KR101857714B1 - Novel amide compounds and use thereof - Google Patents

Novel amide compounds and use thereof Download PDF

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KR101857714B1
KR101857714B1 KR1020170016432A KR20170016432A KR101857714B1 KR 101857714 B1 KR101857714 B1 KR 101857714B1 KR 1020170016432 A KR1020170016432 A KR 1020170016432A KR 20170016432 A KR20170016432 A KR 20170016432A KR 101857714 B1 KR101857714 B1 KR 101857714B1
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phenyl
pyrazole
carboxamido
methyl
chlorothiophen
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KR20170094087A (en
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장성연
이혁
김성환
김범태
김성수
허정녕
임환정
임승길
강명모
노경태
이경로
최지원
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연세대학교 산학협력단
한국화학연구원
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    • 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
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    • 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
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    • 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
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    • 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
    • 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

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Abstract

The present invention relates to novel amide compounds useful for prevention or treatment of bone diseases and their use.

Description

Novel amide compounds and uses thereof < RTI ID = 0.0 >

The present invention relates to novel compounds which can be usefully used for the prevention or treatment of bone diseases and their uses.

Normal bone reshaping is a balance of bone formation and bone uptake, and this bone formation and bone uptake is largely due to the interaction of three cells, cartilage cells, osteoblasts and osteoclasts . Among them, osteoclasts are cells derived from hematopoietic stem cells, which are responsible for the absorption of aged bone. Osteoblasts are derived from bone marrow stromal cells and play a major role in osteogenesis.

In osteoclasts, for example, mouse RAW 264.7 mononuclear cells are differentiated into multinucleated osteoclasts by RANKL (receptor activator of nuclear factor κB (RANK) ligand). This differentiation process promotes the activation of mitogen-activated protein kinase (MAPK) by RANKL binding to RANK in the extracellular region, and this is because the transcription factor NF-κB enters into the nucleus and binds to osteoclast differentiation-related TRAP (MMP-9), c-Src tyrosine kinase, and the like. The multinuclear osteoclasts formed by this process are called mineralized bone ). ≪ / RTI > In addition, when RANKL binds to RANK, the activity of TRAF6 (tumor necrosis factor receptor-associated factor 6) is promoted to promote the activation of transcription factors such as MAPK or NF-κB, AP-1 and NFATc1 HH., Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun 2003 May 30, 305, 211-4). Therefore, blocking of the signaling pathway activated by RANKL is recognized as one of the therapeutic approaches for the treatment of osteoporosis and other bone diseases.

On the other hand, osteoblasts originate from mesenchymal stem cells. 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. Bone formation by osteoblast differentiation is induced by bone morphogenetic protein (BMP), Wnt MAP kinase , Osteoclast differentiation associated with various signal transduction systems such as calcineurin-caldomulin kinase, NF-κB and AP-1. It is known that osteopontin, osteocalcin, type I collagen, etc. associated with mineralization are synthesized after the synthesis of ALP in the early differentiation stage (Pittenger, MF; Mackay, AM; C; Craig, S., Marshak, DR, Multilineage potential of Adult Human Mesenchymal Stem Cells. Science 1999, 284, 143-147). That is, the compounds that promote the activity of the alkaline phosphotase may promote the differentiation of osteocytes and may be targets of therapeutic agents for bone diseases.

As described above, osteogenesis is continuously controlled by bone remodeling due to osteoclast-induced bone resorption and osteoblast-like bone formation. maintain. However, the excessive activity of osteoclasts or the depletion of osteoblasts may cause bone diseases by breaking the equilibrium between osteoclasts and osteoblasts in vivo, resulting in an unbalance in the remodeling process of osteogenesis.

Osteoporosis, a typical example of bone disease, is a disease in which the balance of osteogenesis and bone resorption is broken and the mass of bone is decreased and the risk of fracture is continuously increased due to degeneration of the microstructure of bone tissue. The bone mineral constituent (especially calcium) And the osteoinductive balance is broken, so that the osteoclastic action occurs in a state where the osteoclast action is increased. Inside the normal bone is dense structure like a net, but in the case of osteoporosis, the gap between the bone microstructures is widened and the microstructure is thinned and weakened, thereby increasing the risk of fracture of the bone to a small impact. It is categorized as osteoporosis in the elderly, which gradually develops in men and women aged 70 years or older, with progressive bone loss in the pelvic bone and vertebrae, and secondary osteoporosis due to disease, drug, alcohol, smoking and accident regardless of age.

Osteoporosis is one of the most important social problems nowadays. In the United States, about 262,000 women are born each year, of which about 12% to 20% die. As society becomes aging and women become more active in society, fractures caused by osteoporosis and osteoporosis of elderly or postmenopausal women cause serious problems.

In order to treat the above-mentioned bone diseases, it is necessary to control the balance between osteoclasts and osteoblasts. Therefore, bone resorption inhibitors and bone formation stimulators are widely used as therapeutic agents.

Currently, estrogen, androgenic anagolic atheroid, calcium, phosphate, fluoride, ipriflavone, and vitamin D3 are the drugs that are currently being used to treat osteoporosis. Estrogen suppresses cell apoptosis of osteoblast cells, thereby increasing the cell survival period. It promotes osteoclast cell apoptosis, thereby decreasing the cell survival period. Thus, estrogen is effective for treatment of menopausal symptoms and for maintaining bone density. Breast cancer, endometrial hyperplasia And the like. In addition, there are calcitonin, bacitracin hormone, bisphosphonate preparation, and the like, which inhibit osteoclast activity and inhibit bone destruction or increase the activity of bone regeneration unit through proliferation of osteoblasts. However, existing drugs for osteoporosis are causing many side effects in long-term administration. Therefore, it is required to develop a safe preventive and therapeutic agent that exhibits a continuous increase in bone mineral density even after long-term administration and has fewer side effects.

Accordingly, the present inventors have made intensive researches to discover novel substances that can effectively treat bone diseases while reducing adverse effects in the use of conventional bone diseases such as osteoporosis therapeutic agents. As a result, And the present invention has been completed.

It is an object of the present invention to provide a series of novel amide compounds, stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating bone diseases, which comprises the above compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In one aspect of the present invention, the present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Figure 112017012375202-pat00001

In this formula,

R 1 to R 3 are each independently selected from the group consisting of hydrogen, halogen, -SO 3 H, C 1-4 alkyl, C 6-10 aryl, or two neighboring substituents connected to each other to form a fused Lt; / RTI > heteroaryl,

Wherein said aryl is selected from the group consisting of unsubstituted or 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 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl, or C 3-10 cycloalkyl,

Wherein said aryl, heteroaryl, heterocycloalkyl and cycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, 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 H, (sulfophenyl) oxy, and -CONHW ', or may be substituted with C 1-4 alkylene,

W 'is a protected or unprotected amino acid;

n is an integer of 0 to 3;

Preferably, in Formula 1,

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 form a thiophene ring to which benzothiophene Lt; / RTI &

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, amino formyl 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 iso-lucine protected or unprotected by methyl;

R 5 is selected from the group consisting of: propyl, cyclopropyl, benzodioxolyl, or unsubstituted or substituted phenyl, pyridinyl, piperidinyl or cyclohexyl,

Wherein phenyl, pyridinyl, piperidinyl and cyclohexyl fact, unsubstituted or benzyl, benzyloxy, morpholinyl, -CONH (CH 2) 2 morpholinyl, -CONH (CHCH 3) CONH ( CH 2) 2 mol Pori 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, sulfo-phenoxy, and -CONHW ' and the substituents may be the same or different,

W 'is tryptophan, alanine, aspartic acid, phenylalanine, tyrosine, valine, isoleucine, leucine or methionine protected or unprotected with methyl or tert-butyl;

n may be 0 or 1.

For example, the compound represented by the formula (1)

1. Synthesis of 1- (4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-

2. Preparation of 1- (4-fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-

3. 3- (1- (4-Fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4- carboxamido) benzenesulfonic acid,

4. Methyl 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,

5. Preparation of N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-

6. Preparation of 1- (4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-

7. Preparation of N- (4-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-

8. 3- (1- (4-Fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4- carboxamido) benzoic acid,

9. Preparation of 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,

10. Preparation of methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate,

11. Preparation of (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4- carboxamido) benzoyl)

12. Preparation of methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoyl) -D-alaninate,

13. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl)

14. Preparation of dimethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate,

15. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) benzoyl) -L-aspartic acid,

16. Preparation of 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzenesulfonic acid,

17. Ethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate,

18. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine,

19. A pharmaceutical composition comprising 3- (5-chlorothiophen-2-yl) -N- (3- ((2-morpholinoethyl) carbamoyl) phenyl)

20. Methyl 3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl)

21. A compound according to claim 1 which is 3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-

22. Methyl (3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) methyl) benzoyl) -D-alaninate,

23. (3 - ((3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl)

24. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,

25. Preparation of 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) -5-

26. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L-tryptophanate ,

27. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)

28. Preparation of (S) -3- (5-chlorothiophen-2-yl) -N- (3 - ((1- (2-morpholinoethyl) amino) Yl) phenyl) -1-phenyl-lH-pyrazole-4-carboxamide,

29. Ethyl 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,

30. 3- (3- (Thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,

31. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoate,

32. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) -5- (trifluoromethyl)

33. Methyl 3-chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole-4-carboxamido) benzoate,

34. 3-Chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,

35. A process for the preparation of methyl 3- bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole-

36. 3-Bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,

37. Methyl 2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido)

38. 2- (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) phenyl) acetic acid,

39. Methyl (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophanate ,

40. (2- (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl)

41. Ethyl 3- (3- (5-chlorothiophen-2-yl) -4- (phenylcarbamoyl) -1H-pyrazol-

42. 3- (3- (5-Chlorothiophen-2-yl) -4- (phenylcarbamoyl) -lH-pyrazol-

43. Ethyl 3- (4 - ((3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-

44. 3- (4 - ((3-Chlorophenyl) carbamoyl) -3- (5-chlorothiophen-

45. Ethyl 3- (3- (5-chlorothiophen-2-yl) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-

46. 3- (3- (5-Chlorothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl)

47. Preparation of tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) Allaninate,

48. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)

49. Methyl (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5- chlorothiophen- 4-carboxamido) -5-fluorobenzamido) propanoate,

50. (S) -3- (4- (tert-Butoxy) phenyl) -2- (3- (3- (5- chlorothiophen- -Carboxamido) -5-fluorobenzamido) propanoic acid, < RTI ID = 0.0 >

51. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)

52. Preparation of tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) Nate,

53. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) -5- fluorobenzoyl) -L-

54. A compound according to claim 1 which is selected from the group consisting of tert-butyl (3- (3- (5- chlorothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) -5- fluorobenzoyl) Lucinate,

55. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)

56. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L-

57. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) -5- fluorobenzoyl) -L-

58. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L-methionate ,

59. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)

60. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoate,

61. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) -4-

62. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoate,

63. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl)

64. Preparation of tert-butyl 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H- pyrazole-4-carboxamido) benzoate ,

65. 4- (4 - ((3- (tert- butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen-

66. 3- (3- (5- Chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1 H- pyrazole- 4- carboxamido) benzoic acid,

67. 3- (1- (4-Carboxyphenyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,

68. Methyl 4- (4 - ((3 - ((2R, 3R) -1- (tert-butoxy) -3-methyl-1-oxopentan- 2- yl) carbamoyl) (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate,

69. 4- (4 - ((3 - ((2S, 3S) -l- (tert- butoxy) -3-methyl- 1 -oxopentan- 2- yl) carbamoyl) phenyl) 3- (5-Chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,

70. 4- (4 - ((3 - ((1R, 2R) -1-carboxy- -1H-pyrazol-1-yl) benzoic acid,

71. Methyl 3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoate,

72. 3 - ((3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoic acid,

73. Preparation of tert-butyl (3 - ((3- (5-chlorothiophen-2-yl) -1- phenyl-1H-pyrazole- 4- carboxamido) methyl) -4- fluorobenzoyl) L-isoleucinate,

74. (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) Leucine,

75. Methyl 3- (3- (5-cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,

76. 3- (3- (5-Cyanothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) -5-

77. Methyl 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-

78. 4- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) cyclohexane-

79. Methyl (lS, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ,

80. (lS, 4S) -4- (3- (5-Bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane-

81. Methyl (lR, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane- ,

82. (lR, 4R) -4- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane-

83. Preparation of tert-butyl ((lS, 4R) -4- (3- (5-bromothiophen- Carbonyl) -L-isosuccinate,

1-phenyl-1 H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,

85. Preparation of tert-butyl ((lR, 4S) -4- (3- (5-bromothiophen- Carbonyl) -L-isosuccinate,

86. ((lR, 4S) -4- (3- (5-Bromothiophen-2-yl) -L-isoleucine,

87. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-

88. Preparation of 4- (3- (5-bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl)

89. Methyl (4- (3- (5-bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl) -1 H- pyrazol- 1 -yl) benzoyl) -L- Sorucinate,

90. 2- (4- (3- (5-Bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl) 3-methylpentanoic acid,

91. Methyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- methoxybenzoate,

92. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) -4- methoxybenzoic acid,

93. Methyl (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoyl) -L- ,

94. 2- (3- (5- (Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- methoxybenzamido) -3- Methylpentanoic acid,

95. Methyl (lS, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ,

96. (lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane-

97. Methyl ((lR, 3S) -3- (3- (5-bromothiophen-2-yl) ) -D-iso-lucinate,

2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbaldehyde ≪ / RTI > < RTI ID = 0.0 >

99. Methyl 4 - ((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-

100. 4 - ((3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) methyl) cyclohexane-

1 H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carbonyl) -D - isosulphate,

102. 2- (4 - ((3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxamido ) -3-methylpentanoic acid,

103. Methyl (lS, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ,

104. (lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane-

105. Methyl ((lS, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ) -L-isosuccinate,

106. ((lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- 1 -carbonyl) -L-isoleucine,

107. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3S) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,

108. 4- ((1R, 3S) -3-Carboxycyclohexyl) carbamoyl) -lH-pyrazol-1-yl) benzoic acid,

109. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3R) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,

110. Preparation of 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3R) -3-carboxycyclohexyl) carbamoyl)

111. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1S, 4S) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,

112. 4- (3- (5-Bromothiophen-2-yl) -4 - (((1S, 4S) -4-carboxycyclohexylcarbamoyl)

113. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 4R) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,

114. 4- (3- (5-Bromothiophen-2-yl) -4 - (((1R, 4R) -4-carboxycyclohexyl) carbamoyl)

115. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzenesulfonic acid,

116. 4- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) benzenesulfonic acid,

117. 3- (1-Phenyl-3- (5-sulfothiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,

118. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH- pyrazole-4- carboxamido) benzoic acid,

119. Phenyl-N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-

120. 1-Phenyl-3- (thiophen-2-yl) -N- (m-tolyl) -lH- pyrazole-

121. N- (3-Acetylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-

122. N- (4-Carbamoylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-

123. Methyl (4- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate,

124. 3- (l-Phenyl-3- (thiophen-2-yl) -lH-pyrazole-4- carboxamido) benzoic acid,

125. Ethyl 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,

126. N, 1-Diphenyl-3- (thiophen-2-yl) -1H-pyrazole- 4- carboxamide,

127. N- (3-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-

128. N- (4-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-

129. N- (3-Chlorophenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-

130. N- (Benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen-

131. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoic acid,

132. 3- (5-Chlorothiophen-2-yl) -N, 1 -diphenyl-lH- pyrazole- 4- carboxamide,

133. Ethyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) benzoate,

134. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,

135. N- (3-Chlorophenyl) -3- (5-chlorothiophen-2-yl)

136. 3- (5-Chlorothiophen-2-yl) -N- (4-phenoxyphenyl)

137. N- (Benzo [d] [1,3] dioxol-5-yl) -3- (5- chlorothiophen- ,

138. 3- (5-Chlorothiophen-2-yl) -N- (3-phenoxyphenyl)

139. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N-propyl-lH- pyrazole-

140. 3- (5-Chlorothiophen-2-yl) -N-cyclopropyl-l-phenyl-lH- pyrazole-

141. N- (l-Benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl)

142. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N- (pyridin-

143. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen-

144. 3- (5-Chlorothiophen-2-yl) -N- (4-morpholinophenyl) -1-phenyl-

145. Preparation of N- (4- (benzyloxy) phenyl) -3- (5-chlorothiophen-2-yl)

146. Ethyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoate,

147. 3- (5-Bromothiophen-2-yl) -N, 1 -diphenyl-lH- pyrazole-

148. 3- (5-Bromothiophen-2-yl) -N- (4-phenoxyphenyl)

149. 3- (5-Bromothiophen-2-yl) -N- (3-chlorophenyl)

150. 3- (5-Bromothiophen-2-yl) -N- (3-phenoxyphenyl)

151. Preparation of N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen- ,

152. 3- (5-Methylthiophen-2-yl) -N, 1 -diphenyl-lH-pyrazole-

153. Ethyl 3- (3- (5-methylthiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoate,

154. 3- (3- (5-Methylthiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoic acid,

155. N- (3-Chlorophenyl) -3- (5-methylthiophen-2-yl)

156. 3- (5-Methylthiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H- pyrazole-

157. 3- (5-Methylthiophen-2-yl) -N- (3-phenoxyphenyl)

158. N- (Benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen- ,

159. Ethyl 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoate,

160. A compound according to claim 1 which is 3- (benzo [b] thiophen-2-yl) -N,

161. A process for the preparation of 3- (benzo [b] thiophen-2-yl) -N- (4- phenoxyphenyl)

162. A compound selected from the group consisting of 3- (benzo [b] thiophen-2-yl) -N- (3- chlorophenyl)

163. 3- (3- (Benzo [b] thiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,

164. Preparation of 3- (benzo [b] thiophen-2-yl) -N- (benzo [d] [1,3] dioxol-5-yl) amides,

165. 3- (Benzo [b] thiophen-2-yl) -N- (3-phenoxyphenyl)

166. 3- (Benzo [b] thiophen-3-yl) -N, 1 -diphenyl-lH- pyrazole-

167. Ethyl 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoate,

168. 3- (3- (Benzo [b] thiophen-3-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,

169. 3- (1-Phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,

170. 3- (3- (5- (3-Acetamidophenyl) thiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,

171. 3- (3- (5- (2-Fluoro-4- (trifluoromethyl) phenyl) thiophen-2-yl) Benzoic acid,

172. 3- (3- (5- (3-Cyano-4-fluorophenyl) thiophen-2-yl)

173. 3- (1-Phenyl-3- (5- (4- (trifluoromethyl) phenyl) thiophen-2-yl) -1H- pyrazole- 4- carboxamido) benzoic acid,

174. 3- (3- (5- (3-Fluoro-4-methoxyphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido)

175. 3- (3- (5- (4-carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid.

In another aspect, the present invention provides a compound represented by the following formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

(2)

Figure 112017012375202-pat00002

In this formula,

R 6 is C 6-10 aryl, 3 to 10 membered heterocycloalkyl, or (3- to 10-membered heterocycloalkyl) (C 1-4 alkyl)

And the aryl and heterocycloalkyl are unsubstituted or substituted, C 1-4 halogenated alkyl, -CO (C 6-10 aryl), -CO (1-4 alkyl), -CONH (C 6-10 aryl), -SO 2 (the C 6-10 aryl group unsubstituted or substituted by 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- to 10-membered heteroaryl or -CONHW '';

R 7 is hydrogen, C 6-10 aryloxy, -CONH (C 1-4 alkylene) (3-10 membered heterocycloalkyl), -CO 2 (C 0-4 alkyl), or -CONHW "

Each W " is independently a protected or unprotected amino acid.

Preferably, in Formula 2,

R < 6 > is phenyl, piperidinyl, or piperidinylmethyl,

Said phenyl and piperidinyl is unsubstituted, trifluoromethyl, trifluoromethoxy, -CO 2 H, -CO 2 CH 3, -CO 2 ( phenyl), -CONH (phenyl), halogen, C 1- 4 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, but is not limited to, methyl-protected or unprotected tryptophan.

For example, the compound represented by the general formula (2)

1. Preparation of 4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid,

2. Methyl (4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophanate,

3. Methyl (4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophan,

4. Preparation of 2- (4 - ((2-morpholinoethyl) carbamoyl) phenyl) -N- (3-phenoxyphenyl) thiazole-

5. 3- (5 - ((4-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid,

6. Methyl 3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoate,

7. 3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoic acid,

8. Methyl (4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophanate,

9. Synthesis of (4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan,

10. Methyl 4- (5 - ((Piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,

11. Methyl 4- (5 - ((Piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate,

12. Methyl 4- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-

13. Preparation of 4- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-

14. Methyl 4- (5 - ((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-

15. Preparation of 4- (5 - ((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-

16. Methyl 4- (5 - ((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-

17. Preparation of 4- (5 - ((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-

18. Methyl 3- (5 - ((1-benzylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,

19. 3- (5 - ((1-Benzylpiperidin-4-yl) carbamoyl) thiazol-

20. Methyl 3- (5 - ((Piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl)

21. 3- (5 - ((Piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoic acid,

22. Methyl 3- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-

23. Preparation of 3- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-

24. Methyl 3- (5 - ((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-

25. Preparation of 3- (5 - ((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-

26. Methyl 3- (5 - ((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-

27. 3- (5 - ((1-Tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-

28. Methyl (3- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophanate,

29. (3- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-

30. Methyl 3- (5 - ((1-acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-

31. Methyl 3- (5 - ((1-acetylpiperidin-2-yl) methyl) carbamoyl) thiazol-

32. Methyl 3- (5 - ((1-acetylpiperidin-4-yl) carbamoyl) thiazol-

33. Methyl 3- (5 - ((1-acetylpiperidin-3-yl) carbamoyl) thiazol-

34. 3- (5 - ((1-Acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-

35. 3- (5 - ((1-Acetylpiperidin-2-yl) methyl) carbamoyl) thiazol-

36. 3- (5 - ((1-Acetylpiperidin-4-yl) carbamoyl) thiazol-

37. 3- (5 - ((1-Acetylpiperidin-3-yl) carbamoyl) thiazol-

38. Methyl 3- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-

39. Methyl 3- (5 - ((1- (phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-

40. Methyl 3- (5 - ((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-

41. 3- (5 - ((1-Benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-

42. 3- (5 - ((1- (Phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-

43. 3- (5 - ((1-Tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-

44. Methyl 3- (5 - ((1-benzoylpiperidin-2-yl) methyl) carbamoyl) thiazol-

45. Methyl 3- (5 - ((1- (phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-

46. Methyl 3- (5 - ((1-tosylpiperidin-2-yl) methyl) carbamoyl) thiazol-

47. 3- (5 - ((1-Benzoylpiperidin-2-yl) methyl) carbamoyl) thiazol-

48. 3- (5 - ((1- (Phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-

49. 3- (5 - ((1-Tosylpiperidin-2-yl) methyl) carbamoyl) thiazol-

50. Methyl 3- (5- ((1-benzoylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoate,

51. Methyl 3- (5 - ((1-tosylpiperidin-4-yl) carbamoyl) thiazol-2-yl)

52. Methyl 3- (5 - ((1-benzoylpiperidin-3-yl) carbamoyl) thiazol-

53. Methyl 3- (5 - ((1-tosylpiperidin-3-yl) carbamoyl) thiazol-

54. 3- (5 - ((1-Benzoylpiperidin-4-yl) carbamoyl) thiazol-

55. 3- (5 - ((1-Tosylpiperidin-4-yl) carbamoyl) thiazol-

56. 3- (5 - ((1-Benzoylpiperidin-3-yl) carbamoyl) thiazol-

57. 3- (5 - ((1-Tosylpiperidin-3-yl) carbamoyl) thiazol-

58. N, 2-diphenylthiazole-5-carboxamide,

59. Methyl 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoate,

60. 4- (5- (Phenylcarbamoyl) thiazol-2-yl) benzoic acid,

61. Methyl 4- (5 - ((3,5-bis (trifluoromethyl) phenyl) carbamoyl) thiazol-

62. N- (3-phenoxyphenyl) -2-phenylthiazole-5-carboxamide,

63. N- (4- (1H-Imidazol-1-yl) phenyl) -2-phenylthiazole-

64. Methyl 4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoate,

65. 3- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid, or

66. N- (4-phenoxyphenyl) -2-phenylthiazole-5-carboxamide.

In another aspect, the present invention provides a compound represented by the following formula (3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

(3)

Figure 112017012375202-pat00003

In this formula,

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,

Said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted, 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 2 (C 0-4 alkyl); and R < 2 >

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.

Preferably, in Formula 3,

Z is -CO 2 H, -CO 2 C 2 H 5, -CONH 2, -CONHCH 3, hydroxy, alkyl, methyl, propyl, trifluoromethyl, or hydroxy, bromo, trifluoromethyl alkyl, phenoxy, Substituted or unsubstituted with any one or more substituents selected from the group consisting of phenyl, ethyl, 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 selected from the group consisting of 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 , -CONHCH 3 , -CH 2 CONH 2 , or -CONH 2 ;

R 10 and R 11 may each independently be hydrogen or fluoro.

For example, the compound represented by the general formula (3)

1. 3 - ((3- (Phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,

2. N-methyl-3 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide,

3. 3 - ((3 - ((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid,

4. 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,

5. N-Methyl-3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzamide,

6. 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,

7. N-Methyl-3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzamide,

8. 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid,

9. N-Methyl-3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzamide,

10. 3- (3- (N- (Pyridin-2-yl) sulfamoyl) benzamido) benzoic acid,

11. N-Methyl-3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzamide,

12. 3- (3- (N- (Pyridin-3-yl) sulfamoyl) benzamido) benzoic acid,

13. N-Methyl-3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzamide,

14. 3- (3- (N-Propylsulfamoyl) benzamido) benzoic acid,

15. N-Methyl-3- (3- (N-propylsulfamoyl) benzamido) benzamide,

16. 3- (3- (N-Cyclopropylsulfamoyl) benzamido) benzoic acid,

17. 3- (N-Cyclopropylsulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide,

18. 3- (3- (N-methylsulfamoyl) benzamido) benzoic acid,

19. N-Methyl-3- (3- (N-methylsulfamoyl) benzamido) benzamide,

20. 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetic acid,

21. N- (3- (2- (Methylamino) -2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl)

22. N- (3- (2-Amino-2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl)

23. 3- (3- (N- (4- (Benzyloxy) phenyl) sulfamoyl) benzamido) benzoic acid,

24. Preparation of 3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl)

25. 3- (3- (N- (1-Benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoic acid,

26. 3- (N- (1-Benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl)

27. 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoic acid,

28. N-methyl-3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzamide,

29. 3- (3- (N- (lH-indol-5-yl) sulfamoyl) benzamido) benzoic acid,

30. A compound according to claim 1, which is 3- (N- (lH-indol-5-yl) sulfamoyl) -N- (3- (methylcarbamoyl)

31. 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoic acid,

32. 3- (N- (1H-indol-6-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl)

33. 3- (3- (N- (3,5-Bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoic acid,

34. A pharmaceutical composition comprising 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl)

35. Preparation of 3 - ((3 - ((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid,

36. Ethyl 3 - ((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,

37. 3 - ((2,4-Difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,

38. Ethyl 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoate,

39. 3- (4-Fluoro-3- (N-phenylsulfamoyl) benzamido) benzoic acid,

40. Ethyl 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoate,

41. 3- (2,4-Difluoro-5- (N-phenylsulfamoyl) benzamido) benzoic acid,

42. Methyl 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoate,

43. Methyl 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoate,

44. Methyl 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoate,

45. Methyl 3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoate,

46. Methyl 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoate,

47. Methyl 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoate,

48. Methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate,

49. Methyl 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoate,

50. Methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate,

51. Methyl 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoate,

52. Methyl 3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido) benzoate,

53. Methyl 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoate,

54. Methyl 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate,

55. Methyl 3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoate,

56. Methyl 3 - ((3 - ((3- (methoxycarbonyl) phenyl) carbamoyl) phenyl) sulfonamido) benzoate,

57. Methyl 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetate,

58. Methyl 3-bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoate,

59. Methyl 3-bromo-5 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,

60. 3-Bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid,

61. 3-Bromo-5 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,

62. 3-Bromo-N-methyl-5- (3- (N-phenylsulfamoyl) benzamido) benzamide,

63. 3-Bromo-N-methyl-5 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide,

64. Methyl 3 - ((1-oxo-1,2,3,4-tetrahydroisoquinoline) -7-sulfonamido) benzoate,

65. 3- (N- (2- (Phenylamino) phenyl) sulfamoyl) benzoic acid,

66. 3- (N- (1-Benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl)

67. N- (3-Carbamoylphenyl) -3- (N-phenethylsulfamoyl) benzamide,

68. N- (3-Carbamoylphenyl) -3- (N- (4-phenoxyphenyl) sulfamoyl) benzamide,

69. N- (3-Carbamoylphenyl) -3- (N- (pyridin-2-yl) sulfamoyl)

70. 3- (N- (1-Benzylpiperidin-4-yl) sulfamoyl) -N- (3- carbamoylphenyl)

71. N- (3-Carbamoylphenyl) -3- (N- (3-phenoxyphenyl) sulfamoyl) benzamide,

72. 3- (N- (1H-indazol-5-yl) sulfamoyl) -N- (3- carbamoylphenyl)

73. 3- (N- (1H-indazol-6-yl) sulfamoyl) -N- (3- carbamoylphenyl)

74. N- (3-Carbamoylphenyl) -3- (N- (pyridin-3-yl) sulfamoyl)

75. 2,4-Difluoro-N- (3- (methylcarbamoyl) phenyl) -5- (N-phenylsulfamoyl)

76. 3- (N- (3,5-Bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- carbamoylphenyl)

77. 4-Fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N-phenylsulfamoyl)

78. N- (3-Carbamoylphenyl) -4-fluoro-3- (N-phenylsulfamoyl)

79. Ethyl 3 - ((5 - ((3- (ethoxycarbonyl) phenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoate,

80. 3 - ((5- ((3-carboxyphenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoic acid,

81. 4-Fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl)

82. Ethyl 3 - ((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate,

83. 3 - ((2-Fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid,

84. N- (4-Chlorophenyl) -3- (N-phenylsulfamoyl) benzamide,

85. N- (4-bromophenyl) -3- (N-phenylsulfamoyl) benzamide,

86. N- (3-Chlorophenyl) -3- (N-phenylsulfamoyl) benzamide,

87. N- (3,4-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide,

88. N- (3,5-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide, or

89. N- (2,4-dibromophenyl) -3- (N-phenylsulfamoyl) benzamide.

The compounds represented by formulas (1) to (3) of the present invention can be used in the form of pharmaceutically acceptable salts. Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic, harmless and effective action in a patient, and that side effects due to this salt do not adversely affect the beneficial effects of the compound represented by formula &Quot; means all organic or inorganic addition salts. In addition, the compounds of the present invention may be used alone or in combination with other pharmaceutically active compounds or in aggregates.

The pharmaceutically acceptable salts of the compounds represented by the general formulas (1) to (3) of the present invention refer to salts prepared according to a conventional method in the art, and such methods are known to those skilled in the art. In particular, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable.

The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration. As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. As organic acids, methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid Maleic, succinic, oxalic, benzoic, tartaric, fumaric, mandelic, propionic, citric, lactic, glycolic, Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The pharmaceutically acceptable salts of the compounds of formulas (1) to (3) above include salts of acidic or basic groups which may be present in the compounds of formula (I), unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >

The salts of the compounds represented by the general formulas (1) to (3) of the present invention are pharmaceutically acceptable salts, and any salt of the compound having biological activity equivalent to that of the above compounds can be used without limitation.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating bone diseases, which comprises a compound represented by any of Formulas 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a method of preventing or treating bone diseases, comprising the step of administering the pharmaceutical composition to a subject in need thereof.

As used herein, the term "bone disease" refers to a condition or disease that is caused by excessive production and / or migration of osteoclast or disease or condition in which bone mass increase is required or required by promoting osteoblast activity. Includes low bone mass disorders. The term "lowering bone disease" refers to a condition or disease in which a decrease in bone mass accompanied by a symptom such as a decrease in bone density, a deterioration in a bone tissue or the like occurs, and includes, for example, osteoporosis, Paget's disease, periodontal disease, Rheumatoid arthritis, < / RTI >

Preferably, the composition of the present invention can be used for preventive treatment of osteoporosis or osteopenia. Specifically, the term "osteoporosis" as used herein means a condition in which bone mass is decreased and fracture is likely to occur due to a qualitative change, and "osteopenia" means an initial symptom of osteoporosis. In general, osteopenia is classified as -1.0 to -2.5 based on the bone mineral density (T value), and osteoporosis is classified as -2.5 or more.

As used herein, the term "prevention or treatment of bone disease" includes prevention and complete or partial treatment of the bone disease achieved by administering a composition according to the present invention to a subject. It also includes reduction or amelioration of symptoms of bone disease, relief of the symptoms of pain, reduction in the incidence of bone disease, or any other change in the patient that increases the outcome of the treatment.

As used herein, the term "individual" refers to all animals, including humans, who have developed or are capable of developing 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 may be administered in combination with a conventional bone disease therapeutic agent.

As used herein, the term "administering " means introducing a predetermined substance into a patient in an appropriate manner, and the administration route of the composition of the present invention is administered through any conventional route so long as it can reach the target tissue . But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal.

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 a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dose level is determined by the patient's sex, Including, but not limited to, medicaments and other medical fields that are used in combination, or in combination with, or in combination with, a pharmaceutically acceptable carrier, excipient, Can be readily determined by those skilled in the art according to known factors. Generally, the active substance may be administered at a dose of from about 0.01 mg / kg / day to 1000 mg / kg / day. When administered orally, a dose of 50 to 500 mg / kg may be appropriate, and may be administered at least once a day.

Preferably, the pharmaceutical composition of the present invention may contain 0.001 to 1% by weight of the compound represented by any one of formulas (1) to (3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In addition, the pharmaceutical composition for preventing or treating bone diseases according to the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-mentioned effective ingredient. As used herein, the term "pharmaceutically acceptable" means that the composition is free of toxicity to an individual such as a cell or human being exposed to the composition. Such carriers may be used without limitation as long as they are known in the art such as buffers, preservatives, wetting agents, solubilizers, isotonic agents, stabilizers, bases, excipients and lubricants. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition 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.

When the composition of the present invention is formulated, it can be prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, and surfactants which are usually used.

For oral administration, solid preparations such as tablets, pills, powders, granules, and capsules can be prepared. Such a solid preparation is prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. in addition to the above 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, syrups, and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agent sweeteners, fragrances and preservatives are included . If the active ingredient is susceptible to degradation by an acid, the oral composition may be formulated to coat the active agent or protect it from degradation from above. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like. Carbohydrates such as glucose, sucrose, and dextran, antioxidants such as ascorbic acid, glutathione, chelating agents, low molecular weight proteins, or other stabilizers may be used to increase stability or absorbency of the active ingredient.

The composition of the present invention may also be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

1. Mode of Action of New Drugs to Improve Osteoporosis

end. Wnt signaling and Bone

The Wnt family of 19 glycoproteins plays an important role throughout the developmental and lifetime. In particular, the Wnt signaling system is necessary for skeletal system development, adult skeletal homeostasis and bone aggregate formation. Although the Wnt protein is involved in a variety of signaling pathways (Box 1), it appears that most of the Wnt signaling mechanisms for the skeletal system are accounted for via the canonical wnt-β-catenin signaling pathway. When the Wnt protein binds to the frizzled transmembrane receptor and LRP-5 and LRP-6, the beta-catenin separates from the complex and does not undergo proteolysis. The stabilization of beta-catenin induces the migration of beta-catenin into the nucleus and regulates the transcription of genes such as WISP1 and RUNX2 in association with the transcription factor (TCF-4 or LEF-1) Inhibits lipogenesis by inhibiting adipocyte saturation factors such as C / EBPα (CCAAT / enhancer binding protein α) and PPAR-γ (peroxisome proliferator activated receptor γ). The Wnt signaling system is also important in osteoclast formation and inhibition of bone resorption. It has been reported that inhibition of osteoclast formation by Wnt is induced by induction of osteoprotegerin (also known as TNF receptor superfamily member 11B), which binds to RANKL and inhibits osteoclast formation .

I. Sclerostin and Bone

Mechanical loading activates the Wnt signaling in cells of the osteoblast lineage, suggesting that the action of Wnt may have been implicated in linking mechanical forces to skeletal assimilation. This mechanism is associated with the inhibition of the sclerostin, a Wnt antagonist preferentially expressed by epidemiologically detectable bone cells. Inhibition of the sclerostin appears especially at sites of increased load among the bones, which promotes the Wnt signaling and bone formation. Conversely, sclerostin is increased by no load of the skeletal system, which leads to bone loss due to increased bone resorption and decreased bone formation. This mechanism may be related to the onset of osteoporosis of disuse, which results in bone loss due to persistent bed rest and nerve damage. Insoluble

Osteoporosis significantly increases the risk of fracture occurrence, and prevention or correction of bone loss is believed to be beneficial in these patient populations.

All. Mechanism of action of sclerostin and sclerostin inhibitor

Antagonists that interact with Wnt and the LRP-5-LRP-6 co-receptor include sclerostin and Dickkopf-related protein 1 (Dkk-1). Sclerostin, encoded by SOST, is expressed primarily by bone cells and is responsible for interfering with the Wnt signal by attaching to the LRP5-LRP6 co-receptor. As a result, sclerostin inhibits osteoblast formation and bone formation in vitro and in vivo. The expression of sclerostin is inhibited by mechanical stress and parathyroid hormone (PTH) in osteoblasts and osteocytes, and in patients with hyperparathyroidism, the level of sclerostin is lower than that of normal parathyroid glands .

Although upregulation of the Wnt signal is not essential for the expression of bone anabolic activity in response to parathyroid hormone, inhibition of the expression of sclerostin by parathyroid hormone may explain selective bone anabolic action of parathyroid hormone, Activated mice also showed an effect of bone anabolic action on parathyroid hormone. Elimination of the Sost gene selectively in the mouse results in increased osteoblast cell count, bone formation, and biomechanical properties of cortical bone and cancellous bone. Conversely, overexpressing Sost

Osteoporosis is caused by osteoblast cell count and decreased bone formation. On the other hand, a recently developed antibody to sclerostin has been shown to inhibit the binding of sclerostin to the Lrp-5-Lrp-6 caspase 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 mass by strengthening Wnt signal with PPI agent, not antibody.

 2. Differentiation compared to the same MOA competing substance

The monoclonal anti-body (Ab) for sclerostin is a major competing substance. The problems of monoclonal Ab are as follows.

● 2nd Ab may occur. Some have been reported in the AMG785 phase I study as Neutralizing Ab

● It is currently being developed as a monthly drug and is expected to be expensive.

● In Phase II study, bone formation index increased only at the beginning of treatment. It is anticipated that the production of counterregulatory factors will increase because of the antibody to the local factor Sclerostin. However, the drug developed in this study, developed as a PPI that binds to the high-spot approach, is expected to inhibit the action of Sclerostin and DKK1,4, which may provide sustained efficacy.

A pharmaceutical composition comprising a compound represented by any one of Formulas 1 to 3 according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

SOST or LRP5 / 6 to inhibit the binding of the two to reduce the inhibition of Wnt signaling by SOST, thereby being useful for the prevention or treatment of various bone diseases associated therewith.

1 to 18 show examples of the compound represented by the formula (1) according to an embodiment of the present invention.
19 to 24 show examples of the compound represented by the general formula (2) according to an embodiment of the present invention.
25 to 32 are diagrams illustrating examples of the compound represented by Formula 3 according to an embodiment of the present invention.
Figure 33 shows the results of mineralization assay of compounds according to an embodiment of the present invention.
Figures 34A and 34B show the results of mineralization assay of compounds according to an embodiment of the present invention.
FIG. 35 is a graph showing an ALP (alkaline phosphatase) assay result of the compounds according to an embodiment of the present invention. FIG.
Fig. 36 is a numerical comparison of ALP assay results of compounds according to an embodiment of the present invention. Fig. Compounds that are greater than 120% relative to KY-06003 are indicated in red.
Figure 37 is a numerical comparison of the results of the mineralization assay of compounds according to an embodiment of the present invention. Compounds that are greater than 120% relative to KY-06003 are indicated in red.
Figure 38 shows ALP assay results for OVX loaded compounds of compounds according to an embodiment of the present invention.
Figure 39 shows the results of the mineralization assay of OVX loaded compounds of the compounds according to an embodiment of the present invention.
40 is a diagram showing an example of a method for producing the compound represented by the formula (1) of the present invention.
41 is a diagram showing an example of a method for producing the compound represented by the general formula (2) of the present invention.
42 is a diagram showing an example of a method for producing the compound represented by the general formula (3) of the present invention.
Figure 43 shows the recovery effect on the Wnt signal system by the compounds of the present invention.
Figure 44 shows ELISA binding assays for the compounds of the invention.
Figure 45 shows the SPR binding assay results of the compounds of the present invention.
Figure 46 shows the effect of the compounds of the present invention on bone mineral density.
Fig. 47 is a graph showing the effect of the compound of the present invention on the area of the tibia and the bony circumference.
Figure 48 shows the effect of the compound of the present invention on the bone thickness and bone surface area.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example  1. Preparation of 3 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid (3 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid; KY-06417

The ester compound (100 mg, 0.25 mmol) was dissolved in a tetrahydrofuran (THF) / H 2 O / methanol (MeOH) mixed solvent and then LiOH (21 mg, 0.5 mmol) was added to a 25 mL round- Stir for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, 15 mL of water was added, and 1N HCl was added thereto, followed by extraction three times with ethyl acetate (EA; 30 mL) at pH 2. The organic layer was dried over MgSO 4 to give the title compound (80 mg, 81%).

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 (M, 4H), 7.61 (dq, J = 5.0, 1.7 Hz, 1H), 7.42-7.32 4H), < / RTI > 7.18-7.09 (m, 1H).

Example  2. N-methyl-3- ((3- (phenylcarbamoyl) phenyl ) Sulfonamido) benzamide (N-methyl-3 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzamide; KY-06418

(40 mg, 0.1 mmol), methylamine (3.0 eq.), EDCI (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide; 3.0 eq.), HOBt (N-hydroxybenzotriaxole; 3.0 eq.), 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 a mixed solvent of H 2 O / EA, 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 a silica gel column was carried out to obtain the title compound (36 mg, 89%).

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 (T, J = 7.8 Hz, 3H), 7.53 (t, J = 7.9 Hz, 1H), 7.47 , ≪ / RTI > J = 7.2 Hz, 1H), 2.95 (s, 3H).

Example  3. 3 - ((3 - ((3-carboxy Phenyl ) Carbamoyl) phenyl) sulfonamido) benzoic acid (3 - ((3 - (3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid; KY-06419

The ester compound (200 mg, 0.43 mmol) was dissolved in a mixed solvent of LiOH (5.0 eq.) And THF / H 2 O / MeOH in a 7 mL vial, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure and acid-base extraction was carried out. The water layer was washed with ether, adjusted to pH 3 with 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).

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 J = 7.8 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) ), 7.42-7.33 (m, 2H).

Example  4. 3- (3- (N- (2-phenoxy Phenyl ) Sulfamoyl) benzamido) benzoic acid (3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid; KY-06420

(3.0 equivalents), methylamine (3.0 equivalents), EDCI (3.0 equivalents), HOBt (3.0 equivalents) and DIPEA (3.0 equivalents) were dissolved in DMF (0.3 M) Lt; / RTI > After completion of the reaction, the mixture was extracted three times with a mixed solvent of H 2 O / EA, 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 a silica gel column was carried out to obtain the title compound (66%).

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 = 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).

Example  5. Synthesis of N-methyl-3- (N- (2-phenoxyphenyl) sulfamoyl) benzamide (N-methyl- benzamido) benzamide); KY-06421

KY-06420, the title compound (86%) was obtained.

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 ), 7.00 (t, J = 7.4 Hz, 1H), 6.63 (dd, J = 5.9, 3.6 Hz, 2H), 2.92 (s, 3H).

Example  6. 3- (3- (N- (3-phenoxy Phenyl ) Sulfamoyl) benzamido) benzoic acid (3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid; KY-06422

KY-06420, the title compound (96%) was obtained.

1 H NMR (300 MHz, DMSO)? 12.98 (s, IH), 10.67 (s, IH), 10.50 (s, IH), 8.39 = 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) = 8.0 Hz, 1H), 7.35 (t, J = 8.3 Hz, 2H), 7.24 (t, J = 8.1 Hz, 1H) ), 6.75-6.62 (m, 2H).

Example  7. N-Methyl-3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamide benzamido) benzamide); KY-06423

KY-06420, the title compound (90%) was obtained.

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 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).

Example  8. 3- (3- (N- (4- Phenoxyphenyl ) Sulfamoyl ) Benzamido Benzoic acid (3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoic acid); KY-06424

KY-06420, the title compound (98%) was obtained.

1 H NMR (300 MHz, DMSO) 隆 12.98 (s, 1H), 10.66 (s, IH), 10.27 (s, IH), 8.39 = 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) = 7.8 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).

Example  9. N-methyl-3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamide benzamido) benzamide); KY-06425

KY-06420 to give the title compound (89%).

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 J = 7.2 Hz, 1H), 7.50-7.40 (m, 1H), 7.37-7.26 (m, 2H), 7.98-7.86 m, 2H), 7.15-7.02 (m, 3H), 6.98-6.85 (m, 4H), 2.79 (dd, J = 4.1,2.2 Hz, 3H).

Example  10. 3- (3- (N- (Pyridin-2- Work ) Sulfamoyl) benzamido) benzoic acid (3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoic acid; KY-06426

KY-06420, the title compound (39%) was obtained.

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), J = 7.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 8.05 (t, J = 7.3 Hz, 2H), 7.96 ), 6.85 (t, J = 6.7 Hz, 1 H).

Example  (N-methyl-3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamide) sulfamoyl) benzamido) benzamide); KY-06427

KY-06420 to give the title compound (60%).

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 7.8 (t, J = 7.7 Hz, 2H), 7.75 (dt, J = 15.1,7.9 Hz, 2H), 7.60 J = 6.4 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).

Example  12. 3- (3- (N- (Pyridin-3- Work ) Sulfamoyl) benzamido) benzoic acid (3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoic acid; KY-06428

KY-06420, the title compound (93%) was obtained.

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), J = 7.9 Hz, 2H), 7.30 (dd, J = 8.1, 4.6 Hz, 1H) ).

Example  13. N- methyl -3- (3- (N- (pyridin-3-yl) Sulfamoyl ) Benzamido ) Benzamide (N-methyl-3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzamide); KY-06429

KY-06420, the title compound (35%) was obtained.

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 , J = 8.2, 4.6 Hz, 1H), 2.81 (d, J = 4.6 Hz, 3H).

Example  14. 3- (3- (N- Propyl sulfamoyl ) Benzamido) (3- (3- (N-propylsulfamoyl) benzamido) benzoic acid); KY-06430

KY-06420, the title compound (70%) was obtained.

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 J = 7.8 Hz, 1H), 2.70 (q, J = 6.5 Hz, 2H), 1.35 (q, J = 7.3 Hz, 2H), 7.71 (dt, J = Hz, 2H), 0.82-0.71 (m, 3H).

Example  15. N-Methyl-3- (3- (N-propylsulfamoyl) benzamido ) N-methyl-3- (3- (N-propylsulfamoyl) benzamido) benzamide); KY-06431

KY-06420, the title compound (96%) was obtained.

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 ), 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 < + & gt ; ), 377.2, 112.4.

Example  16. 3- (3- (N-Cyclo Propyl sulfamoyl ) Benzamido) (3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoic acid); KY-06432

KY-06420, the title compound (99%) was obtained.

1 H NMR (300 MHz, DMSO)? 13.03 (s, IH), 10.70 (s, IH), 8.40 (s, IH), 8.27 (d, J = 7.8 Hz, IH), 8.14-7.97 J = 7.8 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.71 , 0.50 (d, J = 6.6 Hz, 2H), 0.43-0.33 (m, 2H).

Example  17. 3- (N-Cyclo Propyl sulfamoyl ) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N-cyclopropylsulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide; KY-06433

KY-06420, the title compound (96%) was obtained.

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 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, t, J = 3.7 Hz, 2H).

Example  18. 3- (3- (N-methylsulfamoyl) benzamido) benzoic acid (3- (3- (N-methylsulfamoyl) benzamido) benzoic acid; KY-06434

KY-06420 to give the title compound (88%).

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 J = 5.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 2.45 (d, J = 5.4 Hz, 3H).

Example  19. N- methyl -3- (3- (N-methylsulfamoyl) benzamido ) Benzamide (N-methyl-3- (3- (N-methylsulfamoyl) benzamido) benzamide); KY-06435

KY-06420, the title compound (99%) was obtained.

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 J = 7.9 Hz, 3 H), 2.46 (t, J = 7.8 Hz, (d, J = 4.6 Hz, 3 H).

Example  20. 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetic acid; 2- (3- (3- (N-phenylsulfamoyl) benzamido) phenyl) acetic acid; KY-06436

The ester compound (100 mg, 0.4 mmol) was dissolved in a THF / H 2 O / MeOH mixed solvent and then LiOH (30 mg, 0.8 mmol) was added to a 7 mL round bottom flask and stirred at room temperature for 16 hours. After the completion of the reaction, the solvent was removed under reduced pressure, 15 mL of water was added, 1N HCl was added, and the mixture was extracted three times with EA (30 mL) at pH 2. The organic layer was dried over MgSO 4 to give the title compound (133 mg, 95%).

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 2H), 7.05 (s, 2H), 7.25 (dt, J = 20.4, 7.8 Hz, 3H), 7.09 (d, J = 7.7 Hz, 2H).

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

After dissolving a carboxylic acid compound (50 mg, 0.1 mmol), methylamine (3.0 equivalents), EDCI (3.0 equivalents), HOBt (3.0 equivalents) and DIPEA (3.0 equivalents) in DMF (0.3 M) Lt; / RTI > for 16 h. After completion of the reaction, the mixture was extracted three times with a mixed solvent of H 2 O / EA, 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 a silica gel column was carried out to obtain the title compound (39.6 mg, 78%).

1 H NMR (300 MHz, CDCl 3 )? 8.68 (s, IH), 8.41 (s, IH), 8.19 (s, IH), 8.11 (d, J = 7.8 Hz, (Ddt, J = 24.8, 16.7, 8.0 Hz, 6H), 7.00 (d, J = 8.6 Hz, 1H) d, J = 7.8 Hz, 1H), 5.78 (s, 1H), 3.55 (s, 2H), 2.76 (d, J = 4.7 Hz, 3H).

Example  22. N- (3- (2-Amino-2- Oxoethyl ) Phenyl) -3- (N- Phenylsulfamoyl ) Benzamide (N- (3- (2-amino-2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06438

The ester compound (100 mg, 0.23 mmol) was dissolved in MeOH (1 mL) and then an aqueous ammonia solution (3 mL) was added to a 25 mL round bottom flask, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was completely removed under reduced pressure to obtain the title compound (90 mg, 94%) as a white solid.

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), (D, J = 20.3, 7.4 Hz, 4H), 2.25 (s, 2H), 2.02 (s, 2H ).

Example  Benzoic acid benzoic acid (3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoic acid ); KY-06439

KY-06420, the title compound (86%) was obtained.

1 H NMR (300 MHz, DMSO) [delta] 13.21-12.74 (m, IH), 10.67 (s, IH), 10.45 (s, IH), 8.46-8. 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 , 2H).

Example  (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06440

KY-06420, the title compound (78%) was obtained.

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), (Dd, J = 7.9 Hz, 2H), 7.92 (t, J = 7.1 Hz, 1H), 7.78 ), 7.32 (q, J = 7.0 Hz, 1 H), 6.96 (d, J = 4.7 Hz, 1 H), 6.87 2.99 (d, J = 4.7 Hz, 3 H).

Example  25. 3- (3- (N- (1- Benzylpiperidine Yl) Sulfamoyl ) Benzamido Benzoic acid (3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoic acid); KY-06442

KY-06420, the title compound (86%) was obtained.

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), 1H), 8.15 (s, 1H), 8.05 (t, J = 9.7 Hz, 2H), 7.83-7.64 (m, 2H), 7.61-7.36 , 3.21-3.07 (m, 2H), 1.77 (s, 4H).

Example  26. Preparation of 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06443

KY-06420 to give the title compound (59%).

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 J = 7.2 Hz, 1H), 7.77 (t, J = 8 Hz, 2H), 8.05-8.01 7.8 Hz, 1H), 7.38-7.26 (m, 2H), 7.23 (dt, J = 7.9, 1.9 J = 4.5 Hz, 3H), 2.64 (d, J = 11.7 Hz, 2H), 3.80 (d, J = 1.89 (t, J = 10.7 Hz, 2H), 1.54 (dd, J = 13.1, 3.9 Hz, 2H), 1.44-1.33 (m, 2H).

Example  27. 3- (3- (N- (4-morpholino Phenyl ) Sulfamoyl) benzamido) benzoic acid (3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoic acid; KY-06445

KY-06420, the title compound (70%) was obtained.

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 J = 7.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.82 Hz), 6.89 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 3.63 (s, 4H), 2.95

Example  28. N-methyl-3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzamido) benzamide); KY-06446

KY-06420 to give the title compound (84%).

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), J = 7.6 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H) (t, J = 7.9 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.80 J = 4.6 Hz, 4H), 2.80 (d, J = 4.2 Hz, 3H).

Example  29. 3- (3- (N- (lH-indol-5- Work ) Sulfamoyl) benzamido) benzoic acid (3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido) benzoic acid; KY-06447

KY-06420, the title compound (90%) was obtained.

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 J = 7.9 Hz, 1H), 8.01 (d, J = 9.6 Hz, 2H), 7.85 ), 7.10 (dd, J = 8.9, 2.0 Hz, 1 H).

Example  30. 3- (N- (lH-Indol-5- Work ) Sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1H-indol-5-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide; KY-06448

KY-06420 to give the title compound (89%).

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 7.8 (d, J = 7.8, 1.4 Hz, 1H), 7.68 (m, 1H), 8.19 (dt, J = 5.6,1.6 Hz, 2H) (d, J = 7.8 Hz, 1H), 7.57 (dt, J = 7.7,1.4 Hz, 1H), 7.48-7.40 (m, 3H), 7.10 d, J = 5.0 Hz, 3H).

Example  31. 3- (3- (N- (lH-indol-6- Work ) Sulfamoyl) benzamido) benzoic acid (3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoic acid; KY-06449

KY-06420, the title compound (94%) was obtained.

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 J = 7.7 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 6.1 Hz, 2H), 7.70 J = 8.0 Hz, 1H), 7.27 (s, 1H), 6.90 (dd, J = 8.4, 2.1 Hz, 1H).

Example  32. 3- (N- (lH-indol-6- Work ) Sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1H-indol-6-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide; KY-06450

KY-06420 to give the title compound (85%).

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 (T, J = 7.9 Hz, 1H), 7.28 (dd, J = 12.1, 7.0 Hz, 3H), 7.70 (s, 1H), 6.91 (dd, J = 8.6,1.8 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H).

Example  33. 3- (3- (3- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) phenyl) sulfamoyl) benzamido) benzoic acid); KY-06451

KY-06420, the title compound (83%) was obtained.

1 H NMR (300 MHz, DMSO)? 13.31 (s, 1H), 11.69 (s, IH), 11.03 (s, IH), 8.78 = 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).

Example  34. 3- (N- (3,5-Bis (Trifluoromethyl) phenyl ) Sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (3,5- bis (trifluoromethyl) phenyl) sulfamoyl) -N- ); KY-06452

KY-06420 to give the title compound (88%).

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), 7.81 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H) Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 2.80 (d, J = 4.3 Hz, 3H).

Example  35. Preparation of 3 - ((3 - ((3-carboxy Phenyl ) Carbamoyl) phenyl) sulfonamido) benzoic acid (3 - ((3 - (3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid; KY-06453

The ester compound (200 mg, 0.43 mmol) was dissolved in a mixed solvent of LiOH (5.0 eq.) And THF / H 2 O / MeOH in a 7 mL vial, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed and acid-base extraction was carried out. The water layer was washed with ether, adjusted to pH 3 with 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).

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 J = 7.8 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) ), 7.42-7.33 (m, 2H).

Example  36. Ethyl 3 - ((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate (ethyl 3 - difluoro -5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate); KY-06454

Aminobenzoate (1.0 eq., 0.38 mL), DIPEA (1.5 eq., 0.35 mL) was added to a 100 mL round bottom flask after dissolving the sulfonyl chloride compound (2.59 mmol, 860 mg) in methylene chloride 0.68 mL), and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the mixture was extracted three times with a mixed solvent of H 2 O / EA, and the organic layer was dried over MgSO 4 . A silica gel column was carried out, then concentrated under reduced pressure, solidified with MC / ether / hexane and then filtered through a sinter to give the title compound (128 mg, 11%) as a yellow solid.

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 s, 1 H), 4.12 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).

Example  37. Preparation of 3 - ((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid (3- difluoro -5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06455

To the 7 mL vial was added an ester compound (128 mg, 0.28 mmol), LiOH (2.0 eq., 24 mg), acetonitrile (ACN, 1.4 mL) and H 2 O (1.4 mL) and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was transferred to a 50 mL round bottom flask and the ACN was removed by a rotavapor. The residue was washed with a mixed solvent of ether: H 2 O = 1: 2. After confirming that the water layer was pH 8 using a pH paper, the pH was adjusted to 2 to 3 while adding 1N HCl. The 1N HCl mixture was extracted with EA and then concentrated under reduced pressure. Finally, solidification with an EA / hexane mixed solvent was followed by filtration through a sinter to obtain the title compound (40%) as a white solid compound.

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).

Example  38. Ethyl 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido ) Benzoate (ethyl 3- (4- fluoro -3- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06456

(1.3 mmol, 346 mg) was dissolved in MC (1.5 mL) and to a 7 mL vial was added ethyl 3-aminobenzoate (0.95 eq, 209 mg, 1.24 mmol), DIPEA 0.218 mL, 1.24 mmol) and MC (1.5 mL) were stirred together. The mixture in a 7 mL vial was slowly added to a 25 mL round bottom flask and the 7 mL vial was washed with MC (0.5 mL) and further stirred at 0 ° C for 30 minutes.

DIPEA (1.0 eq., 0.23 mL, 1.3 mmol) and DMAP (4-dimethylaminopyridine, 15.9 mg, 1.0 eq., 0.13 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours Respectively. After completion of the reaction, MC was extracted with a mixed solvent of H 2 O: MC = 1: 3, MC was extracted with a 1: 1 mixture of MC: 1N HCl, dried over MgSO 4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA: MC = 1: 19) to obtain the title compound (71.7 mg, 12%) as a yellow liquid compound.

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, 8.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 7.5 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) 3H).

Example  39. 3- (4- Fluoro -3- (N- Phenylsulfamoyl ) Benzamido (3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06457

To the 7 mL vial was dissolved the ester compound (65 mg, 0.15 mmol) in THF (1 mL) and stirred. After adding H 2 O (1 mL) and MeOH (0.5 mL) as a syringe, LiOH (12.6 mg, 2.0 eq, 0.30 mmol) was added thereto and stirred at room temperature for 26 hours. After completion of the reaction, the reaction mixture was transferred to a 50 mL round bottom flask, and MeOH and THF were removed using a rotary evaporator. The residue was washed with ether: H 2 O = 1: 2 mixed solvent (25 mL of ether, 45 mL of H 2 O). After confirming that the water layer was pH 8 using a pH paper, the pH was adjusted to 2 to 3 while adding 1N HCl. Solids were observed but not filtered and EA was extracted with a mixed solvent of EA: H 2 O = 2: 1 (100 mL of EA, 50 mL of H 2 O). Concentration under reduced pressure after dried over MgSO 4 to give the title compound (56.4 mg, 93%) as a white solid compound.

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 J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.58 (t, J = Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 7.02 (t, J = 7.1 Hz, 2H).

Example  40. Ethyl 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido ) Benzoate (ethyl 3- (2,4- difluoro -5- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06458

(1.4 mmol, 392.5 mg) was dissolved in MC (1.5 mL) and to a 7 mL vial was added ethyl 3-aminobenzoate (0.95 eq, 224 mg, 1.33 mmol), DIPEA 0.234 mL, 1.33 mmol) and MC (1.5 mL) were stirred together. The mixture in a 7 mL vial was slowly added to a 25 mL round bottom flask and the 7 mL vial was washed with MC (0.5 mL) and further stirred at 0 ° C for 30 minutes.

DIPEA (1.0 eq., 0.25 mL, 1.4 mmol) and DMAP (4-dimethylaminopyridine, 15.9 mg, 1.0 eq., 0.13 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours Respectively. After completion of the reaction, MC was extracted with a mixed solvent of H 2 O: MC = 1: 3, MC was extracted with a 1: 1 mixture of MC: 1N HCl, dried over MgSO 4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA: MC = 1: 19) to obtain the title compound (281.8 mg, 43%) as a white solid compound.

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 (d, J = 7.5 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H), 7.07 (D, J = 17.4 Hz, 2H), 4.33 (q, J = 6.5, 13.5 Hz, 2H), 1.32 .

Example  41. 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoic acid; KY-06459

To a 7 mL vial was dissolved the ester compound (230 mg, 0.49 mmol) in THF (1.5 mL) and stirred. After adding H 2 O (1.5 mL) and MeOH (1.0 mL) as a syringe, LiOH (12.6 mg, 2.0 eq, 0.30 mmol) was added thereto and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was transferred to a 50 mL round bottom flask, and MeOH and THF were removed using a rotary evaporator. The residue was washed with ether: H 2 O = 1: 2 mixed solvent (20 mL of ether, 40 mL of H 2 O). After confirming that the water layer had a pH of 8 to 9 using a pH paper, the pH was adjusted to 2 to 3 while adding 1N HCl. The observed solid was filtered through a filter paper to obtain a mixed compound (101.1 mg) as a white solid. The residue was subjected to silica gel column chromatography (EA: hexane = 1: 2 -> MC: MeOH = 19: 1) to obtain the title compound (41.4 mg, 19%) as a white solid mixture.

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 ( J = 7.7 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 6.99 (d, J = J = 7.4 Hz, 1H).

Example  42. Methyl 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoate; methyl 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido) benzoate; KY-06462

KY-06420, the title compound (22%) was obtained.

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, IH), 7.76-7.66 (m, IH), 7.47 (dt, J = 21.0, 7.9 Hz, 2H) (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

Example  43. methyl  3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamide ) Benzoate (methyl 3- (3- (N- (3- 펜oxyphenyl ) sulfamoyl ) benzamido ) benzoate); KY-06463

KY-06420, the title compound (69%) was obtained.

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 Hz, 3H), 6.98-6.69 (m, 5H), 3.85 (d, J = 2.5 Hz, 3H).

Example  44. Methyl 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoate; methyl 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido) benzoate; KY-06464

KY-06420, the title compound (82%) was obtained.

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 = J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.73 (t, J = 7.2 Hz, 2H) , 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).

Example  45. methyl 3- (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) benzamido) benzoate ) benzoate); KY-06465

KY-06420, the title compound (69%) was obtained.

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 ( 1H), 6.93 (s, 1H), 6.69 (dd, J = 13.3, 8.3 Hz, 2H), 5.00 (s, 2H), 3.93 ).

Example  46. Methyl 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido) benzoate pyridine -2-yl) sulfamoyl) benzamido) benzoate; KY-06466

KY-06420, the title compound (52%) was obtained.

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 = J = 6.7 Hz, 1 H), 3.94 (s, 3 H).

Example  47. Methyl 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido) benzoate (methyl 3- (3- (N- pyridine -3-yl) sulfamoyl) benzamido) benzoate; KY-06467

KY-06420, the title compound (81%) was obtained.

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 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).

Example  48. Methyl 3- (3- (N- Propyl sulfamoyl ) Benzamido) benzoate (methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate; KY-06468

KY-06420, the title compound (93%) was obtained.

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 J = 7.8 Hz, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.86-7.80 (m, (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).

Example  49. Methyl 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoate; KY-06469

KY-06420, the title compound (99%) was obtained.

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, 1 H), 7.59 (t, J = 7.7 Hz, 1 H), 7.39 (t, J = 8.0 Hz, , 0.53 (d, J = 5.0 Hz, 4H).

Example  50. methyl  3- (3- (N-methylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate; KY-06470

KY-06420, the title compound (78%) was obtained.

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 = 8.0 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H) 1H), 5.26 (q, J = 5.2 Hz, 1H), 3.89 (s, 3H), 2.68 (d, J = 5.0 Hz, 3H).

Example  51. Methyl 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoate; methyl 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoate; KY-06471

KY-06420, the title compound (66%) was obtained.

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 J = 8.1 Hz, 1H), 7.80 (d, J = 5.5 Hz, 2H), 7.58-7.50 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 4H), 3.08 (s, 4H).

Example  52. methyl 3- (3- (N- (lH-indol-5-yl) sulfamoyl) benzamido) benzoate indole -5-yl) sulfamoyl) benzamido) benzoate; KY-06472

KY-06420, the title compound (66%) was obtained.

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) (d, J = 8.8 Hz, 1H), 3.87 (s, 3H).

Example  53. methyl 3- (3- (N- (lH-indol-6-yl) sulfamoyl) benzamido) benzoate indole -6-yl) sulfamoyl) benzamido) benzoate; KY-06473

KY-06420, the title compound (86%) was obtained.

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), J = 7.7 Hz, 1H), 7.95 (d, J = 6.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 3H) t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H).

Example  54. methyl 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate; KY-06474

KY-06420, the title compound (25%) was obtained.

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).

Example  55. methyl 3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoate benzylpiperidine -4-yl) sulfamoyl) benzamido) benzoate; KY-06475

KY-06420, the title compound (68%) was obtained.

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 = J = 8.0 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.62 (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).

Example  56. Preparation of methyl 3 - ((3 - ((methoxycarbonyl) phenyl) carbamoyl) phenyl) sulfonamido) benzoate ) phenyl) sulfonamido) benzoate; KY-06476

The 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, and aminobenzoate (1.69 g, 9 mmol, 0.9 mmol) and DIPEA (1.6 mL) were dissolved in MC (8 mL) and stirred at 0 ° C. 3-Chlorosulfonylbenzoyl chloride was dissolved in MC (8 mL) and added slowly. After further stirring at 0 ° C for 30 minutes, the mixture was extracted with distilled water and MC, dried over MgSO 4, and then separated into a silica gel column to obtain the title compound.

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) 3.87 (s, 3H), 3.82 (s, 3H).

Example  57. methyl  2- (3- (3- (N- Phenylsulfamoyl ) Benzamido ) Phenyl) acetate (methyl 2- (3- (3- (N- phenylsulfamoyl ) benzamido ) phenyl) acetate; KY-06477

Was synthesized in the same manner as in step 3 of KY-06420 to give the title compound (76%).

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 = J = 4.7 Hz, 1H), 7.29-7.20 (m, 3H), 7.13-7.12 (m, m, 3H), 7.00 (d, J = 4.5 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 2H).

Example  58. methyl  3-Bromo-5- (3- (N- Phenylsulfamoyl ) Methyl 3-bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoate; KY-06478

To a 7 mL vial was added a carboxylic acid compound (332 mg, 1.2 mmol), methyl 3-amino-5-bromobenzoate (270 mg, 1.2 eq), EDCI (3.0 eq), HOBt (3.0 eq) Was 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 a mixed solvent of H 2 O / EA, 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 a silica gel column was carried out to obtain the title compound (475 mg, 83%).

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).

Example  59. Methyl 3-bromo-5 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoate (methyl 3- bromo -5 - ((3- ( phenylcarbamoyl ) phenyl) ulfonamido ) benzoate); KY-06479

To a 7 mL vial was dissolved a solution of the carboxylic acid compound (330 mg, 1.2 mmol), aniline (0.147 mL, 2.0 eq.), EDCI (3.0 eq.), HOBt (3.0 eq.) And DIPEA , And the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with a mixed solvent of H 2 O / EA, 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 a silica gel column was carried out to obtain the title compound (348 mg, 89%).

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 3H).

Example  60. 3-Bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid; 3-bromo-5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid; KY-06480

To the 7 mL vial was added an ester compound (100 mg, 0.2 mol) with LiOH (20 eq.) And THF / H 2 O / MeOH mixed solution as a solvent at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure and acid-base extraction was carried out. The water layer was washed with ether, adjusted to pH 3 with 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (95 mg, 98%).

1 H NMR (300 MHz, DMSO)? 10.79 (s, IH), 10.45 (s, IH), 8.35 (d, J = 12.7 Hz, 3H), 8.22 7.77 (d, J = 17.5 Hz, 2H), 7.24 (s, 2H), 7.08 (d, J = 21.9 Hz, 3H).

Example  61. 3-Bromo-5 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid; 3-bromo-5 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid; KY-06481

To the 7 mL vial was added an ester compound (100 mg, 0.2 mol) with LiOH (20 eq.) And THF / H 2 O / MeOH mixed solution as a solvent at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure and acid-base extraction was carried out. The water layer was washed with ether, adjusted to pH 3 with 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (85 mg, 83%).

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 , ≪ / RTI > 1H), 7.37 (s, 2H), 7.13 (s, 1H).

Example  62. 3- Bromo -N- methyl -5- (3- (N- Phenylsulfamoyl ) Benzamido ) 3-bromo-N-methyl-5- (3- (N-phenylsulfamoyl) benzamido) benzamide); KY-06482

After dissolving the acid compound (50 mg, 0.1 mmol), methylmethylamine (3.0 equivalents), EDCI (3.0 equivalents), HOBt (3.0 equivalents) and DIPEA (3.0 equivalents) in DMF (0.3 M) The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with a mixed solvent of H 2 O / EA, 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 a silica gel column was carried out to obtain the title compound (38 mg, 72%).

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 (T, J = 7.8 Hz, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.78 d, J = 7.8 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H).

Example  63. 3-Bromo-N-methyl-5 - ((3- (phenylcarbamoyl) phenyl) sulfonamido) sulfonamido) benzamide); KY-06483

After dissolving the acid compound (50 mg, 0.1 mmol), methylmethylamine (3.0 equivalents), EDCI (3.0 equivalents), HOBt (3.0 equivalents) and DIPEA (3.0 equivalents) in DMF (0.3 M) The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with a mixed solvent of H 2 O / EA, 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 a silica gel column was carried out to obtain the title compound (17 mg, 31%).

1 H NMR (300 MHz, DMSO)? 10.85 (s, IH), 10.49 (s, IH), 8.50 (s, IH), 8.35 ), 7.73 (s, 3H), 7.64 (s, IH), 7.57 (s, IH), 7.37 (s, 3H), 7.12 (s, 2H), 2.76-2.

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

(1.2 mmol, 300 mg) and methyl 3-aminobenzoate (2.0 eq., 252 mg) were added to a 100 mL round-bottomed flask, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the mixture was extracted three times with a mixed solvent of H 2 O / EA. 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.

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 J = 8.1 Hz, 1H), 7.39 (dd, J = 4.9, 2.4 Hz, 1H), 7.73 (q, J = 1.4 Hz, 1H), 7.66-7.57 ), 3.82 (s, 3H), 3.37 (dd, J = 10.0, 3.4 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H).

Example  65. 3- (N- (2- ( Phenylamino ) Phenyl) Sulfamoyl ) 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 eq) was slowly added. After completion of the reaction, the pyridine was removed under reduced pressure, and the mixture was extracted three times with a 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 carried out to obtain the title compound (167 mg, 28% .

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 J = 7.2 Hz, 1H), 6.78 (t, J = 7.8 Hz, 1H), 7.13 = 7.4 Hz, IH), 6.62 (d, J = 7.8 Hz, 2H).

Example  66. A compound according to claim 1 which is 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06489

KY-06420 to give the title compound (59%).

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 J = 7.2 Hz, 1H), 7.77 (t, J = 8 Hz, 2H), 8.05-8.01 7.8 Hz, 1H), 7.38-7.26 (m, 2H), 7.23 (dt, J = 7.9, 1.9 J = 4.5 Hz, 3H), 2.64 (d, J = 11.7 Hz, 2H), 3.80 (d, J = 1.89 (t, J = 10.7 Hz, 2H), 1.54 (dd, J = 13.1, 3.9 Hz, 2H), 1.44-1.33 (m, 2H).

Example  67. 1- (4-Fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen- 4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06490

KY-06531 to give the title compound (99%).

1 H NMR (300 MHz, DMSO)? 10.33 (s, 1H), 9.14 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.19 ), 7.60 (dd, J = 1.2,5.4 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 7.49-7.42 , 2.80 (d, J = 4.5 Hz, 3H).

Example  68. 1- (4-Fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -lH-pyrazole-4-carboxamide ) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06491

KY-06531 to give the title compound (30%).

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).

Example  69. 3- (1- (4-Fluorophenyl) -3- (thiophen-2-yl) -lH-pyrazole-4- carboxamido) benzenesulfonic acid (3- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06492

KY-06531 to give the title compound (99%).

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).

Example  70. methyl  3- (1- (4- Fluorophenyl ) -3- (thiophen-2-yl) -1H- Pyrazole -4- Carboxamido ) Benzoate (methyl 3- (1- (4- fluorophenyl ) -3- ( thiophen -2- yl ) -1H-pyrazole-4-carboxamido) benzoate); KY-06493

KY-06531 to give the title compound (85%).

1 H NMR (300 MHz, DMSO)? 10.42 (s, IH), 9.15 (s, IH), 8.40 (s, IH), 8.04-8.00 (m, IH), 7.97-7.92 (t, J = 0.8,8.1 Hz, 1H), 7.60 (dd, J = 1.2, 5.2 Hz, 1H), 7.55 , 7.14 (dd, J = 3.6, 5.1 Hz, 1 H), 3.89 (s, 3H).

Example  71. Preparation of N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H- pyrazole- ) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06494

KY-06531 to give the title compound (99%).

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, IH), 7.13 (dd, J = 3.6, 5.1 Hz, IH).

Example  72. 1- (4-Fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen- 4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide; KY-06496

KY-06531 to give the title compound (10%).

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 J = 8.7 Hz, 2H), 7.14 (dd, J = 3.6, 5.1 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H).

Example  73. Preparation of N- (4-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H- pyrazole- ) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06497

KY-06531 to give the title compound (35%).

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 1H).

Example  74. 3- (1- (4-Fluoro- Phenyl ) -3- (thiophen-2- Work ) -1H-pyrazole-4-carboxamido) benzoic acid; (3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -lH-pyrazole-4-carboxamido) benzoic acid; KY-06498

The title compound (98%) was obtained by the same method as KY-06455.

1 H NMR (300 MHz, DMSO)? 12.95 (s, IH), 10.39 (s, IH), 9.15 (s, IH), 8.37 (s, IH), 8.00-7.92 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).

Example  75. N- (3- Carbamoylphenyl ) -3- (N- Phenethylsulfamoyl ) ≪ / RTI > (N- (3-carbamoylphenyl) -3- (N-phenethylsulfamoyl) benzamide); KY-06500

(50 mg, 0.44 mmol) was dissolved in THF (3 mL) and phenethylamine (54 mg, 0.44 mmol, 1 eq.) Was added. Triethylamine (Et 3 N, TEA, 60 μL) was added thereto, followed by stirring at room temperature for 24 hours. Removal of the solvent and separation into a silica gel column gave the title compound (61%).

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 ), 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).

Example  76. N- (3- Carbamoylphenyl ) -3- (N- (4- Phenoxyphenyl ) Sulfamoyl ) N- (3-carbamoylphenyl) -3- (N- (4-phenoxyphenyl) sulfamoyl) benzamide); KY-06501

KY-06500, the title compound (98%) was obtained.

NMR H 1 (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), 8.58 (t, J = 7.0 Hz, 2H), 8.36-8.28 (m, 3H), 8.13 (d, J = 8.5 Hz, , 2H), 8.01 (d, J = 9.0 Hz, 2H), 7.66 (s, 1H).

Example  77. N- (3- Carbamoylphenyl ) -3- (N- (pyridin-2-yl) Sulfamoyl ) N- (3-carbamoylphenyl) -3- (N- (pyridin-2-yl) sulfamoyl) benzamide); KY-06503

The aniline compound (41 mg) and Et 3 N (0.06 mL) were added to the THF (2.2 mL), and the mixture was stirred at 50 ° C. MC was added, washed with distilled water and dried with MgSO 4 . The column was run with MC: MeOH = 19: 1 mixed solvent to give the title compound (35%).

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 J = 7.5 Hz, 1H), 7.96-7.93 (m, 3H), 7.79-7.68 (m, 2H), 7.62 , ≪ / RTI > 1H), 7.22 (s, 1H), 6.86 (s, 1H).

Example  78. 3- (N- (1- Benzylpiperidine Yl) Sulfamoyl ) -N- (3- Carbamoylphenyl (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06504

KY-06503 to give the title compound (80%).

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 ( (t, J = 7.8 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.75 J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.31-7.21 (m, 6H), 3.37 (s, 2H), 3.06-2.94 ), 1.89 (t, J = 10.7 Hz, 2H), 1.54 (d, J = 12.9 Hz, 2H), 1.37 (q, J = 10.2 Hz, 2H).

Example  79. N- (3- Carbamoylphenyl ) -3- (N- (3- Phenoxyphenyl ) Sulfamoyl ) N- (3-carbamoylphenyl) -3- (N- (3-phenoxyphenyl) sulfamoyl) benzamide); KY-06505

KY-06503 to give the title compound (3%).

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) ), 7.37 (s, IH), 7.30 (s, IH), 7.26-7.19 (m, 2H).

Example  80. 3- (N- (1H- Indazole -5 days) Sulfamoyl ) -N- (3- Carbamoylphenyl (3- (N- (1H-indazol-5-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06506

KY-06503, the title compound (39%) was obtained.

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 = 7.9 Hz, 1H), 7.91 (d, J = d, J = 7.8 Hz, 1H), 7.46-7.37 (m, 4H), 7.10 (dd, J = 1.7 Hz, 8.9 Hz, 1H).

Example  81. 3- (N- (1H- Indazole Yl) Sulfamoyl ) -N- (3- Carbamoylphenyl (3- (N- (1H-indazol-6-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06507

KY-06503 to give the title compound (61%).

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 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H) ), 7.27 (s, 1H), 6.91 (dd, J = 1.4 Hz, 8.6 Hz, 1H).

Example  82. N- (3- Carbamoylphenyl ) -3- (N- (pyridin-3-yl) Sulfamoyl ) N- (3-carbamoylphenyl) -3- (N- (pyridin-3-yl) sulfamoyl) benzamide); KY-06508

KY-06503 to give the title compound (68%).

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 J = 7.8 Hz, 1 H), 7.44 (qd, J = 1.2 Hz, 8.1 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.30 (dd, J = 4.6 Hz, 8.2 Hz, 1H)

Example  83. Preparation of 2,4-difluoro-N- (3- (methylcarbamoyl) phenyl) -5- (N-phenylsulfamoyl) ) -5- (N-phenylsulfamoyl) benzamide); KY-06509

KY-06531 to give the title compound (31%).

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, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 2H), 7.15-7.04 J = 4.2 Hz, 3H).

Example  84. Preparation of 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) ) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06510

KY-06500, the title compound (26%) was obtained.

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), 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 (t, J = 4.8 Hz, 1 H), 7.37 (s, 1 H).

Example  85. 4- Fluoro -N- (3- ( Methylcarbamoyl ) Phenyl) -3- (N- Phenylsulfamoyl (4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06511

KY-06478 to give the title compound (66%).

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 , 7.13 (d, J = 13.0 Hz, 2H), 7.04 (t, J = 12.3 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H).

Example  86. N- (3- Carbamoylphenyl )-4- Fluoro -3- (N- Phenylsulfamoyl (N- (3-carbamoylphenyl) -4-fluoro-3- (N-phenylsulfamoyl) benzamide); KY-06512

KY-06478 to give the title compound (56%).

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 , 7.84 (s, 1H), 7.98 (s, 1H), 7.93 (dd, J = 0.9, 4.8 Hz, 1H), 7.64-7.59 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).

Example  87. Ethyl 3 - ((5 - ((3- ( Ethoxycarbonyl ) Phenyl) Carbamoyl )-2- Fluorophenyl ) Sulfonamido) benzoate (ethyl 3 - ((5 - ((3- ( ethoxycarbonyl ) phenyl) carbamoyl ) -2-fluorophenyl) sulfonamido) benzoate); KY-06513

KY-06633, the title compound (12%) was obtained.

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 J = 8.1 Hz, 1H), 7.34-7.28 (m, 2H), 7.24 (s, 1H), 7.16-7.14 (m, 4H), 4.38 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3 H).

Example  88. 3 - ((5 - ((3- Carboxyphenyl ) Carbamoyl )-2- Fluorophenyl ) Sulfonamido ) Benzoic acid (3 - ((5 - ((3-carboxyphenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoic acid; KY-06514

KY-06455 to give the title compound.

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 J = 7.9 Hz, 1H), 7.47 (d, J = 8 Hz), 8.42-8.37 (m, 5.1 Hz, 2H).

Example  89. 4-Fluoro-N- (3-methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide); KY-06515

KY-06531 to give the title compound (53%).

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 , 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 J = 7.7 Hz, 1H), 7.28 (dd, J = 1.3, 8.2 Hz, 1H), 2.80 Hz, 3H).

Example  90. Ethyl 3- ((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido ) Benzoate (ethyl 3 - ((2- fluoro -5- ( phenylcarbamoyl ) phenyl) ulfonamido ) benzoate); KY-06516

The title compound (11%) was obtained by the same procedure as KY-06454.

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), (D, J = 8.1 Hz, 2H), 7.41-7.29 (m, 5H), 7.18 (t, J = 6.9 Hz, 1H), 4.34 = 7.2 Hz, 3 H).

Example  91. 3 - ((2- Fluoro -5- ( Phenylcarbamoyl ) Phenyl) Sulfonamido Benzoic acid (3 - ((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid; KY-06517

KY-06455 to give the title compound (85%).

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).

Example  92. N- (4- Chlorophenyl ) -3- (N- Phenylsulfamoyl ) N- (4-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06518

KY-06478 to give the title compound (75%).

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 J = 7.8 Hz, 1 H), 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).

Example  93. N- (4- Bromophenyl ) -3- (N- Phenylsulfamoyl ) N- (4-bromophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06519

KY-06478 to give the title compound (69%).

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 (D, J = 7.8 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.10 7.03 (t, J = 7.3 Hz, 1 H).

Example  94. N- (3- Chlorophenyl ) -3- (N- Phenylsulfamoyl ) N- (3-chlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06520

KY-06478 to give the title compound (50%).

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 , ≪ / RTI > J = 7.4 Hz, 1H).

Example  95. N- (3,4- Dichlorophenyl ) -3- (N- Phenylsulfamoyl ) N- (3,4-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06521

KY-06478 to give the title compound (67%).

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 J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.75-7.71 7.10 (d, J = 7.5 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H).

Example  96. N- (3,5- Dichlorophenyl ) -3- (N- Phenylsulfamoyl ) ≪ / RTI > benzamide (N- (3,5-dichlorophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06522

KY-06478 to give the title compound (56%).

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 J = 7.8 Hz, 1 H), 7.37 (t, J = 1.8 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 2H), 7.11 (s, IH), 7.09 (s, IH), 7.03 (t, J = 7.3 Hz, IH).

Example  97. N- (2,4- Dibromophenyl ) -3- (N- Phenylsulfamoyl ) (N- (2,4-dibromophenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06523

KY-06478 to give the title compound (30%).

1 H NMR (300 MHz, DMSO) [delta] 10.42 (s, IH), 10.39 (s, IH), 8.36 (s, IH), 8.20 (d, J = 7.7 Hz, J = 7.9 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 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).

Example  98. 4- (1- (4-Fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid; KY-06524

KY-06455 to give the title compound (89%).

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).

Example  99. 4- (5 - ((3- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06525

An ester compound (32 mg, 0.074 mmol) and a mixed solvent of THF / H 2 O / MeOH were added to a 7 mL vial and stirred. LiOH (15.6 mg, 0.37 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, 1N HCl was added to adjust the pH to 2 to 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%).

1 H NMR (300 MHz, DMSO)? 13.23 (s, IH), 10.56 (s, IH), 8.71 (s, IH), 8.18-7.97 ), 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).

Example  100. methyl  (4- (5 - ((3- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) Benzoyl ) -D- Tryptophanate (methyl (4- (5 - ((3- 펜oxyphenyl ) carbamoyl ) thiazole -2- yl ) benzoyl ) -D-tryptophanate); KY-06527

To a 20 mL vial was added a 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, mL) was added and reacted at room temperature for 16 hours. After completion of the reaction, the reaction 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%).

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 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 , 5.08 (t, IH, J = 6.3 Hz), 3.70 (s, 3H), 3.49-3.32 (m, 2H), 2.34-2.15 (m, 2H).

Example  101. (4- (5 - ((3- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) Benzoyl ) -D-tryptophane (4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophan; KY-06528

The ester compound (45 mg, 0.1 mmol) and THF / H 2 O / MeOH mixed solvent were added to a 20 mL vial and stirred. LiOH (21 mg, 0.5 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, 1N HCl was added to adjust the pH to 2 to 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%).

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), 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 1H), 7.03 (d, 3H, J = 7.6Hz), 6.81 (d, 1H, J = 7.9Hz), 4.68 (q, 1H, J = 7.2Hz), 3.32-3.08 (m, 2H).

Example  102. methyl  (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Benzoyl) -L-tryptophanate (methyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate; KY-06529

To a 20 mL vial was added a 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) mL) was added and reacted at room temperature for 16 hours. After completion of the reaction, the reaction 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%).

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), 1H), 6.75 (d, 1H, J = 7.5 Hz), 5.06-5.04 (m, 1H), 7.31-7.29 (m, , 3.69 (s, 3H), 3.42 (d, 2H, J = 5.3 Hz, 2H).

Example  103. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L- 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan); KY-06530

The ester compound (240 mg, 0.39 mmol) and THF / H 2 O mixed solvent were added to a 20 mL vial and stirred. LiOH (80.7 mg, 1.91 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, 1N HCl was added to adjust the pH to 2 to 3 and extracted with EA and H 2 O. [ The organic layer was dried over MgSO 4 concentrated and the solid was filtered off to give the title compound (175.9 mg, 74%).

1 H NMR (300 MHz, DMSO)? 12.74 (s, IH), 10.83 (s, IH), 10.33 (s, IH), 9.21 2H, J = 7.7 Hz), 7.33 (d, 1H, J = 7.9 Hz), 7.41 (s, 1H), 7.98-7.83 1H), 7.21 (d, 1H, J = 2.3 Hz), 7.18-7.12 (m, 1H), 7.06-6.99 (m, 2H), 4.67 2H).

Example  104. methyl  (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Benzoyl) -D-alaninate (methyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alaninate); KY-06531

Alanine methyl ester hydrochloride (2.0 eq., 131 mg), HBTU (3.0 eq., 535 mg), DIPEA (3.0 eq., 0.25 mL), DMF (1.5 eq. mL) was added and reacted at 40 ° C for 16 hours. After completion of the reaction, the reaction mixture was extracted three times with EA and H 2 O, and the organic layer was washed with a saturated aqueous solution of sodium carbonate and dried over MgSO 4 . The filtrate was concentrated under reduced pressure, solidified with MC / ether / hexane and then filtered through a sinter to obtain the title compound (131 mg, 55%) as a white solid.

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).

Example  105. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D- 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine); KY-06532

To the 7 mL vial was added the ester compound (100 mg, 0.19 mmol), LiOH (2.0 eq., 16 mg), THF (1 mL) and H 2 O (1 mL) and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was transferred to a 50 mL round bottom flask and THF was removed by a rotary evaporator. The residue was washed with a mixed solvent of ether: H 2 O = 1: 2. After confirming that the water layer was pH 8 using a pH paper, the pH was adjusted to 2 to 3 while adding 1N HCl. The 1N HCl mixture was extracted with EA and then concentrated under reduced pressure. The mixture was solidified with an MC / hexane mixed solvent, filtered through a sinter, and subjected to a silica gel column, followed by concentration under reduced pressure to obtain the title compound (70 mg, 74%) as a white solid compound.

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), J = 7.9 Hz), 7.46 (d, J = 7.9 Hz, 1H), 7.66-7.58 (m, 3H), 7.48 4.0 Hz, 1H), 4.44 (q, J = 7.3 Hz, 1H), 1.41 (d, J = 7.3 Hz, 3H).

Example  106. Dimethyl (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Benzoyl) -L-aspartate (dimethyl (3- (3- (5- chlorothiophen -2- yl -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate); KY-06533

To a 7 mL vial was added the acid compound (200 mg, 0.47 mmol), L-aspartic acid dimethyl ester hydrochloride (2.0 eq, 140 mg), HBTU (3.0 eq, 535 mg), DIPEA (3.0 eq, 0.25 mL) 1.5 mL) was added thereto and reacted at 40 ° C for 16 hours. After completion of the reaction, the reaction mixture was extracted three times with EA and H 2 O, and the organic layer was washed with a saturated aqueous solution of sodium carbonate and dried over MgSO 4 . The residue was purified by silica gel column, concentrated under reduced pressure, solidified with MC / ether / hexane and then filtered with a sinter to obtain the title compound (126 mg, 47%) as a white solid.

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).

Example  107. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid; KY-06534

A diester compound (100 mg, 0.18 mmol), LiOH (2.0 eq., 15 mg), THF (1 mL) and 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 reaction mixture was transferred to a 50 mL round bottom flask, and THF was removed by a rotary evaporator. The residue was washed with a mixed solvent of ether: H 2 O = 1: 2. After confirming that the water layer was pH 8 using a pH paper, the pH was adjusted to 3 to 4 by adding 1N HCl. The 1N HCl mixture was extracted with EA and then concentrated under reduced pressure. The reaction mixture was solidified with a mixed solvent of MC / hexane, washed with ether, filtered through a sinter, and subjected to silica gel column, followed by concentration under reduced pressure to obtain the title compound (42 mg, 45%) as a white solid compound.

1 H NMR (300 MHz, DMSO) 隆 12.65 (s, 2H), 10.36 (s, 1H), 9.22 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H) J = 6.6 Hz, 1H), 7.77-7.89 (m, 4H), 7.63-7.59 (m, 3H), 7.51-7.41 , 2.80 (ddd, J = 7.2, 16.3, 40.9 Hz, 2H).

Example  108. 4- (1- (4-Fluorophenyl) -3- (thiophen-2-yl) -lH-pyrazole-4-carboxamido) benzenesulfonic acid 4- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06535

KY-06531 to give the title compound (58%).

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).

Example  109. Ethyl (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Benzoyl) glycinate (ethyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate; KY-06536

To a 7 mL vial was added the acid compound (200 mg, 0.47 mmol), glycine ethyl ester hydrochloride (2.0 eq., 140 mg), HBTU (3.0 eq., 535 mg), DIPEA (3.0 eq., 0.25 mL) And the mixture was reacted at 40 ° C for 16 hours. After completion of the reaction, the reaction mixture was extracted three times with EA and H 2 O, and the organic layer was washed with a saturated aqueous solution of sodium carbonate and dried over MgSO 4 . The residue was purified by silica gel column, concentrated under reduced pressure, solidified with MC / ether / hexane and then filtered through a sinter to obtain the title compound (92 mg, 38%) as a white solid.

1 H NMR (300 MHz, DMSO) 隆 10.35 (s, 1H), 9.22 (s, 1H), 8.93 (t, J = 5.5 Hz, 1H), 8.23 (s, 1H), 7.94-7.89 J = 7.1 Hz, 2H), 4.01 (d, J = 7.6 Hz, 1H), 7.63-7.58 (m, 3H), 7.52-7.41 5.5 Hz, 2H), 1.22 (t, J = 7.1, 3H).

Example  110. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine); KY-06537

A diester compound (60 mg, 0.12 mmol), LiOH (2.0 eq., 10 mg), THF (1 mL) and 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, the reaction mixture was transferred to a 50 mL round bottom flask, and THF was removed by a rotary evaporator. The residue was washed with a mixed solvent of ether: H 2 O = 1: 2. After confirming that the water layer was pH 8 using a pH paper, the pH was adjusted to 3 by adding 1N HCl. The 1N HCl mixture was extracted with EA and then concentrated under reduced pressure. MC / hexane mixed solvent, and then filtered with a sinter to obtain the title compound (26 mg, 45%) as a white solid compound.

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).

Example  111. 2- (4 - ((2-morpholinoethyl) carbamoyl) phenyl) -N- (3- phenoxyphenyl) thiazole- carbamoyl) phenyl) -N- (3-phenoxyphenyl) thiazole-5-carboxamide); KY-06538

DPPA (diphenylphosphorylazide, 0.11 mmol, 24 μL) was added to the 20 mL vial and stirred for 30 minutes. Then, amine (0.18 mmol, 24 μL, ) Were added and reacted overnight at room temperature. After completion of the reaction, the resulting solid was filtered, washed with hexane and then dried to give the title compound (30 mg, 47%).

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 ( 2H, J = 8.1 Hz), 7.59-7.50 (m, 1H), 7.48-7.33 (m, 4H), 7.18 ), 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).

Example  112. 3- (5 - ((4- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((4-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06539

The ester compound (43 mg, 0.1 mmol) and THF / H 2 O / MeOH mixed solvent were added to a 20 mL vial and stirred. LiOH (21 mg, 0.5 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, 1N HCl was added to adjust the pH to 2 to 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%).

1 H NMR (300 MHz, DMSO)? 13.33 (s, IH), 10.54 (s, IH), 8.71 = 7.8 Hz), 8.09 (t, 1H, J = 7.7Hz), 7.83-7.60 (m, 3H), 7.48-7.28 (m, 2H), 7.25-6.90 (m, 5H).

Example  113. methyl  3- (2- (4- Phenoxyphenyl ) Thiazol-5- Carboxamido ) Benzoate (methyl 3- (2- (4- 펜oxyphenyl ) thiazole -5- carboxamido ) benzoate); KY-06540

(100 mg, 0.27 mmol), bronic acid (72.8 mg, 0.34 mmol), K 3 PO 4 (101.0 mg, 0.46 mmol), Pd 2 (dba) 3 mg, 0.028 mmol) and PCy 3 HBF 4 (30.9 mg, 0.084 mmol) were placed in a glove box, and the mixture was poured into a nitrogen needle and dioxane and H 2 O were added thereto, followed by overnight reaction at 100 ° C. After completion of the reaction, the reaction mixture was filtered through Celite, concentrated, and extracted with EA and H 2 O. [ The organic layer was dried with MgSO 4 and concentrated again. Separation and purification by silica gel column chromatography gave the title compound (43.8 mg, 18%, 100 mg twice reaction).

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 2H), 7.43 (t, 3H, J = 7.9 Hz), 7.19 (t, 1H, J = 7.4 Hz), 7.07-7.03 , 3H, J = 7.1 Hz).

Example  114. 3- (2- (4- Phenoxyphenyl ) Thiazol-5- Carboxamido Benzoic acid (3- (2- (4-phenoxyphenyl) thiazole-5-carboxamido) benzoic acid); KY-06541

KY-06539 to give the title compound (58%).

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 = 7.7Hz), 7.50 (t, 2H, J = 7.9Hz).

Example  115. methyl  (4- (5 - ((3- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) Benzoyl ) -L- Tryptophanate (methyl (4- (5 - ((3- 펜oxyphenyl ) carbamoyl ) thiazole -2- yl ) benzoyl ) -L-tryptophanate); KY-06542

The title compound (70 mg, 95%) was obtained by the reaction of Example 104 with the exception that D-tryptophan methyl ester hydrochloride was used instead of L-tryptophan methyl ester hydrochloride.

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 ( 1H, J = 7.6 Hz), 6.80 (d, IH, m, 3H), 7.48-7.40 (m, 2H), 7.36-7.25 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).

Example  116. (4- (5 - ((3- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) Benzoyl ) -L-tryptophan ((4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan; KY-06543

KY-06539 to give the title compound (58%).

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), 2H), 7.09-7.91 (m, 2H), 7.59-7.44 (m, 2H), 7.43-7.31 (m, 5H), 7.21-7.18 J = 8.0 Hz), 4.67 (d, 1H, J = 10.6 Hz), 3.31-3.27 (m, 3H).

Example  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

The title compound (250 mg, 99%) was prepared according to the same procedures as in Example 104, except for using 2-morpholinoethan-1-amine instead of L-alanine methyl ester hydrochloride. ).

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).

Example  118. methyl  3 - ((3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Methyl) benzoate (methyl 3 - ((3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoate; KY-06545

To a 50 mL round bottom flask was added the acid compound (400 mg, 1.31 mmol), 3-aminomethyl benzoic acid methyl ester (1.5 eq, 397 mg), HBTU (3.0 eq, 1.49 mg), DIPEA (3.0 eq, 0.69 mL) (4 mL), and the mixture was stirred at 40 ° C. After completion of the reaction, the mixture was extracted with EA and H 2 O (2: 1). The organic layer was washed with a saturated sodium carbonate aqueous solution and dried over MgSO 4 . The filtrate was concentrated under reduced pressure to obtain a silica gel column, which was solidified by ultrasonic treatment with ether to give the title compound (531 mg, 89%) as a white solid.

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, .

Example  119. 3 - ((3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) methyl) -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoic acid; KY-06546

To the 20 mL vial was dissolved the ester compound (461 mg, 1.09 mmol) in THF (2 mL) and stirred. H 2 O (2 mL) and LiOH (5.0 eq, 228 mg) were added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was transferred to a 50 mL round bottom flask and THF was removed by a rotary evaporator. The residue was washed with a mixed solvent of ether: H 2 O = 1: 2. After confirming that the water layer was pH 8 using a pH paper, the pH was adjusted to 2 to 3 while adding 1N HCl. The mixture was 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.

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 J = 7.6, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.11 (s, 1), 4.54 (d, J = 5.1 Hz, , 2H).

Example  120. methyl  (3 - ((3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Methyl) benzoyl) -D-alaninate (methyl (3 - ((3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alaninate); KY-06547

Alanine methyl ester hydrochloride (1.6 eq, 223 mg), HBTU (3.0 eq, 910 mg), DIPEA (3.0 eq, 0.42 mL), DMF (2.5 mL), and the mixture was stirred at 40 ° C. After completion of the reaction, the mixture was extracted with EA and H 2 O (2: 1). The organic layer was washed with a saturated sodium carbonate aqueous solution and dried over MgSO 4 . The filtrate was concentrated under reduced pressure to obtain a silica gel column, which was solidified by ultrasonic treatment with ether to give the title compound (335 mg, 80%) as a white solid.

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 (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).

Example  121. (3 - ((3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl) -D-alanine); KY-06548

To the 20 mL vial was added an ester compound (250 mg) in THF (2 mL) and H 2 O (2 mL) and stirred. LiOH (40 mg) was added thereto and stirred at room temperature. After completion of the reaction, THF was removed, the 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.

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 , ≪ / RTI > J = 6.8 Hz, 3H).

Example  122. methyl  3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -5-fluorobenzoate (methyl 3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate; KY-06549

The title compound (26%) was obtained by the same method as KY-06545.

1 H NMR (300 MHz, CDCl 3) 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 (D, J = 0.3 Hz, 1 H), 3.93 (s, 3H).

Example  123. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid; KY-06550

KY-06546 to give the title compound (53%).

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).

Example  124. methyl  (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -5-fluorobenzoyl) -L-tryptophanate (methyl (3- (3- (5- chlorothiophen -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophanate; KY-06551

The title compound (69%) was obtained by the same procedure as KY-06545.

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 1H), 7.15 (s, 1H), 7.07 (t, 1H), 7.63-7.56 (m, 3H), 7.46-7.44 J = 6.6 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 4.71 (q, J = 7.4 Hz, 1H) .

Example  125. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L- - (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tryptophan); KY-06552

KY-06546 to give the title compound (93%).

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 2H), 7.33 (d, J = 4.8 Hz, IH), 7.21 (s, IH), 7.90-7.88 (m, 4H), 7.61-7.60 , 7.16 (d, J = 1.7 Hz, 1H), 7.07 (t, J = 4.5 Hz, 1H), 6.99 (t, J = 4.5 Hz, 1H) 4.9 Hz, 2H).

Example  126. (S) -3- (5-Chlorothiophen-2-yl) -N- (3 - ((1 - ((2-morpholinoethyl) amino) (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-06545 to give the title compound (47%).

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 J = 8.0 Hz, 1H), 3.56 (s, 4H), 3.23 (s, 2H), 2.92 , 3H).

Example  127. Ethyl 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate (ethyl 3- (3- thiophen -2- yl ) -1H- pyrazole -4- carboxamido ) benzoate); KY-06554

KY-06545 to give the title compound (47%).

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 J = 7.3 Hz, 2H), 1.34 (t, J < RTI ID = 0.0 > = 6.8 Hz, 3H).

Example  128. 3- (3- (Thiophen-2-yl) -1H- Pyrazole -4- Carboxamido Benzoic acid (3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid); KY-06555

KY-06546 to give the title compound (80%).

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, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.10 (s, 1H).

Example  129. methyl  4- (5 - ((Piperidin-4-ylmethyl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 4- (5 - (( piperidine -4- ylmethyl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06556

N-Boc compound (329 mg, 0.72 mmol) was dissolved in MC (16 mL) in a 100 mL round bottom flask. TFA (trifluoroacetic acid, 3.57 mmol, 0.27 mL) was slowly added dropwise to the solution and reacted at room temperature for 16 hours. After completion of the reaction, the solvent was removed to obtain the title compound quantitatively.

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 = 2H), 1.34 (s, 1 H).

Example  130. methyl  4- (5 - ((Piperidin-4-ylmethyl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 4- (5 - (( piperidine -4- ylmethyl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06557

KY-06539 to give the title compound (91%).

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 , ≪ / RTI > 3H), 1.37 (d, 2H, J = 10.8 Hz).

Example  131. methyl  4- (5 - (((1- Benzoylpiperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 4- (5 - (((1- benzoylpiperidine -4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06558

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 the mixture was reacted at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with an EA / H 2 O mixed solvent and dried with MgSO 4 . The separated and purified by silica gel column chromatography gave the title compound (80%).

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) 2H), 2.97 (s, 3H), 3.72 (d, IH, J = 2.77 (m, 2H), 1.94-1.67 (m, 3H), 1.23 (s, 2H).

Example  132. 4- (5 - (((1- Benzoylpiperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid (4- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06559

KY-06539 to give the title compound (76%).

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), 2H), 1.91-1.67 (m, 3H), 1.221.13 (m, 2H), 2.78 (s, .

Example  133. methyl  4- (5 - (((1- ( Phenylcarbamoyl ) ≪ / RTI > piperidin-4-yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 4- (5 - (((1- ( phenylcarbamoyl ) piperidine -4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06560

KY-06538 to give the title compound (80%).

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) 2H), 7.03 (t, IH, J = 7.2 Hz), 6.34 (s, IH), 6.17 (d, IH, J = , 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).

Example  Yl) benzoic acid (4- (5 - (((1 - ((2- (4-fluorophenyl) phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06561

KY-06539, the title compound (20%) was obtained.

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), 1H, J = 7.3 Hz), 7.41 (d, 2H, J = 7.7 Hz), 7.21 (t, 2H, J = 7.8 Hz), 6.91 d, 2H, J = 6.2 Hz), 2.77 (t, 2H, J = 12.5Hz), 1.78-1.70 (m, 3H), 1.23-1.07 (m, 3H).

Example  135. methyl  4- (5 - (((1- Tosyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 4- (5 - (((1- tosylpiperidine -4- yl ) methyl) carbamoyl ) thiazole -2-yl) benzoate; KY-06562

KY-06538 to give the title compound (78%).

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 ), 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).

Example  136. 4- (5 - (((1- Tosyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (4- (5 - ((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06563

KY-06539, the title compound (20%) was obtained.

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 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).

Example  137. methyl  3- (5 - ((1-benzylpiperidin-4-yl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 3- (5 - ((1- benzylpiperidine -4- yl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06564

5 mL micro bromide compound in a vial for wave (100 mg, 0.26 mmol), hydrobromic 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 mmol) and PCy 3 HBF 4 (23 mg, 0.062 mmol) were placed in a glove box. The reaction mixture was poured into a nitrogen oven and then dioxane and H 2 O were added thereto. After completion of the reaction, the reaction mixture was filtered through Celite, concentrated, and extracted with EA and H 2 O. [ The organic layer was dried with MgSO 4 and concentrated again. Separation and purification through silica gel column chromatography gave the title compound (170.3 mg, 50%).

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 2H), 5.78 (d, 1H, J = 7.9 Hz), 3.90 (s, 3H), 3.47 (s, 2H), 2.82 J = 11.6Hz), 2.00-1.95 (m, 2H), 1.59-1.51 (m, 3H).

Example  138. 3- (5 - ((1- Benzylpiperidine Yl) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-benzylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06565

KY-06539, the title compound (20%) was obtained.

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 2H), 3.97 (s, 1H), 3.07 (s, 2H), 2.04 (d, s, 3H), 1.82 (s, 2H), 1.25 (s, 1H).

Example  139. methyl  3- (5 - ((Piperidin-4-ylmethyl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 3- (5 - (( piperidine -4- ylmethyl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06566

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 remaining solvent was removed under high vacuum to quantitatively yield the title compound.

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).

Example  140. 3- (5 - ((Piperidin-4- Yl methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06567

The ester compound (150 mg, 0.26 mmol) and THF / H 2 O / MeOH mixed solvent were added to a 20 mL vial and stirred. LiOH.H 2 O (109.1 mg, 2.6 mmol) was added thereto, and the reaction was allowed to proceed at room temperature for 18 hours. After completion of the reaction, 1N HCl was added to adjust the pH to 2 to 3, and the mixture was extracted with IPA (isopropyl alcohol) / CHCl 3 in the water layer. The organic layer was dried over MgSO 4 and concentrated to give the title compound (163 mg).

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, 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 Hz), 1.38 (d, 2H, J = 11.1 Hz).

Example  141. methyl  3- (5 - (((1- Benzoylpiperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- benzoylpiperidine -4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06568

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 the mixture was reacted at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with an EA / H 2 O mixed solvent and dried with MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (84%).

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 m, 4H).

Example  142. 3- (5 - (((1- Benzoylpiperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06569

7 mL vial methyl 3- (5 - (((1-benzoyl-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate (63 mg, 0.14 mmol), THF / H 2 O / MeOH mixed solvent was added thereto and stirred. LiOH 占2 2O (28.5 mg, 0.68 mmol) was added thereto, followed by reaction at room temperature overnight. After the reaction was completed, 1 N HCl was added to adjust the pH to 2 to 3, and extraction was performed using EA and H 2 O. [ The organic layer was dried with MgSO 4 and concentrated and the solid was filtered off to give the title compound (87%).

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, 3H), 1.22-1. 14 (m, 2H).

Example  143. methyl  3- (5 - (((1- ( Phenylcarbamoyl ) ≪ / RTI > piperidin-4-yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- ( phenylcarbamoyl ) piperidine -4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06570

KY-06568 to give the title compound (98%).

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), 3.01 (s, 2H), 2.92 (d, 3H, J = 11.9 Hz), 1.86 (t, 3H, J = 13.2 Hz).

Example  144. 3- (5 - (((1 - ((1 - ((2- phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06571

KY-06569 to give the title compound (75%).

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 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 , 2H).

Example  145. methyl  3- (5 - (((1- Tosyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- tosylpiperidine -4- yl ) methyl) carbamoyl ) thiazole -2-yl) benzoate; KY-06572

KY-06568 to give the title compound (92%).

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- 2H, J = 6.4 Hz), 2.24 (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).

Example  146. 3- (5 - (((1- Tosyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06573

KY-06569, the title compound (97%) was obtained.

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), (M, 3H), 7.43 (d, 2H, J = 8.0 Hz), 3.65-3.58 (m, 3H), 3.12 (t, 2H, J = 2H), 1.27-1.14 (m, 2H), 2.39 (s, 3H) m, 2H).

Example  147. methyl  3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -5- (trifluoromethyl) benzoate (methyl 3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoate; KY-06574

KY-06545 to give the title compound (21%).

1 H NMR (300 MHz, CDCl 3 )? 8.50 (s, IH), 8.23 (s, IH), 8.14 (s, IH), 8.06 J = 7.7 Hz, 2H), 7.54-7.37 (m, 4H), 7.01 (s, 1H), 3.97 (s, 3H).

Example  148. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) - (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoic acid; KY-06575

KY-06546 to give the title compound (98%).

1 H NMR (300 MHz, DMSO)? 13.60 (s, IH), 10.65 (s, IH), 9.27 (s, IH), 8.60 (s, IH), 8.45 (s, IH), 7.91-7.87 J = 7.0 Hz, 1H), 7.17 (s, 1H), 7.62 (t, J = 7.5 Hz, 2H).

Example  149. methyl  3- Chloro -5- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole Carboxamido) benzoate (methyl 3- chloro -5- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate; KY-06576

The title compound (32%) was obtained by the same procedure as KY-06545.

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 , 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).

Example  150. 3-Chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid; KY-06577

KY-06546 to give the title compound (97%).

1 H NMR (300 MHz, DMSO)? 13.41 (s, 1H), 10.51 (s, 1H), 9.24 J = 7.8 Hz, 1H), 7.17 (d, J = 3.2 Hz, 1H), 7.64-7.59 (m, 3H), 7.44 (t, J = 7.8 Hz,

Example  151. methyl  3- Bromo -5- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole Carboxamido) benzoate (methyl 3- bromo -5- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate; KY-06578

The title compound (33%) was obtained by the same procedure as KY-06545.

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 (s, 3 H).

Example  152. 3-Bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole-4-carboxamido) - (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid; KY-06579

KY-06546 to give the title compound (98%).

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 J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.61 (t, J = 7.8 Hz, 2H).

Example  153. methyl  2- (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Phenyl) acetate (methyl 2- (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetate; KY-06580

KY-06545 to give the title compound (79%).

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, IH), 7.08 (d, J = 7.6 Hz, IH) .

Example  4- (4-carboxamido) phenyl) acetic acid (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetic acid; KY-06581

KY-06546 to give the title compound (96%).

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).

Example  155. methyl  (2- (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Phenyl) acetyl) -L-tryptophanate (methyl (2- (3- (3- (5- chlorothiophen -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophanate; KY-06582

The title compound (70%) was obtained by the same procedure as KY-06545.

1 H NMR (300 MHz, DMSO)? 10.85 (s, IH), 10.16 (s, IH), 9.17 (s, IH), 8.55 (d, J = 7.2 Hz, 1H), 7.90-7.87 ), 7.62-7.57 (m, 4H), 7.49 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.34 J = 7.7 Hz, 1H), 7.13 (s, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.01-6.92 (s, 3H), 3.48 (s, 2H), 3.13 (qd, J = 7.3,29.3 Hz, 2H).

Example  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-06546 to give the title compound (21%).

1 H NMR (300 MHz, DMSO)? 10.82 (s, IH), 10.16 (s, IH), 9.17 (s, IH), 8.35 (d, J = 7.5 Hz, 1H), 7.90-7.87 ), 7.62-7.57 (m, 4H), 7.53 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.33 J = 7.7 Hz, 1H), 7.12 (s, 2H), 7.05 (t, J = 7.3 Hz, 1H), 7.00-6.91 (s, 2 H), 3.22 - 3.01 (m, 2 H).

Example  157. Ethyl 3- (3- (5- Chlorothiophene Yl) -4- ( Phenylcarbamoyl ) -1H- Pyrazole -1-yl) benzoate (ethyl 3- (3- (5- chlorothiophen -2- yl )-4-( phenylcarbamoyl ) -1H-pyrazol-1-yl) benzoate); KY-06584

The title compound (70%) was obtained by the same procedure as KY-06545.

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, J = 7.9 Hz, 2H), 7.50 (d, J = 4.1 Hz, 1H), 7.39 (t, J = 7.8 Hz, , 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).

Example  158. 3- (5-Chlorothiophen-2-yl) -4- (phenylcarbamoyl) -lH-pyrazol- yl) -4- (phenylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid; KY-06585

KY-06546 to give the title compound (96%).

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 = 3.9 Hz, 1 H), 7.13 (t, J = 7.4 Hz, 1 H).

Example  159. Ethyl 3- (4 - ((3- Chlorophenyl ) Carbamoyl ) -3- (5- Chlorothiophene Yl) -lH-pyrazol-1-yl) benzoate (ethyl 3- (4 - ((3- klorophenyl ) carbamoyl ) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate; KY-06586

0.0 > KY-06545 < / RTI > to give the title compound.

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), (S, 1H), 7.01 (s, 1H), 4.44 (q, J = 7.3 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H).

Example  160. 3- (4 - ((3-Chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -lH-pyrazol- 3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid; KY-06587

KY-06546 to give the title compound (87%).

1 H NMR (300 MHz, DMSO) [delta] 13.42 (s, IH), 10.37 (s, IH), 9.34 ), 7.98 (d, J = 7.6 Hz, 1H), 7.93 (d, J = = 8.7 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.21-7.16 (m, 2H).

Example  161. Ethyl 3- (3- (5- Chlorothiophene Yl) -4 - ((3- Phenoxyphenyl ) Carbamoyl ) -LH-pyrazol-l-yl) benzoate (ethyl 3- (3- (5- chlorothiophen -2- yl ) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate; KY-06588

KY-06545 to give the title compound (78%).

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 J = 8.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.45-7.36 (m, 3H) (M, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.79 (dd, J = 2.2,7.9 Hz, J = 7.1 Hz, 3H).

Example  162. 3- (3- (3-Chlorothiophen-2-yl) -4 - 5-chlorothiophen-2-yl) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid; KY-06589

KY-06546 to give the title compound (53%).

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 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).

Example  163. methyl  (3- (5 - ((3- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) Benzoyl ) -L- Tryptophanate (methyl (3- (5 - ((3- 펜oxyphenyl ) carbamoyl ) thiazole -2- yl ) benzoyl ) -L-tryptophanate); KY-06590

KY-06542 to give the title compound (95%).

1 H NMR (300 MHz, CDCl 3 )? 8.76 (d, IH, J = 1.9 Hz), 8.56 (s, (m, 2H), 7.42 (d, 1H, J = 2.4 Hz), 7.34-7.30 (m, 1H, J = 6.1 Hz), 3.52-3.37 (m, 2H), 2.79 (s, 3H), 7.13-7.02 (m, 7H), 6.83-6.79

Example  164. (3- (5 - ((3- Phenoxyphenyl ) Carbamoyl ) Thiazol-2-yl) Benzoyl ) -L-tryptophane ((3- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -L-tryptophan; KY-06591

KY-06539 to give the title compound (62%).

1 H NMR (300 MHz, DMSO)? 10.83 (s, IH), 10.55 (s, IH), 8.99 (d, IH, J = 7.8 Hz), 8.70 J = 7.7 Hz), 7.98 (d, 1H, J = 7.8 Hz), 7.62 (t, 2H, J = 7.3 Hz), 7.54 (d, (M, 2H), 7.38 (m, 4H), 7.32 (d, 1H, J = 8.0 Hz), 7.21-7.15 1H, J = 5.1 Hz), 3.37-3.20 (m, 2H).

Example  165. methyl  3- (5 - (((1- Acetyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- acetylpiperidine -4- yl ) methyl) carbamoyl ) thiazole -2-yl) benzoate; KY-06592

To the 20 mL vial was added piperidine compound (100 mg, 0.18 mmol), TFA (2.17 mmol, 0.3 mL) and DMA (2.8 mL) and stirred. Acetyl chloride (0.22 mmol, 15 μL) was added to the reaction solution, and the mixture was reacted at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with an EA / H 2 O mixed solvent and dried with MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (54 mg, 75%).

1 H NMR (300 MHz, CDCl 3 )? 8.55 (d, IH, J = 6.7 Hz), 8.19-8.11 (m, 3H), 7.49 2H), 4.07 (t, 1H, J = 6.1 Hz), 3.93 (s, 3H), 3.68-3.58 (m, 2H), 3.25-3.22 2.91 (s, 3H), 2.08-2.01 (m, 4H).

Example  166. methyl  3- (5 - (((1- Acetyl piperidine -2 days) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- acetylpiperidine -2- yl ) methyl) carbamoyl ) thiazole -2-yl) benzoate; KY-06593

KY-06592 to give the title compound (71%).

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).

Example  167. methyl  3- (5 - ((1-acetylpiperidin-4-yl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 3- (5 - ((1- acetylpiperidine -4- yl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06594

KY-06592 to give the title compound (80%).

1 H NMR (300 MHz, CDCl 3 )? 8.60 (d, IH, J = 11.5 Hz), 8.27-8.05 (m, 3H), 7.54 J = 9.0 Hz), 4.66 (d, 1H, J = 14.2 Hz), 4.21 (d, 1H, J = 11.3 Hz), 3.95 (d, 1H, J = 12.9 Hz), 2.21-1.97 (m, 5H), 1.47-1.24 (m, 3H).

Example  168. methyl  3- (5 - ((1-acetylpiperidin-3-yl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 3- (5 - ((1- acetylpiperidine -3- yl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06595

KY-06592, the title compound (79%) was obtained.

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 2H), 2.99 (d, 1H, J = 6.0 Hz), 2.92 (s, 3H) (s, 3H), 2.15-1.88 (m, 5H).

Example  169. 3- (5 - (((1- Acetyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-acetylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06596

KY-06592 to give the title compound (47%).

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).

Example  179. 3- (5 - (((1- Acetyl piperidine -2 days) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-acetylpiperidin-2- yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06597

The title compound (29%) was obtained by the same procedure as KY-06539.

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).

Example  171. 3- (5 - ((1- Acetyl piperidine Yl) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-acetylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06598

The title compound (36%) was obtained by the same procedure as KY-06539.

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).

Example  172. 3- (5 - ((1- Acetyl piperidine -3 days) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-acetylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06599

KY-06539 to give the title compound (68%).

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).

Example  173. methyl  3- (5 - (((1- Benzoylpiperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- benzoylpiperidine -4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06600

(5 - ((piperidin-4-ylmethyl) carbamoyl) thiazol-2-yl) benzoate was added to a 20 mL vial. thiazol-2-yl) benzoate TFA salt (100 mg, 0.18 mmol), TEA (2.17 mmol, 0.3 mL) and DMA (2.8 mL). Benzoyl chloride (0.22 mmol) was added to the reaction solution, and the mixture was reacted at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with an EA / H 2 O mixed solvent and dried with MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (66%).

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 ( 1H, J = 13.9 Hz), 3.22 (d, 2H, J < RTI ID = 0.0 > = 14.6 Hz), 1.90-1.46 (m, 6H).

Example  174. methyl  3- (5 - (((1- ( Phenylcarbamoyl ) ≪ / RTI > piperidin-4-yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- ( phenylcarbamoyl ) piperidine -4-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06601

KY-06600 to give the title compound (45%).

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 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).

Example  175. methyl  3- (5 - (((1- Tosyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- tosylpiperidine -4- yl ) methyl) carbamoyl ) thiazole -2-yl) benzoate; KY-06602

KY-06600 to give the title compound (54%).

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 = 7.8Hz), 7.28 (d, 3H, J = 4.7Hz), 7.15-7.05 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).

Example  176. 3- (5 - (((1- Benzoylpiperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-benzoylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06603

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. Acyl chloride (0.22 mmol) was added to the reaction solution, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with an EA / H 2 O mixed solvent and dried with MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (24%).

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- 2H), 3.18-3.03 (m, 2H), 3.03-2.89 (m, 2H), 3.94 (s, 3H) 2H), 2.23-2.05 (m, 2H).

Example  177. Preparation of 3- (5 - (((1- (4-fluorophenyl) piperazin-4-yl) methyl) carbamoyl) thiazol- phenylcarbamoyl) piperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06604

KY-06603 to give the title compound (21%).

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 , 1.84-1.32 (m, 5H).

Example  178. 3- (5 - (((1- Tosyl piperidine Yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-tosylpiperidin-4-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06605

KY-06603 to give the title compound (49%).

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, ), 2.75-2.58 (m, 2H), 2.52-2.45 (m, 1H), 1.83-1.51 (m, 5H).

Example  179. methyl  3- (5 - (((1- Benzoylpiperidine -2 days) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- benzoylpiperidine -2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06606

KY-06539 to give the title compound (73%).

1 H NMR (300 MHz, DMSO) [delta] 13.33 (s, IH), 8.92 (s, IH), 8.44 (s, IH), 8.33-8.17 (m, 1H), 1.63-1.54 (m, 6H), 1.54-1.17 (m, 1H), 7.37-7.27 , 2H).

Example  180. methyl  3- (5 - (((1- ( Phenylcarbamoyl ) ≪ RTI ID = 0.0 > piperidin-2-yl) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- ( phenylcarbamoyl ) piperidine -2-yl) methyl) carbamoyl) thiazol-2-yl) benzoate; KY-06607

KY-06539 to give the title compound (44%).

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), 2H, J = 7.8 Hz), 6.83 (d, 1H, J = 7.8 Hz) 1H, J = 7.3 Hz), 4.43 (d, 1H, J = 8.1 Hz), 4.00 1H, J = 13.5Hz), 1.80-1.52 (m, 6H).

Example  181. methyl  3- (5 - (((1- Tosyl piperidine -2 days) methyl ) Carbamoyl ) Thiazol-2-yl) benzoate (methyl 3- (5 - (((1- tosylpiperidine -2- yl ) methyl) carbamoyl ) thiazole -2-yl) benzoate; KY-06608

KY-06539 to give the title compound (59%).

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 ( 1H, J = 7.9 Hz, 1H), 8.08 (t, 1H, J = 1.4 Hz), 7.67 (t, 3H, J = 7.8 Hz), 7.28 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).

Example  182. 3- (5 - (((1- Benzoylpiperidine -2 days) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-benzoylpiperidin-2- yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06609

KY-06539 to give the title compound (51%).

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 ( 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 5H).

Example  Yl) benzoic acid (3- (5 - (((1 - ((2- (4-fluorophenyl) phenylcarbamoyl) piperidin-2-yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06610

KY-06539 to give the title compound (34%).

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 ( 2H, J = 7.7 Hz), 6.92 (d, 1H, J = 7.7 Hz), 7.67 (t, 1H, J = 7.9 Hz), 7.43 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).

Example  184. 3- (5 - (((1- Tosyl piperidine -2 days) methyl ) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-tosylpiperidin-2- yl) methyl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06611

KY-06539 to give the title compound (72%).

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), 1H, J = 7.8 Hz), 7.69-7.56 (m, 3H), 7.45 (d, 2H, J = 7.9 Hz), 3.50 1H, J = 6.6 Hz), 2.40 (s, 3H), 2.25 (t, 1H, J = 11.2 Hz), 2.16-1.96 , 1.46 (d, 1 H, J = 12.6 Hz).

Example  185. tert -Butyl (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido (5-chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) -5-fluorobenzoyl) fluorobenzoyl) -L-phenylalaninate); KY-06612

KY-06545 to give the title compound (72%).

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 (D, J = 8.9 Hz, 2H), 7.38-7.28 (m, 2H) 1H), 6.97 (d, J = 3.9 Hz, 1H), 6.74 (d, J = 7.8 Hz, , ≪ / RTI > 1.43 (s, 9H).

Example  186. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) - (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-phenylalanine; KY-06613

To a 25 mL round bottom flask was added tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) -5- fluorobenzoyl) -L-phenylalaninate (100 mg), MC (2 mL) and TFA (0.5 mL) were added thereto, followed by stirring at room temperature for 3 hours. TFA and solvent were removed to give the title compound (98 mg, 88%).

1 H NMR (300 MHz, DMSO)? 12.84 (s, IH), 10.51 (s, IH), 9.22 (s, IH), 8.82 (d, J = 8.2 Hz, 1H), 7.93-7.88 ), 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 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).

Example  187. methyl  (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5- chlorothiophen- 5-fluorobenzamido) propanoate (methyl (S) -3- (4- ( tert - butoxy ) phenyl) -2- (3- (3- (5- chlorothiophen -2- yl -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzamido) propanoate; KY-06614

KY-06545 to give the title compound (59%).

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 J = 8.5 Hz, 2H), 7.01 (d, J = 3.9 Hz, 2H), 7.05-7.50 (m, 3H), 7.43-7.39 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 7.7 Hz, J = 6.7, 21.6 Hz, 2H), 1.34 (s, 9H).

Example  188. (S) -3- (4- (tert-Butoxy) phenyl) -2- (3- (3- (5-chlorothiophen- -5-fluorobenzamido) propanoic acid ((S) -3- (4- (tert-butoxy) phenyl) -2- (3- yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzamido) propanoic acid; KY-06615

Acetonitrile (3 mL) and H 2 O (1 mL) were added to the KY-06614 compound (180 mg, 0.27 mmol) and NaOH (54 mg, 1.35 mmol, 5.0 eq.) And the mixture was stirred at room temperature for 3 hours. 1N HCl was added to adjust the pH to 3, distilled water was added, and then extracted with EtOAc. By drying the organic solvent with MgSO 4 and the solvent removed to give the title compound (99%).

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- 7.8 (m, 3H), 7.60 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H) ), 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 , ≪ / RTI > 1H), 1.20 (s, 9H).

Example  189. (3- (5- (Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L- - (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-tyrosine; KY-06616

KY-06613 to give the title compound (96%).

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), J = 8.0 Hz, 2H), 7.46-7.40 (m, 2H), 7.17 (d, J = 4.0 Hz, 1H), 7.11 (Dd, J = 10.5, 13.8 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.57-4.52 1H).

Example  190. tert -Butyl (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido 5-fluorobenzoyl) -L-valerate (tert-butyl (3- (3- (5-chlorothiophen- -L-valinate); KY-06617

KY-06545 to give the title compound (71%).

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 (M, 2H), 7.25-7.24 (m, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.73 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).

Example  191. (3- (3- (5- Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4- carboxamido) -5- fluorobenzoyl) -L- - (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L valine); KY-06618

KY-06613 to give the title compound (87%).

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 J = 7.4 Hz, 2H), 7.54 (d, J = 9.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H) (D, J = 5.0, 6.6 Hz, 6H). 7.17 (d, J = 4.0 Hz, 1H), 4.30 (t, J = 7.5 Hz, 1H), 2.26-2.14

Example  192. tert -Butyl (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl ) -L-isoleucinate); KY-06619

KY-06545 to give the title compound (74%).

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 (D, J = 8.1 Hz, 1H), 7.31 (d, J = 1H), 1.49 (s, 9H), 1.34-1.21 (m, 2H), 1.01-0.97 (m, 6H) .

Example  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-06613 to give the title compound (88%).

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 J = 7.4 Hz, 1H), 7.91-7.88 (m, 4H), 7.61 (t, J = 7.9 Hz, 2H), 7.53 1H), 1.34-1.24 (m, 1H), 7.17 (d, J = 4.0 Hz, , 0.95 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H).

Example  194. methyl  (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -5-fluorobenzoyl) -L-lucinate (methyl (3- (3- (5- chlorothiophen -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-leucinate; KY-06621

The title compound (70%) was obtained by the same procedure as KY-06545.

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 (D, J = 8.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.20 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).

Example  195. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L- - (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-leucine; KY-06622

KY-06615 to give the title compound (78%).

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 ), 1.18-1.57 (m, 3H), 0.91 (dd, J = 6.1, 12.3 Hz, 6H).

Example  196. methyl  (3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -5-fluorobenzoyl) -L-methionate (methyl (3- (3- (5- chlorothiophen -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methioninate; KY-06623

KY-06545 to give the title compound (74%).

1 H NMR (300 MHz, CDCl 3 )? 8.53 (s, IH), 8.11 (s, IH), 7.81-7.74 (m, 3H), 7.53-7.48 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).

Example  197. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L- - (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) -L-methionine; KY-06624

KY-06615 to give the title compound (97%).

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 Hz, < / RTI > 1H), 2.63-2.50 (m, 4H), 2.06 (s, 3H).

Example  198. methyl  3- (5 - ((1- Benzoylpiperidine Yl) Carbamoyl ) Thiazol-2-yl) Benzoate (methyl 3- (5 - ((1- benzoylpiperidine -4- yl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06625

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 overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with an EA / H 2 O mixed solvent and dried with MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (56%).

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, IH, J = 7.6 Hz), 4.63 (s, IH), 4.11 (s, 2H), 3.82 m, 5H), 1.11 (s, 1H).

Example  199. methyl  3- (5 - ((1-tosylpiperidin-4-yl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 3- (5 - ((1- tosylpiperidine -4- yl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06626

KY-06625 to give the title compound (22%).

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 2H), 2.68 (m, 1H), 3.88 (d, 2H, J = (m, 2H), 2.45 (s, 3H), 2.37 (d, 1H, J = 11.4 Hz), 2.15-1.96 (m, 2H), 1.86-1.67 (m, 2H).

Example  200. methyl  3- (5 - ((1- Benzoylpiperidine -3 days) Carbamoyl ) Thiazol-2-yl) Benzoate (methyl 3- (5 - ((1- benzoylpiperidine -3- yl ) carbamoyl ) thiazole -2-yl) benzoate; KY-06627

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 overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with an EA / H 2 O mixed solvent and dried with MgSO 4 . Separation and purification by silica gel column chromatography gave the title compound (53%).

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 1H), 2.86 (s, 1H), 2.79 (s, 3H), 3.74-3.54 (m, , 3H), 2.00 - 1.74 (m, 2H).

Example  201. methyl  3- (5 - ((1-tosylpiperidin-3-yl) carbamoyl) Thiazol-2-yl) Benzoate (methyl 3- (5 - ((1- tosylpiperidine -3- yl ) carbamoyl ) thiazole -2- yl ) benzoate); KY-06628

KY-06627 to give the title compound (33%).

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, (D, 1H, J = 7.8 Hz), 7.35 (d, 2H, J = 7.9 Hz), 6.56 1H, J = 11.9 Hz), 3.44-3.28 (m, 1H), 2.93-2.83 (m, 1H), 2.67 , ≪ / RTI > 2H), 1.72 (d, 2H, J = 4.8 Hz).

Example  202. 3- (5 - ((1- Benzoylpiperidine Yl) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-benzoylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06629

KY-06539 to give the title compound (95%).

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 1H), 8.08 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.51-7.34 ), 3.61 (s, IH), 3.18 (s, IH), 2.98 (s, IH), 1.99 (s, 2H), 1.50 (s, 2H).

Example  203. 3- (5 - ((1- Tosyl piperidine Yl) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-tosylpiperidin-4-yl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06630

KY-06539 to give the title compound (43%).

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 2H, J = 7.8 Hz), 4.24-3.97 (m, 3H), 2.92 (d, (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).

Example  204. 3- (5 - ((1- Benzoylpiperidine -3 days) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-benzoylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06631

KY-06539 to give the title compound (80%).

1 H NMR (300 MHz, DMSO)? 13.32 (s, 1H), 8.60 (d, 3H, J = 10.2 Hz), 8.21 1H), 3.67 (s, IH), 3.06 (s, 1H), 7.67 (s, ), 2.91-2.64 (m, 1H), 2.00 (d, 1H, J = 11.0Hz), 1.84-1.45 (m, 3H).

Example  205. 3- (5 - ((1- Tosyl piperidine -3 days) Carbamoyl ) Thiazol-2-yl) benzoic acid; (3- (5 - ((1-tosylpiperidin-3-yl) carbamoyl) thiazol-2-yl) benzoic acid; KY-06632

KY-06539 to give the title compound (69%).

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), 1H, J = 7.4 Hz), 7.56 (d, 1H, J = 7.9 Hz), 4.03 (s, 1H), 3.76 (d, 1H, J = (M, 3H), 1.94 (d, 2H, J = 11.9 Hz), 1.67 (d, 1H, J = 11.2 Hz), 1.44-1.35 (m, 1H).

Example  206. methyl  3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -4-fluorobenzoate (methyl 3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoate; KY-06633

The acyl chloride compound (213 mg) was added to a 25 mL round bottom flask and dissolved in MC (1 mL), followed by stirring at 0 ° C for 30 minutes. To a 7 mL vial was dissolved methyl 3-amino-4-fluorobenzoate (134 mg) in MC (2 mL), DIPEA (0.17 mL) was added and stirred. The mixture in a 7 mL vial in an ice bath at 0 < 0 > C was added dropwise over 20 minutes to a 25 mL round bottom flask. Then, the mixture was stirred at room temperature for 14 hours and refluxed for 2 days. EtOAc was added to the reaction mixture, washed with distilled water, dried over MgSO 4 , and the solvent was removed. The residue was subjected to silica gel column chromatography (EA: hexane = 1: 2 - > EA) to obtain the title compound (81 mg, 27%) as a yellow rh body compound.

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 = 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).

Example  207. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1 H-pyrazole-4-carboxamido) chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoic acid; KY-06634

KY-06615 to give the title compound (99%).

1 H NMR (500 MHz, DMSO)? 10.17 (s, 1H), 9.24 (s, 1H), 8.38 (dd, J = 1.7, 7.2 Hz, 1H), 7.91-7.89 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).

Example  208. methyl  3- (3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -4- (trifluoromethyl) benzoate (methyl 3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoate; KY-06635

The acyl chloride compound (213 mg) was added to a 25 mL round bottom flask, toluene (1 mL) was added, and the mixture was stirred at 0 ° C for 30 minutes. To the 7 mL vial was added methyl 3-amino-4- (trifluoromethyl) benzoate (134 mg), toluene (2 mL) and Et 3 N (0.14 mL) and the mixture was stirred. The mixture in a 7 mL vial at 0 < 0 > C was added dropwise over 20 minutes to a 25 mL round bottom flask. Thereafter, the mixture was stirred at room temperature for 1 hour and refluxed for 1 day. EtOAc was added to the reaction mixture, washed with distilled water, dried over MgSO 4 , and the solvent was removed. The residue was separated by silica gel column chromatography (EA: hexane = 1: 4) to obtain the title compound (16 mg, 5%) as a yellowish solid.

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).

Example  209. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) - (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoic acid; KY-06636

KY-06615 to give the title compound (88%).

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, 1 H).

Example  210. tert -Butyl 3- (3- (5- Chlorothiophene Yl) -1- (4- ( Methoxycarbonyl ) Phenyl) -lH-pyrazole-4-carboxamido) benzoate (tert-butyl 3- (3- (5- chlorothiophen -2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoate; KY-06637

KY-06542 to give the title compound (69%).

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 ( 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).

Example  211. 4- (4 - ((3- (tert- butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen- 4- (4 - ((3- (tert-butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid; KY-06638

KY-06539 to give the title compound (86%).

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), 1H, J = 7.6 Hz), 7.50 (t, 1H, J = 7.6 Hz), 8.09 (d, = 7.9 Hz), 7.18 (t, 1H, J = 5.6 Hz), 1.56 (s, 9H).

Example  212. Preparation of 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -lH-pyrazole- 4- carboxamido) benzoic acid 3- 3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H-pyrazole-4-carboxamido) benzoic acid; KY-06639

The 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 and reacted at room temperature. After 24 hours, TLC was used to confirm that the starting material remained. Further, the same amount of TFA was added, and the reaction was further continued at room temperature for 24 hours. After completion of the reaction, the solvent was concentrated and dried under high vacuum to give the title compound (196.7 mg, 89%).

1 H NMR (300 MHz, DMSO) 隆 13.00 (s, 1H), 10.45 (s, 1H), 9.35 (s, 1H), 8.36 (d, 1H, J = 2.8 Hz), 8.24-7.92 1H), 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,

Example  213. 3- (1- (4-Carboxyphenyl) -3- (5-chlorothiophen-2-yl) -lH-pyrazole- carboxyphenyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid; KY-06640

KY-06539 to give the title compound (80%).

1 H NMR (300 MHz, DMSO) 隆 13.09 (s, IH), 10.45 (s, IH), 9.34 7.7 (d, 1H, J = 7.7Hz), 7.71 (d, 1H, J = , J = 4.0 Hz).

Example  214. methyl  2-yl) carbamoyl) phenyl) carbamoyl) -3- (4-fluoropyridin-2-yl) 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

To a 7 mL vial was added an 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, DMF was added and reacted at room temperature for 24 hours. When the reaction was confirmed by TLC and the starting material remained, the reaction was continued for 24 hours. After completion of the reaction, the reaction 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%).

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 = 8.0 Hz), 4.68 (d, 1H, J = 7.9 Hz), 3.96 (s, 3H), 1.99 6H, J = 6.9 Hz).

Example  215. 4- (4 - ((3 - ((2S, 3S) -l- (tert-butoxy) -3-methyl- 1- oxopentan- 2- yl) carbamoyl) phenyl) (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-06539 to give the title compound (94%).

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 ( J = 8.7 Hz), 7.92 (d, 2H, J = 15.8 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.47 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 0.81 (m, 6 H).

Example  Carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazolo [3,4- 2-methylbutyl) carbamoyl) phenyl) carbamoyl) -3- (5-chlorothiophene-1 -yl) -2-yl) -1H-pyrazol-1-yl) benzoic acid; KY-06643

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 under high vacuum and solidified, and the resulting solid was filtered to give the title compound (65.2 mg, 87%).

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 1H, J = 7.8 Hz), 7.47 (t, 1H, J = 7.8 Hz), 7.16 (s, 1H), 4.34 , ≪ / RTI > 2H), 1.10-0.71 (m, 6H).

Example  217. methyl  3 - ((3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Methyl) -4-fluorobenzoate (methyl 3 - ((3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoate; KY-06644

KY-06545 to give the title compound (77%).

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 J = 7.9 Hz, 2H), 7.44-7.35 (m, < RTI ID = 0.0 & , 2H), 7.12 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H).

Example  4-Carboxamido) methyl) -4-fluorobenzoic acid (3 - ((3 (5-chlorothiophen- - (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoic acid; KY-06645

The title compound (92%) was obtained by the same method as KY-06615.

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) 1H), 7.35 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.55 (d, J = 5.7 Hz,

Example  219. tert - butyl (3 - ((3- (5- Chlorothiophene Yl) -1-phenyl-1H- Pyrazole 4-carboxamido) methyl) -4-fluorobenzoyl) -L-isorucinate (tert- pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-isoleucinate; KY-06646

KY-06545 to give the title compound (85%).

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 J = 7.9 Hz, 2H), 7.92 (d, J = 7.9 Hz, 1H), 7.92-7.86 J = 7.4 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.56 J = 7.4 Hz, 1H), 1.95-1.86 (m, 1H), 1.51-1.43 (m, 1H), 1.39 6.8 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

Example  2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-iso 5-chlorothiophen-2-yl-1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) -L-isoleucine; KY-06647

KY-06613 to give the title compound (93%).

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 ( (d, J = 1.9,7.2 Hz, 1H), 7.93-7.88 (m, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.83 = 7.9 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.11 J = 7.5 Hz, 1H), 1.98-1.86 (m, 1H), 1.55-1.42 (m, 1H), 1.33-1.18 6.8 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

Example  221. methyl  3- (3- (5- Cyanothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -5-fluorobenzoate (methyl 3- (3- (5- cyanothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate; KY-06648

The title compound (34%) was obtained by the same procedure as KY-06545.

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) J = 7.9 Hz, 1H), 7.50-7.44 (m, 2H), 3.90 (s, 3H).

Example  222. 3- (3- (5-Cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoic acid; KY-06649

KY-06615 to give the title compound (99%).

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).

Example  223. methyl  4- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Cyclohexane-1-carboxylate (methyl 4- (3- (5- bromothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylate); KY-06650

KY-06545 to give the title compound (59%).

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 ), 2.61-2.58 (m, 1H), 2.02-1.96 (m, 2H), 1.76-1.25 (m, 6H).

Example  224. 4- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) cyclohexane- bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid; KY-06651

KY-06546 to give the title compound (94%).

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 , ≪ / RTI > 2H), 1.72-1.29 (m, 7H).

Example  225. methyl  ( 1S, 4S ) -4- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole 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-06545 to give the title compound (95%).

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), 1H), 3.63 (s, 3H), 2.63-2.57 (m, 1H), 2.02 (d, J = -1.94 (m, 2H), 1.75-1.48 (m, 6H).

Example  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-06546 to give the title compound (98%).

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), 1H, J = 7.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 3.87 (s, 1H), 2.47 (m, 6 H).

Example  227. methyl  ( 1R, 4R ) -4- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole 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-06545 to give the title compound (93%).

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), 1H), 3.61 (s, 3H), 2.36-2.28 (m, 1H), 1.97 (d, J = (d, J = 10.0 Hz, 4H), 1.52-1.26 (m, 4H).

Example  228. (lR, 4R) -4- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane- , 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxylic acid; KY-06655

KY-06546 to give the title compound (90%).

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 (d, J = 10.0 Hz, 4H), 1.49-1.24 (m, 4H).

Example  229. tert - butyl (( 1S, 4R ) -4- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole 4-carboxamido) cyclohexane-1-carbonyl) -L-isorucinate (tert-butyl ((1S, 4R) -4- (3- (5-bromothiophen- phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucinate; KY-06656

KY-06545 to give the title compound (93%).

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), 1H), 3.43 (s, 1H), 2.43 (s, 1H), 1.90-1.80 (m, (m, 5H), 1.65-1.54 (m, 4H), 1.40 (s, 9H), 1.24-1.16 (m, 2H), 0.87-0.82 (m, 6H).

Example  2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) 1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine (( ); KY-06657

KY-06613 to give the title compound (75%).

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) ), 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).

Example  231. tert - butyl (( 1R, 4S ) -4- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole -4-carboxamido) cyclohexane-1-carbonyl) -L-isoricinate (tert-butyl ((1R, 4S) -4- (3- (5-bromothiophen- phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucinate; KY-06658

The title compound (67%) was obtained by the same procedure as KY-06545.

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), 1H), 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), 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).

Example  1-phenyl-1 H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) 1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine (( ); KY-06659

KY-06613 to give the title compound (91%).

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) 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).

Example  233. Ethyl 4- (3- (5- Bromothiophene Yl) -4 - ((3- Phenoxyphenyl ) Carbamoyl ) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5- bromothiophen -2- yl ) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoate; KY-06660

KY-06542 to give the title compound (63%).

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 ( 1H, J = 7.9 Hz), 4.40 (q, 2H, J = 7.1 Hz), 1.42 (t, 3H, J = 7.0 Hz).

Example  234. Preparation of 4- (3- (5-bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl) -lH-pyrazol- 1- yl) 5-bromothiophen-2-yl) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-1-yl) benzoic acid; KY-06661

KY-06539 to give the title compound (78%).

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 1H), 7.78 (d, 1H, J = 4.0 Hz), 7.60-7.48 (m, 1H), 7.47-7.34 (m, 4H), 7.26 J = 7.3 Hz), 7.10-7.01 (m, 2H), 6.78 (dd, 1H, J = 8.1, 2.4 Hz).

Example  235. methyl  (4- (3- (5- Bromothiophene Yl) -4 - ((3- Phenoxyphenyl ) Carbamoyl (5-bromothiophen-2-yl) -4 - ((3-phenoxyphenyl) carbamoyl) - 1 H- pyrazol-1-yl) benzoyl) -L-alloisorinate -pyrazol-1-yl) benzoyl) -L-alloisoleucinate; KY-06662

KY-06542 to give the title compound (57%).

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 1H, J = 8.5 Hz), 3.78 (s, 3H), 1.72 (d, 2H, J = 1.46 (m, 3H), 0.99-0.97 (m, 6H)

Example  236. 2- (4- (3- (5-Bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl) 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-06539 to give the title compound (79%).

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 J = 7.9 Hz), 7.48-7.35 (m, 3H), 7.26 (s, 1H, J = 7.8 Hz) 1H), 7.17 (t, 1H, J = 6.9 Hz), 7.06 (d, 2H, J = 7.8 Hz), 6.78 1.99 (s, 1H), 1.54 (s, 1H), 1.25 (s, 2H), 1.04-0.81 (m, 6H).

Example  237. methyl  3- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -4-methoxybenzoate (methyl 3- (3- (5- bromothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoate; KY-06664

KY-06542 to give the title compound (30%).

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 (D, 1H, J = 8.4 Hz), 3.90 (s, 3H), 3.82 (s, 3H).

Example  238. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoic acid; KY-06665

KY-06539 to give the title compound (94%).

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), 1H, J = 7.5 Hz), 7.30-7.15 (m, 2H), 3.91 (s, 3H).

Example  239. methyl  (3- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) -4-methoxybenzoyl) -L-isorucinate (methyl (3- (3- (5- bromothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoyl) -L-isoleucinate; KY-06666

KY-06542 to give the title compound (96%).

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 (m, 1H), 6.69 (d, 1H, J = 13.6 Hz), 4.82-4.77 1.22 (m, 2H), 0.99-0.81 (m, 6H).

Example  240. 2- (3- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- methoxybenzamido) -3- 2- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzamido) -3-methylpentanoic acid; KY-06667

KY-06539 to give the title compound (75%).

1 H NMR (300 MHz, DMSO)? 12.50 (s, IH), 9.48 (s, IH), 9.21 (s, IH), 8.30 (s, IH), 7.98-7.74 2H, J = 7.9 Hz), 7.43 (t, 1H, J = 7.7 Hz), 7.24-7.10 (m, 2H), 4.33 (d, 1H, J = 14.7Hz), 1.51 (d, 1H, J = 11.5Hz), 1.37-1.17 (m, 2H), 0.96-0.78 (m, 6H).

Example  241. methyl  ( 1S, 3R ) -3- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole 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-06542 to give the title compound (50%).

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 Hz), 2.01-1.85 (m, 2H), 1.48-1.09 (m, 4H).

Example  242. (lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1-phenyl- lH- 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-06539 to give the title compound (74%).

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 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,

Example  243. methyl  2-(( 1S, 3R ) -3- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole (Methylsulfonyl) -4-carboxamido) cyclohexane-1-carboxamido) -3-methylpentanate (methyl 2 - ((1S, 3R) -3- 1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carboxamido) -3-methylpentanate; KY-06670

KY-06542 to give the title compound (22%).

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 = 1H, J = 7.6 Hz), 7.08 (t, 1H, J = 5.6 Hz), 6.24 (s, 1H), 5.97 2H), 1.30-1. 14 (m, 3H), 3.73 (s, 3H) ), 1.03-0.85 (m, 6H).

Example  244. 2 - ((lS, 3R) -3- (3- (5-Bromothiophen-2-yl) 2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) cyclohexane-1 < / RTI > / RTI > carboxamido) -3-methylpentanoic acid); KY-06671

KY-06539 to give the title compound (67%).

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 ( (t, 1H, J = 3.9 Hz), 4.18 (d, 1H, J = 7.6 Hz), 7.57 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).

Example  245. methyl  4 - ((3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Methyl) cyclohexane-1-carboxylate (methyl 4 - ((3- (5- bromothiophen -2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylate; KY-06672

KY-06542 to give the title compound (55%).

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, IH, J = 5.7 Hz), 6.00 (d, IH, J = 7.4 Hz), 3.67 (s, 3H), 3.27 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).

Example  4-carboxamido) methyl) cyclohexane-1-carboxylic acid (4 - ((3 (S) -2-fluoro- - (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxylic acid; KY-06673

KY-06539 to give the title compound (40%).

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 1H, J = 3.9Hz), 3.11 (t, 2H, J = 6.3Hz), 2.21-2.30 (m, 1H), 7.57 (t, 2H, J = 7.8Hz), 7.44-7.35 2H), 1.11-0.89 (m, 2H), 1.98-1.30 (m, 2H)

Example  247. methyl  (4 - ((3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole -4- Carboxamido ) Methyl) cyclohexane-1-carbonyl) -D-isorucinate (methyl (4 - ((3- (5-bromothiophen- ) methyl) cyclohexane-1-carbonyl) -D-isoleucinate; KY-06674

KY-06542 to give the title compound (85%).

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 2H, J = 7.9 Hz), 4.62 (t, 1H, J = 8.5 Hz), 3.74 (s, 3H), 3.27 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).

Example  248. 2- (4 - ((3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) methyl) cyclohexane- ) -3-methylpentanoic acid (2- (4- (5-bromothiophen-2-yl) -1-phenyl-1H- pyrazole-4- carboxamido) methyl) cyclohexane- methylpentanoic acid); KY-06675

KY-06539 to give the title compound (99%).

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), (M, 1H), 4.12 (q, 1H, J = 6.8 Hz), 3.09 (d, 2H J = 6.3 Hz), 2.23 (t, IH, J = 12.2 Hz), 1.84-1.71 (m, 5H), 1.53-1.09 -0.79 (m, 6H).

Example  249. methyl  ( 1S, 3R ) -3- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole 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-06542 to give the title compound (83%).

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) 1.84 (m, 2H), 1.76-1.61 (m, 4H), 1.30-1.26 (m, 1H).

Example  250. (lS, 3R) -3- (3- (5-Bromothiophen-2-yl) -1-phenyl- lH- 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-06539 to give the title compound (94%).

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 , 7.24 (d, 1H, J = 10.0Hz), 4.09 (s, 1H), 1.98-1.37 (m, 8H).

Example  251. methyl  (( 1R, 3S ) -3- (3- (5- Bromothiophene Yl) -1-phenyl-1H- Pyrazole 4-carboxamido) cyclohexane-1-carbonyl) -D-isorucinate (methyl ((1R, 3S) -3- (5- 1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -D-isoleucinate; KY-06678

KY-06542 to give the title compound (81%).

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 = 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) 6H).

Example  252. ((lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1- phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- 1 -carbonyl) 1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine ((1S, ); KY-06679

KY-06539 to give the title compound (78%).

1 H NMR (300 MHz, DMSO)? 12.53 (s, IH), 9.00 (s, IH), 7.89-7.80 (m, 4H), 7.75-7.49 1H), 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 1.18 (t, 1H, J = 13.2 Hz, 1H), 0.99-0.69 (m, 6H).

Example  253. Ethyl 4- (3- (5- Bromothiophene -2-yl) -4 - ((( 1R, 3S ) -3- ( Methoxycarbonyl ) Cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5- bromothiophen -2-yl) -4 - (((1R, 3S) -3- (methoxycarbonyl) cyclohexylcarbamoyl) -1H-pyrazol-1-yl) benzoate; KY-06680

KY-06542 to give the title compound (94%).

1 H NMR (300 MHz, CDCl 3 )? 8.47 (s, 1H), 8.26-8.10 (m, 2H), 7.87-7.75 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 (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).

Example  254. Preparation of 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3S) -3-carboxycyclohexylcarbamoyl) -lH-pyrazol- 1-yl) benzoic acid 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3S) -3-carboxycyclohexylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid; KY-06681

KY-06539 to give the title compound (90%).

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 (D, 1H, J = 12.5 Hz), 3.94 (s, 1H), 2.35 1.84 (d, 3H, J = 33.4 Hz), 1.50-1.06 (m, 5H).

Example  255. Ethyl 4- (3- (5- Bromothiophene -2-yl) -4 - ((( 1R, 3R ) -3- ( Methoxycarbonyl ) - cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5-bromothiophen- ) cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate; KY-06682

KY-06542 to give the title compound (88%).

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) 2H), 3.81 (s, 3H), 2.40 (s, 1H, J = 7.9 Hz), 7.21-7.06 ), 1.98-1.61 (m, 6H), 1.42 (t, 3H, J = 7.5 Hz), 1.35-1.22 (m, 1H).

Example  256. 4- (3- (5- Bromothiophene -2-yl) -4 - ((( 1R, 3R ) -3- Carboxycyclohexyl ) Carbamoyl) -1H-pyrazol-2-yl) -4 - (((1R, 3R) -3-carboxycyclohexyl) pyrazol-1-yl) benzoic acid); KY-06683

KY-06539 to give the title compound (79%).

1 H NMR (300 MHz, DMSO) 隆 13.05 (s, 2H), 9.10 (s, 1H), 8.18-7.94 (m, 4H), 7.83 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).

Example  257. Ethyl 4- (3- (5- Bromothiophene -2-yl) -4 - ((( 1S, 4S )-4-( Methoxycarbonyl ) Cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5- bromothiophen -2-yl) -4 - (((1S, 4S) -4- (methoxycarbonyl) cyclohexylcarbamoyl) -1H-pyrazol-1-yl) benzoate; KY-06684

KY-06542 to give the title compound (87%).

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- 1H, J = 9.0 Hz), 3.77 (s, 3H), 2.57 (s, 2H) , 1H), 1.84-1.69 (m, 5H), 1.61 (d, 3H, J = 24.3 Hz), 1.49-1.36 (m, 3H).

Example  258. 4- ((1S, 4S) -4-Carbocyclohexyl) carbamoyl) -lH-pyrazol-1-yl) benzoic acid ( 4- (3- (5-bromothiophen-2-yl) -4 - (((1S, 4S) -4-carboxycyclohexylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid; KY-06685

KY-06542 to give the title compound (77%).

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 = 2H), 3.94 (q, 1H, J = 10.9 Hz), 3.68 (d, (s, 3H), 2.34-2.18 (m, 1H), 2.18-1.95 (m, 3H), 1.63 (d, 2H, J = 14.2 Hz), 1.42 1.04 (m, 3 H).

Example  259. Ethyl 4- (3- (5- Bromothiophene -2-yl) -4 - ((( 1R, 4R )-4-( Methoxycarbonyl ) Cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate (ethyl 4- (3- (5-bromothiophen- ) cyclohexyl) carbamoyl) -1H-pyrazol-1-yl) benzoate; KY-06686

KY-06539 to give the title compound (63%).

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 2H, J = 7.9 Hz), 1.65 (d, 6H, J = 34.7 Hz).

Example  260. Preparation of 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 4R) -4-carboxycyclohexylcarbamoyl) -lH-pyrazol- 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 4R) -4-carboxycyclohexylcarbamoyl) -1H-pyrazol-1-yl) benzoic acid; KY-06687

KY-06539 to give the title compound (63%).

1 H NMR (300 MHz, DMSO) 隆 12.55 (s, 2H), 9.18-8.98 (m, 1 H), 8.18-8.06 (m, 3H), 8.02-7.93 J = 3.4 Hz), 7.34-7.19 (m, 1H), 3.88-3.60 (m, 1H), 2.36-2.11 , J = 12.5 Hz).

Example  261. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06688

KY-06533, the title compound (93%) was obtained.

MC: MeOH = 19: 1 → MC: MeOH = 10: 1 93%

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 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).

Example  262. 4- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06689

KY-06533, the title compound (72%) was obtained.

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).

Example  263. 3- (1-Phenyl-3- (5- Sulfothiophene Yl) -1H- Pyrazole -4- Carboxamido (3- (1-phenyl-3- (5-sulfothiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid; KY-06690

To a 7 mL vial was added a sulfonyl chloride compound (50 mg), THF (1 mL), and H 2 O (5 mL), and the mixture was stirred. LiOH (15 mg) was added thereto and stirred at room temperature for 16 hours. The distilled water was then added and washed with ether. Using a 1N HCl align the pH of the aqueous layer with 1, IPA: CHCl 3 = 1 : 3, and extracted with a mixed solvent. The organic layer was dried with MgSO 4 to give the title compound (64%).

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 J = 7.7 Hz, 2H), 7.74 (d, J = 3.7 Hz, 1H), 7.69 7.47 (m, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 3.8 Hz, 1H).

Example  264. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid); KY-06277

To the 20 mL vial was dissolved the ester compound (4.31 mmol, 1.95 g) in THF (6 mL) and stirred. After adding H 2 O (6 mL) and MeOH (3 mL), LiOH (5.0 eq., 904 mg) was added and stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was transferred to a 100 mL round-bottomed flask, and MeOH and THF were removed by a rotary evaporator and washed with a mixed solvent of ether: H 2 O = 1: 2. The pH of the water layer was confirmed to be 8 by litmus paper, and the pH was adjusted to 2 to 3 while adding 1N HCl. The 1N HCl mixture was filtered while washing with hexanes using a sinter. The title compound was obtained as a white solid (64%).

Remove MeOH and THF with a rotavapor. Wash with ether: H20 = 1: 2. The pH of the H2Olayer is checked with a pH test paper, and the pH is adjusted to 2 to 3 with 1N HCl. 1N HCl mixture is washed with a hexane using a sinter and filtered. 83% of a white solid compound can be obtained.

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) J = 7.9 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H).

In addition, the following compounds were further synthesized:

265. Synthesis of phenyl-N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole- -2-yl) -1H-pyrazole-4-carboxamide),

266. 1-Phenyl-3- (thiophen-2-yl) -N- (m-tolyl) -lH-pyrazole- N- (m-tolyl) -1H-pyrazole-4-carboxamide),

267. Synthesis of N- (3-acetylphenyl) -1-phenyl-3 (thiophen-2-yl) - (thiophen-2-yl) -1H-pyrazole-4-carboxamide),

268. Synthesis of N- (4-carbamoylphenyl) -1-phenyl-3- (thiophen-2-yl) 3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide),

269. Methyl (4- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate - (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate),

270. 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) -1H-pyrazole-4-carboxamido) benzoic acid),

271. Preparation of ethyl 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate -yl) -1H-pyrazole-4-carboxamido) benzoate),

272. N, 1-Diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide -4-carboxamide),

273. Synthesis of N- (3-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) 3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide),

274. Synthesis of N- (4-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) 3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide),

275. N- (3-Chlorophenyl) -1-phenyl-3- (thiophen-2-yl) -lH-pyrazole- - (thiophen-2-yl) -1H-pyrazole-4-carboxamide),

276. N- (Benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen- (benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-

277. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),

278. Preparation of 3- (5-chlorothiophen-2-yl) -N, 1 -diphenyl-lH-pyrazole- diphenyl-lH-pyrazole-4-carboxamide),

279. Preparation of ethyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),

280. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),

281. N- (3-Chlorophenyl) -3- (5-chlorothiophen-2-yl) (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4- carboxamide),

282. 3- (5-Chlorothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole- yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

283. N- (Benzo [d] [1,3] dioxol-5-yl) -3- (5- chlorothiophen- (Benzo [d] [1,3] dioxol-5-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H- pyrazole-

284. 3- (5-Chlorothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole- yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

285. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N-propyl-1 H-pyrazole- -N-propyl-1H-pyrazole-4-carboxamide),

286. 3- (5-Chlorothiophen-2-yl) -N- (4-chlorothiophen- cyclopropyl-1-phenyl-1H-pyrazole-4-carboxamide),

287. N- (1-Benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl) -benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H- pyrazole-4- carboxamide),

288. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N- (pyridin- yl) -1-phenyl-N- (pyridin-3-yl) -1H-pyrazole-4- carboxamide),

289. Preparation of 3- (5-chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen- 5-chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen-2-yl) phenyl) -1H-pyrazole-

290. 3- (5-Chlorothiophen-2-yl) -N- (4-morpholinophenyl) -1-phenyl-1H-pyrazole- yl) -N- (4-morpholinophenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

291. Preparation of N- (4- (benzyloxy) phenyl) -3- (5-chlorothiophen-2-yl) phenyl) -3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4- carboxamide),

292. Preparation of ethyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),

293. 3- (5-Bromothiophen-2-yl) -N, 1 -diphenyl-lH- pyrazole- diphenyl-lH-pyrazole-4-carboxamide),

294. 3- (5-Bromothiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole- yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

295. 3- (5-Bromothiophen-2-yl) -N- (3- chlorophenyl) -1-phenyl-1H-pyrazole- ) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

296. 3- (5-Bromothiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole- yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

297. N- (Benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen- (Benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen-2-yl) -1-phenyl-1H- pyrazole-

298. Preparation of 3- (5-methylthiophen-2-yl) -N, 1 -diphenyl-lH-pyrazole- diphenyl-lH-pyrazole-4-carboxamide),

299. Ethyl 3- (3- (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) benzoate (ethyl 3- (3- 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate),

300. 3- (3- (5-Methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),

301. Preparation of N- (3-chlorophenyl) -3- (5-methylthiophen-2-yl) (5-methylthiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamide),

302. Preparation of 3- (5-methylthiophen-2-yl) -N- (4-phenoxyphenyl) yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

303. 3- (5-Methylthiophen-2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole- yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4-carboxamide),

304. N- (Benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen- (Benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen-2-yl) -1-phenyl-1H- pyrazole-

305. Preparation of ethyl 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate (ethyl 3- ] thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,

306. Synthesis of 3- (benzo [b] thiophen-2-yl) -N, 1 -diphenyl-lH-pyrazole- , 1-diphenyl-1H-pyrazole-4-carboxamide),

307. Synthesis of 3- (benzo [b] thiophen-2-yl) -N- (4- phenoxyphenyl) -1-phenyl-1H- pyrazol- -2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H-pyrazole-4- carboxamide),

308. Preparation of 3- (benzo [b] thiophen-2-yl) -N- (3-chlorophenyl) 2-yl) -N- (3-chlorophenyl) -1-phenyl-1H-pyrazole-4- carboxamide),

309. Preparation of 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-lH- pyrazole-4-carboxamido) 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),

310. Preparation of 3- (benzo [b] thiophen-2-yl) -N- (benzo [d] [1,3] dioxol-5-yl) 5-yl) -1-phenyl-1H-pyrazole-4-carboxamide),

311. Preparation of 3- (benzo [b] thiophen-2-yl) -N- (3- phenoxyphenyl) -1- phenyl- lH- pyrazol- -2-yl) -N- (3-phenoxyphenyl) -1-phenyl-1H-pyrazole-4- carboxamide),

312. Synthesis of 3- (benzo [b] thiophen-3-yl) -N, 1 -diphenyl-lH-pyrazole- , 1-diphenyl-1H-pyrazole-4-carboxamide),

Benzo [b] thiophene-3-yl) -1-phenyl-1H-pyrazole- ] thiophen-3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoate,

314. Preparation of 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-lH- pyrazole-4-carboxamido) 3-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),

315. Preparation of 3- (1-phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen- 1-phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen-2-yl) -1H-pyrazole-4- carboxamido) benzoic acid)

316. A method for preparing 3- (3- (5- (3-acetamidophenyl) thiophen-2-yl) (3-acetamidophenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),

317. 3- (3- (5- (2-Fluoro-4- (trifluoromethyl) phenyl) thiophen-2-yl) 2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid),

318. 3- (3- (5- (3-Cyano-4-fluorophenyl) thiophen-2-yl) (3- (5- (3-cyano-4-fluorophenyl) thiophen-2-yl) -1-phenyl-1H- pyrazole-4- carboxamido) benzoic acid)

319. 3- (1-Phenyl-3- (5- (4- (trifluoromethyl) phenyl) thiophen-2-yl) -lH-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-Fluoro-4-methoxyphenyl) thiophen-2-yl) (3-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid; and

321. 3- (3- (5- (4-Carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) - (4-carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid.

In addition, a series of compounds represented by the following general formula (2) were further synthesized.

322. N, 2-diphenylthiazole-5-carboxamide,

323. Methyl 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoate, methyl 4- (5- (phenylcarbamoyl) thiazol-

324. 4- (5- (phenylcarbamoyl) thiazol-2-yl) benzoic acid), 4-

325. Synthesis of methyl 4- (5 - ((3,5-bis (trifluoromethyl) phenyl) carbamoyl) thiazol- trifluoromethyl) phenyl) carbamoyl) thiazol-2-yl) benzoate),

326. N- (3-phenoxyphenyl) -2-phenylthiazole-5-carboxamide), N-

327. N- (4- (1H-imidazol-1-yl) phenyl) -2-phenylthiazole-5-carboxamide -phenylthiazole-5-carboxamide),

328. Methyl 4- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoate),

329. 3- (5 - ((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid, And

330. N- (4-phenoxyphenyl) -2-phenylthiazole-5-carboxamide.

Experimental Example  One: Mineralization (mineralization) and ALP (alkaline 포스화제 ) Experimental Screening

ST2 cells were plated in 24-well plates and mineralized with culture medium containing 10% FBS, 50 [mu] g / mL ascorbic acid and 10 mM beta-glycerophosphate, every 14 days while culturing for 14-18 days . The mineralization was confirmed by Alizarin Red S staining.

When Wnt3a-CM (Wnt3a over-expressing conditioned media) was treated at a volume ratio of 1/3, it was confirmed that the mineralization was increased compared to the control group not treated with Wnt3a-CM. At the same time, it was confirmed that treatment of sclerostin (SOST) at 1/100 volume ratio inhibited the increase of mineralization by Wnt-CM. The compounds of the present invention were co-treated at a concentration of 3 [mu] M in such a manner as described above to confirm their effect on mineralization, and the results are shown in FIGS. 37 and 38.

As shown in Figs. 37 and 38, KY-06234 among the compounds of the present invention was found to have the best activity to restore Wnt-induced mineralization inhibited by SOST.

In order to reduce the long incubation time and / or inter-individual variability of 14-18 days, compounds with primarily good activity were selected through ALP staining.

After treatment under the same conditions as above, it was confirmed whether the active compound could be selected through ALP staining on the 6th day of culturing. As shown in Figure 37, human SOST inhibited induced mineralization by treating Wnt 3a.

ALP activity was quantified by measuring absorbance, and the results for each compound were tabulated (Figure 38). As shown in Fig. 38, KY-06424, KY-06428, KY-06449 and KY-06492 exhibited particularly excellent activity.

The mineralization assay was then performed to evaluate its effectiveness. As shown in Fig. 37, KY-06448, KY-06449, KY-06450 and KY-06492 exhibited particularly excellent effects under the Wnt7 condition although they are not in the Wnt3a condition.

In conclusion, the compounds of the present invention were found to be capable of restoring Wnt-induced ALP induction, mineralization, or both, inhibited by SOST.

Further, the compound of the present invention was injected into an OVX mouse which had lost ovary function and lost its function, and the effect on ALP and mineralization was confirmed. The results are shown in FIGS. 37 and 38, respectively. As shown in FIGS. 37 and 38, KY-06277 showed the effect of restoring the induction of Wnt-induced ALP suppressed by SOST, but the mineralization analysis results showed that the recovery effect in KY-06277, KY-06439 and KY-06525 Respectively.

Experimental Example  2: Luciferase Assay

MC3T3-E1 Top cells stably expressing the TCF / LEF element, a target element of the WNT / beta-catenin pathway, were prepared. Fetal bovine serum (Fetal bovine serum), streptomycin (100 μg / mL) and penicillin (100 U / mL) were inoculated in a cell incubator at 37 ° C. in which 5% ≪ / RTI > containing Alpha MEM. Cells were subcultured periodically for 3 days, and when the compound was dosed at a density of 50,000 cells / well in a 24-well plate one day before treatment and then the next day was 80% confluence, WNT7 conditioning medium, SOST, The low molecular weight compound of the present invention was treated. The next day, the cells were collected, proteins were extracted with a lysis buffer, mixed with luciferin, and then measured with a luminometer. The results are shown in FIG.

Although the activity was reduced to 50% when the antagonistic SOST was added to the Wnt signal system, it was confirmed that 100% was recovered when KY-06003, which had an abrogation effect on the Wnt signal system, was treated in the previous study. In addition, it was confirmed that 100% agrogation effect was apparent also for the newly synthesized low-molecular compounds KY-06424, KY-06425, KY-06426, and KY-06427. Based on these experimental methods, the assay was carried out in the same manner on the novel synthetic low molecular weight compound of the present invention.

Experimental Example  3: ELISA binding and Assay SPR Assay

In WNT signaling, SOST is known to bind to the LRP5 / 6 protein. Thus, by measuring the effect of a low-molecular compound interfering with the binding of LRP5 / 6 protein ALP to a protein conjugated to a 96-well plate coated with the E1 and E2 domains of SOST, the E1 and E2 domains of SOST and the low- The degree of binding was measured and the results are shown in Fig. Further, the binding and dissociation ability of the low-molecular compound to SOST was evaluated through the SPR assay, and the results are shown in Fig.

Experimental Example  4: mouse skull formation

After the mouse was anesthetized, the skin of the head was cut and the skin was closed with a 0.5 mm diameter 3M paper loaded with the compound of the present invention (5 mM, 3 μL) on the skull. After 2 weeks, the mouse skull was incised and fixed with 10% neutral formalin for 2 days. After washing for 1 day, it was put into the demineralized solution and replaced with fresh solution every day for 3 days. Thereafter, 10% neutral formalin was fixed for 1 day and then washed for 1 hour to incise the drug-treated area. To make the paraffin tissue, the tissue process was run for 1 day and then paraffin embedded. Histopathologic evaluation of paraffin-embedded tissues was performed using a tissue sectioner with a thickness of 3 μm and H-E staining and special staining (Masson trichrome). As a result, it was confirmed that compounds such as KY-06277 and KY-06525 showed a skull-forming effect.

Experimental Example  5: OVX  Animal experiment

In order to evaluate the effect of selected low molecular weight compounds on the maintenance of osteoarthritis, OVX mice, which had been surgically removed by ovariectomy and lost their function, were purchased from Japan SLC. The animals were subjected to a purification process for one week at an appropriate temperature and humidity in the laboratory animal room of the Evison Research Center, Evison, Yonsei University. Feed and water were freely consumed. All experimental procedures were carried out in accordance with the safety regulations of the laboratory animal committee of Yonsei Livestock Research Institute.

As a control drug, PTH and Alendronate · Na, which have been proven to be effective in improving osteoporosis, were prepared by dissolving in saline solution. The selected four small molecule compounds were completely dissolved in a mixed solution of (DMSO / Tween80 / PEG400 / DW = 10/3/30/57 (v / v)% volume ratio). The dissolved compounds were injected into the abdominal cavity at 5 mg / kg for 5 weeks each week for 8 weeks. The control drug PTH Alendronate · Na was injected subcutaneously

After the experiment, blood was collected from the eyes of the mice. After autopsy, Tibia, Femur and Spine were removed and stored in formalin solution.

After the end of the animal study, BMD was measured in the right femur using a PIXImus ™ series Densitometer BMD instrument to measure changes in BMD. As a result, SOST inhibitors significantly increased femoral bone mineral density. Was superior to control PTH, and was similar to excess Alendronate treatment group. In order to confirm the dose dependency, 5 mg and 20 mg / Kg of medication were tried, but the maximum bone mineral density (+) was increased at 5 mg / kg, No further dose dependence was observed (Figure 46). This study is a result of the experiment of candidate compound with IP injection and it is considered positive result in terms of the proof of concept of the target.

Experimental Example  6: Micro CT  analysis

The right tibia of the recovered mouse was photographed using SkyScan 1076, a high-performance computerized tomography (CT) apparatus. The images were analyzed using Skyscan CT analyzer software to analyze trabecular and cortical bones. As a result, the results for cortical bone surface area and cortical bone perimeter were found to be effective in both Alendronate and SOST inhibitor treatment groups. There was no difference in% bone volume among the Alendronate and SOST inhibitor groups. There was no difference between the SOST inhibitor groups as well as Alendronate.

These results are consistent with the results of periosteal bone formation in the cortical bone, which is effective in all groups in BMD of the femur, which accounts for about 80% of the cortical bone. In addition, the above results are similar to the result of cortical bone change by Irisin treatment recently published in the paper.

On the other hand, in most of the parameters, Alendronate showed a clear effect on fibrous bone, but SOST inhibitor was not effective, and it was also reported that IRISIN treatment results published in recent articles have no effect.

Claims (14)

Claims 1. A compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure 112018003175975-pat00004

In this formula,
R 1 to R 3 are each independently selected from the group consisting of hydrogen, halogen, -SO 3 H, C 1-4 alkyl, C 6-10 aryl, or two neighboring substituents connected to each other to form a fused Lt; / RTI > heteroaryl,
Wherein said aryl is selected from the group consisting of unsubstituted or 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 H, -CO 2 (C 1-4 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 to 10 membered heteroaryl, 3 to 10 membered heterocycloalkyl, or C 3-10 cycloalkyl,
Wherein said aryl, heteroaryl, heterocycloalkyl and cycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, C 6-10 aryl, (C 6-10 aryl) -oxy, (C 6-10 aryl) - (C 1-4 alkyl) oxy, halogen, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, -COH, -CO C 1-4 alkyl), -CONH 2, -CONH (C 1-4 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 H, (phenyl sulfone) via oxy, and -CONHW 'group either directly or C 1-4 alkylene group with one or more substituents selected from the consisting of Lt; / RTI >
W ' is a protected or unprotected amino acid;
n is an integer from 0 to 3;
Provided that R 1 to R 4 are all hydrogen, n is 0, and R 5 is C 6 aryl substituted with -CONH 2 .
The method according to claim 1,
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 form a thiophene ring to which benzothiophene Lt; / RTI &
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, amino formyl 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 iso-lucine protected or unprotected by methyl;
R 5 is selected from the group consisting of: propyl, cyclopropyl, benzodioxolyl, or unsubstituted or substituted phenyl, pyridinyl, piperidinyl or cyclohexyl,
Wherein phenyl, pyridinyl, piperidinyl and cyclohexyl fact, unsubstituted or benzyl, benzyloxy, morpholinyl, -CONH (CH 2) 2 morpholinyl, -CONH (CHCH 3) CONH ( CH 2) 2 mol Pori 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, sulfo-phenoxy, and -CONHW ' and the substituents may be the same or different,
W 'is tryptophan, alanine, aspartic acid, phenylalanine, tyrosine, valine, isoleucine, leucine or methionine protected or unprotected with methyl or tert-butyl;
n is 0 or 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The compound
1. Synthesis of 1- (4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-
2. Preparation of 1- (4-fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-
3. 3- (1- (4-Fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4- carboxamido) benzenesulfonic acid,
4. Methyl 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
5. Preparation of N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-
6. Preparation of 1- (4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-
7. Preparation of N- (4-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-
8. 3- (1- (4-Fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4- carboxamido) benzoic acid,
9. Preparation of 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,
10. Preparation of methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate,
11. Preparation of (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4- carboxamido) benzoyl)
12. Preparation of methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoyl) -D-alaninate,
13. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl)
14. Preparation of dimethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate,
15. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) benzoyl) -L-aspartic acid,
16. Preparation of 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzenesulfonic acid,
17. Ethyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate,
18. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycine,
19. A pharmaceutical composition comprising 3- (5-chlorothiophen-2-yl) -N- (3- ((2-morpholinoethyl) carbamoyl) phenyl)
20. Methyl 3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl)
21. A compound according to claim 1 which is 3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-
22. Methyl (3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) methyl) benzoyl) -D-alaninate,
23. (3 - ((3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) benzoyl)
24. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,
25. Preparation of 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) -5-
26. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L-tryptophanate ,
27. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)
28. Preparation of (S) -3- (5-chlorothiophen-2-yl) -N- (3 - ((1- (2-morpholinoethyl) amino) Yl) phenyl) -1-phenyl-lH-pyrazole-4-carboxamide,
29. Ethyl 3- (3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
30. 3- (3- (Thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid,
31. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- (trifluoromethyl) benzoate,
32. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) -5- (trifluoromethyl)
33. Methyl 3-chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole-4-carboxamido) benzoate,
34. 3-Chloro-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,
35. A process for the preparation of methyl 3- bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole-
36. 3-Bromo-5- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,
37. Methyl 2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido)
38. 2- (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) phenyl) acetic acid,
39. Methyl (2- (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl) -L-tryptophanate ,
40. (2- (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) phenyl) acetyl)
41. Ethyl 3- (3- (5-chlorothiophen-2-yl) -4- (phenylcarbamoyl) -1H-pyrazol-
42. 3- (3- (5-Chlorothiophen-2-yl) -4- (phenylcarbamoyl) -lH-pyrazol-
43. Ethyl 3- (4 - ((3-chlorophenyl) carbamoyl) -3- (5-chlorothiophen-2-yl) -1H-
44. 3- (4 - ((3-Chlorophenyl) carbamoyl) -3- (5-chlorothiophen-
45. Ethyl 3- (3- (5-chlorothiophen-2-yl) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-
46. 3- (3- (5-Chlorothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl)
47. Preparation of tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) Allaninate,
48. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)
49. Methyl (S) -3- (4- (tert-butoxy) phenyl) -2- (3- (3- (5- chlorothiophen- 4-carboxamido) -5-fluorobenzamido) propanoate,
50. (S) -3- (4- (tert-Butoxy) phenyl) -2- (3- (3- (5- chlorothiophen- -Carboxamido) -5-fluorobenzamido) propanoic acid, < RTI ID = 0.0 >
51. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)
52. Preparation of tert-butyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoyl) Nate,
53. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) -5- fluorobenzoyl) -L-
54. A compound according to claim 1 which is selected from the group consisting of tert-butyl (3- (3- (5- chlorothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) -5- fluorobenzoyl) Lucinate,
55. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)
56. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L-
57. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) -5- fluorobenzoyl) -L-
58. Methyl (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl) -L-methionate ,
59. (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5- fluorobenzoyl)
60. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-fluorobenzoate,
61. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) -4-
62. Methyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl) benzoate,
63. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- (trifluoromethyl)
64. Preparation of tert-butyl 3- (3- (5-chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1H- pyrazole-4-carboxamido) benzoate ,
65. 4- (4 - ((3- (tert- butoxycarbonyl) phenyl) carbamoyl) -3- (5-chlorothiophen-
66. 3- (3- (5- Chlorothiophen-2-yl) -1- (4- (methoxycarbonyl) phenyl) -1 H- pyrazole- 4- carboxamido) benzoic acid,
67. 3- (1- (4-Carboxyphenyl) -3- (5-chlorothiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,
68. Methyl 4- (4 - ((3 - ((2R, 3R) -1- (tert-butoxy) -3-methyl-1-oxopentan- 2- yl) carbamoyl) (5-chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoate,
69. 4- (4 - ((3 - ((2S, 3S) -l- (tert- butoxy) -3-methyl- 1 -oxopentan- 2- yl) carbamoyl) phenyl) 3- (5-Chlorothiophen-2-yl) -1H-pyrazol-1-yl) benzoic acid,
70. 4- (4 - ((3 - ((1R, 2R) -1-carboxy- -1H-pyrazol-1-yl) benzoic acid,
71. Methyl 3 - ((3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoate,
72. 3 - ((3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoic acid,
73. Preparation of tert-butyl (3 - ((3- (5-chlorothiophen-2-yl) -1- phenyl-1H-pyrazole- 4- carboxamido) methyl) -4- fluorobenzoyl) L-isoleucinate,
74. (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) -4-fluorobenzoyl) Leucine,
75. Methyl 3- (3- (5-cyanothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -5-fluorobenzoate,
76. 3- (3- (5-Cyanothiophen-2-yl) -1-phenyl-lH-pyrazole-4-carboxamido) -5-
77. Methyl 4- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-
78. 4- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) cyclohexane-
79. Methyl (lS, 4S) -4- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ,
80. (lS, 4S) -4- (3- (5-Bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane-
81. Methyl (lR, 4R) -4- (3- (5-bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane- ,
82. (lR, 4R) -4- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane-
83. Preparation of tert-butyl ((lS, 4R) -4- (3- (5-bromothiophen- Carbonyl) -L-isosuccinate,
1-phenyl-1 H-pyrazole-4-carboxamido) cyclohexane-1-carbonyl) -L-isoleucine,
85. Preparation of tert-butyl ((lR, 4S) -4- (3- (5-bromothiophen- Carbonyl) -L-isosuccinate,
86. ((lR, 4S) -4- (3- (5-Bromothiophen-2-yl) -L-isoleucine,
87. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - ((3-phenoxyphenyl) carbamoyl) -1H-pyrazol-
88. Preparation of 4- (3- (5-bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl)
89. Methyl (4- (3- (5-bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl) -1 H- pyrazol- 1 -yl) benzoyl) -L- Sorucinate,
90. 2- (4- (3- (5-Bromothiophen-2-yl) -4 - ((3- phenoxyphenyl) carbamoyl) 3-methylpentanoic acid,
91. Methyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- methoxybenzoate,
92. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) -4- methoxybenzoic acid,
93. Methyl (3- (3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4-methoxybenzoyl) -L- ,
94. 2- (3- (5- (Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) -4- methoxybenzamido) -3- Methylpentanoic acid,
95. Methyl (lS, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ,
96. (lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane-
97. Methyl ((lR, 3S) -3- (3- (5-bromothiophen-2-yl) ) -D-iso-lucinate,
2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) cyclohexane-1-carbaldehyde ≪ / RTI >< RTI ID = 0.0 >
99. Methyl 4 - ((3- (5-bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-
100. 4 - ((3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole- 4- carboxamido) methyl) cyclohexane-
1 H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carbonyl) -D - isosulphate,
102. 2- (4 - ((3- (5-Bromothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) methyl) cyclohexane-1-carboxamido ) -3-methylpentanoic acid,
103. Methyl (lS, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ,
104. (lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) cyclohexane-
105. Methyl ((lS, 3R) -3- (3- (5-bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- ) -L-isosuccinate,
106. ((lS, 3R) -3- (3- (5- Bromothiophen-2-yl) -1-phenyl- lH- pyrazole- 4- carboxamido) cyclohexane- 1 -carbonyl) -L-isoleucine,
107. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3S) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,
108. 4- ((1R, 3S) -3-Carboxycyclohexyl) carbamoyl) -lH-pyrazol-1-yl) benzoic acid,
109. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3R) -3- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,
110. Preparation of 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 3R) -3-carboxycyclohexyl) carbamoyl)
111. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1S, 4S) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,
112. 4- (3- (5-Bromothiophen-2-yl) -4 - (((1S, 4S) -4-carboxycyclohexylcarbamoyl)
113. Ethyl 4- (3- (5-bromothiophen-2-yl) -4 - (((1R, 4R) -4- (methoxycarbonyl) cyclohexyl) carbamoyl) 1-yl) benzoate,
114. 4- (3- (5-Bromothiophen-2-yl) -4 - (((1R, 4R) -4-carboxycyclohexyl) carbamoyl)
115. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzenesulfonic acid,
116. 4- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) benzenesulfonic acid,
117. 3- (1-Phenyl-3- (5-sulfothiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,
118. 3- (3- (5-Bromothiophen-2-yl) -1-phenyl-lH- pyrazole-4- carboxamido) benzoic acid,
119. Phenyl-N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-
120. 1-Phenyl-3- (thiophen-2-yl) -N- (m-tolyl) -lH- pyrazole-
121. N- (3-Acetylphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-
123. Methyl (4- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoyl) glycinate,
124. 3- (l-Phenyl-3- (thiophen-2-yl) -lH-pyrazole-4- carboxamido) benzoic acid,
125. Ethyl 3- (1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoate,
126. N, 1-Diphenyl-3- (thiophen-2-yl) -1H-pyrazole- 4- carboxamide,
127. N- (3-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-
128. N- (4-phenoxyphenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-
129. N- (3-Chlorophenyl) -1-phenyl-3- (thiophen-2-yl) -1H-pyrazole-
130. N- (Benzo [d] [1,3] dioxol-5-yl) -1-phenyl-3- (thiophen-
131. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoic acid,
132. 3- (5-Chlorothiophen-2-yl) -N, 1 -diphenyl-lH- pyrazole- 4- carboxamide,
133. Ethyl 3- (3- (5-chlorothiophen-2-yl) -1-phenyl-lH-pyrazole-4- carboxamido) benzoate,
134. 3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,
135. N- (3-Chlorophenyl) -3- (5-chlorothiophen-2-yl)
136. 3- (5-Chlorothiophen-2-yl) -N- (4-phenoxyphenyl)
137. N- (Benzo [d] [1,3] dioxol-5-yl) -3- (5- chlorothiophen- ,
138. 3- (5-Chlorothiophen-2-yl) -N- (3-phenoxyphenyl)
139. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N-propyl-lH- pyrazole-
140. 3- (5-Chlorothiophen-2-yl) -N-cyclopropyl-l-phenyl-lH- pyrazole-
141. N- (l-Benzylpiperidin-4-yl) -3- (5-chlorothiophen-2-yl)
142. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N- (pyridin-
143. 3- (5-Chlorothiophen-2-yl) -1-phenyl-N- (4- (thiophen-
144. 3- (5-Chlorothiophen-2-yl) -N- (4-morpholinophenyl) -1-phenyl-
145. Preparation of N- (4- (benzyloxy) phenyl) -3- (5-chlorothiophen-2-yl)
146. Ethyl 3- (3- (5-bromothiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoate,
147. 3- (5-Bromothiophen-2-yl) -N, 1 -diphenyl-lH- pyrazole-
148. 3- (5-Bromothiophen-2-yl) -N- (4-phenoxyphenyl)
149. 3- (5-Bromothiophen-2-yl) -N- (3-chlorophenyl)
150. 3- (5-Bromothiophen-2-yl) -N- (3-phenoxyphenyl)
151. Preparation of N- (benzo [d] [1,3] dioxol-5-yl) -3- (5-bromothiophen- ,
152. 3- (5-Methylthiophen-2-yl) -N, 1 -diphenyl-lH-pyrazole-
153. Ethyl 3- (3- (5-methylthiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoate,
154. 3- (3- (5-Methylthiophen-2-yl) -1-phenyl-lH-pyrazole- 4- carboxamido) benzoic acid,
155. N- (3-Chlorophenyl) -3- (5-methylthiophen-2-yl)
156. 3- (5-Methylthiophen-2-yl) -N- (4-phenoxyphenyl) -1-phenyl-1H- pyrazole-
157. 3- (5-Methylthiophen-2-yl) -N- (3-phenoxyphenyl)
158. N- (Benzo [d] [1,3] dioxol-5-yl) -3- (5-methylthiophen- ,
159. Ethyl 3- (3- (benzo [b] thiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoate,
160. A compound according to claim 1 which is 3- (benzo [b] thiophen-2-yl) -N,
161. A process for the preparation of 3- (benzo [b] thiophen-2-yl) -N- (4- phenoxyphenyl)
162. A compound selected from the group consisting of 3- (benzo [b] thiophen-2-yl) -N- (3- chlorophenyl)
163. 3- (3- (Benzo [b] thiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,
164. Preparation of 3- (benzo [b] thiophen-2-yl) -N- (benzo [d] [1,3] dioxol-5-yl) amides,
165. 3- (Benzo [b] thiophen-2-yl) -N- (3-phenoxyphenyl)
166. 3- (Benzo [b] thiophen-3-yl) -N, 1 -diphenyl-lH- pyrazole-
167. Ethyl 3- (3- (benzo [b] thiophen-3-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoate,
168. 3- (3- (Benzo [b] thiophen-3-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,
169. 3- (1-Phenyl-3- (5- (4- (trifluoromethoxy) phenyl) thiophen-2-yl) -1H-pyrazole- 4- carboxamido) benzoic acid,
170. 3- (3- (5- (3-Acetamidophenyl) thiophen-2-yl) -1-phenyl-lH- pyrazole- 4- carboxamido) benzoic acid,
171. 3- (3- (5- (2-Fluoro-4- (trifluoromethyl) phenyl) thiophen-2-yl) Benzoic acid,
172. 3- (3- (5- (3-Cyano-4-fluorophenyl) thiophen-2-yl)
173. 3- (1-Phenyl-3- (5- (4- (trifluoromethyl) phenyl) thiophen-2-yl) -1H- pyrazole- 4- carboxamido) benzoic acid,
174. 3- (3- (5- (3-Fluoro-4-methoxyphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido)
175. A compound which is 3- (3- (5- (4-carbamoylphenyl) thiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoic acid, its stereoisomer , Or a pharmaceutically acceptable salt thereof.
delete delete delete delete delete delete A pharmaceutical composition for preventing or treating bone diseases, which comprises a compound according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
11. The method of claim 10,
The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, binds to sclerostin (SOST), LPR5 / 6 (low-density lipoprotein receptor-related protein 5/6) A pharmaceutical composition.
12. The method of claim 11,
Wherein said compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof inhibits the binding of SOST to LPR5 / 6.
11. The method of claim 10,
Wherein said bone disease is selected from the group consisting of osteoporosis, fracture, loss of jaw bone due to periodontal disease, atypical fracture and bisphosphonate related osteonecrosis in jaw (BRONJ) associated with bisphosphonate.
delete
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