척하면서 여과하였다. 흰색 고체로 표제 화합물(64%)을 수득하였다.In 20 mL vials, the ester compound (4.31 mmol, 1.95 g) was dissolved in THF (6 mL) and stirred. H 2 O (6 mL) and MeOH (3 mL) were added, LiOH (5.0 eq. 904 mg) was added thereto, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the resultant was transferred to a 100 mL round bottom flask to remove MeOH and THF with a rotavapor, and the mixture was washed with an ether: H 2 O = 1: 2 mixed solvent. After confirming that the pH of the water layer was 8 by litmus paper, the pH was adjusted to 2-3 while adding 1N HCl. The 1N HCl mixture was filtered, washing with hexane using Sinter. The title compound (64%) was obtained as a white solid.
rotavapor로 MeOH와 THF를 제거한다. 여기에 Ether : H20=1:2로 washing한다. H2Olayer를 pH test paper로 pH 8 확인한 후, 1N HCl를 넣으면서 pH 2~3으로 맞춘다. 1N HCl mixture를 신터를 사용해 Hexane으로 Washing하며 filter한다. 흰색고체의 화합물을 83%로 얻을 수 있다.Remove MeOH and THF with rotavapor. Wash Ether here with H20 = 1: 2. Check the pH of the H2Olayer with a pH test paper 8, and then adjust the pH to 2-3 with 1N HCl. Wash the 1N HCl mixture with Hexane using sinter and filter. 83% of a white solid compound can be obtained.
1H NMR (300 MHz, DMSO) δ 13.02 (s, 1OH), 10.37 (s, 1NH), 9.22 (s, 1H), 8.36 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.7 Hz, 2H), 7.84 (d, J = 4.0, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.9 Hz, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H). 1 H NMR (300 MHz, DMSO) δ 13.02 (s, 1OH), 10.37 (s, 1NH), 9.22 (s, 1H), 8.36 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.7 Hz, 2H), 7.84 (d, J = 4.0, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.9 Hz, 2H), 7.50 (t , J = 7.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H).
또한, 하기 화합물들을 추가로 합성하였다:In addition, the following compounds were further synthesized:
265. 페닐-N-(3-설파모일페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(phenyl-N-(3-sulfamoylphenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),265.Phenyl-N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (phenyl-N- (3-sulfamoylphenyl) -3- (thiophen -2-yl) -1H-pyrazole-4-carboxamide),
266. 1-페닐-3-(티오펜-2-일)-N-(m-톨릴)-1H-피라졸-4-카르복스아미드(1-phenyl-3-(thiophen-2-yl)-N-(m-tolyl)-1H-pyrazole-4-carboxamide),266. 1-phenyl-3- (thiophen-2-yl) -N- (m-tolyl) -1H-pyrazole-4-carboxamide (1-phenyl-3- (thiophen-2-yl)- N- (m-tolyl) -1 H-pyrazole-4-carboxamide),
267. N-(3-아세틸페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(3-acetylphenyl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),267.N- (3-acetylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (3-acetylphenyl) -1-phenyl-3 -(thiophen-2-yl) -1H-pyrazole-4-carboxamide),
268. N-(4-카바모일페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(4-carbamoylphenyl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),268.N- (4-carbamoylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (4-carbamoylphenyl) -1-phenyl- 3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide),
269. 메틸 (4-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조일)글리시네이트(methyl (4-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoyl)glycinate),269.Methyl (4- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate (methyl (4- (1-phenyl-3 -(thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate),
270. 3-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산(3-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid),270. 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid),
271. 에틸 3-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트(ethyl 3-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoate),271.Ethyl 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate (ethyl 3- (1-phenyl-3- (thiophen-2) -yl) -1H-pyrazole-4-carboxamido) benzoate),
272. N,1-디페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N,1-diphenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),272. N, 1-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N, 1-diphenyl-3- (thiophen-2-yl) -1H-pyrazole -4-carboxamide),
273. N-(3-페녹시페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(3-phenoxyphenyl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),273.N- (3-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (3-phenoxyphenyl) -1-phenyl- 3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide),
274. N-(4-페녹시페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(4-phenoxyphenyl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),274.N- (4-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (4-phenoxyphenyl) -1-phenyl- 3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide),
275. N-(3-클로로페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(3-chlorophenyl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),275.N- (3-chlorophenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (3-chlorophenyl) -1-phenyl-3 -(thiophen-2-yl) -1H-pyrazole-4-carboxamide),
276. N-(벤조[d][1,3]디옥솔-5-일)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드(N-(benzo[d][1,3]dioxol-5-yl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide),276.N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide),
277. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),277. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (5-chlorothiophen-2-yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
278. 3-(5-클로로티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-N,1-diphenyl-1H-pyrazole-4-carboxamide),278. 3- (5-chlorothiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide (3- (5-chlorothiophen-2-yl) -N, 1- diphenyl-1H-pyrazole-4-carboxamide),
279. 에틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트(ethyl 3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoate),279. Ethyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- (3- (5-chlorothiophen- 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),
280. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),280. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (5-chlorothiophen-2-yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
281. N-(3-클로로페닐)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드(N-(3-chlorophenyl)-3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamide),281.N- (3-chlorophenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (N- (3-chlorophenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
282. 3-(5-클로로티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-N-(4-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),282. 3- (5-chlorothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-chlorothiophen-2- yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
283. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드(N-(benzo[d][1,3]dioxol-5-yl)-3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamide),283.N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
284. 3-(5-클로로티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-N-(3-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),284. 3- (5-chlorothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-chlorothiophen-2- yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
285. 3-(5-클로로티오펜-2-일)-1-페닐-N-프로필-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-1-phenyl-N-propyl-1H-pyrazole-4-carboxamide),285. 3- (5-chlorothiophen-2-yl) -1-phenyl-N-propyl-1H-pyrazole-4-carboxamide (3- (5-chlorothiophen-2-yl) -1-phenyl -N-propyl-1H-pyrazole-4-carboxamide),
286. 3-(5-클로로티오펜-2-일)-N-사이클로프로필-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-N-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxamide),286. 3- (5-chlorothiophen-2-yl) -N-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxamide (3- (5-chlorothiophen-2-yl) -N- cyclopropyl-1-phenyl-1H-pyrazole-4-carboxamide),
287. N-(1-벤질피페리딘-4-일)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드(N-(1-benzylpiperidin-4-yl)-3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamide),287.N- (1-benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (N- (1 -benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
288. 3-(5-클로로티오펜-2-일)-1-페닐-N-(피리딘-3-일)-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-1-phenyl-N-(pyridin-3-yl)-1H-pyrazole-4-carboxamide),288. 3- (5-chlorothiophen-2-yl) -1-phenyl-N- (pyridin-3-yl) -1H-pyrazole-4-carboxamide (3- (5-chlorothiophen-2- yl) -1-phenyl-N- (pyridin-3-yl) -1H-pyrazole-4-carboxamide),
289. 3-(5-클로로티오펜-2-일)-1-페닐-N-(4-(티오펜-2-일)페닐)-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-1-phenyl-N-(4-(thiophen-2-yl)phenyl)-1H-pyrazole-4-carboxamide),289. 3- (5-chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen-2-yl) phenyl) -1H-pyrazole-4-carboxamide (3- ( 5-chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen-2-yl) phenyl) -1H-pyrazole-4-carboxamide),
290. 3-(5-클로로티오펜-2-일)-N-(4-몰포리노페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-chlorothiophen-2-yl)-N-(4-morpholinophenyl)-1-phenyl-1H-pyrazole-4-carboxamide),290. 3- (5-chlorothiophen-2-yl) -N- (4-morpholinophenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-chlorothiophen-2- yl) -N- (4-morpholinophenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
291. N-(4-(벤질옥시)페닐)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드(N-(4-(benzyloxy)phenyl)-3-(5-chlorothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamide),291.N- (4- (benzyloxy) phenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (N- (4- (benzyloxy ) phenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
292. 에틸 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트(ethyl 3-(3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoate),292.Ethyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- (3- (5-bromothiophen- 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),
293. 3-(5-브로모티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드(3-(5-bromothiophen-2-yl)-N,1-diphenyl-1H-pyrazole-4-carboxamide),293. 3- (5-bromothiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide (3- (5-bromothiophen-2-yl) -N, 1- diphenyl-1H-pyrazole-4-carboxamide),
294. 3-(5-브로모티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-bromothiophen-2-yl)-N-(4-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),294. 3- (5-Bromothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-bromothiophen-2- yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
295. 3-(5-브로모티오펜-2-일)-N-(3-클로로페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-bromothiophen-2-yl)-N-(3-chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide),295. 3- (5-Bromothiophen-2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-bromothiophen-2-yl ) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
296. 3-(5-브로모티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-bromothiophen-2-yl)-N-(3-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),296. 3- (5-Bromothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-bromothiophen-2- yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
297. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드(N-(benzo[d][1,3]dioxol-5-yl)-3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamide),297.N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
298. 3-(5-메틸티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드(3-(5-methylthiophen-2-yl)-N,1-diphenyl-1H-pyrazole-4-carboxamide),298. 3- (5-methylthiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide (3- (5-methylthiophen-2-yl) -N, 1- diphenyl-1H-pyrazole-4-carboxamide),
299. 에틸 3-(3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트(ethyl 3-(3-(5-methylthiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoate),299. Ethyl 3- (3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- (3- (5-methylthiophen- 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),
300. 3-(3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-methylthiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),300. 3- (3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (5-methylthiophen-2-yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
301. N-(3-클로로페닐)-3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드(N-(3-chlorophenyl)-3-(5-methylthiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamide),301.N- (3-chlorophenyl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (N- (3-chlorophenyl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
302. 3-(5-메틸티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-methylthiophen-2-yl)-N-(4-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),302. 3- (5-methylthiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-methylthiophen-2- yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
303. 3-(5-메틸티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(5-methylthiophen-2-yl)-N-(3-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),303. 3- (5-methylthiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (5-methylthiophen-2- yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
304. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드(N-(benzo[d][1,3]dioxol-5-yl)-3-(5-methylthiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamide),304. N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide (N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
305. 에틸 3-(3-(벤조[b]티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트(ethyl 3-(3-(benzo[b]thiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoate),305. Ethyl 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- (3- (benzo [b ] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),
306. 3-(벤조[b]티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드(3-(benzo[b]thiophen-2-yl)-N,1-diphenyl-1H-pyrazole-4-carboxamide),306. 3- (benzo [b] thiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide (3- (benzo [b] thiophen-2-yl) -N , 1-diphenyl-1H-pyrazole-4-carboxamide),
307. 3-(벤조[b]티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(benzo[b]thiophen-2-yl)-N-(4-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),307. 3- (benzo [b] thiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (benzo [b] thiophen -2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
308. 3-(벤조[b]티오펜-2-일)-N-(3-클로로페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(benzo[b]thiophen-2-yl)-N-(3-chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide),308. 3- (benzo [b] thiophen-2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (benzo [b] thiophen- 2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
309. 3-(3-(벤조[b]티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(benzo[b]thiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),309. 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (benzo [b] thiophen- 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
310. 3-(벤조[b]티오펜-2-일)-N-(벤조[d][1,3]디옥솔-5-일)-1-페닐-1H-피라졸-4-카르복스아미드(3-(benzo[b]thiophen-2-yl)-N-(benzo[d][1,3]dioxol-5-yl)-1-phenyl-1H-pyrazole-4-carboxamide),310. 3- (benzo [b] thiophen-2-yl) -N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-1H-pyrazole-4-carbox Amide (3- (benzo [b] thiophen-2-yl) -N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-1H-pyrazole-4-carboxamide),
311. 3-(벤조[b]티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드(3-(benzo[b]thiophen-2-yl)-N-(3-phenoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide),311. 3- (benzo [b] thiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide (3- (benzo [b] thiophen -2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),
312. 3-(벤조[b]티오펜-3-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드(3-(benzo[b]thiophen-3-yl)-N,1-diphenyl-1H-pyrazole-4-carboxamide),312. 3- (benzo [b] thiophen-3-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide (3- (benzo [b] thiophen-3-yl) -N , 1-diphenyl-1H-pyrazole-4-carboxamide),
313. 에틸 3-(3-(벤조[b]티오펜-3-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트(ethyl 3-(3-(benzo[b]thiophen-3-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoate),313. Ethyl 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- (3- (benzo [b ] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),
314. 3-(3-(벤조[b]티오펜-3-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(benzo[b]thiophen-3-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),314. 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (benzo [b] thiophen- 3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
315. 3-(1-페닐-3-(5-(4-(트리플루오로메톡시)페닐)티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산(3-(1-phenyl-3-(5-(4-(trifluoromethoxy)phenyl)thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid),315. 3- (1-phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (3- ( 1-phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid),
316. 3-(3-(5-(3-아세트아미도페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-(3-acetamidophenyl)thiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),316. 3- (3- (5- (3-acetamidophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- ( 5- (3-acetamidophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
317. 3-(3-(5-(2-플루오로-4-(트리플루오로메틸)페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-(2-fluoro-4-(trifluoromethyl)phenyl)thiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),317. 3- (3- (5- (2-fluoro-4- (trifluoromethyl) phenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) Benzoic acid (3- (3- (5- (2-fluoro-4- (trifluoromethyl) phenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
318. 3-(3-(5-(3-시아노-4-플루오로페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-(3-cyano-4-fluorophenyl)thiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid),318. 3- (3- (5- (3-cyano-4-fluorophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (5- (3-cyano-4-fluorophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),
319. 3-(1-페닐-3-(5-(4-(트리플루오로메틸)페닐)티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산(3-(1-phenyl-3-(5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)-1H-pyrazole-4-carboxamido)benzoic acid),319. 3- (1-phenyl-3- (5- (4- (trifluoromethyl) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (3- ( 1-phenyl-3- (5- (4- (trifluoromethyl) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid),
320. 3-(3-(5-(3-플루오로-4-메톡시페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-(3-fluoro-4-methoxyphenyl)thiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid), 및320. 3- (3- (5- (3-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (5- (3-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid), and
321. 3-(3-(5-(4-카바모일페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산(3-(3-(5-(4-carbamoylphenyl)thiophen-2-yl)-1-phenyl-1H-pyrazole-4-carboxamido)benzoic acid).321. 3- (3- (5- (4-carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid (3- (3- (5 -(4-carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid).
아울러, 하기 일련의 화학식 2로 표시되는 화합물도 추가로 합성하였다.In addition, compounds represented by the following series of Formula 2 were also synthesized.
322. N,2-디페닐티아졸-5-카르복스아마이드(N,2-diphenylthiazole-5-carboxamide),322.N, 2-diphenylthiazole-5-carboxamide,
323. 메틸 4-(5-(페닐카바모일)티아졸-2-일)벤조에이트(methyl 4-(5-(phenylcarbamoyl)thiazol-2-yl)benzoate),323. Methyl 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoate (methyl 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoate),
324. 4-(5-(페닐카바모일)티아졸-2-일)벤조산(4-(5-(phenylcarbamoyl)thiazol-2-yl)benzoic acid),324. 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoic acid (4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoic acid),
325. 메틸 4-(5-((3,5-비스(트리플루오로메틸)페닐)카바모일)티아졸-2-일)벤조에이트(methyl 4-(5-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)thiazol-2-yl)benzoate),325.Methyl 4- (5-((3,5-bis (trifluoromethyl) phenyl) carbamoyl) thiazol-2-yl) benzoate (methyl 4- (5-((3,5-bis ( trifluoromethyl) phenyl) carbamoyl) thiazol-2-yl) benzoate),
326. N-(3-페녹시페닐)-2-페닐티아졸-5-카르복스아마이드(N-(3-phenoxyphenyl)-2-phenylthiazole-5-carboxamide),326.N- (3-phenoxyphenyl) -2-phenylthiazole-5-carboxamide (N- (3-phenoxyphenyl) -2-phenylthiazole-5-carboxamide),
327. N-(4-(1H-이미다졸-1-일)페닐)-2-페닐티아졸-5-카르복스아마이드(N-(4-(1H-imidazol-1-yl)phenyl)-2-phenylthiazole-5-carboxamide),327.N- (4- (1H-imidazol-1-yl) phenyl) -2-phenylthiazole-5-carboxamide (N- (4- (1H-imidazol-1-yl) phenyl) -2 -phenylthiazole-5-carboxamide),
328. 메틸 4-(5-((3-페녹시페닐)카바모일)티아졸-2-일l)벤조에이트(methyl 4-(5-((3-phenoxyphenyl)carbamoyl)thiazol-2-yl)benzoate),328. Methyl 4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yll) benzoate (methyl 4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoate),
329. 3-(5-((3- 페녹시페닐)카바모일)티아졸-2-일)벤조산(3-(5-((3-phenoxyphenyl)carbamoyl)thiazol-2-yl)benzoic acid), 및329. 3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid (3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid), And
330. N-(4-페녹시페닐)-2-페닐티아졸-5-카르복스아마이드(N-(4-phenoxyphenyl)-2-phenylthiazole-5-carboxamide).330. N- (4-phenoxyphenyl) -2-phenylthiazole-5-carboxamide (N- (4-phenoxyphenyl) -2-phenylthiazole-5-carboxamide).
실험예Experimental Example 1:  One: 무기질화Mineralization (mineralization) 및 ALP(alkaline (mineralization) and ALP (alkaline) phosphatasephosphatase ) 실험 스크리닝Experimental Screening
ST2 세포를 24-웰 플레이트에 분주하고, 10% FBS, 50 μg/mL 아스코르브산 및 10 mM 베타-글리세로포스페이트를 포함하는 배양액으로 3일마다 배지를 교환하면서 14 내지 18일 동안 배양하면서 무기질화하는 것을 관찰하였다. 무기질화 여부는 알리자린 레드 S 염색을 통해 확인하였다.ST2 cells were aliquoted into 24-well plates and mineralized while incubating for 14-18 days with medium change every three days with a culture medium containing 10% FBS, 50 μg / mL ascorbic acid and 10 mM beta-glycerophosphate Was observed. Mineralization was confirmed by Alizarin Red S staining.
Wnt3a-CM(Wnt3a over-expressing conditioned media)을 부피비로 1/3 처리하면, Wnt3a-CM을 처리하지 않은 대조군에 비해 무기질화가 증가하는 것을 확인하였다. 또한 동시에 스클레로스틴(sclerostin; SOST)을 1/100 부피비로 처리하면, Wnt-CM에 의한 무기질화의 증가가 억제되는 것을 확인하였다. 이와 같이 고안된 방법으로 본 발명의 화합물을 3 μM 농도로 공동처리(co-treatment)하여 이들이 무기질화에 미치는 영향을 확인하고, 그 결과를 도 37 및 38에 나타내었다.When Wnt3a-CM (Wnt3a over-expressing conditioned media) 1/3 treated by volume ratio, it was confirmed that mineralization increased compared to the control group not treated with Wnt3a-CM. At the same time, when sclerostin (SOST) was treated at a 1/100 volume ratio, it was confirmed that the increase in mineralization by Wnt-CM was suppressed. Co-treatment of the compound of the present invention in a concentration of 3 μM by the method designed as described above confirmed the effect on mineralization, and the results are shown in FIGS. 37 and 38.
도 37 및 38에 나타난 바와 같이, 본 발명의 화합물 중 KY-06234가 SOST에 의해 억제된 Wnt-유도 무기질화를 회복시키는 활성이 가장 우수한 것으로 확인되었다.As shown in FIGS. 37 and 38, it was confirmed that among the compounds of the present invention, KY-06234 has the best activity of restoring Wnt-induced mineralization inhibited by SOST.
14 내지 18일의 긴 배양시간 및/또는 개체 간의 편차를 줄이기 위하여, ALP 염색을 통해 1차적으로 우수한 활성을 갖는 화합물을 선별하였다.In order to reduce long incubation times of 14 to 18 days and / or deviations between individuals, compounds with primary good activity were selected via ALP staining.
위와 동일한 조건으로 처리 후, 배양 6일째에 ALP 염색을 통해 활성 화합물을 선별하는 것이 가능한지 확인하였다. 도 37에 나타난 바와 같이, 인간 SOST는 Wnt 3a을 처리하여 유도된 무기질화를 억제하였다.After treatment under the same conditions as above, it was confirmed that it is possible to select the active compound through ALP staining on the 6th day of culture. As shown in FIG. 37, human SOST inhibited mineralization induced by treatment with Wnt 3a.
흡광도를 측정함으로써 ALP 활성을 수치화하였고, 각 화합물들에 대한 결과를 표로 비교하였다(도 38). 도 38에 나타난 바와 같이, KY-06424, KY-06428, KY-06449 및 KY-06492가 특히 우수한 활성을 나타내었다.ALP activity was quantified by measuring absorbance, and the results for each compound were compared in a table (FIG. 38). As shown in FIG. 38, KY-06424, KY-06428, KY-06449 and KY-06492 showed particularly good activity.
이후 무기질화 어세이를 수행하여 그 효과를 평가하였다. 도 37에 나타난 바와 같이, Wnt3a 조건에서는 없지만, Wnt7 조건에서는 KY-06448, KY-06449, KY-06450 및 KY-06492가 특히 우수한 효과를 나타내었다.The mineralization assay was then performed to evaluate the effect. As shown in FIG. 37, under Wnt3a conditions, KY-06448, KY-06449, KY-06450 and KY-06492 showed particularly excellent effects under Wnt7 conditions.
결론적으로, 본 발명의 화합물들은 SOST에 의해 억제된 Wnt-유도 ALP 유도, 무기질화 또는 둘 모두를 회복시킬 수 있음을 확인하였다.In conclusion, it was confirmed that the compounds of the present invention can restore Wnt-induced ALP induction, mineralization or both inhibited by SOST.
나아가, 난소를 적출하여 기능을 상실시킨 OVX 마우스에 본 발명의 화합물을 투입하여 ALP와 무기질화에 대한 효과를 확인하고 그 결과를 각각 도 37 및 38에 나타내었다. 도 37 및 38에 나타난 바와 같이, KY-06277은 SOST에 의해 억제된 Wnt-유도 ALP 유도를 회복시키는 효과를 나타내었으나, 무기질화 분석 결과는 KY-06277, KY-06439 및 KY-06525에서 회복 효과가 관찰되었다.Furthermore, the compounds of the present invention were injected into OVX mice whose ovaries were extracted and lost their function. The effects on ALP and mineralization were confirmed, and the results are shown in FIGS. 37 and 38, respectively. As shown in Figures 37 and 38, KY-06277 showed the effect of restoring the Wnt-induced ALP induction inhibited by SOST, but the mineralization assay results in a recovery effect in KY-06277, KY-06439 and KY-06525 Was observed.
실험예Experimental Example 2:  2: 루시퍼라아제Luciferase 어세이Assay
WNT/베타 카테닌 경로의 표적 요소인 TCF/LEF 요소(element)를 안정적으로 발현하는 MC3T3-E1 Top 세포를 제작하였다. 상기 세포주를 5% 이산화탄소가 자동으로 공급되는 37℃의 세포배양기에서 10%의 소태아 혈청 (Fetal bovine serum), 스토렙토마이신(streptomycin, 100 μg/mL), 페니실린(penicillin, 100U/mL)을 포함하는 Alpha MEM에서 배양하였다. 세포는 3일을 주기로 계대 배양하였고, 화합물을 처리하기 1일 전에 24-웰 플레이트에 50,000 세포/웰의 밀도로 분주한 후 다음날 80% 정도의 컨플루언스가 되었을 때, WNT7 conditioning 배지와 SOST 그리고 본 발명의 저분자 화합물을 처리하였다. 다음날 세포를 회수하여 용해 완충액(lysis buffer)으로 단백질을 추출하여 루시페린(luciferin)과 혼합한 후 광도계(luminometer)로 측정하고 그 결과를 도 43에 나타내었다. MC3T3-E1 Top cells stably expressing the TCF / LEF element, which is a target element of the WNT / beta catenin pathway, were constructed. 10% fetal bovine serum, Streptomycin (100 μg / mL) and penicillin (penicillin, 100U / mL) were added to the cell line at 37 ° C. incubator with 5% carbon dioxide automatically supplied. Incubated in the Alpha MEM containing. Cells were subcultured every 3 days, and were seeded at a density of 50,000 cells / well in 24-well plates one day before compound treatment, and then at 80% confluence the next day, WNT7 conditioning medium and SOST and The low molecular weight compound of the present invention was treated. The next day, the cells were collected, the protein was extracted with lysis buffer, mixed with luciferin, measured with a luminometer, and the results are shown in FIG. 43.
Wnt 신호 체계에 길항적인 SOST를 첨가하였을 때 활성이 50%로 감소했지만, 선행연구에서 이 Wnt 신호 체계에 abrogation 효과를 보였던 KY-06003을 처리하였을 때 다시 100%로 회복되는 것을 확인하였다. 또한 새롭게 합성된 저분자 화합물들인 KY-06424, KY-06425, KY-06426, 및 KY-06427에 대해서도, 뚜렷하게 100% agrogation 효과가 나타남을 확인하였다. 이러한 실험방법에 근거하여 본 발명의 신규합성 저분자 화합물에 대해서 동일한 방법으로 어세이를 진행하였다.When the antagonistic SOST was added to the Wnt signaling system, the activity was reduced to 50%, but the previous study showed that the KY-06003, which had abrogation effect on the Wnt signaling system, returned to 100% again. In addition, it was confirmed that the newly synthesized low molecular weight compounds KY-06424, KY-06425, KY-06426, and KY-06427 also exhibited a distinctly 100% agrogation effect. Based on this experimental method, the assay was carried out in the same manner for the novel synthetic low molecular weight compounds of the present invention.
실험예Experimental Example 3: ELISA 결합 및  3: ELISA binding and 어세이Assay SPRSPR 어세이Assay
WNT 신호전달에서 SOST는 LRP5/6 단백질에 결합하는 것으로 알려져 있다. 이에 SOST의 E1, E2 도메인이 코팅되어 있는 96-웰 플레이트에 LRP5/6 단백질 ALP가 콘쥬게이션되어 있는 단백질과의 결합을 간섭하는 저분자 화합물의 효과를 측정함으로써 SOST의 E1, E2 도메인과 저분자 화합물간의 결합정도를 측정하고 그 결과를 도 44에 나타내었다. 또한, SPR 어세이를 통해서 저분자 화합물의 SOST와의 결합 및 해리 능력을 평가하고, 그 결과를 도 45에 나타내었다.In WNT signaling, SOST is known to bind to LRP5 / 6 protein. In this study, we measured the effect of low-molecular weight compounds that interfered with the binding of LRP5 / 6 protein ALP conjugated to 96-well plates coated with the E1 and E2 domains of SOST. The degree of binding was measured and the results are shown in FIG. 44. In addition, the SPR assay evaluated the binding and dissociation ability of the low molecular weight compound to SOST, and the results are shown in FIG. 45.
실험예Experimental Example 4: 마우스 두개골 형성 4: mouse skull formation
마우스를 마취한 후 머리부분의 피부를 절개하여 두개골위에 본 발명의 화합물(5 mM, 3 μL)이 점적된 0.5mm 직경의 3M 페이퍼를 넣고 피부를 봉합하였. 2주후, 마우스 두개골 부위를 절개하여 10% 중성포르말린으로 2일 동안 고정하고 1일동안 세척한 후 탈회액에 넣어 3일 동안 매일 새 용액으로 갈아주었다. 이후 다시 10% 중성포르말린에 1일 동안 재고정한 후 1시간 동안 세척하여 약물을 처리한 부위를 위주로 절개하였다. 파라핀 조직을 만들기 위해 조직 프로세스를 1일 동안 가동시킨 후 파라핀 포매를 실시하였다. 파라핀 포매가 완료된 조직을 조직절편기를 이용하여 3 μm 정도의 두께로 절편하여 H-E염색 및 특수염색(Masson trichrome)을 실시하여 골형성 조직학적 평가를 수행하였다. 그 결과, KY-06277과 KY-06525 등의 화합물이 두개골 형성 효과를 나타냄을 확인하였다.After anesthetizing the mouse, the skin of the head was dissected, and 0.5M diameter 3M paper in which the compound of the present invention (5 mM, 3 μL) was deposited was placed on the skull and the skin was sutured. Two weeks later, the mouse skull was incised and fixed with 10% neutral formalin for 2 days, washed for 1 day, and then placed in a demineralized solution for 3 days and replaced with fresh solution every day. After re-establishing for 1 day in 10% neutral formalin again and washed for 1 hour to dissection mainly the drug treated site. The tissue process was run for 1 day to produce paraffin tissue and then paraffin embedded. Paraffin-embedded tissue was sliced to a thickness of about 3 μm using a tissue slicer and subjected to H-E staining and special staining (Masson trichrome) for bone formation histological evaluation. As a result, it was confirmed that compounds such as KY-06277 and KY-06525 exhibit the skull-forming effect.
실험예Experimental Example 5:  5: OVXOVX 동물실험 Animal testing
이전의 실험을 통해 선정된 저분자 화합물들의 골(骨) 향상성 유지에 대한 효과를 평가하기 위해, 수술로 난소를 적출하여 그 기능을 상실시킨 OVX 마우스를 일본 SLC로부터 구입하여 사용하였다. 실험 전 동물은 연세대학교 에비슨의생명연구센타 실험동물실에서 적정온도와 습도에서 일주일간 순화과정을 거쳤다. 사료와 물은 자유롭게 섭취하도록 하였다. 모든 실험과정은 연세의생연구원의 실험동물위원회의 안전규정을 준수하여 시행하였다.In order to evaluate the effect of the small molecule compounds selected through the previous experiment on the maintenance of bone improvement, OVX mice were surgically extracted from ovaries and lost their function. Before the experiment, the animals were purified for one week at the appropriate temperature and humidity in the laboratory of the laboratory of the life research center of Avison, Yonsei University. Feed and water were taken freely. All experiments were conducted in compliance with safety regulations of Yonsei Institute of Biomedical Research.
약효 검증 대조군 약물로서 임상에서 골다공증 개선에 약효가 입증된 PTH와 Alendronate·Na을 식염수에 용해시켜 준비하였다. 선정된 4종류 저분자 화합물은 (DMSO/Tween80/PEG400/DW=10/3/30/57 (v/v) %부피 비율로)의 혼합용액에 완전히 용해시켰다. 용해된 화합물은 매주 5회 8주 동안 5mg/kg로 복강에 주사하였다. 대조군 약물인 PTH Alendronate·Na은 피하에 주사하였다Pharmacologic Validation As a control drug, PTH and Alendronate Na were proved to improve osteoporosis in the saline solution. Four selected low molecular weight compounds were completely dissolved in a mixed solution of (DMSO / Tween 80 / PEG400 / DW = 10/3/30/57 (v / v)% by volume). The dissolved compounds were injected intraperitoneally at 5 mg / kg five times weekly. The control drug PTH AlendronateNa was injected subcutaneously.
실험종료 후 마우스의 눈으로부터 혈액을 채취하였다. 또한 부검후 경골(Tibia), 대퇴골(Femur) 및 척추(Spine)를 적출한 후 포르말린 용액 안에 보관하였다.After the experiment, blood was collected from the eyes of the mice. After necropsy, tibia, femur and spine were extracted and stored in formalin solution.
동물 실험종료 후 골밀도 변화를 측정하기 위해 PIXImus™ 시리즈 Densitometer BMD 장비를 사용하여 우측 대퇴골에서 골밀도를 측정하였다. 그 결과, SOST 저해제들은 모두 대퇴부 골밀도를 유의미하게 증가시켰다. 대조군인 PTH 보다 우수하였으며, 과량의 Alendronate 치료군과 유사하였다. 용량 의존성을 확인하기 위하여 5 mg, 20 mg/Kg의 용량으로 약물 치료를 시도하였으나, 이미 5 mg/kg에서 최대 골밀도 증가효과(+)를 나타내었으므로, 그 이상의 용량으로 투여하는 것을 무의미하여, 더이상의 용량 의존성은 관찰하지 않았다(도 46). 본 연구는 후보화합물을 IP주사로 실험한 결과로서 표적에 대한 개념의 입증(proof of concept)이란 측면에서 긍정적 결과로 사료된다.Bone density was measured in the right femur using the PIXImus ™ Series Densitometer BMD instrument to determine bone density change after the end of the animal experiment. As a result, all of the SOST inhibitors significantly increased femoral bone mineral density. It was superior to the control group PTH and was similar to the excess Alendronate treatment group. At the dose of 5 mg and 20 mg / Kg, the drug treatment was attempted to confirm the dose dependency. However, since the maximum bone density increase effect (+) was already shown at 5 mg / kg, it was meaningless to administer at a higher dose, No further dose dependence was observed (FIG. 46). This study is a positive result in terms of proof of concept of the target compound by IP injection.
실험예Experimental Example 6:  6: 마이크로CTMicro CT 분석 analysis
고성능 컴퓨터 단층 장비(CT)인 SkyScan 1076을 사용하여 상기 회수한 마우스의 오른쪽 경골을 촬영하였다. 촬영된 영상은 Skyscan CT analyzer software 활용하여 섬유골 및 피질골(trabecular and cortical bones)을 분석하였다. 그 결과, 피질골 표면적 및 피질골 주위 길이(perimeter)에 대한 결과는 Alendronate 및 SOST 저해제 치료군 모두에서 효과가 있는 것으로 나타났다. % 골 부피에 대해서는 Alendronate는 물론 SOST 저해제 군 간에 차이가 없었다. 단면 두께에서도 Alendronate는 물론 SOST 저해제 군 간에 차이가 없었다.The right tibia of the retrieved mouse was photographed using SkyScan 1076, a high performance computed tomography equipment (CT). The captured images were analyzed for trabecular and cortical bones using Skyscan CT analyzer software. As a result, the results on the cortical bone surface area and the perimeter of the cortical bone were found to be effective in both Alendronate and SOST inhibitor treatment groups. There was no difference between Alendronate and SOST inhibitor groups in% bone volume. In cross-sectional thickness, there was no difference between Alendronate and SOST inhibitor groups.
이상의 결과들은 피질골에서 골막골 형성(periosteal bone formation)을 보여진 현상들이며, 이는 피질골이 약 80%를 차지하는 대퇴골의 BMD에서 모든 군에서 효과가 있었던 결과와 일치하였다. 또한, 상기 결과는 최근에 논문에 공표된 Irisin 치료에 의한 피질골의 변화 결과와도 유사한 결과를 나타내었다.The above results were indicative of periosteal bone formation in the cortical bone, which is consistent with the results in all groups in the BMD of the femur, which occupies about 80%. In addition, the results showed similar results to changes in the cortical bone by Irisin treatment recently published in the paper.
한편, 대부분의 파라미터에 있어서, 섬유골에 대해 Alendronate는 명확하게 효과를 나타내었으나 SOST 저해제는 효과가 없었으며, 이는 또한 최근 논문에 공표된 IRISIN 처리 실험결과에서도 효과가 나타나지 않는 것으로 보고되었다.On the other hand, for most parameters, Alendronate was clearly effective on fibroblasts, but SOST inhibitors were ineffective, which was also reported to be ineffective in the results of IRISIN treatments published in recent papers.

Claims (14)

  1. 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 또는 이들의 약학적으로 허용 가능한 염:A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2017001288-appb-I000004
    Figure PCTKR2017001288-appb-I000004
    상기 식에서,Where
    R1 내지 R3은 각각 독립적으로 수소, 할로겐, -SO3H, C1-4 알킬, C6-10 아릴, 또는 서로 이웃한 두개의 치환기가 서로 연결되어 이들이 결합된 티오펜 고리와 함께 융합된 헤테로 아릴을 형성하며,R 1 to R 3 are each independently hydrogen, halogen, —SO 3 H, C 1-4 alkyl, C 6-10 aryl, or two adjacent substituents connected to each other and fused together with a thiophene ring to which they are bonded; Form hetero aryl,
    상기 아릴은 비치환 또는 할로겐, C1-4 알킬, C1-4 알콕시, C1-4 플루오르화 알킬, C1-4 플루오르화 알콕시, 시아노, 카르복스아미도 및 아세트아미노로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The aryl is unsubstituted or from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluorinated alkyl, C 1-4 fluorinated alkoxy, cyano, carboxamido and acetamino May be substituted with any one or more substituents selected;
    R4는 수소, 할로겐, -CO2(C0-4 알킬), -CO2(C6-10 아릴), 또는 -CONHW이며, 상기 W는 보호되거나 보호되지 않은 아미노산;R 4 is hydrogen, halogen, —CO 2 (C 0-4 alkyl), —CO 2 (C 6-10 aryl), or —CONHW, wherein W is a protected or unprotected amino acid;
    R5는 C1-4 알킬, 또는 비치환 또는 치환된 C6-10 아릴, 5 내지 10원 헤테로아릴, 3 내지 10원 헤테로사이클로알킬, 또는 C3-10 사이클로알킬로서,R 5 is C 1-4 alkyl, or unsubstituted or substituted C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, or C 3-10 cycloalkyl,
    상기 아릴, 헤테로아릴, 헤테로사이클로알킬 및 사이클로알킬은 비치환 또는 C1-4 알킬, C1-4 알콕시, C1-4 플루오르화 알킬, C1-4 플루오르화 알콕시, C6-10 아릴, (C6-10 아릴)-(C0-4 알킬)옥시, 할로겐, 3 내지 10원 헤테로사이클로알킬, 5 내지 10원 헤테로아릴, -CO(C0- 4알킬), -CONH(C0- 4알킬), -CONH(C1- 4알킬렌)(C=O)-O-(C1- 4알킬), -SO2NH2, -CO2(C1- 4알킬), -SO3H, (설폰페닐)옥시, 및 -CONHW'로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 직접 또는 C1-4 알킬렌을 통해 치환될 수 있으며,The aryl, heteroaryl, heterocycloalkyl and cycloalkyl may be unsubstituted or C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluorinated alkyl, C 1-4 fluorinated alkoxy, C 6-10 aryl, (C 6-10 aryl), - (C 0-4 alkyl) oxy, halogen, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -CO (C 0- 4 alkyl), -CONH (C 0- 4 alkyl), -CONH (C 1- 4 alkylene) (C = O) -O- ( C 1- 4 alkyl), -SO 2 NH 2, -CO 2 (C 1- 4 alkyl), -SO 3 May be substituted directly or via C 1-4 alkylene with any one or more substituents selected from the group consisting of H, (sulfonphenyl) oxy, and -CONHW ',
    상기 W'은 보호되거나 보호되지 않은 아미노산;W 'is a protected or unprotected amino acid;
    n은 0 내지 3의 정수이다.n is an integer of 0-3.
  2. 제1항에 있어서,The method of claim 1,
    R1 내지 R3은 각각 독립적으로 수소, 클로로, 브로모, -SO3H, 시아노, 메틸, 페닐, 또는 R1과 R2가 서로 연결되어 이들이 결합된 티오펜 고리와 함께 벤조티오펜을 형성하며,R 1 to R 3 are each independently hydrogen, chloro, bromo, -SO 3 H, cyano, methyl, phenyl, or R 1 and R 2 are linked to each other to form benzothiophene together with the thiophene ring to which they are bonded. Forming,
    상기 페닐은 비치환 또는 플루오로, 메틸, 메톡시, 트리플루오로메틸, 트리플루오로메톡시, 시아노, 아미노포르밀 및 아세트아미노로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The phenyl may be unsubstituted or substituted with any one or more substituents selected from the group consisting of fluoro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, aminoformyl and acetamino;
    R4는 수소, 플루오로, -CO2H, -CO2CH3, -CO2C2H5, 또는 -CONHW이며, 상기 W는 메틸로 보호되거나 보호되지 않은 이소루신;R 4 is hydrogen, fluoro, —CO 2 H, —CO 2 CH 3 , —CO 2 C 2 H 5 , or —CONHW, wherein W is isoleucine, protected or unprotected with methyl;
    R5는 프로필, 사이클로프로필, 벤조디옥솔릴, 또는 비치환 또는 치환된 페닐, 피리디닐, 피페리디닐 또는 사이클로헥실로서,R 5 is propyl, cyclopropyl, benzodioxolyl, or unsubstituted or substituted phenyl, pyridinyl, piperidinyl or cyclohexyl,
    상기 페닐, 피리디닐, 피페리디닐 및 사이클로헥실은 비치환 또는 벤질, 벤질옥시, 몰포리닐, -CONH(CH2)2몰포리닐, -CONH(CHCH3)CONH(CH2)2몰포리닐, 플루오로, 클로로, 브로모, 메틸, 트리플루오로메틸, 티오페닐, -CONH2, -CONHCH3, -CONHC2H5, -SO2NH2, -CH2CO2H, -CH2CO2CH3, -COCH3, -CO2H, -CO2CH3, -CO2C2H5, -CO2(tert-부틸), -SO3H, 페녹시, 설포페녹시, 및 -CONHW'로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있으며,The phenyl, pyridinyl, piperidinyl and cyclohexyl may be unsubstituted or benzyl, benzyloxy, morpholinyl, -CONH (CH 2 ) 2 morpholinyl, -CONH (CHCH 3 ) CONH (CH 2 ) 2 morpholi Nyl, fluoro, chloro, bromo, methyl, trifluoromethyl, thiophenyl, -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -SO 2 NH 2 , -CH 2 CO 2 H, -CH 2 CO 2 CH 3 , -COCH 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 C 2 H 5 , -CO 2 (tert-butyl), -SO 3 H, phenoxy, sulfofenoxy, and -CONHW 'may be substituted with any one or more substituents selected from the group consisting of
    상기 W'은 메틸 또는 tert-부틸로 보호되거나 보호되지 않은 트립토판, 알라닌, 아스파르트산, 페닐알라닌, 티로신, 발린, 이소루신, 루신 또는 메티오닌;W 'is tryptophan, alanine, aspartic acid, phenylalanine, tyrosine, valine, isoleucine, leucine or methionine, protected or unprotected with methyl or tert-butyl;
    n은 0 또는 1인 화합물, 이의 입체이성질체, 또는 이의 약학적 허용 가능한 염.n is 0 or 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서,The method of claim 1,
    상기 화합물은 The compound is
    1. 1-(4-플루오로페닐)-N-(3-(메틸카바모일)페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,1.1- (4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    2. 1-(4-플루오로페닐)-N-(3-설파모일페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,2. 1- (4-fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    3. 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤젠설폰산,3. 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid,
    4. 메틸 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트,4. methyl 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
    5. N-(3-카바모일페닐)-1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,5. N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    6. 1-(4-플루오로페닐)-N-(4-(메틸카바모일)페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,6. 1- (4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    7. N-(4-카바모일페닐)-1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,7.N- (4-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    8. 3-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,8. 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    9. 4-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,9. 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    10. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-트립토파네이트,10. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate,
    11. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-트립토판,11. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan,
    12. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-D-알라니네이트,12. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanineate,
    13. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-D-알라닌,13. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine,
    14. 디메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-아스파테이트,14. Dimethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate,
    15. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)-L-아스파르트산,15. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid,
    16. 4-(1-(4-플루오로페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤젠설폰산,16. 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid,
    17. 에틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)글리시네이트,17. ethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate,
    18. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조일)글리신,18. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine,
    19. 3-(5-클로로티오펜-2-일)-N-(3-((2-몰포리노에틸)카바모일)페닐)-1-페닐-1H-피라졸-4-카르복스아미드,19. 3- (5-chlorothiophen-2-yl) -N- (3-((2-morpholinoethyl) carbamoyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    20. 메틸 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조에이트,20. Methyl 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoate,
    21. 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조산,21. 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoic acid,
    22. 메틸 (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조일)-D-알라니네이트,22. Methyl (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alanineate,
    23. (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)벤조일)-D-알라닌,23. (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alanine,
    24. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조에이트,24. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,
    25. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조산,25. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid,
    26. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-트립토파네이트,26. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophanate ,
    27. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-트립토판,27. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophan,
    28. (S)-3-(5-클로로티오펜-2-일)-N-(3-((1-((2-몰포리노에틸)아미노)-1-옥소프로판-2-일)카바모일)페닐)-1-페닐-1H-피라졸-4-카르복스아미드,28. (S) -3- (5-chlorothiophen-2-yl) -N- (3-((1-((2-morpholinoethyl) amino) -1-oxopropan-2-yl) carba Moyl) phenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    29. 에틸 3-(3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트,29. ethyl 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
    30. 3-(3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,30. 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    31. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-(트리플루오로메틸)벤조에이트,31.Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoate,
    32. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-(트리플루오로메틸)벤조산,32. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoic acid,
    33. 메틸 3-클로로-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,33. Methyl 3-chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
    34. 3-클로로-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,34. 3-chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    35. 메틸 3-브로모-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,35. Methyl 3-bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
    36. 3-브로모-5-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,36. 3-bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    37. 메틸 2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세테이트,37. Methyl 2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetate,
    38. 2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세트산,38. 2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetic acid,
    39. 메틸 (2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세틸)-L-트립토파네이트,39. Methyl (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophanate ,
    40. (2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)페닐)아세틸)-L-트립토판,40. (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophan,
    41. 에틸 3-(3-(5-클로로티오펜-2-일)-4-(페닐카바모일)-1H-피라졸-1-일)벤조에이트,41. ethyl 3- (3- (5-chlorothiophen-2-yl) -4- (phenylcarbamoyl) -1H-pyrazol-1-yl) benzoate,
    42. 3-(3-(5-클로로티오펜-2-일)-4-(페닐카바모일)-1H-피라졸-1-일)벤조산,42. 3- (3- (5-chlorothiophen-2-yl) -4- (phenylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid,
    43. 에틸 3-(4-((3-클로로페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조에이트,43. ethyl 3- (4-((3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate,
    44. 3-(4-((3-클로로페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,44. 3- (4-((3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
    45. 에틸 3-(3-(5-클로로티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조에이트,45. ethyl 3- (3- (5-chlorothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate,
    46. 3-(3-(5-클로로티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조산,46. 3- (3- (5-chlorothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
    47. tert-부틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-페닐알라니네이트,47. tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-phenyl Alanine,
    48. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-페닐알라닌,48. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-phenylalanine,
    49. 메틸 (S)-3-(4-(tert-부톡시)페닐)-2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤즈아미도)프로파네이트,49.Methyl (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1 H-pyrazole- 4-carboxamido) -5-fluorobenzamido) propane,
    50. (S)-3-(4-(tert-부톡시)페닐)-2-(3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤즈아미도)프로판산,50. (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4 -Carboxamido) -5-fluorobenzamido) propanoic acid,
    51. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-티로신,51. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tyrosine,
    52. tert-부틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-발리네이트,52. tert-Butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-vari Nate,
    53. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-발린,53. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-valine,
    54. tert-부틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-이소루시네이트,54. tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-iso Lucinate,
    55. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-이소루신,55. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-isoleucine,
    56. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-루시네이트,56. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-lucinate,
    57. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-루신,57. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-leucine,
    58. 메틸 (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-메티오네이트,58. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methionate ,
    59. (3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조일)-L-메티오닌,59. (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methionine,
    60. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-플루오로벤조에이트,60. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoate,
    61. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-플루오로벤조산,61. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoic acid,
    62. 메틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-(트리플루오로메틸)벤조에이트,62. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoate,
    63. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-(트리플루오로메틸)벤조산,63. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoic acid,
    64. tert-부틸 3-(3-(5-클로로티오펜-2-일)-1-(4-(메톡시카보닐)페닐)-1H-피라졸-4-카르복스아미도)벤조에이트,64. tert-Butyl 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoate ,
    65. 4-(4-((3-(tert-부톡시카보닐)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,65. 4- (4-((3- (tert-butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
    66. 3-(3-(5-클로로티오펜-2-일)-1-(4-(메톡시카보닐)페닐)-1H-피라졸-4-카르복스아미도)벤조산,66. 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoic acid,
    67. 3-(1-(4-카르복시페닐)-3-(5-클로로티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,67. 3- (1- (4-carboxyphenyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    68. 메틸 4-(4-((3-(((2R,3R)-1-(tert-부톡시)-3-메틸-1-옥소펜탄-2-일)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조에이트,68.Methyl 4- (4-((3-(((2R, 3R) -1- (tert-butoxy) -3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1 H-pyrazol-1-yl) benzoate,
    69. 4-(4-((3-(((2S,3S)-1-(tert-부톡시)-3-메틸-1-옥소펜탄-2-일)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,69. 4- (4-((3-(((2S, 3S) -1- (tert-butoxy) -3-methyl-1-oxopentan-2-yl) carbamoyl) phenyl) carbamoyl)- 3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
    70. 4-(4-((3-(((1R,2R)-1-카르복시-2-메틸부틸)카바모일)페닐)카바모일)-3-(5-클로로티오펜-2-일)-1H-피라졸-1-일)벤조산,70. 4- (4-((3-(((1R, 2R) -1-carboxy-2-methylbutyl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
    71. 메틸 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조에이트,71. Methyl 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoate,
    72. 3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조산,72. 3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoic acid,
    73. tert-부틸 (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조일)-L-이소루시네이트,73.tert-butyl (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl)- L-isorushinate,
    74. (3-((3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)-4-플루오로벤조일)-L-이소루신,74. (3-((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-iso Leucine,
    75. 메틸 3-(3-(5-시아노티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조에이트,75. Methyl 3- (3- (5-cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,
    76. 3-(3-(5-시아노티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-5-플루오로벤조산,76. 3- (3- (5-cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid,
    77. 메틸 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,77. Methyl 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate,
    78. 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,78. 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
    79. 메틸 (1S,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,79. Methyl (1S, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
    80. (1S,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,80. (1S, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
    81. 메틸 (1R,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,81. Methyl (1R, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
    82. (1R,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,82. (1R, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
    83. tert-부틸 ((1S,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트,83. tert-Butyl ((1S, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1- Carbonyl) -L-isorushinate,
    84. ((1S,4R)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신,84. ((1S, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,
    85. tert-부틸 ((1R,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트,85. tert-butyl ((1R, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1- Carbonyl) -L-isorushinate,
    86. ((1R,4S)-4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신,86. ((1R, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,
    87. 에틸 4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조에이트,87. ethyl 4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate,
    88. 4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조산,88. 4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
    89. 메틸 (4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤조일)-L-알로이소루시네이트,89. Methyl (4- (3- (5-bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoyl) -L-alloy Sorcinate,
    90. 2-(4-(3-(5-브로모티오펜-2-일)-4-((3-페녹시페닐)카바모일)-1H-피라졸-1-일)벤즈아미도)-3-메틸펜탄산,90. 2- (4- (3- (5-Bromothiophen-2-yl) -4-((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzamido)- 3-methylpentanoic acid,
    91. 메틸 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤조에이트,91. Methyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoate,
    92. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤조산,92. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoic acid,
    93. 메틸 (3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤조일)-L-이소루시네이트,93. Methyl (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoyl) -L-isorushinate ,
    94. 2-(3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)-4-메톡시벤즈아미도)-3-메틸펜탄산,94. 2- (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzamido) -3- Methylpentanoic acid,
    95. 메틸 (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,95. Methyl (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
    96. (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,96. (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
    97. 메틸 ((1R,3S)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-D-이소루시네이트,97. Methyl ((1R, 3S) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl ) -D-isorushinate,
    98. 2-((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복스아미도)-3-메틸펜탄산,98. 2-((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-car Voxamido) -3-methylpentanoic acid,
    99. 메틸 4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복실레이트,99. Methyl 4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylate,
    100. 4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복시산,100. 4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylic acid,
    101. 메틸 (4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카보닐)-D-이소루시네이트,101.Methyl (4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carbonyl) -D Isorushinate,
    102. 2-(4-((3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)메틸)사이클로헥산-1-카르복스아미도)-3-메틸펜탄산,102. 2- (4-((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxamido ) -3-methylpentanoic acid,
    103. 메틸 (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복실레이트,103. Methyl (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate ,
    104. (1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카르복시산,104. (1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid,
    105. 메틸 ((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루시네이트,105. Methyl ((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl ) -L-isorushinate,
    106. ((1S,3R)-3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)사이클로헥산-1-카보닐)-L-이소루신,106. ((1S, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,
    107. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3S)-3-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,107. Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3S) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
    108. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3S)-3-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,108. 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3S) -3-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
    109. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3R)-3-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,109. Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3R) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
    110. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,3R)-3-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,110. 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 3R) -3-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
    111. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1S,4S)-4-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,111.Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1S, 4S) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
    112. 4-(3-(5-브로모티오펜-2-일)-4-(((1S,4S)-4-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,112. 4- (3- (5-bromothiophen-2-yl) -4-(((1S, 4S) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
    113. 에틸 4-(3-(5-브로모티오펜-2-일)-4-(((1R,4R)-4-(메톡시카보닐)사이클로헥실)카바모일)-1H-피라졸-1-일)벤조에이트,113. Ethyl 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 4R) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) -1H-pyrazole- 1-yl) benzoate,
    114. 4-(3-(5-브로모티오펜-2-일)-4-(((1R,4R)-4-카르복시사이클로헥실)카바모일)-1H-피라졸-1-일)벤조산,114. 4- (3- (5-bromothiophen-2-yl) -4-(((1R, 4R) -4-carboxycyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid,
    115. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤젠설폰산,115. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid,
    116. 4-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤젠설폰산,116. 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid,
    117. 3-(1-페닐-3-(5-설포티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,117. 3- (1-phenyl-3- (5-sulfothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    118. 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,118. 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    119. 페닐-N-(3-설파모일페닐)-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,119. Phenyl-N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamide,
    120. 1-페닐-3-(티오펜-2-일)-N-(m-톨릴)-1H-피라졸-4-카르복스아미드,120. 1-phenyl-3- (thiophen-2-yl) -N- (m-tolyl) -1H-pyrazole-4-carboxamide,
    121. N-(3-아세틸페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,121.N- (3-acetylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    122. N-(4-카바모일페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,122. N- (4-carbamoylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    123. 메틸 (4-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조일)글리시네이트,123. Methyl (4- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate,
    124. 3-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,124. 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    125. 에틸 3-(1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조에이트,125. ethyl 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
    126. N,1-디페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,126. N, 1-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    127. N-(3-페녹시페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,127.N- (3-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    128. N-(4-페녹시페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,128.N- (4-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    129. N-(3-클로로페닐)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,129.N- (3-chlorophenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    130. N-(벤조[d][1,3]디옥솔-5-일)-1-페닐-3-(티오펜-2-일)-1H-피라졸-4-카르복스아미드,130. N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide,
    131. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,131. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    132. 3-(5-클로로티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,132. 3- (5-chlorothiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
    133. 에틸 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,133. ethyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
    134. 3-(3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,134. 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    135. N-(3-클로로페닐)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,135. N- (3-chlorophenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
    136. 3-(5-클로로티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,136. 3- (5-chlorothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    137. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,137.N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide ,
    138. 3-(5-클로로티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,138. 3- (5-chlorothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    139. 3-(5-클로로티오펜-2-일)-1-페닐-N-프로필-1H-피라졸-4-카르복스아미드,139. 3- (5-chlorothiophen-2-yl) -1-phenyl-N-propyl-1H-pyrazole-4-carboxamide,
    140. 3-(5-클로로티오펜-2-일)-N-사이클로프로필-1-페닐-1H-피라졸-4-카르복스아미드,140. 3- (5-chlorothiophen-2-yl) -N-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxamide,
    141. N-(1-벤질피페리딘-4-일)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,141.N- (1-benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
    142. 3-(5-클로로티오펜-2-일)-1-페닐-N-(피리딘-3-일)-1H-피라졸-4-카르복스아미드,142. 3- (5-chlorothiophen-2-yl) -1-phenyl-N- (pyridin-3-yl) -1H-pyrazole-4-carboxamide,
    143. 3-(5-클로로티오펜-2-일)-1-페닐-N-(4-(티오펜-2-일)페닐)-1H-피라졸-4-카르복스아미드,143. 3- (5-chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen-2-yl) phenyl) -1H-pyrazole-4-carboxamide,
    144. 3-(5-클로로티오펜-2-일)-N-(4-몰포리노페닐)-1-페닐-1H-피라졸-4-카르복스아미드,144. 3- (5-chlorothiophen-2-yl) -N- (4-morpholinophenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    145. N-(4-(벤질옥시)페닐)-3-(5-클로로티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,145.N- (4- (benzyloxy) phenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
    146. 에틸 3-(3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,146. ethyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
    147. 3-(5-브로모티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,147. 3- (5-Bromothiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
    148. 3-(5-브로모티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,148. 3- (5-Bromothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    149. 3-(5-브로모티오펜-2-일)-N-(3-클로로페닐)-1-페닐-1H-피라졸-4-카르복스아미드,149. 3- (5-Bromothiophen-2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    150. 3-(5-브로모티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,150. 3- (5-bromothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    151. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-브로모티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,151.N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide ,
    152. 3-(5-메틸티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,152. 3- (5-methylthiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
    153. 에틸 3-(3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,153. ethyl 3- (3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
    154. 3-(3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,154. 3- (3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    155. N-(3-클로로페닐)-3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,155.N- (3-chlorophenyl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide,
    156. 3-(5-메틸티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,156. 3- (5-methylthiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    157. 3-(5-메틸티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,157. 3- (5-methylthiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    158. N-(벤조[d][1,3]디옥솔-5-일)-3-(5-메틸티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미드,158. N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide ,
    159. 에틸 3-(3-(벤조[b]티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,159. ethyl 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
    160. 3-(벤조[b]티오펜-2-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,160. 3- (benzo [b] thiophen-2-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
    161. 3-(벤조[b]티오펜-2-일)-N-(4-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,161. 3- (benzo [b] thiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    162. 3-(벤조[b]티오펜-2-일)-N-(3-클로로페닐)-1-페닐-1H-피라졸-4-카르복스아미드,162. 3- (benzo [b] thiophen-2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    163. 3-(3-(벤조[b]티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,163. 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    164. 3-(벤조[b]티오펜-2-일)-N-(벤조[d][1,3]디옥솔-5-일)-1-페닐-1H-피라졸-4-카르복스아미드,164. 3- (benzo [b] thiophen-2-yl) -N- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-1H-pyrazole-4-carbox amides,
    165. 3-(벤조[b]티오펜-2-일)-N-(3-페녹시페닐)-1-페닐-1H-피라졸-4-카르복스아미드,165. 3- (benzo [b] thiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide,
    166. 3-(벤조[b]티오펜-3-일)-N,1-디페닐-1H-피라졸-4-카르복스아미드,166. 3- (benzo [b] thiophen-3-yl) -N, 1-diphenyl-1H-pyrazole-4-carboxamide,
    167. 에틸 3-(3-(벤조[b]티오펜-3-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조에이트,167. ethyl 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,
    168. 3-(3-(벤조[b]티오펜-3-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,168. 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    169. 3-(1-페닐-3-(5-(4-(트리플루오로메톡시)페닐)티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,169. 3- (1-phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    170. 3-(3-(5-(3-아세트아미도페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,170. 3- (3- (5- (3-acetamidophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    171. 3-(3-(5-(2-플루오로-4-(트리플루오로메틸)페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,171. 3- (3- (5- (2-fluoro-4- (trifluoromethyl) phenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) Benzoic Acid,
    172. 3-(3-(5-(3-시아노-4-플루오로페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산,172. 3- (3- (5- (3-cyano-4-fluorophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid,
    173. 3-(1-페닐-3-(5-(4-(트리플루오로메틸)페닐)티오펜-2-일)-1H-피라졸-4-카르복스아미도)벤조산,173. 3- (1-phenyl-3- (5- (4- (trifluoromethyl) phenyl) thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
    174. 3-(3-(5-(3-플루오로-4-메톡시페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산, 또는174. 3- (3- (5- (3-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid, or
    175. 3-(3-(5-(4-카바모일페닐)티오펜-2-일)-1-페닐-1H-피라졸-4-카르복스아미도)벤조산인 것인 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염.175. A compound, wherein the stereoisomer thereof is 3- (3- (5- (4-carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid , Or pharmaceutically acceptable salts thereof.
  4. 하기 화학식 2로 표시되는 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용가능한 염:A compound represented by Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 2][Formula 2]
    Figure PCTKR2017001288-appb-I000005
    Figure PCTKR2017001288-appb-I000005
    상기 식에서,Where
    R6은 C6-10 아릴, 3 내지 10원 헤테로사이클로알킬, 또는 (3 내지 10원 헤테로사이클로알킬)(C1-4 알킬)로서,R 6 is C 6-10 aryl, 3 to 10 membered heterocycloalkyl, or (3 to 10 membered heterocycloalkyl) (C 1-4 alkyl),
    상기 아릴 및 헤테로사이클로알킬은 비치환되거나, C1-4 할로겐화 알킬, -CO(C6-10 아릴), -CO(1-4 알킬), -CONH(C6-10 아릴), -SO2(비치환 또는 C1-4 알킬로 치환된 C6-10 아릴), (C6-10 아릴)(C1-4 알킬), -CO2(C0-4 알킬), 할로겐, C1-4 알콕시, C6-10 아릴옥시, 5 내지 10원 헤테로아릴 또는 -CONHW''로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The aryl and heterocycloalkyl are unsubstituted or C 1-4 halogenated alkyl, -CO (C 6-10 aryl), -CO ( 1-4 alkyl), -CONH (C 6-10 aryl), -SO 2 (C 6-10 aryl unsubstituted or substituted with C 1-4 alkyl), (C 6-10 aryl) (C 1-4 alkyl), -CO 2 (C 0-4 alkyl), halogen, C 1- 4 alkoxy, C 6-10 aryloxy, 5-10 membered heteroaryl, or -CONHW '', which may be substituted with any one or more substituents selected from the group consisting of:
    R7은 수소, C6-10 아릴옥시, -CONH(C1-4 알킬렌)(3 내지 10원 헤테로사이클로알킬), -CO2(C0-4 알킬), 또는 -CONHW''로서,R 7 is hydrogen, C 6-10 aryloxy, -CONH (C 1-4 alkylene) (3 to 10 membered heterocycloalkyl), -CO 2 (C 0-4 alkyl), or -CONHW '',
    상기 W''은 각각 독립적으로 보호되거나 보호되지 않은 아미노산이다.Each W ″ is an independently protected or unprotected amino acid.
  5. 제4항에 있어서,The method of claim 4, wherein
    R6은 페닐, 피페리디닐, 또는 피페리디닐메틸로서,R 6 is phenyl, piperidinyl, or piperidinylmethyl,
    상기 페닐 및 피페리디닐은 비치환되거나, 트리플루오로메틸, 트리플루오로메톡시, -CO2H, -CO2CH3, -CO2(페닐), -CONH(페닐), 할로겐, C1-4 알콕시, 벤질, 이미다졸릴, 토실, 또는 페녹시로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The phenyl and piperidinyl are unsubstituted or trifluoromethyl, trifluoromethoxy, -CO 2 H, -CO 2 CH 3 , -CO 2 (phenyl), -CONH (phenyl), halogen, C 1- 4 may be substituted with any one or more substituents selected from the group consisting of alkoxy, benzyl, imidazolyl, tosyl, or phenoxy;
    R7은 수소, -CO2H, -CO2CH3 또는 -CONHW''로서,R 7 is hydrogen, -CO 2 H, -CO 2 CH 3 or -CONHW '',
    상기 W''은 메틸로 보호되거나 보호되지 않은 트립토판인 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염.Wherein W ″ is tryptophan, protected or unprotected with methyl, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  6. 제4항에 있어서,The method of claim 4, wherein
    상기 화합물은 The compound is
    1. 4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조산,1. 4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid,
    2. 메틸 (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-D-트립토파네이트,2. methyl (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophanate,
    3. 메틸 (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-D-트립토판,3. Methyl (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophan,
    4. 2-(4-((2-몰포리노에틸)카바모일)페닐)-N-(3-페녹시페닐)티아졸-5-카르복스아미드,4. 2- (4-((2-morpholinoethyl) carbamoyl) phenyl) -N- (3-phenoxyphenyl) thiazole-5-carboxamide,
    5. 3-(5-((4-페녹시페닐)카바모일)티아졸-2-일)벤조산,5. 3- (5-((4-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid,
    6. 메틸 3-(2-(4-페녹시페닐)티아졸-5-카르복스아미도)벤조에이트,6. Methyl 3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoate,
    7. 3-(2-(4-페녹시페닐)티아졸-5-카르복스아미도)벤조산,7. 3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoic acid,
    8. 메틸 (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토파네이트,8. Methyl (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophanate,
    9. (4-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토판,9. (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan,
    10. 메틸 4-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조에이트,10. methyl 4- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,
    11. 메틸 4-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조에이트,11.Methyl 4- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,
    12. 메틸 4-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,12. Methyl 4- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    13. 4-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,13. 4- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    14. 메틸 4-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,14. Methyl 4- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    15. 4-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,15. 4- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    16. 메틸 4-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,16. Methyl 4- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    17. 4-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,17. 4- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    18. 메틸 3-(5-((1-벤질피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,18. Methyl 3- (5-((1-benzylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
    19. 3-(5-((1-벤질피페리딘-4-일)카바모일)티아졸-2-일)벤조산,19. 3- (5-((1-benzylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
    20. 메틸 3-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조에이트,20. Methyl 3- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,
    21. 3-(5-((피페리딘-4-일메틸)카바모일)티아졸-2-일)벤조산,21. 3- (5-((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoic acid,
    22. 메틸 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,22. Methyl 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    23. 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,23. 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    24. 메틸 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,24. Methyl 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    25. 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,25. 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    26. 메틸 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,26. Methyl 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    27. 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,27. 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    28. 메틸 (3-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토파네이트,28. Methyl (3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophanate,
    29. (3-(5-((3-페녹시페닐)카바모일)티아졸-2-일)벤조일)-L-트립토판,29. (3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan,
    30. 메틸 3-(5-(((1-아세틸피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,30. Methyl 3- (5-(((1-acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    31. 메틸 3-(5-(((1-아세틸피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,31. Methyl 3- (5-(((1-acetylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    32. 메틸 3-(5-((1-아세틸피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,32. Methyl 3- (5-((1-acetylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
    33. 메틸 3-(5-((1-아세틸피페리딘-3-일)카바모일)티아졸-2-일)벤조에이트,33. Methyl 3- (5-((1-acetylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoate,
    34. 3-(5-(((1-아세틸피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,34. 3- (5-(((1-acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    35. 3-(5-(((1-아세틸피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,35. 3- (5-(((1-acetylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    36. 3-(5-((1-아세틸피페리딘-4-일)카바모일)티아졸-2-일)벤조산,36. 3- (5-((1-acetylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
    37. 3-(5-((1-아세틸피페리딘-3-일)카바모일)티아졸-2-일)벤조산,37. 3- (5-((1-acetylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid,
    38. 메틸 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,38. Methyl 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    39. 메틸 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,39. Methyl 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    40. 메틸 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조에이트,40. Methyl 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    41. 3-(5-(((1-벤조일피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,41. 3- (5-(((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    42. 3-(5-(((1-(페닐카바모일)피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,42. 3- (5-(((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    43. 3-(5-(((1-토실피페리딘-4-일)메틸)카바모일)티아졸-2-일)벤조산,43. 3- (5-(((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    44. 메틸 3-(5-(((1-벤조일피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,44. Methyl 3- (5-(((1-benzoylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    45. 메틸 3-(5-(((1-(페닐카바모일)피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,45. Methyl 3- (5-(((1- (phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    46. 메틸 3-(5-(((1-토실피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조에이트,46. Methyl 3- (5-(((1-tosylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate,
    47. 3-(5-(((1-벤조일피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,47. 3- (5-(((1-benzoylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    48. 3-(5-(((1-(페닐카바모일)피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,48. 3- (5-(((1- (phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    49. 3-(5-(((1-토실피페리딘-2-일)메틸)카바모일)티아졸-2-일)벤조산,49. 3- (5-(((1-tosylpiperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid,
    50. 메틸 3-(5-((1-벤조일피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,50. methyl 3- (5-((1-benzoylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
    51. 메틸 3-(5-((1-토실피페리딘-4-일)카바모일)티아졸-2-일)벤조에이트,51. methyl 3- (5-((1-tosylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,
    52. 메틸 3-(5-((1-벤조일피페리딘-3-일)카바모일)티아졸-2-일)벤조에이트,52. Methyl 3- (5-((1-benzoylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoate,
    53. 메틸 3-(5-((1-토실피페리딘-3-일)카바모일)티아졸-2-일)벤조에이트,53. methyl 3- (5-((1-tosylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoate,
    54. 3-(5-((1-벤조일피페리딘-4-일)카바모일)티아졸-2-일)벤조산,54. 3- (5-((1-benzoylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
    55. 3-(5-((1-토실피페리딘-4-일)카바모일)티아졸-2-일)벤조산,55. 3- (5-((1-tosylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid,
    56. 3-(5-((1-벤조일피페리딘-3-일)카바모일)티아졸-2-일)벤조산,56. 3- (5-((1-benzoylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid,
    57. 3-(5-((1-토실피페리딘-3-일)카바모일)티아졸-2-일)벤조산,57. 3- (5-((1-tosylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid,
    58. N,2-디페닐티아졸-5-카르복스아마이드,58. N, 2-diphenylthiazole-5-carboxamide,
    59. 메틸 4-(5-(페닐카바모일)티아졸-2-일)벤조에이트,59. Methyl 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoate,
    60. 4-(5-(페닐카바모일)티아졸-2-일)벤조산,60. 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoic acid,
    61. 메틸 4-(5-((3,5-비스(트리플루오로메틸)페닐)카바모일)티아졸-2-일)벤조에이트,61. Methyl 4- (5-((3,5-bis (trifluoromethyl) phenyl) carbamoyl) thiazol-2-yl) benzoate,
    62. N-(3-페녹시페닐)-2-페닐티아졸-5-카르복스아마이드,62. N- (3-phenoxyphenyl) -2-phenylthiazole-5-carboxamide,
    63. N-(4-(1H-이미다졸-1-일)페닐)-2-페닐티아졸-5-카르복스아마이드,63. N- (4- (1H-imidazol-1-yl) phenyl) -2-phenylthiazole-5-carboxamide,
    64. 메틸 4-(5-((3-페녹시페닐)카바모일)티아졸-2-일l)벤조에이트,64. Methyl 4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yll) benzoate,
    65. 3-(5-((3- 페녹시페닐)카바모일)티아졸-2-일)벤조산, 또는65. 3- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid, or
    66. N-(4-페녹시페닐)-2-페닐티아졸-5-카르복스아마이드인 것인 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염.66. A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, which is N- (4-phenoxyphenyl) -2-phenylthiazole-5-carboxamide.
  7. 하기 화학식 3으로 표시되는 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용가능한 염:A compound represented by Formula 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 3][Formula 3]
    Figure PCTKR2017001288-appb-I000006
    Figure PCTKR2017001288-appb-I000006
    상기 식에서,Where
    Z는 -CO2H, -CO2(C1-4 알킬), -CONH(C1-4 알킬), 히드록시, C1-4 알킬, C1-4 할로겐화 알킬, C3-8 사이클로알킬, 3 내지 10원 헤테로사이클로알킬, C6-10 아릴 또는 5 내지 10원 헤테로아릴로서,Z is -CO 2 H, -CO 2 (C 1-4 alkyl), -CONH (C 1-4 alkyl), hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 3-8 cycloalkyl , 3 to 10 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl,
    상기 사이클로알킬, 헤테로사이클로알킬, 아릴 및 헤테로아릴은 비치환되거나, 히드록시, C1-4 알킬, C1-4 할로겐화 알킬, C6-10 아릴옥시, (C6-10 아릴)(C1-4 알킬), (C6-10 아릴)(C1-4 알킬)옥시, -CONH(C0-4 알킬), 3 내지 10원 헤테로사이클로알킬, 및 -(C0-4 알킬렌)CO2(C0-4 알킬)로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환될 수 있고;The cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted, hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 6-10 aryloxy, (C 6-10 aryl) (C 1 -4 alkyl), (C 6-10 aryl) (C 1-4 alkyl) oxy, -CONH (C 0-4 alkyl), 3 to 10 membered heterocycloalkyl, and - (C 0-4 alkylene) CO Can be substituted with any one or more substituents selected from the group consisting of 2 (C 0-4 alkyl);
    R8 및 R9는 각각 독립적으로 수소, -(C0-4 알킬렌)CO2(C0-4 알킬), -CONH(C0-4 알킬), 또는 할로겐;R 8 and R 9 are each independently hydrogen, — (C 0-4 alkylene) CO 2 (C 0-4 alkyl), —CONH (C 0-4 alkyl), or halogen;
    R10 및 R11은 각각 독립적으로 수소 또는 할로겐이다.R 10 and R 11 are each independently hydrogen or halogen.
  8. 제7항에 있어서,The method of claim 7, wherein
    Z는 -CO2H, -CO2C2H5, -CONH2, -CONHCH3, 히드록시, 메틸, 프로필, 트리플루오로알킬, 또는 히드록시, 브로모, 트리플루오로알킬, 페녹시, 페닐에틸, 벤질, 벤질옥시, 몰포리닐, -CONHCH3, -CO2H, -CO2CH3, 및 -CO2C2H5로 구성된 군으로부터 선택되는 어느 하나 이상의 치환기로 치환 또는 비치환된 사이클로프로필, 피페리디닐, 몰포리닐, 인돌릴, 인다졸릴, 페닐 또는 피리디닐;Z is -CO 2 H, -CO 2 C 2 H 5 , -CONH 2 , -CONHCH 3 , hydroxy, methyl, propyl, trifluoroalkyl, or hydroxy, bromo, trifluoroalkyl, phenoxy, Unsubstituted or substituted with any one or more substituents selected from the group consisting of phenylethyl, benzyl, benzyloxy, morpholinyl, -CONHCH 3 , -CO 2 H, -CO 2 CH 3 , and -CO 2 C 2 H 5 Cyclopropyl, piperidinyl, morpholinyl, indolyl, indazolyl, phenyl or pyridinyl;
    R8 및 R9는 각각 독립적으로 수소, -CO2H, -CH2CO2H, -CH2CO2CH3, -CO2CH3, -CO2C2H5, 클로로, 브로모, -CONHCH3, -CH2CONH2, 또는 -CONH2;R 8 and R 9 are each independently hydrogen, —CO 2 H, —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —CO 2 CH 3 , —CO 2 C 2 H 5 , chloro, bromo, -CONHCH 3 , -CH 2 CONH 2 , or -CONH 2 ;
    R10 및 R11은 각각 독립적으로 수소 또는 플루오로인 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염.R 10 and R 11 are each independently hydrogen or fluoro, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  9. 제7항에 있어서,The method of claim 7, wherein
    상기 화합물은 The compound is
    1. 3-((3-(페닐카바모일)페닐)설폰아미도)벤조산,1. 3-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
    2. N-메틸-3-((3-(페닐카바모일)페닐)설폰아미도)벤즈아미드,2.N-methyl-3-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide,
    3. 3-((3-((3-카르복시페닐)카바모일)페닐)설폰아미도)벤조산,3. 3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid,
    4. 3-(3-(N-(2-페녹시페닐)설파모일)벤즈아미도)벤조산,4. 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,
    5. N-메틸-3-(3-(N-(2-페녹시페닐)설파모일)벤즈아미도)벤즈아미드,5.N-methyl-3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzamide,
    6. 3-(3-(N-(3-페녹시페닐)설파모일)벤즈아미도)벤조산,6. 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,
    7. N-메틸-3-(3-(N-(3-페녹시페닐)설파모일)벤즈아미도)벤즈아미드,7.N-methyl-3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzamide,
    8. 3-(3-(N-(4-페녹시페닐)설파모일)벤즈아미도)벤조산,8. 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,
    9. N-메틸-3-(3-(N-(4-페녹시페닐)설파모일)벤즈아미도)벤즈아미드,9.N-methyl-3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzamide,
    10. 3-(3-(N-(피리딘-2-일)설파모일)벤즈아미도)벤조산,10. 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoic acid,
    11. N-메틸-3-(3-(N-(피리딘-2-일)설파모일)벤즈아미도)벤즈아미드,11.N-methyl-3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzamide,
    12. 3-(3-(N-(피리딘-3-일)설파모일)벤즈아미도)벤조산,12. 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoic acid,
    13. N-메틸-3-(3-(N-(피리딘-3-일)설파모일)벤즈아미도)벤즈아미드,13.N-methyl-3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzamide,
    14. 3-(3-(N-프로필설파모일)벤즈아미도)벤조산,14. 3- (3- (N-propylsulfamoyl) benzamido) benzoic acid,
    15. N-메틸-3-(3-(N-프로필설파모일)벤즈아미도)벤즈아미드,15.N-methyl-3- (3- (N-propylsulfamoyl) benzamido) benzamide,
    16. 3-(3-(N-사이클로프로필설파모일)벤즈아미도)벤조산,16. 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoic acid,
    17. 3-(N-사이클로프로필설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,17. 3- (N-cyclopropylsulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
    18. 3-(3-(N-메틸설파모일)벤즈아미도)벤조산,18. 3- (3- (N-methylsulfamoyl) benzamido) benzoic acid,
    19. N-메틸-3-(3-(N-메틸설파모일)벤즈아미도)벤즈아미드,19.N-methyl-3- (3- (N-methylsulfamoyl) benzamido) benzamide,
    20. 2-(3-(3-(N-페닐설파모일)벤즈아미도)페닐)아세트산,20. 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetic acid,
    21. N-(3-(2-(메틸아미노)-2-옥소에틸)페닐)-3-(N-페닐설파모일)벤즈아미드,21.N- (3- (2- (methylamino) -2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide,
    22. N-(3-(2-아미노-2-옥소에틸)페닐)-3-(N-페닐설파모일)벤즈아미드,22.N- (3- (2-amino-2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide,
    23. 3-(3-(N-(4-(벤질옥시)페닐)설파모일)벤즈아미도)벤조산,23. 3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoic acid,
    24. 3-(N-(4-(벤질옥시)페닐)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,24. 3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
    25. 3-(3-(N-(1-벤질피페리딘-4-일)설파모일)벤즈아미도)벤조산,25. 3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoic acid,
    26. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,26. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
    27. 3-(3-(N-(4-몰포리노페닐)설파모일)벤즈아미도)벤조산,27. 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoic acid,
    28. N-메틸-3-(3-(N-(4-몰포리노페닐)설파모일)벤즈아미도)벤즈아미드,28.N-methyl-3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzamide,
    29. 3-(3-(N-(1H-인돌-5-일)설파모일)벤즈아미도)벤조산,29. 3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido) benzoic acid,
    30. 3-(N-(1H-인돌-5-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,30. 3- (N- (1H-indol-5-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
    31. 3-(3-(N-(1H-인돌-6-일)설파모일)벤즈아미도)벤조산,31. 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoic acid,
    32. 3-(N-(1H-인돌-6-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,32. 3- (N- (1H-indol-6-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
    33. 3-(3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)벤즈아미도)벤조산,33. 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoic acid,
    34. 3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,34. 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
    35. 3-((3-((3-카르복시페닐)카바모일)페닐)설폰아미도)벤조산,35. 3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid,
    36. 에틸 3-((2,4-디플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조에이트,36. ethyl 3-((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,
    37. 3-((2,4-디플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조산,37. 3-((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
    38. 에틸 3-(4-플루오로-3-(N-페닐설파모일)벤즈아미도)벤조에이트,38. ethyl 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoate,
    39. 3-(4-플루오로-3-(N-페닐설파모일)벤즈아미도)벤조산,39. 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoic acid,
    40. 에틸 3-(2,4-디플루오로-5-(N-페닐설파모일)벤즈아미도)벤조에이트,40. ethyl 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoate,
    41. 3-(2,4-디플루오로-5-(N-페닐설파모일)벤즈아미도)벤조산,41. 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoic acid,
    42. 메틸 3-(3-(N-(2-페녹시페닐)설파모일)벤즈아미도)벤조에이트,42. Methyl 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoate,
    43. 메틸 3-(3-(N-(3-페녹시페닐)설파모일)벤즈아미도)벤조에이트,43. Methyl 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoate,
    44. 메틸 3-(3-(N-(4-페녹시페닐)설파모일)벤즈아미도)벤조에이트,44. Methyl 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoate,
    45. 메틸 3-(3-(N-(4-(벤질옥시)페닐)설파모일)벤즈아미도)벤조에이트,45. Methyl 3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoate,
    46. 메틸 3-(3-(N-(피리딘-2-일)설파모일)벤즈아미도)벤조에이트,46. Methyl 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoate,
    47. 메틸 3-(3-(N-(피리딘-3-일)설파모일)벤즈아미도)벤조에이트,47. Methyl 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoate,
    48. 메틸 3-(3-(N-프로필설파모일)벤즈아미도)벤조에이트,48. Methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate,
    49. 메틸 3-(3-(N-사이클로프로필설파모일)벤즈아미도)벤조에이트,49. Methyl 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoate,
    50. 메틸 3-(3-(N-메틸설파모일)벤즈아미도)벤조에이트,50. Methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate,
    51. 메틸 3-(3-(N-(4-몰포리노페닐)설파모일)벤즈아미도)벤조에이트,51. Methyl 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoate,
    52. 메틸 3-(3-(N-(1H-인돌-5-일)설파모일)벤즈아미도)벤조에이트,52. Methyl 3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido) benzoate,
    53. 메틸 3-(3-(N-(1H-인돌-6-일)설파모일)벤즈아미도)벤조에이트,53. Methyl 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoate,
    54. 메틸 3-(3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)벤즈아미도)벤조에이트,54. Methyl 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate,
    55. 메틸 3-(3-(N-(1-벤질피페리딘-4-일)설파모일)벤즈아미도)벤조에이트,55. Methyl 3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoate,
    56. 메틸 3-((3-((3-(메톡시카보닐)페닐)카바모일)페닐)설폰아미도)벤조에이트,56. Methyl 3-((3-((3- (methoxycarbonyl) phenyl) carbamoyl) phenyl) sulfonamido) benzoate,
    57. 메틸 2-(3-(3-(N-페닐설파모일)벤즈아미도)페닐)아세테이트,57. Methyl 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetate,
    58. 메틸 3-브로모-5-(3-(N-페닐설파모일)벤즈아미도)벤조에이트,58. Methyl 3-bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoate,
    59. 메틸 3-브로모-5-((3-(페닐카바모일)페닐)설폰아미도)벤조에이트,59. Methyl 3-bromo-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,
    60. 3-브로모-5-(3-(N-페닐설파모일)벤즈아미도)벤조산,60. 3-bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid,
    61. 3-브로모-5-((3-(페닐카바모일)페닐)설폰아미도)벤조산,61. 3-bromo-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
    62. 3-브로모-N-메틸-5-(3-(N-페닐설파모일)벤즈아미도)벤즈아미드,62. 3-bromo-N-methyl-5- (3- (N-phenylsulfamoyl) benzamido) benzamide,
    63. 3-브로모-N-메틸-5-((3-(페닐카바모일)페닐)설폰아미도)벤즈아미드,63. 3-bromo-N-methyl-5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide,
    64. 메틸 3-((1-옥소-1,2,3,4-테트라하이드로이소퀴놀린)-7-설폰아미도)벤조에이트,64. Methyl 3-((1-oxo-1,2,3,4-tetrahydroisoquinoline) -7-sulfonamido) benzoate,
    65. 3-(N-(2-(페닐아미노)페닐)설파모일)벤조산,65. 3- (N- (2- (phenylamino) phenyl) sulfamoyl) benzoic acid,
    66. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-(메틸카바모일)페닐)벤즈아미드,66. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,
    67. N-(3-카바모일페닐)-3-(N-펜에틸설파모일)벤즈아미드,67.N- (3-carbamoylphenyl) -3- (N-phenethylsulfamoyl) benzamide,
    68. N-(3-카바모일페닐)-3-(N-(4-페녹시페닐)설파모일)벤즈아미드,68. N- (3-carbamoylphenyl) -3- (N- (4-phenoxyphenyl) sulfamoyl) benzamide,
    69. N-(3-카바모일페닐)-3-(N-(피리딘-2-일)설파모일)벤즈아미드,69.N- (3-carbamoylphenyl) -3- (N- (pyridin-2-yl) sulfamoyl) benzamide,
    70. 3-(N-(1-벤질피페리딘-4-일)설파모일)-N-(3-카바모일페닐)벤즈아미드,70. 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
    71. N-(3-카바모일페닐)-3-(N-(3-페녹시페닐)설파모일)벤즈아미드,71.N- (3-carbamoylphenyl) -3- (N- (3-phenoxyphenyl) sulfamoyl) benzamide,
    72. 3-(N-(1H-인다졸-5-일)설파모일)-N-(3-카바모일페닐)벤즈아미드,72. 3- (N- (1H-indazol-5-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
    73. 3-(N-(1H-인다졸-6-일)설파모일)-N-(3-카바모일페닐)벤즈아미드,73. 3- (N- (1H-indazol-6-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
    74. N-(3-카바모일페닐)-3-(N-(피리딘-3-일)설파모일)벤즈아미드,74.N- (3-carbamoylphenyl) -3- (N- (pyridin-3-yl) sulfamoyl) benzamide,
    75. 2,4-디플루오로-N-(3-(메틸카바모일)페닐)-5-(N-페닐설파모일)벤즈아미드,75. 2,4-difluoro-N- (3- (methylcarbamoyl) phenyl) -5- (N-phenylsulfamoyl) benzamide,
    76. 3-(N-(3,5-비스(트리플루오로메틸)페닐)설파모일)-N-(3-카바모일페닐)벤즈아미드,76. 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide,
    77. 4-플루오로-N-(3-(메틸카바모일)페닐)-3-(N-페닐설파모일)벤즈아미드,77. 4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N-phenylsulfamoyl) benzamide,
    78. N-(3-카바모일페닐)-4-플루오로-3-(N-페닐설파모일)벤즈아미드,78. N- (3-carbamoylphenyl) -4-fluoro-3- (N-phenylsulfamoyl) benzamide,
    79. 에틸 3-((5-((3-(에톡시카보닐)페닐)카바모일)-2-플루오로페닐)설폰아미도)벤조에이트,79. Ethyl 3-((5-((3- (ethoxycarbonyl) phenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoate,
    80. 3-((5-((3-카르복시페닐)카바모일)-2-플루오로페닐)설폰아미도)벤조산,80. 3-((5-((3-carboxyphenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoic acid,
    81. 4-플루오로-N-(3-(메틸카바모일)페닐)-3-(N-(3-(메틸카바모일)페닐)설파모일)벤즈아미드,81. 4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide,
    82. 에틸 3-((2-플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조에이트,82. ethyl 3-((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,
    83. 3-((2-플루오로-5-(페닐카바모일)페닐)설폰아미도)벤조산,83. 3-((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,
    84. N-(4-클로로페닐)-3-(N-페닐설파모일)벤즈아미드,84. N- (4-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide,
    85. N-(4-브로모페닐)-3-(N-페닐설파모일)벤즈아미드,85.N- (4-bromophenyl) -3- (N-phenylsulfamoyl) benzamide,
    86. N-(3-클로로페닐)-3-(N-페닐설파모일)벤즈아미드,86. N- (3-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide,
    87. N-(3,4-디클로로페닐)-3-(N-페닐설파모일)벤즈아미드,87.N- (3,4-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide,
    88. N-(3,5-디클로로페닐)-3-(N-페닐설파모일)벤즈아미드, 또는88. N- (3,5-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide, or
    89. N-(2,4-디브로모페닐)-3-(N-페닐설파모일)벤즈아미드인 것인 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염.89. A compound, stereoisomer, or pharmaceutically acceptable salt thereof, which is N- (2,4-dibromophenyl) -3- (N-phenylsulfamoyl) benzamide.
  10. 제1항 내지 제9항 중 어느 한 항에 따른 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 골질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating bone diseases, comprising the compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  11. 제10항에 있어서,The method of claim 10,
    상기 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염은 스클레로스틴(sclerostin; SOST), LPR5/6(Low-density lipoprotein receptor-related protein 5/6) 또는 둘 모두에 결합하는 것인 약학적 조성물.The compound, its stereoisomers, or pharmaceutically acceptable salts thereof, binds to sclerostin (SOST), low-density lipoprotein receptor-related protein 5/6, or both. Pharmaceutical compositions.
  12. 제11항에 있어서,The method of claim 11,
    상기 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염은 SOST와 LPR5/6의 결합을 저해하는 것인 약학적 조성물.Wherein said compound, its stereoisomer, or pharmaceutically acceptable salt thereof inhibits the binding of SOST to LPR5 / 6.
  13. 제10항에 있어서,The method of claim 10,
    상기 골질환은 골다공증, 골절, 치주질환에 의한 턱뼈 소실, 비전형 골절 및 비스포스포네이트와 연관된 악골괴사(Bisphophonate Related Osteonecrosis in Jaw; BRONJ)로 구성된 군으로부터 선택되는 것인 약학적 조성물.The bone disease is selected from the group consisting of osteoporosis, fracture, jaw bone loss due to periodontal disease, atypical fracture and bisphosphonate (Bisphophonate Related Osteonecrosis in Jaw; BRONJ).
  14. 제1항 내지 제9항 중 어느 한 항에 따른 화합물, 이의 입체이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 SOST와 LPR5/6의 결합 저해용 조성물.10. A composition for inhibiting binding of SOST and LPR5 / 6 comprising the compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
PCT/KR2017/001288 2016-02-05 2017-02-06 Novel amide compound and use thereof WO2017135786A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20160015230 2016-02-05
KR10-2016-0015230 2016-02-05

Publications (1)

Publication Number Publication Date
WO2017135786A1 true WO2017135786A1 (en) 2017-08-10

Family

ID=59500884

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2017/001288 WO2017135786A1 (en) 2016-02-05 2017-02-06 Novel amide compound and use thereof

Country Status (2)

Country Link
KR (3) KR101857714B1 (en)
WO (1) WO2017135786A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109970654A (en) * 2019-05-21 2019-07-05 郑州大学 A series of substitution 2- phenylpyrazole derivatives and its preparation method and application

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043951A1 (en) * 2002-10-24 2004-05-27 Carex S.A. Pyrazole derivatives as modulators of peroxisome proliferator activated receptors
WO2007087427A2 (en) * 2006-01-25 2007-08-02 Synta Pharmaceuticals Corp. Thiazole and thiadiazole compounds for inflammation and immune-related uses
US20080119402A1 (en) * 2003-09-22 2008-05-22 Jie Zheng Compositions and methods for the inhibition of dishevelled proteins
US8969339B2 (en) * 2003-09-22 2015-03-03 Enzo Biochem, Inc. Compositions and methods for bone formation and modeling

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8597949B2 (en) * 2007-07-28 2013-12-03 The University Of Chicago Methods and compositions for modulating RAD51 and homologous recombination
EP3085368A1 (en) * 2011-07-01 2016-10-26 Baruch S. Blumberg Institute Sulfamoylbenzamide derivatives as antiviral agents against hbv infection

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043951A1 (en) * 2002-10-24 2004-05-27 Carex S.A. Pyrazole derivatives as modulators of peroxisome proliferator activated receptors
US20080119402A1 (en) * 2003-09-22 2008-05-22 Jie Zheng Compositions and methods for the inhibition of dishevelled proteins
US8969339B2 (en) * 2003-09-22 2015-03-03 Enzo Biochem, Inc. Compositions and methods for bone formation and modeling
WO2007087427A2 (en) * 2006-01-25 2007-08-02 Synta Pharmaceuticals Corp. Thiazole and thiadiazole compounds for inflammation and immune-related uses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOKOOJI, A.: "Palladium-catalyzed direct arylation of thiazoles with aryl bromides", TETRAHEDRON, vol. 59, no. 30, 2003, pages 5685 - 5689, XP004437442, DOI: doi:10.1016/S0040-4020(03)00879-2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109970654A (en) * 2019-05-21 2019-07-05 郑州大学 A series of substitution 2- phenylpyrazole derivatives and its preparation method and application

Also Published As

Publication number Publication date
KR101857714B1 (en) 2018-05-15
KR20180064334A (en) 2018-06-14
KR101969553B1 (en) 2019-04-16
KR20180064333A (en) 2018-06-14
KR20170094087A (en) 2017-08-17
KR101905647B1 (en) 2018-10-10

Similar Documents

Publication Publication Date Title
WO2017065473A1 (en) Oxadiazole amine derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
EP3328844A1 (en) 1,3,4-oxadiazole sulfamide derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2017018804A1 (en) 1,3,4-oxadiazole amide derivative compound as histone deacetylase 6 inhibitor, and pharmaceutical composition containing same
CN101522637A (en) Benzimidazole derivatives useful in treatment of vallinoid rece tor trpvl related disorders
EP3116859A1 (en) Novel compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same
WO2013081400A2 (en) Novel benzamide derivative and use thereof
AU2019310508B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and pharmaceutical composition comprising the same
WO2017018751A1 (en) Novel compound having blt inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient
WO2016190630A1 (en) Heterocyclicalkyl derivative compounds as selective histone deacetylase inhibitors and pharmaceutical compositions comprising the same
AU2019217094A1 (en) Compounds for inhibiting TNIK and medical uses thereof
WO2013019091A2 (en) A COMPOUND FOR INHIBITING 11β-HYDROXY STEROID DEHYDROGENASE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
AU2021225683B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
AU2021226297B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2017135786A1 (en) Novel amide compound and use thereof
EP3060549A1 (en) Novel antifungal oxodihydropyridinecarbohydrazide derivative
WO2017123038A1 (en) Pyridinol derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition containing same as active ingredient
AU2021255176B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2022086110A1 (en) Thiobenzimidazole derivative or pharmaceutically acceptable salt thereof and use thereof
WO2021034087A1 (en) Novel compound having cancer metastasis inhibitory activity, preparation method therefor, and pharmaceutical composition for inhibiting cancer metastasis and invasion or treating colorectal cancer, comprising compound
WO2011149213A2 (en) Novel derivative having inhibitory activity against 11β-hsd1, preparation method thereof, and pharmaceutical composition containing same as active ingredient
WO2023085785A1 (en) Isoindolinone derivative having glutarimide mother nucleus, and use thereof
WO2022255764A1 (en) Novel oxazole derivative and pharmaceutical composition containing same for prevention or treatment of allergic disease
WO2011043519A2 (en) Sulfonamide derivatives as serotonin receptor antagonist and serotonin reuptake inhibitor
WO2022164239A1 (en) Pyrazole-carboxamide derivative compound and use thereof
WO2024080792A1 (en) Novel heterobicyclic compound for inhibiting yap-tead interaction and pharmaceutical composition comprising same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17747829

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17747829

Country of ref document: EP

Kind code of ref document: A1