WO2020175957A1

WO2020175957A1 - Pyrazole amide derivative compound and use of same

Info

Publication number: WO2020175957A1
Application number: PCT/KR2020/002897
Authority: WO
Inventors: 양민규; 김좌진
Original assignee: 주식회사 마더스제약
Priority date: 2019-02-28
Filing date: 2020-02-28
Publication date: 2020-09-03
Also published as: KR102396602B1; KR20200105443A

Abstract

The present invention relates to a derivative compound having a pyrazole amide structure, an enantiomer thereof, or a pharmaceutically acceptable salt thereof. According to the present invention, the pyrazole amide derivative compound, the enantiomer thereof, and the pharmaceutically acceptable salt thereof, by inhibiting mitsugumin 53(MG53), can increase insulin secretion, and even when taken over a long period of time, can lower blood glucose levels extremely effectively without inducing hypoglycemia, while having a protective function on pancreatic beta cells, and at the same time, can dramatically resolve the issue of weight gain and insulin resistance.

Description

2020/175957 1»（：1/10公020/002897 Specification

Name of the invention: Pyrazolamide derivative compound and its use Technical field

[1] The present invention relates to a pyrazole amide derivative compound and its use.

Specifically, the present invention relates to a pyrazole amide derivative compound exhibiting MG53 inhibitory activity and its use.

Background

[2] Diabetes is type 1 depending on insulin deficiency or resistance to insulin action.

Diabetes (insulin-dependent) task Type 2 diabetes (non-insulin-dependent) and malnutrition-producing diabetes were classified by the World Health Organization (¥3) in 1985.

[3] Existing diabetes treatments are largely insulin drugs, sulfone urea drugs, ^ZD series

Inhibitor, Miglitinide, 1110161111

In the case of failure of treatment using exercise or diet after diagnosis of diabetes, diabetes treatment is generally used alone or in combination with antidiabetic drugs by referring to the guidelines of the American Diabetes Association. Is a biguanide-based metformin, and the second and third drugs are sulfone urea and glycerol.

Inhibitors, etc., and subsequently (31 -1 ^ ^ 1 injections or insulin injections are used. Current clinically used oral diabetes treatments have a positive aspect of maintaining normal blood sugar levels, but long-term administration procedures cause blood sugar, Not only does it cause various side effects such as diarrhea, abdominal bloating, weight gain, lactic acid blood, heart toxicity, and liver toxicity, but eventually the beta cells of the pancreas, which function to secrete insulin, are irreversibly damaged/destructed and insulin resistance develops. In addition, in the case of insulin, which is most often used as a treatment for diabetes, 2, daily,

Because 3 subcutaneous injections are required, the inconvenient and rejection of injections is great, and the possibility of inducing hypoglycemia also has a very large problem. For this reason, the development of new diabetes treatment drugs that do not have the above side effects is required.

[4] On the other hand, research results showed that the protein that regulates insulin signaling ^«}53 decomposes 11« (insulin receptor substrate), a key protein in the insulin signaling process. Accordingly, MG53 inhibitors are the target of new diabetes treatments. Has become

Detailed description of the invention

Technical task

[5] The task to be solved by the present invention is to provide a pyrazole amide derivative compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof, as an inhibitor of ^«}53, and a preparation method thereof.

[6] In addition, the problem to be solved by the present invention is the pyrazole amide derivative compound, 2020/175957 1»（：1^1{2020/002897 To provide the use of its optical isomer or its pharmaceutically acceptable salt.

Problem solving means

[7] The present inventors

The present invention was completed by discovering the represented pyrazole amide derivative compound, its optical isomer or its pharmaceutically acceptable salt.

[8] compounds of formula 1

[9] In order to solve the technical problems described above, the present invention

An amide derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[1] [Formula 1]

At least one hydrogen of the aryl or heteroaryl is hydroxy, halo, (:1 4 alkyl, (:1 4 alkoxy, 0^4)

Alkyl ester, may be substituted with 01-04 haloalkyl or phenoxy｝,

[15]

Independently ¾hydroxy, halo, 01-04 alkyl, 01-04

Alkoxy, (the 1 4 alkyl ester or (: 1 4 haloalkyl,

[16] and 11 ₂ are each independently or 0-04 alkyl.

[17] According to one specific example of the present invention,

[18] X is- ₂ -or -（：（=0） -,

[19] \ is aryl or heteroaryl, and wherein at least one hydrogen of aryl or the heteroaryl may be substituted with halo, (: 1 4 alkoxy, (: 1 4 alkyl ester or phenoxy), and of the phenoxy One or more hydrogen may be substituted with hydroxy, halo or 01-04 alkyl｝,

[2 is II _! Is,

[21] element ₂ is or (:1 4 alkyl,

[22] å _! To å ₅ are each independently ¾ halo or 01-04 alkoxy.

[23] According to a specific example of the present invention, \ may be an aryl. Specifically, the aryl may be phenyl or a ring in which a 5- to 6-membered non-aromatic ring is fused to phenyl. In addition, the fused ring is It may contain 1 or 2 oxygen atoms. 2020/175957 1»（：1^1{2020/002897

[24] Further, according to an embodiment of the present invention, V may be heteroaryl. Specifically, the heteroaryl may be a 5 to 6 membered heteroaryl. In addition, the above

Heteroaryl may contain 1 to 3 N. Furthermore, the heteroaryl may be pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or

1,3, 5-may be triazinyl.

[25] Further, according to a specific example of the present invention, when X is aryl, the compound of Formula 1 may be any one selected from the group consisting of the following compounds.

[26]

[27] [28]

2020/175957 1»（：1/10公020/002897

[29] In addition, according to a specific example of the present invention, in case of heteroaryl, the compound of Formula 1 may be any one selected from the group consisting of the following compounds.

[3

2020/175957 1»（：1^Mo2020/002897

[31] The compound represented by Formula 1 of the present invention may contain one or more asymmetric carbons, and thus racemates, racemic mixtures, single enantiomers,

Diastereomeric mixtures and the respective diastereoisomers can exist. Such isomers are known in the art, e.g., compounds represented by Formula 1

Separation is possible by chromatography or separation such as: 1. Or, the stereoisomers of each of the compounds represented by the formula 1 are stereospecific using optically pure starting materials and/or reagents of a known sequence. Can be synthesized.

[32] In the present invention, a pharmaceutically acceptable salt refers to a salt commonly used in the pharmaceutical industry, for example, an inorganic ion salt made of calcium, potassium, sodium and magnesium; hydrochloric acid, nitric acid, phosphoric acid, Inorganic acid salts prepared from bromic acid, iodic acid, perchloric acid and sulfuric acid; acetic acid, trifluoroacetic acid, citric acid, maleic acid, 2020/175957 1»（：1^1{2020/002897 Succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucu Organic acid salts made of Ronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, hydroiodic acid, etc.; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, I)-toluenesulfonic acid and naphthalenesulfonic acid. Sulfonates; amino acid salts made from glycine, arginine, lysine, etc.; and amine salts made from trimethylamine, triethylamine, ammonia, pyridine, and ficoline, etc., but the listed salts mean in the present invention. The type of salt is not limited.

[33] Crime prevention for the manufacture of compounds of formula 1

[34] The preparation of the compound of Formula 1 of the present invention can be carried out through a sequential or convergent synthetic route through the reaction route of Scheme 1 below.

[38] According to a specific example of the present invention, the pyrazole amide derivative of Formula 1 above

The synthesis route of the compound may be prepared according to the order described in the reaction scheme, but may be prepared by the method presented therein or a similar method, and is not limited to the order of the reaction scheme below. The starting material is commercially available or similar to the method presented below. It can be manufactured in a way.

[39] Isolation and purification of the pyrazole amide derivative compound or intermediate produced by the above method is a suitable separation or purification procedure used in the pharmaceutical industry, such as filtration, extraction, crystallization, column chromatography, thin film chromatography, thick film

It can be achieved with chromatography, preparative low pressure or high pressure liquid chromatography, or a combination of these procedures.

[Use of the compound of formula 1

[41] The present invention provides a use of a pyrazole amide derivative compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[42] [Formula 1]

[43] 2020/175957 1»（：1^1{2020/002897

[44] Formula 1 is as defined above.

[45] The present invention provides a pharmaceutical composition for the treatment or prevention of diabetes comprising the pyrazole amide derivative compound of Formula 1, its optical isomer, or its pharmaceutically acceptable salt as an active ingredient.

[46] According to one embodiment of the present invention, the diabetes may be type 2 diabetes.

[47] According to a specific example of the present invention, the pyrazole amide derivative of the above formula 1

The compound, its optical isomer or its pharmaceutically acceptable salt may inhibit MG53. Accordingly, the pyrazole amide derivative compound of Formula 1, its optical isomer, or its pharmaceutically acceptable salt increases the secretion of insulin. In addition to being able to reduce the blood sugar level very effectively without causing hypoglycemia, it has the function of protecting the pancreatic beta cells even if it is taken for a long period of time, and at the same time, it shows an effect that can dramatically resolve weight gain and insulin resistance.

[48] For administration, the pharmaceutical composition of the present invention may contain one or more pharmaceutically acceptable carriers in addition to the pyrazole amide derivative compound of Formula 1 above, its optical isomer or its pharmaceutically acceptable salt. .

Pharmaceutically acceptable carriers can be used by mixing saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these ingredients, and if necessary, antioxidants and buffers. In addition, diluents, dispersants, surfactants, binders and lubricants can be added to form injection formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets. Therefore, the pharmaceutical composition of the present invention can be a patch, a solution, a pill, a capsule, a granule, a tablet, a suppository, etc. These formulations are conventional methods used for formulation in the art, or Remington's Pharmaceutical Science (latest edition). , Mack Publishing Company, Easton PA, and can be prepared in a variety of formulations depending on each disease or ingredient.

[49] The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dosage is the weight, age, and sex of the patient. ,The range varies according to health status, diet, administration time, administration method, excretion rate, and severity of disease. The daily dose of the compound of formula 1 of the present invention is about 1 to 1000 mg/kg, preferably 5 to 100 mg/kg, per day 2020/175957 1»（：1^1{2020/002897 Can be administered once or several times.

[5] In addition to the pyrazole amide derivative compound of Formula 1 above, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present invention may contain one or more active ingredients that exhibit the same or similar drug efficacy.

[51] The present invention comprises administering a therapeutically effective amount of a pyrazole amide derivative compound of the above formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a mammal, including humans, to treat diabetes or Provides a way to prevent it.

[52] The term "therapeuticly effective amount" used in the present invention

It shows the amount of the pyrazole amide derivative compound of Formula 1 that is effective for treatment.

[53] The treatment method of the present invention also includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding its symptoms by administering the compound of Formula 1 above. In the management of diseases, specific active ingredients The prophylactic or therapeutic dose of the disease or condition will vary depending on the nature of the disease or condition (additional severity, and the route to which the active ingredient is administered; the dose and frequency of the dose will vary with the age, weight and response of the individual patient. The dosage regimen can be easily selected by those with ordinary knowledge in the field who take these factors for granted. In addition, the treatment method of the present invention includes the compound of Formula 1 above and an additional active agent that aids in the treatment of diseases. The administration of a therapeutically effective amount may further be included, and an additional activator may exhibit a synergistic or auxiliary effect with the compound of Formula 1 above.

[54] In addition, the present invention is a pyrazole amide derivative of the formula 1,

It provides the use of an optical isomer or a pharmaceutically acceptable salt thereof.

[55] In addition, the present invention provides a pyrazole amide derivative compound of Formula 1, an optical isomer thereof, or a pharmaceutically thereof for the manufacture of a drug for the treatment of diabetes.

It provides acceptable use of salt. The compound of Formula 1 above for the manufacture of pharmaceuticals can be mixed with acceptable adjuvants, diluents, carriers, etc.

It can have a synergistic effect of the active ingredients as it is made in a combination formulation with an active agent.

[56] The matters mentioned in the composition, use, and treatment method of the present invention apply equally unless contradictory to each other.

Effects of the Invention

[57] The pyrazole amide derivative compound, its optical isomer, or its pharmaceutically acceptable salt according to the present invention can inhibit MG53 (mitsugumin53). Accordingly, the pyrazole amide derivative compound, its optical isomer according to the present invention Or its pharmaceutically acceptable salt may not only increase the secretion of insulin, 2020/175957 1»（：1^1{2020/002897 It has a pancreatic beta-cell protection function even if taken for a long time, and it is very effective to lower blood sugar levels without causing hypoglycemia, and at the same time, it has an effect that can dramatically resolve weight gain and insulin resistance. Represents.

Brief description of the drawing

Fig. 1 shows the results of expression analysis of ^-1 and MG53 in 02 (: 12 cells (skeletal muscle cells) for the compound of Example 13).

Fig. 2 shows the results of expression analysis of ^-1 and MG53 in 02 (: 12 cells (skeletal muscle cells) for the compound of Example 30).

[6] Fig. 3 shows the results of the expression analysis of ^-1 and MG53 in 02 (: 12 cells (skeletal muscle cells) for the compound of Example 38).

Fig. 4 shows the results of the expression analysis of ^-1 and MG53 in 02 (: 12 cells (skeletal muscle cells) for the compound of Example 40).

[62] Fig. 5 shows the results of expression analysis of ^-1 and MG53 in 02 (: 12 cells (skeletal muscle cells) of the compound of Example 41).

Best mode for carrying out the invention

[63] Hereinafter, embodiments of the present invention will be described in detail so that those with ordinary knowledge in the technical field to which the present invention belongs can be easily implemented. However, the present invention can be implemented in various forms, and the implementation described herein. It is not limited to examples.

[64] Simulated vision example 1:: Ni 4 -Methoxybezim ^' ）- -Phenim- 111-pyramid- 5 -Preparation of carboxamide

[65] 「Multi-Gye 11 Ethim 5-（4-methoxyphenim ^」）- 2.4 -Manufacture of dioxopetanoate

[66]

[67] To a solution in which 4-methoxyphenylacetone (5.06 30.8 11111101) was stirred in 50 toluene, A:8110 (37.0 1111, 37.0 11111101, 1.0 M 111 11 silk) was added at 0° (: at the same temperature). After stirring for 30 minutes, diethyl oxalate (4.60 1111, 33.9 11111101) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 hours, and then diluted with a saturated aqueous solution of NH ₄ 01. Was extracted with ¾0 sho0, and the combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (¾0 sho 11-nucleic acid = 1:7) and the title compound 5.73 Silver (70%) was obtained as a dark orange oil.

[68] ¾ NMR（000 ₃ , 400

8.3

6.88

8.8

6.35知, 1¾, 4.31 female, 211, / = 7.1 3.79知, 3¾, 3.70知, 211), 1.34比 311, / = 7.2 ¾).

[69] Production of “Multi-Gye 21 Ethim 3- (4-methoxybezim”)-Monoacid-Pyrazome-5-Carboxylate 2020/175957 1»（：1^1{2020/002897 this

One]

5-(4-methoxyphenyl)-2,4-dioxopentanoate (for 3.47, 13.1 _ ₀ 1) was added hydrazine monohydrate (1.27 1111, 26.2 11111101) to the cross-stirred solution at room temperature. After stirring for 12 hours, the reaction mixture was referred to as a saturated aqueous solution of NaHCO ₃ and extracted using ¾0 sho (:). The combined organic layer was dried with 4 and then concentrated under vacuum. The residue was flashed on silica gel. Purified by column chromatography (¾0 show (1-nucleic acid = 1:3)) to obtain 3.10 ¾ (91%) of the title compound as orange oil.

2] ¾ NMR（0003, 400 MHz): 6 7.11

/ = 8.3

6.82（山

/ = 8.7

6.53知

7.1

¾).

3] 『Step 31 3-（4 -Methoxybenzyl ^' ）-Monoacid-pyramid-5 -Preparation of carboxylic acid

4]

5] Ethyl produced in step 2 during 11 or (30 1111)

3-(4-Methoxybenzyl)-in-parazole-5-carboxylate (2.28 is 8.76 11111101) To the cross-stirred solution, add 00比11 ₂ 0 (1.10 is 26.3 11111101) ₂ 0 (20) It was added at room temperature. After stirring for 6 hours at 50 ᄋ（：, the reaction mixture is acidified with 2N 11（and then

The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was subjected to flash column chromatography on silica gel (¾0:11-nucleic acid = 1:2 MeOH:EtOAc = 1: 10 Purified with) to obtain the title compound 1.45 (71%) as a white solid.

2020/175957 1»(：1^1{2020/002897

After drying, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (¾0 show 11-nucleic acid = 1:2) to obtain the title compound 58.3.

It was obtained as a white solid.

[8 2 ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.25知, 1¾, 9.96知, 1¾, 7.80 (

7.9

6.89 (山

211, / = 8.2 6.48 知, 1¾, 3.95( 211), 3.72( 3¾,

[81] Sim vision example 2: 八^ -(4 -fluorophenim) -3-(4 -methoxybenzim)- 1 table

-Pyrazome-5 -Preparation of carboxamide

[82]

[83]

As a solid

Obtained.

[84] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.26知, 1¾, 10.10知, 1¾, 7.83 (1¾, 7.19 ((1, 211, / = 8.4

7.15 (III, 211), 6.88 (山 211, / = 8.2

6.48 知, 1¾, 3.95 知, 211),

3.72知, 3¾,

[85] Sim vision example 3: /V -(3 -Polorofenim ^' )-：Nee 4 -Methoxybezim ^' )- 1 11

-Pyrazole-5-Preparation of carboxamide

[86]

[87] In a method similar to Example 1, the title compound 30.0

As a solid

Obtained.

[88] 400 MHz): 6 13.30 7.77

12.1

8 1¾), 7.33 (1¾, ¾), 6.88

6.9 6.85 (111, 1¾, 6.49知, 1¾, 3.95知,

[89] Simsi Example 4: /V 444 Turt-Boutimneim 44-

-Pyrazole-5-Preparation of carboxamide 2020/175957 1»（：1^1{2020/002897

[9 this

[91]

With pale yellow oil

Obtained.

[92] ¾ NMR（000 ₃ , 400

8.6

7.34（山

/

= 8.6

7.12（（1, 211, /= 8.5

6.84（山 211, /= 8.5

6.68知, 1¾, 3.97知, 2¾,

3.77知, 3¾, 1.30知, 9¾,

[93] Simulated vision example 5: 3- (4-methoxybenzim)-八^-(4- (trifluoromethim) penim)-1 vote

-Pyrazome-5 -Preparation of carboxamide

[94]

[95]

To pale yellow solid

Obtained.

[96] ¾ NMR（DMSO-d ₆ , 400 MHz): 613.31 知, 1 ¾, 10.36 知, 1 ¾, 8.04（山 2¾ / = 6.2

6.52 知, 1¾, 3.96 知, 2¾, 3.72 知, 3¾

[97] Example 6: Preparation of 3- (4 -methoxybenzyl)--(4 -phenoxyphenyl)-1 -pyrazole-5 -carboxamide

[98]

[99]

As a solid

Obtained.

[100] ¾ NMR（DMSO-d ₆ , 400

8.0

7.36（b

/ = 7.2

7.19

/ = 7.6

7.09,

/ = 7.1

6.99（山

211, /= 9.5

6.97（山 211, /= 8.3 6.88（山 211, / = 7.2

6.47 知, 1¾, 3.95 知, 2¾, 3.72 知, 3¾,

[101] Example 7: Methyl 4- (3- (4 -methoxybenzyl)-1 table-pyrazole-5-carboxamido) of benzoate 2020/175957 1»(：1^1{2020/002897 manufacture

[102]

[103]

Obtained as a pale yellow solid.

[104] ¾ NMR ₆ , 400 MHz): 6 13.32 知, 1 ¾, 10.34 知, 1 ¾, 7.97

8.8

7.91 (8.6

7.19 (山

/= 8.6

6.89 (山

/ = 8.6

6.51 知, 1¾, 3.9 3.82 知, 3¾, 3.72 知, 3¾

[105] Deep vision example 8

Sibezim ^' )- / V 44 -Methoxybezim VI -Pyrazome-5 -Preparation of carboxamide

8.8 ¾),

7.11

9.0

8.6 Hz), 6.66 知,

1¾, 3.96知, 2¾, 3.78知, 3¾, 3.77知, 3¾,

[109] Simulated visual example 9: 3-(4-methoxybenzim V八^-(3-methoxyphenim V: [pyo-pyramid-5-carboxamide preparation

[11 this

[111] Title compound 59.3 in a manner similar to Example 1

(58%) was obtained as a pale yellow solid.

[112] ¾ NMR (000 ₃ , 400 MHz): 6 8.76知, 1¾, 7.43知, 1¾, 7.21,

/ = 8.1

7.09 (111, 3¾, 6.82 (山 211, / = 7.8

6.66 (111, 1¾, 6.65知, 1¾, 3.95知, 2¾, 3.77知,

3¾, 3.75知, 3¾,

[113] Simultaneous vision example 10: 3-(4-methoxybenzim V八^-(2-methoxyphenim V: [pyo-pyramid-5-carboxamide preparation) 2020/175957 1»(：1^1{2020/002897

Obtained.

[124] ¾ NMR (00\ ₃ , 400 MHz): 8 9.04知, 1¾, 8.36

9.5

7.10 (山

/

= 8.5

6.82 ((1, 211, /= 8.6

6.65知, 1¾, 6.49 (111, 1¾, 6.48 (111, 1¾, 3.97知,

2¾, 3.83知, 3¾, 3.79知, 3¾, 3.77知, 3¾,

[125] Example 13: 八^2.5 -dimethoxyphenyl ^' ) -3-(4 -methoxybenzyl ^' ) -1 table

-Pyrazole-5-Preparation of carboxamide

[126] 2020/175957 1»(：1^1{2020/002897

[127] Title compound 9.00 by a method similar to Example 1

With oil

Obtained.

[128] ¾ NMR (000 ₃ , 400 MHz): 6 9.27知, 1¾, 8.26

3.0

7.14 (

= 8.4 degrees ¾), 6.87 ((1, 2H，/ = 8.6 Hz), 6.81 ((1, 1H，/ = 8.8 Hz), 6.69 知, 1¾, 6.59 ((in ¾, / = 8.8, 3.1 ¾) , 4.01知, 2¾, 3.86知, 3¾, 3.81知, 3¾, 3.80知, 3¾,

[129] Sim vision example 14: 八 benzo / 1『1.31 dioxon-5 -im)- 3-(4 -methoxybenzim)- 1 table

-Pyrazole- 5 -Production of carboxamide

[13 this

[131]

As a solid

Obtained.

[132] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.21知, 1¾, 9.90知, 1¾, 7.46知, 1¾, 7.26 (山 111, / = 7.4

7.18 ((1, 211, / = 8.5

6.88 (山 211, / = 8.6

6.86 (111, 1¾, 6.45 知, 1¾, 5.98 知, 2¾, 3.94 知, 211), 3.72 知, 3¾,

[133] Simulated vision example 15: Preparation of 3-(4-fluorobenzim)-八 penim- 1 table-pyramid-5-carboxamide

[134] 『Step 11 Preparation of ethyl 5-(4-fluorophenyl)-2.4-dioxopentanoate

[135]

[136] To a solution in which 4-fluorophenylacetone (1.19 7.82 11111101) was stirred in toluene 20 was added I -:8110 (9.38 sen, 9.38 11111101, 1.0 M 1¾ seal at 0) (: at the same temperature at 30 30). After stirring for a minute, diethyloxalate (1.17 1111, 8.60 11111101) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 hours, and then diluted with saturated NH ₄ C1 aqueous solution. of

Extraction was carried out using Osho 0, and the combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (¾0 sho-nucleic acid = 1:7) to obtain the title compound 1.38% ( 67%) was obtained as an orange oil. 2020/175957 1»（：1^1{2020/002897

[137] ¾ NMR（000 ₃ , 400 MHz) 6 7.20（ 2¾, 7.04（ 2¾, 6.35 知, 1¾, 4.33（small / = 7.1 3.75 知, 211）, 1.35（b 311, /= 7.2

[138] 『Step 21 Ethyl 3-(4-fluorobenzyl ^' ) -Monoacid-pyramid-5 -Production of carboxylate

[139]

[14 this

Crude ethyl

5- (4-fluoro-phenyl) - 2, 4-dioxo-pentanoate (2.25 is 8.92 _ ₀ 1) cross-linked with hydrazine monohydrate in a half solution (0.865; 1111, 17.8 11,111,101) was added at room temperature. After stirring for 12 hours, the reaction mixture was referred to as a saturated aqueous solution of NaHCO ₃ and extracted using ¾0 sho(:). The combined organic layer was obtained

After drying with 4, it was concentrated in vacuum. The residue was purified by flash column chromatography (¾0 show-nucleic acid = 1:3) on silica gel to obtain 1.48 ¾ (67%) of the title compound as yellow oil.

[141] ¾ NMR (0)0 ₃ , 400 MHz) 6 7.71 (III, 2¾, 6.98 (III, 2¾, 6.55知, 1¾, 4.34 F, 211,

= 7.1 4.02知, 211), 1.34 (b 311, /= 7.1

[142] 「Many system 31 344 -Fluorovezim') -1 Pyrazome-5 -Production of carboxylic acid

[143]

[144] Ethyl 3-(4-fluorobenzyl)- 1好 prepared in step 2 in 11 and (15 1111)

After stirring, the reaction mixture was acidified to 2N 11 (:1, and then extracted with ¾0 sho0. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was subjected to flash column chromatography on silica gel (0). Show 0-at nucleic acid = 1:2

MeOH:EtOAc = 1:10) to give the title compound 766 11¾ (87%) as a white solid.

[145] ¾ NMR (DMSO-d ₆ , 400 MHz) 6 7.28

6.1

7.12 (

8.1

6.40知, 1¾, 3.94知, 2¾,

[146] 「Multi-system 41 3-(4-fluorobezim ^' )- -Phenim- Monoacid-pyramid- 5 -Carboxamide production

[147] 2020/175957 1 ^» (：1^1{2020/002897

[148] 3-(4-fluorobenzyl)- 1好 prepared in step 3 of 01 ₂ 01 ₂ (5 1111)

0.243 11111101)

0.0486 11111101) was added at room temperature. After stirring for 2 hours, the reaction mixture was reduced to ₂₀

The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was flash column on silica gel.

Purification by chromatography (¾0 show £:11-nucleic acid = 2:3 to 3:1) gave the title compound 40.1 11¾ (56%) as a white solid.

[149] ¾ NMR (DMSO -(1 ₆ , 400, 9. .8 Hz), 7.33 (111, 2¾, 7. 29 (

8.7

6.53知, 1¾, 4.03知, 2¾,

[15 is simplicity example 16: 3-(4 -fluorobenzim)-八^ -(4 -fluorophenim) -1 vote

-Pyrazome-5 -Production of carboxamide

[151]

[152] Title compound 37.7 in a manner similar to Example 15

As a solid

Obtained.

[153] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.29 知, 1 ¾, 10.10 知, 1 ¾, 7.83 (2 ¾, 7.32 (111, 2 ¾, 7.17 (111, 2 ¾, 7.14 (2 ¾, 6.52 知, 1 ¾)) , 4.03知, 2¾,

[154] Example 17:

Preparation of 3-(4 -fluorobenzyl)-> 3 -fluorophenyl)-111-pyrazole-5 -carboxamide

[155]

[156] Title compound 34.2 in a manner similar to Example 15

As a solid

Obtained.

[157] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.32知, 1¾, 10.23知, 1¾, 7.77 (1¾, 7.64

8.2

Within 7.35凡, /= 8.2 7.31 (!!!, 2¾, 7.15比 2比 /= 8.8 Hz), 2020/175957 1»(：1^1{2020/002897

6.87（111, 1¾, 6.53知, 1¾, 4.03知, 2¾,

[158] Sim vision example 18: 八 4- (tert-buttim) penim)-3- (4-fluorobenzim)-1 vote

[159]

[160] Title compound 78.8 in a manner similar to Example 15

As a solid

Obtained.

[161] ¾ NMR (000 ₃ , 400 MHz): 6 11.60知, 1¾, 8.80知, 1¾, 7.54

8.6

7.33 ((1, 211, / = 8.6

7.09 (111, 211), 6.91 (b 211, /= 8.6

6.62知, 1¾, 3.94知,

2¾, 1.30知, 9¾,

[162] Simultaneous vision example 19:

Preparation of 3-(4 -polluorobezim)->44tripolluorometim, penimni 11 -pyramid-5 -carboxamide

[163]

[164]

Obtained.

[165] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.35 知, 1 ¾, 10.37 知, 1 ¾, 8.05

6.4

6.56知, 1¾, 4.03知, 2¾

[166] Sim vision example 20: 3-(4 -fluorobenzim)-八^ -(4 -phenoxyfenim) -1 vote

-Pyrazome-5 -Preparation of carboxamide

[167]

[168] Title compound 24.5 in a manner similar to Example 15

As a solid

Obtained.

[169] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.30知, 1¾, 10.08知, 1¾, 7.84 (

8.8

7.12比111, / = 7.1

, 4.05知, 2¾, 2020/175957 1»(：1^1{2020/002897

[17, Example 21: Methim 4-(3-(4-fluorobenzim) -1 table

-Pyrazome _ ₅ _Carboxamido) benzoate production

[171]

[172] Title compound 44.2 in a manner similar to Example 15

(40%) was obtained as a pale yellow solid.

[173] ¾ NMR (DMSO-d ₆ , 400 MHz): 1¾, 10.36知, 1¾, 7.98

8.7

/ = 8.4 1¾), 7.31 8.4, 5.7 1¾), 7.15

8.8 1¾),

6.55知, 1¾, 4.03知, 2¾, 3.82知, 3

[174] Example 22: 3-(4-fluorobenzyl)-

Cyphenyl)-1 vote

-Pyrazome-5 -Preparation of carboxamide

[175]

[176]

As a solid

Obtained.

[177] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.25 知, 1 ¾, 9.88 知, 1 ¾, 7.69 (2 ¾, 7.31 知 1, 2 ¾, 7.15 (111, 2 ¾, 6.88 (2¾, 6.49 知, 1¾) , 4.01 知, 2¾, 3.71 知, 3¾,

[178] Simultaneous vision example 23: Preparation of 3-(4-fluorobenzim)-> 3-methoxyphenim)-111-pyramid-5-carboxamide

[179]

[18 in the same manner as in Example 15 title compound 39.9

Obtained as an oil.

[181] 111 NMR (DMSO-d6, 400 MHz): 6 13.27知, 1¾, 9.92知, 1¾, 7.50知, 1¾, 7.41 (山

I = 8.9 Hz), 6.63

((¾ I = 8.2, 2.1 degrees ¾), 6.51 知, 1 ¾, 4.02 知, 2¾, 3.73 知, 3¾,

[182] Simultaneous vision example 24: 3-(4 -fluorobenzim)-八^ -(2 -methoxyphenim) -1 table

-Pyrazome-5 -Preparation of carboxamide 2020/175957 1»(：1^1{2020/002897

[183]

[184] Title compound 61.7 in a manner similar to Example 15

(53%) was obtained as a pale yellow solid.

[185] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.31知, 1¾, 9.32知, 1¾, 8.30 (山 1¾ / = 7.6

7.08 (III, 1¾, 7.06 (III, 1¾, 6.95 (III, 1¾,

6.53知, 1¾, 4.03知, 2¾, 3.89知, 3¾,

[186] Sim Si Example 25: /V 423 -Dimethoxyphenim 344 -Pouluorobezim ^' )- 111

-Pyrazome-5 -Production of carboxamide

[187]

[188] Title compound 58.4 in a manner similar to Example 15

(52%) was obtained as a pale yellow solid.

[189] ¾ NMR (DMSO-d ₆ , 400 MHz):, 1¾, 9.40知, 1¾, 7.94 (

8.2

7.31比

/= 6.1

7.15 8.8

7.06 (b

/ = 8.3

6.81 (in the mountain, / = 8.4 ¾), 6.54 知, 1 ¾, 4.03 82 知, 3 ¾, 3.81 知, 3¾.

[190] Simulated vision example 26: /V 42.4-dimethoxy

-Polo Orovezim ^' )- 1ᄍ

-Pyrazome-5 -Production of carboxamide

[191]

[192]

It was obtained as an oil.

[193] ¾ NMR (00\ ₃ , 400 MHz): 6 10.90 知, 1 ¾, 9.04 知, 1¾, 8.34 (in the mountain, / = 7.6 ¾), 7.14 (111, 2¾, 6.97 (2¾, 6.64 知, 1¾) , 6.50 (1¾, 6.48 (1¾, 4.00知, 2¾, 3.85 知, 3¾, 3.80 知, 3¾,

[194] Sim visual example 27: 八^ -(2.5 -dimethoxyphenim) -3-(4 -fluorobenzim)- 1 table

-Pyrazome-5 -Production of carboxamide

[195] 2020/175957 1»(：1^1{2020/002897

[196] Title compound 11.0 in a method similar to Example 15

As oil

Obtained.

[197] ¾ NMR (000 ₃ , 400 MHz): 6 9.25知, 1¾, 8.24 (山

/ = 2.7

7.17 (2¾,

7.00 (b

/ = 8.2 1¾), within 6.81凡, / = 8.8 1¾), 6.67知, 1¾, 6.59

8.8,

2.4 ¾), 4.03 知, 2 ¾, 3.86 知, 3 ¾, 3.80 知, 3 ¾,

[198] Sim Si Example 28: /V-(Bezo『¥131 Dioksong- 5 -Im Ni 4 -Polo Orovezimni 11

-Pyrazole- 5 -Production of carboxamide

[199]

[200]

Obtained as a solid.

[201] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.25 知, 1 ¾, 9.91 知, 1 ¾, 7.46 知, 1 ¾, 7.30, 211, / = 6.4

7.26 (山 111, / = 8.6

7.15 (b 211, / = 8.7

6.85 (山 111, / = 8.4

6.49 Chi, 1¾, 5.98 Chi, 2¾, 4.01 Chi, 211).

[202] Simulated vision example 29: 3-(4 -Diatrorobezim -Penim- 1ᄍ-pyramid- 5 -Production of carboxamide

[203] 「Daegye 1 1eteam 5- (4 -Diablo Roope-nim ^' ) -2.4 -Manufacture of dioxopetanoate

[204]

[205] In toluene (120), 4 -chlorophenylacetone (12.1 is, Gi. 7 11111101) is added to the agitated solution: 8110 (86.1 1111, 86.1 11111101, 1.0 M no 11 silk) at 0。 After stirring at the same temperature for 30 minutes, diethyloxalate (10.7 1111, 78.9 11111101) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 hours, and then saturated NH ₄ C1 aqueous solution was used. The reaction mixture was

It was extracted using Osho 0, and the combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was purified by flash column chromatography (¾0 sho -nucleic acid = 1:7 10 1:2) on silica gel and titled Compound 18.6 silver (97%) dark red 2020/175957 1»(:1^1{2020/002897 Acquired as oil.

[209] Ethyl prepared in step 1 in acetic acid (40 1111)

5-(4-chlorophenyl)-2, 4-dioxopentanoate (2.47 ^ 9.20 _ ₀ 1) was added hydrazine monohydrate (0.893 1111, 18.4 11111101) to the stirred solution at room temperature. After stirring for 12 hours, the reaction mixture was referred to as a saturated aqueous solution of NaHCO ₃ and extracted using ¾0 sho(:. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was concentrated on a silica gel. Purification by flash column chromatography (¾0 show-nucleic acid = 1:3) gave the title compound 2.26 silver (93%) as a dark red oil.

[21 ¾ NMR (000 ₃ , 400 MHz) 6 7.27

8.5

7.15

8.2

6.56知, 1¾, 4.35 (C, 211, / = 7.2 11 ₂ ), 4.01 (8, 2¾, 1.36 (b 311, / = 7.1 11 ₂ ).

[211] 『Step 31 3-(4 -Chlorobenzyl ^' ) -Table 1-pyramid-5 -Preparation of carboxylic acid

[212]

[213] Ethyl 3-(4-chlorobenzyl)- 1好 prepared in step 2 in 11 and (90 1111)

-Pyrazole- 5 -carboxylate (10.3 silver, 39.0 11111101) to the agitated solution 00比11 ₂ 0 (3.27 ^ 78.0 11111101) 111

₂ 0 (70:Shin) was added at room temperature. After stirring for 6 hours at 50 o(:, the reaction mixture was acidified with 2N 11 (gross acidified, then extracted with ¾0 sho(:). The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was made into silica gel. Flash column chromatography on phase. After purification with -nucleic acid = 1:2 to MeOH:EtOAc = 1: 10), the title compound 8.24 (89%) was obtained as a pale yellow solid.

[214] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 7.34

7.6

7.26

7.5

6.30知, 1¾, 3.92知, 2¾,

[215] 『Step 41 3-(4 -Chlorobenzyl)- -phenyl-monoacid-pyrasome- 5 -Production of carboxamide

[216] 2020/175957 1»（：1^1{2020/002897

2020/175957 1»(：1^1{2020/002897

Hz), 7.64 (

8.1

8.3 Hz), 7.34 (1¾, 7.30 (

8.2 ¾), 6.88 (Bin, /= 8.2 ¾), 6.54知, 1¾, 4.04知, 2¾.

[227] Simsi Example 32:八^ -(4-(Turt-Boo-Tim) Penim)- 3-(4 -Big Roro Benjim) -1 vote

-Pyrazome-5 -Preparation of carboxamide

[228]

[229] Title compound 20.3 in a manner similar to Example 29

(27%) was obtained as a pale yellow solid.

[23 ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.24知, 1¾, 9.86知, 1¾, 7.67

8.8 Hz), 7.37 (1,

/ = 8.0 1¾), 7.30凡

/= 7.8 1¾), 7.28

/ = 8.2 1¾), 6.50 知, 1¾, 4.01 知, 2¾, 1.24 知, 9¾

[231] Example 33: 3- (4-chlorobenzyl)--(4- (trifluoromethyl) phenyl)-1 table

-Pyrazome-5 -Preparation of carboxamide

[232]

[233] Title compound 17.1 in a similar manner to Example 29

(18%) was obtained as a pale yellow solid.

[234] ¾ NMR (DMSO-d ₆ , 400 MHz) 6 13.36知, 1¾, 10.39知, 1¾, 8.04 (

8.4 Hz), 7.67 (1,

/ = 8.4 1¾), 7.39凡

/= 7.5 1¾), 7.29 (山

/ = 8.2 1¾), 6.56 知, 1¾, 4.04 知, 2¾

[235] Example 34: Preparation of 3-(4-chlorobenzyl ^' )-八na 4-phenoxyphenyl ^' )-table-1-pyrazole-5-carboxamide

[236]

[237]

Ivory color

It was obtained as a solid.

[238] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.26知, 1¾, 10.03知, 1¾, 7.81 (1, 2¾ / = 8.7

7.09 2020/175957 1»(：1^1{2020/002897 比 111, / = 7.0 1¾), 6.99 ((1, 211, /= 8.9 1¾), 6.97 (<1, 211, / = 7.9 1¾), 6.52知, 1¾, 4.03知, 2¾,

[239] Sim visual example 35: Methym 4- (3- (4-large roro benzim) -1 vote

-Pyrazome _ ₅ _Carboxamido) benzoate production

[24 this

[241] Title compound 24.0 by a method similar to Example 29

(7%) was obtained as a pale yellow solid.

[242] ¾ NMR (DMSO-d ₆ , 400 MHz): 5 13.37 知, 1 ¾, 10.36 知, 1 ¾, 7.97

8.8

6.55 知, 1¾, 4.04 知, 2¾, 3.82 知, 3¾

[243] Example 36: Preparation of 3-(4-chlorobenzyl ^' )-八na 4-methoxyphenyl ^' )-table-1-pyrazole-5-carboxamide

[244]

[245]

Obtained as a solid.

[246] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.24知, 1¾, 9.84知, 1¾, 7.68

7.4

8.1 Hz), 6.50 知, 1¾, 4.02 知, 2¾, 3.73 知, 3¾,

[247] Example 37: 3- (4 -chlorobenzyl)--(3-methoxyphenyl)-1-pyrazole-5-carboxamide

Produce

[248]

[249] Title compound 30.3 in a manner similar to Example 29

Obtained as an oil.

(25 ¾ NMR 400 MHz): 知, 1 ¾, 7.40 知, 1¾, 7.38

4 1¾), 7.30

8.1 1¾), 6.64 2020/175957 1»(：1^1{2020/002897

((1, 111, / = 7.4 6.52 知, 1¾, 4.03 知, 211), 3.73 知, 311).

[251] Simulated visual example 38: 3-(4-large rorobenzyl、-IV-(2-methoxyphenim V: [pyo-pyramid-5-carboxamide preparation)

[252]

[253] Title compound 20.2 in a manner similar to Example 29

(31%) was obtained as a pale yellow solid.

[254] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.33知, 1¾, 9.31知, 1¾, 8.28

/ = 7.9

7.3 1¾), 7.08 (2¾, within 6.95 ratio, / =

,

[255] Sim visual example 39: 3- (4-large loro benzim) -八^-(2.3-dimethoxyphenim)-1 vote

-Pyrazome-5 -Production of carboxamide

[256]

[257] Title compound 20.7 in a manner similar to Example 29

(25%) was obtained as a pale yellow solid.

[258] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.34知, 1¾, 9.38知, 1¾, 7.92 (

8.2

6.81

((1, 111, / = 8.6 6.54知, 1¾, 4.03知, 211), 3.82知, 311), 3.80知, 3¾,

[259] Sim vision example 40: 3- (4-large loro benzim) -八^-(2.4-dimethoxyphenim)-1 vote

-Pyrazome-5 -Production of carboxamide

[26 this

[261]

Ivory color

It was obtained as a solid.

[262] ¾ NMR (000 ₃ , 400 MHz): 6 9.01知, 1¾, 8.31 (山

/ = 8.4

7.22 (

= 8.3 Hz), 7.08 (山 2比 /= 8.4 Hz), 6.61, 1¾, 6.48 知, within 1 ¾, 6.47 凡, /= 8.0 1 ¾ ₎ , 3.97 知, 2 ¾, 3.82 知, 3¾, 3.79 知, 3¾, 2020/175957 1»(：1^1{2020/002897

[263] Sim visual example 41: 3- (4-large loro benzim) -八^-(2.5-dimethoxyphenim) -1 vote

-Pyrazome-5 -Preparation of carboxamide

It was obtained as a solid.

[266] ¾ NMR (000 ₃ , 400 MHz): 6 9.22知, 1¾, 8.24 (1¾, 7.28 (2¾, 7.14 (

2¾, 6.81凡

/= 9.0 1¾), 6.66知, 1¾, 6.59

8.9, 3.0 1¾), 4.03知, 2¾,

3.86知, 3¾, 3.80知, 3¾,

[267] Sim Si Example 42: 八 Benzo / ¥1.31 Dioxong-5-Im-3- (4-Big loro benzim)-1 vote

-Pyrazome-5 -Preparation of carboxamide

[268]

[269]

Obtained as a pale yellow solid.

[27 ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.26 知, 1 ¾, 9.92 知, 1 ¾, 7.45 知, 1 ¾, 7.38 (山

/ = 7.8 1¾), 6.49

[271] Example 43:

Preparation of 3-(3-large lorobenzim)-> 2.4-dimethoxyphenim)-111-pyramid-5-carboxamide

[272] 「Daegye 11eteam 5-(3 -Grand Lorofenim ^' )- 2.4 -Manufacture of dioxopetanoate

[273]

[274] To a solution in which 3-chlorophenylacetone (5.34 31.7 11111101) was stirred in toluene (50) was added I -:8110 (38.0 sen, 38.0 11111101, 1.0 M 1¾ seal at 0 o (:). At the same temperature) After stirring for 30 minutes, diethyl oxalate (4.74 1111, 34.9 11111101) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 hours, and then diluted with saturated NH ₄ C1 aqueous solution. Mixture 2020/175957 1»（：1^1{2020/002897 0 Show 0 was used for extraction, and the combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was flash column chromatography on silica gel (¾0 show- Purification with nucleic acid = 1:4) yielded the title compound 5.77 (68%) as a dark red oil.

[275] 『Step 21 Ethyl 3-(3-chlorobenzyl ^' ) -Monoacid-pyramid-5 -Preparation of carboxylate

60 is 9.68 _ ₀ 1)

Hydrazine monohydrate (0.941 1111, 19.4 11111101) was added to the solution at room temperature. After stirring for 24 hours, the reaction mixture was diluted with a saturated aqueous solution of NaHCO ₃ and extracted using ¾0 sho(:. The combined organic layer was dried and then concentrated under vacuum. The residue was subjected to flash column chromatography on silica gel. The title compound 1.78 § (69%) was obtained as a red solid by purifying with graphy (¾0 show-nucleic acid = 1:3).

[278] 『Step 31 3- (3 -Chlorobenzim ^' )-Monoacid-Pyrazome-5-Preparation of carboxylic acid

[279]

[Ethyl 3-(3-chlorobenzyl)- 1好 prepared in step 2 in 28 is 11 or (20 1111)

-Pyrazole- 5 -carboxylate (1.78 silver, 6.72 11111101) to the agitated solution 00比11 ₂ 0 (562 13.4 11111101) 111

₂ 0 (10) was added at room temperature. After stirring for 24 hours at 50° (:), the reaction mixture was acidified with 2N 11 (:1, and then extracted with ¾0 sho0. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was concentrated under vacuum. Flash column chromatography on silica gel (at 0 show 0 -nucleic acid = 1:2

Purification with MeOH:EtOAc = 1:10) gave the title compound 1.13 (71%) as a pale pink solid.

[281] 「Daegye 41 343 -Diatrorobezim ^' )- 2.4 -Dimethoxyphenim ^' ) -1

-Pyrazome-5 -Preparation of carboxamide

[282]

2020/175957 1»（：1^1{2020/002897

[283] 3-(3-chlorobenzyl)- 1好 prepared in step 3 in 01 ₂₍ ：1 ₂ (5 1111)

-Pyrazole- 5 -carboxylic acid (61.8 0.261 11111101) and 2, 4 -dimethoxyaniline (37.2,

0.261 11111101) to this stirred solution

0.522 11111101) and DMAP (3.19

26.1 011101) was added at room temperature. After stirring for 72 hours, the reaction mixture was

The combined organic layer was dried over MgSO ₄ and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel by flash column chromatography-nucleic acid = 1:2) to obtain the title compound 90.3.

It was obtained as a brown solid.

[284] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.29 知, 1 ¾, 9.12 (8, 1 ¾, 8.13 ((1, my, / = 8.6 Hz), 7.32 (111 6.52 (1 ¾, 4.05 知, 2¾,

[285] Example 44: Preparation of 3-(2-chlorobenzyl)- -(4-methoxyphenyl)-1 -pyrazole-5-carboxamide

[286] 「Daegye 11Eteam 5-(2 -Grand Lorofenim ^' )- 2.4 -Manufacture of dioxopetanoate

[287]

[288] To a solution in which 2-chlorophenylacetone (2.98 is, 17.7 11111101) in toluene (30 1111) was stirred, I -: 8110 (21.1 ^, 21.2 11111101, 1.0 M 1¾ seal was added at 0 o (:). After stirring at the same temperature for 30 minutes, diethyloxalate (2.65 1111, 19.5 11111101) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours, and then diluted with saturated NH ₄ C1 aqueous solution. .The reaction mixture

Extraction was performed using Osho0, and the combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was flash column chromatography on silica gel.

Purification with (¾0 show-nucleic acid = 1:4) gave the title compound 2.35 (49%) as a dark red oil.

[289] 「Daegye 21 Ethym 3 2 -Kumlovrobezym ^' )-1-Pyrazome-5-Preparation of carboxylate

[29 this

[291] Ethyl prepared in step 1 in acetic acid (12 1111)

5- (2-chlorophenyl) - 2, 4-dioxo-pentanoate (2.35 is 8.75 _ ₀ 1) cross-linked with hydrazine monohydrate in the half was added to (0.849; 1111, 17.5 11,111,101) at room temperature. After stirring for 24 hours, the reaction mixture was referred to as a saturated aqueous solution of NaHCO ₃ , and extracted using ¾0 sho(:). The combined organic layer was obtained. 2020/175957 1»（：1^1{2020/002897

_After drying with ₄ , it was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (¾0 sho0 -nucleic acid = 1:2) to obtain the title compound 1.71 silver (74%) as an orange oil.

[292] 『Step 31 3-(2 -Chlorobenzyl ^' ) -1 table-pyramid-5 -Preparation of carboxylic acid

[293]

[294] Ethyl 3-(2-chlorobenzyl)- 1好 prepared in step 2 in 11 and (10 1111)

After stirring, the reaction mixture was acidified to 2N 11 (:1, and then extracted with ¾0 sho0. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was flash column chromatography on silica gel (¾0). Show 0-at nucleic acid = 1:1

MeOH:EtOAc = 1:10) to give the title compound 685 11¾ (89%) as a pale yellow solid.

[295] Preparation of 「Daegye 41 342 -Kumlovrobezim ^' )- 4 -methoxyphenim ^' )- 1 -pyramid-5 -carboxamide

[296]

[297] 3-(2-chlorobenzyl)- 1好 prepared in step 3 in 01 ₂₍ ：1 ₂ (6 1111)

-Pyrazole-5 -carboxylic acid (74.0

0.313 11111101) and 4-methoxyaniline (38.5 11¾, 0.313 11111101) were added to the stirred solution at room temperature with £00^01 (120 0.626 11111101) and DMAP (3.82 31.3 Na 11101). After stirring for 24 hours, quenched the reaction mixture rodwen ₂ 0 and extracted with ₂ 01 _2. The combined organic layer was dried over ₄ then concentrated in vacuo. The residue was purified on silica gel flash column

The title compound 66.6 was purified by chromatography (¾0 show: -nucleic acid = 1:2 to 2:1).

(62%) was obtained as a pale brown solid.

[298] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.29 知, 1 ¾, 9.85 知, 1 ¾, 7.69 (2 ¾, 7.47 凡 111, / = 6.2

7.35 (111, 1¾, 7.31 (111, 2¾, 6.89) (山 211, / = 6.3

6.42知, 1¾,

4.14知, 2¾, 3.72知, 3¾,

[299] Example 45: Preparation of 3-(2-chlorobenzyl)- -(3-methoxyphenyl)-Table 1 -pyrazole-5-carboxamide

[300] 2020/175957 1»(：1^1{2020/002897

[301] Title compound 71.6 in a manner similar to Example 44

Obtained as a solid.

[302] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.34知, 1¾, 9.92知, 1¾, 7.47 (2¾, 7.39凡 111, / = 6.1

7.33 (111, 3¾, 7.20比 111, / = 6.5

6.64 (山 111, / = 6.2

6.43 知, 1¾, 4.14 知, 2¾, 3.73 知, 3¾,

[303] Example 46: Preparation of 3-(2-chlorobenzyl ^' )-八nemethoxyphenyl ^' )-table-1-pyrazole-5-carboxamide

[304]

[305] Title compound 79.6 in a similar manner to Example 44

(77%) was obtained as a pale brown solid.

[306] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.38知, 1¾, 9.34知, 1¾, 8.31 (山

I = 7.2 ¾), 7.47 ((1,

I = 6.9 ¾), 7.33 (3¾, 7.07 (2¾, 6.96 (1¾, 6.45 知, 1 ¾, 4.15 知, 2 ¾, 3.89 知, 3¾,

[307] Example 47: 3- (2-chlorobenzyl)--(2.4-dimethoxyphenyl)-1 table

-Pyrazome-5 -Production of carboxamide

[308]

[309] In a method similar to Example 44, the title compound 67.4 !!¾ (60%) ivory color

It was obtained as a solid.

[31 ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.32知, 1¾, 9.13知, 1¾, 8.11

8.1 ¾), 7.47 ((1,

I = 6.6 ¾), 7.32 (8.8 ¾), 6.41 知, 1 ¾, 4.14 知, 2 ¾, 3.87 CHI, 3¾, 3

[311] Sim visual example 48: 3- (2-large loro benzim) -八^-(2.5-dimethoxyphenim) -1 vote

-Pyrazome-5 -Production of carboxamide

[312] 2020/175957 1»(：1^1{2020/002897

[313] Title compound 44.0 in a similar manner to Example 44

(38%) was obtained as a pale yellow solid.

[314] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.38知, 1¾, 9.32知, 1¾, 8.00知, 1¾, 7.47 (山

I = 8.9 Hz), 6.44 知, 1¾, 4.14 知, 2¾, 3.84 知, 3¾, 3.70 知, 3¾,

[315] Example 49: 3-(4-chlorobenzyl)- -(2.4-dimethoxyphenyl)- -methyl- 1 Table

-Pyrazome-5 -Preparation of carboxamide

[316]

[317] Title compound 76.1 in a similar manner to Example 29

(54%) was obtained as a pale yellow solid.

[318] ¾ NMR (000 ₃ , 400 MHz): 6 7.18 (山

I = 8.4

7.02 (山

I = 8.7

6.97 I = 8.3 2.6 Hz), 4.68 知, 1¾, 3.83 知, 3¾, 3.78 知, 2¾, 3.

[319] Example 50:

> 4 -Polorofenim ni4 -Methoxybezim ^' >-1 -Methim -111-Pyrazome-5 -Preparation of carboxamide

[32 is 「Daegye 1 1 Ethim 3 4 -Methoxybezim ^' ) Ni -Methim -1 -Pyrazome-5 -Production of carboxylate

[321]

[322] Ethyl 3-(4-methoxybenzyl)- 1好-pyrazole-5-carboxylate (724 !!¾, 2.78 11111101) in DMF (10 11 1 1 1) in a solution of X ₂ 00 ₃ ( 462!!¾, 3.34 11111101) and iodomethane (0.208 1111, 3.34 11111101) were added at room temperature. After stirring for 18 hours, the reaction mixture was referred to as ₂₀ , and extracted using ¾0 sho(:. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was subjected to flash column chromatography on silica gel. Titled by purifying with graphics (¾0 show 0-nucleic acid = 1:6) 2020/175957 1» (: 1^1 {2020/002897 Compound 347 (46%) was obtained as a colorless oil.

After stirring, the reaction mixture was acidified to 1N 11 (:1, and then extracted with ¾0 sho0. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was flashed on silica gel.

Purification gave the title compound 312 (92%) as a white solid.

[326] 「Daegye 31 344 -Methoxybezim')---Methoxyphenim')- 1 -Methim- 1

-Pyrazome-5 -Production of carboxamide

[327]

[328] 3-(4 -methoxybenzyl)- 1 -methyl- 1好 prepared in step 2 in 01 ₂₍ ：1 ₂ (4 1111)

-Pyrazole- 5 -Carboxylic acid (52.1 0.212 11111101) was added oxalyl chloride (53.8, 0.636 1^101) to the stirred solution at room temperature. After stirring for 30 minutes, the reaction mixture was concentrated under vacuum and diluted with (：11 _{2 (} ：1 ₂ (2 1111)). 4 -Fluoroaniline in (：!! 201 ₂ (1 1111)) to the reaction mixture A solution of (20.1, 0.212 11111101) and (59.2, 0.424 11111101) were added at room temperature, after stirring for 2 hours, the reaction mixture was diluted with NH ₄ 01 saturated aqueous solution and extracted with ₂ 01 ₂ . Organic layer

It was dried over MgSO ₄ and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (¾0 sho-nucleic acid = 1:2) to give the title compound 38.0 (53%) as yellow oil.

[329] ¾ NMR (000 ₃ , 400 MHz): 6 7.68知, 1¾, 7.48 (2¾, 7.17 (&,

I = 8.7

7.03 (111, 2¾, 6.84 (山 211, 1 = 8.7)

6.29 知, 1¾, 4.14 知, 3¾, 3.91 知, 211), 3.78 知,

3¾,

[33 is a similitude example 51:

Preparation of 3-(4 -methoxybenzim)-> 4 -methoxyphenim VI -methim -111-pyramid-5 -carboxamide

[331] 2020/175957 1»（：1^1{2020/002897

[332]

Obtained as an oil.

[333] ¾ NMR (000 ₃ , 400 MHz) 6 7.71知, 1¾, 7.41 (山

I = 9.0

7.16

I =

8.5 ¾), 6.84 (111, 4¾, 6.28 知, 1 ¾, 4.13 知, 3 ¾, 3.89 知, 2 ¾, 3.78 知, 3 ¾, 3.77 知, 3¾,

[334] Example 52:

344 -Diatrorobezim ^' )-> 2.4 -Dimethoxybezim VI -Methim -111-Pyrazome-5 -Preparation of carboxamide

[335] 「Daegye 1 1 Ethim 3 4 -Kumlovrobezym ^' ) Ni-Methim- Pyrazome-5 -Production of carboxylate

[336]

[337] Ethyl 3-(4-chlorobenzyl)-in-pyrazole-5-carboxylate in DMF (3 1111) (278

1.05 11111101) to the agitated solution

1.58 11111101) and iodomethane (98.4, 1.58 11111101) were added at room temperature. After stirring for 10 hours, the reaction mixture was referred to as 1120 and extracted using 0. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was subjected to flash column chromatography on silica gel. Purified with 11-nucleic acid = 1:5) and the title compound 129

It was obtained in solid form.

[338] 『Step 21 3-(4-chlorobenzim ^' )- 1 -methim-na-pyramid- 5 -Preparation of carboxymic acid

[339]

[34] Ethyl prepared in step 1 in 11 silk (4 1111)

3-(4-chlorobenzyl)- 1 -methyl-in-pyrazole- 5 -carboxylate (237 0.850 11111101) was added to the agitated solution of 1 0比₂ 0 (71.3 11¾, 1.70 11111101) ₂ 0 (2). It was added at room temperature. After stirring for 20 hours, the reaction mixture was acidified with 1N 11 (gross acidified and then extracted with 0 sho(:. The combined organic layer was dried with MgSO ₄ and then vacuum) 2020/175957 1»（：1^1{2020/002897. The residue was purified by flash column chromatography on silica gel (¾0 show. MeOH:EtOAc = 1: 1) and the title compound 202

(95%) was obtained as a pale yellow solid.

[341] 「Management 31

Preparation of 3-(4-big lorobezimᅵwater-and-dimethoxyphenim VI-methim-in-pyramid-5-carboxamide

[342]

[343]

Manufactured

To a solution in which 3-(4-chlorobenzyl)-1-methyl-in-pyrazole-5-carboxylic acid (74.7 11¾, 0.298 11111101) was stirred was added oxalyl chloride (75.7, 0.894 11111101) at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under vacuum

Diluted with ₂ 01 ₂ (4 1111). In the reaction mixture, 2, 4 -dimethoxyaniline (42.5, 0.2982 11111101) and

(83.2, 0.596 1^101) was added at room temperature. After stirring for 40 minutes, the reaction mixture was diluted with saturated aqueous NH ₄ 01 and extracted with ₂ 01 _2. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was flashed on a silica gel.

1:1) to the title compound 100

(87%) was obtained as an ivory solid.

[344] ¾ NMR (000 ₃ , 400 MHz): 6 8.21 (山

I = 9.5

8.02知, 1¾, 7.27 (山

I

= 8.6 Hz), 7.19 (山 2比 I = 8.7 degrees ¾), 6.49 (2¾, 6.33 知, 1 ¾, 4.17 知, 3 ¾, 3.95 知, 2¾, 3.85 知, 3¾, 3.80 知, 3¾,

[345] Sim visual example 53: 3-(4-large rorobenzoim)-八^-(2.4-dimethoxyphenim)- 1 vote

-Pyrazome-5 -Production of carboxamide

[346] 「Daegye 11 Ethim 3-(4 -Big Rorobezoim ^' )-1 table-Pyrazome-5-Preparation of carboxylate

[347]

[348] ethyl 3- (4 -chlorobenzyl)-1好-pyrazole-5-carboxyl

2.42 11111101)

(5.82 1111, 29.1 11111101, 5.0 M decane) was added at room temperature. After stirring at 120° (: for 22 hours, the reaction mixture was referred to as ₂₀ , and extracted using ¾0 sho(;) The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was concentrated in a vacuum. The title compound 645 was purified by flash column chromatography on silica gel (¾0 Show 11-nucleic acid = 1:4).

It was obtained in solid form. 2020/175957 1»（：1^1{2020/002897

[349] 「Daegye 21 3-(4 -Kumlovrobejoim ^' )-1好-pyramid- 5 -Manufacture of carboxylic acid

After stirring, the reaction mixture was acidified with 1N 11 (:1, and then extracted with ¾0 Sho0. The combined organic layer was dried with MgSO ₄ and then concentrated under vacuum. The residue was flash column chromatography _£ 0 on silica gel. Purify with 兄01 ₂₍ ：1 ₂ = 1:10) and obtain the title compound 534

(92%) was obtained as a white solid.

[352] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 8.18

5.1

7.63

7.0

7.23知, 1¾,

[353] 「Daegye 31 344 -Large Lorobe Tightening ^' )- -作.4 -Dimethoxyphenim ^' ) -1 ¥!

-Pyrazome-5 -Production of carboxamide

[355] 3-(4-chlorobenzoyl)- 1好 prepared in step 2 in DMF (2)

-Pyrazole-5 -carboxylic acid (93.7 0.37411111101) and 2, 4 -dimethoxyaniline (58.6,

0.411 11111101) to this stirred solution

0.561

0.561 11111101), (4.57 !!¾, 37.4^01) and å>0¾show (97.7 1, 0.561 11111101) were added at room temperature. After stirring for 7 hours, quenched dwen the reaction mixture was ₂ 0 ¾0 show (... And extracted with an organic layer was washed with 1N HC1 The organic layer was dried to 4, and then concentrated in vacuo on silica gel of the residue Purified by flash column chromatography (¾0 show ₀ -nucleic acid = 1:3 1 ₀ 1:1) to obtain the title compound 117 ₁₁ ¾ (81%) as a burgundy solid.

[356] ¾ NMR (00\ ₃ , 400 MHz): 6 11.91知, 1¾, 9.09知, 1¾, 8.39凡

I = 8.2

8.02 ((1, 211, 1 = 7.8

7.50 (山 211, 1 = 6.8

7.46 知, 1¾, 6.53 (III, 211), 3.88 知,

3¾, 3.81知, 3¾,

[357] Simultaneous vision example 54: Preparation of 3-(4-methoxybezim 休 (pyridine-2-im VI-pyramid-5-carboxamide)

[358] 2020/175957 1»(：1^1{2020/002897

[359] 3-(4-methoxybenzyl)-111-pyrazole-5-carboxylic acid (122) in DMF (2 1111)

0.525

[36 2 ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.32 知, 1 ¾, 10.27 知, 1 ¾, 8.98 知, 1¾, 8.27 (山

/

= 8.6 6.89 ((1, 211, /= 8.6 6.52知, 1¾, 3.96知, 2¾, 3.72知, 3¾

[361] Simultaneous vision example 55: 3-(4-methoxybenzim)-> pyridine-3 -im)-111-pyramid-5-carboxamide

[363] Title compound 105.7 in a manner similar to Example 54

yellow

It was obtained as a solid.

[364] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.32知, 1¾, 10.27知, 1¾, 8.98知, 1¾, 8.27 (山

/

= 8.6 6.89 ((1, 211, /= 8.6 6.52知, 1¾, 3.96知, 2¾, 3.72知, 3¾

[365] Sim visual example 56: Preparation of 3-(4-methoxybenzim) -(pyridine-4-im)-111-pyramid-5-carboxamide

[366]

[367] Title compound 57.5 in a manner similar to Example 54

As a solid

Obtained. 2020/175957 1»(：1^1{2020/002897

[368] ¾ NMR (000 ₃ , 500 MHz): 6 9.08知, 1¾, 8.39

6.3

7.62 (&,

/

= 6.5 7.08 ((1, 211, /= 8.6 6.80 (山 211, / = 8.7

6.69知, 1¾, 3.98知, 2¾,

3.74知, 3¾,

[369] Example 57:

Preparation of 3-(4-methoxybenzim)-> 6-methoxypyridine-3-im)-111-pyramid-5-carboxamide

[37

[371] Title compound 137.3 in a similar manner to Example 54

(82%) was obtained as a reddish brown solid.

[372] ¾ NMR (DMSO-d ₆ , 500 MHz): 6 13.24知, 1¾, 10.08知, 1¾, 8.55

1.8 Hz), 8.07 ((¾

/ = 8.8, 2.1

/ =8.7 degrees ¾), 6.88 (山

/ = 8.7 degrees ¾),

6.79 ((1, 111, / = 8.9 6.48知, 1¾, 3.96知, 211), 3.82知, 311), 3.72知, 3¾,

[373] Simultaneous vision example 58: Preparation of 3-(4-fluorobenzim) -(pyridine-2-im)-111-pyramid-5-carboxamide

[374]

[375] Title compound 27.3 in a manner similar to Example 54

It was obtained as a solid.

[376] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.43知, 1¾, 9.52知, 1¾, 8.34 (山

/ = 4.0 Hz), 8.16凡

/ = 8.4 Hz), 7.83 (1¾, 7.31 (2¾, 7.15 (3¾, 6.60知, 1¾, 4.02知, 2¾);

[377] Example 59: Preparation of 3-(4-fluorobenzyl)-pyridine-3-yl)-111-pyrazole-5-carboxamide

[378]

[379] Title compound 19.8 in a method similar to Example 54

yellow

It was obtained as a solid.

[38 2 ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.34 知, 1 ¾, 10.28 知, 1 ¾, 8.97 知, 1¾, 8.27 2020/175957 1 ^» (：1^1{2020/002897

(111, 1¾, 8.21

6.8 Hz), 7.35 (1¾, 7.32 (2¾, 7.15 (2¾, 6.54 知,

1¾, 4.03知, 2¾,

[381] Simultaneous vision example 60: 3-(4-fluorobenzim)-> pyridine-4-im)-111-pyramid-5-carboxamide

[383] Title compound 10.0 in a method similar to Example 54

(9%) was obtained as a pale yellow solid.

[384] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.40 知, 1 ¾, 10.44 知, 1 ¾, 8.43 (2 ¾, 7.83 (111, 2 ¾, 7.31 (111, 2 ¾, 7.16 (2 ¾, 6.56 知, 1 ¾)) , 4.03知, 2¾,

[385] Example 61:

Preparation of 3-(4-fluorobenzyl ^' )-> 6-methoxypyridine-3 -yl ^' )-111-pyrazole-5-carboxamide

[386]

[387] Title compound 139 in a manner similar to Example 54

Red

It was obtained as a solid.

[388] ¾ NMR (DMSO-d ₆ , 500 MHz): 6 13.27知, 1¾, 10.08知, 1¾, 8.53知, 1¾, 8.06 (山

= 8.9 6.50知, 1¾, 4.02知, 211), 3.82知, 3¾,

[389] Simultaneous vision example 62: Preparation of 3-(4-large rorobenzim) -(pyridine-2-im)-111-pyramid-5-carboxamide

[39 this

[391] Title compound 27.5 in a similar manner to Example 54

As a solid

Obtained.

[392] 400 MHz): 6 13.45 知, 1¾, 9.52 知, 1¾, 8.34 (

3.4

4 1¾), 7.86 (1¾, 7.38凡

/ = 8.3 1¾), 7.30 (

6.62知, 1¾, 4.02知, 2¾, 2020/175957 1»(：1^1{2020/002897

[393] Simultaneous vision 63: 3- (4-large lorobenzim)-(pyridine-3-im)-111-pyramid-5-carboxamide

[395] Title compound 19.1 in a similar manner to Example 54

As a solid

Obtained.

[396] ¾ NMR (DMSO-d ₆ , 500 MHz): 6 13.33知, 1¾, 10.26知, 1¾, 8.96知, 1¾, 8.26 (山

8.1, 4.7 7.30 ((1, 211, / = 8.3 6.54知, 1¾, 4.04知, 2¾,

[397] Simulated vision example 64: 3-(4-Derurorobenzim) -(Pyridi- 4 -Im)-111-pyramid-5-Carboxamide

[399] Title compound 25.3 in a manner similar to Example 54

As a solid

Obtained.

[400] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.40知, 1¾, 10.42知, 1¾, 8.43 (2¾, 7.82 (111, 2¾, 7.39)

/ = 8.1 Hz), 7.29凡

/ = 8.0 Hz), 6.57 知, 1¾, 4.03 知, 2¾.

[401] Sim vision example 65:

Preparation of 3-(4-chlorobenzyl)- (6-methoxypyridin- 3 -yl)-111-pyrazole-5-carboxamide

[402]

[403] Title compound 71.3 in a similar manner to Example 54

(59%) was obtained as an orange solid.

[404] ¾ NMR (DMSO-d6, 400 MHz): 6 13.30知, 1¾, 10.12知, 1¾, 8.54知, 1¾, 8.06 (山 111, / = 8.6

7.39 (山 211, / = 7.2

7.29 (山 211, / = 6.8

6.80 (山 111, / = 8.8

¾), 6.52知, 1¾, 4.03知, 2¾, 3.82知, 3¾,

[405] Sim vision example 66: 3- (3-large roro benzim)-(pyridine-2-im)-111-pyramid-5-Preparation of carboxamide 2020/175957 1 ^» (：1^1{2020/002897

[406]

[407] Title compound 32.8 in a manner similar to Example 54

Obtained.

[408] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.46知, 1¾, 9.54知, 1¾, 8.34 (山

/ = 4.0

Hz), 8.17凡

/ = 8.4 Hz), 7.83 (1¾, 7.36 (1¾, 7.34 (1¾, 7.30凡)

/ = 8.2 7.24 ((1, 111, /= 7.5 7.14 (III, 1¾, 6.67知, 1¾, 4.04知, 2¾,

[409] Simulated vision 67: Preparation of 3-(3-large rorobenzim)-(pyridine-3-im)-111-pyramid-5-carboxamide

6.62知, 1¾, 4.06知, 2¾,

[417] Example 69:

Preparation of 3-(3 -large lorobenzim) -(6 -methoxypyridine-3 -im)-111 -pyramid-5 -carboxamide

[418] 2020/175957 1 ^» (：1^1{2020/002897

[419] Title compound 92.8 in a similar manner to Example 54

(74%) was obtained as a pink solid.

[42 ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.31 知, 1 ¾, 10.12 知, 1 ¾, 8.55 (1 ¾, 8.07 (( ¾ / = 8.8, 2.0 1 ¾), 7.35 (2 ¾, 7.30 (山

/ = 7.7 1¾), 7.24 (山

/ = 7.3

6.80 ((1, 111, / = 8.8 6.56知, 1¾, 4.05知, 211), 3.82知, 3¾,

[421] Simulated vision example 70: Preparation of 3-(2-Chanrobezym pyridine-2-Im)-111-pyramid-5-carboxamide

[422]

[423] Title compound 60.7 in a manner similar to Example 54

yellow

It was obtained as a solid.

[424] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.48 知, 1 ¾, 9.54 知, 1¾, 8.34 (1¾, 8.16凡 111, / = 8.4 1¾), 7.82, 111, / = 7.9

7.46 (山 111, /= 6.8

7.35 (III, 1¾, 7.31 知1, 2¾, 7.13 0-, / = 5.9 1¾), 6.52 知, 1¾, 4.14 知, 2¾.

[425] Simultaneous vision example 71: Preparation of 3-(2-Derrobezim pyridine-Im VI-pyramid-5-carboxamide

[426]

[427] Title compound 66.7 in a manner similar to Example 54

Obtained as an orange solid.

[428] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.41 知, 1 ¾, 10.30 知, 1 ¾, 8.97 知, 1 ¾, 8.28 (111, 1 ¾, 8.20 (111, 1¾, 7.47)

/ = 7.0 Hz), 7.33 (4¾, 6.47, 1¾, 4.15知, 2¾,

[429] Simultaneous vision example 72: Preparation of 3-(2-large rorobenzim) -(pyridine-4-im)-111-pyramid-5-carboxamide 2020/175957 1»(：1^1{2020/002897

[431] Title compound 80.0 in a similar manner to Example 54

It was obtained as a solid.

[432] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.48 知, 1 ¾, 10.44 知, 1 ¾, 8.44 (

4.5

Hz), 7.83

7.0 Hz), 7.34 (3¾, 6.49, 1¾, 4.15, 2¾.

[433] Example 73:

Preparation of 3- (2 -chlorobenzyl) -> 6 -methoxypyridine-3 -yl)-111-pyrazole-5 -carboxamide

[434]

[435] In a similar manner to Example 54, 140.5 mg (75%) of the title compound was obtained as a light brown solid.

[436] ¾ NMR (DMSO-d ₆ , 400 MHz): 6 13.35 (s, 1H), 10.11 (s, 1H), 8.54 (d, lH, / = 1.6 Hz), 8.07 (dd, 1H, / = 9.0, 2.2 Hz), 7.47 (d, 1H, / = 7.7 Hz), 7.33 (m, 3H), 6.80 (d, 1H, / = 9.0 Hz), 6.43 (s, 1H), 4.14 (s, 2H) , 3.82 (s, 3H).

[437] Comparative Example

[438] Gliclazide was purchased and used from Sigma-Aldrich (Yongin, Korea). Gliclazide is a therapeutic drug for diabetic patients and is an insulin secretion promoter.

[439] Test Example 1. Evaluation of isium rin secretion ability of INS-1 cells (pancreatic cells)

[440] 1. INS-1 cell culture

[441] 10% FBS, streptomycin (0.1 mg/mL), penicillin (100 U/ml), 10 mM hepes, 2 mM L-glutamine, I at 37°C, 90% air and 10% CO ₂ INS-1 cells were cultured in RPMI 1640 medium containing mM sodum-pyruvate and 0.05 mM 2-mercaptoethanol.

[442] 2. Insulin secretion due to glucose stimulation (GSIS, glucose stimulated insulin)

secretion)

[443] In order to confirm the glucose-dependent insulin secretion hyperstimulation pattern by each component in INS-1 cells, the stimulation index (SI) by component concentration was immediately determined.

[444] INS- 1 cell line was inoculated into a 12 well tissue culture dish at ⁵ ×10 ⁵ cells per well, and 24 hours later Krebs-Ringer buffer (1 mM KH ₂ PO ₄ , 24 mM NaHCO ₃ , 115 mM NaCl, 5 mM KCI, 1 ₂ times with mM MgSO ₄ -7H ₂ 0, 2.5 mM CaCl ₂ .2H ₂ 0, 0.25% BSA, pH 7.4) 2020/175957 1»（：1^1{2020/002897 After washing, starvation was carried out in Krebs-Ringer buffer for 2 hours. Candidate materials were Krebs- at a concentration of 2.5 _[ xM, 5 _[,i M, 10 _[ xM, respectively. After pre-treatment in each well by dilution in Ringer buffer, 3.3 mM of low-concentration glucose (Basal working solution) and 16.7 mM of high-concentration glucose (glucose working solution) were treated. After incubation for 1 hour, 12,000 rpm,

After centrifugation at 4 °C for 10 minutes, the supernatant was measured with a rat insulin ELISA kit (ALPCO, 80-INSMSH-E01). Gliclazide (Sigma Aldrich/ CAS Number:

21187-98-4) was measured in the same manner as in the above measurement method, except that the concentrations of 2.5, 5, and 10 ^ iM were used.

[445] 3. Experimental results

[446] Examples 1, 13, 28, 30, 32, 34, 36, 38, 39, 51, 54, 60, 63 and 68 when the insulin secretion for 1 hour was investigated in the presence of the compound according to the present invention It can be seen that the concentration-dependent increase of is appeared in compounds of

[447] INS-1 cells have an SI value in the presence of 10 pM of the compound according to the present invention.

Compared with SI value in the presence of 10 pM of Gliclazide, a positive control, which is a type 2 diabetes treatment used, it can show an equal or higher level of insulin secretion.

It was confirmed that the pancreatic cells were not damaged even under high blood sugar conditions over a long period of time.

[448] Example 2. simheom MG53 and bamhyeo analysis of IRS-1 in C2C12 cells (myocytes gomgyeok ^')

[449] Examples 1, 13, 30, 34, 36, 38, 40 and 41 C2C12 for each of the compounds

Expression analysis of MG53 and IRS-1 in cells (skeletal muscle cells) was performed.

[45 is 1. Cell culture

[451] 10% fetalbovine serum (FBS, Gibco-Brl, Grand Island, NY, USA), penicillin G (100 ^ ig/ml), streptomycin sulfate (100 ^ ig/ml), amphoteric muscle cell line C2C12 cells It was cultured in DMEM medium containing tericin B (0.25 ^ ig/ml) and 2-mercaptoethanol (50 pm), and cultured in a humid condition with 37 ^O C temperature and 5% CO ₂ processing.

[452] 2. C2C12 cell differentiation

[453] To induce differentiation of C2C12 cells, when the C2C12 myoblast reached 90% confluency, the culture medium was replaced with 2% horse serum instead of 10% FBS. After culture for 3-4 days, the cells were differentiated into multinuclear myotubes, which were then used for experiments.

[454] 3. Evaluation of MG53 protein expression

[455] After washing the treated cells in an incubator with PBS (phosphate buffer saline), add PBS and remove the cells from the culture dish using a cell scraper, and centrifuge the cells at 13,200 rpm for 10 minutes at 4 ^O C. Collected. In a lysis buffer (pH 7.2) composed of 320 mM sucrose, 200 mM Hepes, and 1 mM EDTA (ethylenediaminetetraacetic acid), a protease inhibitor cocktail and a phosphatase inhibitor cocktail·^：Additional 7]· and then put into the blast cells from above, 4 ^O In C, the cell membrane is 2020/175957 1»（：1^1{2020/002897 It was shredded. Using the BCA protein assay kit, quantify the total protein amount, take 20 [xg each, and mix it with the sample buffer, and then use 10% SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) at 65 volt for 3 hours at room temperature. Protein was separated by electrophoresis at. The protein isolated on the gel was transferred to a polyvinylidene fluoride (PVDF) microporous membrane using a blocking solution containing 25 mM tris, 192 mM glycine, and 10% methanol at 4 °C for more than 12 hours at 15 volts. Silver TBS-T buffer (40 mM Tris-HCl pH 7.4, 25 mM NaCl, 0.1% Tween-20) was added with 5% non-fat dry milk or 5% bovine serum albumin to inhibit non-specific binding with antibodies. The reaction was carried out on a shaker for 1 hour. After that, the blocking solution was reacted with an antibody for 2 hours at room temperature, and washed 5 times with TBS-T buffer for 5 minutes each, followed by HRP-conjugated reaction with the primary antibody. The secondary antibody was added to the blocking solution and reacted for 2 hours under the same conditions as the primary antibody. After washing 5 times with TBS-T buffer for 5 minutes each, the film was sensitized using an ECL system in a dark room to observe the expression pattern of each protein.

[456] 4. IRS-1 expression evaluation

[457] INS-1 cell line was inoculated into a 6-well tissue culture dish at 4×10 ⁵ cells per well, and after 24 hours, glucose was diluted in RPMI 1640 medium to 16.7 mM and treated in each well. After 48 hours, the candidate materials were treated at various concentrations (5 ^ iM, 10 ^ iM, 20 ^ iM, 50 [xM). After incubation for 24 hours, the cells were collected and washed once with phosphate-buffered saline, and RIP A buffer (Cell Signaling, MA, USA) containing 1 mM phenylmethylsulfonyl fluoride was added and left for 20 minutes, and then 4 ^O C Cell lysate was separated by centrifugation at 12,000 rpm for 20 minutes. The separated cell lysate was assayed for protein using a protein detection kit (BCA protein detection kit, Thermo Scientific, Rockford, IL, USA). And 10% SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel) of 20 cell lysates per well.

electrophoresis). The protein was transferred to a PVDF membrane (Merck Millipore, Darmstadt, Germany), and the membrane was used for 2 hours at room temperature using 5% skim milk to prevent non-specific binding of the antibody.

After blocking, TBST buffer (20 nM tris-HCl, 150 mM NaCl, 0.05%

Tween-20, pH 7.5) was washed 3 times for W minutes each, and a primary antibody (Cell Signaling, Danvers, MN, USA) was used to measure the expression level of apoptotic protein in the cell.

1: Diluted to 1,000, reacted at room temperature for 1 hour, and washed 3 times for 10 minutes with TBST buffer. Afterwards, secondary antibody (goatantirabbit lgG, Calbiochem, La Jolla, CA,

USA) was diluted 1: 2,000 and reacted at room temperature for 2 hours, and the protein was confirmed with an ECL detection kit (GE healthcare).

[458] 5. Experimental results

[459] Examples 13, 30, 38, 40 and 41 of C2C12 cells (skeletal muscle cells) for each of the compounds 2020/175957 1»（：1^1{2020/002897

The results of expression analysis of MG53 and 11 «-1 are shown in Fig. 1.

[46] When the compounds of Examples 13 and 30 were treated at different concentrations (0, 5, 10, 29, 50), the expression amount of 11 «-1 protein tended to increase in a concentration-dependent manner, and ^ «} 53 protein the expression amount was found to decrease in a dose-dependent manner. in particular, 50 _{l ·} exhibited a large effect on the iM concentration. example 38, 40 and the compound 41, respectively concentrations (0, 5, 10, 29 , 50 l · When treated by _l M), the expression amount of ^- 1 showed a tendency to increase in a concentration-dependent manner, especially at concentrations of 10, 20, and 50 _l· iM. In particular, at the concentration of 50 µm, it showed a tendency to increase significantly. Increased. The expression level of MG53 protein is 20, 50

There was a significant decrease in concentration.

[461] From the above experimental results, the pyrazole amide derivative compound according to the present invention

It can effectively inhibit the activity of MG53 in skeletal muscle cells, from which

11«- 1 can reduce the decomposition, and 11«- 1 can increase sensitivity to insulin, and protect pancreatic beta cells from exposure to sugar over a long period of time, so that blood sugar levels are very effective without causing hypoglycemia. You can lower it.

[462] In the above, a specific part of the content of the present invention has been described in detail.

It will be apparent to those of ordinary skill in the art that these specific descriptions are merely preferred embodiments, and that the scope of the invention is not limited by it. Therefore, the practical scope of the invention is determined by the appended claims and them. It will be said to be defined by the equivalent of

Claims

2020/175957 1»（：1^1{2020/002897 Claims

[Claim 1] A pyrazole amide derivative compound represented by the following formula (1), an optical isomer thereof

Or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

0 (= 0)-and

Teroaryl and {wherein, at least one hydrogen of the aryl or heteroaryl may be substituted with hydroxy, halo, 01-04 alkyl, 01-04 alkoxy, 0^4 alkyl ester, 01-04 haloalkyl or phenoxy), å ₁ to

Are each independently non-hydroxy, halo, 01-04 alkyl, 01-04 alkoxy, (the 1 4 alkyl ester or 01-04 haloalkyl,

Independently or 0-04 alkyl.

[Claim 2]

0 (= 0)-and

Teroaryl and {wherein, aryl or at least one hydrogen of the heteroaryl is halo, 01-04 alkoxy, 0^4 alkylester or

May be substituted with, and at least one hydrogen of the phenoxy may be substituted with hydroxy, may be substituted with 01-04 alkyl},

ego,

Or 01-04 alkyl,

å ₅ is each independently bihalo or 01-04 alkoxy,

Pyrazolamide derivative compound, its optical isomer or its

Pharmaceutically acceptable salts.

[Claim 3] The method of claim 1,

Is an aryl inpyrazole amide derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Claim 4] In paragraph 3,

The aryl is phenyl, or a ring in which a 5 to 6 membered non-aromatic ring is fused to phenyl, a pyrazole amide derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Claim 5] The method of claim 4, 2020/175957 1 ^» （：1^1{2020/002897 A pyrazole amide derivative compound, its optical isomer or its pharmaceutically acceptable salt, wherein the fusion ring contains 1 or 2 oxygen atoms.

[Claim 6] In paragraph 3,

A pyrazole amide derivative compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 is selected from the following compounds:

2020/175957 1»（：1^¾2020/002897

[Claim 7] The method of claim 1,

¥ is a heteroaryl inpyrazole amide derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Claim 8] The method of claim 7,

The heteroaryl is a 5 to 6 membered heteroaryl, a pyrazole amide derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Claim 9] In clause 8,

The heteroaryl is one containing 1 to 3 N, a pyrazole amide derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Claim] In paragraph 9,

The heteroaryl is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or 1,3, 5-triazinyl, a pyrazole amide derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Claim 11] The method of claim 7,

A pyrazole amide derivative compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 is selected from the following compounds: 2020/175957 1»（：1^1{2020/002897

[Claim 12] Pyrazolamide derivative according to any one of paragraphs 1 to 11

A pharmaceutical composition for the treatment or prevention of diabetes, comprising a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[The pharmaceutical composition according to claim 12, wherein the diabetes is type 2 diabetes.

[Claim 14] The pharmaceutical composition according to claim 12, which inhibits MG53.

[Claim 15] Pyrazolamide derivative according to any one of paragraphs 1 to 11

A method for treating or preventing diabetes, comprising administering a therapeutically effective amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, to a mammal, including humans.

[Claim 16] Use of the pyrazole amide derivative compound, its optical isomer or its pharmaceutically acceptable salt according to any one of items 1 to 11 for the manufacture of a drug for the treatment of diabetes.