KR20210152312A - 4-(4,5-dihydro-1h-pyrazol-1-yl)pyrimidine compound as cannabinoid receptor (cb1 receptor) antagonists and pharmaceutical composition including the same - Google Patents

Abstract

The present invention provides a compound represented by chemical formula I, an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same. A_1, A_2, R_1, and R_2 in the chemical formula I are the same as defined in claim 1.

Description

4-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidine compound as cannabinoid receptor (CB1 receptor) antagonist and pharmaceutical composition comprising the same {4-(4,5-DIHYDRO-1H-PYRAZOL) -1-YL)PYRIMIDINE COMPOUND AS CANNABINOID RECEPTOR (CB1 RECEPTOR) ANTAGONISTS AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME}

The present invention provides a novel 4-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidine compound acting as an inverse agonist or antagonist of CB1 receptor among cannabinoid receptors, optical isomers thereof, and pharmaceutically acceptable It relates to salts, their use in the manufacture of a medicament for the treatment of CB1 receptor mediated diseases, pharmaceutical compositions containing them and methods of treatment using the compositions, and methods for their preparation.

Obesity is caused by several causes, but in common it is a cause of various adult diseases such as hypertension, diabetes, hyperlipidemia, arteriosclerosis, fatty liver, cholelithiasis, arthritis, pulmonary dysfunction, gynecological disease, breast cancer, and endometritis. In particular, obesity is the biggest cause of metabolic syndrome, including vascular diseases such as diabetes, hypertension, hyperlipidemia, and arteriosclerosis, and is one of the biggest problems in modern medicine.

It has been known that CB1 receptor antagonists can affect energy homeostasis through central and peripheral mechanisms of action through many in vitro and in vivo experiments. CB1 receptor has become a promising target for the treatment of obesity and obesity-related metabolic syndrome since it has been proven that it can effectively reduce body weight and alleviate metabolic syndrome diseases such as diabetes and cardiovascular disease associated with obesity.

At the end of 2008, despite the excellent weight loss effects of CB1 receptor antagonists, CNS side effects such as depression and anxiety were highlighted, and the development of CB1 receptor antagonists faced a critical crisis. The first-generation CB1 receptor antagonists targeted the CNS CB1 receptor as the main target and aimed at weight loss due to anorexia, so they focused on the development of compounds that pass the blood-brain-barrier (BBB) well. Since the development of second-generation CB1 receptor antagonists poses a problem with CNS side effects, the development of antagonists that can selectively modulate peripheral CB1 receptors without touching the CNS CB1 receptors will play a very important role in the development of treatments for obesity and metabolic syndrome related to obesity. will be.

International Patent Publication No. WO 2007/131219

One object of the present invention is to provide a novel compound having CB1 receptor antagonistic activity, an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of a CB1 receptor-mediated disease comprising a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of obesity, or obesity-related metabolic disease, comprising a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

Another object of the present invention is a CB1 receptor antagonistic activity-related disease comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient To provide a method for preventing or treating

Another object of the present invention is to provide the use of a compound represented by Formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a CB1 receptor-mediated disease.

The present invention provides a compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula I]

In Formula I, A ₁ and A ₂ may each independently represent -(C6-C12 aryl) or 5-10 membered heteroaryl including at least one heteroatom selected from N, O, and S. Each of the hydrogen atoms of A ₁ and A ₂ may be independently substituted or unsubstituted with at least one halogen.

,

, NHR₃, 또는 OR₄일 수 있다. 상기 R₁에서 상기 -(C6-C12 아릴)의 수소 원자들은 각각 독립적으로 할로겐 및 CF₃ 중 선택되는 적어도 하나로 치환 또는 비치환될 수 있다.R ₁ is hydrogen, -(C6-C12 aryl), halogen, -S(C1-C4 alkyl), -S(=O) ₂ (C1-C4 alkyl), -CF ₃ ,

,

, NHR ₃ , or OR ₄ . The hydrogen atoms of -(C6-C12 aryl) in _{R 1} may be each independently substituted or unsubstituted with at least one selected from _{halogen and CF 3 .}

In the present specification, C1-C4 in parentheses of -(C1-C4)alkyl means the number of carbon atoms. That is, C1-C4 means 1 or more and 4 or less carbon atoms.

Y ₁ and Y ₂ may each independently be CR ₅ R ₆ , O or S.

R ₅ and R ₆ may each independently be -H, halogen, -CF ₃ , -(C1-C4 alkyl) or -C(=O)NH ₂ .

a to d may each independently be an integer of 0 or more and 3 or less, at least one of a and b may be an integer of 1 or more, and at least one of c and d may be an integer of 1 or more.

는 d가 2인 경우

로 표시된다.For example,

is when d is 2

is displayed as

R ₃ and R ₄ are each independently hydrogen, halogen, -(C1-C4 alkyl), -(C6-C12 aryl), 3-6 membered heterocycloalkyl containing O as a hetero atom, -(C3-C6 cyclo alkyl), or -n(CH2)Ph, where n is an integer greater than or equal to 1 and less than or equal to 5, and Ph is a phenyl group. For example, n(CH2)Ph may be benzyl (ie, n=1). can be In R ₃ and R ₄ , each hydrogen of -(C1-C4 alkyl), -(C6-C12 aryl) and -n(CH2)Ph is each independently substituted or unsubstituted with at least one selected from _{halogen and CF 3} can be

또는

일 수 있다.each R ₂ is independently -NO ₂ , -NH ₂ , -C(=O)-O(C1-C4 alkyl), -NHS(=O) ₂ (C1-C4 alkyl), -S(=O) ₂ (C1-C4alkyl), -C(=O)(C1-C4alkyl), -C(=O)CH ₂ CF ₃ ,

or

can be

R ₇ to R ₁₀ are each independently hydrogen, -NH2, -CF3, -C(=O)(C3-C6cycloalkyl), -O(C1-C4alkyl), -(C1-C4alkyl)CF3, - (C3-C6 cycloalkyl), -(C1-C13 alkyl) or phenyl.

A ₁ may be an unsubstituted phenyl group, and A ₂ may be a phenyl group in which at least one hydrogen is substituted with a halogen. For example, A ₂ may be a phenyl group in which at least one hydrogen is substituted with F or Cl.

,

, NHR₃ 또는 OR₄일 수 있다. 상기 R₁에서 아릴의 수소 원자들은 각각 독립적으로 할로겐 또는 CF₃로 치환 또는 비치환될 수 있다.상기 R₁에서 아릴의 수소 원자들은 각각 독립적으로 Cl 또는 CF₃로 치환 또는 비치환될 수 있다.wherein R ₁ is aryl, halogen, -S(C1-C4 alkyl), -S(=O) ₂ (C1-C4 alkyl), -CF ₃ ,

,

, NHR ₃ or OR ₄ . In R ₁ , hydrogen atoms of aryl may be independently substituted or unsubstituted _{with halogen or CF 3} . Hydrogen atoms of aryl in _{R 1} may be independently substituted or unsubstituted _{with Cl or CF 3 .}

The Y ₁ may be CR ₅ R ₆ or O, and Y ₂ may be CR ₅ R ₆ , O or S.

The R ₅ and R ₆ may be each independently -H, halogen, -CF ₃ , or -C(=O)NH ₂ . For example, when R ₅ and R ₆ are halogen, the halogen may be F.

A to c may each independently be an integer of 0 or more and 2 or less. The d may be an integer of 1 or more and 2 or less.

R ₃ and R ₄ may each independently be -(C1-C4alkyl), aryl, oxetane, -(C3-C6cycloalkyl) or benzyl. In R ₃ and R ₄ , hydrogen atoms of -(C1-C4 alkyl), -(C6-C12 aryl), and benzyl may each independently be substituted or unsubstituted with at least one selected from _{halogen and CF 3 .}

또는

일 수 있다.The R ₂ are each independently -NO ₂ , -C(=O)-O(C1-C4alkyl), -NHS(=O) ₂ (C1-C4alkyl),

or

can be

R ₇ to R ₁₀ are each independently hydrogen, -NH2, -O(C1-C4 alkyl), -(C1-C4 alkyl)CF3, -(C3-C6 cycloalkyl), -(C1-C4 alkyl) or It may be phenyl.

A ₁ may be an unsubstituted phenyl group. Each of the hydrogens of A ₂ may independently be a halogen-substituted phenyl group. The _{hydrogen of A 2} may be each independently a -F or -Cl substituted phenyl group.

The R ₁ may be -CF ₃ or OR ₄ . R ₄ may be -(C1-C4alkyl), aryl, oxetane, -(C3-C6cycloalkyl), or benzyl. In R ₄ , hydrogen atoms of -(C1-C4 alkyl), -(C6-C12 aryl) and benzyl may each independently be substituted or unsubstituted _{with halogen or CF 3 .}

,

, NHR₃, 또는 OR₄일 수 있다. 상기

은

,

,

,

,

,

,

,

,

및

를 포함할 수 있다. 상기

은

,

,

및

를 포함할 수 있다.More specifically, the R ₁ is phenyl, -Cl, -SCH ₃ , -S(=O) ₂ CH ₃ , -CF ₃ ,

,

, NHR ₃ , or OR ₄ . remind

silver

,

,

,

,

,

,

,

,

and

may include remind

silver

,

,

and

may include

일 수 있다.wherein R ₂ is

can be

wherein R ₇ to R ₁₀ are each independently hydrogen, -NH2, -O(C1-C4 alkyl), -(C1-C4 alkyl)CF3, -(C3-C6 cycloalkyl), -(C1-C4 alkyl), or It may be phenyl.

In the present specification, aryl refers to a monocyclic aromatic or polycyclic aromatic functional group consisting only of carbon and hydrogen, and the number of carbon atoms of the aryl may be 6 or more and 12 or less. Examples of aryl include, but are not limited to, phenyl, naphthyl or biphenyl.

As used herein, heteroaryl refers to a monocyclic or polycyclic heterocyclic ring in which at least one carbon of the monocyclic or polycyclic aromatic functional group is substituted with nitrogen (N), oxygen (O) or sulfur (S), monocyclic or polycyclic can Heteroaryl may be a 5-10 membered, 5-8 membered or 5-6 membered ring. When heteroaryl includes two or more hetero atoms, the two or more hetero atoms may be the same as or different from each other. Examples of heteroaryl include thiophene, furan, pyrrole, imidazole, thiazole, oxazole, oxadiazole, triazole, pyridine, bipyridine, pyrimidine, triazine, pyridazine, pyrazine, quinoline, quinazoline, iso quinoline or indole, but is not limited thereto.

Cycloalkyl herein may be monocyclic cycloalkyl or polycyclic cycloalkyl. The number of carbon atoms of the cycloalkyl may be 3 or more and 6 or less. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Heterocycloalkyl herein may be monocyclic heterocycloalkyl or polycyclic heterocycloalkyl. Heterocycloalkyl may be a 3-6 membered or 4-5 membered ring. Examples of heterocycloalkyl include, but are not limited to, propylene oxide, oxetane, tetrahydrofuran, or tetrahydropyran.

In the present specification, "alkyl" of -(C1-C4)alkyl or -(C1-C13)alkyl may be a straight-chain or branched alkyl group. When -(C1-C13)alkyl is branched chain alkyl, -(C1-C13)alkyl may be represented, for example, by -C(C1-C4alkyl) ₃ or -CH(C1-C4alkyl) ₂ .

In this specification, halogen may be F, Cl, Br or I.

은 연결되는 부분을 표시한 것이다.in this specification

indicates the parts to be connected.

The formula used herein is defined with reference to the following formula (a) in the present specification.

For example, Formula I may include Formula II below.

[Formula II]

In the above formula (II),

X may be halogen. For example, X can be F or Cl. R ₁ and R ₂ may be the same as defined in Formula I above.

The compound represented by Formula I may be any one selected from the compounds shown in the following table.

In the present invention, the pharmaceutically acceptable salt of the compound according to the present invention refers to a salt commonly used in the pharmaceutical industry, for example, prepared from calcium, potassium, sodium and magnesium. inorganic acid salts prepared from inorganic ionic salts, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, 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, glucuronic acid, aspartic acid acid, ascorbic acid, carbonic acid, vanillic acid, an organic acid salt prepared from hydroiodic acid and the like; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; amino acid salts prepared from glycine, arginine, lysine, and the like; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like. Alternatively, the pharmaceutically acceptable salt of the compound may include a salt with an alkali metal such as sodium, potassium or lithium, and the types of salts in the present invention are not limited by these listed salts.

In the present invention, optical isomers include not only enantiomers, but also mixtures of enantiomers and racemates.

The present invention provides a pharmaceutical composition comprising the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicinal effects in addition to the compound represented by Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof.

The compound represented by Formula I for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients when it is prepared as a complex formulation together with other active ingredients.

The composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the weight, age, sex, and health status of the patient. , diet, administration time, administration method, excretion rate and the severity of the disease, etc., the range varies. The daily dose of the compound represented by the formula (I) of the present invention is about 1 to 1000 mg/kg, preferably 5 to 100 mg/kg, and may be administered once to several times a day in divided doses.

The pharmaceutical composition treats or prevents a CB1 receptor mediated disease. The CB1 receptor mediated disease includes obesity or obesity-related metabolic disease.

The present invention relates to a pharmaceutical composition comprising a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preparing a pharmaceutical preparation for the treatment or prevention of obesity or obesity-related metabolic disease use can be provided.

The compound represented by the above formula (I) may act as an antagonist of the CB1 receptor. The CB1 receptor is one of two different subtypes of the cannabinoid receptor (CB1 and CB2) and belongs to the G protein coupled receptor superfamily. The compound of one embodiment can effectively reduce the body weight of obese patients by acting as an antagonist to the CB1 receptor involved in energy metabolism and appetite regulation. It can also alleviate metabolic diseases associated with obesity.

When a drug acts on the CB1 receptor of the central nervous system (CNS), side effects such as depression or anxiety may occur. Meanwhile, it may selectively act on the CB1 receptor of the peripheral nervous system among the CB1 receptors of the central nervous system and the CB1 receptors of the peripheral nervous system (PNS) according to an embodiment. Accordingly, the compound of one embodiment may reduce or prevent side effects caused by acting on the CB1 receptor of the central nervous system.

As used herein, obesity-related metabolic disease is defined as a metabolic disease caused by or partially due to obesity. Examples of obesity-related metabolic disease include type 2 diabetes, angina, hypertension, congestive heart attack, hyperlipidemia, nonalcoholic fatty liver disease, or thrombolytic disorder.

In the present specification, non-alcoholic fatty liver disease refers to liver disease when the cause of fatty liver is not caused by alcohol. Examples of nonalcoholic fatty liver disease include simple fatty liver, nonalcoholic steatohepatitis, or nonalcoholic fatty liver cirrhosis. For example, in one embodiment, the nonalcoholic fatty liver disease may be nonalcoholic steatohepatitis.

The present invention provides the use of a CB1 receptor antagonist of a pharmaceutical composition comprising the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition may selectively act on CB1 receptors in the peripheral nervous system.

The present invention may provide a method for treating or preventing obesity or obesity-related metabolic disease, comprising administering to a subject in need of treatment a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

As used herein, the term “subject in need of treatment” refers to mammals including humans, and the term “administration” refers to providing a predetermined substance to a subject by any suitable method. It is apparent to those skilled in the art that the therapeutically effective dosage and frequency of administration for the active ingredient of the present invention will vary depending on the desired effect.

In the present invention, the term “mammal including humans” refers to mammals such as monkeys, cattle, horses, dogs, cats, rabbits, rats, and mice, and in particular includes humans.

As used herein, the term “therapeutically effective dose” refers to an amount of the compound represented by Formula I effective for the prevention or treatment of obesity or obesity-related metabolic disease.

As used herein, the term “prevention” means delaying the onset of a disease, disorder or disease. Prevention may be considered complete if the onset of the disease, disorder or condition is delayed for a predetermined period.

As used herein, the term “treatment” refers to partially or completely alleviating, ameliorating, alleviating, inhibiting or delaying the onset of a particular disease, disorder and/or condition, reducing the severity, or preventing the occurrence of one or more symptoms or features. means to reduce

The pharmaceutical composition for the treatment or prevention of obesity or obesity-related metabolic disease of one embodiment may be used in the form of a general pharmaceutical formulation. The pharmaceutical formulation may be administered in various oral and parenteral formulations at the time of administration, and the formulation may be variously determined according to the method of use.

Matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applicable as long as they do not contradict each other.

Method for preparing 4-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidine compound

The preparation method of the compound of formula (I) is described together with the reaction scheme.

A preferred method for preparing the 4-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidine compound represented by Formula I, its optical isomer, or a pharmaceutically acceptable salt thereof is shown in Schemes 1 to 7 And, a manufacturing method modified to a level apparent to those skilled in the art is also included therein.

[Scheme 1]

In Scheme 1, in the reaction condition (Condition) A, R ₁ Y, Pd(PPh ₃ ) ₄ , Na ₂ CO ₃ and DME (dimethoxyethane)/H ₂ O are used as a reaction reagent and a reaction solvent. In reaction condition B, R ₁ NH ₂ , DIPEA(N,N-diisopropylethylamine) and CH ₃ CN are used as a reaction reagent and a reaction solvent. In reaction condition C, R ₁ OH, DIPEA, CH ₃ CN (or NaH) and DME (or K ₂ CO ₃ ) are used as reaction reagents and reaction solvents. In reaction condition D, LiOH, THF (tetrahydrofuran), CH ₃ OH, and H ₂ O are used as a reaction reagent and a reaction solvent under heating conditions.

)을 의미하고, MW는 Microwave 조건을 의미한다. 본 명세서에서, 모순되지 않는 이상 MW는 Microwave 반응 조건을 의미한다.In reaction condition A, R ₁ Y is boronic acid (

) and MW means microwave conditions. In the present specification, unless contradictory, MW means microwave reaction conditions.

Reaction conditions of each of the compounds prepared according to Scheme 1, each of X ₁ , R ₁ and R ₂ are shown in the table below.

As shown in [Scheme 1], starting materials 1a and 1b compounds represented by Formula 1-1 were prepared by a known method (JMC. 2004, 47, 627; J. Agric. Food. Chem. 1979, 27, 406). After synthesis through the reaction with methyl 2,4-dichloropyrimidine-5-carboxylate represented by Formula 1-1-2, novel compounds 3-1 and 3-2 are synthesized. In compounds 3-1 and 3-2, in order to introduce various kinds of substituents at position 2 of pyrimidine, the reaction conditions are varied from A to D to prepare novel compounds according to the present invention. Examples of the compound prepared at this time include compounds 108, 109, 110, 111, 112, 116, 117, 128, 130, 131, 132, 133, 134, 135, 136, 188, 189, 190, 303, 320, 329, 377 and the like.

Thereafter, the compounds obtained in the above step were hydrolyzed using lithium hydroxide to obtain acid compounds 5a to 5i, and various types of amino esters or amino amides were subjected to EDC (3-dimethylaminopropyl) carbodiimide) coupling. The novel compounds according to the present invention can be prepared. As the compound prepared at this time, compounds 163, 165, 192, 193, 194, 195, 196, 197, 207, 208, 209, 210, 211, 212, 213, 214, 215, 227, 228, 229, 230, 231 , 232, 234, 243, 244, 245, 246, 247, 248, 282, 283, 318, 321, 322, 323, 378, 379, 380 and the like.

[Scheme 2]

_{S 1} and R ₄ in Scheme 2 are respectively as shown in the table below.

As shown in [Scheme 2], the novel compound 160 of the present invention is synthesized by reacting the pyrazole compound represented by Formula 1a synthesized using known literature and the pyridine compound represented by Formula 1-2-1 at room temperature.

Then, the compound 161 of the present invention having a sulfone group is synthesized using mCPBA.

With respect to compound 161, it is reacted with various secondary amines to synthesize novel compounds 168, 169, 179, 180, 183, 225, and 226 of the present invention.

Next, hydrolysis is performed using lithium hydroxide to obtain acid compounds 7a to 7b, and EDC coupling with various types of amino esters is performed to synthesize novel compounds 220, 221, 222, 223, and 224 of the present invention.

[Scheme 3]

In Scheme 3, S ₂ is the same as in the table below, and X in the table below represents X in the compound represented _{by S 2 .}

As shown in [Scheme 3], pyrazole compounds 1a and 1b as starting materials and pyridine compounds 1-3-1 are reacted at room temperature to synthesize novel compounds 162 and 372 according to the present invention.

Subsequently, for compound 162 or 372, hydrolysis using lithium hydroxide to obtain acid compounds 9a and 9b, and then EDC coupling with various kinds of amino esters or amino amides to proceed with EDC coupling to the novel compounds 164, 199, 200, 201, 202, 203, 204, 205, 206, 233, 317, 373, 374, 375 are synthesized.

[Scheme 4]

As shown in [Scheme 4], a novel compound 184 according to the present invention is synthesized by reacting pyrazole compound 1a and pyrimidine compound 1-4-1 as starting materials at room temperature to synthesize a reverse amide structure.

Subsequently, the Suzuki reaction is performed on the novel compound 184 to obtain compounds 185 and 186 according to the present invention.

Thereafter, SnCl ₂ is used to reduce 1-4-3 obtained by performing an acylation reaction or a sulfonylation reaction to proceed with a novel compound 187, 216, 217, 218, 250, 251 according to the present invention. to synthesize

[Scheme 5]

As shown in [Scheme 5], pyrazole compounds 1a and 1b as starting materials and pyrimidine compounds 1-5-1 are reacted at room temperature to synthesize novel compounds 14a and 14b. Subsequently, compounds 353, 387, 1-5-2, 1-5-3, 1-5-4, and 385 are synthesized by reaction with various types of alcohol reagents.

Subsequently, compounds 1-5-5 to 1-5-10 were synthesized by reacting with trifluoroacetic acid to remove the protecting group, and then EDC coupling with various types of amine amides was performed to remove the protective group according to the present invention. , 327, 354, 355, 356, 360, 361, 388, 389, 390, 392, 393, 394, 408, 409, 410 are synthesized.

[Scheme 6]

As shown in [Scheme 6], the reaction proceeds as follows to stereoselectively synthesize compounds 426 and 427. After synthesizing compound 1-6-1 by conducting a Mitsunobu reaction of the starting material 9a with (S)-methyl 2-hydroxy-2-phenylacetate, the diastereomers obtained were separated by column, and then BBr ₃ was reacted at -78 ° C. The reaction proceeds to synthesize compound 1-6-2. By EDC coupling with acid compounds and 2-amino-2-methylpropanamide, 426 of (R)-form and 427 of (S)-form are synthesized as stereoselective compounds, respectively.

[Scheme 7]

As shown in [Scheme 7], the reaction proceeds as follows to stereoselectively synthesize compound 417. As a starting material, compound 1-6-3 of Scheme 7 was synthesized by a Mitsunobu reaction with (S)-methyl 2-hydroxy-2-phenylacetate to synthesize compound 1-6-4, and then diastereomers were added to the column (R After separation into )-form and (S)-form, BBr ₃ was reacted at -78 ° C. to prepare compound _{1-6-5, which was then reacted with (Boc) 2} O and DMAP to prepare compound 1- After synthesizing 6-6, it is reacted with 2,2,2-trifluoroethanol to obtain compound 1-6-7. After the deprotection reaction is carried out using trifluoroacetic acid to obtain compounds 1-6-8, the stereoselective compound 417 is synthesized by EDC coupling with 2-amino-2-methylpropanamide.

The compound represented by Formula I of the present invention acts as a CB1 receptor antagonist with excellent selectivity for the CB1 receptor of the peripheral nervous system, and thus can be usefully used for the prevention or treatment of obesity and/or obesity-related metabolic diseases.

1 is a graph showing the evaluation results for the weight loss rate in a diet-induced obesity mouse model.
2 is a graph showing the evaluation results for the amount of change in blood glucose in a mouse model of diet-induced obesity.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the content of the present invention is not limited by the examples.

The reagents and solvents mentioned below were purchased from Sigma-Aldrich, TCI unless otherwise specified, and Waters e2695 was used for HPLC, and Merck (230-400 mesh) was used for silica gel for column chromatography. ¹ HNMR data were measured using a Bruker 400 MHz, and mass spectrometry spectra were measured using an Agilent 1100 series.

Preparation of 4-(4,5-dihydro-1H-pyrazol-1-yl)pyrimidine compound

A specific method for preparing the compound of Formula I is as follows.

Example 1: Synthesis of compound 108. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-4-yl)-2-(4-(trifluoromethyl)phenyl)pyrimidine-5- carboxylate)

Starting material 3-1 (0.094 g, 0.220 mmol), 4-(trifluoromethyl)phenylboronic acid as boronic acid (0.054 g, 0.286 mmol), Pd(PPh ₃ ) ₄ (0.013 g, 0.011 mmol) and sodium carbonate (0.061 g, 0.572 mmol) was added with dimethoxyethane (3 mL) / water (1 mL), heated at 120 ° C. for 30 minutes by microwave irradiation, then lowered to room temperature, water was poured into the reaction mixture, and ethyl acetate solution extracted with The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = from 10 % to 30 %) and concentrated to obtain the desired compound 108 (0.042 g, 35.6 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.63 (s, 1 H), 8.52 (d, 2 H, J = 8.1 Hz), 7.71 (d, 2 H, J = 8.2 Hz), 7.58-7.54 (m, 2 H), 7.40-7.26 (m) , 7 H), 4.77 (dd, 1 H, J = 11.2, 4.6 Hz), 4.70 (t, 1 H, J = 11.4 Hz), 4.37 (dd, 1 H, J = 11.4, 4.7 Hz), 3.97 ( s, 3 H).

MS (ESI) m/z 537.4 (M ⁺ + H).

Example 2: Synthesis of compound 109. (methyl 2- (4-chlorophenyl) -4- (3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazol-1-yl) pyrimidine-5-carboxylate)

Except for changing the reactant (starting material, type of boronic acid) according to the structure of compound 109, substantially the same process as described for the synthesis of compound 108 was performed, and compound 109 in the form of a white solid (0.047 g, 41.1 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.59 (s, 1 H), 8.32 (m, 2 H), 7.54-751 (m, 2 H), 7.42-7.23 (m, 9 H), 4.74 (dd, 1 H, J = 11.3, 4.7 Hz) ), 4.66 (t, 1 H, J = 11.3 Hz), 4.33 (dd, 1 H, J = 11.4, 4.7 Hz), 3.93 (s, 3 H).

MS (ESI) m/z 503.3 (M ⁺ + H).

Example 3: Synthesis of compound 110. (Methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-cyclohexenylpyrimidine-5-carboxylate)

Except for changing the reactant (starting material, type of boronic acid) according to the structure of compound 110, substantially the same process as described for the synthesis of compound 108 was performed, and compound 110 in the form of a white solid (0.089 g, 80.4) %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.48 (s, 1 H), 7.51 (m, 2 H), 7.35-7.21 (m, 8 H), 4.68 (dd, 1 H, J = 11.3, 5.0 Hz), 4.56 (t, 1 H, J) = 11.6 Hz), 4.22 (dd, 1 H, J = 11.6, 5.0 Hz), 3.90 (s, 3 H), 2.51 (m, 2 H), 2.67 (m, 2 H), 1.75-1.59 (m, 4H).

MS (ESI) m/z 473.4 (M ⁺ + H).

Example 4: Synthesis of compound 111. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4,4-dihydrocyclohexen-1-yl)pyrimidine -5-carboxylate)

Except for changing the reactant (starting material, type of boronic acid) according to the structure of compound 111, substantially the same process as described for the synthesis of compound 108 was performed, and compound 111 in the form of a white solid (0.060 g, 46.5 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.51 (s, 1 H), 7.55-7.51 (m, 2 H), 7.37-7.22 (m, 8 H), 4.70 (dd, 1 H, J = 11.2, 5.0 Hz), 4.59 (t, 1 H) , J = 11.6 Hz), 4.26 (dd, 1 H, J = 11.7, 5.0 Hz), 3.92 (s, 3 H), 2.55 (m, 2 H), 2.07 (m, 2 H), 1.50 (t, 2 H, J = 6.4 Hz), 0.96 (s, 6 H).

MS (ESI) m/z 501.4 (M ⁺ + H).

Example 5: Synthesis of compound 112. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl) pyrimidine-5-carboxylate)

Except for changing the reactant (starting material, type of boronic acid) according to the structure of compound 112, substantially the same process as described for the synthesis of compound 108 was performed, and compound 112 in the form of a white solid (0.080 g, 72.7 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.51 (s, 1 H), 7.54-7.51 (m, 2 H), 7.38-7.24 (m, 8 H), 4.71 (dd, 1 H, J = 11.3, 5.0 Hz), 4.58 (t, 1 H) , J = 11.6 Hz), 4.39 (m, 2 H), 4.23 (dd, 1 H, J = 11.8, 5.1 Hz), 3.93 (s, 3 H), 3.90 (t, 2 H, J = 5.8 Hz) , 2.65 (m, 2 H).

MS (ESI) m/z 475.4 (M ⁺ + H).

Example 6: Synthesis of compound 116. (methyl 2-(azetidin-1-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxylate )

Starting material 3-1 (72 mg, 0.16 mmol), azetidine hydrochloric acid (18.9 mg) was dissolved in acetonitrile (3 mL), and DIPEA (N,N-diisopropylethylamine) (0.044 mL) was dissolved at 25 ° C. After addition and stirring at 50° C. for 12 hours, water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = from 15 % to 40 %) and concentrated to give the desired compound 116 (0.041 g, 54.3 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.31 (s, 1 H), 7.52 (m, 2 H), 7.36-7.23 (m, 7 H), 4.63 (dd, 1 H, J = 11.2, 4.9 Hz), 4.47 (t, 1 H, J) = 11.7 Hz), 4.11 (m, 5 H), 3.86 (s, 3 H), 2.34 (m, 2 H).

MS (ESI) m/z 448.1 (M ⁺ + H).

Example 7: Synthesis of compound 117. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,3-difluoroazetidin-1-yl)pyri midine-5-carboxylate)

Compound 117 (0.065 g, 78.6 %) as a white solid was obtained in the same manner as in the synthesis of Compound 116, except that 3,3-difluoroazetidine was used instead of azetidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.31 (s, 1 H), 7.53 (m, 2 H), 7.37-7.23 (m, 7 H), 4.67 (dd, 1 H, J = 12.0, 4.9 Hz), 4.51-4.40 (m, 5 H) ), 4.13 (dd, 1 H, J = 11.9, 5.0 Hz), 3.88 (s, 3 H).

MS (ESI) m/z 484.1 (M ⁺ + H).

Example 8: Synthesis of compound 128. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,3-difluoropyrrolidin-1-yl) pyrimidine-5-carboxylate)

Compound 128 (0.072 g, 87.0 %) as a white solid was obtained in the same manner as in the synthesis of Compound 116, except that 3,3-difluoropyrrolidine was used instead of azetidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.31 (s, 1 H), 7.52-7.49 (m, 2 H), 7.35-7.21 (m, 7 H), 4.63 (dd, 1 H, J = 11.2, 4.9 Hz), 4.48 (t, 1 H) , J = 11.6 Hz), 4.12 (dd, 1 H, J = 11.8, 5.0 Hz), 3.93-3.80 (m, 7 H), 2.42 (m, 2 H).

MS (ESI) m/z 498.1 (M ⁺ + H).

Example 9: Synthesis of compound 130. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(methylamino)pyrimidine-5-carboxylate)

A reaction solution of starting material 3-1 (0.105 g, 0.246 mmol), methylamine hydrochloric acid (0.022 g, 0.319 mmol) and potassium carbonate (0.102 g, 0.737 mmol) in dimethylformamide (3 mL) at 25 ° C. After stirring at 60° C. for 12 hours, water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = from 20 % to 60 %) and concentrated to obtain the desired compound 130 (0.057 g, 55.0 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.27 (brs, 1 H), 7.52-7.49 (m, 2 H), 7.34-7.19 (m, 7 H), 5.11 (brs, 1 H), 4.62 (dd, 1 H, J = 11.2, 4.8 Hz) ), 4.50 (t, 1 H, J = 4.0 Hz), 4.13 (m, 1 H), 3.84 (s, 3 H), 2.95 (d, 3 H, J = 5.0 Hz).

MS (ESI) m/z 422.1 (M ⁺ + H).

Example 10: Synthesis of compound 131. (Methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclobutylamine)pyrimidine-5-carboxylate)

Compound 131 (0.061 g, 54.8 %) as a white solid was obtained in the same manner as in the synthesis of Compound 130, except that cyclobutylamine was used instead of methylamine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.25 (s, 1 H), 7.52-7.48 (m, 2 H), 7.35-7.21 (m, 7 H), 5.30 (brs, 1 H), 4.62 (dd, 1 H, J = 11.1, 4.8 Hz) ), 4.80-4.32 (m, 2 H), 4.11 (m, 1 H), 3.84 (s, 3 H), 2.36 (m, 2 H), 1.87 (m, 2 H), 1.71 (m, 2 H) ).

MS (ESI) m/z 462.1 (M ⁺ + H).

Example 11: Synthesis of compound 132. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclohexylamino)pyrimidine-5-carboxylate)

Compound 132 (0.064 g, 54.2 %) as a white solid was obtained in the same manner as in the synthesis of Compound 130, except that cyclohexylamine was used instead of methylamine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.26 (s, 1 H), 7.54-7.49 (m, 2 H), 7.35-7.19 (m, 7 H), 5.08 (m, 1 H), 4.61 (dd, 1 H, J = 11.2, 4.8 Hz) ), 4.47 (m, 1 H), 4.08 (m, 1 H), 3.84 (s, 3 H), 3.76 (m, 1 H), 1.99 (m, 2 H), 1.73-1.56 (m, 4 H) ), 1.35 (m, 2 H), 1.26-1.15 (m, 4 H).

MS (ESI) m/z 490.1 (M ⁺ + H).

Example 12: Synthesis of compound 133. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclopentylamino)pyrimidine-5-carboxylate)

Compound 133 (0.062 g, 54.0 %) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 130, except that cyclopentylamine was used instead of methylamine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.26 (s, 1 H), 7.52-7.47 (m, 2 H), 7.35-7.18 (m, 7 H), 5.18 (s, 1 H), 4.62 (dd, 1 H, J = 11.2, 4.8 Hz) ), 4.48 (m, 1 H), 4.26-4.11 (m, 2 H), 3.84 (s, 3 H), 2.03 (m, 2 H), 1.74-1.59 (m, 5 H), 1.45 (m, 2H).

MS (ESI) m/z 476.1 (M ⁺ + H).

Example 13: Synthesis of compound 134. (methyl 2-(4-chlorobenzylamino)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxylate)

Compound 134 (0.062 g, 47.4 %) as a white solid was obtained in the same manner as in the synthesis of Compound 130, except that 4-chlorobenzylamine was used instead of methylamine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.25 (s, 1 H), 7.52-7.48 (m, 2 H), 7.35-7.20 (m, 11 H), 4.63-4.54 (m, 3 H), 4.39 (t, 1 H, J = 11.6 Hz) ), 4.05 (dd, 1 H, J = 11.8, 5.0 Hz), 3.85 (s, 3 H).

MS (ESI) m/z 532.1 (M ⁺ + H).

Example 14: Synthesis of compound 135. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl)benzylamino)pyrimidine-5 -carboxylate)

Compound 135 (0.065 g, 45.4 %) as a white solid was obtained in the same manner as in the synthesis of Compound 130 except that (4-(trifluoromethyl)phenyl)methanamine was used instead of methylamine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.28 (s, 1 H), 7.53 (m, 2 H), 7.50-7.45 (m, 2 H), 7.40 (m, 2 H), 7.34-7.17 (m, 7 H), 5.68 (brs, 1 H), 4.68-4.58 (m, 3 H), 4.36 (t, 1 H, J = 11.2 Hz), 4.02 (dd, 1 H, J = 11.8, 5.9 Hz), 3.85 (s, 3 H).

MS (ESI) m/z 566.1 (M ⁺ + H).

Example 15: Synthesis of compound 136. (Methyl 2-(tert-butylamino)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxylate)

Compound 136 (0.017 g, 18.2 %) in the form of a colorless oil was obtained in the same manner as in the synthesis of compound 130 except that tert-butylamine was used instead of methylamine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.25 (S, 1 H), 7.52-7.49 (m, 2 H), 7.37-7.21 (m, 7 H), 5.24 (brs, 1 H), 4.62 (dd, 1 H, J = 11.1, 4.7 Hz) ), 4.52 (t, 1 H, J = 7.2 Hz), 4.11 (m, 1 H), 3.86 (s, 3 H), 1.35 (s, 9 H).

MS (ESI) m/z 464.1 (M ⁺ + H).

Example 16: Synthesis of compound 160. (Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(methylthio)pyrimidine-5-carboxylate)

Starting material la (3.85 g, 14.996 mmol), ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 6 (4.54 g, 19.50 mmol) and DIPEA (3.93 mL, 22.49 mmol) were mixed with acetonitrile at room temperature. After the reaction solution in nitrile (100 mL) was stirred at the same temperature for one night, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate solution. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 10 % to 20 %) and concentrated to give the desired compound 160 (2.12 g, 31.2 %) as a light yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.33 (s, 1H), 7.52 - 7.50 (m, 2H), 7.35 - 7.21 (m, 7H), 4.68 (dd, 1H, J = 11.1, 4.6 Hz), 4.54 (t, 1H, J = 11.5 Hz) ), 4.42 - 4.30 (m, 2H), 4.21 (dd, 1H, J = 11.9, 4.7 Hz), 2.50 (s, 3H), 1.29 (t, 1H, J = 7.2 Hz).

MS (ESI) m/z 453.1 (M ⁺ + H).

Example 17: Synthesis of compound 161. (Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(methylsulfonyl)pyrimidine-5-carboxylate)

A reaction solution of starting material 160 (1.00 g, 2.21 mmol) and mCPBA (1.09 g, 4.42 mmol; 0.7 %) in methylene chloride (20 mL) at room temperature was stirred at the same temperature for one night, and then saturated carbonic acid was added to the reaction mixture. An aqueous sodium hydrogen solution was poured therein, and the mixture was extracted with an ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 40 % to 50 %) and concentrated to obtain the desired compound 161 (0.66 g, 62.0 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.50 (s, 1H), 7.53 - 7.50 (m, 2H), 7.35 - 7.25 (m, 5H), 7.19 - 7.17 (m, 2H), 4.76 (dd, 1H, J = 11.2, 4.8 Hz), 4.60 (t, 1H, J = 11.6 Hz), 4.43 - 4.38 (m, 2H), 4.29 (dd, 1H, J = 12.1, 4.7 Hz), 3.28 (s, 3H), 1.31 (t, 1H, J = 7.2) Hz).

MS (ESI) m/z 485.0 (M ⁺ + H).

Example 18: Synthesis of compound 162. (Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-5-carboxylate)

The starting material 1a (0.19 g, 0.7 mmol) and DIPEA (0.2 mL) were dissolved in dioxane (3 mL), and 1-3-1 (0.2 g) was added at 25 ° C. After stirring at the same temperature for 12 hours, the reaction Water was poured into the mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = from 10 % to 40 %) and concentrated to obtain the desired compound 162 (0.240 g, 72.1 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.54 (s, 1 H), 7.54-7.50 (m, 2 H), 7.36-7.19 (m, 7 H), 4.74 (dd, 1 H, J = 11.2, 4.8 Hz, 1 H), 4.55 (t , 1 H, J = 11.2 Hz), 4.42 (m, 2 H), 4.25 (dd, 1 H, J = 12.1, 4.8 Hz), 1.32 (t, 3 H, J = 7.1 Hz).

MS (ESI) m/z 475.1 (M ⁺ + H).

Example 19: Synthesis of compound 163. (Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4) -yl)pyrimidine-5-carboxamido)acetate)

Starting material 5a (26 mg, 0.06 mmol), glycine methyl ester hydrochloride (9.2 mg), HOBt(1-Hydroxybenzotriazole) (11.4 mg) and DIPEA (0.03 mL) were dissolved in methylene chloride (1 mL). Dissolve, add EDC (13.1 mg) at 25 °C, and stir at the same temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by PTLC (hexane/ethyl acetate, 1:2) to give compound 163 (2 mg, 6.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.48 (s, 1 H), 7.45 (m, 2 H), 7.35-7.20 (m, 7 H), 6.41 (t, 1 H, J = 4.8 Hz), 4.69 (dd, 1 H, J = 11.6) , 5.5 Hz), 4.58 (t, 1 H, J = 11.7 Hz), 4.36 (m, 2 H), 4.32 (dd, 2 H, J = 4.9, 2.2 Hz), 4.20 (dd, 1 H, J = 11.8, 5.5 Hz), 3.89 (t, 2 H, J = 5.9 Hz), 3.70 (s, 3 H), 2.62 (m, 2H).

MS (ESI) m/z 532.1 (M ⁺ + H)

Example 20: Synthesis of compound 164. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-5-carbox amido) acetate)

Starting material 9a (0.1 g, 0.2 mmol), methyl 2-aminoacetate (36.5 mg), HOBt (45.4 mg) and DIPEA (0.12 mL) were dissolved in methylene chloride (3 mL) and EDC (52.1 mg) was dissolved at 25 °C. After addition and stirring at the same temperature for 12 hours, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = from 15 % to 50 %) and concentrated to obtain the desired compound 164 (0.048 g, 41.4 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.48 (s, 1 H), 7.48-7.44 (m, 2 H), 7.35-77.18 (m, 7 H), 6.45 (t, 1 H, J = 4.8 Hz), 4.74 (dd, 1 H, J) = 11.4, 5.4 Hz), 4.60 (t, 1 H, J = 12.0 Hz), 4.33 (dd, 2 H, J = 4.9, 2.6 Hz), 4.21 (dd, 1 H, J = 12.2, 5.4 Hz), 3.70 (s, 3 H).

MS (ESI) m/z 518.0 (M ⁺ + H).

Example 21: Synthesis of compound 165. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-difluoroazetidin-1-yl)pyrimidine-5 -carboxamido)carboxylate)

Compound 165 (0.05 g, 36.2 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 163, except that starting material 5b was used instead of starting material 5a.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.22 (s, 1 H), 7.46-7.43 (m, 2 H), 7.35-7.19 (m, 7 H), 6.39 (t, 1 H, J = 4.9 Hz), 4.65 (dd, 1 H, J) = 11.5, 5.6 Hz), 4.49 (t, 1 H, J = 11.8 Hz), 4.40 (t, 4 H, J = 12.0 Hz), 4.28 (d, 2 H, J = 5.0 Hz), 4.11 (dd, 1 H, J = 11.9, 5.5 Hz), 3.67 (s, 3 H).

MS (ESI) m/z 541.2 (M ⁺ + H).

Example 22: Synthesis of compound 168. (Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(pyrazolidin-1-yl)pyrimidine)

Acetonitrile (1 mL) was added to the starting material 161 (0.080 g, 0.165 mmol), pyrrolidine (0.015 g, 0.214 mmol) and DIPEA (0.043 mL, 0.247 mmol), and microwaved at 150 ° C for 15 minutes. After cooling to room temperature, water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = from 20 % to 30 %) and concentrated to obtain the desired compound 168 (0.036 g, 45.7 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.32 (s, 1H), 7.52 - 7.49 (m, 2H), 7.34 - 7.21 (m, 7H), 4.61 (dd, 1H, J = 11.1, 4.5 Hz), 4.46 (t, 1H, J = 11.3 Hz) ), 4.38 - 4.27 (m, 2H), 4.12 (dd, 1H, J = 11.6, 4.5 Hz), 3.83 - 3.66 (m, 8H), 1.27 (t, 1H, J = 7.1 Hz).

MS (ESI) m/z 492.2 (M ⁺ + H).

Example 23: Synthesis of compound 169. (Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-morpholinopyrimidine-5-carboxylate)

Compound 169 (0.064 g, 63.0%) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 168, except that morpholine was used instead of pyrrolidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.32 (s, 1H), 7.52 - 7.49 (m, 2H), 7.34 - 7.21 (m, 7H), 4.61 (dd, 1H, J = 11.1, 4.5 Hz), 4.46 (t, 1H, J = 11.3 Hz) ), 4.38 - 4.27 (m, 2H), 4.12 (dd, 1H, J = 11.6, 4.5 Hz), 3.83 - 3.66 (m, 8H), 1.27 (t, 1H, J = 7.1 Hz).

MS (ESI) m/z 492.2 (M ⁺ + H).

Example 24: Synthesis of compound 179. ((R)-Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3-fluoropyrrolidin-1-yl )pyrimidine-5-carboxylate)

Compound 179 (0.087 g, 84.9%) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 168, except that (R)-(-)-3-fluoropyrrolidine hydrochloride was used instead of pyrrolidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.33 (s, 1H), 7.52 - 7.50 (m, 2H), 7.34 - 7.22 (m, 7H), 5.37 - 5.24 (m, 1H), 4.63 - 4.61 (m, 1H), 4.51 - 4.46 (m, 1H), 4.37 - 4.26 (m, 2H), 4.16 - 4.09 (m, 1H), 4.01 - 3.58 (m, 4H), 2.35 - 2.17 (m, 2H), 1.28 (t, 1H, J = 7.2 Hz)

MS (ESI) m/z 494.2 (M ⁺ + H).

Example 25: Synthesis of compound 180. ((S)-ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3-fluoropyrrolidin-1-yl )pyrimidine-5-carboxylate)

Compound 180 (0.078 g, 76.8 %) as a white solid was obtained in the same manner as in the synthesis of Compound 168, except that (S)-(+)-3-fluoropyrrolidine hydrochloric acid was used instead of pyrrolidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.33 (s, 1H), 7.52 - 7.49 (m, 2H), 7.35 - 7.21 (m, 7H), 5.37 - 5.24 (m, 1H), 4.61 (dd, 1H, J = 11.2, 4.3 Hz), 4.48 (t, 1H, J = 11.4 Hz), 4.36 - 4.27 (m, 2H), 4.14 (dd, 1H, J = 11.7, 4.5 Hz), 3.95 - 3.73 (m, 4H), 2.33 - 2.04 (m, 2H) ), 1.27 (t, 1H, J = 7.2 Hz)

MS (ESI) m/z 494.2 (M ⁺ + H).

Example 26: Synthesis of compound 183. (Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4,4-difluoropiperidin-1-yl) pyrimidine-5-carboxylate)

Compound 183 (0.057 g, 52.6 %) as a white solid was obtained in the same manner as in the synthesis of Compound 168, except that 4,4-difluoropiperidine hydrochloride was used instead of pyrrolidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.32 (s, 1H), 7.52 - 7.49 (m, 2H), 7.34 - 7.22 (m, 7H), 4.62 (dd, 1H, J = 11.3, 4.4 Hz), 4.47 (t, 1H, J = 11.4 Hz) ), 4.37 - 4.19 (m, 2H), 4.12 (dd, 1H, J = 11.6, 4.5 Hz), 4.02 - 3.95 (m, 4H), 1.98 - 1.90 (m, 4H), 1.28 (t, 1H, J) = 7.1 Hz).

MS (ESI) m/z 526.1 (M ⁺ + H).

Example 27: Synthesis of compound 184. (2-chloro-4- (3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazol-1-yl) -5-nitropyrimidine)

The starting material 1a (2.77 g, 10.8 mmol), DIPEA (2.83 mL) was dissolved in acetonitrile (10 mL), and 1-4-1 (2.2 g, 11.3 mmol) was added at 25 °C and stirred at the same temperature for 12 hours. After the reaction mixture was filtered through a celite pad, water was poured into the filtrate from which the solid was removed, and the mixture was extracted with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = from 15 % to 60 %) and concentrated to give the desired compound 184 (1.500 g, 33.6 %) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.51 (s, 1 H), 7.53-7.49 (m, 2 H), 7.37-7.18 (m, 7 H), 4.77 (dd, 1 H, J = 11.1, 4.6 Hz), 4.59 (t, 1 H) , J = 12.2 Hz), 4.26 (dd, 1 H, J = 12.2, 4.7 Hz).

MS (ESI) m/z 414.0 (M ⁺ + H).

Example 28: Synthesis of compound 185. (4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl)- 5-nitropyrimidine)

Starting material 184 (0.210 g, 0.507 mmol), 3,6-dihydro-2H-pyran-4-yl boronic acid as boronic acid (0.138 g, 0.659 mmol), Pd(PPh ₃ ) ₄ (0.029 g, 0.025 mmol) ) And dimethoxyethane (3 mL) / water (1 mL) was added to sodium carbonate (0.140 g, 1.318 mmol) and heated at 120 ° C for 30 minutes by microwave irradiation, then lowered to room temperature, and water was poured into the reaction mixture. It was extracted with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = from 20 % to 60 %) and concentrated to give the desired compound 185 (0.078 g, 33.3 %) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.67 (s, 1 H), 7.52-7.49 (m, 2 H), 7.37-7.25 (m, 8 H), 4.73 (dd, 1 H, J = 11.2, 4.7 Hz), 4.60 (t, 1 H) , J = 11.8 Hz), 4.38 (m, 2 H), 4.26 (dd, 1 H, J = 11.8, 4.7 Hz), 3.88 (m, 2 H), 2.61 (m, 2 H).

MS (ESI) m/z 462.1 (M ⁺ + H).

Example 29: Synthesis of compound 186. (4-(3-(4-Chlorophenyl)-4-phenyl-4,5-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-thio pyran-4-yl)-5-nitropyrimidine)

Compound 186 (0.023 g, 9.5%) in the form of a yellow solid was obtained in the same manner as in the synthesis of compound 185, except that the reactant (starting material, type of boronic acid) was changed according to the structure of compound 186.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.69 (s, 1 H), 7.55-7.51 (m, 2 H), 7.39-7.25 (m, 8 H), 4.73 (dd, 1 H, J = 11.1 Hz), 4.62 (t, 1 H, J) = 11.7 Hz), 4.28 (dd, 1 H, J = 11.8, 4.7 Hz), 3.44 (m, 2H), 2.85 (d, 4 H, J = 1.3 Hz).

MS (ESI) m/z 478.1 (M ⁺ + H).

Synthesis of compound 1-4-3, 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H -Pyran-4-yl)pyrimidin-5-amine

A reaction solution of starting material 185 (0.190 g, 0.411 mmol) and SnCl ₂ .2H ₂ O (0.278 g, 1.234 mmol) in ethanol (5 mL) at 25 ° C. After stirring at 80 ° C for 12 hours, the reaction mixture Water was poured into it, and the mixture was extracted with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = from 20 % to 60 %) and concentrated to obtain the desired compound 1-4-3 (0.034 g, 19.1 %) as a yellow solid. got it

Example 30: Synthesis of compound 187. (N-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4- yl) pyrimidin-5-yl) -2,2,2-trifluoroacetamide methyl)

The starting material 1-4-3 (23 mg, 0.05 mmol), DIPEA (0.01 mL) was dissolved in methylene chloride (1 mL), TFAA (Trifluoroacetic anhydride) (0.01 mL) was added at 25 °C, and then at the same temperature for 1 hour. After stirring, water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by PTLC (hexane/ethyl acetate 2:1) to obtain compound 187 (7.0 mg, 24.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 9.58 (s, 1 H), 7.53-7.50 (m, 2 H), 7.39-7.20 (m, 7 H), 7.10 (m, 1 H), 4.78-4.66 (m, 2 H), 4.37-4.32 (m, 3 H), 3.89 (t, 2 H, J = 5.9 Hz), 2.63 (m, 2 H).

MS (ESI) m/z 528.1 (M ⁺ + H).

Example 31: Synthesis of compound 188. (Methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-methoxypyrimidine-5-carboxylate)

A reaction solution of starting material 3-1 (0.500 g, 1.170 mmol) and lithium hydroxide monohydrate (0.246 g, 5.851 mmol) in tetrahydrofuran/methanol/water (3/3/3 mL) at room temperature was dissolved at the same temperature. After stirring for one night, a 1 M aqueous hydrochloric acid solution was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = from 30 % to 50 %) and concentrated to obtain the desired compound 188 (0.128 g, 25.9 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.35 (s, 1 H), 7.52 - 7.50 (m, 2 H), 7.32 - 7.19 (m, 7 H), 4.68 (dd, 1 H, J = 11.6, 4.9 Hz), 4.53 (t, 1 H) , J = 11.6 Hz), 4.19 (dd, 1 H, J = 11.6, 4.9 Hz), 3.96 (s, 3 H), 3.88 (s, 3 H).

MS (ESI) m/z 423.1 (M ⁺ + H).

Example 32: Synthesis of compound 189. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(oxetan-3-ylamino)pyrimidine-5-carboxyl rate)

Compound 189 (0.020 g, 15.4 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 116, except that oxetan-3-amine was used instead of azetidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.29 (2s, 1 H), 7.51 (m, 2 H), 7.35-7.20 (m, 7 H), 4.65 (m, 2 H), 4.50 (m, 2 H), 4.12 (m, 1 H) , 3.85 (2s, 3 H), 3.79 (m, 1 H), 3.57 (m, 2 H).

MS (ESI) m/z 464.1 (M ⁺ + H).

Example 33: Synthesis of compound 190. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-thiopyran-4-yl )pyrimidine-5-carboxylate)

Compound 190 (0.062 g, 41.5 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 108.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.49 (s, 1 H), 7.55-7.51 (m, 2 H), 7.43 (m, 1 H), 7.44-7.26 (m, 7 H), 4.75 (dd, 1 H, J = 11.2, 5.0 Hz ), 4.55 (t, 1 H, J = 6.8 Hz), 4.23 (m, 1 H), 3.93 (s, 3 H), 3.41 (d, 2 H, J = 3.3 Hz), 2.85 (s, 6 H) ).

MS (ESI) m/z 491.1 (M ⁺ + H).

Example 34: Synthesis of compound 192. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-methoxypyrimidine-5-carboxamido)acetate )

Compound 192 (0.250 g, 43.9 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 163 except that the starting material 5h was used instead of the starting material 5a.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.15 (s, 1 H), 7.57 (d, 1 H, J = 8.6 Hz), 7.32 - 7.21 (m, 7 H), 4.91 - 4.88 (M, 1 H), 4.56 (t, 1 H, J) = 11.8 Hz), 4.26 - 4.09 (m, 3 H), 4.19, 3.91 (s, 3 H), 3.69 (s, 3 H).

MS (ESI) m/z 480.1 (M ⁺ + H).

Example 35: Synthesis of compound 193. (methyl 2-(2-(4-chlorobenzylamino)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-car voxamido) acetate)

Compound 193 (0.018 g, 40.7 %) as a white solid was obtained in the same manner as in the synthesis of compound 163 except that the starting material 5f was used instead of the starting material 5a.

¹ H NMR (400 MHz, CDCl ₃ ); 8.08 (brs, 1 H), 7.45 (d, 1 H, J = 8.6 Hz), 7.34 - 7.15 (m, 11 H), 4.64 (dd, 1 H, J = 11.4, 5.4 Hz), 4.56 - 4.52 ( m, 1H) 4.43 (t, 1 H, J = 11.8 Hz), 4.27 (d, 1 H, J = 5.0 Hz), 4.05 (dd, 1 H, J = 12.0, 5.5 Hz 1H, 3.67 (s, 3) H).

MS (ESI) m/z 589.1 (M ⁺ + H).

Example 36: Synthesis of compound 194. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl)benzylamino)pyrimidine -5-carboxamido)acetate)

Compound 194 (0.031 g, 63.7 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 163, except that 5 g of the starting material was used instead of the starting material 5a.

¹ H NMR (400 MHz, CDCl ₃ ); 8.14 (brs, 1 H), 7.55 (d, 1 H, J = 7.8 Hz), 7.47 - 7.19 (m, 11 H), 6.64 (brs, 1 H), 4.70 - 4.59 (m, 3 H), 4.42 (t, 1 H, J = 11.4 Hz), 4.29 (d, 1 H, J = 4.9 Hz), 3.69 (s, 3 H).

MS (ESI) m/z 623.1 (M ⁺ + H).

Example 37: Synthesis of compound 195. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclobutylamino)pyrimidine-5-carboxami Figure) Acetate)

Compound 195 (0.022 g, 51.3 %) as a white solid was obtained in the same manner as in the synthesis of Compound 163, except that starting material 5c was used instead of starting material 5a.

¹ H NMR (400 MHz, CDCl ₃ ); 8.08 (brs, 1 H), 7.46 - 7.43 (m, 2 H), 7.35 - 7.19 (m, 7 H), 6.62 (brs, 1 H), 4.67 (dd, 1 H, J = 11.4, 5.0 Hz) , 4.55 - 4.54 (m, 1 H), 4.35 - 4.34 (m, 1 H), 4.26 (d, 2 H, J = 5.0 Hz), 4.13 - 4.08 (m, 1 H), 3.67 (s, 3H) , 2.35 - 2.28 (m, 2 H), 1.93 - 1.86 (m, 2 H), 1.72 - 1.63 (m, 2 H).

MS (ESI) m/z 519.1 (M ⁺ + H).

Example 38: Synthesis of compound 196. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclopentylamino)pyrimidine-5-carboxami Figure) Acetate)

Compound 196 (0.018 g, 37.3 %) in the form of a yellow solid was obtained in the same manner as in the synthesis of compound 163, except that the starting material 5e was used instead of the starting material 5a.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.13 (s, 1 H), 7.46 - 7.43 (m, 2 H), 7.34 - 7.16 (m, 7 H), 6.55 (brs, 1 H), 4.64 (dd, 1 H, J = 11.4, 5.5 Hz ), 4.54 - 4.52 (m, 1 H), 4.27 (d, 2H, J = 5.0 Hz), 4.17 - 4.09 (m, 2 H), 3.67 (s, 3 H), 2.03 - 1.94 (m, 2 H) ), 1.70 - 1.41 (m, 6 H).

MS (ESI) m/z 533.1 (M ⁺ + H).

Example 39: Synthesis of compound 197. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclohexylamino)pyrimidine-5-carboxami Figure) Acetate)

Compound 197 (0.019 g, 42.2 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 163, except that the starting material 5d was used instead of the starting material 5a.

¹ H NMR (400 MHz, CDCl ₃ ); 8.13 (brs, 1H), 7.45 (d, 1H, J = 8.5 Hz), 7.34 - 7.19 (m, 7H), 6.56 (brs, 1H), 4.64 (dd, 1H, J = 11.0, 5.2 Hz), 4.50 - 4.48 (m, 1H), 4.26 (d, 1H, J = 4.9 Hz), 4.10 - 4.06 (m, 1H), 3.78 - 3.76 (m, 1H), 3.67 (s, 3H), 1.99 - 1.88 (m) , 2H), 1.71 - 1.70 (m, 2H).

MS (ESI) m/z 547.2 (M ⁺ + H).

Example 40: Synthesis of compound 199. (Methyl (S)-2-(4-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(tri Fluoromethyl)pyrimidine-5-carboxamido)-2-phenylacetate)

Compound 164, except that the optically resolved (R)-coordinated starting material 9a was used instead of the stereo mixture starting material 9a, and (S)-methyl 2-amino-2-phenylacetate hydrochloric acid was used instead of methyl 2-aminoacetate. Compound 199 (0.011 g, 8.1 %) in the form of a white solid was obtained in the same manner as in the synthesis of

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.52 (s, 1 H), 7.45 - 7.31 (m, 10 H), 7.25 - 7.17 (m, 4 H), 7.02 (d, 1 H, J = 7.6 Hz), 5.96 (d, 1 H, J) = 7.7 Hz), 4.75 (dd, 1 H, J = 11.4, 5.0 Hz), 4.59 (t, 1 H, J = 11.8 Hz), 4.25 (dd, 1 H, J = 12.2, 5.0 Hz), 3.55 ( s, 3 H).

MS (ESI) m/z 594.1 (M ⁺ + H).

Example 41: Synthesis of compound 200. (Methyl (S)-2-(4-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(tri Fluoromethyl)pyrimidine-5-carboxamido)-2-phenylacetate)

A compound except that the optically resolved (S)-coordinated starting material 9a was used instead of the steric mixture starting material 9a, and (S)-methyl 2-amino-2-phenylacetate hydrochloric acid was used instead of methyl 2-aminoacetate. Compound 200 (0.009 g, 6.8 %) in the form of a white solid was obtained in the same manner as in the synthesis of 164.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.52 (s, 1 H), 7.45 - 7.31 (m, 10 H), 7.20 - 7.12 (m, 4 H), 6.89 (d, 1 H, J = 7.8 Hz), 5.92 (d, 1 H, J) = 7.6 Hz), 4.75 (dd, 1 H, J = 11.4, 5.3 Hz), 4.62 (t, 1 H, J = 11.8 Hz), 4.23 (dd, 1 H, J = 12.5, 7.2 Hz), 3.61 ( s, 3 H).

MS (ESI) m/z 594.1 (M ⁺ + H).

Example 42: Synthesis of compound 201. (methyl (4-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyrimidine -5-carbonyl)-L-valinoate)

Except for using the optically resolved (S)-coordinated starting material 9a instead of the stereo mixture starting material 9a and using (S)-methyl 2-amino-3-methylbutanoate hydrochloric acid instead of methyl 2-aminoacetate Compound 201 (0.028 g, 22.7 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 164.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.50 (s, 1 H), 7.47 - 7.44 (m, 2 H), 7.40 - 7.36 (m, 2 H), 7.33 - 7.29 (m, 1 H), 7.27 - 7.23 (m, 4 H), 6.39 (d, 1 H, J = 8.7 Hz), 4.89 (dd, 1 H, J = 8.8, 4.9 Hz), 4.72 (dd, 1 H, J = 11.4, 4.8 Hz), 4.58 (t, 1 H, J) = 11.8 Hz), 4.25 (dd, 1 H, J = 12.2, 4.8 Hz), 3.41 (s, 3 H), 2.26 (m, 1 H), 1.04 (d, 3 H, J = 6.8 Hz), 0.99 (d, 3 H, J = 6.9 Hz).

MS (ESI) m/z 560.1 (M ⁺ + H).

Example 43: Synthesis of compound 202. (methyl (4-((R)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyri midine-5-carbonyl)-L-valinoate)

Except for using the optically resolved (R)-coordinated starting material 9a instead of the steric mixture starting material 9a and using (S)-methyl 2-amino-3-methylbutanoate hydrochloric acid instead of methyl 2-aminoacetate and compound 202 (0.030 g, 23.5 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 164.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.49 (s, 1 H), 7.48 - 7.44 (m, 2 H), 7.34 - 7.29 (m, 3 H), 7.26 - 7.22 (m, 2 H), 7.20 - 7.17 (m, 2 H), 6.38 (d, 1 H, J = 8.6 Hz), 4.89 (dd, 1 H, J = 8.9, 4.8 Hz), 4.79 (dd, 1 H, J = 11.5, 6.0 Hz), 4.67 (t, 1 H, J) = 11.8 Hz), 4.25 (dd, 1 H, J = 12.1, 6.0 Hz), 3.50 (s, 3 H), 2.29 (m, 1 H), 1.05 (d, 3 H, J = 6.8 Hz), 0.97 (d, 3 H, J = 6.9 Hz).

MS (ESI) m/z 560.1 (M ⁺ + H).

Example 44: Synthesis of compound 203. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(trifluoromethyl)pyrimidine- 5-carboxamido)-3,3-dimethylbutanoate)

Compound 203 (0.088 g, 73.9 %) as a white solid was obtained in the same manner as in the synthesis of Compound 164, except that (S)-methyl 2-aminopropanoate hydrochloric acid was used instead of methyl 2-aminoacetate.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.51 (s, 1 H), 7.50 - 7.47 (m, 2 H), 7.38 - 7.29 (m, 3 H), 7.27 - 7.18 (m, 4 H), 6.55 (d, 1 H, J = 7.5 Hz ), 4.93 (m, 1 H), 4.76 (m, 1 H), 4.61 (m, 1 H), 4.23 (m, 1 H), 3.64 (d, 3 H, J = 12.8 Hz), 1.56 (dd , 3 H, J = 7.2, 3.4 Hz).

MS (ESI) m/z 532.1 (M ⁺ + H).

Example 45: Synthesis of compound 204. (Methyl (S)-2-(4-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(tri Fluoromethyl)pyrimidine-5-carboxamido)-3,3-dimethylbutanoate)

Optically resolved (S)-coordinated starting material 9a was used instead of starting material 9a as a stereo mixture, and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloric acid was used instead of methyl 2-aminoacetate. Compound 204 (0.040 g, 31.1 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 164, except that.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.49 (s, 1 H), 7.48 - 7.44 (m, 2 H), 7.41 - 7.37 (m, 2 H), 7.34 - 7.30 (m, 1 H), 7.28 - 7.25 (m, 4 H), 6.41 (d, 1 H, J = 9.4 Hz), 4.80 (d, 1 H, J = 9.4 Hz), 4.69 (dd, 1 H, J = 11.4, 4.3 Hz), 4.54 (t, 1 H, J = 11.8) Hz), 4.24 (dd, 1 H, J = 12.1 4.3 Hz), 3.21 (s, 3 H), 1.07 (s, 9 H).

MS (ESI) m/z 574.1 (M ⁺ + H).

Example 46: Synthesis of compound 205. (Methyl (S)-2-(4-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(tri Fluoromethyl)pyrimidine-5-carboxamido)-3,3-dimethylbutanoate)

Optically resolved (R)-coordinated starting material 9a was used instead of starting material 9a as a stereo mixture, and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloric acid was used instead of methyl 2-aminoacetate. Compound 205 (0.036 g, 28.0 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 164, except that.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.48 (s, 1 H), 7.47 - 7.45 (m, 2 H), 7.34 - 7.29 (m, 3 H), 7.27 - 7.24 (m, 2 H), 7.19 - 7.17 (m, 2 H), 6.37 (d, 1 H, J = 9.3 Hz), 4.80 (m, 2 H), 4.68 (t, 1 H, J = 11.9), 4.21 (dd, 1 H, J = 12.2, 6.4 Hz), 3.35 (s) , 3 H), 1.07 (s, 9 H).

MS (ESI) m/z 574.1 (M ⁺ + H).

Example 47: Synthesis of compound 206. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-5-carbox amido)-2-methylpropanoate)

Compound 206 (0.072 g, 58.8 %) as a white solid was obtained in the same manner as in the synthesis of Compound 164, except that methyl 2-amino-2-methylpropanoate was used instead of methyl 2-aminoacetate.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.52 (s, 1 H), 7.58 - 7.54 (m, 2 H), 7.37 - 7.29 (m, 3 H), 7.26 - 7.20 (m, 4 H), 6.68 (s, 1 H), 4.80 (dd , 1 H, J = 11.3, 5.2 Hz), 4.61 (t, 1 H, J = 11.7 Hz), 4.21 (dd, 1 H, J = 12.1, 5.2 Hz), 3.82 (s, 3 H), 1.76 ( d, 6 H, J = 2.8 Hz).

MS (ESI) m/z 546.1 (M ⁺ + H).

Example 48: Synthesis of compound 207. (Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-methoxypyrimidine-5-carboxamido)- 2-methylpropanoate)

In the same manner as in the synthesis of compound 163, compound 207 in the form of a white solid (0.040 g , 32.5%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); 8.34 (s, 1 H), 7.56 (d, 2 H, J = 8.7 Hz), 7.41 - 7.20 (m, 7 H), 6.64 (s, 1 H), 4.68 (dd, 1 H, J = 11.3, 5.1 Hz), 4.55 (t, 1 H, J = 11.5 Hz), 4.18 (d, 1 H, J = 11.8, 5.1 Hz), 3.83 (s, 3 H), 3.80 (s, 3 H), 1.72 ( s, 6 H).

MS (ESI) m/z 508.1 (M ⁺ + H).

Example 49: Synthesis of compound 208. ((S)-methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-methoxypyrimidine-5-carbox amido)-3-methylbutanoate)

In the same manner as in the synthesis of compound 163, except that the starting material 5h was used instead of the starting material 5a and (S)-methyl 2-amino-3-methylbutanoate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid, a white foamy solid was obtained. Compound 208 (0.040 g, 32.5%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); 8.30 (s, 1 H), 7.36 - 7.19 (m, 9 H), 6.38 - 6.36 (m, 1 H), 4.86 (dd, 1 H, J = 8.7, 4.7 Hz), 4.71 - 4.52 (m, 2 H), 3.96 (s, 3 H), 3.50 - 3.41 (m, 3 H), 2.15 - 2.10 (m, 1 H), 1.04 - 0.94 (m, 6 H).

MS (ESI) m/z 522.1 (M ⁺ + H).

Example 50: Synthesis of compound 209. ((S)-methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-methoxypyrimidine-5-carbox amido) propanoate)

Compound 209 in the form of a white foamy solid (0.050 g, 41.8%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); 8.30 (s, 1 H), 7.49 - 7.19 (m, 9 H), 6.53 (d, 1 H, J = 7.4 Hz), 4.94 - 4.88 (m, 1 H), 4.70 - 4.54 (m, 2 H) , 4.21 - 4.16 (m, 1 H), 3.96 (s, 3 H), 3.65 - 3.60 (m, 3 H), 1.52 (d, 3 H, J = 7.2 Hz).

MS (ESI) m/z 494.1 (M ⁺ + H).

Example 51: Synthesis of compound 210. ((S)-methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-methoxypyrimidine-5-carbox amido)-3,3-dimethylbutanoate)

White foam in the same manner as in the synthesis of compound 163, except that starting material 5h was used instead of starting material 5a, and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloric acid was used instead of glycinemethyl ester hydrochloric acid. Compound 210 (0.030 g, 23.1 %) was obtained in solid form.

¹ H NMR (400 MHz, CDCl ₃ ); 8.26 (d, 1 H, J = 3.6 Hz), 7.49 - 7.17 (m, 9 H), 6.39 (dd, 1 H, J = 9.3, 3.1 Hz), 4.78 - 4.74 (m, 1 H), 4.62 - 4.59 (m, 1 H), 4.51 - 4.48 (m, 1 H), 4.47 - 4.20 (m, 1 H), 3.95 (s, 3 H), 3.36 (s, 1.5 H), 3.20 (s, 1.5 H) ), 1.04 (s, 9 H).

MS (ESI) m/z 537.1 (M ⁺ + H).

Example 52: Synthesis of compound 211. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclobutylamino)pyrimidine-5 -Carboxamido)-2-phenylacetate)

In the same manner as in the synthesis of Compound 163, Compound 211 in the form of a white solid (compound 211 ( 0.062 g, 19.8%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.21 (m, 1 H), 7.44 - 7.14 (m, 14 H), 5.92 - 5.86 (m, 1 H), 4.64 - 4.30 (m, 3 H), 4.10 - 4.00 (m, 1 H), 3.54 - 3.49 (m, 3 H), 2.19 - 2.10 (m, 2 H), 2.07 - 1.90 (m, 1 H), 1.88 - 1.80 (m, 2 H), 1.74 - 1.60 (m, 2 H).

MS (ESI) m/z 595.2 (M ⁺ + H).

Example 53: Synthesis of compound 212. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclobutylamino)pyrimidine-5-carboxami Figure)-2-methylpropanoate)

In the same manner as in the synthesis of compound 163, compound 212 in the form of a white solid (0.016 g , 16.4%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.26 (m, 1 H), 7.56 - 7.54 (m, 2 H), 7.35 - 7.19 (m, 7 H), 6.68 (s, 1 H), 6.13 (s, 1 H), 4.63 (dd, 1 H, J = 11.2, 5.0 Hz), 4.50 - 4.30 (m, 2 H), 3.77 (s, 3 H), 2.37 - 2.22 (m, 2 H), 2.06 - 1.69 (m, 5 H), 1.67, 1.66 (2s, 6H).

MS (ESI) m/z 547.2 (M ⁺ + H).

Example 54: Synthesis of compound 213. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclobutylamino)pyrimidine-5 -carboxamido)propanoate)

Compound in the form of a white solid in the same manner as in the synthesis of Compound 163, except that the starting material 5c was used instead of the starting material 5a, and (S)-methyl 2-amino-3-methylbutanoate hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid. 213 (0.025 g, 24.9%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 9.88 (m, 1 H), 7.84 (d, 1 H, J = 5.6 Hz), 7.46 (d, 2 H, J = 8.4 Hz), 7.41 - 7.20 (m, 7 H), 6.90 - 6.70 (m) , 1 H), 4.82 - 4.74 (m, 2 H), 4.65 - 4.60 (m, 1 H), 4.40 - 4.30 (m, 1 H), 4.20 - 4.11 (m, 1 H), 3.56 (d, 3 H, J = 10.2 Hz), 2.40 - 2.06 (m, 5 H), 1.79 - 1.69 (m, 2 H), 1.03 - 0.91 (m, 6 H).

MS (ESI) m/z 561.2 (M ⁺ + H).

Example 55: Synthesis of compound 214. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cycloamino)pyrimidine-5- Carboxamido) propanoate)

In the same manner as in the synthesis of Compound 163, Compound 214 in the form of a white solid (0.010 g , 10.5%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.18 (s, 1 H), 7.49 - 7.46 (m, 2 H), 7.37 - 7.19 (m, 7 H), 6.80 - 6.60 (m, 1 H), 4.90 - 4.85 (m, 1 H), 4.66 - 4.60 (m, 1 H), 4.60 - 4.30 (m, 2 H), 4.16 - 4.08 (m, 1 H), 3.62 - 3.59 (m, 3 H), 2.40 - 2.20 (m, 2 H), 1.90 - 1.67 (m, 4 H), 1.53 - 1.47 (m, 3 H).

MS (ESI) m/z 533.2 (M ⁺ + H).

Example 56: Synthesis of compound 215. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclobutylamino)pyrimidine-5 -carboxamido)-3,3-dimethylbutanoate)

White solid in the same manner as in the synthesis of compound 163, except that starting material 5c was used instead of starting material 5a and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloric acid was used instead of glycinemethyl ester hydrochloric acid. The form of compound 215 (0.015 g, 14.6 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.12 - 8.00 (m, 1 H), 7.45 - 7.18 (m, 9 H), 4.75 (dd, 1 H, J = 9.4, 1.5 Hz), 4.66 - 4.20 (m, 3 H), 4.16 - 4.05 ( m, 1 H), 3.32 - 3.21 (m, 3 H), 2.40 - 2.20 (m, 2 H), 1.90 - 1.83 (m, 2 H), 1.72 - 1.68 (m, 2 H), 1.05 - 1.00 ( m, 9 H).

MS (ESI) m/z 575.2 (M ⁺ + H).

Example 57: Synthesis of compound 216.

N-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(3,6-dihydro-2H-pyran- 4-yl)pyrimidin-5-yl)-3,3,3-trifluoropropanamide

Dissolve starting material 12 (40 mg, 0.09 mmol), DIPEA (0.024 mL) in methylene chloride (2 mL), add 3,3,3-trifluoropropanoyl chloride (0.013 mL) at 0 °C, and at the same temperature After stirring for 12 hours, water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was separated by PTLC (hexane/ethyl acetate, 1:2) to obtain compound 216 (20 mg, 37.4%) as a pink oil.

¹ H NMR (400 MHz, CDCl ₃ ); δ 10.24 (s, 1 H), 8.71 (s, 1 H), 7.54-7.49 (m, 2 H), 7.37-7.23 (m, 8 H), 4.68 (m, 1 H), 4.62 (m, 1 H), 4.36-4.32 (m, 3 H), 3.94-3.86 (m, 4 H), 2.62 (m, 2 H).

MS (ESI) m/z 578.1 (M ⁺ + H).

Example 58: Synthesis of compound 217. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4-yl) pyrimidin-5-yl carbamate)

Compound 217 (0.012 g, 21.2 %) as a white solid was obtained in the same manner as in the synthesis of Compound 187, except that methyl chloride was used instead of TFAA.

¹ H NMR (400 MHz, CDCl ₃ ); δ 9.93 (brs, 1 H), 9.27 (brs, 1 H), 7.58-7.51 (m, 2 H), 7.36-7.21 (m, 7 H), 7.01 (brs, 1 H), 4.71-4.62 (m) , 2 H), 4.35-4.27 (m, 3 H), 3.91-3.87 (m, 5 H), 2.63 (m, 2 H).

MS (ESI) m/z 490.0 (M ⁺ + H).

Example 59: Synthesis of compound 218. (N-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4- Day) pyrimidin-5-yl) methanesulfonamide)

Compound 218 (0.015 g, 30.2 %) as a white solid was obtained in the same manner as for the synthesis of compound 216. The starting material 1-4-3 (42 mg, 0.097 mmol), DIPEA (0.025 ml) was dissolved in methylene chloride (2 mL), methanesulfonyl chloride (0.01 mL) was added at 25 °C, and stirred at the same temperature for 12 hours. After that, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = from 20 % to 70 %) and concentrated to give the desired compound 218 (0.015 g, 30.2 %) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 9.58 (brs, 1 H), 8.50 (s, 1 H), 7.45-7.33 (m, 2 H), 7.30-7.20 (m, 8 H), 4.84-4.64 (m, 2 H), 4.40-4.27 (m, 3 H), 3.87 (m, 2 H), 3.07 (s, 3 H), 2.62 (m, 2 H).

MS (ESI) m/z 510.1 (M ⁺ + H).

Example 60: Synthesis of compound 220. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4,4-dihydropiperidine-1- Day) pyrimidine-5-carboxamido) acetate)

Compound 220 (0.018 g, 47.7 %) in the form of a white solid was carried out in the same manner as in the synthesis of Compound 163, except that the starting material 1-2-2 was used instead of the starting material 5a and methyl 2-aminoacetate was used instead of the glycine methyl ester hydrochloric acid. ) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.26 (s, 1 H), 7.49-7.37 (m, 2 H), 7.37-7.21 (m, 7 H), 6.49 (m, 1 H), 4.67 (dd, 1 H, J = 11.4, 5.5 Hz ), 4.53 (t, 1 H, J = 11.6 Hz), 4.29 (d, 2 H, J = 4.9 Hz), 4.11 (dd, 1 H, J = 11.6, 5.6 Hz), 3.95 (t, 2 H, J = 5.4 Hz), 3.70 (s, 3 H), 1.98 (m, 4 H).

MS (ESI) m/z 569.1 (M ⁺ + H).

Example 61: Synthesis of compound 221. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4,4-difluoropiperidine-1 -yl)pyrimidine-5-carboxamido)-2-methylpropanoate)

Compound in the form of a white solid in the same manner as in the synthesis of Compound 163, except that the starting material 1-2-2 was used instead of the starting material 5a and methyl 2-amino-2-methylpropanoate hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid. 221 (0.017 g, 44.3 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.31 (s, 1 H), 7.56-7.53 (m, 2 H), 7.35-7.18 (m, 7 H), 6.64 (s, 1 H), 4.62 (dd, 1 H, J = 11.2, 5.1 Hz) ), 4.49 (t, 1 H, J = 11.6 Hz), 4.07 (dd, 1 H, J = 9.2, 5.2 Hz), 3.92 (t, 4 H, J = 5.4 Hz), 3.77 (s, 3 H) , 1.95 (m, 4 H), 1.66 (d, 6 H, J = 2.1 Hz).

MS (ESI) m/z 597.1 (M ⁺ + H).

Example 62: Synthesis of compound 222. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4,4-difluoropyr peridin-1-yl)pyrimidine-5-carboxamido)propanoate)

Compound in the form of a colorless oil in the same manner as in the synthesis of Compound 163, except that the starting material 1-2-2 was used instead of the starting material 5a, and (S)-methyl 2-aminopropanoate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. 222 (0.029 g, 61.9%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.25 (2s, 1 H), 7.47-7.43 (m, 2 H), 7.36-7.18 (m, 7 H), 6.54 (t, 1 H, J = 10.6 Hz), 4.89-4.4.83 (m, 1 H), 4.64 (m, 1 H), 4.51 (m, 1 H), 4.08 (m, 1 H), 3.92 (brs, 4 H), 3.61, 3.57 (2s, 3 H), 1.95 (m, 4 H), 1.48, 1.47 (2d, 3 H, J = 1.6 Hz).

MS (ESI) m/z 583.1 (M ⁺ + H).

Example 63: Synthesis of compound 223. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)--(4,4-difluoropiperi) Din-1-yl)pyrimidine-5-carboxamido)-3-methylbutanoate)

In the same manner as in the synthesis of compound 163, except that the starting material 1-2-2 was used instead of the starting material 5a, and (S)-methyl 2-amino-3-methylbutanoate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. Compound 223 (0.019 g, 43.0 %) was obtained as an oil.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.22 (2s, 1 H), 7.44-7.41 (m, 2 H), 7.38-6.99 (m, 7 H), 6.38, 6.34 (2d, 1 H, J = 8.7 Hz), 4.82-4.78 (m, 1 H), 4.70-4.43 (m, 2 H), 4.11-4.04 (m, 1 H), 3.92 (m, 4 H), 3.46, 3.39 (2s, 3 H), 2.20 (m, 1 H), 1.98 (m, 4 H), 1.02-0.85 (m, 6 H).

MS (ESI) m/z 611.2 (M ⁺ + H).

Example 64: Synthesis of compound 224. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4,4-dihydropiperi) Din-1-yl)pyrimidine-5-carboxamido)-2-phenylacetate)

In the same manner as in the synthesis of compound 163, in the form of a colorless oil, except that the starting material 1-2-2 was used instead of the starting material 5a and (S)-methyl 2-amino-2-phenylacetate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. of compound 224 (0.001 g, 7.2 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.30 (brs, 1 H), 7.39-7.11 (m, 14 H), 5.83 (d, 1 H, J = 7.3 Hz), 4.51 (m, 1 H), 4.17 (m, 1 H), 4.04 ( dd, 1 H, J = 12.0, 5.4 Hz), 3.92 (m, 4 H), 3.57 (s, 3 H), 1.95 (m, 4 H).

MS (ESI) m/z 645.1 (M ⁺ + H).

Example 65: Synthesis of compound 225. ((S)-Ethyl 2-(2-carbamoylpyrrolidin-1-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl )pyrimidine-5-carboxylate)

Compound 225 (0.130 g, 55.9 %) as a white solid was obtained in the same manner as in the synthesis of compound 168, except that L-prolinamide was used instead of pyrrolidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.33 (brs, 1 H), 7.51 (m, 2 H), 7.33-7.20 (m, 7 H), 4.52-4.27 (m, 5 H), 3.72 (brs, 1 H), 2.31-1.96 (6 H), 1.27 (m, 3 H).

MS (ESI) m/z 519.1 (M ⁺ + H).

Example 66: Synthesis of compound 226. (Ethyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl)piperidin-1-yl )pyrimidine-5-carboxylate)

Compound 226 (0.170 g, 70.1 %) as a white solid was obtained in the same manner as in the synthesis of compound 168, except that 4-(trifluoromethyl)piperidine was used instead of pyrrolidine.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.35 (s, 1 H), 7.53 (m, 2 H), 7.36-7.22 (m, 7 H), 4.89 (m, 2 H), 4.62 (dd, 1 H, J = 10.0, 4.4 Hz), 4.48 (t, 1 H, J = 11.6 Hz), 4.39-4.30 (m, 2 H), 4.16-4.11 (m, 2 H), 2.83 (m, 2 H), 2.29 (m, 2 H), 1.89 (m, 2 H), 1.52 (m, 2 H), 1.28 (q, 3 H, J = 8.5 Hz).

MS (ESI) m/z 558.1 (M ⁺ + H).

Example 67: Synthesis of compound 227. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl) benzylamino)pyrimidine-5-carboxamido)propanoate)

In the same manner as in the synthesis of compound 163, compound 227 in the form of a light yellow solid (0.028 g, 24.6%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.16 (s, 1 H), 7.55 (d, 2 H, J = 8.3 Hz), 7.46 (dd, 2 H, J = 8.7, 3.2 Hz), 4.42 (d, 1 H, J = 8.0 Hz), 7.36 - 7.30 (m, 3 H), 7.22 - 7.18 (m, 4 H), 6.66 (brs, 1 H), 4.90 - 4.84 (m, 1 H), 4.69 - 4.60 (m, 3 H), 4.42 - 4.34 (m, 1 H), 4.06 - 4.00 (m, 1 H), 3.62 (d, 1 H, J = 11.5 Hz), 1.54 - 1.45 (m, 3 H).

MS (ESI) m/z 637.1 (M ⁺ + H).

Example 68: Synthesis of compound 228. (methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl)benzylamino)pyri midine-5-carboxamido)-2-methylpropanoate)

In the same manner as in the synthesis of compound 163, compound 228 in the form of a white solid (0.012 g , 10.1 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.21 (s, 1H), 7.56 - 7.54 (m, 4H), 7.42 - 7.41 (m, 2H), 7.36 - 7.30 (m, 3H), 7.23 - 7.19 (m, 4H), 6.73 (brs, 1H) , 4.68 - 4.61 (m, 3H), 4.40 (t, 1H, J = 11.4 Hz), 4.04 - 4.00 (s, 3H), 1.69 (s, 6H).

MS (ESI) m/z 651.1 (M ⁺ + H).

Example 69: Synthesis of compound 229. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl) benzylamino)pyrimidine-5-carboxamido)-3-methylbutanoate)

Compound in the form of a white solid in the same manner as in the synthesis of Compound 163, except that 5g of the starting material was used instead of the starting material 5a, and (S)-methyl 2-amino-3-methylbutanoate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. 229 (0.012 g, 10.1 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 7.93 (s, 1H), 7.54 - 7.42 (m, 6H), 7.35 - 7.24 (m, 7H), 4.83 - 4.77 (m, 1H), 4.64 - 4.53 (m, 3H), 4.43 - 4.42 (m, 1H), 3.55 - 3.42 (m, 3H), 2.18 - 2.11 (m, 1H), 0.98 - 0.94 (m, 6H).

MS (ESI) m/z 666.2 (M ⁺ + H).

Example 70: Synthesis of compound 230. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl) benzylamino)pyrimidine-5-carboxamido)-3,3-dimethylbutanoate)

In the same manner as in the synthesis of compound 163, except that 5 g of the starting material was used instead of the starting material 5a, and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. The form of compound 230 (0.064 g, 51.9 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 7.91 - 7.89 (m, 1H), 7.52 - 7.47 (m, 6H), 7.35 - 7.21 (m, 7H), 4.48 - 4.75 (m, 1H), 4.60 - 4.59 (m, 3H), 4.41 - 4.38 ( m, 1H), 3.97 - 3.94 (m, 1H), 3.44 - 3.24 (m, 3H), 1.02 (d, 1H, J = 3.8 Hz).

MS (ESI) m/z 680.2 (M ⁺ + H).

Example 71: Synthesis of compound 231. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl) Benzylamino)pyrimidine-5-carboxamido)-2-phenylacetate)

In the same manner as in the synthesis of compound 163, compound 231 in the form of a white solid (compound 231 ( 0.050 g, 39.4%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 7.98 - 7.97 (m, 1H), 7.58 - 7.10 (m, 18H), 5.82 - 5.75 (m, 1H), 4.81 - 4.75 (m, 1H), 4.65 - 4.55 (m, 2H), 4.42 - 4.37 ( m, 1H), 3.97 - 3.96 (m, 1H), 3.63 - 3.53 (m, 3H).

MS (ESI) m/z 699.1 (M ⁺ + H).

Example 72: Synthesis of compound 232. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl) Benzylamino)pyrimidine-5-carboxamido)-2-cyclohexylacetate)

Compound in the form of a light yellow solid in the same manner as in the synthesis of Compound 163, except that 5g of the starting material was used instead of the starting material 5a, and (S)-methyl 2-amino-2-cyclosecylacetate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. 232 (0.072 g, 56.3%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 7.93 (d, 1H, J = 2.8 Hz), 7.57 - 7.42 (m, 6H), 7.33 - 7.24 (m, 7H), 4.80 - 4.76 (m, 1H), 4.64 - 4.60 (m, 2H), 4.54 (dd, 1H, J = 17.6, 6.6 Hz), 4.42 - 4.35 (m, 1H), 4.01 - 3.98 (m, 1H), 3.58 - 3.41 (m, 3H), 1.77 - 1.63 (m, 7H), 1.16 - 1.05 (m, 4H)

MS (ESI) m/z 706.2 (M ⁺ + H).

Example 73: Synthesis of compound 233. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-(4,4-difluoropiperidine) -1-yl)pyrimidine-5-carboxamido)-3-methylbutanoate)

Compound 233 (0.036 g, 27.0%) in the form of a white solid was prepared in the same manner as in the synthesis of Compound 164, except that (S)-methyl 2-amino-2-cyclohexylaetate hydrochloric acid was used instead of methyl 2-aminoacetate. got it

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.51 (d, 1 H, J = 7.5 Hz), 7.48-7.45 (m, 2 H), 7.40-7.31 (m, 4 H), 7.28-7.23 (m, 2 H), 7.20-7.01 (m, 1 H), 6.36 (dd, 1 H, J = 12.1, 8.9 Hz), 4.89-4.85 (m, 1 H), 4.80-4.70 (m, 1 H), 4.70-4.54 (m, 1 H), 4.27 -4.13 (m, 1 H), 3.50-3.38 (m, 3 H), 1.87 (m, 1 H), 1.76 (m, 3 H), 1.70-1.66 (m, 1 H), 1.22-1.07 (m) , 6 H).

MS (ESI) m/z 600.2 (M ⁺ + H).

Example 74: Synthesis of compound 234. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(cyclobutylamino)pyrimidine-5 -carboxamido)-2-cycloacetate)

Compound 234 in the form of a white solid in the same manner as in the synthesis of Compound 163, except that the starting material 5c was used instead of the starting material 5a, and (S)-methyl 2-amino-2-cyclosecylacetate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. (0.040 g, 26.6 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.20 (s, 1 H), 7.46 (dd, 2 H, J = 7.0, 1.6 Hz), 6.50 - 6.40 (m, 1 H), 4.80 (dd, 1 H, J = 8.8, 5.5 Hz), 4.62 (dd, 1 H, J = 11.4, 4.8 Hz), 4.50 - 4.30 (m, 3 H), 4.15 - 4.11 (m, 1 H), 3.38 (s, 3 H), 2.40 - 2.20 (m, 2 H) ), 2.00 - 1.00 (m, 14 H).

MS (ESI) m/z 601.2 (M ⁺ + H).

Example 75: Synthesis of compound 243. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H -Pyran-4-yl)pyrimidine-5-carboxamido)-2-phenylacetate)

Compound 243 (0.020 g, 30.3 %) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 163, except that (S)-methyl 2-amino-2-phenylacetate hydrochloric acid was used instead of glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.58 - 8.53 (m, 1 H), 7.54 - 7.11 (m, 14 H), 6.49 - 6.45 (m, 1 H), 6.00 - 6.93 (m, 1 H), 4.80 - 4.45 (m, 4 H) , 4.41 (m, 2 H), 4.28 - 4.22 (m, 2 H), 3.87 - 3.37 (m, 2 H), 3.72 - 3.56 (m, 3 H), 2.64 - 2.63 (m, 2 H).

MS (ESI) m/z 608.3 (M ⁺ + H).

Example 76: Synthesis of compound 244. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H -Pyran-4-yl)pyrimidine-5-carboxamido)-3-methylbutanoate)

Compound 244 (0.020 g, 32.1 %) in the form of a yellow solid was obtained in the same manner as in the synthesis of compound 163 except that ((S)-methyl 2-amino-3-methylbutanoate hydrochloric acid was used instead of glycine methyl ester hydrochloric acid. .

¹ H NMR (400 MHz, CDCl ₃ ); 8.50 - 8.45 (m, 1 H), 7.48 - 7.21 (m, 9 H), 6.51 - 6.41 (m, 1 H), 5.94 (br s, 1 H), 4.87 (dd, 1 H, J = 6.6, 3.6 Hz), 4.74 - 4.53 (m, 3 H), 4.40 (d, 2 H, J = 1.9 Hz), 4.27 - 4.21 (m, 1 H), 3.91 - 3.88 (m, 1 H), 3.50 - 3.42 (m, 3 H), 2.64 (s, 2 H), 2.27 - 2.20 (m, 1 H).

MS (ESI) m/z 574.3 (M ⁺ + H).

Example 77: Synthesis of compound 245. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H -Pyran-4-yl)pyrimidine-5-carboxamido)propanoate)

Compound 245 (0.020 g, 33.8 %) in the form of a yellow solid was obtained in the same manner as in the synthesis of Compound 163, except that (S)-methyl 2-aminopropanoate hydrochloric acid was used instead of glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.51 - 8.47 (m, 1 H), 7.51 - 7.22 (m, 9 H), 6.58 - 6.52 (m, 1 H), 6.12 - 6.02 (m, 1 H), 4.95 - 4.90 (m, 1 H) , 4.75 - 4.72 (m, 1 H), 4.64 - 4.61 (m, 2 H), 4.39 (d, 2 H, J = 2.3 Hz), 4.26 - 4.22 (m, 1 H), 3.91 - 3.88 (m, 1 H), 3.67 - 3.61 (m,3 H), 1.57 - 1.50 (m, 3 H).

MS (ESI) m/z 546.2 (M ⁺ + H).

Example 78: Synthesis of compound 246. (Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4) -yl)pyrimidine-5-carboxamido)-2-methylpropanoate)

Compound 246 (0.015 g, 24.7 %) as a yellow solid was obtained in the same manner as in the synthesis of Compound 163, except that methyl 2-amino-2-methylpropanoate hydrochloric acid was used instead of glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); 8.50 (s, 1 H), 7.59 - 7.56 (m, 2 H), 7.38 - 7.23 (m, 7 H), 6.85 (br s, 1 H), 6.06 (br s, 1 H), 4.73 - 4.69 ( m, 1 H), 4.63 - 4.52 (m, 2 H), 4.40 - 4.38 (m, 2 H), 4.22 (dd, 1 H, J = 8.9, 3.8 Hz), 3.91 - 3.89 (m, 2 H) , 3.81 - 3.79 (m, 3 H), 2.64 - 2.63 (m, 2 H), 1.75 - 1.74 (m, 6 H).

MS (ESI) m/z 560.2 (M ⁺ + H).

Example 79: Synthesis of compound 247. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H -Pyran-4-yl)pyrimidine-5-carboxamido)-3,3-dimethylbutanoate)

Compound 247 (0.020 g, 31.3 %) as a yellow solid in the same manner as in the synthesis of Compound 163 except that (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloric acid was used instead of glycinemethyl ester hydrochloric acid got

¹ H NMR (400 MHz, CDCl ₃ ); 8.49 - 8.43 (s, 1 H), 7.47 - 7.20 (m, 9 H), 6.44 - 6.36 (m, 1 H), 6.01 - 5.98 (m, 1 H), 4.81 - 4.75 (m, 1 H), 4.69 - 4.63 (m, 1 H), 4.60 - 4.52 (m, 1 H), 4.40 (d, 1 H, J = 2.7 Hz), 4.25 - 4.19 (m, 1 H), 3.91 - 3.89 (m, 2 H), 3.35 (s, 1.5 H), 3.21 (s, 1.5 H), 2.64 (s, 2 H), 1.06 - 1.05 (m, 9 H).

MS (ESI) m/z 588.3 (M ⁺ + H).

Example 80: Synthesis of compound 248. ((S)-Methyl 2-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H -Pyran-4-yl)pyrimidine-5-carboxamido)-2-cyclohexylacetate)

Compound 248 (0.015 g, 22.5 %) in the form of a yellow solid was obtained in the same manner as in the synthesis of Compound 163, except that (S)-methyl 2-amino-2-cyclosecyl acetate hydrochloric acid was used instead of glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.46 - 8.45 (m, 1 H), 7.48 - 7.20 (m, 9 H), 6.48 - 6.44 (m, 1 H), 5.98 - 5.96 (m, 1 H), 4.89 - 4.84 (m, 1 H) , 4.78 - 4.65 (m, 1 H), 4.59 - 4.51 (m, 1 H), 4.38 (d, 2 H, J = 2.6 Hz), 4.23 - 4.16 (m, 1 H), 3.49 (s, 1.5 H) ), 3.39 (s, 1.5 H), 2.63 (s, 2 H), 2.00 - 1.00 (m, 12 H).

MS (ESI) m/z 614.3 (M ⁺ + H).

Example 81: Synthesis of compound 250. (N-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4- Day) pyrimidin-5-yl) cyclopropanecarboxamide)

Compound 250 (0.045 g, 77.7 %) in the form of a light yellow solid was obtained in the same manner as in the synthesis of compound 187, except that cyclopropanecarbonyl chloride was used instead of TFAA.

¹ H NMR (400 MHz, CDCl ₃ ); δ 10.24 (s, 1 H), 8.67 (s, 1 H), 7.75 (d, 1 H, J = 7.0 Hz), 7.46 (d, 1 H, J = 7.3 Hz), 7.34 - 7.22 (m, 5 H), 7.05 (brs, 1 H), 5.03 - 4.99 (m, 1 H), 4.59 (t, 1 H, J = 11.6 Hz), 4.24 - 4.23 (m, 2 H), 4.17 - 4.13 (m, 2 H), 3.75 (t, 1 H, J = 5.0 Hz), 3.38 - 3.35 (m, 2 H), 1.93 - 1.92 (m, 1 H), 0.88 - 0.81 (m, 4 H).

MS (ESI) m/z 500.2 (M ⁺ + H).

Example 82: Synthesis of compound 251. (N-(4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,6-dihydro-2H-pyran-4- Day) pyrimidin-5-yl) cyclopentanecarboxamide)

Compound 251 (0.026 g, 42.5 %) in the form of a light yellow solid was obtained in the same manner as in the synthesis of Compound 187, except that cyclopentanecarbonyl chloride was used instead of TFAA.

¹ H NMR (400 MHz, CDCl ₃ ); δ 10.11 (s, 1 H), 8.93 (s, 1 H), 7.71 (d, 1 H, J = 8.6 Hz), 7.47 (d, 1 H, J = 8.5 Hz), 7.32 - 7.31 (m, 4 H), 7.03 (brs, 1 H), 5.02 - 5.00 (m, 1 H), 4.62 - 4.00 (m, 1H), 4.24 - 4.23 (m, 2H), 4.18 - 4.15 (m, 1 H), 3.75 (t, 1 H, J = 5.4 Hz), 3.35 - 3.34 (m, 2 H), 2.99 - 2.98 (m, 1 H), 1.89 - 1.57 (m, 8H).

MS (ESI) m/z 528.1 (M ⁺ + H).

Example 83: Synthesis of compound 282. ((S)-Methyl 2-(2-(4-chlorobenzylamido)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyri midine-5-carboxamido)-3-methylbutanoate)

Compound in the form of a white solid in the same manner as in the synthesis of compound 163, except that the starting material 5f was used instead of the starting material 5a and (S)-methyl 2-amino-3-methylbutanoate hydrochloric acid was used instead of the glycinemethyl ester hydrochloric acid. 282 (0.079 g, 64.8%) was obtained.

MS (ESI) m/z 631.1 (M ⁺ + H).

Example 84: Synthesis of compound 283. ((S)-N-(1-amino-3-methyl-1-oxobutan2-yl)-2-(4-chlorobenzylamino)-4-(3-(4-chlorophenyl)-4-phenyl -4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, compound 283 in the form of a white solid (compound 283 in the form of a white solid) 0.052 g, 40.5%) was obtained.

MS (ESI) m/z 619.2 (M ⁺ + H).

Example 85: Synthesis of compound 303. (methyl 2-(4-chlorophenoxy)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxylate)

Compound 303 (0.023 g, 11.1 %) in the form of a colorless oil was obtained in the same manner as in the synthesis of compound 163, except that starting material 105 was used instead of starting material 5a and 4-chlorophenol was used instead of glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.32 (s, 1 H), 7.50 (m, 2 H), 7.35-7.10 (m, 11 H), 4.67 (dd, 1 H, J = 11.1, 4.8 Hz), 4.42 (t, 1 H, J) = 11.3 Hz), 4.05 (dd, 1 H, J = 11.3, 4.8 Hz), 3.90 (s, 3 H).

MS (ESI) m/z 519.0 (M ⁺ + H).

Example 86: Synthesis of compound 317. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydroparizol-1-yl )-2-(trifluoromethyl)pyrimidine-5-carboxamide)

Compound 317 (0.110 g, 84.2 %) as a white solid was obtained in the same manner as in the synthesis of Compound 164, except that 2-amino-2-methylpropanamide hydrochloric acid was used instead of methyl 2-aminoacetate.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.50 (s, 1 H), 7.51 (m, 2 H), 7.37-7.20 (m, 7 H), 6.87 (s, 1 H), 6.44 (brs, 1 H), 5.33 (brs, 1 H) , 4.74 (dd, 1 H, J = 11.3, 5.4 Hz), 4.61 (t, 1 H, J = 11.8 Hz), 4.22 (dd, 1 H, J = 12.1, 5.4 Hz), 1.74 (d, 6 H) , J = 4.5 Hz).

MS (ESI) m/z 531.1 (M ⁺ + H).

Example 87: Synthesis of compound 318. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl )-2-Methoxypyrimidine-5-carboxamide)

Compound 318 in the form of a white solid (0.005 g, 12.7 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); 8.35 (s, 1 H), 7.48 (m, 2 H), 7.35-7.19 (m, 7 H), 6.84 (brs, 1 H), 6.79 (brs, 1 H), 5.28 (brs, 1 H), 4.69 (dd, 1 H, J = 11.0, 5.3 Hz), 4.57 (t, 1 H, J = 11.6 Hz), 4.17 (dd, 1 H, J = 11.9, 5.3 Hz), 3.96 (s, 3 H) , 1.67 (d, 6 H, J = 4.1 Hz).

MS (ESI) m/z 493.1 (M ⁺ + H).

Example 88: Synthesis of compound 320. (Methyl 2-(4-chlorobenzyloxy)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxylate)

To a mixture of sodium hydride (60.00 %, 0.087 g, 2.171 mmol) in dimethoxyethane (10 mL) at room temperature, 4-chlorobenzyl alcohol (0.310 g, 2.171 mmol) was added and stirred at 45 °C for 15 minutes. did After adding the starting material 3-1 (0.515 g, 1.206 mmol) at room temperature and stirring at the same temperature for 1 hour, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The precipitated solid was filtered and dried to obtain the desired compound 320 (0.549 g, 85.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.37 (s, 1 H), 7.54-7.52 (m, 2 H), 7.39-7.29 (m, 8 H), 7.26-7.20 (m, 3 H), 5.38 (m, 2 H), 4.71 (dd , 1 H, J = 11.2, 4.9 Hz), 4.52 (t, 1 H, J = 11.5), 4.19 (dd, 1 H, J = 11.9, 5.0 Hz), 3.91 (s, 3 H).

MS (ESI) m/z 534.1 (M ⁺ + H).

Example 89: Synthesis of compound 321. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-2-(4-chlorobenzyloxy)-4-(3-(4-chlorophenyl)-4-phenyl-4, 5-dihydropyrazol-1-yl)pyrimidine-5-carboxamide)

Compound 321 in the form of a white solid (0.025 g, 48.9%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.36 (s, 1 H), 8.25 (s, 1 H), 7.62 (d, 2 H, J = 8.6 Hz), 7.47 - 7.40 (m, 6 H), 7.35 - 7.25 (m, 5 H), 7.18 (s, 1 H), 6.93 (s, 1 H), 5.36 (q, 2 H, J = 11.7 Hz), 4.98 (dd, 1 H, J = 11.0, 4.1 Hz), 4.47 (t, 1 H) , J = 11.5 Hz), 4.03 (dd, 1 H, J = 11.8, 4.2 Hz), 1.44 (d, 6 H, J = 6.2 Hz).

MS (ESI) m/z 603.1 (M ⁺ + H).

Example 90: Synthesis of compound 322. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-2-(4-chlorobenzyloxy)-4-(3-(4-chlorophenyl)-4- Phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, compound 322 in the form of a white solid (compound 322 ( 0.062 g, 54.0%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.37 - 8.26 (m, 1 H), 8.10 - 8.08 (m, 1 H), 7.62 - 7.53 (m, 2 H), 7.53 - 7.38 (m, 7 H), 7.38 - 7.22 (m, 5 H) , 7.10 (s, 1 H), 5.40 - 5.31 (m, 2 H), 5.06 - 4.94 (m, 1 H), 4.52 - 4.41 (m, 1 H), 4.41 - 4.33 (m, 1 H), 4.05 - 4.01 (m, 1 H), 2.09 - 1.99 (m, 1 H), 0.94 - 0.89 (m, 6 H).

MS (ESI) m/z 617.1 (M ⁺ + H).

Example 91: Synthesis of compound 323. (N-(2-amino-2-oxoethyl)-2-(4-chlorobenzyloxy)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazole-1 -yl) pyrimidine-5-carboxamide)

Compound 323 (0.020 g, 37.4 %) as a white solid was obtained in the same manner as in the synthesis of Compound 163, except that the starting material 5f was used instead of the starting material 5a and aminoacetamide hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.38 (s, 1 H), 7.49 - 7.46 (m, 2 H), 7.35 - 7.14 (m, 14 H), 5.42 -5.30 (m, 2 H), 4.78 - 4.77 (m, 1 H), 4.67 - 4.57 (m, 1 H), 4.20 - 4.05 (m, 3 H).

MS (ESI) m/z 575.2 (M ⁺ + H).

Synthesis of compound 14a. (tert-Butyl 2-chloro-4- (3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazol-1-yl) pyrimidine-5-carboxylate)

A solution of starting material 1a (2.418 g, 9.709 mmol), 1-5-1 (2.493 g, 9.709 mmol) and DIPEA (3.346 mL, 19.418 mmol) in acetonitrile (40 mL) at room temperature was dissolved at the same temperature for 12 hours. stirred for a while. The precipitated solid was filtered, washed with hexane and dried to obtain the desired compound 14a (1.785 g, 40.6 %) as a white solid.

Synthesis of compound 14b. (tert-Butyl 2-chloro-4- (3- (4-fluorophenyl) -4-phenyl-4,5-dihydropyrazol-1-yl) pyrimidine-5-carboxylate)

Compound 14b (2.056 g, 44.8 %) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 14a, except that the starting material 1b was used instead of the starting material 1a.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.28 (s, 1H), 7.61 - 7.58 (m, 2H), 7.34 - 7.21 (m, 5H), 6.97 - 6.92 (m, 2H), 4.67 (dd, 1H, J = 10.9, 4.5 Hz), 4.50 (t, 1H, J = 11.5 Hz), 4.19 (dd, 1H, J = 12.0, 4.6 Hz), 1.56 (s, 9H).

Synthesis of compounds 1-5-2. (tert-Butyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,3,3-trifluoropropoxy)pyri midine-5-carboxylate)

A solution of 3,3,3-trifluoropropan-1-ol (0.076 mL, 0.859 mmol) and sodium hydride (60.00 %, 0.040 g, 0.991 mmol) in dimethoxyethane (3 mL) was dissolved at room temperature for 10 After stirring for a minute, starting material 14a (0.310 g, 0.660 mmol) was added, followed by further stirring at the same temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 5 % to 40 %) and concentrated to give 1-5-2 (0.110 g, 30.4 %) as a white foam solid. .

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.36 (s, 1 H), 7.56 (m, 2 H), 7.37-7.22 (m, 7 H), 4.59 (dd, 1 H, J = 11.2, 7.0 Hz), 4.57-4.49 (m, 3 H) ), 4.18 (dd, 1 H, J = 11.7, 4.5 Hz), 2.65 (m, 2 H), 1.59 (s, 9 H)

MS (ESI) m/z 547.1 (M ⁺ + H).

Synthesis of compounds 1-5-3. (tert-Butyl 2- (4-chlorophenoxy) -4- (3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazol-1-yl) pyrimidine-5-carboxyl rate)

Acetonitrile (3 mL) was added to the starting material 14a (0.480 g, 1.023 mmol), 4-chlorophenol (0.171 g, 1.329 mmol) and DIPEA (0.268 mL, 1.534 mmol), and microwaved for 2 hours at room temperature. After cooling to room temperature, water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = from 5 % to 20 %) and concentrated to give the desired compound 1-5-3 (0.480 g, 83.6 %) as a yellow solid. got it

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.29 (s, 1 H), 7.33-7.09 (m, 10 H), 6.78 (m, 2 H), 4.67 (dd, 1 H, J = 11.0, 4.6 Hz), 4.51 (t, 1 H, J) = 11.9 Hz), 4.19 (dd, 1 H, J = 12.0, 4.7 Hz), 1.57 (s, 9 H).

MS (ESI) m/z 561.1 (M ⁺ + H).

Synthesis of compounds 1-5-4. (tert-butyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-ethoxypyrimidine-5-carboxylate)

A solution of ethanol (0.187 mL, 3.196 mmol) and sodium hydride (60.00 %, 0.128 g, 3.196 mmol) in dimethoxyethane (10 mL) was stirred at room temperature for 30 minutes, and starting material 14a (1.000 g, 2.131) mmol) was added and the mixture was further stirred at the same temperature for 2 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0 % to 20 %) and concentrated to obtain the desired compound 1-5-4 (0.657 g, 64.4 %) as a white solid. got it

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.34 (s, 1 H), 7.55 - 7.52 (m, 3 H), 7.34 - 7.20 (m, 7 H), 4.64 - 4.61 (m, 1 H), 4.50 (t, 1 H, J = 11.4 Hz) ), 4.40 - 4.36 (m, 2 H), 4.17 (dd, 1 H, J = 11.7, 4.5 Hz), 1.57 (s, 9 H), 1.38 (t, 3 H, J = 7.1 Hz).

MS (ESI) m/z 479.1 (M ⁺ + H).

Synthesis of compounds 1-5-5. (4-(3-(4-Chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5 -carboxylic acid)

A solution of the starting material 353 (0.280 g, 0.525 mmol) and trifluoroacetic acid (0.402 mL, 5.254 mmol) in methylene chloride (3 mL) at room temperature was stirred at the same temperature for 5 hours. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 5 % to 30 %) and concentrated to 1-5-5 (0.160 g, 63.9 %) was obtained in the form of a white foamy solid.

MS (ESI) m/z 477.0 (M ⁺ + H).

Synthesis of compounds 1-5-6. (4-(3-(4-Chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3-(trifluoromethyl)benzyloxy)pyrimidine-5- carboxylic acid)

Compound 1-5-6 (0.546 g, 67.1 %) in the form of an orange solid was obtained in the same manner as in the synthesis of Compound 1-5-5, except that starting material 387 was used instead of starting material 353.

Synthesis of compounds 1-5-7. (4-(3-(4-Chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3,3,3-trifluoropropoxy)pyrimidine-5 -carboxylic acid)

Compound 1-5-7 (0.085 g, 94.7 %) in the form of a white foamy solid was obtained in the same manner as in the synthesis of Compound 1-5-5, except that starting material 1-5-2 was used instead of starting material 353.

Synthesis of compounds 1-5-8. (2-(4-chlorophenoxy)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxylic acid)

Compound 1-5-8 (0.280 g, 64.8 %) in the form of a yellow solid was obtained in the same manner as in the synthesis of Compound 1-5-5, except that starting material 1-5-3 was used instead of starting material 353.

Synthesis of compounds 1-5-9. (4-(3-(4-Chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-ethoxypyrimidine-5-carboxylic acid)

Compound 1-5-9 (0.567 g, 99.3 %) in the form of a pale yellow solid was obtained in the same manner as in the synthesis of Compound 1-5-5, except that starting material 1-5-4 was used instead of starting material 353.

Synthesis of compounds 1-5-10. (4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl)benzyloxy)pyrimidine-5 -carboxylic acid)

Compound 1-5-10 (0.831 g, 100%) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 1-5-5, except that the starting material 385 was used instead of the starting material 353.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.30 (s, 1H), 7.72 - 7.62 (m, 6H), 7.34 - 7.20 (m, 7H), 5.52 - 5.46 (m, 2H), 5.05 (dd, 1H, J = 11.0, 4.1 Hz), 4.47 (t, 1H, J = 11.4 Hz), 4.06 - 4.03 (m, 2H).

Example 92: Synthesis of compound 325. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-2-(4-chlorophenoxy)-4-(3-(4-chlorophenyl)-4-phenyl-4, 5-dihydropyrazol-1-yl)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of Compound 163, Compound 325 in the form of a white solid ( 0.026 g, 40.5%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.22 (s, 1 H), 8.02 (s, 1 H), 7.50-7.07 (m, 12 H), 7.01 (s, 1 H), 6.61 (s, 1 H), 5.43 (s, 1 H) , 4.55 (dd, 1 H, J = 11.2, 5.4 Hz), 4.07 (t, 1 H, J = 12.7 Hz), 3.63 (dd, 1 H, J = 12.3, 5.5 Hz), 1.66 (d, 6 H) , J = 5.2 Hz).

MS (ESI) m/z 589.1 (M ⁺ + H).

Example 93: Synthesis of compound 326. (N-(2-amino-2-oxoethyl)-2-(4-chlorophenoxy)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazole-1 -yl)pyrimidine-5-carboxamide)

Compound 326 in the form of a white solid (0.016 g, 29.4 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.22 (s, 1 H), 7.51-6.34 (m, 14 H), 6.37 (s, 1 H), 5.69 (s, 1 H), 4.71 (dd, 1 H, J = 11.4, 5.4 Hz), 4.54 (t, 1 H, J = 11.6 Hz), 4.17 (m, 3 H).

MS (ESI) m/z 561.1 (M ⁺ + H).

Example 94: Synthesis of compound 327. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-2-(4-chlorophenoxy)-4-(3-(4-chlorophenyl)-4- Phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, except that starting material 1-5-8 was used instead of starting material 5a and (S)-2-amino-3-methylbutanamide hydrochloric acid was used instead of glycinemethylester hydrochloric acid, as a white solid form of compound 327 (0.036 g, 52.9 %) was obtained.

MS (ESI) m/z 604.1 (M ⁺ + H).

Example 95: Synthesis of compound 329. (methyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(2,22-trifluoroethoxy)pyrimidine-5- carboxylate)

Compound 329 (0.230 g, 43.5 %) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 320, except that 2,2,2-fluoroethanol was used instead of 4-chlorobenzyl alcohol.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.35 (s, 1 H), 7.54 (m, 2 H), 7.36-7.20 (m, 7 H), 4.83-4.71 (m, 3 H), 4.54 (t, 1 H, J = 11.4 Hz), 4.19 (dd, 1 H, J = 11.9, 5.0 Hz), 3.91 (s, 3 H).

MS (ESI) m/z 491.0 (M ⁺ + H).

Example 96: Synthesis of compound 353. (tert-Butyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(2,2,2-trifluoroethoxy)pyri midine-5-carboxylate)

A solution of 2,2,2-trifluoroethanol (0.137 mL, 1.918 mmol) and sodium hydride (60.00 %, 0.077 g, 1.918 mmol) in dimethylformamide (5 mL) was dissolved at 0 °C for 10 min. After stirring, starting material 14a (0.600 g, 1.278 mmol) was added and further stirred at room temperature for 1 h. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 5 % to 40 %) and concentrated to give 353 (0.290 g, 42.6 %) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.33 (s, 1 H), 7.56-7.53 (m, 2 H), 7.35-7.22 (m, 7 H), 4.81-4.65 (m, 3 H), 4.54 (t, 1 H, J = 11.8 Hz) ), 4.17 (dd, 1 H, J = 11.8, 4.6 Hz), 1.57 (s, 9 H).

MS (ESI) m/z 533.1 (M ⁺ + H).

Example 97: Synthesis of compound 354. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl )-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, compound 354 in the form of a white solid (compound 354 in the form of a white solid ( 0.025 g, 50.6%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.40 (s,1 H, 8.31 (brs, 1 H), 7.64-7.61 (m, 2 H), 7.42-7.40 (m, 2 H), 7.35-7.23 (m, 5 H), 7.20 (brs, 1 H), 6.93 (brs, 1 H), 5.04-4.97 (m, 3 H), 4.51 (t, 1 H, J = 11.8 Hz), 4.08 (dd, 1 H, J = 11.9, 4.2 Hz), 1.44 (d, 6 H, J = 7.2 Hz).

MS (ESI) m/z 561.1 (M ⁺ + H).

Example 98: Synthesis of compound 355. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazole -1-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, except that starting material 1-5-5 was used instead of starting material 5a and (S)-2-amino-3-methylbutanamide hydrochloric acid was used instead of glycinemethylester hydrochloric acid, as a white solid in the form of a white solid. of compound 355 (0.032 g, 53.1 %) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.38 (2d, 1 H), 8.11, 8.10 (2s, 1 H), 7.61-7.08 (m, 11 H), 4.99 (m, 3 H), 4.53 (m, 1 H), 4.35 (m, 1 H), 4.08 (m, 1 H), 2.01 (m, 1 H), 0.91 (m, 6 H).

MS (ESI) m/z 375.1 (M ⁺ + H).

Example 99: Synthesis of compound 356. (N-(2-amino-2-oxoethyl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(2,2 ,2-trifluoroethoxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of Compound 163, Compound 356 (0.036 g, 63.2 %) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.57 (t, 1 H, J = 5.8 Hz), 8.23 (s, 1 H), 7.61-7.57 (m, 2 H), 7.44-7.42 (m, 3 H), 7.34-7.16 (m, 6 H) ), 5.05 - 4.96 (m, 3 H), 4.51 (t, 1 H, J = 11.8 Hz), 4.08 (dd, 1 H, J = 12.1, 4.4 Hz), 3.89 (d, 2 H, J = 5.8 Hz).

MS (ESI) m/z 533.1 (M ⁺ + H).

Example 100: Synthesis of compound 360. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl )-2-(3,3,3-trifluoropropoxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, compound 360 in the form of a white solid (compound 360 ( 0.011 g, 19.2%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.34 (s, 1 H), 7.49 (m, 2 H), 7.35-7.18 (m, 7 H), 6.82 (brs, 1 H), 6.79 (brs, 1 H), 5.40 (brs, 1 H) , 4.69 (dd, 1 H, J = 11.1, 5.4 Hz), 4.60-4.49 (m, 3 H, 4.15 (dd, 1 H, J = 11.9, 5.4 Hz), 2.62 (m, 2 H), 1.68 ( d, 6 H, J = 3.9 Hz).

MS (ESI) m/z 575.1 (M ⁺ + H).

Example 101: Synthesis of compound 361. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazole -1-yl)-2-(3,3,3-trifluoropropoxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, except that starting material 1-5-7 was used instead of starting material 5a, and (S)-2-amino-3-methylbutanamide hydrochloric acid was used instead of glycinemethylester hydrochloric acid, as a white solid in the form of a white solid. of compound 361 (0.015 g, 25.0 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD); δ 8.11, 8.10 (2s, 1 H), 7.46-7.38 (m, 3 H), 7.29-7.12 (m, 7 H), 4.64 (m, 1 H), 4.51-4.36 (m, 4 H), 4.08 (m, 1 H), 2.55 (m, 2 H), 2.08 (m, 1 H), 0.93 (m, 6 H).

MS (ESI) m/z 589.1 (M ⁺ + H).

Example 102: Synthesis of compound 372. (Ethyl 4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-5-carboxylate)

To a solution of starting material 1b (0.830 g, 3.454 mmol) and DIPEA (0.905 mL, 5.181 mmol) in acetonitrile (5 mL) at room temperature, 1-3-1 (1.143 g, 4.491 mmol) was added and at the same temperature. Stirred for 3 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0 % to 30 %) and concentrated to obtain the desired compound 372 (1.290 g, 81.5 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.54 (s, 1 H), 7.61-7.56 (m, 2 H), 7.36-7.19 (m, 5 H), 7.02-6.96 (m, 2 H), 4.74 (dd, 1 H, J = 11.1, 4.7 Hz), 4.57 (t, 1 H, J = 12.1 Hz), 4.46-4.38 (m, 2 H), 4.24 (dd, 1 H, J = 12.1, 4.8 Hz), 1.32 (t, 3 H, J) = 7.2 Hz).

MS (ESI) m/z 459.1 (M ⁺ + H).

Example 103: Synthesis of compound 373. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-fluorophenyl)4-phenyl-4,5-dihydropyrazol-2-yl )-2-(trifluorophenyl)pyrimidine-5-carboxamide)

Compound 373 in the form of a white solid (0.095 g, 0.095 g, 75.7%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.41 (s, 1 H), 7.56-7.51 (m, 2 H), 7.32-7.16 (m, 5 H), 6.96-6.91 (m, 2 H), 4.71 (dd, 1 H, J = 11.2, 5.3 Hz), 4.56 (t, 1 H, J = 11.3 Hz), 4.17 (dd, 1 H, J = 12.2, 5.4 Hz), 1.63 (d, 6 H, J = 4.5 Hz).

MS (ESI) m/z 516.1 (M ⁺ + H).

Example 104: Synthesis of compound 374. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyra zol-1-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide)

Compound 374 in the form of a white solid was carried out in the same manner as in the synthesis of Compound 164, except that the starting material 9b was used instead of the starting material 9a, and (S)-2-amino-3-methylbutanamide hydrochloric acid was used instead of methyl 2-aminoacetate. (0.096 g, 73.7 %) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ); δ 8.55 (m, 1 H), 8.38, 8.37 (2s, 1 H), 7.66-7.51 (m, 3 H), 7.32-7.06 (m, 8 H), 5.08 (m, 1 H), 4.58-4.41 (m, 2 H), 4.03 (m, 1 H), 2.02 (m, 1 H), 0.91 (m, 6 H).

MS (ESI) m/z 529.1 (M ⁺ + H).

Example 105: Synthesis of compound 375. (N-(2-amino-2-oxoethyl)-4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(trifluoro romethyl)pyrimidine-5-carboxamide)

Compound 375 (0.096 g, 83.3 %) in the form of a white solid was prepared in the same manner as in the synthesis of Compound 164 except that the starting material 9b was used instead of the starting material 9a and 2-aminoacetamide hydrochloric acid was used instead of methyl 2-aminoacetate. got it

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.35 (s, 1 H), 7.48-7.44 (m, 2 H), 7.27-7.11 (m, 5 H), 6.93-6.88 (m, 2 H), 4.69 (dd, 1 H, J = 11.3, 5.3 Hz), 4.53 (t, 1 H, J = 12.2 Hz), 4.14 (dd, 1 H, J = 12.3,5.4 Hz), 4.08 (s, 2 H).

MS (ESI) m/z 489.1 (M ⁺ + H).

Example 106: Synthesis of compound 377. (Methyl 2-(4-chlorobenzyloxy)-4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxylate )

Compound 377 (0.802 g, 63.1 %) in the form of a white solid was obtained in the same manner as in the synthesis of compound 320, except that starting material 3-2 was used instead of starting material 3-1.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.36 (s, 1 H), 7.60 - 7.57 (m, 2 H), 7.39 - 7.32 (m, 5 H), 7.29 - 7.27 (m, 2 H), 7.01 - 6.96 (m, 2 H), 5.41 - 5.32 (m, 2 H), 4.73 - 4.68 (m, 1 H), 4.50 (t, 1 H, J = 11.5 Hz), 4.20 - 4.16 (m, 1 H), 3.91 (m, 3 H).

MS (ESI) m/z 517.1 (M ⁺ + H).

Example 107: Synthesis of compound 378. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-2-(4-chlorobenzyloxy)-4-(3-(4-fluorophenyl)-4-phenyl-4 ,5-dihydropyrazol-1-yl)pyrimidine-5-carboxamide)

Compound 378 (0.036 g, 63.5 %) in the form of a yellow solid was obtained in the same manner as in the synthesis of Compound 163, except that the starting material 5j was used instead of the starting material 5a and 2-methylalaninamide hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid. .

¹ H NMR (400 MHz, CDCl ₃ ); 8.29 (s, 1 H), 7.77 (d, 1 H, J = 8.1 Hz), 7.62 (d, 1 H, J = 8.3 Hz), 7.55 - 7.51 (m, 2 H), 7.37 - 7.29 (m, 5 H), 7.21 - 7.19 (m, 2 H), 7.05 (s, 1H), 6.95 (t, 3 H, J = 8.5 Hz), 5.55 (bs, 1 H), 5.32 - 5.23 (m, 2 H) ), 4.70 - 4.65 (m, 1 H), 4.52 - 4.46 (m, 1 H), 4.16 - 4.08 (m, 1 H), 1.67 (d, 6 H, J = 4.4 Hz).

MS (ESI) m/z 587.1 (M ⁺ + H).

Example 108: Synthesis of compound 379. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-2-(4-chlorobenzyloxy)-4-(3-(4-fluorophenyl)-4 -Phenyl-4,5-dihydropyrazol-1-yl)pyrimidine-5-carboxamide)

Compound 379 (0.043 g, 75.9 %) as a white solid was obtained in the same manner as in the synthesis of Compound 163, except that the starting material 5j was used instead of the starting material 5a and L-valinamide hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); 8.25 - 8.22 (m, 1 H), 7.77 - 7.75 (m, 1 H), 7.70 - 7.67 (m, 1 H), 7.53 - 7.49 (m, 2 H), 7.40 - 7.30 (m, 6 H), 7.23 - 7.19 (m, 2 H), 6.96 - 6.90 (m, 2 H), 6.72 - 6.69 (m, 1 H), 5.67 - 5.63 (m, 1 H), 5.34 - 5.23 (m, 2 H), 4.77 - 4.71 (m, 1 H), 4.65 - 4.52 (m, 2 H), 4.15 - 4.11 (m, 1 H), 2.32 - 2.23 (m, 1 H), 1.04 - 0.97 (m, 6 H)

MS (ESI) m/z 601.1 (M ⁺ + H).

Example 109: Synthesis of compound 380. (N-(2-amino-2-oxoethyl)-2-(4-chlorobenzyloxy)-4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyrazole- 1-yl)pyrimidine-5-carboxamide)

Compound 380 (0.044 g, 77.9 %) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 163, except that the starting material 5j was used instead of the starting material 5a and glycinamide hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); 8.30 (s, 1 H), 7.73 (d, 1 H, J = 7.8 Hz), 7.68 (d, 1 H, J = 8.1 Hz), 7.61 (bs, 1 H), 7.52 - 7.48 (m, 2 H) ), 7.40 - 7.30 (m, 5 H), 7.20 - 7.19 (m, 2 H), 6.96 - 6.92 (m, 2 H), 6.81 (bs, 1 H), 5.76 (bs, 1 H), 5.34 - 5.25 (m, 2 H), 4.76 - 4.71 (m, 1 H), 4.58 - 4.48 (m, 1 H), 4.16 - 4.11 (m, 1 H), 3.69 - 3.61 (m, 1 H), 3.13 - 3.07 (m, 1 H).

MS (ESI) m/z 559.1 (M ⁺ + H).

Example 110: Synthesis of compound 385. (tert-Butyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoromethyl)benzyloxy)pyrimidine -5-carboxylate)

In the same manner as in the synthesis of compound 353, compound 385 in the form of a white solid (compound 385 ( 0.981 g, 75.6%) was obtained.

¹ H NMR (400 MHz, CDCl3); δ 8.33 (s, 1H), 7.61 - 7.48 (m, 7H), 7.34 - 7.23 (m, 4H), 6.95 - 6.91 (m, 2H), 5.48 - 5.39 (m, 2H), 4.64 (dd, 1H, J = 10.9, 4.5 Hz), 4.45 (t, 1H, J = 11.4 Hz), 4.16 - 4.12 (m, 1H), 1.56 (s, 9H)

MS (ESI) m/z 593.1 (M ⁺ + H).

Example 111: Synthesis of compound 387. (tert-Butyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3-(trifluoromethyl)benzyloxy)pyrimidine -5-carboxylate)

Compound 387 (0.897 g, 94.8 %) as a colorless oil was obtained in the same manner as in the synthesis of Compound 353, except that 3-(trifluoromethyl)benzyl alcohol was used instead of 2,2,2-trifluoroethanol.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.37 (s, 1 H), 7.72 (s, 1 H), 7.64 (d, 1 H, J = 7.8 Hz), 7.56 (d, 3 H, J = 8.5 Hz), 7.49 - 7.46 (m, 1 H), 7.36 - 7.22 (m, 7 H), 5.48 - 5.39 (m, 2 H), 4.67 - 4.63 (m, 1 H), 4.50 - 4.44 (m, 1 H), 4.19 - 4.14 (m, 1 H), 1.59 (bs, 9 H)

MS (ESI) m/z 609.1 (M ⁺ + H).

Example 112: Synthesis of compound 388. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl )-2-(3-(trifluoromethyl)benzyloxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, compound 388 in the form of a white solid (compound 388 ( 0.023 g, 27.2%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.40 (s, 1 H), 7.68 (s, 1 H), 7.64 - 7.62 (m, 1 H), 7.57 - 7.55 (m, 1 H), 7.51 - 7.47 (m, 2 H), 7.37 - 7.30 (s, 4 H), 7.26 - 7.19 (m, 4 H), 5.48 - 5.41 (m, 3 H), 4.74 - 4.70 (m, 1 H), 4.57 - 4.52 (m, 1 H), 4.17 - 4.13 (m, 1 H), 1.68 (s, 6 H)

MS (ESI) m/z 637.2 (M ⁺ + H).

Example 113: Synthesis of compound 389. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazole -1-yl)-2-(3-(trifluoromethyl)benzyloxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, except that starting material 1-5-6 was used instead of starting material 5a, and (S)-2-amino-3-methylbutanamide hydrochloric acid was used instead of glycinemethylester hydrochloric acid, in the form of a white solid of compound 389 (0.062 g, 54.0 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.30 - 8.28 (m, 1 H), 7.69 (s, 1 H), 7.64 - 7.62 (m, 1 H), 7.57 - 7.54 (m, 1 H), 7.47 - 7.45 (m, 3 H), 7.36 - 7.30 (m, 3 H), 7.23 - 7.18 (m, 4 H), 6.47 - 6.39 (m, 1 H), 6.10 - 5.86 (m, 1 H), 5.63 - 5.58 (m, 2 H), 5.47 - 5.39 (m, 1 H), 4.72 - 4.68 (m, 1 H), 4.61 - 4.49 (m, 2 H), 4.16 - 4.08 (m, 1 H), 2.20 - 2.13 (m, 1 H), 1.05 - 0.98 (m, 6 H).

MS (ESI) m/z 651.2 (M ⁺ + H).

Example 114: Synthesis of compound 390. (N-(2-amino-2-oxoethyl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(3-( trifluoromethyl)benzyloxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of Compound 163, Compound 390 (0.021 g, 23.9 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.32 (s, 1 H), 7.69 - 7.67 (m, 1 H), 7.61 - 7.59 (m, 1 H), 7.56 - 7.54 (m, 1 H), 7.56 - 7.54 (m, 1 H), 7.46 - 7.44 (m, 3 H), 7.41 - 7.37 (m, 1 H), 7.35 - 7.31 (m, 3 H), 7.26 - 7.18 (m, 4 H), 6.75 (s, 1 H), 5.74 (s) , 1 H), 5.44 - 5.36 (m, 2 H), 4.73 (dd, 1 H, J = 10.8, 5.5 Hz), 4.55 (t, 1 H, J = 11.7 Hz), 4.21 - 4.20 (m, 2 H), 4.16 - 4.11 (m, 1 H).

MS (ESI) m/z 609.1 (M ⁺ + H).

Example 115: Synthesis of compound 392. (N-(2-Amino-2-oxoethyl)-2-(4-fluorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(4-(trifluoro Romethyl)benzyloxy)pyrimidine-5-carboxamide)

Compound 392 in the form of a white solid (0.041 g, 36.1 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.27 (s, 1H), 7.67 - 7.60 (m, 6H), 7.33 - 7.22 (m, 5H), 7.06 - 7.02 (m, 2H), 5.49 (q, 2H, J = 6.8 Hz), 4.93 - 4.92 (m, 1H), 4.52 (t, 1H, J = 11.7 Hz), 4.11 - 4.06 (m, 3H)

MS (ESI) m/z 593.1 (M ⁺ + H).

Example 116: Synthesis of compound 393. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyrazole-1- yl)-2-(4-(trifluoromethyl)benzyloxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, compound 393 in the form of a white solid (compound 393 ( 0.035 g, 29.8%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.30 (s, 1H), 7.69 - 7.67 (m, 2H), 7.61 - 7.60 (m, 4H), 7.32 - 7.27 (m, 5H), 7.04 - 7.02 (m, 2H), 5.48 (q, 2H, J = 6.4 Hz), 4.91 - 4.90 (m, 1H), 4.55 - 4.52 (m, 1H), 4.10 - 4.06 (m, 1H), 3.34 (s, 1H), 1.56 (s, 6H).

MS (ESI) m/z 621.1 (M ⁺ + H).

Example 117: Synthesis of compound 394. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-(3-(4-fluorophenyl)-4-phenyl-4,5-dihydropyra zol-1-yl)-2-(4-(trifluoromethyl)benzyloxy)pyrimidine-5-carboxamide)

In the same manner as in the synthesis of compound 163, except that starting material 1-5-10 was used instead of starting material 5a, and (S)-2-amino-3-methylbutanamide hydrochloric acid was used instead of glycinemethylester hydrochloric acid, in the form of a white solid of compound 394 (0.025 g, 20.8 %) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.14 (s, 1H), 7.67 - 7.60 (m, 6H), 7.33 - 7.23 (m, 5H), 7.05 - 7.01 (m, 2H), 5.48 (q, 2H, J = 6.4 Hz), 4.93 - 4.91 (m, 1H), 4.52 - 4.45 (m, 2H), 4.12 - 4.09 (m, 1H), 2.11 - 2.09 (m, 1H), 1.05 - 0.97 (m, 6H).

MS (ESI) m/z 635.2 (M ⁺ + H).

Example 118: Synthesis of compound 408. (N-(2-amino-2-oxoethyl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-ethoxypyrimidine -5-carboxamide)

Compound 408 (0.043 g, 32.2 %) as a white solid was obtained in the same manner as in the synthesis of Compound 163, except that the starting material 5i was used instead of the starting material 5a and glycinamide hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.48 (t, 1H, J = 5.6 Hz), 8.18 (s, 1H), 7.58 (d, 2H, J = 8.6 Hz), 7.42 - 7.21 (m, 8H), 7.14 (brs, 1H), 4.99 ( dd, 1H, J = 11.1, 4.2 Hz), 4.49 (t, 1H, J = 11.6 Hz), 4.30 (q, 2H, J = 7.1 Hz), 4.01 (dd, 1H, J = 11.9, 4.2 Hz), 3.89 (d, 2H, J = 5.7 Hz), 1.28 (t, 3H, J = 7.0 Hz).

MS (ESI) m/z 479.1 (M ⁺ + H).

Example 119: Synthesis of compound 409. (N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl )-2-ethoxypyrimidine-5-carboxamide)

Compound 409 (0.048 g, 33.9 %) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 163, except that the starting material 5i was used instead of the starting material 5a and 2-methylalaninamide hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid. .

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.35 (s, 1H), 8.21 (s, 1H), 7.62 - 7.60 (m, 2H), 7.41 - 7.38 (m, 2H), 7.34 - 7.21 (m, 5H), 7.17 (brs, 1H), 6.93 (brs, 1H), 4.96 (dd, 1H, J = 11.1, 4.2 Hz), 4.48 (t, 1H, J = 11.5 Hz), 4.33 - 4.27 (m, 2H), 4.00 (dd, 1H, J = 11.8) , 4.2 Hz), 1.45 (s, 3H), 1.43 (s, 3H), 1.28 (t, 3H, J = 7.0 Hz).

MS (ESI) m/z 507.1 (M ⁺ + H).

Example 120: Synthesis of compound 410. ((S)-N-(1-amino-3-methyl-1-oxobutan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazole -1-yl)-2-ethoxypyrimidine-5-carboxamide)

Compound 410 (0.084 g, 57.8 %) in the form of a white solid was obtained in the same manner as in the synthesis of Compound 163, except that the starting material 5i was used instead of the starting material 5a and L-valinamide hydrochloric acid was used instead of the glycine methyl ester hydrochloric acid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.32 - 8.22 (m, 1H), 8.08 (d, 1H, J = 6.4 Hz), 7.60 - 7.23 (m, 10H), 7.17 (m, 0.5H), 7.09 (m, 0.5H), 5.04 - 4.99 (m, 0.5H), 4.96 - 4.92 (m, 0.5H), 4.53 - 4.27 (m, 4H), 4.01 - 3.97 (m, 1H), 2.04 - 1.99 (m, 1H), 1.28 (t, 1H, J = 7.0 Hz), 0.93 - 0.89 (m, 6H).

MS (ESI) m/z 521.1 (M ⁺ + H).

Synthesis of compounds 1-6-4. ((S)-2-Methoxy-2-oxo-1-phenylethyl 2-chloro-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole- 1-yl)pyrimidine-5-carboxylate)

The starting materials 1-6-3 (1.620 g, 3.920 mmol), (S)-methyl 2-hydroxy-2-phenylacetate (0.847 g, 5.096 mmol) and triphenylphosphine (1.337 g, 5.096 mmol) were mixed with 0 DIAD (1.000 mL, 5.096 mmol) was added to a solution in tetrahydrofuran (10 mL) at ℃ and stirred at room temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) and concentrated to give 1-6-4 (0.540 g, 24.5 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.47 (s, 1 H), 7.40-7.16 (m, 14 H), 6.21 (s, 1 H), 4.65 (dd, 1 H, J = 11.3, 5.5 Hz), 4.53 (t, 1 H, J) = 12.0 Hz), 4.17 (dd, 1 H, J = 12.0, 5.5 Hz), 3.69 (s, 3 H)

MS (ESI) m/z 561.1 (M ⁺ + H).

Synthesis of compounds 1-6-5. (2-chloro-4- (3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-1H-pyrazol-1-yl) pyrimidine-5-carboxylate)

_{BBr 3} (1.00 M solution , 2.191 mL, 2.191 mmol) was added to a solution of the starting material 1-6-4 up spot (0.410 g, 0.730 mmol) in methylene chloride (5 mL) at 0 ° C., and 3 hours at room temperature. After stirring for a while, water (3 mL) was added to the reaction mixture at 0° C. and stirred for 10 minutes to complete the reaction. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 20 % to 80 %) and concentrated to obtain the desired compound 1-6-5 (0.184 g, 61.0 %) as a white foamy solid. obtained with

MS (ESI) m/z 413.0 (M ⁺ + H).

Synthesis of compounds 1-6-6. (tert-Butyl 2-chloro-4- (3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-1H-pyrazol-1-yl) pyrimidine-5-carboxylate)

Starting materials 1-6-5 (0.130 g, 0.315 mmol), (Boc) ₂ O (0.145 mL, 0.629 mmol) and DMAP (0.003 g, 0.003 mmol) were mixed at room temperature with tert-butanol (5 mL) / tetrahydrofuran (1 mL) was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 5 % to 40 %) and concentrated to obtain the desired compound 1-6-6 (0.032 g, 21.7 %) as a white solid. got it

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.30 (s, 1 H), 7.54 (m, 2 H), 7.34-7.21 (m, 7 H), 4.67 (dd, 1 H, J = 11.0, 4.6 Hz), 4.50 (t, 1 H, J) = 11.1 Hz), 4.19 (dd, 1 H, J = 12.0, 4.6 Hz), 1.56 (s, 9 H).

MS (ESI) m/z 469.1 (M ⁺ + H).

Synthesis of compounds 1-6-7. (tert-Butyl 4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(2,2,2-trifluoroethoxy)pyri midine-5-carboxylate)

To a solution of 2,2,2-trifluoroethanol (0.010 mL, 0.109 mmol) in dimethylformamide (1 mL) at room temperature, sodium hydride (60.00 %, 0.004 g, 0.102 mmol) was added and at the same temperature. Stir for 10 minutes. Starting material 1-6-6 (0.032 g, 0.068 mmol) was added to the reaction mixture, and the mixture was further stirred at the same temperature for 2 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) and concentrated to obtain the desired compound 1-6-7 (0.023 g, 63.3 %) as a white foam solid. obtained with

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.33 (s, 1 H), 7.54 (m, 2 H), 7.35-7.21 (m, 7 H), 4.78-4.64 (m, 3 H), 4.50 (t, 1 H, J = 11.7 Hz), 4.17 (dd, 1 H, J = 11.8, 3.8 Hz), 1.57 (s, 9 H)

MS (ESI) m/z 533.1 (M ⁺ + H).

Synthesis of compounds 1-6-8. (4-(3-(4-Chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5 -carboxylic acid)

A solution of the starting material 1-6-7 (0.023 g, 0.043 mmol) and trifluoroacetic acid (0.017 mL, 0.216 mmol) in methylene chloride (1 mL) at room temperature was stirred at the same temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / methylene chloride = 5 % to 30 %) and concentrated to obtain the desired compound 1-6-8 (0.017 g, 82.6 %) as a white solid. got it

MS (ESI) m/z 477.0 (M ⁺ + H).

Example 121: Synthesis of compound 417. (N-(1-amino-2-methyl-1-oxoprodan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazole-1- yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carboxamide)

Starting materials 1-6-8 (0.017 g, 0.035 mmol), 2-amino-2-methylpropanamide hydrochloric acid (0.006 g, 0.046 mmol), hydroxybenzotriazole (0.007 g, 0.053 mmol) and diisopropylethyl To a solution of amine (0.025 mL, 0.142 mmol) in dimethylformamide (1 mL) at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.008 g, 0.053 mmol) was added and The mixture was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / methylene chloride = 0 % to 30 %) and concentrated to obtain the desired compound 417 (0.001 g, 6.5 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.31 (s, 1 H), 7.69-7.61 (m, 2 H), 7.57-7.19 (m, 7 H), 6.72 (brs, 1 H), 6.69 (brs, 1 H), 5.30 (brs, 1 H), 4.83-4.68 (m, 3 H), 4.56 (t, 1 H, J = 11.6 Hz), 4.16 (dd, 1 H, J = 11.9, 5.4 Hz), 1.68 (m, 6 H).

MS (ESI) m/z 561.1 (M ⁺ + H).

(up spot) synthesis of compound 1-6-1, (S)-2-methoxy-2-oxo-1-phenylethyl 4- (3- (4-chlorophenyl) -4-phenyl-4,5- Dihydropyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-4-carboxylate

Starting materials 9a (2.100 g, 4.700 mmol), (S)-methyl 2-hydroxy-2-phenylacetate (1.015 g, 6.110 mmol) and triphenylphosphine (1.603 g, 6.110 mmol) were mixed with tetrahydrogen at 0 °C. DIAD (1.200 mL, 6.110 mmol) was added to a solution in furan (10 mL) and stirred at room temperature for 1 hour. Water was poured into the reaction mixture, followed by extraction with an ethyl acetate solvent. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 0 % to 25 %) to obtain 1-6-1 up spot (0.450 g, 16.1 %) as a white solid. got it

(up spot) synthesis of compound 1-6-2, (R)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-( Trifluoromethyl)pyrimidine-5-carboxylic acid

_{BBr 3} (1.00 M solution , 2.269 mL, 2.269 mmol) was added to a solution of the starting material 1-6-1 up spot (0.450 g, 0.756 mmol) in methylene chloride (5 mL) at -78 ° C. After stirring for an hour, water (3 mL) was added to the reaction mixture at 0° C. and stirred for 5 minutes to complete the reaction. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0 % to 40 %) to form 1-6-2 up spot (0.180 g, 53.3 %) as a white solid. got it

Example 122: Synthesis of compound 426. ((R)-N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H -pyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide)

Starting material 1-6-2 up spot (0.180 g, 0.403 mmol), 2-amino-2-methylpropanamide hydrochloric acid (0.073 g, 0.524 mmol), hydroxybenzotriazole (0.082 g, 0.604 mmol) and diiso To a solution of propylethylamine (0.211 mL, 1.209 mmol) in dimethylformamide (5 mL) at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.094 g, 0.604 mmol) was added. was added and stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0 % to 30 %) and concentrated to give 426 (0.156 g, 72.9 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.49 (s, 1 H), 7.49 (m, 2 H), 7.36-7.18 (m, 7 H), 6.74 (s, 1 H, 6.38 (s, 1 H), 5.32 (s, 1 H), 4.71 (dd, 1 H, J = 11.2, 5.4 Hz), 4.60 (t, J = 12.0 Hz), 4.20 (dd, J = 12.1, 5.4 Hz), 1.73 (d, 6 H, J = 4.0 Hz).

MS (ESI) m/z 531.0 (M ⁺ + H).

(down spot) synthesis of compound 1-6-1, (S)-2-methoxy-2-oxo-1-phenylethyl 4- (3- (4-chlorophenyl) -4-phenyl-4,5- Dihydropyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-4-carboxylate

Starting materials 9a (2.100 g, 4.700 mmol), (S)-methyl 2-hydroxy-2-phenylacetate (1.015 g, 6.110 mmol) and triphenylphosphine (1.603 g, 6.110 mmol) were mixed with tetrahydrogen at 0 °C. DIAD (1.200 mL, 6.110 mmol) was added to a solution in furan (10 mL) and stirred at room temperature for 1 hour. Water was poured into the reaction mixture, followed by extraction with an ethyl acetate solvent. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 0 % to 25 %) to form 1-6-1 down spot (0.580 g, 20.7%) as a colorless oil. got it

(down spot) synthesis of compound 1-6-2, (S)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl)-2-( Trifluoromethyl)pyrimidine-5-carboxylic acid

_{BBr 3} (1.00 M solution , 2.269 mL, 2.269 mmol) was added to a solution of the starting material 1-6-1 down spot (0.450 g, 0.756 mmol) in methylene chloride (5 mL) at -78 ° C. After stirring for an hour, water (3 mL) was added to the reaction mixture at 0° C. and stirred for 5 minutes to complete the reaction. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0 % to 40 %) to form 1-6-2 down spot (0.180 g, 53.3 %) as a white solid. got it

Example 123: Synthesis of compound 427. ((S)-N-(1-amino-2-methyl-1-oxopropan-2-yl)-4-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H -pyrazol-1-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide)

Starting material 1-6-2 down spot (0.160 g, 0.358 mmol), 2-amino-2-methylpropanamide hydrochloric acid (0.065 g, 0.466 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbo A solution of diimide (0.083 g, 0.537 mmol), hydroxybenzotriazole (0.073 g, 0.537 mmol) and diisopropylethylamine (0.188 mL, 1.074 mmol) in dimethylformamide (5 mL) at room temperature was The mixture was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0 % to 30 %) and concentrated to give 427 (0.140 g, 73.6 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ); δ 8.44 (s, 1 H), 7.47 (m, 2 H), 7.33-7.16 (m, 7 H), 4.70 (dd, 1 H, J = 11.2, 5.4 Hz), 4.57 (t, 1 H, J) = 12.0 Hz), 4.18 (dd, 1 H, J = 12.1, 5.4 Hz), 1.67 (d, 6 H, J = 3.8 Hz).

MS (ESI) m/z 531.1 (M ⁺ + H).

Protocol for measuring and assaying the activity of the compounds of the present invention

<Test Example 1> Confirmation of CB1 antagonistic effect (in vitro CB1 reporter gene assay)

In order to measure the adverse or antagonistic effects of the example compounds on the CB1 receptor, an in vitro CB1 reporter gene assay was performed in TangoTM CNR1-bla U2OS cells. Through this, it was confirmed that the compound according to an embodiment has an excellent CB1 antagonistic effect, as will be described later.

1. Experimental method

A CB1 reporter gene assay was performed to measure the adverse or antagonistic effect of the compound of Examples on the CB1 receptor. TangoTM CNR1-bla U2OS cells (Cat.No. K1513A) were purchased from Invitrogen and used in the experiment. 3x104/well cells in the assay buffer, FreestyleTM expression medium, were aliquoted into 96 well plates and cultured for 48 hours. After incubation for 48 hours, the example compound as an antagonist was repeatedly treated twice in each well. After 30 minutes of the antagonist treatment, the agonist was treated, and then incubated for 5 hours. Thereafter, LiveBLAzer™ FRET B/G Substrate Mixture was treated in a light-shielded state and reacted for 2 hours. Then, using a plate reader device (FlexStation3), the fluorescence value was measured. (Exitation: 409 nm, Emission: 460 and 530 nm). The result value was calculated by calculating the ratio of the emission measurement value, and it was converted into % and summarized. Each plate contained a solvent group and a control group, respectively, and each of the solvent group and control plate was treated as an independent experiment. The measured values and graphs were calculated using the Prism5 program.

2. Experimental results

The results are shown in Table 2 (results of CB1 in vitro reporter gene assay).

As shown in Table 2, when the compound 427 was treated, the IC ₅₀ (Half maximal inhibitory concentration) value was 0.03 nM, confirming that it had an excellent antagonistic effect.

<Test Example 2> Efficacy of compound 427 in diet-induced obesity (DIO) mouse model

1. Experimental method

C57BL/6J mice were subjected to a 60% high fat diet for 14 weeks to make a disease animal model, and then the drug was orally administered and evaluated once a day for 2 weeks according to each concentration.

Body weight change was measured on the last day of drug administration (14th day), and blood glucose was measured once a week from the first drug administration day.

2. Experimental results

Experimental results are shown in FIGS. 1 and 2 . By evaluating the effect of reducing body weight and reducing blood glucose in a diet-induced obesity (DIO) mouse model, the excellent pharmacological effect of the compound of one embodiment on obesity and obesity-related metabolic diseases was confirmed.

As shown in FIG. 1 , as a result of measuring the change in body weight during the administration period, the weight loss rate when compound 427 (3 mg/kg/day) was administered was higher by 8.4% compared to the (Vehicle) group that was not treated with the drug. was confirmed, and the weight loss rate when compound 427 (10 mg/kg/day) was administered was found to be 15.4% higher than that of the non-drug treatment (Vehicle) group.

As shown in FIG. 2 , as a result of measuring changes in blood glucose in diet-induced obesity (DIO) mice at 1-week intervals, it was confirmed that the compound 427 (10 mg/kg/day) group significantly decreased compared to the Vehicle.

As described above, it is confirmed that the compound of one embodiment exhibits an excellent effect in preventing and treating type 2 diabetes among obesity-related metabolic diseases.

The present invention may provide a compound represented by the above formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which acts as a CB1 receptor antagonist. The pharmaceutical composition according to an embodiment of the present invention may include the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Therefore, the pharmaceutical composition of one embodiment may exhibit an excellent effect in the treatment or prevention of obesity and obesity-related metabolic diseases.

Claims (9)

A compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula I]

In the above formula (I),
A ₁ and A ₂ are each independently -(C6-C12 aryl) or 5-10 membered heteroaryl including at least one heteroatom selected from N, O and S;
Each of the hydrogen atoms of A ₁ and A ₂ may be independently substituted or unsubstituted with at least one halogen,
R ₁ is hydrogen, -(C6-C12 aryl), halogen, -S(C1-C4 alkyl), -S(=O) ₂ (C1-C4 alkyl), -CF ₃ ,

,

,

, NHR ₃ , or OR ₄ ,
The hydrogen atoms of -(C6-C12 aryl) in _{R 1} may each independently be substituted or unsubstituted _{with halogen or CF 3 ,}
R ₃ and R ₄ are each independently hydrogen, halogen, -(C1-C4 alkyl), -(C6-C12 aryl), 3-6 membered heterocycloalkyl containing O as a hetero atom, -(C3-C6 cyclo alkyl) or -n(CH2)Ph (wherein n is an integer from 1 to 5 and Ph is a phenyl group);
The hydrogen atoms of -(C1-C4alkyl), -(C6-C12 aryl) or -n(CH2)Ph in _{R 3} and R ₄ may each independently be substituted or unsubstituted _{with halogen or CF 3 ,}
Y ₁ and Y ₂ are each independently CR ₅ R ₆ , O or S,
wherein R ₅ and R ₆ are each independently -H, halogen, -CF ₃ , -(C1-C4 alkyl) or -C(=O)NH ₂ ,
a to d are each independently an integer of 0 or more and 3 or less, one of a and b is an integer of 1 or more, and one of c and d is an integer of 1 or more,
R ₂ is -NO ₂ , -NH ₂ , -C(=O)-O(C1-C4 alkyl), -NHS(=O) ₂ (C1-C4 alkyl), -S(=O) ₂ (C1- C4alkyl), -C(=O)(C1-C4alkyl), -C(=O)CH ₂ CF ₃ ,

or

ego,
R ₇ to R ₁₀ are each independently hydrogen, -NH2, -CF ₃ , -C(=O)(C3-C6cycloalkyl), -O(C1-C4alkyl), -(C1-C4alkyl)CF3, -(C3-C6cycloalkyl), -(C1-C13alkyl) or phenyl.
The method of claim 1,
Formula I is a compound represented by Formula I represented by Formula II, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula II]

In the above formula (II),
X is F or Cl;
R ₁ and R ₂ are the same as defined in Formula I above.
According to claim 1,
wherein A ₁ is a phenyl group;
wherein A ₂ is a phenyl group in which at least one hydrogen is substituted with F or Cl;
Wherein R ₁ is aryl, -Cl, -S(C1-C4alkyl), -S(=O) ₂ (C1-C4alkyl), -CF ₃ ,

,

, NHR ₃ , or OR ₄ ,
Each of the hydrogen atoms of the aryl in R ₁ may be independently substituted or unsubstituted _{with Cl or CF 3 ,}
The Y ₁ is CR ₅ R ₆ or O, the Y ₂ is CR ₅ R ₆ , O or S,
The R ₅ and R ₆ are each independently -H, -F, -CF ₃ , or -C(=O)NH ₂ ,
Wherein a to c are each independently an integer of 0 or more and 2 or less, a and b cannot be 0 at the same time, and d is 1 or 2,
wherein R ₃ and R ₄ are each independently -(C1-C4alkyl), aryl, oxetane, -(C3-C6cycloalkyl) or benzyl;
In R ₃ and R ₄ , hydrogen atoms of -(C1-C4alkyl)-(C6-C12 aryl) and benzyl are each independently substituted or unsubstituted with at least one selected from _{Cl and CF 3 ,}
The R ₂ are each independently -NO ₂ , -C(=O)-O(C1-C4alkyl), -NHS(=O) ₂ (C1-C4alkyl),

or

ego,
wherein R ₇ to R ₁₀ are each independently hydrogen, -NH2, -O(C1-C4 alkyl), -(C1-C4 alkyl)CF3, -(C3-C6 cycloalkyl), -(C1-C4 alkyl), or phenyl,
A compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
Wherein A ₁ is a phenyl group,
The A ₂ is a Cl substituted phenyl group,
wherein R ₁ is —CF ₃ or OR ₄ ;
Wherein R ₄ is substituted or unsubstituted by CF ₃ - (C1-C4 alkyl), optionally substituted with Cl or unsubstituted aryl group, oxetane, substituted by (C3-C6 cycloalkyl), or Cl or CF ₃ or unsubstituted substituted benzyl,
wherein R ₂ is

ego;
wherein R ₇ to R ₁₀ are each independently hydrogen, -NH2, -O(C1-C4 alkyl), -(C1-C4 alkyl)CF3, -(C3-C6 cycloalkyl), -(C1-C4 alkyl), or phenyl,
A compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by Formula I is any one selected from the group consisting of the compounds shown in the following table,
A compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

. According to claim 1, wherein the compound represented by the formula (I) is any one selected from the compounds listed in the table,
A compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

.
The compound represented by Formula I according to any one of claims 1 to 6, comprising an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient,
A pharmaceutical composition for the treatment or prevention of obesity or obesity-related metabolic disease.
8. The method of claim 7,
The obesity-related metabolic disease is type 2 diabetes, angina pectoris, hypertension, congestive heart attack, hyperlipidemia, nonalcoholic fatty liver disease or thrombolytic disorder;
A pharmaceutical composition for the treatment or prevention of obesity or obesity-related metabolic disease.
9. The method of claim 8,
The nonalcoholic fatty liver disease is simple fatty liver, nonalcoholic steatohepatitis or nonalcoholic fatty liver cirrhosis,
A pharmaceutical composition for the treatment or prevention of obesity or obesity-related metabolic disease.

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