UA86774C2 - Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto - Google Patents

Abstract

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HTserotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the prophylaxis or treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de syndrome, manic-disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders and the like. The present invention also relates to the method of prophylaxis or treatment of 5-НТserotonin receptor mediated disorders in combination with a dopamine D2 receptor antagonist such as haloperidol, administered separately or together.

Description

The present invention relates to some diaryl and arylheteroaryl derivatives of urea of formula (1) and their pharmaceutical compositions that modulate the activity of the 5-HTga-serotonin receptor. The compounds and their pharmaceutical compositions are directed to methods suitable for the prevention or treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attacks, angina pectoris, stroke, atrial fibrillation, reducing the risk of blood clots, asthma or its symptoms, agitation or its symptoms , behavioral disorders, drug-induced psychosis, reactive psychosis, syndrome

Gilles de la Tourette, manic syndrome, organic or MO5 (unspecified, atypical) psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, MO5 schizophrenia and family diseases, sleep disorders, diabetes-related disorders, etc.

The present invention also relates to a method of prevention or treatment of diseases mediated by the 5-HTga-serotonin receptor, in combination with an antagonist of the Y2-dopamine receptor, such as haloperidol, which is prescribed separately or together.

Receptors associated with c-protein

Receptors bound to c-protein have a common structural fragment. All these receptors contain seven sequences containing from 22 to 24 hydrophobic amino acids and forming seven alpha helices, each of which spans the membrane. Transmembrane helices are joined by chains of amino acids, where a larger loop is located between the fourth and fifth transmembrane helices on the extracellular side of the membrane. Another larger loop, mainly composed of hydrophilic amino acids, connects the fifth and sixth transmembrane helices on the intracellular part of the membrane. The carboxyl end of the receptor is located inside the cell, where the amine end is in the extracellular space. It is believed that the loop connecting the fifth and sixth helix, as well as the carboxyl end, interact with C-protein. At this time, sd-, C8-, (3i- and bo-proteins were identified from c-proteins. The general structure of receptors bound to c-protein is shown in Fig. 1.

Under physiological conditions, receptors bound to C-protein exist on the cell membrane in two distinct equilibrium states or conformations: an "inactive" state and an "active" state. As schematically shown in

Fig. 2, the receptor in an inactive state is not able to communicate with the intracellular direction of transduction with the receipt of a biological reaction in response. Changing the conformation of the receptor into an active state allows you to communicate with the direction of transduction and receive a biological reaction in response.

The receptor can be stabilized in an active state by an endogenous ligand or a ligand of an exogenous agonist. Recent discoveries, such as, but not limited to, modifications of the amino acid sequences of the receptor, provide means of stabilizing the conformation of the active state other than ligands. These agents effectively stabilize the receptor in an active state by stimulating the binding effect of the ligand to the receptor. Stabilization by such ligand-dependent means is called "constitutive activation of the receptor."

Serotonin receptors

Serotonin receptors (5-hydroxytryptamine, 5-HT) are an important class of receptors bound to c-protein. Serotonin is believed to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behavior, appetite, neurodegenerative regulation, and biological rhythms. Not surprisingly, serotonin is associated with such pathophysiological conditions as anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicidal thoughts, autism, migraines, vomiting, alcoholism, and neurodegenerative disorders. As for approaches to treatment with antipsychotic agents that target serotonin receptors, these types of therapeutic agents can generally be divided into two classes, "typical" and "atypical."

Both of them have an antipsychotic effect, however, the action of typical drugs is also accompanied by movement-related side effects (extrapyramidal syndromes, in particular, lip smacking, slurred speech, movement disorders, etc.). Similar side effects are believed to be associated with compounds interacting with other receptors, such as the human dopamine 02 receptor in the nigrostriatal pathway. For this reason, treatment with the use of atypical means is preferred.

A typical antipsychotic is haloperidol, and an atypical antipsychotic is clozapine.

Serotonin receptors are divided into seven subfamilies, which mean both 5-HTI and up to and including 5-HT7. These subfamilies are further divided into two subtypes. For example, the 5-HT2 subfamily is divided into three subtypes of receptors: 5-HTgah, 5-HTzv and 5-HTos. The human 5-HT2 receptor was first isolated and cloned in 1987, and the human 5-HTgd receptor was first isolated and cloned in 1990. These two receptors are believed to be the site of action of hallucinogenic drugs. In addition, it is believed that antagonists to the 5-HTgda receptor and 5-HT2 receptor may be useful in the treatment of depression, anxiety, psychosis, and eating disorders.

US patent Mo4985352 describes the isolation, characterization of properties, and expression of a functional cDNA clone encoding the entire human 5-HT1s receptor (also known as the 5-HT2c receptor). US patents Me5661024 and Mob541209 describe the isolation, characteristics of properties, and expression of a functional cDNA clone that encodes the human 5-HTα receptor in its entirety.

It is reported that mutations of the endogenous forms of the rat 5-HTα receptor and the rat 5-HTα receptor lead to constitutive activation of these receptors (5-HTα: Sazeu, S. ei a! (1996) Bbosieiu g

Meitsgossiepse Arzigasiv, 22: 699.10, hereinafter referred to as "Sazeu"; 5-NTes: Nepisk-Oamiv, K., and Tesheg, M. (1996) zosiefu og Meigozsiepse Arzigasiv, 22: 699.18, hereafter referred to as "Negtisk-Oamiv 1"; and Negtisk-Oamiv, K. ei ai (1997) U. Meyhospetivigu 69(3): 1138, hereinafter referred to as "Neytisk-Oami5 2". Sazeu describes a mutation of the cysteine residue at position 322 of the rat 5-HTα receptor to lysine (C322K), glutamine (C32209), and arginine (C322K), which reportedly results in constitutive activation. Negtisk-Oami5 1 and Negtisk-Oami5 2 describe the mutation of the serine residue at position 312 of the rat 5-HTG receptor to phenylalanine (5312P) and lysine (5312K), which is reported to result in constitutive activation.

One aspect of the present invention relates to certain diaryl and arylheteroaryl urea derivatives represented by formula (1):

Neva vo Yas v x 5. A la z ak;

Kos v t. Va t 13) 1 or their pharmaceutically acceptable salt, hydrate or solvate; where: i) Ki means aryl or heteroaryl, each of which is optionally substituted with the substituent Ka», Vo, Vi, Vi,

Wiz, Aza and Keys, each independently selected from the group consisting of C1-6-acyl, C1-6-acyloxy, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylcarboxamide, Co --alkynyl, C1-6-alkylsulfonamide, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C1-6-alkylamino, C1-6-dialkylamino,

C 1 -C 6 -alkylimino, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -7-cycloalkyl, C 1 -dialkylcarboxamide,

C2-6-dialkylsulfonamide, halogen, C1-6-haloalkoxy, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C1-6-haloalkylthio, heterocycle, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent substituents K», Bo, Ni1, Bi2, Wiz, Via and Ki5, together with the atoms to which they are attached, form a C5-7 cycloalkyl group or a heterocyclic group, each of which is optionally substituted by BE, SI or B, and where indicated is C1-6-alkenyl, C1-6-alkyl, C1-6-alkynyl, C1-6-alkylamino, C1-6-alkylimino, C1-6-dialkylamino, heterocycle and phenyl, each optionally substituted 1-5 substituents independently selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C1-6-alkenyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6-alkynyl,

C1-6-alkylsulfonamide, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C1-6-alkylamino, C1-6-dialkylamino, carbo-C1--alkyl , carboxamide, carboxy, cyano, C3-cycloalkyl, C3-8-dialkylcarboxamide, halogen, Ci-6-haloalkyl, Ci-6-haloalkyl, Ci-6-haloalkylsulfinyl, Ci1-6-haloalkylsulfonyl, Ci-6-haloalkylthio, hydroxyl, thiol and nitro; her) E2 is selected from the group consisting of H, C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl and C3-7-cycloalkyl; iii) "c is selected from the group consisting of H, C1-6-alkenyl, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, carbo-C1-6-alkyl, carboxamide, carboxy, cyano, C3-cycloalkyl, C3-dialkylcarboxamide, halogen, heteroaryl and phenyl; and where each of the specified C1-6-alkenyl, C1-6-alkyl, C2-6-alkynyl, C1-6-alkylsulfonamide, C3-7-cycloalkyl, heteroaryl and phenyl groups can be optionally substituted with 1-5 substituents, independently selected from the group consisting of C-5-acyl, C-5-acyloxy, C-6-alkenyl, C-4-alkoxy, C-6-alkyl, C-6-alkylamino, C2-6-dialkylamino, C-4-alkylcarboxamide, C2-6-alkynyl, C----alkylsulfonamide, C-4-alkylsulfinyl, C-4--alkylsulfonyl, C-4-alkylthio, C-4-alkylureyl, amino, carbo-C-ve -Alkoxy, Carboxamide, Carboxy, Cyano, C3-E-Cycloalkyl, C2-E-Dialkylcarboxamide, Halogen, C1-4- Halogenalkoxy, C1-4-Haloalkyl, C1-4-Haloalkylsulfinyl, C1-4-Haloalkylsulfonyl, C1-4 - haloalkylthio, hydroxyl, nitro and sulfonamide; them) Va" is selected from the group consisting of H, C-C-acyl, C-C-acyloxy, C-C-C-alkenyl, C-C-Alkoxy, C-C-Alkyl,

C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, C6-6-alkylsulfinyl, C6-6-alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C6-6-alkylamino, C2-C-Dialkylamino, Carbo-Ci-C-Alkoxy, Carboxamide, Carboxy, Cyano, C3-7-Cycloalkyl, C2-C-Dialkylcarboxamide, C2-C-Dialkylsulfonamide, Halogen, C1-6-Halo-Alkoxy, C1-6 - haloalkyl, Ci-E-haloalkylsulfinyl, Ci-E-haloalkylsulfonyl, Ci-E-haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; m) A is selected from the group consisting of C1-6-acyl, C1-6-acyloxy, C1-6-alkenyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6 -alkynyl, C-C-alkylsulfonamide, C-C-alkylsulfinyl, C-C-alkylsulfonyl, C-C-alkylthio,

C-C-alkylureyl, amino, C-C-alkylamino, C-C-dialkylamino, carbo-C-C-Alkoxy, carboxamide, carboxy, cyano,

C3-7-cycloalkyl, C1-6-dialkylcarboxamide, C2-6-dialkyl sulfonamide, halogen, C1-6-haloalkyl, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C6-haloalkylthio, hydroxyl, thiol, nitro and sulfonamide, where the specified C 1 - alkoxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of C 5 -acyl, C 5 -acyloxy, C 1 -alkenyl, C ---Alkoxy, C1-C-alkyl, amino, C1-C-alkylamino, C1-C-dialkylamino, C1-4-alkylcarboxamide, C1-C-alkynyl, C1-4-alkylsulfonamide, C1-4-alkylsulfinyl, Si -«-alkylsulfonyl, C1-4-alkylthio, C1-4--alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6-cycloalkyl, C0---dialkylcarboxamide, halogen, C1- 4-haloalkyl, C1-4-haloalkyl, C1-4-haloalkylsulfinyl, C1-4-haloalkylsulfonyl, C1-4-haloalkylthio, hydroxyl, nitro and phenyl, and where amino and phenyl substituents are indicated, each is optionally substituted with 1- 5 substituents selected from the group consisting of halogen and carbo-Ci-v-alcoc you are; mi) Ava, Nvo and Kvs, each independently selected from the group consisting of H, C1-acyl, C1-acyloxy, C2-6-alkenyl, C1-alkoxy, C1-alkyl, C1-6 alkylcarboxamide, Co-alkynyl, C1-6-alkylsulfonamide, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C1-6-alkylamino, C1-6-dialkylamino, carbo -Ci-C-Alkoxy, carboxamide, carboxy, cyano, C3-7-Cycloalkyl, C2-C-dialkylcarboxamide, C2-C-8-dialkylsulfonamide, halogen, C1-6-haloalkyl, C6-haloalkyl, C6- haloalkylsulfinyl, Ci1-6-haloalkylsulfonyl, Ci-6-haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; miii) B and Kv independently mean H or C1-6-alkyl; mii) X means O or 5; and their) O represents C1-C3-alkylene optionally substituted with 1-4 substituents selected from the group consisting of

C-C-alkyl, C-C-Alkoxy, carboxy, cyano, C-C-haloalkyl, halogen and oxo group; or O means connection.

One aspect of the present invention relates to pharmaceutical compositions comprising compounds of the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to methods of modulating the activity of the 5-HTgda serotonin receptor by contacting the receptor with a compound according to any of the embodiments of the present invention provided herein, or with a pharmaceutical composition.

One aspect of this invention relates to methods of preventing or treating platelet aggregation in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of this invention provided herein, or a pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating symptoms selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attacks, angina pectoris, stroke, and atrial fibrillation in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound at any - any of the variants of implementation of this invention, given in this description, or pharmaceutical composition.

One aspect of the present invention relates to methods of prevention or treatment for reducing the risk of blood clot formation in angioplasty or coronary artery bypass grafting in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention set forth herein, or pharmaceutical compositions.

One aspect of the present invention relates to methods of prevention or treatment for reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention set forth herein, or pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating asthma in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating an asthma symptom in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating agitation or a symptom thereof in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention set forth herein, or a pharmaceutical composition. In some embodiments of the present invention, the individual is an elderly individual with no signs of cognitive impairment.

One aspect of the present invention relates to methods of preventing or treating agitation or a symptom thereof in an individual suffering from dementia, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention set forth herein, or a pharmaceutical composition. In some embodiments of the present invention, the dementia is caused by a degenerative disease of the nervous system. In some embodiments of the present invention, dementia is caused by Alzheimer's disease, Lewy bodies,

Parkinson's or Huntington's disease. In some embodiments of the present invention, dementia results from diseases that affect blood vessels. In some embodiments of the present invention, the dementia is caused by stroke or multi-infarct dementia.

One aspect of the present invention relates to methods of preventing or treating an individual suffering from at least one of the manifestations selected from the group consisting of conduct disorder, drug-induced psychosis, reactive psychosis, Gilles de la Tourette syndrome, manic syndrome, organic or MOB psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, MOH schizophrenia, which include the administration of a therapeutically effective amount of a dopamine Y2 receptor antagonist and a compound according to any of the embodiments of the present invention listed in this description, or a pharmaceutical composition, to the specified individual in need thereof. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One aspect of the present invention relates to methods of preventing or treating an individual with infantile autism, Huntington's chorea, or suffering from nausea and vomiting induced by chemotherapy or chemotherapeutic antibodies, comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine O2 receptor antagonist and a compound of any which of the variants of implementation of this invention, given in this description, or pharmaceutical composition. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One aspect of the present invention relates to methods of preventing or treating schizophrenia in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a dopamine O2 receptor antagonist and a compound according to any of the embodiments of the present invention set forth herein, or a pharmaceutical composition. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One aspect of the present invention relates to methods of prevention or treatment for alleviating negative symptoms of schizophrenia caused by the administration of haloperidol to an individual suffering from schizophrenia, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention set forth in this description, or a pharmaceutical composition. In some embodiments of the present invention, the haloperidol and the compound or pharmaceutical composition are administered as separate dosage forms. In some embodiments of the present invention, the haloperidol and the compound or pharmaceutical composition are administered as a single dosage form.

One aspect of the present invention relates to methods of preventing or treating a sleep disorder in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition. In some embodiments of the present invention, the sleep disorder is a fragmented sleep pattern. In some embodiments of the present invention, an effective amount of a compound of any of the embodiments of the present invention provided herein, or a pharmaceutical composition provided herein, promotes sleep. In some embodiments of the present invention, an effective amount of a compound of any of the embodiments of the present invention provided herein, or a pharmaceutical composition provided herein, increases delta energy.

In some embodiments of the present invention, the sleep disorder is dyssomnia. In some embodiments of the present invention, the dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep pattern perception disorder, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement syndrome, restless legs syndrome, sleep disorder caused by poor sleep hygiene, sleep disorder caused by environmental factors, high-altitude insomnia, sleep disorder caused by adaptive responses, insufficient sleep syndrome, sleep disorder caused by disturbed bedtime routine, associative sleep disorder, night eating or drinking syndrome , sleep disorder caused by the use of sleeping pills, sleep disorder caused by the use of stimulants, sleep disorder caused by the use of alcohol, sleep disorder caused by toxic exposure, jet lag syndrome (flying syndrome), sleep disorder caused by variable work patterns, irregular sleep patterns -wake, sleep phase delay syndrome, early sleep phase syndrome, and sleep disorder caused by a non-24-hour sleep-wake cycle.

In some embodiments of the present invention, the sleep disorder is a parasomnia. In some embodiments of the present invention, the parasomnia is selected from the group consisting of confusional states upon awakening, sleepwalking and night terrors, rhythmic movement disorder, sleep tremors, sleep talking, and nocturnal leg cramps.

In some embodiments of the present invention, the sleep disorder is associated with an organic or psychiatric illness. In some embodiments of the present invention, the organic or psychiatric disease is selected from the group consisting of psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, degenerative brain diseases, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrographic signs epileptic seizure in sleep, sleep-related headaches, hypersomnia due to trypanosomosis, nocturnal myocardial ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, gastric and duodenal ulcer disease, syndrome fibrositis, osteoarthritis, rheumatoid arthritis, fibromyalgia and post-surgical sleep disorders.

One aspect of the present invention relates to methods of preventing or treating diabetes-related disorders in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

In some embodiments of the present invention, the diabetes-related disorder is diabetic peripheral neuropathy.

In some embodiments of the present invention, the diabetes-related disorder is diabetic nephropathy.

In some embodiments of the present invention, the diabetes-related disorder is diabetic retinopathy.

One aspect of the present invention relates to methods of preparing a composition comprising mixing a compound according to any of the embodiments of the present invention set forth herein and a pharmaceutically acceptable carrier.

One aspect of the present invention is the use of the compound for the preparation of a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgA.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is platelet aggregation.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke and atrial fibrillation.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is the formation of blood clots during angioplasty or coronary bypass surgery in an individual.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is the formation of blood clots in an individual suffering from atrial fibrillation.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is asthma.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is a symptom of asthma.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is agitation or its symptom in an individual. In some embodiments of the present invention, the individual is an elderly individual with no signs of cognitive impairment.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is agitation or a symptom thereof in an individual suffering from dementia. In some embodiments of the present invention, the dementia is caused by a degenerative disease of the nervous system. In some embodiments of the present invention, the dementia is caused by Alzheimer's disease, Lewy bodies, Parkinson's disease, or Huntington's disease. In some embodiments of the present invention, dementia results from diseases that affect blood vessels. In some embodiments of the present invention, the dementia is caused by stroke or multi-infarct dementia.

One of the variants of the implementation of this invention is the use of a compound for obtaining a medicinal product, which additionally contains an antagonist of the O2-dopamine receptor, for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is selected from the group including conduct disorder, psychosis, drug-induced, reactive psychosis, Gilles de la Tourette syndrome, manic syndrome, organic or MOB psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, MOH schizophrenia. In some embodiments of the present invention, the 02-dopamine receptor antagonist is haloperidol.

One of the variants of the implementation of this invention is the use of a compound for obtaining a medicinal product, which additionally contains an antagonist of the O2-dopamine receptor, for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is infantile autism, chorea

Huntington's disease or nausea and vomiting caused by chemotherapy or chemotherapy antibodies. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product, which additionally contains an antagonist of the O2-dopamine receptor, for use in the prevention or treatment of a disease mediated by the action of 5-HThi, where the disease is schizophrenia. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is a negative symptom or symptoms of schizophrenia caused by the administration of haloperidol.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where haloperidol and the compound or pharmaceutical composition are administered in the form of separate dosage forms.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where haloperidol and the compound or pharmaceutical composition are administered in the form of a single dosage form.

One aspect of the present invention is a compound according to any of the embodiments of the invention provided herein for use in a method of treating a human or animal by therapy.

One aspect of the present invention is a compound according to any one of the embodiments of the invention provided herein for use in a method of prevention or treatment by therapy of a disorder mediated by the action of 5-HTgaA in a human or animal as provided herein.

One aspect of the present invention is a compound according to any one of the embodiments of the invention provided herein for use in a method of prevention or treatment by means of therapy of a sleep disorder specified herein in a human or animal.

One aspect of the present invention is a compound according to any one of the embodiments of the invention provided herein for use in a method of preventing or treating platelet aggregation therapy in a human or animal.

This invention is related to two prior US patent applications, serial number 60/489572, filed July 22, 2003, and 60/503,586, filed September 16, 2003, both of which are incorporated herein by reference in their entirety.

These and other aspects of the present invention will become more apparent from the following description of the present invention.

In the figures below, bold text indicates the location of the mutation in the non-endogenous constitutively activated receptor relative to the corresponding endogenous receptor.

Figure 1 shows the generalized structure of the receptor bound to the OS protein, and the transmembrane helices, intracellular loops and extracellular loops are indicated by numbers.

Figure 2 schematically shows the active and inactive states for a typical protein-bound receptor and the relationship of the active state to the direction of transduction of the second messenger.

Figure 3 shows the nucleic acid sequence of the human endogenous 5-HTα receptor (5EO.

IO Mo:21).

Fig. 305 shows the sequence of amino acids of the human endogenous 5-HTα receptor (5EO. IO.

Mo:22).

Figure 4a shows the nucleic acid sequence of the human endogenous 5-HT2 receptor (5EO.

IO Mo:23).

Figure 4 shows the sequence of amino acids of the human endogenous 5-HT2 receptor (5EO. IO.

Mo:24).

Figure 5a shows the sequence of nucleic acids of the constitutively activated form of the human 5-HT2c receptor ("KDNA AR-1"-5E2. IU. Mo:25).

Figure 5 shows the corresponding sequence of amino acids for cDNA AP-1 ("AP-1"-BEO. 10.Mo:26).

Figure 1ba shows the nucleic acid sequence of the constitutively activated form of the human 5-HTα receptor, where the ISZ3 part and the cytoplasmic tail of the endogenous 5-HTα receptor are replaced by the ISZ part and the cytoplasmic tail of the human 5-HTα receptor ("AR-3 cDNA "-

ZEO. IU Mo:27).

Figure 6 shows the corresponding sequence of amino acids for cDNA AR-Z3 ("AR-3"-BEO 10. Mo:28).

Fig.bs schematically shows AP-3, where dotted lines indicate the part isolated from the human 5-HT2 receptor.

Figure 7a shows the nucleic acid sequence of the constitutively active form of the human 5-HTα receptor, where (1) the region between the proline in TM5 and the proline in TMb of the endogenous human 5-HTα receptor is replaced by the corresponding region of the human 5-HTα receptor (including the dot mutation 5310K); and (2) the cytoplasmic tail of the endogenous 5-HTα receptor is replaced by the cytoplasmic tail of the human endogenous 5-HT2 receptor ("AP-4"-5EO cDNA). IU Mo:29).

Figure 7p shows the corresponding sequence of amino acids for cDNA AP-4 ("AP-4"-BEO. 10. Mo:30).

Figure 7c schematically shows the mutant 5-HTα receptor shown in Figure 7p, where the dashed lines indicate the part isolated from the human 5-HT2 receptor.

Figure 8 shows the preferred vector, RSMU, used in this description.

Figure 9 is a diagram illustrating (1) enhanced binding of (355)2TRu5 to a membrane derived from CO5 cells expressing endogenous human 5-HT2 receptor in response to serotonin, and (2) inhibition by mianserin using wheat germ agglutinin beads for scintillation proximal analysis. The concentration of (355)2TRu5 is kept constant at the level of 0.3nM, and the concentration

SOR is supported at the level of iMkM. The concentration of membrane protein is 12.5 μg.

Figure 1000 shows a diagram showing serotonin stimulation of (325)STRU5 binding to membranes expressing AP-1 receptors in 293T cells, and inhibition by ZOmM mianserin on U/aNastm scintillation plates.

Figure 11 shows a diagram showing the effect of protein concentration on the binding of (355)0TRUu5 to membranes obtained from 293T cells transfected with the control vector (rom) alone in the absence (A) and in the presence (B) of 10 μM serotonin. The concentration of (355)2TRUu5 containing a radioactive label is kept constant at the level of 0.3 nM, and the concentration of SOR is kept constant at the level of 1 μm.

The analysis is carried out in the format of a 96-well tablet using Umaiiast scintillation plates,

Figure 12 shows a comparison of inositol triphosphate (IN) production between the human endogenous 5-HTα receptor and AP-2, a mutant form of the receptor, using histograms.

Figure 13 shows a comparison of inositol triphosphate (IN) production between the human endogenous 5-HTα receptor and AP-4, a mutant form of the receptor, using histograms.

Figure 14 shows a comparison of IRZ production between the human endogenous 5-HTga receptor and AP-3, a mutant form of the receptor, using histograms.

Figure 15 shows a comparison of IRZ production between the human endogenous 5-HT2 receptor and AR-1 using histograms.

Figures 16A, 168 and 16C show individual autoradiograms in gray scale, showing the replacement of 7251-

І5О in brain regions with spiperone and a compound previously obtained and identified by the authors of this invention, which is designated in this description as 5-1610 and which has the following name: 4-methoxyphenyl ether (2-(4-bromo-2-methyl-2H-pyrazole -3-isophenylcarbamic acid.

Figure 17 shows a general synthesis scheme for obtaining intermediate compounds according to the present invention. On

Fig. 17 shows the general method of condensation of pyrazolboronic acid and aryl triflate; it should be understood that similar methods of condensation can be used in the case when a halogen such as I, Bg or SI is used instead of the triflate.

Figure 18 shows a general synthesis scheme for obtaining intermediate compounds according to the present invention.

Figure 19 shows a general synthesis scheme for the preparation of intermediate compounds that can be used to prepare the compounds of the present invention.

Figure 20 shows a general synthesis scheme for the preparation of intermediates that can be used to prepare the compounds of the present invention.

Figure 21 shows a general synthesis scheme for obtaining compounds according to the present invention. Figure 21 shows a general method of condensation of phenylamine, as indicated in the previous figures, with isocyanate or thioisocyanate to form ureas and thioureas, respectively.

Figure 22 shows the effect of compound 1 on OO!-induced reduction in locomotor activity in rats.

Figure 23 shows the effect of compound 26 on CO|!-induced reduction of locomotor activity in rats.

Fig. 24 shows the plan of the experiment for studying the degree of employment of 5-HTgaA in monkeys.

Figure 25 shows pictures obtained during a bath PET scan (positron emission tomography method) of the brain of monkeys 8-24 hours after exposure to compound 1, compared to a baseline PET scan (transaxial view).

Figure 26 shows PET scans of monkey brains 8-24 hours after exposure to compound 1 compared to baseline PET scans (sagittal view).

Fig. 27 shows tabulated data for the degree of occupation of 5-HTα receptors by compound 1 in monkeys.

Figure 28 shows the effect of compound 1 and compound 26 on sleep and wakefulness in rats, expressed by the value of delta energy, in comparison with zolpidem.

Figure 29 shows a general synthesis scheme for obtaining intermediate compounds according to the present invention. On

Fig. 29 shows the general method of condensation of pyrazolboronic acid and aryl triflate; it should be understood that analogous condensation techniques known in the art may also be used, and a halogen such as I, Bg, or Si may be used instead of the triflate.

Figure 30 shows a general synthesis scheme for obtaining intermediate compounds according to the present invention.

Fig. 30 illustrates the formation of pyrazoles from various substituted chromen-4-ones. Alkylation and "Mitsunobi-type" examples for the modification of phenol and explanatory examples of the reduction of a nitro group to an amino group are also given.

Figure 31 shows a general synthesis scheme for the preparation of intermediate compounds that can be used to prepare the compounds of the present invention. Fig. 31 illustrates alkylation and examples "by type

Mitsunobi" for the modification of phenol. It should be understood that various haloalkyls and alcohols can be used in the specified reactions. Individual examples of alcohols are 2-dimethylaminoethanol, 3-dimethylaminopropanol, etc.

Figure 32 shows a general synthesis scheme for the preparation of intermediate compounds that can be used to prepare the compounds of the present invention. Fig. 32 illustrates general methods of introducing various halogens into the compounds of the present invention. It should be understood that the indicated halogenation reactions can be carried out during the synthesis later, for example, at the last stage.

Figure 33 shows a general synthesis scheme for obtaining compounds according to the present invention. Figure 33 shows a general method of combining phenylamine, as indicated in the previous figures, with isocyanates or thioisocyanates to give ureas and thioureas, respectively. Fig. 33 also shows the general method of introducing K" and Kv groups into compounds according to the present invention.

Figure 34 shows an additional general synthesis scheme for the preparation of compounds of the present invention.

Definition

In the scientific literature devoted to receptors, a number of terms have been adopted to designate ligands that exert different effects on receptors. For clarity and consistency, the following definitions are used in this description. "Agonists" mean substances that interact with a receptor and activate a receptor, such as a 5-HThA receptor, and initiate a physiological or pharmacological response specific to that receptor. For example, in the case when these substances activate an intracellular reaction in response to binding to a receptor or enhance the binding of STRs to the membrane.

The used abbreviations of "amino acids" are given in Table 1:

Table 1

Arginine AB | In / oAspartic acid | AR | 0

Glutamn. Her cm | 0 ssoleacin/////////// | PE | !

Methionine. | MET | M

Proln. | RVO | R

Shafts 777 | MA | M

The term "antagonists" refers to chemicals that competitively bind to a receptor at the same site as agonists (eg, an endogenous ligand), but that do not activate the intracellular response initiated by the active form of the receptor, and are therefore capable of inhibit intracellular reactions in response to agonists or partial agonists. Antagonists do not reduce the baseline intracellular response in the absence of agonist or partial agonist.

A chemical group, fragment or radical

The term "C 1-6 acyl" means a C 1-6 alkyl radical attached to a carbonyl group, wherein alkyl has the meanings given herein; some examples include, but are not limited to, acetyl, propionyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl (ie, pivaloyl), pentanoyl, and the like.

The term "C 1-6 acyloxy" means an acyl radical attached to an oxygen atom, where acyl is as defined herein; some examples include, but are not limited to, acetyloxy-, propionyloxy-, butanoyloxy-, isobutanoyloxy-, sec-butanoyloxy-, tert-butanoyloxy, and the like.

The term "Ci-6-alkenyl" means a radical that contains 2-6 carbon atoms, in which at least one carbon-carbon double bond is present, and in some embodiments of the present invention contains 2-4 carbon atoms, in some embodiments contains 2-3 carbon atoms, in some variants contains 2 carbon atoms.

The term "alkenes" includes both E- and 2-isomers. In addition, the term "alkenes" includes di- and trialkenyls. Thus, if more than one double bond is present, the bonds may be entirely E- or 7-isomers or a mixture of E- and 2-isomers. Examples of alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, etc. .p.

The term "Ci-C-Alkoxy group" means an alkyl radical, as defined herein, directly attached to an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, and the like.

The term "C 1-6 alkyl" means a hydrocarbon radical with a straight or branched chain that contains 1-8 carbon atoms, and in some embodiments of the present invention contains 1-6 carbon atoms, in some embodiments contains 1-4 carbon atoms, in in some variants contains 1-3 carbon atoms, in some variants contains 1-2 carbon atoms. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl (ie - CH(CHNi)CHNaCH»cSnH»z), 2-methylbutyl (i.e. -CH-CH(CH3)CHneSNIi, n-hexyl, etc.

The term "C 1-6 alkylcarboxamido" or "C 1-6 alkylcarboxamide" means a single C 1-6 alkyl group attached to the nitrogen of an amide group, wherein alkyl has the meanings given herein. The C1-e-alkylcarboxamide group can be represented by the following groups: zu M M S..in Galkil

Examples include, but are not limited to,

M-methylcarboxamide, M-ethylcarboxamide, M-n-propylcarboxamide, M-isopropylcarboxamide, /- M-n-butylcarboxamide, M-tert-butylcarboxamide, M-isobutylcarboxamide, M-tert-butylcarboxamide, etc.

The term "C 1 -C 3 -alkylene" means a straight chain C 1 -C 2 divalent carbon group. In some embodiments of the present invention, C-C-alkylene means, for example, -СНе-, -СНаСНе-, -СНаСНесСнН-, and the like. In some embodiments of the present invention, C-C-alkylene means -CH-, -SHOCH»-, -СНСНеCH»-, etc., where the specified examples generally belong to the variable "C".

The term "Ci-c-alkylimino" means a Ci-c-alkyl radical attached to a carbon atom of the group -С(-МН)-, where alkyl has the meanings given in this description; some examples include, but are not limited to, 1-iminoethyl (i.e., -C(-MH)CHnZi), 1-iminopropyl (i.e., -C(-MH)CNeCnHzI), 1-imino-2-methylpropyl (i.e.

C(-MNSN(SNZ)»I, etc.

The term "C 1-6 alkylsulfinyl" means a C 1-6 alkyl radical attached to a sulfoxide radical of the formula: -5(0)-, where the alkyl radical has the meanings given in this description. Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, isobutylsulfinyl, tert-butylsulfinyl, and the like.

The term "Ci-ve-alkylsulfonamide" belongs to the groups deme chn pud alkyl ka -5- alkyl

N. Ov. with where C 1 -alkyl has the meanings given in this description.

The term "C 1-6 alkylsulfonyl" means a C 1-6 alkyl radical attached to a sulfonic radical of the formula: -5(0)2-, where the alkyl radical has the meanings given in this description. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, and the like.

The term "Ci-C alkylthio" means a Ci-C alkyl radical attached to a sulfide of the formula -5-, where the alkyl radical has the meanings given in this description. Examples include, but are not limited to, methylsulfanyl (ie, CH35-), ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, tert-butylsulfanyl, and the like.

The term "C 1-6 -alkylthiocarboxamide" means a thioamide of the following formula:

Z 5 alkyl Kx Z a - Silkyl z H 7 where Ci-C alkyl has the values given in this description.

The term "Ci-6-alkylthioureyl" means a group of the formula: -MOS(5)M-, where one or both nitrogen atoms are replaced by the same or different Ci-6-alkyl groups, where alkyl has the meanings given in this description.

Examples of an alkylthioureyl group include, but are not limited to, CH3MnHCe(5)MH-, MHgC(5)MSH3-, (Cnzam(3)MH-, (CH3)4M()MH-, (CH3)a.5M(5 )MSH3-, CH3Sngmne()Mn-, ENzaSngMnHO(5)MSH3-, etc.

The term "Ci-6 alkylureyl" means a group of the formula: -MS(O)M-, where one or both nitrogen atoms are replaced by the same or different C1-6 alkyl groups, where alkyl has the meanings given in this description.

Examples of an alkylthioureyl group include, but are not limited to, CHzMnNe(mMn-, MnHgS(O)MeHz-, (Cnz2m(O)MnH-, (Cnz)g5mz(O)MH-, (CHz)gm(O)MeHz- , SnzaSnNgmne(O)Mn-, SnzaSnaMnOe(O)MeHz-, etc.

The term "Ci-6-alkynyl" means a radical that contains 2-6 carbon atoms and at least one carbon-carbon triple bond, and in some embodiments of the present invention contains 2-4 carbon atoms, in some embodiments contains 2-3 carbon atoms, in some variants contains 2 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.

The term "alkynyl" includes di- and triynes. "Amino" means the -MN group."

The term "C 1-6 alkylamino group" means a single alkyl radical attached to an amino group, wherein alkyl has the meanings given herein. Some examples include, but are not limited to, methylamino-, ethylamino-, n-propylamino-, isopropylamino-, n-butylamino-, t-butylamino-, isobutylamino-, tert-butylamino, and the like. Some embodiments of this invention include "Ci1-2-alkylamino".

The term "aryl" means an aromatic cyclic radical containing 6-10 carbon atoms in the ring.

Examples include phenyl and naphthyl.

The term "arylalkyl" means a Cm-alkylene, such as -CNeo-, -CH»SnNoe-, etc., which is additionally substituted with an aryl group. Examples of "arylalkyl" include benzyl, phenethylene, and the like.

The term "arylcarboxamido group" means one aryl group attached to the nitrogen of the amide group, where aryl has the meanings given herein. An example is M-arylcarboxamide.

The term "arylureyl" means the group -MS(O)M-, where one of the nitrogen atoms is replaced by an aryl group.

The term "benzyl" means the group -CHNaSenH5.

The term "carbo-Ci-C-Alkoxy group" refers to a complex C-C-C alkyl ester of a carboxylic acid, where the alkyl group is defined herein. Examples include, but are not limited to, carbomethoxy-, carboethoxy-, carbopropoxy-, carboisopropoxy-, carbobutoxy-, carbo-t-butoxy-, carboisobutoxy-, carbo-tert-butoxy-, carbo-n-pentoxy-, carboisopentoxy- , carbo-tert-pentoxy-, carbone-pentoxy-, carbon-n-hexyloxy group, etc.

The term "carboxamide" belongs to the group -СОМН».

The term "carboxy" or "carboxyl" means the group -"СО2Н; also called a carboxylic acid group.

The term "cyano" means the -CM group.

The term "C47-cycloalkenyl" means a non-aromatic cyclic radical containing 4-7 carbon atoms in the ring and at least one double bond; in some embodiments, the implementation of this invention contains 4-6 carbon atoms; in some variants contains 4-5 carbon atoms; in some embodiments, contains 4 carbon atoms.

Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

The term "C3-;-cycloalkyl" means a saturated cyclic radical containing 3-7 carbon atoms; in some embodiments, the implementation of this invention contains 3-6 carbon atoms; in some variants contains 3-5 carbon atoms; in some versions contains 5-7 carbon atoms; in some variants contains 3-4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "C 1-6 -dialkylamino group" means an amino group substituted by two identical or different C 1-4 alkyl radicals, where the alkyl group has the meanings given in this description. Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino, and the like. Some embodiments of this invention include "C1-4-dialkylamino group".

The term "C 6 -dialkylcarboxamido" or "C 6 -dialkylcarboxamide" means two alkyl radicals, which are the same or different, attached to an amide group, where alkyl has the meanings given in this description. Co-8b-dialkylcarboxamide group can be represented by the following groups:

Kt and Y 14 alkyl with and where C-4 has the values given in this description. Examples of C1-3-dialkylcarboxamide include, but are not limited to, M,M-dimethylcarboxamide, M-methyl-M-ethylcarboxamide, M,M-diethylcarboxamide, M-methyl-M-isopropylcarboxamide, and the like.

The term "Cg---dialkylsulfonamide" belongs to one of the following groups: | 1" sticks

C 1 -C 4 alkyl is as defined herein, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

The term "C 1 -C 6 -dialkylthiocarboxamido" or "C 6 -C 6 -dialkylthiocarboxamide" means two alkyl radicals, which are the same or different, attached to a thioamide group, where alkyl has the meanings given in this description. The Cg-v-dialkylthiocarboxamide group can be represented by the following groups:

From 5

A and Sta glkil ka AD 7; m | MO Silalkil

S. Lylekill. Alkyl seed

Examples of dialkylthiocarboxamide include, but are not limited to, M,M-dimethylthiocarboxamide,

M-methyl-M-ethylthiocarboxamide, etc.

The term "ethynylene" belongs to the group with a triple carbon-carbon bond, presented below: d-----5

The term "formyl" belongs to the -CHO group.

The term "Ci-e-haloalkyloxy" means a haloalkyl, as defined herein, which is directly attached to an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

The term "Ci-6-haloalkyl" means Ci-6-alkyl as defined above, wherein the alkyl is substituted by one halogen and up to fully substituted, where a fully substituted Ci-c-haloalkyl may be represented by the formula

Sp gly, where G. means halogen, and "n" is equal to 1, 2, C or 4; if more than one halogen is present, they can be the same or different and are selected from the group consisting of E, SI, Bg or I, preferably PE.

Examples of C1-4-haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

The term "C 1-6 -haloalkylcarboxamide" means an alkylcarboxamide group as defined herein, wherein the alkyl is substituted by one halogen and up to full substitution, wherein the fully substituted haloalkyl is represented by the formula Spi, where H is halogen, and "n" is 1, 2, C or 4. If more than one halogen is present, they can be the same or different and are selected from the group consisting of E, CI, Bg or I, preferably PE.

The term "C 1-6 -haloalkylsulfinyl" means a haloalkyl radical attached to a sulfoxide group of the formula: -5(0)-, where the haloalkyl radical has the meanings given in this description. Examples include, but are not limited to, trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl, and the like.

The term "C 1-6 -haloalkylsulfonyl" means a haloalkyl radical attached to a sulfonic group of the formula: -5(0)2-, where haloalkyl has the meanings given in this description. Examples include, but are not limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, and the like.

The term "Ci-C-haloalkylthio" means a haloalkyl radical directly attached to a sulfur atom, where haloalkyl has the meanings given in this description. Examples include, but are not limited to, trifluoromethylthio (ie, CE35-, also referred to as trifluoromethylsulfanyl), 1,1-difluoroethylthio-, 2,2,2-trifluoroethylthio, and the like.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "heteroaryl" means an aromatic ring system, which may be one ring, two fused rings, or three fused rings, in which at least one ring carbon atom is replaced by a heteroatom selected from, but not limited to, the group consisting of o, 5 and M, where M can be optionally substituted by H, C1-4-acyl or C1-4-alkyl. Examples of heteroaryl groups include, but are not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole, benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinoxaline, and the like. In some embodiments of the present invention, the heteroatom is 0, 5 or MH, and examples include, but are not limited to, pyrrole, indole, and the like. Other examples include, but are not limited to, those shown in Table 2, Table

Zitlp.

The term "heterocycle" means a non-aromatic carbon ring (ie, C3--cycloalkyl or Ca-7-

Cycloalkenyl as defined herein) wherein one, two, or three ring carbon atoms are replaced by a heteroatom selected from, but not limited to, the group consisting of 0, 5, M, where M may optionally be substituted by H, C-4-acyl or C-4-alkyl, and the carbon atoms in the ring may optionally be substituted with an oxo- or thioxo group, thus forming a carbonyl or thiocarbonyl group.

The heterocyclic group is a 3-, 4-, 5-, b- or 7-membered ring. Examples of a heterocyclic group include, but are not limited to, aziridin-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-4 -yl, morpholin-4-yl, piperazin-1-yl, piperazin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, (1,3|dioxolan-2-yl, etc.

The term "heterocyclic carboxamido group" means a heterocyclic group, as defined herein, containing a nitrogen atom in the ring, where the nitrogen atom in the ring is directly bonded to a carbonyl to form an amide. Examples include, but are not limited to,

So ' ' etc.

The term "heterocyclic sulfonyl" means a heterocyclic group, as defined herein, containing a nitrogen atom in the ring, where the nitrogen atom in the ring is directly linked to the -502- group to form a sulfonamide. Examples include, but are not limited to, muscles

K- KM Kk cm

So, etc.

The term "hydroxyl" belongs to the group -OH.

The term "hydroxylamino" belongs to the group -MNON.

The term "nitro" belongs to the -MO group.

The term "C4-7-oxocycloalkyl" refers to C4-7-cycloalkyl, the definition of which is given in this description, where one of the carbon atoms in the ring is replaced by a carbonyl. Examples of C 1 -7-oxocycloalkyl include, but are not limited to, 2-oxocyclobutyl, 3-oxocyclobutyl, 3-oxocyclopentyl, 4-oxocyclohexyl, and the like. and, accordingly, are represented by the following structures:

Uh "h iy "to

Pe fo Sha ZE o tia Ko

OO

!

The term "perfluoroalkyl" means a group of the formula -SpEopti; otherwise, perfluoroalkyl is an alkyl as defined herein, wherein the alkyl is fully substituted with fluorine atoms, and is therefore to be considered a subgroup of haloalkyl. Examples of perfluoroalkyls include CE3, CE3CE3, CESE3,

СЕ(СЕз)», СЕ2СЕ»СЕ»СЕ», СР»СЕ(СЕз)2, СЕ(СЕз)СР»СЕ: etc.

The term "phenoxy" belongs to the group SenNzo-.

The term "phenyl" belongs to the group SeHb-.

The term "sulfonic acid" belongs to the -5OzH group.

The term "thiol" means the group -5H.

"Codon" means a group of three nucleotides (or nucleotide equivalents), which generally make up the nucleoside I (adenosine (A), guanosine (b), cytidine (C), uridine (/)) and thymidine (T))Y, conjugated with a phosphate group, which encodes an amino acid during translation. "Composition" means a substance containing at least two compounds or two components; for example and without limitation, a "pharmaceutical composition" is a composition that contains a compound of the present invention and a pharmaceutically acceptable carrier.

The term "compound efficacy" refers to the degree of a compound's ability to inhibit or stimulate the functional abilities of a receptor as opposed to receptor binding affinity.

The term "constitutively activated receptor" means a receptor that is constitutively activated.

The term "constitutive activation of the receptor" means stabilization of the receptor in an active state by means other than binding of the receptor to an endogenous ligand or its chemical equivalent. "Contacting" refers to bringing certain chemical compounds into contact with each other both under conditions of ip miigo and under conditions of ip mimo. Thus, "contacting" a 5-HTα receptor with a compound of the present invention includes administering a compound of the present invention to an individual, preferably a human having a 5-HTα receptor, as well as, for example, administering a compound of the present invention to a sample containing cellular or a purer drug that contains the 5-HTgda receptor.

The term "endogenous" means a substance that is naturally produced by a mammal. For example and without limitation, endogenous with respect to the term "receptor" means a receptor that is naturally produced by a mammal (eg, without limitation, a human) or a virus.

In contrast, the term "non-endogenous" in this context means a substance that is not produced naturally by a mammal (eg, without limitation, a human) or a virus. For example and without limitation, a receptor that is not constitutively active in its endogenous form, but upon exposure becomes constitutively active, is most preferably defined herein as a "non-endogenous constitutively activated receptor".

Both terms can be used to describe both ip migo and ip mimo systems. For example and without limitation, when performing a screening, an endogenous or non-endogenous receptor may belong to the ip migo screening system. As another example and without limitation, when the genome of a mammal is manipulated to include a non-endogenous constitutively activated receptor, it becomes possible to select candidate compounds using the ip mimo system.

The term "in need of prevention or treatment" in this description means a conclusion made by a person who provides care services for a patient (in particular, a doctor, nurse, orderly, etc. in the case of a person; a veterinarian in the case of animals, including exceptional from human mammals), that the individual or animal requires or would benefit from prevention or treatment. This conclusion is made based on various factors within the competence of the person performing the care of the patient, and which include knowledge that the individual or animal has or will develop a disease, condition or disorder that can be treated with the compounds of this invention. In the general case, the term "in need of prophylaxis" refers to the conclusion made by the person providing patient care services that the individual will get sick. In this context, the compounds of the present invention are used as a protective or preventive agent. However, the term "in need of treatment" refers to the conclusion made by the person providing the care of the patient that the individual already has the disease, and therefore the compounds of the present invention are used to alleviate, suppress, or reduce the intensity of the symptoms of the disease, condition, or disorder.

The term "individual" is used herein to refer to any animal, including humans, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and most preferably humans .

The term "inhibit or inhibit" in conjunction with the term "response" means that the response is weakened or inhibited in the presence of the compound as opposed to when the compound is absent.

The term "inverse agonist" refers to chemicals that bind the endogenous form of the receptor or the constitutively activated form of the receptor and that suppress the basal level of the intracellular response to the response initiated by the active form of the receptor to less than the basal level of activity observed in the absence of agonist or a partial agonist, or reduce the binding of STR to the membrane. Preferably, the baseline intracellular response is suppressed in the presence of the inverse agonist by at least 3095, more preferably at least 5095, and most preferably at least 7595, compared to the baseline intracellular response in the absence of the inverse agonist. "Ligand" means an endogenous, naturally occurring molecule specific for an endogenous, naturally occurring receptor.

As used herein, the terms "modulate or modulate" mean increasing or decreasing the amount, quality, response, or effect of a particular activity, function, or molecule. "Pharmaceutical composition" means a composition containing at least one active ingredient; including, but not limited to, salts, solvates or hydrates of compounds of formula (I); wherein the composition may be tested to determine a particular effective outcome in a mammal (eg, without limitation, a human). One of ordinary skill in the art will be aware of and able to appreciate the methods that can be used to determine whether an active ingredient has the required effective effect as expected by the skilled artisan.

The term "therapeutically effective amount" as used herein refers to an amount of an active compound or pharmaceutical agent that elicits a biological or healing response in a tissue, system, animal, individual, or human that is sought by a researcher, veterinarian, therapist, or other medical practitioner, and which includes one or more of the following effects: (1) disease prevention; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but not yet experiencing it or exhibiting the pathology or symptomatology of the disease,

(2) disease suppression; for example, suppressing the disease, condition, or disorder in an individual suffering from or exhibiting the pathology or symptomatology of the disease, condition, or disorder (ie, delaying the further development of the pathology and/or symptomatology), and (3) reducing the intensity of the symptoms of the disease; for example, reducing the intensity of the symptoms of the disease, condition or disorder in an individual who is experiencing or in whom the pathology or symptomatology of the disease, condition or disorder (ie, cessation of the pathology and/or symptomatology) is manifested.

Compounds of the present invention

One aspect of the present invention relates to certain diaryl or arylheteroaryl urea derivatives represented by formula (1):

Eva t Co

In h

M A o no M We i

Kos and; Av

University of Applied Sciences

F 7 or their pharmaceutically acceptable salt, hydrate or solvate; where Ki, P", Nz, Va, H5, Nva, Ner, Nes, H7, Nav, X and O have the meanings given above and below in this description.

Some embodiments of the present invention relate to some diaryl or arylheteroaryl urea derivatives represented by the following formula

Do not sing with her,

In the

Kk c z where: i) K1i is aryl or heteroaryl, optionally substituted with Ka", Vo, Wit, Vig, Wiz, Via and Kis, independently selected from the group consisting of C1-acyl, C1-e-acyloxy, Co-alkenyl, C-C-Alkoxy, C-C-Alkyl, C-C-Alkylcarboxamide, C-C-Alkynyl, C-C-Alkylsulfonamide, C-C-Alkylsulfinyl, C-C-Alkylsulfonyl, C-C -alkylthio,

C-C-alkylureyl, amino, C-C-alkylamino, C-C-dialkylamino, carbo-C-C-Alkoxy, carboxamide, carboxy, cyano,

C3-7-cycloalkyl, C1-6-dialkylcarboxamide, C1-6-dialkylsulfonamide, halogen, C1-6-haloalkyl, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C1-6-haloalkylthio, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent substituents Ka», No, Bi1, Bi2, Vis, Via and Kis together with the atoms to which they are attached, form a C1-7-cycloalkyl group or a heterocyclic group, each of which are optionally substituted by E, SI or Bg atoms; and wherein each of said C1-6-alkenyl, C1-6-alkyl, C1-6-alkynyl and phenyl groups is optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6-acyl, C1-6 -acyloxy, C1-6-alkenyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, C-C-alkylthio, C-C-V-alkylureyl, amino, C-6-alkylamino, C-C-C-dialkylamino, carbo-Ci--alkyloxy, carboxamide, carboxy, cyano, C3--cycloalkyl, C3-8-dialkylcarboxamide, halogen, C1-6 haloalkyl, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, and nitro; her) E2 is selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl and C3-7-cycloalkyl; iii) "c is selected from the group consisting of H, C1-6-alkenyl, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, carbo-C1-6-alkyl, carboxamide, carboxyl, cyano, C3-cycloalkyl, C3-8-dialkylcarboxamide, halogen, heteroaryl and phenyl; and where each of the indicated C1-6-alkenyl, C1-6-alkyl, C2-6-alkynyl, C1-6-alkylsulfonamide, C3-7-cycloalkyl, heteroaryl and phenyl groups may be optionally substituted with 1-5 substituents, independently selected from the group consisting of C-5-acyl, C-5-acyloxy, C-6-alkenyl, C-4-alkoxy, C-6-alkyl, C-6-alkylamino, C2-6-dialkylamino, C-4-alkylcarboxamide, C2-6-alkynyl, C----alkylsulfonamide, C-4-alkylsulfinyl, C-4--alkylsulfonyl, C-4-alkylthio, C-4-alkylureyl, amino, carbo-C-ve -Alkoxy, Carboxamide, Carboxy, Cyano, C3-E-Cycloalkyl, C2-E-Dialkylcarboxamide, Halogen, C1-4- Halogenalkoxy, C1-4-Haloalkyl, C1-4-Haloalkylsulfinyl, C1-4-Haloalkylsulfonyl, C1-4 - haloalkylthio, hydroxyl, nitro and sulfonamide; them) Va" is selected from the group consisting of H, C-C-acyl, C-C-acyloxy, C-C-C-alkenyl, C-C-Alkoxy, C-C-Alkyl,

C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, C6-6-alkylsulfinyl, C6-6-alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C6-6-alkylamino, C2-C-Dialkylamino, Carbo-Ci-C-Alkoxy, Carboxamide, Carboxy, Cyano, C3-7-Cycloalkyl, C2-C-Dialkylcarboxamide, C2-C-Dialkylsulfonamide, Halogen, C1-6-Halo-Alkoxy, C1-6 - haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C6-haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; m) A is selected from the group consisting of C1-6-acyl, C1-6-acyloxy, C1-6-alkenyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6 -alkynyl, C-C-alkylsulfonamide, C-C-alkylsulfinyl, C-C-alkylsulfonyl, C-C-alkylthio,

C-C-alkylureyl, amino, C-C-alkylamino, C-C-dialkylamino, carbo-C-C-Alkoxy, carboxamide, carboxy, cyano,

C3-7-cycloalkyl, C3-6-dialkylcarboxamide, C3-7-dialkylsulfonamide, halogen, C1-6-haloalkyl, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C6-haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide, where the indicated C1-6-hydroxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of C1-5-acyl, C1-5-acyloxy, C1-6-alkenyl, C-1-Alkoxy, C-C-Alkyl, C1-

c-alkylamino, C2-c-dialkylamino, C-4-alkylcarboxamide, C-c-alkynyl, C-4-alkylsulfonamide, -C-4- alkylsulfinyl, C-4-alkylsulfonyl, C-4-alkylthio, C- 4--alkylureyl, amino, carbo-Ci-e-alkoxy, carboxamide, carboxy, cyano, C3-e-cycloalkyl, Co---dialkylcarboxamide, halogen, C-4--haloalkyl, C-4--haloalkyl, Ch - α-haloalkylsulfinyl, C1-4-haloalkylsulfonyl, C-4-haloalkylthio, hydroxyl, nitro and phenyl, and where the specified phenyl group is optionally substituted by 1-5 halogen atoms; mi) Ve is selected from the group consisting of H, C1-4 acyl, C1-6 acyloxy, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkyl,

C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, C6-6-alkylsulfinyl, C6-6-alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C6-6-alkylamino, C2-C-Dialkylamino, Carbo-Ci-C-Alkoxy, Carboxamide, Carboxy, Cyano, C3-7-Cycloalkyl, C2-C-Dialkylcarboxamide, C2-C-Dialkylsulfonamide, Halogen, C1-6-Halo-Alkoxy, C1-6 - haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C6-haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; miii) B and Kv independently mean H or C1-6-alkyl; mii) X means O or 5; and their) O represents C1-C3-alkylene optionally substituted with 1-4 substituents selected from the group consisting of

C-C-alkyl, C-4-Alkoxy, carboxy, cyano, C-C-haloalkyl, halogen and oxo group; or O means connection; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

It should be understood that certain features of the present invention, which for clarity are described in the context of individual embodiments of the present invention, may also be presented as a combination in one embodiment of the present invention. On the contrary, the various features of the present invention, which are briefly described in the context of one embodiment of the present invention, may also be presented individually or in the form of any suitable subcombination.

As used herein, "substituted" means that at least one atom of a chemical group is replaced by a non-hydrogen substituent or group, where the non-hydrogen substituent or group may be monovalent or divalent. When a substituent or group is divalent, it is understood that this group is further substituted by another substituent or group. If a chemical group in this description is "substituted", then it may be substituted up to full substitution according to its valency; for example, a methyl group may be substituted with 1, 2, or C substituents, a methylene group may be substituted with 1 or 2 substituents, a phenyl group may be substituted with 1, 2, 3, 4, or 5 substituents, a naphthyl group may be substituted with 1, 2, 3, 4, 5, 6 or 7 substitutes, etc. Similarly, the expression "substituted with one or more substituents" refers to a group with one substituent and up to the full number of substituents that are physically possible for that group. Also, when a group is substituted with more than one substituent, they may be the same or different.

The compounds of the present invention may also include tautomeric forms such as ketoenol tautomers and the like. The tautomeric forms may be in equilibrium or may be sterically fixed as one form by appropriate substitution. It should be understood that various tautomeric forms are included in the scope of the compounds of this invention.

The compounds of the present invention may also include all isotopes of atoms found in intermediate and/or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

It should be understood and taken into account that the compounds of this invention may have one or more chiral centers and therefore may exist as enantiomers and/or diastereomers. It is to be understood that the present invention extends to and encompasses similar enantiomers, diastereomers, and mixtures thereof, including, but not limited to, racemates. Thus, some embodiments of the present invention relate to compounds of the present invention that are K-enantiomers. In addition, some embodiments of the present invention relate to compounds of the present invention that are 5-enantiomers. For example, where there is more than one chiral center, some embodiments of the present invention include compounds that are

B5- or 5E-enantiomers. In other embodiments of the invention, the compounds of the present invention are Kt- or 55-enantiomers. It should be understood that the present invention, unless otherwise specified or established, includes all individual enantiomers and their mixtures.

In some embodiments of the present invention, Ki represents an aryl or heteroaryl group, each of which is optionally substituted with Ka, Vo, Bi, Bi2, Wiz, Via, and Ki5, each of which is independently selected from the group consisting of Ci- acyl, C1-e-acyloxy, C1-e-alkenyl, C1-c-alkoxy, C1-c-alkyl, C1-c-alkylcarboxamide, C1-c-alkynyl, C1-e-alkylsulfonamide, C1-c-alkylsulfinyl, Si -C6-alkylsulfonyl, C6-C6-alkylthio, C6-C6-alkylureyl, amino, C6-C6-alkylamino, C6-C6-dialkylamino, C6-C6-alkylimino, carbo-C6-6-Alkoxy, carboxamide, carboxy, cyano . heterocycle, hydroxyl, thiol, nitro, phenoxy and phenyl, where Co2-in-alkenyl, C-in-alkyl, Co-in-alkynyl, C-i-alkylamino,

C1-6-alkylimino, C1-6-dialkylamino, heterocyclic group and phenyl, each optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6-acyl, C1-6-acyloxy, C1-6-acyl Alkenyl, C-6-Alkoxy,

C-C-alkyl, C-C-alkylcarboxamide, C-C-alkynyl, C-C-alkylsulfonamide, C-C-alkylsulfinyl, C-C-alkylsulfonyl, C-C-alkylthio, C-C-alkylureyl, amino, C -C 6 -alkylamino, C 6 -C 6 -dialkylamino, carbo-C 6 -C 6 -alkyloxy, carboxamide, carboxy, cyano, C 3 -cycloalkyl, C 6 -C 6 -dialkylcarboxamide, halogen, C 6 -haloalkyl, C 1 -6 - haloalkyl, Ci-6-haloalkylsulfinyl, Ci-6-haloalkylsulfonyl, Ci-6-haloalkylthio, hydroxyl, thiol and nitro.

Some embodiments of the present invention relate to compounds wherein Ki is phenyl or naphthyl, each of which is optionally substituted with Ka", Vo, Ni, Bi2, Wiz, Via, and Ki5, each of which is independently selected from the group consisting of Ci- C-acyl, C-C-6-Alkoxy, C-C-Alkyl, C-C-Alkylsulfonyl, Amino, C-C-Alkylamino, C-C-C-Dialkylamino, C-C-Alkylimino, Carbo-Ci-C-Alkoxy, Carboxamide ...

Vi, Vi», Viz, Via and Ki5, together with the atoms to which they are attached, form a C5-cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an E atom; and wherein C 1-6 alkyl, C 1-6 alkylimino, and heterocycle are each optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 acyl, C 1-6 alkoxy, C 1-6 alkyl, C---alkylsulfonyl, amino, C-c-alkylamino, Cg-c-dialkylamino,

carboxamide, cyano, C3-7-cycloalkyl, halogen, C1-6-haloalkyl, C1-6-haloalkyl and hydroxyl.

Some embodiments of the present invention relate to compounds in which Ki is phenyl optionally substituted with Ka, Bo, Vi, Bi2, and Kis, each of which is independently selected from the group consisting of C1-acyl, C1-6-Alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, amino, C1-6-alkylamino, C2-6-dialkylamino, C1-6-alkylimino, carbo-C1-6- alkoxy, carboxamide, carboxy, cyano, C3--cycloalkyl , halogen, Ci-e-halogenalkoxy, Ci-6-haloalkyl, heterocycle, hydroxyl, nitro and phenyl, or two adjacent substituents Co», Vo, Vy, Vy» and Kis, together with the atoms to which they are attached, form CzU7- a cycloalkyl group or a heterocyclic group, each of which is optionally substituted with an E atom; and wherein C 1-6 alkyl, C 1-6 alkylimino, and heterocycle are each optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 acyl, C 1-6 alkoxy, C 1-6 alkyl, C1-6-alkylsulfonyl, amino, C1-6-alkylamino, C1-6-dialkylamino, carboxamide, cyano, C3-7-cycloalkyl, halogen, C1-6-haloalkyl, C6-6-haloalkyl, and hydroxyl.

Some embodiments of the present invention relate to compounds wherein Ki is phenyl or naphthyl, each of which is optionally substituted with Ka", Vo, Ni, Bi2, Wiz, Via, and Ki5, each of which is independently selected from the group consisting of Ci- -acyl, C1-6-alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, C1-6-dialkylamino, C1-6-alkylimino, cyano, halogen, C1-6-haloalkyl, C1-6-haloalkyl , heterocycle, hydroxyl, nitro and phenyl, or two adjacent substituents K», Vio, Ni, HBi2, Viz, Ni and Viz, together with the atoms to which they are attached, form

C5-7-cycloalkyl group or heterocyclic group, each of which is optionally substituted by an EC atom; and wherein is C1-6 alkyl, C1-6 alkylimino and heterocycle, each optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6 alkyl, amino, C1-6 alkylamino, C1- β-dialkylamino and hydroxyl.

Some embodiments of the present invention relate to compounds wherein Ki is phenyl, optionally substituted with Ka, Bo, Bi, Bi2, and Kis, each of which is independently selected from the group consisting of C1-6-acyl, C1-6-Alkoxy or two adjacent substituents Ka», Vo,

АВчи, Ви2 and Киз, together with the atoms to which they are attached, form a C5--cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an E atom; and where indicated is C1-6-alkyl, C1-6-alkylimino and heterocycle, each optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6-alkyl, amino, C1-6-alkylamino, C1- β-dialkylamino and hydroxyl.

Some embodiments of the present invention relate to compounds wherein Ki is phenyl or naphthyl, optionally substituted with Ka, Ni, Ni, Bi2, Wiz, Na, and Ki5, each independently selected from the group consisting of -C(O) CH3, -OCH»z, -CH3, -"CH(CH3)", -CH(OH)CH", -M(CH3)", (2-dimethylaminoethyl)methylamino (ie, -M(CH3)CHNaCnoM(CH3 )2gI, 0 (Z-dimethylaminopropylmethylamino (i.e., M(CH3)CHNaCnNo.CHnM(CH3)gI, CsC-

C(-MONISN", cyano, -E, -SI, -Vg, -OSEz, -SEz, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro and phenyl .

Some embodiments of the present invention relate to compounds in which Ki is phenyl optionally substituted with Ka", Vio, Vi, Vig, Wiz, and K1i4, each of which is independently selected from the group consisting of -C(O)CH", -

ОоСН3, -СН3, -СН(СН3)», -СН(ОНИ)СН», -М(СнН3)», (2-dimethylaminoethyl)methylamino (i.e.,

M(CH3)СНаСноМ(СН3)г|

C(-MONISN", cyano, -E, -SI, -Vg, -OSEz, -SEz, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro and phenyl .

Some embodiments of the present invention relate to compounds in which Ki is phenyl or naphthyl, optionally substituted with Ka", No, Vi, Bi2, Wiz, Na and Ki5, each of which is independently selected from the group consisting of -OSN", - SNvz, cyano, -P, -SI, -Vg, -OSE: and -SEz.

Some embodiments of the present invention relate to compounds in which Ki is phenyl, optionally substituted with Ka", No, Vy, Bi2 and Kis, each of which is independently selected from the group consisting of -OSH»z, -CHZ, cyano, - E, -SI, -Vg, -OSE:z and -SEz.

Some embodiments of the present invention relate to compounds in which Ki is phenyl and which may be represented by the following formula:

Ka in; Ve Ka o

In kh n Zh ssh SU

And in Kos B; in Az Vo 7 where each variable in the above formula has the values given above and below in this description. In some variants of the implementation of this invention KE"; and Kz both stand for -H, O stands for bond, and X stands for 0.

Some embodiments of the present invention relate to compounds in which Ki is phenyl and which can be represented by the formula (Ia) below:

Re

Ex Kv X ke and XX -8a Vo

M M M c

Az t "vo Ki k i (Iz) 12 where the substituents are Ke-Vis, each independently selected from the group consisting of H, C-c-acyl, C-e-acyloxy, C-1-6- alkoxy, C-c- alkyl, C1-6-alkylcarboxamide, C1-6-alkylsulfonamide, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl,

C-C-alkylthio, amino, C-C-alkylamino, C-C-dialkylamino, carbo-Ci-C-alkoxy, carboxamide, carboxy, cyano, halogen, C-C-haloalkyl, C-6C-haloalkyl, hydroxyl, nitro and phenyl, or two adjacent substituents together with the phenyl group form a C-7-cycloalkyl group, which optionally contains 1-2 oxygen atoms; and wherein each of the C 1-6 alkyl and phenyl groups may be optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkyl, amino, cyano, halogen, C- ε-haloalkyl, C1-6-haloalkyl, hydroxyl and nitro.

In some embodiments of the present invention, Ki is phenyl, optionally substituted with Ke-BNis substituents independently selected from the group consisting of C1-6-acyl, C1-6-alkyl, C1-6-alkyl, cyano, halogen, C1-6 ε-haloalkyl, C1-6-haloalkyl, nitro and phenyl; wherein said phenyl may be optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkyl, cyano, halogen, C 1-6 -haloalkyl, C 1-6 -haloalkyl, and nitro .

In some embodiments of the present invention, Ki is phenyl, optionally substituted with Ke-BNis substituents independently selected from the group consisting of C1-6-acyl, C1-6-alkyl, C1-6-alkyl, cyano, halogen, C1-6 is-haloalkyl, C-6-haloalkyl, nitro and phenyl.

In some embodiments of the present invention, Ki is phenyl, optionally substituted with Ke-Wiz substituents independently selected from the group consisting of -C(O)CH3, -C(O)CHNegCHnz, -C(O)CH(CH533)" , - (Сн. Ннсн», -Ф«(О)СнНгСНн(СНЗз)»2, -ОСН»з, -ОСНегсСН»з, -ОСН(СНЗз)26, -ОСН»СНегсН», -ОСН.СН( СНЗзи), -СН»в, -

СносНН», -СН(СН3)», -«СНаСНесСН», -«СН-СН(СН3)», -«СНаСНосСНоснН», cyano, E, SI, Vg, I, -OSEz, -OSNE», -OSEN» .

In some embodiments of the present invention, Ki is phenyl optionally substituted with K»e-Niz substituents, each of which is independently selected from the group consisting of -C(O)CH3, -OCH»z, -CHnz, -cn(CH3 )", -"СН(ОН)сСН", -М(СнНвз)", (2-dimethylaminoethyl)methylamino, (3-dimethylaminopropyl)methylamino, -

C(-MONISN", cyano, -E, -SI, -Vg, -OSEz, -SEz, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro and phenyl .

In some embodiments of the present invention, Ki is phenyl, optionally substituted with Ka, No, B,

Bi" and Keys, each of which is independently selected from the group consisting of -С(О)СН3, -"ОСН", -СНвз, cyano, -Е, -СИ, -Вг, -

OSE;», -SEz, nitro and phenyl.

Some embodiments of the present invention relate to compounds wherein Ki is naphthyl, optionally substituted with K»e, No, Ni, HBi2, Wiz, Bi4, and Ki5, independently selected from the group consisting of Ci-C-acyl, Ci1-6 - acyloxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6-alkylsulfonamide, C6-6-alkylsulfinyl, C1-6- alkylsulfonyl, C6-6-alkylthio, amino, C6-6- alkylamino, C1-6-dialkylamino, carbo-Ci-- alkoxy, carboxamide, carboxy, cyano, halogen, C1-6-haloalkyl, C1-6-haloalkyl, hydroxyl and nitro; and wherein said C 1 -C 6 -alkyl may be optionally substituted with 1-5 substituents independently selected from the group consisting of C 1 -C 6 -Alkoxy, C 1 -C 6 -Alkyl, amino, cyano, halogen, C 1 -C 6 -haloalkyl, Ci-6-haloalkyl, hydroxyl and nitro.

In some embodiments of the present invention, Ki is naphthyl, optionally substituted with Ka», Vo,

Vi, Vi", Wiz, Via and Ki5, independently selected from the group consisting of C1-6-acyl, C1-6-alkyl, C1-6-alkyl, cyano, halogen, C1-6-halo-alkyl, C1-6- haloalkyl and nitro.

In some embodiments of the present invention, Ki is naphthyl, optionally substituted with Ka», Vo,

Vi, Vi», Wiz, Vij and Ki5, independently selected from the group consisting of -С(О)СН3, -С(О)СНаСН3, -ФС(О)СН(СН С)», - (Сн. Ннсн» . in, -

СноснН»з, -СН(СНЗз)», -«СНаСНосСН»з, -«СНаСН(СНЗз)», -«СНаСнНосSN»есSN», cyano, -Е, -СИ, -ВИ, -И. -OSEz, -OSNE,», -

OSEN"e, -OSE2SE", -OSNeSE with, -SEz, "SNE", -"SEN", -"SE"SEz, -"SNeSE: and nitro.

In some embodiments of the present invention, Ki is naphthyl, optionally substituted with Ka», Vo,

Vi, Wi», Wiz, Via and Ki5, independently selected from the group consisting of -С(О)СНвз, -ОСН», -СНвз, cyano, -Е, -СИ, -Вг, -

OSE;», -SEz and nitro.

Some embodiments of the present invention relate to compounds in which Ki is heteroaryl, optionally substituted with Ka, Vo, Vit, Vi, and Kis, each of which is independently selected from the group consisting of C1-6-acyl, C-ve- Alkoxy, C1-6-alkyl, amino, C1-6-alkylamino, C1-6-dialkylamino, C1-6-alkylimino, cyano, halogen, C1-6- haloalkoxy, C1-6-haloalkyl, heterocycle, hydroxyl, nitro and phenyl, or two adjacent substituents K», Vo,

Vii, Bi2, Viz and Ki4, together with the atoms to which they are attached, form a Cvz-7-cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an E atom; and where indicated is C1-6-alkyl, C1-6-alkylimino and heterocycle, each optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6-alkyl, amino, C1-6-alkylamino, C1- β-dialkylamino and hydroxyl.

Some embodiments of the present invention relate to compounds wherein Ki is heteroaryl, optionally substituted with Ka, Ni, B, B, and K, each independently selected from the group consisting of -

С(О)СНзИ, -ОСНзи, -СНз, -СН(СН3)», -СН(ОН)СН3, -М(СН3)», (2-dimethylaminoethyl)methylamino, (3-dimethylaminopropyl)umethylamino, -С( -MON)CHz, cyano, -P, -SI, -VI, -OSEz, -SEz, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro and phenyl.

Some embodiments of the present invention relate to compounds wherein Ki is heteroaryl, optionally substituted with Ka, Ni, B, B, and K, each independently selected from the group consisting of -

Osn", -CH", cyano, -E, -SI, -Hg, -OSE:z and -SEz.

Some embodiments of the present invention relate to compounds wherein Ki is heteroaryl, optionally substituted with Ka, Vo, Vit, Vi, and Kis, each of which is independently selected from the group consisting of C1-6-acyl, C1-6-acyloxy, C-salkoxy, C-6-alkyl, C-6-alkylcarboxamide, C-6-alkylsulfonamide, C1-6-alkylsulfinyl, C6-6-alkylsulfonyl, C6-6-alkylthio, amino, C6-6-alkylamino, C6-6 -dialkylamino, carbo-C1-6- alkoxy, carboxamide, carboxy, cyano, halogen, Ci-6e-halogenalkoxy, Ci-6e-haloalkyl, hydroxyl, nitro and phenyl, or two adjacent Ca», No, Ni, Vi» Viz and K1" together with the atoms to which they are attached form a C5-7 cycloalkyl group or a heterocyclic group; and wherein said C1-6 alkyl and phenyl groups may be optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6 alkoxy, C1-6 alkyl, amino, cyano, halogen, C6 -haloalkyl, C-6-haloalkyl, hydroxyl and nitro.

In some embodiments of the present invention, Ki is heteroaryl, optionally substituted with Co,

Vo, Wit, Wis and Keys, each independently selected from the group consisting of C1-6-acyl, C1-6-alkyl, C1-6-alkyl, cyano, halogen, C1-6-haloalkyl, C1-6-haloalkyl , nitro and phenyl; and wherein said phenyl may be optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkyl, cyano, halogen, C 1-6 -haloalkoxy, C 1-6 -haloalkyl and nitro

In some embodiments of the present invention, Ki is heteroaryl, optionally substituted with Co,

Vo, Wit, Wiz, and Keys, each independently selected from the group consisting of C1-6-acyl, C1-6-alkoxy, C1-6-alkyl, cyano, halogen, C1-6-haloalkoxy, C1-6- haloalkyl, nitro and phenyl.

In some embodiments of the present invention, Ki is heteroaryl, optionally substituted with Co,

Acho, Ach, Bi2 and Kis, each of which is independently selected from the group consisting of -С(О)СН3, -С(О)СНоСН», - с(ОсСн(СН3), -ФС(О0)СНаСНасСН:, - С(О)СНгСНн(СН3)", -ОСНзи, -ОСНоСН3, -ОСН(СН3)г., -ОСН.СНоСнН», -

Oosnesn(СнНЗ3)», -СН3, -«СНаСН3, -СН(СН3)2, -«СНаСНоСН», -СНАСН(СНЗ3)»2, -СНаСНоСНеснН 5», cyano, -Р, -СИ, -ВГ, - And, -OSEz, -OSNE", -OSEN", -OSE2SE", -OSNoSE with, -SEz, "SNE", -"SEN", -SE»SEz, -SNoSE", nitro and phenyl.

In some embodiments of the present invention, Ki is heteroaryl, optionally substituted with Co,

Who, Whit, You?" and Keys, each of which is independently selected from the group consisting of -С(О)СНвз, -ОСН»з, -СН»вз, cyano, -Е, -

SI, -Vg, -OSEz, -SEz, nitro and phenyl. In some embodiments of the present invention, Ki is heteroaryl, optionally substituted with Ka", Vo, Ni, Vi", and Kis independently selected from the group consisting of H, -C(O)CH", -

OSN», -CH», cyano, -E, -SI, -Vg, -OSEz», -SEz, nitro and phenyl.

In some embodiments of the present invention, Ki is a heteroaryl containing 5 atoms in an aromatic ring, examples of which are represented by the following formulas:

TABLE 2 ge ge Ge Se (R o v m" s Mn fa) . , nn , z 7 - wn nene nn-y

S lo b Ko yan ko

Mr, my m-

OM , MeV , Mu MH , Mi M , rest 1 z , where the 5-membered heteroaryl is attached at any available position in the ring, for example, the imidazolyl ring can be attached to one of the nitrogen atoms of the ring (that is, imidazole-1 -yl group) or one of the carbon atoms of the ring (ie means imidazol-2-yl, imidazol-4-yl or imidazol-5-yl group).

In some embodiments of the present invention, Ki is a b-membered heteroaryl, for example, a 6-membered heteroaryl shown in Table 3:

TABLE 3 sr is is is I

I y, - ne na nn cy a 1 15, -y , ES , M i "ki z where the heteroaryl group is attached to any ring carbon atom. In some embodiments of the implementation of this invention, Ki is selected from the group including pyridinyl, pyridazinyl , pyrimidinyl, and pyrazinyl In some embodiments of the present invention, Ki is pyridinyl.

In some embodiments of the present invention, Ki is heteroaryl, such as, but not limited to, the groups shown in Tables 2 and 3, which are optionally substituted with 1-3 substituents selected from the group consisting of Ci--acyl, Ci- E-acyloxy, C1-6-alkenyl, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl , C-v-alkylthio,

C-C-alkylureyl, amino, C-C-alkylamino, C-C-dialkylamino, carbo-C-C-Alkoxy, carboxamide, carboxy, cyano,

C3-7-cycloalkyl, C1-6-dialkylcarboxamide, C1-6-dialkylsulfonamide, halogen, C1-6-haloalkyl, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C6-haloalkylthio, hydroxyl, thiol, nitro, phenoxy and phenyl; and wherein each of said C2-6-alkenyl, C1-6-alkyl, C2-6-alkynyl and phenyl groups may be optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6-acyl,

Cb-acyloxy, Cb-alkenyl, Cb-alkoxy, Cb-alkyl, Cb-alkylcarboxamide, Cb-alkynyl, Cb-alkylsulfonamide, Cb-alkylsulfinyl, Cb -alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C1-6-alkylamino, C1-6-dialkylamino, carbo-C1--alkyl, carboxamide, carboxy, cyano, C3--cycloalkyl, C3-8 - dialkylcarboxamide, halogen, C1-6-haloalkyl, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C1-6-haloalkylthio, hydroxyl, thiol and nitro.

Some embodiments of the present invention relate to compounds in which Eg 2 is H or C 1-6 alkyl.

Some embodiments of the present invention relate to compounds in which Co is C 1-6 alkyl. In some embodiments of the invention, K2 is selected from the group consisting of -CH3, -CH»CH3, -"CH(CH3)2", -"CHNaSNeCnH 5, -

СсНЖсСнН(СНЗз)» and -СНаСНосSNеоснН:». In some embodiments of the invention, Co means -CH3 or -CH(CH33)".

Some variants of the implementation of this invention can be represented by the following formulas (IB) and (Is), respectively:

Ve Ve

Vk v

Wa x Az x y Moch, Y MO,

NN on, in; Wed MM hijacked, Ve ns av) | by , where each variable in formulas (IB) and (Ic) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds in which Kg is H.

It should be understood that in the case when EK" means H, tautomers are possible. It is well known and should be understood that pyrazole can exist in various tautomeric forms. The two possible tautomeric forms are shown below:

Java Java

Ne Ke kh n Re Ne kh n-k nn, - kun, - tk t v Ve Me Wu ta t V y ag Ya

In addition, it should be understood that the tautomeric forms have appropriate nomenclature names for each given tautomer, for example, formula (4) and formula (4) can be represented by the common chemical names 1H-pyrazol-3-yl and 2H-pyrazol-3-yl , respectively. Thus, this invention includes all tautomeric forms and various nomenclatural names.

Some embodiments of the present invention relate to compounds in which Kg is Cg-cs-alkenyl. In some embodiments of the invention, K" means -"CHg2SNASN".

Certain embodiments of the present invention relate to compounds in which Kg is Cg-6-alkynyl.

Some embodiments of the present invention relate to compounds in which Co is C3-7-cycloalkyl. In some embodiments of the invention, Kg is cyclopropyl.

Some embodiments of the present invention relate to compounds in which Kz is selected from the group consisting of

H, C1-6-alkenyl, C1-6-alkyl, C1-6-alkylcarboxamide, C2-6-alkynyl, carbo-C16-alkoxy, carboxamide, carboxy, cyano, C3-7-cycloalkyl, halogen, heteroaryl and phenyl; and wherein each of said C1-6 alkenyl, C1-6 alkyl, C6-6 alkynyl, heteroaryl and phenyl groups may be optionally substituted with 1-5 substituents independently selected from the group consisting of C1-6 alkylamino .

In some embodiments of the present invention, Kz is selected from the group consisting of H, C1-6-alkenyl, C1-6-alkyl, C1-6-alkynyl, carbo-Ci-6-alkoxy, carboxy, cyano, C3-7-- cycloalkyl, halogen, heteroaryl and phenyl; and wherein each of said Cg-c-alkenyl, Cg-c-alkyl, Cg-c-alkynyl and phenyl groups may be optionally substituted with 1-5 substituents independently selected from the group consisting of Cg-c-dialkylamino, Cg -is-alkenyl, C1-4- alkoxy, C2-c-alkynyl, halogen, C1-4-halogenalkoxy and hydroxyl.

In some embodiments of the present invention, Kz is selected from the group consisting of Н, -СН-СнН», -СНВ, -

СНагсСН3, -СН(СН3)», -СНаСНосСН:з, -СНоСНн(СН3)», -СНагСНа.СН»сСН:И, -ОСН, -К(О0ОСН3, -С(О0ОСНоСН3), carboxy, cyano, cyclopropyl, E .

C-methoxyphenyl, 4-methoxyphenyl, -СНА-CH-С-CH, 4-fluorophenyl, 4-trifluoromethoxyphenyl, -CH»2OH and - snsnon.

Some embodiments of the present invention relate to compounds in which Ez is H or halogen.

In some embodiments of the present invention, Kz means H, E, SI, or HG.

Some embodiments of the present invention relate to compounds of formula (Ie) below:

Kv she Her ih! to Utah

In ke

I

Che) with where each variable in the formula (Ie) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds of formula (I) below:

va in Re x ke

M what you and 1 ki Mes B, Re 0) where each variable in the formula (Ii) has the values given above and below in this description.

Some variants of implementation of this invention relate to compounds of formula (Id) given below:

Not in

M. a

GO Hn I

H o

IN; ke

E av) , where each variable in the formula (Id) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds of formula (iii) below:

Kva o Rv t H

M. a

WHAT in i'm in

Kk V ni E t Va av) , where each variable in formula (I) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds of formula (iii) below:

Not with co x

M u u v,

Kk; a t sp (5) where each variable in formula (II) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds of the formula (HER) below:

Kva ve Kvy " AH m o

Ka) yuya fe Kk ti s 7 Ka a) where each variable in formula (I) has the values given above and below in this description.

Some variants of implementation of this invention relate to compounds of the formula (IC) given below: ve e7 x

M

GO a vk; y tk B (ik) , where each variable in the formula (IK) has the values given above and below in this description.

Some embodiments of this invention relate to compounds of the formula (IC) below:

you

Ve Ne t X that Cya, es tk vv t be (pe) , where each variable in the formula (IC) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds in which Ka is selected from the group consisting of

H, C-C-alkyl or C-C-haloalkyl.

In some embodiments of the present invention, Ka is selected from the group consisting of H, -CH3, -CHNoCHNuv, -

СсНн(СнНз)», -СНаСНосСН», -СНСН(СНвз)»2, -СНаСНагСНесСН», -СЕз, -СНЕ», «СЕН», -СР»СЕ:з and -СНоСЕ з.

In some embodiments of the present invention, the CA is selected from the group consisting of H or -SEz.

Some variants of implementation of this invention can be represented by the following formulas (It) and (Ip):

M. M re jur

IN; in B? vv

Ee Ezs Vz "ash) , (c) , where each variable in the formulas (It) and (Ip) has the values given above and below in this description.

Some variants of implementation of this invention can be represented by the following formulas (Io) and (0:

Nva va in Re Kv" x in Re Nv 2 2

WHAT on, KO over,

Weight Wu Vv Weight ku Ve

Rz zo v

Ов) and ио, where each variable in the formulas (Іs) and (Іо) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds in which KE5 is selected from the group consisting of

C-C-Alkoxy, C-C-Alkylthio, amino, C-C-Alkylamino, C-C-C-Dialkylamino, halogen, C-C-Halo-Alkoxy and hydroxyl, where the specified C-C-Alkoxy group may be optionally substituted 1-5 substituents independently selected from the group consisting of amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, amino, carbo-C 1 -alkyloxy, carboxamide, carboxy, cyano, halogen and phenyl, and where the amino group and phenyl, each optionally substituted with 1 to 5 additional substituents selected from the group consisting of halogen and carbo-Ci-6-alkyl.

Some embodiments of the present invention relate to compounds in which K5 is C 1-6 alkoxy or hydroxyl, where the specified C 1-6 alkoxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-4 alkoxy . haloalkyl sulfinyl, C-4-haloalkylsulfonyl, C-4-haloalkylthio, hydroxyl and phenyl, and where said phenyl is optionally substituted with 1-5 halogen atoms.

Some embodiments of the present invention relate to compounds in which H5 is selected from the group consisting of

C 1-6 -Alkoxy, C 1-6 -Halo-Alkoxy and Hydroxyl, where the indicated C 1-6-Alkoxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of amino, C 1-6 -dialkylamino, carboxy and phenyl , and where amino and phenyl are indicated, each optionally substituted with 1 to 5 additional substituents selected from the group consisting of halogen and carbo-Ci-6-alkyl.

In some embodiments of the present invention, K5 means C1-C6-Alkoxy or hydroxyl, where the specified C1-C6-Alkoxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of C1-C4-Alkoxy, C1-C6 -alkylamino, C1-6-dialkylamino, amino, C1-4-halogenalkoxy, hydroxyl and phenyl, and where the specified phenyl is optionally substituted with 1-5 halogen atoms.

Some embodiments of the present invention relate to compounds in which E5 is selected from the group consisting of -OSH3, -OSNoCH3, -OSH(CH3)", -OCE3, hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy (ie, - OSNa.CHNoM(CH3)g|, 3-dimethylaminopropoxy (i.e., -OSH».CHNaCH»M(CH3)hy, carboxymethoxy I(hobto, -bOsnNesoPhony and 2-tert-butoxycarbonylaminoethoxy Ihobto, -

OoSnH.CH.MnNOe(OyuC(CH5Zi)zi.

In some embodiments of the present invention, K5 is selected from the group consisting of -ОСН3, -ОСНеСНв, -

ОосНн(СНЗз)2, -"ОСН".СНосСН», -ОСНоСН(СнНз)», hydroxyl, -ОСН.СНно, -ОСНХСНngОоснН», -ОСНасНнгОосСНесН 5, осн: nosn(СнНЗз)г, -ОСНсСнНгосСнНснесН», -ОСнНнгосНнесН» (SNZz)", -OSNaSNoMN", -"OSNaSNoMNe NV, -

OoSNn.SNnaM(SNz)», -OSNaSN»OsSE»z, -OSNa.SnNgOSNne», -OSNaSNgOSEnN», -OSNeSvN5, -OSNaSNeSvN5, -

OSNegSeNv-ortho-Si, -OSNeSvH5-meta-SiI and -OSNeagSeNe-para-SI.

In some embodiments of the present invention, K5 is selected from the group consisting of -ОСН3, -ОСНеСНв, -

ОоСН(СНЗ)", hydroxyl, -ОСНа.СН»М(СН3)", -"ОСНоСеНв5, -"ОСНаСНеСвнв and -"ОСНоСеНв-para-сСИ.

In some variants of the implementation of this invention, K5 means -OSN".

In some embodiments of the present invention, K is selected from the group consisting of H, C1-C6-Alkoxy, carbo-C1-C6-Alkoxy, carboxamide, carboxy, cyano, halogen, and hydroxyl.

In some embodiments of the present invention, Kv means H.

Some embodiments of the present invention relate to compounds in which Nva, Nev, and Kvs are each independently selected from the group consisting of H, C1-6-alkyl, C1-6-alkyl, amino, C1-6-alkylamino, C1-6- dialkylamino, cyano, halogen, C1-6-haloalkyl, C1-6-haloalkyl, hydroxyl and nitro.

Some embodiments of the present invention relate to compounds in which Hva, Nev and Kvs are each independently selected from the group consisting of H, -OSH3, -CH3, -M(CH3)", cyano, -E, -CI, -Hg, -OSE", hydroxyl and nitro.

Some embodiments of the present invention relate to compounds in which Hva, Nev and Kvs are each independently selected from the group consisting of H, C1-C6-Alkoxy, carbo-C1-C6-Alkoxy, carboxamide, carboxy, cyano, halogen and hydroxyl.

Some embodiments of the present invention relate to compounds in which Vva, Ne, and Kes are all H.

Some variants of the implementation of this invention relate to compounds in which K5 stands for C1-C-Alkoxy, and Bva, Ver and

Ves all mean N.

In some variants of the implementation of this invention, K5 means -OSN".

Some embodiments of the present invention relate to compounds of formula (II) below:

BUT, that i,m ms od,

M and I 1

X 5 Ve t (Ir) ; where each variable in formula (Ir) has the values given above and below in this description. In some embodiments of the invention, the compounds of the present invention have the formula (II) and OO is a bond.

Some variants of implementation of this invention relate to compounds of formula (Id) given below:

Java

NSO. Rv

Roh

M Z o o te

Kv VR Kv z pa) z where each variable in the formula (Id) has the values given above and below in this description. In some embodiments, the compounds of the present invention have formula (Id) and O is a bond.

Some embodiments of the present invention relate to compounds in which K7 is H or C1-6 alkyl.

In some embodiments of the present invention, K7 is selected from the group consisting of H, -CH3, -CHNoCHn, -

СсНн(СнНз)", -СНаСНосСН», -"СНСН(СН3)» and -СНаСНоСНосСнН».

In some embodiments of the present invention, K7 means H.

Some embodiments of the present invention relate to compounds in which Kz is H or C 1-6 alkyl.

In some embodiments of the present invention, Kz is selected from the group consisting of H, -CH3, -CHNoCH3, -

СсНн(СнНз)", -СНаСНосСН», -"СНСН(СН3)» and -СНаСНоСНосСнН».

In some embodiments of the present invention, Kz means H.

Some embodiments of the present invention relate to compounds in which both EC"; and Kz mean N.

Some variants of the implementation of this invention relate to the compounds of the formula (II) given below: where each variable in the formula (II) has the values given above and below in this description.

Some variants of the implementation of this invention relate to the compounds of formula (I5) given below:

o Av t h n Z a ie Z

KO ud

In with where each variable in formula (Iz) has the values given above and below in this description.

Some embodiments of the present invention relate to compounds in which X is O (ie, oxygen).

Some embodiments of the present invention relate to compounds in which X is 5 (i.e., sulfur).

Some embodiments of the present invention relate to compounds in which OO means C1-3-alkylene, optionally substituted with C1-3-alkyl, C1-3-haloalkyl, halogen and oxo.

Some embodiments of the present invention relate to compounds in which OO is C1-3-alkylene optionally substituted with an oxo group. As used herein, an oxo group means an oxygen attached to a double bond. In some embodiments of the present invention, O is -C(O)- (ie, carbonyl).

In some embodiments of the present invention, O represents -СНе-.

Some embodiments of the present invention relate to compounds in which O is a bond.

Some variants of implementation of this invention can be represented by the following formula (I): 7 x

M Zh v

Hey

M mb"

M / ! and Va

Re Kz i a , where each variable in formula (I) has the values given above and below in this description.

Some variants of the implementation of this invention can be represented by the following formula (Im):

Square with Square

X mia X te

Q) i

Ks Tu, Kv 7

IN

(yiv) t where each variable in formula (I) has the values given above and below in this description.

In some embodiments of the present invention, Ki is phenyl and may be represented by the formula (Im) below:

Not in t x You or in y Kg

VC; Kv z z ah)

KZ where each variable in the formula (Im) has the values given above and below in this description. In some embodiments of the invention, both K7 and Kv are H. In some embodiments of the invention, X is OO (ie, oxygen).

In some embodiments of the present invention, Ki is phenyl and may be represented by the following formula(s):

in Ne Ko

В и в х Ne ky Ж that km Kz

Kaye V; in Ko - (t) , where each variable in the formula (m/) has the values given above and below in this description. In some embodiments of the invention, both K7 and Kv are H. In some embodiments of the invention, X is O (ie, oxygen).

Some variants of implementation of this invention relate to compounds of the formula (Pa):

M i h mod, and |!

Company B; in

Kk with (Pa) in de

Bi is phenyl or naphthyl optionally substituted with Ka", No, Vit, Bi2, Wiz, Na and Ki5, EACH OF WHICH are independently selected from the group consisting of C1-6-acyl, C1-6-Alkoxy, C1-6 -alkyl, amino, C-C-alkylamino, C-C-dialkylamino, C-C-alkylimino, cyano, halogen, C-C-haloalkyl, C-C-haloalkyl, heterocycle, hydroxyl, nitro and phenyl, or two adjacent substituents K»e, Vo, Vii, Vi2, Viz, Ni4 and Ki5, together with the atoms to which they are attached, form a Sv5-7-cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an E atom; and wherein is C1-C alkyl, C1-C alkylimino, and heterocycle, each optionally substituted with 1-5 substituents independently selected from the group consisting of C1-C alkyl, amino, C1-C alkylamino, C2-C -dialkylamino and hydroxyl;

B: means C1-6-alkyl;

Az means H or halogen;

Ba is selected from the group consisting of H, C-C-alkyl and C-C-haloalkyl;

A5 is selected from the group consisting of C1-C6-Alkoxy, C1-C6-Alkoxy, and hydroxyl, where the specified C1-6-Alkoxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of amino, C2- β-dialkylamino, carboxy, and phenyl, and where amino and phenyl are indicated, each is optionally substituted with 1-5 additional substituents selected from the group consisting of halogen and carbo-Ci-v-alkoxy;

Ava, Ne, and Kes are each independently selected from the group consisting of H, C1-6-alkyl, C1-6-alkyl, amino, C1-6-alkylamino, C1-6-dialkylamino, cyano, halogen, C1-6-haloalkyloxy , C1-C-haloalkyl, hydroxyl and nitro;

IN; and Ez both mean H;

X stands for O and o stands for bond.

Some variants of implementation of this invention relate to compounds of the formula (Pa):

Vo pache Re kh n Zh

F / M "My

Reve in the village

WITH

(Sha) in where

Bi is phenyl or naphthyl optionally substituted with Ka», No, Wit, Bi2, Wiz, Na and Ki5, EACH OF WHICH are independently selected from the group consisting of -C(O)CH3, -OSH»3, -CH3, -"CH(CH3)", -CH(OH)cH", -M(CH33)", (2-dimethylaminoethyl)methylamino, (3-dimethylaminopropyl)umethylamino, -C(-MON)CH»3, cyano, - E, -SI, -VI, -OSE", -SEz, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro and phenyl;

Ag means -CH3 or -CH(CH3)";

Az means H, E, SI or Bg;

Ba means -Н or -СЕз;

A5 is selected from the group consisting of -OCH3, -OCNeaCH3, -OCH(CH3)2, -OCE», hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, carboxymethoxy and 2-tert-butoxycarbonylaminoethoxy;

Bva, Nvrb and Kvs, each independently selected from the group consisting of Н, -ОСН»з, -СНз, -М(СНвз)», cyano, -Е, -СИ, -

Vg, -OSE", hydroxyl and nitro;

IN; and Ez both mean H;

Xx stands for O and o stands for connection.

Some variants of implementation of this invention relate to compounds of formula (Ia):

Kv poh Ke h

M yuch a

Rv V Ve with (Pa) , where

B is phenyl, optionally substituted with Ka", N, B1, B1: and Ks, each independently selected from the group consisting of /--C(O)CH"3, -OSH3, -CH3, -CH( СН3», -СН(ОН)СН», -М(СнН3)», (2-dimethylaminoethyl)methylamino, (3-dimethylaminopropyl)umethylamino, -С(-МОН)СН»3, cyano, -Е, -СИ , -VI, -OSE", -SEz, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro and phenyl;

Ag means -CH3 or -CH(CH3)";

Az means -Н, -Е, -СИ or -Вг;

Ba means -Н or -СЕз;

A5 is selected from the group consisting of -OCH3, -OCNeaCH3, -OCH(CH3)2, -OCE», hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, carboxymethoxy and 2-tert-butoxycarbonylaminoethoxy;

Bva, Ne, and Ks are each independently selected from the group consisting of -H, -ОСН3z. -СН3, -М(СН3)», cyano, -Е, -СИ, -Вг, -ОСЕ», hydroxyl and nitro;

IN; and Ez both mean H;

Xx stands for O and o stands for connection.

Some variants of implementation of this invention relate to compounds of the formula (Pa):

Eva Gey

BUT I'm sorry

Kk V wa Va shi (Pa)

B. where

B is phenyl, optionally substituted with Ka", B, B, B, and K, each independently selected from the group consisting of -C(O)CH3, -OSH33, -CH3, -CH(CH3) », -«M(СНвЗ3)», cyano, -Е, -СИ, -ВИ, -ОСЕ»з, -СЕз, hydroxyl and nitro;

Bg2 means -CH3;

Az means -Н, -Е, -СИ or -Вг;

Ba means -H;

A5 is selected from the group consisting of -OCH3, -OCNeaCH3, -OCH(CH3)2, -OCE», hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, carboxymethoxy and 2-tert-butoxycarbonylaminoethoxy;

Vva, Nvrb and Kvs, each means -H;

IN; and Ez both mean -H;

X stands for O; and o stands for connection.

Some embodiments of the present invention include the compounds shown in Table A below:

Table A

M Chemical name mo. 1-I3-44-bromo-2-methyl-2H-pyrazol-3-yl)-1MI 4-methoxyphenyl|-3-(4-!c chlorophenpyl)urea and in 1-I(3-(4-bromo -2-methyl-2H-pyrazole-3-1l)-

I sha fluorophenyl)urea and 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-3 ven 4-methoxyphenyl|-3-(2,4-

My "dichlorophenyl)urea om" 1-I3-(4-orom-2-methyl-2H-pyrazol-3-yl)-4 uv, 4-methoxyphenyl|-3-(4-ni methoxyphenyl)urea

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N. of N

N x x BIB Fumoet nis pra niv : : VM hu 3 Her Y :

And Her Anna and NI t. picture N

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ZHE: r: - Zh kya u tlomesukhocieno 4 H : и SU x : и H : ikh ех х Н gema и : "py iaifitsnrnaikapvhmo. N : : ok Well, let's take a name

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I: and rust zunuyuma vechomknh and

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In addition, compounds of the present invention, such as compounds of formula (I) and related compounds, include all their pharmaceutically acceptable salts, solvates, in particular hydrates.

Compounds of formula (I) according to the present invention can be obtained according to the general synthesis schemes shown in Figs. 17-21 and Figs. 29-33, as well as corresponding synthesis schemes published in the literature, which are used by specialists in this field. Possible reagents and methods of carrying out these reactions will be presented below in the examples. Introduction and removal of protecting groups can be accomplished by methods generally known in the art (see, for example, Ogeepe, T.UM. and Mutsi5,

R.O.M., Rgoiesiipd Sgopr5 ip Ogdapis BZupipeziz, Zga Eaiiop, 1999 (M/Peu)|; incorporated herein by reference in its entirety.

The present invention covers, in addition, diastereomers, as well as optical isomers, in particular mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers, which are a consequence of the structural asymmetry of some compounds of the present invention. The separation of individual isomers and the selective synthesis of individual isomers are carried out by various methods well known to those skilled in the art.

Constitutively active human 5-HTα receptor

For convenience, sequence information relating to the non-endogenous constitutively active 5-

The human NTha receptor and identifiers are presented in Table 4:

Table 4

DNAAR-Z | 5NTa | 27 | ba

ARZ | BNTd | 28 | 65

Indications and methods of prevention and/or treatment

In addition to the previous therapeutic uses of 5-HTα receptor activity modulators disclosed herein, the authors believe that the compounds disclosed herein may be useful in the treatment of various additional diseases and disorders and in alleviating the severity of their symptoms. These include, without limitation, the following: 1. Antithrombotic therapy (5-HTA-mediated platelet aggregation):

Antithrombotic agents are prescribed for a number of conditions. For example, in coronary artery disease, they are used to help prevent myocardial infarction or stroke in patients who are at risk of developing blood clots (including coronary thrombosis).

During a myocardial infarction (heart attack), the heart muscles do not receive a sufficient amount of oxygen-enriched blood due to the blockage of the coronary blood vessels. Antithrombotic agents can reduce heart damage if they are taken during the development of an attack or immediately after it (mainly during the ZOV.).

A transient ischemic attack ("TIA" or "mini-stroke") is a temporary interruption of oxygen supply to the brain due to reduced blood flow through the arteries, usually caused by the formation of an obstructing blood clot. Antithrombotic agents have been shown to effectively prevent transient ischemic attacks.

Angina is a fast-moving and often recurring chest pain, pressure or discomfort caused by insufficient flow of oxygen-enriched blood (ischemia) to some parts of the heart. In patients with angina, antithrombotic therapy can reduce the impact of angina and reduce the risk of myocardial infarction.

A stroke is an event in which the brain does not receive enough oxygenated blood,

usually due to blockage of a blood vessel in the brain caused by a blood clot. In high-risk patients, regular use of antithrombotic agents has been shown to prevent the formation of blood clots that cause a first or second stroke.

Angioplasty is a technique based on the use of a catheter, which is used to open arteries blocked by blood clots. Regardless of whether a stent is used immediately after surgery to keep the artery open, antithrombotic agents can reduce the risk of new blood clots after the surgery(s).

Coronary bypass surgery is a surgical operation in which an artery or vein is taken from any part of the body and implanted into a blocked coronary artery, redirecting blood flow around the blockage through the newly attached vessel. After surgery, antithrombotic drugs can reduce the risk of new blood clots.

Atrial fibrillation is the most common type of irregular heart rhythm experienced by patients (arrhythmias). Atrial fibrillation affects about two million Americans each year. In atrial fibrillation, the atria (the upper chambers of the heart) rapidly fire electrical signals that cause it to quiver instead of contracting normally. The result is an abnormally fast and very irregular heartbeat. Antithrombotic drugs can reduce the risk of blood clots forming in the heart and getting into the brain (embolism), if they are administered after an attack of atrial fibrillation. 5-HTα receptors are expressed by the smooth muscles of blood vessels, and 5-HT secreted by activated platelets causes blood vessels to constrict, as well as activation of additional platelets in the process of clot formation. 5-HThd inverse agonists have been shown to inhibit platelet aggregation and are thus potentially useful in antithrombotic therapy (see

Zaiitiga, K., ei ai., Siip. Sagaiyo!., 2002, Uap. 25 (1): 28-32; and M/isop, N.S. her aI., Tygotr. Recently, 1991, Ber. 2, 66(3): 355-60).

The 5-HTgal inverse agonists disclosed in this description allow to significantly improve blood microcirculation in patients requiring antithrombotic therapy by counteracting vasoconstrictor products produced by aggregating platelets, for example, but not limited to the above symptoms. Thus, in some embodiments of the present invention, methods of reducing platelet aggregation in patients in need thereof are proposed, which include administering to the specified patient a composition containing the inverse agonist 5-HTga, which is disclosed in this description. In other embodiments, the present invention provides methods of treating coronary artery disease, myocardial infarction, transient ischemic attacks, angina pectoris, stroke, atrial fibrillation, or symptoms of any of said disorders in a patient in need of said treatment, comprising administering to said patient a composition containing a reverse agonist 5-HTga, which is disclosed in this description.

In other embodiments, the present invention provides methods of reducing the risk of blood clots in patients undergoing angioplasty or coronary bypass surgery, or in patients suffering from atrial fibrillation, which include administering to said patient a composition containing a 5-HTga inverse agonist, which is disclosed in this description, in those cases where a similar risk arises. 2. Asthma

It has been suggested that 5-HT (5-hydroxytryptamine) will play a role in the pathophysiology of acute asthma

Go Sa;2oia, M. and Maiega, M.O., TIRB5, 2000, 21, 13; and Oye Vieye, u... ei ai., Vyyi5N u. Ripagt., 1998, 124, 857-864).

The compounds of the present invention disclosed herein may be useful in the treatment of asthma and its symptoms.

Thus, in some embodiments of the present invention, methods of treating asthma in a patient in need of the specified treatment are provided, which include administering to the specified patient a composition containing a 5-HTga inverse agonist, which is disclosed in this description. In other embodiments of the present invention, methods of treating an asthma symptom in a patient in need of the specified treatment are provided, which include administering to the specified patient a composition containing a 5-HTga inverse agonist, which is disclosed in this description. 3. Agitation

Agitation is a well-known behavioral syndrome characterized by a range of symptoms including hostility, overexcitement, uncontrolled impulsivity, tension, and incoherence.

Go Sopep-Mapzpeii 9. and Weed, M., (1986), Adiagea Vepamioge ip She EiIidepu. I. A. Sopsershai! Nehemiah U. At.

Segiaig. boss. 24(10): 711-7211.

Agitation often occurs in the elderly and is often associated with dementia, such as dementia caused by Alzheimer's disease, Lewy body dementia, Parkinson's disease, and Huntington's disease, which are degenerative diseases of the nervous system, and diseases that affect the blood vessels, such as stroke, or dementia can develop under the influence of multi-infarct dementia, which is caused by multiple strokes in the brain. Alzheimer's disease is the cause of approximately 50-7095 cases of dementia. Kov5 E., vii ai., (1997), Azzezzipud racego5 oi adyayop ip AI2peiteg5 disease raiepiv myp Sopep-Mapvieii

Adygayop Ipulepiogu. Tne AI2peiteg» Oizease Sooregaime Zschchau. AI2peiteg Oiv. Avvos. Oizoga. 11 (v. 2): 545-

FAILURES

An estimated five percent of people age 65 and older and up to 20 percent of people age 80 and older are affected by dementia; of these people with dementia, almost half experience behavioral disturbances such as agitation, wandering, and outbursts of rage.

Agitational behavior can also be observed in elderly people without cognitive impairment and in people suffering from psychiatric disorders other than dementia.

In private hospitals and other care facilities, agitation is often treated with antipsychotic drugs such as haloperidol. There is increasing evidence that agents that affect 5-HTgda receptors in the brain reduce agitation in patients, including dementia caused by Alzheimer's disease. Kail, I.K. ei ai., U. Siip. Rzuspiayu 1999 Rer., 60(2): 107-115; and

Zgevi, 9.5. her ai., Agoep. Sept. Rzuspianu 2000 Osi., 57(10): 968-976).

Compounds of the present invention disclosed herein may be useful in the treatment of agitation and its symptoms. Thus, in some embodiments of the present invention, methods of treating agitation in a patient in need of the specified treatment are provided, which include administering to the specified patient a composition containing a 5-HTga inverse agonist, which is disclosed in this description. In some embodiments of the present invention, agitation is caused by a psychiatric disorder other than dementia. In some embodiments, the present invention provides methods of treating agitation or its symptoms in a patient suffering from dementia, which include administering to said patient a composition containing a 5-HTgl inverse agonist disclosed herein. In some embodiments of the present invention, dementia is caused by a degenerative disease of the nervous system, such as, but not limited to, Alzheimer's disease, Lewy bodies, Parkinson's disease, Huntington's disease, or dementia caused by diseases that affect blood vessels, including but not limited to them, stroke and multi-infarct dementia. In some embodiments, the present invention provides methods of treating agitation or symptoms thereof in a patient in need of such treatment, wherein the patient is an elderly patient with no evidence of cognitive impairment, comprising administering to said patient a composition comprising a 5-HTα inverse agonist as disclosed in this description. 4. Additional therapy to haloperidol in the treatment of schizophrenia and other disorders

Schizophrenia is a psychopathic disorder of unknown origin, which usually first appears in early youth and is characterized by a number of signs and psychotic symptoms, progression, phase development and deviation from social behavior and a decrease in professional skills to a lower level, compared to the highest previously achieved level. Characteristic psychotic symptoms are thought disorder (fuzziness, discontinuity, incoherence, implausibility and simply delusional disorder and persecutory mania) and mental disorders (loss of association, ideas of fantastic content, incoherence of thoughts to the point of obscurity), as well as disorders of the ability to perceive reality (hallucinations), disorder of emotions (smoothness or inadequacy of emotional reactions), sense of self, intentions and impulses, disorder of interpersonal relations and finally psychomotor disorders (such as catatonic syndrome). Other symptoms are associated with this disorder.

IDiv. Athegasap of the Curtain! and Oiadpowiis Naparooki.

Haloperidol (haldol) is an active antagonist of the Y2 dopamine receptor. It is often prescribed for acute symptoms of schizophrenia and is very effective for positive symptoms of schizophrenia. However, Haldol is not effective in the negative symptoms of schizophrenia and may actually cause negative symptoms as well as cognitive impairment. According to some embodiments of the present invention, the use of a 5-HTγ inverse agonist in addition to galdol has a beneficial effect, including allowing the use of lower doses of galdol without losing its effect on positive symptoms, while reducing or eliminating the effect of galdol on negative symptoms, and also allows you to delay the recurrence of further attacks of schizophrenia in the patient.

Haloperidol is used to treat various behavioral disorders, drug-induced psychosis, reactive psychosis, Gilles de la Tourette syndrome, manic syndrome, psychosis (organic or MOB psychosis), psychotic disorder, psychosis, schizophrenia (acute, chronic, and MO5 schizophrenia). Other uses include the treatment of infantile autism, Huntington's chorea, and nausea and vomiting caused by chemotherapy or chemotherapy antibodies. Administration of the 5-HTgl inverse agonist disclosed herein along with haloperidol also has a beneficial effect in these conditions.

In some embodiments, the present invention provides methods of treating drug-induced conduct disorder, psychosis, reactive psychosis, Gilles de la Tourette syndrome, manic syndrome, psychosis (organic or MOB psychosis), psychotic disorder, psychosis, schizophrenia (acute, chronic and

MOB of schizophrenia), which include the administration of a dopamine O2-receptor antagonist and a 5-HTga inverse agonist disclosed in this description to the specified patient.

In some embodiments, the present invention provides methods of treating drug-induced conduct disorder, psychosis, reactive psychosis, Gilles de la Tourette syndrome, manic syndrome, psychosis (organic or MOB psychosis), psychotic disorder, psychosis, schizophrenia (acute, chronic and

MOB of schizophrenia), which include the administration of haloperidol and the inverse agonist 5-HTga, which is disclosed in this description, to the specified patient.

In some embodiments, the present invention provides methods of treating infantile autism, Huntington's chorea, or nausea and vomiting caused by chemotherapy or chemotherapeutic antibodies, which include administering to said patient a dopamine O2 receptor antagonist and a 5-HTga inverse agonist disclosed herein.

In some embodiments of the present invention, methods of treating infantile autism, Huntington's chorea, or nausea and vomiting caused by chemotherapy or chemotherapeutic antibodies are provided, which include administering to said patient haloperidol and a 5-HTga inverse agonist disclosed herein.

In other embodiments of the present invention, methods of treating schizophrenia in a patient in need of the specified treatment are proposed, which include administering to the specified patient a dopamine 02-receptor antagonist and a 5-HTγ inverse agonist disclosed in this description. An antagonist of the 02-receptor of dopamine is mainly haloperidol.

The introduction of the antagonist of the Y2-receptor of dopamine can be carried out together with the introduction of the inverse agonist 5-HTga, or they can be introduced at different times. Those skilled in the art will be able to readily determine appropriate dosage regimens to most effectively reduce or eliminate the adverse effects of haloperidol. In some embodiments of the present invention, haloperidol and the inverse agonist 5-HTgD are administered as a single dosage form, and in other embodiments of the present invention, they are administered as separate dosage forms.

The present invention further provides methods of alleviating the negative symptoms of schizophrenia caused by the administration of haloperidol to a patient suffering from said schizophrenia, which include administering to said patient a 5-HTga inverse agonist disclosed herein. 5. Sleep disorders

More than half of the adults surveyed (5,895) reported experiencing one or more symptoms of insomnia at least a few nights a week during the past year, according to the National Sleep Foundation's 2002 report, "Ziver Yip Ategis Roi!". In addition, about three people out of ten

(3595) stated that they experienced symptoms of insomnia every night or almost every night.

The normal sleep cycle and sleep structure can be interrupted by various organic causes, as well as under the influence of the surrounding environment. According to the International Classification of Sleep Disorders, more than 80 sleep disorders have been identified. Of these, the compounds of the present invention are effective, for example, for any or more of the following sleep disorders PS5O - Ipsgegpaiopai! Siazviiysayop oi Zieer Oizogaegv5: Oiadpoviis and Sodipd

Mapiai!. Oiadpowiis Siazviysayop 5ieegppd Sottineye, Ategisap Zieer Oizogayegv5 Avzosiayop, 19901:

A. Dysomnias a. Endogenous sleep disorders: psychophysiological insomnia, impaired perception of sleep structure, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement syndrome, restless legs syndrome, and unspecified endogenous sleep disorder. p. Exogenous sleep disorders: sleep disorder caused by poor sleep hygiene, sleep disorder caused by environmental factors, high-altitude insomnia, sleep disorder caused by adaptive reactions, insufficient sleep syndrome, sleep disorder caused by disturbed bedtime routine, associative sleep disorder , nocturnal eating/drinking syndrome, hypnotic sleep disorder, stimulant sleep disorder, alcohol sleep disorder, toxic sleep disorder, and unspecified exogenous sleep disorder. b. Sleep disorders associated with disruption of circadian rhythms: jet lag syndrome (flying syndrome), sleep disorder caused by variable work mode, irregular sleep-wake pattern, delayed sleep phase syndrome, early onset sleep phase syndrome, sleep disorder caused by 24-hour sleep-wake cycle, and an unspecified sleep disorder associated with circadian rhythms.

B. Parasomnias a. Disorders associated with activation: confusion on awakening, sleepwalking and night terrors. p. Disorders of the sleep-wake transition: rhythmic movement disorder, tremors when falling asleep, sleep talking, and night leg cramps.

C. Sleep disorders associated with organic/psychiatric diseases a. Sleep disorders associated with mental illness: psychosis, mood disorders, anxiety disorders, panic disorders, and alcoholism. r. Sleep disorders associated with neurological diseases: degenerative brain diseases, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrographic signs of epileptic seizures in sleep, and sleep-related headaches. b. Sleep disorders associated with other diseases: hypersomnia due to trypanosomiasis, nocturnal myocardial ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, gastric and duodenal ulcers, fibrositis syndrome, osteoarthritis , rheumatoid arthritis, fibromyalgia and post-surgical sleep disorders.

The consequence of sleep loss is not just excessive daytime sleepiness. As reported, chronic insomnia increases the level of stress, anxiety, depression and diseases (Maiiopai Ipziyshev oi Neatsy, Maiopai Neagi, I po, and

Viosa Ipeishshshe, Ipsotpia Rasi5 Zpeei, Osi. 1995). Preliminary evidence suggests that a sleep disorder that leads to significant sleep loss may contribute to increased susceptibility to infections due to immunosuppression, to cardiovascular complications such as hypertension, cardiac arrhythmias, stroke and myocardial infarction, decreased glucose tolerance, increased obesity and metabolic syndrome. The compounds according to the present invention may be useful for the prevention of the indicated complications or the mitigation of their symptoms by improving the quality of sleep.

The most common drug class for most sleep disorders is benzodiazepines, but the benzodiazepine adverse effect profile includes daytime sedation, decreased motor coordination, and cognitive impairment. Moreover, in 1984, at the conference of the National Institute of Health "Sopzepvyv sopiehepse op biIeripd Riy i Ipsotpia" methodical recommendations were developed, in which it is advised not to use sedative hypnotic drugs for more than 4-6 weeks due to fears that arise in connection with drug abuse, development of addiction, abstinence and reversible insomnia. Thus, it would be desirable to have a pharmacological agent for the treatment of insomnia that is more effective and/or has fewer side effects than currently used agents. In addition, benzodiazepines are used to induce sleep, but they do little to maintain sleep, strengthen sleep, and are not effective in the stage of slow-wave sleep. For this reason, there are currently no good treatments for sleep maintenance disorders.

Clinical studies of agents with a similar mechanism of action as the compounds of this invention have shown a significant improvement in objective and subjective parameters of sleep in normal healthy volunteers, as well as in patients suffering from sleep disorders and mood disorders (Zpagrieu A. .. hey ay.,

Ziozh UMame biIeerz ip Nitape: Voie oi 5-HTgaA and 5-HTos Nesrioge. Meigorpaptas!iodu, 1994, Moi. 393(3/4): 467-71; MMpokyg A., egai,, Asshe EPesiv oi Mipagaripe op 5iIeer Sopiipiyu and Zieer Agospiesishge ip Oergezzei Rybepiv:

And Riioi Zschau. boss. Oh Vishy. Reusp., 2000, Moi. 48: 75-78; and poi N.R. ei aI., Zegoiopip-2-Keseriogv and Nytap 5ieer:

Enesi oi ZeIesiime Apiadopivi op EES Romeg 5resiga. Meigorzusporpagtaso!odu, 1999, Moi. 21(3): 455-661).

Certain sleep disorders are sometimes seen in combination with other conditions and thus these conditions can be treated with the compounds of formula (I). For example, but without limitation, patients suffering from mood disorders typically suffer from a sleep disorder that can be treated with the compounds of formula (I). The use of a single pharmacological agent that treats two or more existing or potential conditions, as in the case of the present invention, is more cost-effective, leads to better adherence to the regimen and regimen, and causes fewer side effects than taking two or more agents.

The object of this invention is a therapeutic agent for use in the treatment of sleep disorders. Another object of the present invention is a single therapeutic agent that can be used to treat two or more conditions where one of the conditions is a sleep disorder. The compounds of this invention described herein may be used alone or in combination with a mild sleep-inducing drug (ie, an antihistamine).

Sleep structure:

Sleep includes two physiological states: the stage without rapid eye movement (REM sleep) and the stage of rapid eye movement (REM sleep). MKEM sleep consists of four stages, each characterized by gradually slowing electroencephalogram (EEG) patterns, with slower patterns indicating deeper sleep. The so-called delta phase of sleep, stages C and 4 of MEEM sleep, is the deepest and most refreshing type of sleep. Many patients with sleep disorders are unable to adequately achieve restorative sleep stages C and 4. In clinical terms, the patient's sleep patterns are described as fragmented, which means that the patient spends a lot of time alternating between stages 1 and 2 sleep (half-awake). and wakefulness and only a short time in deep sleep. As used herein, the term "fragmented sleep" means that an individual, such as a patient with a sleep disorder, spends a large portion of sleep in stages 1 and 2

MAEM-sleep. light periods of sleep, from which the individual easily returns to a state of wakefulness with minimal influence of an external stimulus. As a result, the individual undergoes a cycle of frequent episodes of light sleep, interrupted by frequent awakenings during the sleep period. Many sleep disorders are characterized by the fragmented nature of sleep. For example, many elderly patients with sleep complaints have a hard time getting into the stage of deep refreshing sleep (stages 3 and 4 of MEEM sleep) and instead spend much of their sleep in stages 1 and 2 of MKEM sleep.

In contrast to the fragmented nature of sleep, the term "strengthening sleep" means a state in which the number of MKEM-sleep alternations, in particular, stages C and 4, as well as the duration of these alternations increases, and the number and length of wakefulness alternations decreases. As a result, the sleep pattern of a patient with a sleep disorder is strengthened to a sleep state characterized by increased periods of sleep and fewer awakenings during the night, as well as a large amount of time spent in slow-wave sleep (stages C and 4) with fewer oscillations stages 1 and 2 of sleep. As noted herein, the compounds of the present invention are effective in enhancing sleep patterns such that a patient previously experiencing fragmented sleep can achieve restorative delta phase sleep for longer and more sustained periods of time.

As sleep progresses from stage 1 to later stages, heart rate and blood pressure decrease, metabolic rate slows, glucose consumption falls, and muscles relax. With a normal sleep structure, MKEM-sleep makes up to 7595 of the total sleep time; stage 1 is 5-1095 of total sleep time, stage 2 is approximately 45-5095, stage C is approximately 12905, and stage 4 is 13-1595. About 90 minutes after sleep onset, MEEM sleep gives way to the first episode of CEM sleep during the night. KEM-sleep accounts for approximately 2595 of the total sleep time. Unlike MEEM-sleep, VEM-sleep is characterized by an increased frequency of pulse, breathing and blood pressure, as well as other physiological modes similar to those characteristic of an active state of wakefulness. Therefore, KEM sleep is also called "paradoxical sleep". The onset of sleep occurs during MKEM-sleep and takes 10-20 minutes in healthy young people. Four stages of MKEM-sleep together with the phase

VEM sleep consists of one complete cycle, which is repeated as sleep continues, usually from four to five times. The cyclic nature of sleep is regular and reliable; KEM-sleep occurs approximately every 9 Ohv. overnight. However, the first period of CEM sleep is the shortest and often lasts less than 1 min, while later periods of CEM sleep can last up to 40 min. With increasing age, the time between bedtime and sleep onset increases, and the total time spent sleeping at night decreases due to changes in sleep patterns that impair sleep maintenance as well as sleep quality. Both MKEM-sleep (especially stages C and 4) and EEM-sleep are shortened. However, stage 1 MKEM sleep, which is the lightest sleep, increases with age.

As noted herein, the compounds of the present invention are capable of increasing delta sleep energy (see Figure 28). As used herein, the term "delta energy" refers to the duration of EEG activity in the frequency range of 0.5 to 3.5 Hz during MKEEM sleep and is believed to be a measure of deeper, more restorative sleep. Delta energy is hypothesized to be a measure of a theoretical process called process 5, and is thought to be inversely proportional to the amount of sleep an individual experiences during a certain amount of time allotted for sleep. Sleep is controlled by homeostatic mechanisms; therefore, the less a person sleeps, the higher the urge to sleep. It is believed that process 5 is formed during the waking period and is most efficiently discharged during the delta phase of sleep. Delta energy is measured by the process value 5 before the sleep period. The longer a person is awake, the greater the process 5 or sleep drive and thus the greater the delta energy during MEEM sleep. However, individuals with sleep disorders have difficulty achieving and maintaining delta-phase sleep and thus have a large accumulation of process 5 with limited ability to discharge this accumulation during sleep. Preliminary and clinical trials of 5-HTgA inverse agonists have shown that they mimic the effect of a sleep source on delta energy and lead to the prediction that sleep-disordered subjects treated with a 5-HTgA inverse agonist

NTga, will be able to experience a deeper or more refreshing sleep. The same effects were not observed when using means available on the pharmacotherapeutic market. In addition, the means currently on the pharmacotherapeutic market for sleep support have side effects, such as the hangover effect or addiction, which are related to the SABA receptor. Inverse agonists of 5-HTod do not target the SABA receptor, and therefore do not cause the specified side effects.

Subjective and objective definitions of sleep disorders:

There are a number of possibilities to determine whether the onset of sleep worsens or improves, its duration and quality of sleep (in particular, whether sleep is refreshing or not). One of the methods is the subjective determination of the patient, in particular, whether he feels sleepy or rested upon awakening. Other methods include observing one patient after another while he sleeps, in particular, observing how long the patient falls asleep, how many times the patient wakes up during the night, how restless the patient is in his sleep, etc. Another method is the objective determination of sleep stages using polysomnography.

Polysomnography is a method of monitoring a variety of electrophysiological parameters during sleep and usually includes measurements of EEG activity, electroculographic activity and electromyographic activity, as well as other measurements. These results, together with observations, allow us to assess not only the latent state of sleep (the amount of time it takes to fall asleep), but also the integrity of sleep (the overall balance of sleep and wakefulness) and the consolidation of sleep (the percentage of sleep spent in the delta phase or in the restorative sleep phase), which can serve as an indicator of sleep quality.

There are five stages of sleep that can be determined using polysomnography: the stage of sleep with rapid eye movements (REM sleep) and the stage of sleep without rapid eye movements (MEEM sleep) (stages 1, 2, C and 4). Stage 1 MAEM sleep represents the transition from wakefulness to sleep and takes approximately 595 times the time spent in sleep in healthy adults. Stage 2 of MKEM-sleep, which is characterized by specific EEG signals (sleep spindles and K-complexes). takes about 5095 of the time spent in sleep. Stages 3 and 4 of MEEM sleep (collectively also known as slow-wave sleep and delta sleep) are the deepest sleep states and occupy approximately 10-2095 of sleep time. EEM sleep, during which most vivid dreams occur, takes approximately 20-2595 of the total sleep time.

These stages of sleep differ in temporal organization during the night. Stages 3 and 4 of MKEM sleep tend to occur in the first third to midnight, and their duration increases depending on the need for sleep. KEM-sleep occurs cyclically during the night, alternating with MKEM-SLEEP every 80-100 minutes. The duration of FEM-sleep periods increases until the morning. A person's sleep typically changes throughout his life. After some stability with large amounts of slow-wave sleep during childhood and early adolescence, the duration and depth of sleep deteriorates as an adult ages. This disturbance is reflected in increased insomnia and stage 1 sleep and a decrease in stages C and 4 sleep.

In addition, the compounds of the present invention can be used to treat sleep disorders characterized by excessive daytime sleepiness, such as narcolepsy. Inverse agonists of the 5-HTA receptor of serotonin improve the quality of sleep at night, which leads to a decrease in excessive sleepiness during the day.

Thus, another aspect of the present invention relates to the therapeutic use of the compounds of the present invention for the treatment of sleep disorders. The compounds according to the present invention are active inverse agonists for the 5-HTα-receptor of serotonin and are effective in the treatment of sleep disorders due to the following: shortening the latent period of sleep onset (a measure of sleep induction), reducing the number of awakenings during the night and increasing the amount of time in the delta phase of sleep (is a measure of sleep quality and sleep strengthening), without affecting

VEM sleep. In addition, the compounds of the present invention are effective both as monotherapy and in combination with sleep-inducing agents, such as, but not limited to, antihistamines. 6. Diabetes-related pathologies

Although hyperglycemia is the main cause of the pathogenesis of diabetic complications, such as diabetic peripheral neuropathy (DPN), diabetic nephropathy (DM) and diabetic retinopathy (DC), elevated levels of serotonin in the plasma of diabetic patients are also involved in the progression of the disease (Rieigaz2ek, M .N., ei ani. Tpgotrozi5 Kev5. 1992, 66(6), 765-74; and IgledemuzKa-Vysako 9., ei ai., Kiip.

Osgpa. 1996, 98(2), 101-4). It is believed that serotonin plays a role in the narrowing of blood vessels and the increased ability of platelets to aggregate. Improvement of blood flow in microvessels can bring relief in diabetic complications.

In recent studies Sategop and Sobeg, Mashpup Zsptiederego5 Agsp. Rpaptosai 2003 dip, 367(6): 607-14 used the experimental compound AT-105, which is a 5-HTga antagonist, and other non-specific 5-HTga antagonists, including ritaserin and sarpogrelate. These studies showed that all three drugs are able to cause a noticeable correction (82.6-99.795) of the 19.895-th deficit of gluteal motor conduction in diabetic rats. Similarly, 44.7905 and 14.995 reductions in sciatic endoneural blood flow and paw saphenous vein sensory conduction velocity were fully reversible.

In a separate study, sarpogrelat was evaluated in patients to prevent the development or progression of diabetic nephropathy (Takapazpi, T., et al., Oiareie5 Kev. Siip. Rgasi., 2002 Mom, 58(2): 123-9). When conducting a study during a 24-month course of treatment, sarpogrelat significantly reduced the level of albumin excretion together with urine. 7. Glaucoma

Local injection of 5-HT2-receptor antagonists into the eye leads to a decrease in intraocular pressure (IOP) in monkeys |Snapod ei ai., 9. Osy). Rpaptosai 1: 137-147 (1985)) and in humans |Mazigorazdtsa ei ai., Asia

Orpshatoi bsapa Zirri 224: 24-25 (1997) |), indicating the suitability of similar compounds, such as 5-HTgaA inverse agonists, for the treatment of ocular hypertension due to glaucoma. It was shown that the antagonist 5-

Ht2-receptor ketanserin |Mazigorazdtsa, see above) and sarpogrelat (Takepaka ei a/!., Ipmeviid. Oripa!toi. Miv. zsi. 36: 5734 (1995)| significantly reduce intraocular pressure in patients suffering from glaucoma.

Characteristic methods according to the present invention

One aspect of the present invention relates to methods of modulating the activity of the 5-HTgda serotonin receptor by contacting the receptor with a compound according to any of the embodiments of the present invention provided herein, or with a pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating platelet aggregation in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating symptoms selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, and atrial fibrillation in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound at any - any of the variants of implementation of this invention, given in this description, or pharmaceutical composition.

One aspect of the present invention relates to methods of prevention or treatment for reducing the risk of blood clot formation during angioplasty or coronary artery bypass grafting in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound for any

which of the variants of implementation of this invention, given in this description, or pharmaceutical composition.

One aspect of the present invention relates to methods of prevention or treatment for reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof a therapeutically effective amount of a compound of any of the embodiments of the present invention set forth herein, or pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating asthma in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating an asthma symptom in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

One aspect of the present invention relates to methods of preventing or treating agitation or a symptom thereof in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention set forth herein, or a pharmaceutical composition. In some embodiments of the present invention, the individual is an elderly individual with no signs of cognitive impairment.

One aspect of the present invention relates to methods of preventing or treating agitation or a symptom thereof in an individual suffering from dementia, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention set forth herein, or a pharmaceutical composition. In some embodiments of the present invention, the dementia is caused by a degenerative disease of the nervous system. In some embodiments of the present invention, dementia is caused by Alzheimer's disease, Lewy bodies,

Parkinson's or Huntington's disease. In some embodiments of the present invention, dementia results from diseases that affect blood vessels. In some embodiments of the present invention, the dementia is caused by stroke or multi-infarct dementia.

One aspect of the present invention relates to methods of preventing or treating an individual suffering from at least one of the manifestations selected from the group consisting of conduct disorder, drug-induced psychosis, reactive psychosis, Gilles de la Tourette syndrome, manic syndrome, organic or MOB psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, MOH schizophrenia, which include the administration of a therapeutically effective amount of a dopamine Y2 receptor antagonist and a compound according to any of the embodiments of the present invention listed in this description, or a pharmaceutical composition, to the specified individual in need thereof. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One aspect of the present invention relates to methods of preventing or treating an individual with infantile autism, Huntington's chorea, or an individual suffering from nausea and vomiting induced by chemotherapy or chemotherapeutic antibodies, comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine O2-receptor antagonist and a compound of any of the variants of the implementation of this invention, given in this description, or a pharmaceutical composition. In some embodiments of the present invention, the dopamine O2 receptor antagonist is haloperidol.

One aspect of the present invention relates to methods of preventing or treating schizophrenia in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a dopamine O2 receptor antagonist and a compound according to any of the embodiments of the present invention set forth herein, or a pharmaceutical composition. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One aspect of the present invention relates to methods of prevention or treatment for ameliorating the negative symptoms of schizophrenia caused by the administration of haloperidol to an individual suffering from schizophrenia, comprising administering to said individual in need thereof a therapeutically effective amount of a compound of any one of the embodiments of the present invention set forth herein description, or pharmaceutical composition. In some embodiments of the present invention, the haloperidol and the compound or pharmaceutical composition are administered as separate dosage forms. In some embodiments of the present invention, the haloperidol and the compound or pharmaceutical composition are administered as a single dosage form.

One aspect of the present invention relates to methods of preventing or treating a sleep disorder in an individual, which include administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

In some embodiments of the present invention, the sleep disorder is dyssomnia. In some embodiments of the present invention, the dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep pattern perception disorder, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement syndrome, restless legs syndrome, sleep disorder caused by poor sleep hygiene, sleep disorder caused by environmental factors, high-altitude insomnia, sleep disorder caused by adaptive responses, insufficient sleep syndrome, sleep disorder caused by disturbed bedtime routine, associative sleep disorder, night eating or drinking syndrome , sleep disorder caused by the use of sleeping pills, sleep disorder caused by the use of stimulants, sleep disorder caused by the use of alcohol, sleep disorder caused by toxic exposure, jet lag syndrome (flying syndrome), sleep disorder caused by variable work patterns, irregular sleep patterns -wake, sleep phase delay syndrome, early sleep phase syndrome, and sleep disorder caused by a non-24-hour sleep-wake cycle.

In some embodiments of the present invention, the sleep disorder is a parasomnia. In some embodiments of the present invention, the parasomnia is selected from the group consisting of confusional states upon awakening, sleepwalking and night terrors, rhythmic movement disorder, sleep tremors, sleep talking, and nocturnal leg cramps. In some embodiments of the present invention, the sleep disorder is characterized by excessive daytime sleepiness, such as narcolepsy.

In some embodiments of the present invention, the sleep disorder is associated with an organic or psychiatric illness. In some embodiments of the present invention, the organic or psychiatric disease is selected from the group consisting of psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, degenerative brain diseases, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrographic signs epileptic seizure in sleep, sleep-related headaches, hypersomnia caused by trypanosomosis, nocturnal myocardial ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, gastric and duodenal ulcer disease, syndrome fibrositis, osteoarthritis, rheumatoid arthritis, fibromyalgia and post-surgical sleep disorders.

One aspect of the present invention relates to methods of preventing or treating diabetes-related disorders in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the present invention provided herein, or a pharmaceutical composition.

In some embodiments of the present invention, the diabetes-related disorder is diabetic peripheral neuropathy.

In some embodiments of the present invention, the diabetes-related disorder is diabetic nephropathy.

In some embodiments of the present invention, the diabetes-related disorder is diabetic retinopathy.

One aspect of the present invention relates to methods of preventing or treating glaucoma or other eye diseases associated with abnormal intraocular pressure.

One aspect of the present invention relates to methods of preparing a composition which include mixing the compounds of any of the embodiments of the present invention set forth herein and a pharmaceutically acceptable carrier.

One aspect of the present invention is the use of the compound for the preparation of a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgA.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is platelet aggregation.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke and atrial fibrillation.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is the formation of blood clots during angioplasty or coronary bypass surgery in an individual.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is the formation of blood clots in an individual suffering from atrial fibrillation.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is asthma.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is a symptom of asthma.

One of the embodiments of the present invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is agitation or its symptom in an individual. In some embodiments of the present invention, the individual is an elderly individual with no signs of cognitive impairment.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is agitation or a symptom thereof in an individual suffering from dementia. In some embodiments of the present invention, the dementia is caused by a degenerative disease of the nervous system. In some embodiments of the present invention, the dementia is caused by Alzheimer's disease, Lewy bodies, Parkinson's disease, or Huntington's disease. In some embodiments of the present invention, dementia results from diseases that affect blood vessels. In some embodiments of the present invention, the dementia is caused by stroke or multi-infarct dementia.

One of the variants of the implementation of this invention is the use of a compound for obtaining a medicinal product, which additionally contains an antagonist of the O2-dopamine receptor, for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is selected from the group including conduct disorder, psychosis, drug-induced, reactive psychosis, Gilles de la Tourette syndrome, manic syndrome, organic or MOB psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, MOH schizophrenia. In some embodiments of the present invention, the 02-dopamine receptor antagonist is haloperidol.

One of the variants of the implementation of this invention is the use of a compound for obtaining a medicinal product, which additionally contains an antagonist of the O2-dopamine receptor, for use in the prevention or treatment of a disease mediated by the action of 5-HTga, where the disease is infantile autism, chorea

Huntington's disease or nausea and vomiting caused by chemotherapy or chemotherapy antibodies. In some embodiments of the present invention, the dopamine Y2 receptor antagonist is haloperidol.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product, which additionally contains an antagonist of the O2-dopamine receptor, for use in the prevention or treatment of a disease mediated by the action of 5-HThi, where the disease is schizophrenia. In some embodiments of the present invention, the dopamine O2 receptor antagonist is haloperidol.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where the disease is a negative symptom or symptoms of schizophrenia caused by the administration of haloperidol.

One of the variants of the implementation of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where haloperidol and the compound or pharmaceutical composition are administered in the form of individual dosage forms.

One of the embodiments of this invention is the use of the compound to obtain a medicinal product for use in the prevention or treatment of a disease mediated by the action of 5-HTgaA, where haloperidol and the compound or pharmaceutical composition are administered in the form of a single dosage form.

One aspect of the present invention is a compound according to any of the embodiments of the invention provided herein for use in a method of treating a human or animal by therapy.

One aspect of the present invention is a compound according to any one of the embodiments of the invention provided herein for use in a method for the prevention or treatment by therapy of a 5-HThA-mediated disorder in a human or animal.

One aspect of the present invention is a compound according to any one of the embodiments of the invention provided herein for use in a method of prevention or treatment by means of therapy of a sleep disorder specified herein in a human or animal.

One aspect of the present invention is a compound according to any one of the embodiments of the invention provided herein for use in a method of preventing or treating platelet aggregation therapy in a human or animal.

Pharmaceutical compositions

Another aspect of the present invention relates to pharmaceutical compositions containing one or more of the compounds described herein and one or more pharmaceutically acceptable carriers. Some embodiments of the present invention relate to compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of preparing a pharmaceutical composition, which includes mixing at least one compound according to any of the embodiments of the invention, with respect to the compounds, and a pharmaceutically acceptable carrier.

The compositions may be prepared in any suitable manner, generally by thoroughly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the necessary proportions and then, if necessary, giving the resulting mixture the necessary forms

Tablets or capsules for oral administration may use conventional excipients, such as binders, fillers, acceptable wetting agents, lubricants and disintegrants used in tableting. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral preparations may be in the form of a dry powder which may be reconstituted with water or another suitable vehicle before use. Additional additives such as suspending agents or emulsifiers, non-aqueous carriers (including edible oils), preservatives and flavorants or dyes may be added to liquid preparations. Parenteral dosage forms can be obtained by dissolving the compound of the present invention in a suitable liquid carrier, sterilizing the solution before filling by filtration and sealing in a bottle or ampoule. These are just a few examples of the many suitable dosage forms known in the art.

The compound of the present invention can be formulated into a pharmaceutical composition using methods well known in the field. Suitable pharmaceutically acceptable carriers, in addition to those already discussed above, are well known in the art; (see, for example, Ketipdiop, Tpe bsieepse i Rgasiise oi Rpagtasu, 207 Eaiiop, 2000,

Prripsoy UMiShatv 8 UMIKip5 (Ediyugev: Seppago, A.V., ей а1.)|.

Despite the fact that for use in prevention or treatment, the compound according to the present invention can, as an alternative application, be administered in the form of a crude substance or in the form of an individual compound, however, it is more preferable to present the compound or active ingredient in the form of a pharmaceutical composition or composition, which additionally contain a pharmaceutically acceptable carrier.

The present invention further provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers and/or prophylactic ingredients. Carriers must be "acceptable" in the sense that they are compatible with the other ingredients of the composition and do not have a harmful effect on the recipient.

Pharmaceutical compositions include compositions suitable for oral, rectal, intranasal, topical (including buccal or sublingual), vaginal or parenteral (including intramuscular, subcutaneous or intravenous) administration, or compositions suitable for administration by inhalation insufflation or by transdermal patch

Transdermal patches release the drug at a rate that is controlled by the fact that the drug is effectively prepared for absorption and its minimal decomposition is ensured. Typically, transdermal patches include an impermeable backing layer, a single pressure-sensitive adhesive, and a removable protective layer with a release liner. Those skilled in the art know and understand methods suitable for obtaining the desired effective transdermal patch in accordance with the requirements of the specialist.

The compounds of the present invention, together with a conventional excipient, carrier or diluent, may thus be prepared in the form of pharmaceutical compositions and unit dosage forms derived therefrom, and as such may be administered as solids such as tablets or filled capsules. or liquid substances, such as solutions, suspensions, emulsions, elixirs, gels or liquid-filled capsules, all of which are intended for oral administration, or in the form of suppositories for rectal administration; or they can be obtained in the form of sterile solutions for parenteral (including subcutaneous) injections. Certain pharmaceutical compositions and unit dosage forms prepared therefrom, which may or may not contain additional active substances or excipients, may include conventional ingredients in conventional proportions, and such unit dosage forms may contain any suitable effective amount of active ingredient appropriate to the intended use. daily dose range.

For oral administration, the pharmaceutical composition may be, for example, in the form of a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably obtained in the form of a single dose, which contains a certain amount of the active ingredient. Examples of such unit doses are capsules, tablets, powders, granules, or suspensions that include conventional additives such as lactose, mannitol, corn starch, or potato starch; conventional binders such as crystalline cellulose, cellulose derivatives, gum, corn starch or gelatin; disintegrants such as corn starch, potato starch or sodium derivative of carboxymethyl cellulose; and lubricants such as talc or magnesium stearate.

The active ingredient can also be administered by injection in the form of a composition in which a suitable pharmaceutically acceptable carrier is used, for example, saline, dextrose or water.

The compounds of the present invention or their solvate or their physiologically functional derivative can be used as active ingredients in pharmaceutical compositions, in particular, as modulators of the 5-HTgA receptor. The term "active ingredient" is defined in the context of "pharmaceutical composition" and means the component of the pharmaceutical composition that exerts the main pharmacological effect, in contrast to the "inactive ingredient", which is generally considered to have no pharmaceutical effect.

The dose when using the compounds according to this invention can vary widely and, of course, as the attending physician knows, in each individual case, it must be selected for individual conditions. It depends, for example, on the type and severity of the disease being treated, on the condition of the patient, on the compound being used, or on whether the treatment is for an acute or chronic disease state, or on whether preventive treatment is being carried out, or on whether , or introduce other active compounds in addition to the compounds of the present invention. Exemplary doses of the present invention are, but are not limited to, from about 0.001 mg to about 500 Ωg, from about 0.001 mg to about 2500 mg, from about 0.001 mg to about 1000 mg, from about 0.001 mg to about 50 Ωg, from about 0.001 mg to about 2500 mg, from about 0.001 mg to about 10 mg, from about 0.001 mg to about 5 mg, and from about 0.001 mg to about 25 mg. Several doses may be administered during the day, especially when large amounts of the drug are expected to be needed, such as 2, 3, or 4 doses. Depending on the individual and the opinion of the attending physician or the person caring for the patient, there may be a need to change the doses given in this description both in the direction of their increase and in the direction of their decrease.

The amount of active ingredient or active salt or derivative thereof required for use in treatment will depend not only on the particular salt selected, but also on the route of administration, the type of condition being treated, and the age and condition of the patient and is ultimately determined by at the discretion of the attending physician or consultant. In general, one skilled in the art knows how to extrapolate data from a system model, typically an animal model, to another model, such as a human. In some circumstances, these extrapolations simply consider the weight of the animal model compared to another model, such as a mammalian model, preferably a human, but more often these extrapolations do not simply consider weight, but include various factors. Individual factors include the type, age, weight, sex, diet and medical condition of the individual, severity of disease, route of administration, pharmacological factors such as activity, efficacy, pharmacokinetic and toxicological profiles of the particular compound used, and whether the system is used delivery of a medicinal product, or treatment of an acute or chronic disease state, or prophylactic treatment, or other active compounds are administered in addition to the compounds of the present invention and as part of a combination of medicinal products.

Dosage regimens for the treatment of a disease state using the compounds and/or compositions of the present invention are selected according to the various factors listed above. Thus, the dosage regimens actually used may vary widely and therefore may differ from the preferred dosage regimens, and it will be appreciated by those skilled in the art that doses and dosage regimens outside of typical limits may be tried and, if convenient, used in the methods of the present invention.

The required dose may be conveniently presented as a single dose or divided doses administered at appropriate time intervals, for example as two, three, four or more subdoses per day.

The subdose, in turn, can be further divided, in particular, into a number of discrete parts that are administered at small intervals. The daily dose can be divided, in particular, in the case when it is intended to use relatively large doses, into 2, 3 or 4 partial administrations. If necessary, depending on individual behavior, there may be a need to increase or decrease the indicated daily doses.

The compounds of the present invention can be administered in a variety of oral or parenteral dosage forms. One of ordinary skill in the art will appreciate that the following dosage forms may include as an active ingredient either a compound of the present invention or a pharmaceutically acceptable salt of a compound of the present invention.

To obtain pharmaceutical compositions from compounds according to the present invention, the selection of a suitable pharmaceutically acceptable carrier can be made either from a solid substance, or from a liquid substance, or from a mixture thereof. Preparations in solid form include powders, tablets, pills, capsules, sachets, suppositories and dispersible granules. The solid carrier may be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating agents.

In powders, the carrier is a finely ground solid substance that is mixed with a finely ground active ingredient.

In tablets, the active component is mixed with a carrier that has the necessary binding properties in a suitable proportion and pressed to give the required shape and size.

Powders and tablets can have various percentages of the active compound. Exemplary amounts in a powder or tablet may range from 0.5 to about 9095 of the active compound; however, one of ordinary skill in the art will know when quantities beyond these limits will be required. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methylcellulose, carboxymethylcellulose, low-melting wax, cocoa butter, etc. The term "preparation" is intended to include a composition based on an active compound together with an encapsulating substance as a carrier, thereby obtaining a capsule in which the active substance, whether with a carrier or without a carrier, is surrounded by a carrier that is thus bound to the active substance Similarly, sachets and cakes are included here. Tablets, powders, capsules, sachets and cakes can be used as solid forms suitable for oral administration.

When preparing suppositories, a low-melting wax, such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and, for example, with the help of stirring, the active component is homogeneously dispersed in it. The molten homogeneous mixture is then poured into molds of the appropriate size and allowed to cool and at the same time harden.

Compositions suitable for vaginal administration can be presented in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art as suitable for these purposes.

Preparations in liquid form include solutions, suspensions and emulsions, for example, solutions in water or in a mixture of water and propylene glycol. For example, liquid drugs for parenteral injections are made as solutions in aqueous polyethylene glycol. Preparations for injections, for example, sterile aqueous and oily suspensions for injections can be formulated according to known methods using suitable dispersing or wetting agents. Sterile preparations for injection may also be a sterile solution for injection or a sterile suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example in a solution of 1,3-butanediol. Acceptable carriers and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are usually used as a solvent or suspending medium. For this purpose, any soft non-volatile oils can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injectable preparations.

Thus, the compounds of the present invention can be prepared for parenteral administration (in particular by injection, e.g. bolus injection, or by continuous infusion) and can be presented as a unit dosage form in ampoules, prefilled syringes, small volume containers infusion container or multiple-dose containers with an added preservative). Pharmaceutical compositions can take the form of suspensions, solutions or emulsions in oil or water carriers and they can contain agents used to obtain compositions, such as suspending agents, stabilizers and/or dispersants. Alternatively, the active ingredient may be in the form of a powder, which is obtained by aseptic isolation of a sterile solid or by lyophilization from a solution, the moisture content of which is restored before use with a suitable carrier, in particular sterile pyrogen water.

Aqueous compositions suitable for oral use can be obtained by dissolving or dispersing the active ingredient in water with the addition, if necessary, of suitable dyes, flavors, stabilizers and thickeners.

Aqueous suspensions suitable for oral use can be obtained by dispersing the finely divided active ingredient in water containing a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium derivative of carboxymethylcellulose or other known suspending agents.

Also included are preparations in solid form, which are intended to be converted immediately before use into preparations in liquid form for oral administration. Such liquid forms include solutions, suspensions and emulsions. These drugs, in addition to the active component, may contain dyes, flavors, stabilizers, buffer additives, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

For local application to the epidermis, the compounds of the present invention can be obtained in the form of ointments, creams or lotions or in the form of transdermal patches.

Ointments and creams can be, for example, obtained using an aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Lotions can be prepared using an aqueous or oil base and, in general, contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or dyes.

Compositions suitable for topical oral administration include tablets in which the active agent is placed in a flavored base, typically sucrose and gum or gum tragacanth; pastilles in which the active ingredient is placed in an inert base such as gelatin and glycerin or sucrose and gum; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are injected directly into the nasal cavity in the usual ways, for example, using a dropper, pipette or spray. The compositions can be obtained in the form of a single or repeated dose. In the latter case, when using a dropper or pipette, this can be done by injecting the patient with an appropriate, predetermined volume of solution or suspension. In the case of a spray, the indicated management can be carried out, for example, with the help of a dosing pump for an atomizer.

Introduction into the respiratory tract can also be carried out using aerosol compositions in which the active ingredient is packaged in a compressed state together with a suitable propellant gas for aerosols. If the compounds of the present invention or pharmaceutical compositions containing them are administered in the form of an aerosol, for example, by means of a nasal spray or by inhalation, then said administration can be carried out, for example, by means of a spray, a nebulizer, a nebulizer with a pump, an inhalation device , metered dose inhaler or dry powder inhaler.

Pharmaceutical forms for the administration of compounds according to the present invention in the form of aerosols can be obtained using methods well known to a person skilled in the art. For their preparation can be used, for example, solutions or dispersions of compounds according to the present invention in water, water/alcohol mixtures or suitable salt solutions together with usual additives, for example benzyl alcohol and other suitable preservatives that increase bioavailability by absorption enhancers, solubilizers, dispersants and others , and if necessary, together with conventional propellant gases for aerosols, which include carbon dioxide, chlorofluorocarbons such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; etc. The aerosol preferably also contains a surfactant such as lecithin. The dose of the medicine can be controlled using the dosing valve.

In compositions intended for administration through the respiratory tract, including intranasal compositions, the compound is usually contained in the form of particles of a small size, for example, on the order of 10 microns or less. Particles with similar sizes are obtained by methods known in the field, for example, micronization. If necessary, compositions adapted for prolonged release of the active ingredient can be used.

Alternatively, the active ingredients may be prepared in dry powder form, for example as a powder mixture of the compound with a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP). The powder carrier mainly forms a gel in the nasal cavity. Powder compositions can be presented in the form of a single dosage form, for example, in the form of capsules or cartridges made, for example, of gelatin, or in the form of a blister pack, from which the powder can be administered using an inhaler.

Pharmaceutical preparations are mainly prepared in the form of a single dosage form. In a similar form, the drug is divided into doses containing suitable amounts of the active component. A single dosage form can be a drug in a package, where the package contains discrete amounts of the drug, such as tablets in a package, capsules and powders in bottles or ampoules. In addition, the single dosage form can itself be a tablet, a sachet, a cake or any of them in a package.

Preferred compositions are tablets or capsules for oral administration or liquids for intravenous administration.

The compounds of this invention may optionally exist in the form of pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts, obtained from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Specific examples of acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrogen chloride, isethionic, lactic, maleic, mandelic, methanesulfonic, mucinic , nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, paratoluenesulfonic acid, etc., and similar pharmaceutically acceptable salts are given in Juoiptpai oi Rpagtaseshisa! Zsiepse, 66, 2 (1977); incorporated herein by reference in its entirety.

Acid addition salts can be obtained as a direct product during the synthesis of the compound. Alternatively, the free base can be dissolved in a suitable solvent containing a suitable acid and the salt isolated by evaporation of the solvent or by any other method to separate the salt from the solvent.

The compounds of this invention, when using methods known to a person skilled in the art, can form solvates with standard low molecular weight solvents.

The compounds of this invention can be converted into "prodrugs". The term "prodrugs" refers to compounds that are modified using specific chemical groups known in the field; when administered to an individual, the specified groups undergo biotransformation with the formation of the original compound. Thus, prodrugs can be considered as compounds of the present invention that contain one or more specialized non-toxic protecting groups that are temporarily used to modify or eliminate the properties of the compound. In general, a "prodrug" approach is used to facilitate oral absorption. A detailed discussion of this issue is presented in IT. Nidispi and M.21eiYiia, "Rgo-dgyde az Mome! Oeiiimegu buvietv", Moi. 14, A. Sat. 5. Butrozisht zZegie5; and Vioghemegzirie Sagpieg5 ip Ogyd Oezidp, ey. Eduag V. Kospe, Ategisap

Rpagtaseshisa! Azzosiaiop and Regdatop Rgevs5, 1987; incorporated herein by reference in their entirety.

Some embodiments of the present invention relate to a method of preparing a pharmaceutical composition for "combination therapy", which includes mixing at least one compound that corresponds to one of the compound variants of this specification together with at least one known pharmaceutical agent as specified in this specification, and pharmaceutically acceptable carrier.

It should be noted that in the case when 5-HTα receptor modulators are used as an active ingredient in a pharmaceutical composition, it is assumed that they will be used not only for humans, but also for other non-human mammals. Indeed, recent advances in animal health support the need for active agents such as 5-HTα receptor modulators for the treatment of 5-HTα-mediated diseases or conditions in domestic animals (especially cats and dogs) and other domestic animals ( in particular, cows, chickens, fish, etc.). Those skilled in the art will understand the necessity of using such compounds for the specified purposes.

Other applications

Another object of the present invention relates to the radiolabeled compounds of the present invention, which may be useful not only in radiography, but also for both ip migo and ip mmo assays for localization and quantification of 5-HTha -receptor in tissue samples, including human tissue, and to identify ligands of the 5-HTga receptor by inhibiting the binding of a compound that contains a radioactive label. Another object of this invention is the development of new assays for the 5-HTga receptor, which include the use of compounds that contain a radioactive label.

The present invention encompasses compounds of the present invention that contain an isotopic label. Compounds that contain an "Isotopic Label" or a "Radioactive Label" are those compounds that are identical to the compounds disclosed herein, except that one or more atoms are replaced or replaced by an atom having an atomic mass or atomic number different from the atomic mass or atomic number that is usually found in nature (that is, a natural isotope). Suitable radionuclides that may be incorporated into the compounds of the present invention include, but are not limited to, 2H (also denoted O as deuterium), ЗН (also denoted T as tritium), "c, 136, c, 13, 15 , 150, 170, 180, 18, 355, Z6(|, 82Vu, 7zVu, 76vu, 7 VI, 123, 124), 125), and 191|, Radionuclides,

which are included in the radiolabeled compounds of the present invention depend on the specific application of the radiolabeled compound. For example, for IP, the introduction of a label into the 5-HTgA receptor and conducting a competitive analysis are usually the most suitable compounds, which include ЗН, "с, 82Вг, 125), 191), 3555. For radiography, the most suitable are usually "С, 18Е, 125 |, 128), 124), 1913, 75Vu, "6Vg or "Vu.

It should be understood that "a compound containing a radioactive label" means a compound of formula (I) that contains at least one radionuclide; in some embodiments of the present invention, the radionuclide is selected from the group consisting of ZN, 14C, 125, 355 and 82Bu.

Some compounds that contain an isotopic label, according to the present invention, can be used in the analysis of the distribution of the compound and/or substrate in tissues. In some variants of the implementation of this invention, ZN and/or 17C isotopes can be used as a radionuclide when conducting the specified studies. Additionally, substitution with heavier isotopes such as deuterium (i.e., H) may provide additional benefits as a consequence of greater metabolic stability (in particular, through increased half-life and reduced dosage requirements) and thus may in some circumstances to be more predominant. The isotopically labeled compounds of the present invention can generally be prepared by methods similar to those discussed above in the Schemes and below in the Examples, by replacing a reagent that does not contain a radioactive label with a reagent with a reactive label. Other useful synthetic methods have already been discussed above. In addition, it should be understood that all the atoms included in the compounds of the present invention can be either isotopes of these atoms, which are most often found, or radioisotopes or non-radioactive isotopes, which are more rarely found.

Synthetic methods of introducing radioisotopes into organic compounds can be applied to the compounds of the present invention and are well known in the art. The specified methods of synthesis, for example, to introduce tritium activity levels into the target molecule, are the following:

A. Catalytic reduction with gaseous tritium: This technique usually leads to products with high specific activity and requires the use of halogenated or unsaturated precursors.

B. Boron hydride reduction "NO: This technique is quite cheap and requires the use of precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, etc.

C. Recovery with lithium aluminum hydride IZN)|: This technique makes it possible to obtain products with almost theoretical specific activity. It also requires the use of precursors containing recoverable functional groups, such as aldehydes, ketones, lactones, esters, etc.

O. Gaseous Tritium Labeling: This technique involves the action of gaseous tritium on precursors containing exchangeable protons in the presence of a suitable catalyst.

E. M-Methylation with IZNI methyl iodide: This technique is commonly used to obtain O-methyl- or M-methyl IZNI-derivatives by treating the corresponding precursors with methyl iodide

IINI with high specific activity. This technique in general allows to achieve a higher specific activity, which is, for example, about 70-90 Ki/mmol.

Synthetic methods of introducing activity levels 125) into the target molecule include:

A. Sandmeyer reaction and similar reactions This technique allows the conversion of arylamines or heteroarylamines into a diazonium salt, such as tetrafluoroborate, and then with Ma!"| into a labeled "25| compound

The presented technique is given | pi, O.-o. and so-mogkKegv5, in u. Ogd. Spet., 2002, 67, 943-948).

B. Ortho-!25|-iodination of phenols: This technique allows the introduction of 7"25I into the ortho position of phenol as indicated in (Soieg, T.G. and so-zhogKkegv, 9. I areied Sotra. Nadiornagt. 1999, 42, 5264 -5266.

C. Exchange of aryl and heteroaryl bromides with 725I: This method is usually carried out as a two-step process. The first stage is the conversion of aryl- and heteroaryl bromides into the corresponding trialkyltin derivative using, for example, a palladium-catalyzed reaction (in particular, using Pa(RPzP)a4|) or through aryl- or heteroaryllithiums in the presence of a trialkyltin halide or hexaalkyldiol (in particular, using (CH3 )зб5поп(СНзи)з|. The presented technique is given by |Vazv,

M.-O. and so-zhogkegv5, in y). | Areii Sotra. Kadiorpagt. 2001, 44, 5-280-52821.

The compound of formula (I) containing a radioactive label for the 5-HTgal receptor can be used in screening for the identification and evaluation of compounds. In short, a newly synthesized or identified compound (ie, a test compound) can be evaluated for its ability to weaken the binding of "a compound of formula (I) containing a radioactive label" to the 5-HTα receptor. Thus, the ability of the tested compound to compete with the "compound of formula (I) containing a radioactive label" for binding to the 5-HTα receptor directly correlates with the binding affinity.

Compounds that contain a label according to the present invention bind to the 5-HTod receptor. In one embodiment of the present invention, the labeled compound has an IC of less than about 500 µM, in another embodiment of the present invention, the labeled compound has an IC of less than about 100 µM, in yet another embodiment of the present invention, the compound , which contains the label, has an IC value of less than about 10 µM, in another embodiment of the present invention, the compound that contains the label has an IC value of less than about 1 µM, and finally, in yet another embodiment of the present invention, the compound that contains label, has an IC value of less than about 0.1 µM.

Other applications of the receptors disclosed in this invention will become apparent to those skilled in the art upon, among other things, reading this description.

It should be understood that the steps in the methods of the present invention do not necessarily have to be carried out any specific number of times or in a specific sequence. Additional objects, advantages, and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are to be construed as illustrative and non-limiting examples of the present invention.

Examples

Example 1. Synthesis of compounds according to the present invention

Explanations for the syntheses of the compounds of the present invention are given in Fig. 17-21 and in Fig. 29-34, where the symbols have the same meanings as used throughout the description.

The compounds of the present invention and their synthesis are further illustrated by the following examples. The following examples are intended to further explain the invention, but the invention is not limited to these specific examples. The compounds given above and below in this description are named in accordance with C5 Spet

Ogamz Oiga Megwiop 7.0.1, AshoMot megsiop 2.2. In some cases, trivial names are used, and it should be understood that these trivial names should be known to those skilled in the art.

Chemical methods: Proton magnetic resonance ("7 NMR) spectra are recorded on a Magiap spectrometer

Megsig Ukh-400, equipped with an autoswitching probe for 4 cores and 2-gradient, and on the spectrometer

Vgykeg Amapse-400 equipped with OMR (four-core probe) or VVI (broadband signal inversion) and 2-gradient. Chemical shifts are given in parts per million (ppm), and the residual solvent signal is used as the standard. The following abbreviations accepted in NMR are used: c-: singlet, d-doublet, dd-doublet of doublets; t-triplet, q-quartet, m-multiplet, ear-wide signal; Hertz Microwave radiation is generated using Etug5 Zupipezigeg (Regzopa! SPpetivigh). Thin-layer chromatography (TLC) is performed on silica gel 60 Rosi (MegsKk), preparative thin-layer chromatography (prep. TLC) is performed on RKbE plates made of silica gel 6b0A with a thickness of mm (UMpaitap), and column chromatography is performed on a column with silica gel KiezeiYide! 60 (Megsk), with a particle size of 0.063-0.200 mm.

Evaporation is carried out in a vacuum on a Vysp rotary evaporator. Seyye 545F is used for filtering palladium).

LC/MS spectrometry: 1) PC (personal computer); HPLC pumps: GS-10AO MR, 5 feed Ips.; HPLC system controller: 5SI-10A MR, 5Ppitai?y IPS.; UV detector: 5РО-10А MR, 5Ppitayly Ips.; autoloader: STO NT5, RAI,, Gear Zsiepiis; mass spectrometer: АРИ 150ЭХ with Tigro Iop Zrgau source,

AV/MOZ5 Zsieh; software: Apaiuzi 1.2. 2) Mas (Mackintosh): HPLC pumps: I. S-8AO UR, Zpitaidgy

Ips.; HPLC system controller: 5SI-10A MR, Zpitayd7y IPS.; UV detector: 5РО-10А MR, 5pitaai Ips.; autoloader: 215 I iiidtsia Napayeg, siizop Ips.; mass spectrometer: АРИ 150ЭХ with Tigro Iop Zrgau source,

AV/MOZ5 Zsieh; software: Mazzspgot 1.5.2.

Example 1.1: Preparation of intermediate 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine.

5psSi2.2HgO (5.306g, 23, 05 mmol, 4.0 equiv.), the mixture is refluxed with stirring for 2 hours and the EUN is removed in vacuo. The resulting solid is dissolved in EOAc, sodium hydroxide (Zbml) is added, and the mixture is stirred overnight. The white precipitate is filtered through celite and the aqueous phase is extracted with EtOAc (ZhvOml). The organic phases are combined, dried over anhydrous Maoa5O4, filtered and evaporated. The crude reaction mixture is purified by column chromatography at 5% (eluent: EIOAc/hexane-1/3, then 1/1) and 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is obtained (1.430g, 5.07mmol, 88905) in the form of a white solid: RHMOS t/2 (90)-282 (MaANVg, 98), 284 (MaNU!'Vg, 100). "H NMR (400MHz, SOSIz) 6: 7.52 (s, 1H), 6.86 (d, U-8.8Hz, 1H), 6.80 (dd, y-2.8, 8.8Hz, 1).

Intermediate 4-bromo-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole is obtained as follows:

A. 2-Methyl-2H-pyrazole-3-boronic acid: M-methylpyrazole (25 ml, 0.3 mol) is dissolved in 500 ml of THF.

Then the solution is cooled to -78"C in a dry ice/isopropanol bath. After the temperature of the solution reaches 78"C, n-Via (140 ml, 0.40 mol) is added dropwise through a dropper. The reaction mixture is stirred at -78"C for 1.5 hours. Then triisopropylborate (280 ml, 1.2 mol) is added to the indicated mixture through a drop funnel. It is stirred overnight, while the temperature is gradually raised from -78"C to 0"C. The pH of the mixture was adjusted to b with 1N HCl. The THF was removed under reduced pressure and the aqueous layer was extracted with EtOAc (2 x 100 mL). The solid was then filtered to give 108 g (10095) of 2-methyl-2H-pyrazole-3-boronic acid as a yellow solid (The final product contains about 6090 inorganic salt).

B. 2-Methoxy-5-nitrophenyl ether of trifluoromethanesulfonic acid: Trifluoromethanesulfonic anhydride is added dropwise to a stirred solution of 2-methoxy-5-nitrophenol (5.092 g, 0 mmol) in a mixture of SneaSi" (3 ml) and pyridine (20 ml) at 0"C (16.478g, 9.ml, 2.0eq). The mixture was warmed to room temperature and stirred for 2 hours. Most of the pyridine was removed in vacuo. The residue was diluted with EOAc, washed with HCl solution and water, the aqueous phase was extracted with EtOAc (3x100ml) .

The organic phases are combined, washed with a saturated salt solution, dried over anhydrous NaCl, filtered and evaporated. The crude reaction mixture is purified by column chromatography on 5iO2 (eluent: EOAc/hexane-1/3, then 1/2) and 2-methoxy-5-nitrophenyl ether of trifluoromethanesulfonic acid is obtained, which contains a trifluoromethanesulfonate group (8.943g, ZOmmol, 10095) in in the form of a yellow solid: LCMS t/l2 (96)-302 (MH, 100). "H NMR (400 MHz, SOSIz) 6: 8.30 (dd, y-4.0, 8.0 Hz, 1H), 8.16 (d, y-4.0 Hz, 1), 7.15 (d, U-8.0Hz, 1H), 4.06 (c, 3H). b. 5-(2-Methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole: 2-Methoxy-5-nitrophenyl ether of trifluoromethanesulfonic acid from stage B (2.561g, 8.50mmol), 2-methyl-2H-pyrazole-3-boronic acid from stage A (4.283g, 34.01mmol, 4.Eq.) and MgCO3 (10.816g, 102.04mmol, 12, beq.) is dissolved in a mixture of THF (200 ml) and water (1000 ml). The resulting mixture is degassed for 5 minutes with nitrogen and then added

RAD(PPz)4 (0.486 g, 0.42 mmol, 0.05 eq.). Degas for another 5 minutes. and stirred in an argon atmosphere overnight at a temperature of 70°C. After the reaction is complete, THF is removed under reduced pressure and the aqueous phase is extracted with EIOAc (4x100 ml). The organic phases are combined, dried over anhydrous Ma5Oa, filtered and evaporated. the reaction mixture is purified by column chromatography on 5iO2 (eluent: EIOAc/hexane-1/1) and 5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (1.799g, 7.71mmol, 91965) is obtained in in the form of a white solid substance: LCMS ti/ya (95)-234 (MAN, 100). "H NMR (400 MHz, SOSIZz) 6: 8.34 (dd, y-2.8, 9.2 Hz, 1H), 8 ,19 (d, U-2.8Hz, 1H). 7.56 (d, U-2.0Hz, 1), 7.08 (d, 9-9.2Hz, 1H), 6.31 (d, 9-1.6Hz, 1H), 3.96 (s , ZN), 3.74 (c, ZN).

O. 4-Bromo-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole: At 0"C to a moving solution of 5-(2-methoxy-5-nitrophenyl)-1-methyl-1H -pyrazole (1.787g, 7.66bmmol) in DMF (20ml) is added dropwise to the solution

Mv5 (M-bromosuccinimide) (1.515g, 8.43mmol, 1 eq.) in DMF (5ml). After stirring for 3 hours at 0"C, TLC shows the completion of the reaction. The mixture is diluted with EtOAc (300ml), washed with water (3x10ml) and saturated salt solution. The EtOAc phase is dried over anhydrous Ma5O", filtered and evaporated. The crude reaction mixture is purified by column chromatography on 5 µg (eluent: EIAs/hexane-1/3, then 1/1) and obtain 4-bromo-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (2.214 g, 7.09 mmol, 9390) in the form of a light yellow solid: LCMS t/z (95)-312 (MaNVg, 100), 314 (MaNV'Vu, 100). "H NMR (400 MHz,

SOS z) 6: 8.40 (dd, 9U-2,4,6,9HZ, 1H), 8.22 (m, 1H), 7.57 (s, 1H), 7.14 (d, 9- 9.2 HzC, 1H), 3.98 (s, ZN), 3.74 (s, ZN).

Example 1.2: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chloro-2-trifluoromethylphenyl)urea (Compound 9)

Urea synthesis (General method): To a mobile solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.034 g, 0.12 mol, example 1.1) in CH2Cl2 (1 ml ) at room temperature, add 4-chloro-2-(trifluoromethyl)phenyl isocyanate (0.029 g, 20.00 μl, 0.1 μmol, 1.05 eq.). The white precipitate that precipitated was filtered and washed with cold SiO2 to give compound 9 (0.037g, 0.074mmol, 6095) as a white solid. LCMS t/z (95)-503 (MAN"VHg, 77), 439 (MANU'Vu, 100). "H NMR (400 MHz, acetone-iv) δ: 8.82 (s, 1H), 8.22 (d. 9U-9.6Hz, 1H), 7.62-7.72 (m, 4H), 7.49 (s, 1H), 7.43 (d, 9U-2.6Hz, 1H), 7 .15 (d, 9U-9.0Hz, 1), 3.83 (s, ZN), 3.68 (s, ZN).

Example 1.3: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-fluorophenyl)urea (Compound 2) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (2.965g, 10.5mmol) is treated with 4-fluorophenylisocyanate (1.601g, 1.31ml, 11.bmmol, 1.1eq.) in SNeosSi» (20ml) similar to the method given in example 1.2, and compound 2 (3.755g, 8.94mmol, 8595) is obtained as a white solid. MaNU!'Vg, 100). "H NMR (400MHZ, acetone-iv) 6: 8.49 (b, 2H), 7.77 (d, U-59.0Hz, 1H), 7.50- 7.58 (m, 2H), 7.50 (s, 1H), 7.43 (s, 1H), 7.12 (d, U-8.9Hz, 1H), 6.98-7.06 ( m, 2H), 3.81 (s, ZN), 3.68 (s, zn).

Example 1.4: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2,4-dichlorophenyl)urea (Compound 3) 3-(4- Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.031 g, 0.1 mmol) is treated with (-)2,4-dichlorophenyl isocyanate (0.021 g, 0.1 x 7 mmol, 1.0 equiv.) in SneoSi" (2ml) similarly to the method given in example 1.2, and compound C (0.036g, 0.07bmmol, 6995) is obtained as a white solid. RHMS t/2 (95)-469 (MAN"VIZ5SIV5SI, 60), 471. (MAN"ZVIZZSIVSIV81VI35SI85SI, 100), 473 (MAN VISI SIYA VISI, 54), 475 (MannNe VISI, 4). "H NMR (400 MHz, acetone-av) 6: 8.81 (s, 1H), 8.36 (d, 9U-9.0HzC, 1), 7.91 (s, 1H), 7.69 (dd , U-2.7, 9.0Hz, 1H), 7.50 (s, 1H), 7.48 (d, 9-2.4Hz, 1H), 7.45 (d, U-2.7Hz , 1H), 7.34 (dd, U-2.4, 9.0Hz, 1H), 7.15 (d, --9.0Hz, 1H), 3.83 (s, ЗН), 3, 69 (c, ZN).

Example 1.5: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-methoxyphenyl)urea (Compound 4) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.031 g, 0.11 mmol) is treated with 4-methoxyphenyl isocyanate (0.016 g, 14.2 μl, 0.1 mmol, 1.0 equiv.-) in СНоСи» (2ml) similarly to the method given in example 1.2, and compound 4 (0.037g, 0.08bmmol, 78905) is obtained as a white solid.

RHMS ti/a (95)-431 (MaANVg, 89), 433 (Ma-NU'Vg, 100). "IN NMR (400 MHz, acetone-iv) 6: 8.02 (s, 1H), 7.89 (s, 1H), 7.67 (dd, U-2.7, 9.0 Hz, 1), 7 .49 (s, 1H), 7.43 (s, 1H), 7.42 (d, 9-9.0Hz, 2H), 7.12 (d, U59.0Hz, 1H), 6.85 (d , 9-9.0Hz, 2H), 3.81 (s, ЗН), 3.75 (s, ЗН), 3.68 (s, ЗН).

Example 1.6: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-bromophenyl)urea (Compound 5) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.032g, 0.11mmol) is treated with 4-bromophenylisocyanate (0.022g, 0.11mmol, 1, eq.) in CH2Cl2 (2ml) similarly method given in example 1.2, and compound 5 (0.040g, O0.08mmol, 75905) is obtained as a white solid. LCMS t/2 (95)-479 (MAN"VIVg, 51), 481 (MAN"B/ Z1Vu, 100), 483 (MANU'VIZ'Vu, 50). "H NMR (400 MHz, acetone-av) δ: 8.22 (s, 1H), 8.14 (s, 1H), 7.68 ( dd, 952.7, 9.0 Hz, 1H), 7.48-7.54 (m, ZN), 7.39-7.46 (m, ZN), 7.14 (d, U-9.0 Hz , 1H), 3.82 (s, ЗН), 3.68 (s, ЗН).

Example 1.7: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chloro-3-trifluoromethylphenyl)urea (Compound 6) 3-( 4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.035g, 0.12mmol) is treated with 4-chloro-3-(trifluoromethyl)phenylisocyanate (0.027g, 0.12mmol, 1.0eq .) in СНоСі" (2 ml) similarly to the method given in example 1.2, and compound 6 (0.051 g, 0.010 mmol, 8195) is obtained as a white solid. RHMSO t/2 (95)-503 (MANUVIZSI, 78), 505 (MANUVIZSI, 100), 507 (MANUVIZ7SI, 28). "H NMR (400 MHz, acetone-dv) 6: 8.52 (s , 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.74 (d, U-8.7Hz, 1H), 7.68 (d, U-9.0HzC, 1H ), 7.53 (d, U-8.7 Hz, 1H), 7.49 (s, 1H), 7.AZ (s, 1H), 7.14 (d, 9-9.0HzC, 1H) , 3.82 (c, ZN), 3.68 (c, ZN).

Example 1.8: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3,5-difluorophenyl)urea (Compound 7) 3-(4- Bromo-2-methyl-2H-pyrazol-3-yl)y-4-methoxyphenylamine (0.032g, 0.1mmol) was treated with /3,5-difluorophenylisocyanate (0.018g, 14μL, 0.11mmol, 1.0eq.) in SneoSi" (2ml) similarly to the method given in example 1.2, and compound 7 (0.038g, 0.09mmol, 77905) is obtained as a white solid. RHMSO t/2 (95)-437 (MaeH"Vg, 100), 439 (MANU!'Vg, 100). "H NMR (400 MHz, acetone-dv) 6: 8.47 (s, 1H), 8, 23 (s, 1H), 7.68 (dd, 2.7, 9.0Hz, 1H), 7.50 (s, 1H), 7.42 (d, U9-52.7Hz, 1H), 7, 18-7.27 (m, 2H), 7.15 (d, U959.0Hz, 1H), 6.59 (ttt, y-2,3.9,1.9.1Hz, 1H), 3.82 (c, ZN), 3.68 (c, ZN).

Example 1.9: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2,4-difluorophenyl)urea (Compound 8) 3-(4- Bromo-2-methyl-2H-pyrazol-3-yl)y-4-methoxyphenylamine (0.027g, 0.095mmol) is treated with /-2,4-difluorophenylisocyanate (0.015g, 11.5μl, 0.095mmol, 1.0eq.- ) in SNeoSi" (2ml) similarly to the method given in example 1.2, and compound 8 (0.030g, 0.069mmol, 71905) is obtained as a white solid.

LCMS ti/i (965)-437 (MaeH"Vg, 100), 439 (MaNU!'Vg, 100). "H NMR (400 MHz, acetone-av) o: 8.45 (s, 1H), 8, 23 (dt,

U-6.1, 9.2Hz, 1H), 7.93 (s, 1H), 7.68 (dd, 252.6, 9.0Hz, 1H), 7.49 (s, 1H), 7, 44 (d, U52.6HzC, 1H), 7.14 (d, U929.0Gu, 1H), 7.07 (ddd, uU-2.7, 8.7, 11.3Hz, 1H), 6.93 -7.02 (m, 1H), 3.82 (s, ЗН), 3.69 (s, ЗН).

Example 1.10: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-chlorophenyl)urea (Compound 20)

To the stirred solution / 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)y-4-methoxyphenylamine (0.015g,

0.051 mmol) in SN (ml) add 3-chlorophenyl isocyanate (0.008 g, 7 μl, 0.054 mmol, 1.05 eq.). After TLC shows that the starting material has reacted, it is isolated by preparative thin layer chromatography (TLC) (eluent: E(Ac/hexane-1/1)) to give compound 20 (0.020g, 0.047mmol, 9295) as a solid film . LCMS. t/a (95)-435 (MaH"Vg, 68), 437 (Ma-NU!Vu, 100). "H NMR (400 MHz, acetone-adv) o: 8.29 (s, 1H) , 8.19 (s, 1H), 7.80 (t, 9U-1.9Hz, 1H), 7.29 (dd, U-2.7, 9.0Hz, 1H), 7.49 (s, 1H), 7.43 (d, 9U-2.7Hz, 1H), 7.34 (d, U-8.4HzC, 1), 7.26 (t, 9-8.0HzC, 1H), 7, 14 (d, 9U-9.0Hz, 1), 7.00 (d, 9-7.8Hz, 1H), 3.82 (s, ZN), 3.68 (s, zn).

Example 1.11: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-cyanophenyl)urea (Compound 21) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.037 tg, 0.1 mmol) is treated with 3-cyanophenyl isocyanate (0.020 g, 0.14 mmol, 1.05 equiv.) in СНоСи" (ml) similarly to the method , given in example 1.10, and compound 21 (0.032g, 0.08mmol, 5890) is obtained in the form of a white powder. . "H NMR (400 MHz, acetone-av) about: 8.45 (s, 1H), 8.26 (d, 9-9.6Hz, 1), 8.05 (t, U-1.7Hz, 1H ), 7.74 (dd, U9-1.5, 8.2Hz, 1H), 7.70 (dd, U-2.7, 9.0Hz, 1H), 7.50 (s, 1H), 7 .48 (t, U-8.1Hz, 1H), 7.AZ (d, 9-2.7Hz, 1H), 7.36 (d, U9-7.6Hz, 1H), 7.15 (d, U-9.0 HZ, 1H), 3.83 (s, ZN), 3.69 (s, ZN).

Example 1.12: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3,4-difluorophenyl)urea (Compound 10) 3-(4- Bromo-2-methyl-2H-pyrazol-3-yl)y-4-methoxyphenylamine (0.035g, 0.12mmol) was treated with /3,4-difluorophenylisocyanate (0.021g, 16μL, 0.1Zmmol, 1.05eq.) in CHOSi" (1 ml) similarly to the method given in example 1.2, and compound 10 (0.021 g, 0.047 mmol, 3895) is obtained as a white solid. LCMS t/2 (963-437 (MANVg, 100), 439 (M--NU'Vu, 99). "H NMR (400 MHz, acetone-av) o: 8.29 (s, 1H), 8.16 (c, 1H), 7.74 (dddd, --2.5, 7.4, 13, АХцЦ, 1Х), 7.68 (dd, У-2.7, 9.0ХцЦ, 1), 7, 49 (s, 1H), 7.42 (d, 922.7 Hz, 1), 7.11-7.26 (m, 2H), 7.13 (d, U-9.0Hz, 1H), 3 .82 (c, ZN), 3.69 (c, ZN).

Example 1.13: Preparation of 1-biphenyl-2-yl-3-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 22) 3-(4-Bromo- 2-Methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.036g, 0.13mmol) was treated with 2-biphenyl isocyanate (0.027g, 24.0ml, 0.14mmol, 1.05eq) in CH2Cl2 (1ml ) similarly to the method given in example 1.10, and compound 22 (0.031g, 0.0bmol, 5190) is obtained in the form of a white powder. LCMS t/2 (95)-477 (MAN"Vg, 100), 479 (MaNU'Vg, 100). "H NMR (400 MHz, acetone-dv) 6: 8.41 (s, 1H), 8.17 (d, 9-8.3Hz, 1H), 7.60 (d, 9U-2.7, 9.0Hz, 1), 7.43-7.51 (m, ZN), 7.37-7, 43 (m, ZN), 7.29-7.37 (m, 2H), 7.24 (s, 1H), 7.20 (dd, y-1.6, 7.6GuC, 1), 7, 11 (dd, 91.0, 7.4Hz, 1H), 7.08 (d, U-9.0Hz, 1H), 3.80 (s, ЗН), 3.66 (s, ЗН).

Example 1.14; Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-trifluoromethylphenyl)urea (Compound 11) 3-(4-Bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.035g, 0.12mmol) is treated with c,c,o-trifluoro-m-tolylysocyanate (0.025g, 18.O0μl, 0.1Zmmol, 1.05eq. ) in CH2Si" (ml) similarly to the method given in example 1.2, and compound 11 (0.038g, 0.08Omol, 6595) is obtained as a white solid. РХМСО t/2 (953-469 (MaАНВГг, 91), 471 (MeNZ!Vg, 99). "IN NMR (400 MHz, acetone-iv) 6: 8.42 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.64 -7.73 (m, 2H), 7.45-7.53 (m, 2H), 7.44 (s, 1H), 7.30 (d, 9-7.6Hz, 1H), 7.15 (d, U-8.9Hz, 1H), 3.82 (s, ZN), 3.69 (s, ZN).

Example 1.15: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-trifluoromethylphenyl)urea (Compound 12) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.035g, 0.12mmol) is treated with c,c,o-trifluoro-p-tolyl isocyanate (0.025g, 18.00μl, 0.13mmol, 1 .05 equiv.) in СНоСі" (1 ml) similarly to the method given in example 1.2, and compound 12 (0.038 g, O0.08 mol, 6595) is obtained as a white solid. LCMS t/2 (95)-469 (MaNVHg, 91), 471 (MaNe!Vg, 99). "H NMR (400 MHz, acetone-av) 6: 8.51 (s, 1H), 8.27 (s, 1H), 7.76 (d, 98, 3Hz, 2H), 7.71 (dd, U-2.3, 9.0Hz, 1), 7.62 (d, 9U-8.4Hz, 2H), 7.52 (s, 1H), 7, 46 (d, 9U-2.3Hz, 1), 7.16 (d, y-8.9Hz, 1H), 3.84 (s, ZN), 3.70 (s, ZN).

Example 1.16; Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chlorophenyl)urea (Compound 1) 3-(4-Bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.260g, 0.92mmol) is treated with 4-chlorophenylisocyanate (0.144g, 0.92mmol, 1.0eq.) in CH2Cl2 (ml) similarly to the method given in example 1.2, and compound 1 (0.340g, 0.78mmol, 84905) is obtained as a white solid. LCMS t/z2 (95)-435 (MANU'VIZ5SI, 77), 437 (MANU'VIZSI, 100), 439 (MANU'VIZSI, 25). "H NMR (400MHz, SOSIv) 6: 7.56 (s, 1H), 7.44 (dd, U-2.7, 8.9Hz, 1H), 7.34 ( d, U-9.0Hz, 1H), 7.29 (d, 9U-9.0Hz, 1H), 7.19 (d, 9U-2.7Hz, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.84 (s, ЗН), 3.74 (s, ЗН).

Example 1.17: Preparation of /1-(3,5-bis-trifluoromethylphenyl)-3-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 13) 3- (4-Bromo-2-methyl-2H-pyrazol-3-yl)y-4-methoxyphenylamine (0.037 g, 0.1 mmol) is treated with /3,5-bis(trifluoromethyl)phenyl isocyanate (0.036 g, 24.00 μl, 0 ,14mmol, 1.05equiv.) in СНоСи" (ml) similarly to the method given in example 1.2, and compound 13 (0.030g, 0.0bmmol, 4395) is obtained as a white solid. LCMS ti/ya (95)-537 (M.a-H"Vg, 99), 539 (M-NU!Vg, 100). "IN NMR (400 MHz, acetone-aiv) 6: 8.77 (s, 1H), 8.42 (s, 1H), 8.22 (s, 2H), 7.73 (dd, U-22.5, 9.0Hz, 1H), 7.51 (s, 1H), 7 .46 (d, 9-2.5Hz, 1), 7.18 (d, U-9.0Hz, 1H), 3.85 (s, ЗН), 3.71 (s, ЗН).

Example 1.18: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-isopropylphenyl)urea (Compound 23) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.035g, 00.12mmol) is treated with 4-isopropylphenylisocyanate (0.022g, 21.0μl, 0.1Zmmol, 1.05eq.) in SNeoSi" ( ml) similarly to the method given in example 1.10, and compound 23 (0.028g, O0.0bmol, 5095) is obtained in the form of a solid film. 99). "H NMR (400 MHz, acetone-av) about: 8.08 (s, 1H), 8.00 (s, 1H), 7.68 (dd, U-2.6, 8.9Hz, 1H ), 7.49 (s, 1H), 7.40-7.46 (m, ЗН), 7.09-7.17 (m, ЗН), 3.81 (s, ЗН), 3.68 ( c, ZN), 2.78-2.92 (m, 1H)U, 1.21 (c, ZN), 1.20 (c, ZN).

Example 1.19: Preparation of / 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-naphthalene-2-

ylurea (Compound 14) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.035g, 0O.12mmol) is treated with 2-naphthylisocyanate (0.023g, 0.1Zmmol, 1, 05 equiv.) in SNeoSi" (ml) similarly to the method given in example 1.2, compound 14 (0.040g, O0.09mmol, 70905) is iodinated as a white solid. RHMS t/l (90)-451 (MaANVG, 95), 453 (MANU!Vg, 100). "H NMR (400 MHz, acetone-dv) 6: 8.30 (s, 1H), 8.20 (s, 1H), 8.19 (d, 9-1.8Hz, 1H), 7.56-7 .84 (m, ZN), 7.72 (dd, U-2.7, 9.0Hz, 1H), 7.56 (dd, 9U-2.1, 8.8Hz, 1H), 7.50 ( s, 1H), 7.48 (d, 952.7 Gu, 1H), 7.44 (t, U-8.0Hz, 1H), 7.14 (t, U-8.0Hz, 1H), 3 .83 (c, ZN), 3.70 (c, ZN).

Example 1.20: Preparation of / 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3Z-naphthalen-1-ylurea (Compound 24) 3-(4-Bromo- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.036 g, 0.1 mmol) is treated with 1-naphthyl isocyanate (0.023 g, 0.14 mmol, 1.05 equiv.) in SNCl (Iml) similarly to the method, given in example 1.10, compound 24 (0.039g, 0.09mmol, 6895) is obtained as a white powder. RHMOS t/2 (90)-451 (MaANVG, 95), 453 (MANU!Vg, 100). "H NMR (400 MHz, acetone-dv) 6: 8.58 (s, 1H), 8.32 (s, 1H), 8.16 (d, 9U-7.0Hz, 1H), 8.10 (d , 9U-7.9Hz, 1H), 7.91 (d, U-9.4Hz, 1H), 7.75 (dd, U-2.7, 9.0Hz, 1H), 7.65 (d, U-8.2Hz, 1H), 7.44-7.57 (m, 5H), 7.14 (d, U-9.0Hz, 1H), 3.83 (s, ЗН), 3.69 ( with, ZN).

Example 1.21: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chlorophenyl)thiourea (Compound 71) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.037 g, 0.1 mmol) is treated with 4-chlorophenylisothiocyanate (0.024 g, 0.14 mmol, 1.05 equiv.) in СНоСи» (Iml) similarly to the method , given in example 1.10, and compound 71 (0.048 g, 0.10 mmol, 8095) is obtained in the form of a solid film. . .48 (dd, uU-2.7, 8.8Hz, 1H), 7.37 (s, 4H), 7.30 (d, 9-52.7Hz, 1), 7.08 (d, 9- 88 Hz, 1H), 3.87 (s, ЗН), 3.75 (s, ЗН).

Example 1.22: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-nitrophenyl)urea (Compound 15) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.036g, 0.1Zmmol) is treated with 3-nitrophenyl isocyanate (0.023g, 0.1Zmmol, 1.05eq.) in СНоСи» (Iml) similarly to the method , given in example 1.2, and compound 15 (0.040g, 0.09mmol, 7095) was obtained as a yellow solid. 89). "H NMR (400 MHz, acetone-dv) about: 8.63 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.80-7.86 ( m, 2H), 7.72 (dd, U-2.7, 9.0Hz, 1H), 7.55 (t, U-8.2Hz, 1H), 7.50 (s, 1H), 7, 45 (d, 952.7 Hz, 1H), 7.16 (d, --9.0 Hz, 1H), 3.83 (s, ЗН), 3.69 (s, ЗН).

Example 1.23: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl/|-3-(4-fluoro-3-nitrophenyl)urea (Compound 16) 3 -(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.037 g, 0.1 mmol) is treated with 4-fluoro-3-nitrophenyl isocyanate (0.025 g, 0.14 mmol, 1.05 equiv. ) in СНоСі" (Iml) similarly to the method given in example 1.2, and compound 16 (0.042g, O0.09mmol, 6995) is obtained in the form of a yellow solid. РХМСО t/2 (953-464 (MaAN"VHg, 100) . , 1H), 7.77-7.83 (s, 1H), 7.70 (dd, 9U-2.7, 9.0HzC, 1), 7.49 (s, 1H), 7.37-7 .46 (m, 2H), 7.16 (d, U-8.9Hz, 1H), 3.83 (s, ЗН), 3.69 (s, ЗН).

Example 1.24: Preparation of 1-(acetylphenyl)-3-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 17) 3-(4-Bromo-2 -methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.031g, 0.11mmol) is treated with 3-acetylphenylisocyanate (0.019g, 15.8µl, 0.11mmol, 1.05eq.) in СНоСи» (1ml) similarly to the method given in example 1.2, and compound 17 (0.038g, 0.09mmol, 79905) is obtained as a white solid.

RHMS ti/ya (95)-443 (MaANVg, 99), 466 (MaANU'Vg, 100). "H NMR (400 MHz, acetone-yv) 6: 8.30 (s, 1H), 8.19 (s, 1H), 8.13 (t, 9-1.8 Hz, 1), 7.80 (dd , U-1.4, 8.1Hz, 1), 7.70 (dd, 922.7, 9.0Hz, 1H), 7.62 (d, 927.7 Hz, 1H), 7.49 (s, 1H), 7.44 (d, 9-2.7 Hz, 1H), 7.41 (t, U-7.9 Hz, 1H), 7.15 (d, 9-9.0 Hz, 1H).

Example 1.25: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-methoxyphenyl)urea (Compound 72) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.032g, 00.12mmol) is treated with 3-methoxyphenyl isocyanate (0.018g, 16.00µl, 0.14mmol, 1.05eq.) in СНоСи» ( Iml) similar to the method given in example 1.10, and compound 72 (0.047g, 0.11mmol, 9495) is obtained in the form of a solid film. LCMS t/2 (95)-431 (MaeNVHg, 100), 433 (Ma-NU! Wu, 93). "H NMR (400MHz, acetone-av) 6: 8.13 (s, 2H), 7.68 (d, U-8.9Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.16 (d, U-8.1Hz, 1H), 7.12 (d, 9-7.3Hz, 1H), 6, 98 (d, U-8.0Hz, 1H), 3.81 (s, ZN), 3.76 (s, ZN), 3.68 (s, ZN).

Example 1.26: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-fluorophenyl)urea (Compound 18) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphthalamine (0.033 g, 0.12 mmol) is treated with 3-fluorophenyl isocyanate (0.017 g, 14.3 ml, 0.12 mmol, 1.05 equiv.) in СНоСи» ( ml) similar to the method given in example 1.2, and compound 18 (0.040g, 0.09mmol, 8295) is obtained as a white solid. !Vg, 91). "H NMR (400 MHz, acetone-av) 6: 8.31 (s, 1H), 8.17 (s, 1H), 7.69 (dd, y-2.7, 9, 0Hz, 1H), 7.59 (dt, U-2.2, 12.0Hz, 1), 7.50 (s, 1H), 7.43 (d, 9U-2.6Hz, 1H), 7, 27 (dd, 9U-8.1, 15.0Hz, 1), 7.11-7.19 (m, 2H), 6.73 (ddd, 922.4, 8.4Hz, 1H), 3.82 (c, 1H), 3.69 (c, 1H).

Example 1.27: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2-fluorophenyl)urea (Compound 25) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.034 g, 0.12 mmol) is treated with 2-fluorophenyl isocyanate (0.018 g, 14 4 μl, 0.12 mmol, 1.05 equiv.) in СНоСі» (ml ) similar to the method given in example 1.10, and compound 25 (0.045g, 011mmol, 9195) is obtained in the form of a solid film. LCMS p/2 (953-419 (MaAN"VHg, 99), 421 (MaANVU!'Vu, 100 ). "H NMR (400MHz, SOS") 6: 8.08 (t, 9U-8.1Hz, 1), 7.59 (s, 1H), 7.54 (s, 1H), 7.53- 7.59 (m, 1H), 7.40 (s, 1H), 7.12 (d, 9U-1.5Hz, 1H), 6.95-7.12 (m, ЗН), 6.94 ( d, 9-5.7 Hz, 1H), 3.77 (s,

ZN), 3.70 (c, ZN).

Example 1.28: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-

trifluoromethoxyphenyl)urea (Compound 19) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.032g, 0.11mmol) is treated with 4-(trifluoromethoxy)phenylisocyanate (0.025g, 18 ,4μl, 0.12mmol, 1.05eq.) in СНоСі» (Iml) similarly to the method given in example 1.2, and compound 19 (0.032g, 0.07mmol, 5895) is obtained as a white solid. LCMS ti/ya (95)-485 (M.aAN"Vg, 92), 487 (MANU!Vg, 100). "IN NMR (400 MHz, acetone-aiv) 6: 8.31 (s, 1H), 8 .19 (s, 1H), 7.70 (d, U-9.0Hz, 1), 7.66 (d, U-8.4Hz, 2H), 7.51 (s, 1H), 7.45 (s, 1H), 7.25 (d, U-8.4Hz, 2H), 7.15 (d, --8.9HzC, 1H), 3.83 (s, ЗН), 3.70 (s , ZN).

Example 1.29: Preparation of 1-benzoyl-3-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 73) 3-(4-Bromo-2-methyl) -2H-pyrazol-3-yl)-4-methoxyphenylamine (0.033g, 0.12mmol) is treated with benzoyl isocyanate (0.020g, 0.12mmol, 1.05eq.) in SNeoSi" (ml) similarly to the method given in example 1.2, compound 73 (0.036g, 0.0d8mmol, 72905) was obtained as a white solid. LCMS ti/ya (90)-429 (MeANVH, 99), 431 (MeNU!'VH, 100). "H NMR (400MHz, acetone-av) 6: 10.92 (s, 1H), 9.85 (s, 1H), 8.12 (d, 9-7 AHC, 2H), 7.76 (dd, U-2.6, 9.0Hz, 1H), 7.68 (t, U927.3HzC, 1H), 7.62 (d, 9-2.6HzC, 1), 7.57 (t, 9-7.8HzC, 2H), 7.51 (s, 1H), 7.21 (d, U-9.0 Hz, 1H), 3.86 (s, ZN), 3.71 (s, ZN).

Example 1.30: Preparation of 1-benzyl-3-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 74) 3-(4-Bromo-2-methyl) -2H-pyrazol-3-yl)-4-methoxyphenylamine (0.034g, 0O.12mmol) is treated with benzyl isocyanate (0.017g, 16.OmCl, 0.1Zmmol, 1.05eq.) in CH2Cl2 (ml) similarly to the method given in example 1.10, and compound 74 (0.031g, О0.08mmol, 6295) is obtained in the form of a solid film. РХМСО t/z (95)-415 (MaANVg, 86), 417 (Ma-NU'Vg, 100). H NMR (400 MHz, acetone-α) 6: 8.05 (s, 1H), 7.64 (dd, uU-2.7, 9.0Hz, 1H), 7.A7 (s, 1H), 7, 40 (d, 9-2.7Hz, 1H), 7.27-7.37 (m, AN), 7.22 (t, U9-7.0Hz, 1H), 7.07 (d, U-9 ,0Hz, 1H), 6.21 (s, 1H), 4.A1 (d, U-4, ОГцу, 2H), 3.79 (s, ЗН), 3.66 (s, ЗН).

Example 1.31: Preparation of intermediate 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxyphenylamine 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4- ethoxyphenylamine is obtained according to a method similar to that given in example 1.1, using 4-bromo-5-(2-ethoxy-5-nitrophenyl)-1-methyl-1H-pyrazole, ZpSi".2H2g2O in ЕУН

10,225g, 0.7bmmol, 8195 in three stages from 2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenol) | RKHMOS t/2 (90)-296 (maANVg, 100), 298 (M-ANU'VI, 98). "H NMR (400MHz, SOSIz) 6: 7.52 (s, 1H), 6.86 (d, 9-8.7Hz, 1), 6.77 (dd, 9-22, 8.5Hz, 1H) , 6.62 (d, 9U-2.3Hz, 1H), 3.82-4.00 (m, 2H), 3.73 (s, ZH), 3.24-3.58 (width 2H), 1.24 (t, 9-6.8Hz, tn).

Intermediate 4-bromo-5-(2-ethoxy-5-nitrophenyl)-1-methyl-1H-pyrazole is obtained as follows:

A. 2-(2-Methyl-2H-pyrazol-3-yl)-4-nitrophenol: To methylhydrazine (1.106g, 1.3ml, 23.5mmol, 4.Eq.) at a temperature of 707"C dropwise using 4-nitrochromone in DMSO (1.159g/40ml, 5.88mmol, 1.0eq.) is added to the piston pump and the crude reaction mixture is isolated by HPLC to give 2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenol (0.567g, 2.59mmol, 4495) as a white solid. LCMS t/2 (95)-220 (MAN). "H NMR (400Mhz, acetone-av) 6: 8.24 (dd, 9U-2 ,9, 9.0Hz, 1H), 8.13 (d, 9-2.8Hz, 1H), 7.46 (d, 9-1.8Hz, 1H), 7.26 (d, 9U-9, 0Hz, 1H), 6.36 (d, U-1.8Hz, 1H), 3.77 (s, ЗН).

B. 5-(2-Ethoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (General alkylation technique): To a stirred solution of 2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenol ( 0.206g, 0.94mmol) in a mixture of DMF/THF (1ml/5ml) add Mann (60905, 0.082g, 1.88mmol, 2.0eq.) at 0"C. Stir for 30 minutes, add iodomethane (0.444g, 0.2 ml, Z3, beq.), the mixture is heated to 70"C and stirred until the starting substance is completely consumed.

The reaction is quenched by adding a saturated solution of MNACI, diluted with EtOAc, washed with water, and the aqueous phase is extracted with EtOAc (3x5Oml). The organic extracts are combined, washed with a saturated salt solution, dried over anhydrous Ma5O»x, filtered and evaporated. The crude reaction mixture is brominated without further purification. РХМСО t/: (95)-2248 (MN). "H NMR (400MHz, SOSIz) 6: 8.33 (dd, 9U-2.5, 91Hz, 1), 8.21 (d, 9-2.5Hz, 1H), 7.57 (d, 9U- 1.3Hz, 1H), 7.07 (d, 9-9.1Hz, 1), 6.34 (s, 1H), 4.22 (dd, 9-7.0, 13.9Hz, 2H), 3.78 (s, ЗН), 1.44 (t, 2-6 8Hz, ЗН). b. 4-Bromo-5-(2-ethoxy-5-nitrophenyl)-1-methyl-1H-pyrazole: Crude the reaction mixture, which contains 5-(2-ethoxy-5-nitrophenyl)-1-methyl-1H-pyrazole, is treated with МВ5 in DMF similarly to the method given in example 1.1 at stage O, and the bromine-containing compound 4-bromo-5- (2-ethoxy-5-nitrophenyl)-1-methyl-1H-pyrazole. It is directly reduced to aniline, as described above in this example. LCMS t/l (95)-326 (MaANVg, 88), 328 (MaNU "Hg, 100). "H NMR (400MHz, SOSIv) 6: 8.38 (dd, 9U-2.7, 9.2Hz, 1H), 8.22 (d, 9-52.7Hz, 1H), 7.59 (s, 1H), 7.11 (d, 9-9.2 Hz, 1H), 4.14-4.32 (m, 2H), 3.76 (s, ЗН), 1.43 ( t, U-6.8Hz, ZN).

Example 1.32: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxyphenyl|-3-(4-chlorophenyl)urea (Compound 67) 3-(4-Bromo- 2-methyl-2H-pyrazol-3-yl)-4-ethoxyphenylamine (0.040g, 0.1mmol) is treated with 4-chlorophenylisocyanate (0.023g, 0.15mmol, 1.1eq.) in СНоСи» (ml) similarly to the method, given in example 1.2, compound 67 (0.034g, 0.0d8mmol, 56905) is obtained as a white solid. X-ray mass spectrometry (90)-449 (MAN"VIZ5SI, 72), 451 (M.-NUVIZ5SI, 100), 453 (Ma-NUVIZ7SI, 26). "H NMR (400 MHz, acetone-dv) 5: 8, 22 (s, 1H), 8.14 (s, 1H), 7.66 (dd, 9U-2.7, 9.0Hz, 1), 7.56 (d, 9U-8.9Hz, 2H), 7.49 (c, 1), 7.43 (d, U-2.7Hz, 1H), 7.28 (d, y-8.6Hz, 2H), 7.12 (d, U-9.0Hz , 1H), 3.98-4.18 (m, 2H), 3.71 (s, ЗН), 1.28 (t, 9-71 Hz, ЗН).

Example 1.33: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxyphenyl|-3-(4-fluorophenyl)urea (Compound 68) 3-(4-Bromo- 2-Methyl-2H-pyrazol-3-yl)-4-ethoxyphenylamine (0.039 g, 0.1 mmol) was treated with 4-fluorophenyl isocyanate (0.020 g, 16 mmol, 0.14 mmol, 1.1 equiv) in CH2Cl2 ( 1ml) similarly to the method given in example 1.2, and compound 68 (0.034g, 0.08mmol, 5995) is obtained as a white solid. RHMO t/2 (95)-433 (MAN"VHg, 100), 435 (Ma-NU!Vg, 99). "H NMR (400 MHz, acetone-av) 6: 8.13 (s, 1H), 8 .11 (s, 1H), 7.66 (dd, y-2.7, 8.9Hz, 1), 7.50-7.57 (m, 2H), 7.49 (s, 1H), 7 .42 (d, 9-2.7Hz, 1H), 7.11 (d, U-8.9Hz, 1H), 7.04 (t, U-8.8Hz, 2H), 3.96-4, 18 (m, 2H), 3.71 (s, ЗН), 1.28 (t, 9-7 1Hz, ЗН).

Example 1.34: Preparation of intermediate 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxyphenylamine

The crude reaction mixture containing 4-bromo-5-(2-isopropoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (as described below) is reduced in the presence of ZpSiI».2HgO, similarly to the method given in example 1.1, and obtain 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxyphenylamine (0.043g, 0.14mmol, 5095 steps). RHMO ti/z (95)-310 (MAN"VHg, 99), 312 (MANU'Vu, 100). "H NMR (400MHz, SOSIz) 6: 7.51 (s, 1H), 6.89 (d , y-8.8Hz, 1H), 6.76 (dd, y-2.7, 8.6Hz, 1H), 6.62 (d, 9U-2.7Hz, 1H), 4.08 (ddd . 6.1 Hz, ZN).

Intermediate 4-bromo-5-(2-isopropoxy-5-nitrophenyl)-1-methyl-1H-pyrazole is obtained as follows:

A. 5-(2-Isopropoxy-5-nitrophenyl)-1-methyl-1H-pyrazole: To a stirred solution of 2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenol (0.061 g, O0, 28mmol) in DMF (3ml) add K»CO3 (0.077g, 0.5bmmol, 2.eq.) at room temperature, stir for 30 minutes. and isopropyl bromide (11 µL, 0.146 Hg, 1.1 b6 mmol, 4.0 eq.) is added. The mixture is stirred at 50°C until the starting substance is completely consumed. The reaction mixture is diluted with EIOAc, washed with water, and the aqueous phase is extracted with EIAs. The organic phases are combined, washed with a saturated salt solution, dried over anhydrous Md5O", filtered and evaporated. РХМСО t/2 (96)-5262 (MN). "H NMR (400MHz, SOSIz) at: 8.31 (dd, 922.8, 9.2Hz, 1H), 8.20 (d, 9:2.8Hz, 1H) , 7.56 (s, 1H), 7.06 (d, --9.2Hz, 1H), 6.3 (s, 1H), 4.74 (ddd, 9U-6,1,6,1, 12.1Gu, 1H), 1.37 (s, ЗН), 1.36 (s, ЗН).

B. 4-Bromo-5-(2-isopropoxy-5-nitrophenyl)-1-methyl-1H-pyrazole: A crude reaction mixture containing 5-(2-isopropoxy-5-nitrophenyl)-1-methyl-1H- pyrazole is brominated similarly to the method given in example 1.1 at stage O, and 4-bromo-5-(2-isopropoxy-5-nitrophenyl)-1-methyl-1H-pyrazole is obtained. RHMS t/2 (9o)-340 (MaANVg, 85), 342 (M.-NU!Vg, 100). "H NMR (400MHz, SOSIz) 6: 8.36 (dd, 9U-2.8, 9.2Hz, 1H), 8.20 (d, U-2.8Hz, 1H), 7.57 (s, 1H), 7.10 (d, 9-59.2Hz, 1H), 4.73 (ddd, 9-61, 6.1, 12.1Gu, 1H), 1.39 (d, 9U-6.1Hz , ZN), 1.32 (d,

U-6, oHz, ZN).

Example 1.35: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxyphenyl|-3-(4-chlorophenyl)urea (Compound 59) 3-(4-Bromo- 2-methyl-2H-pyrazol-3-yl)-4-isopropoxyphenylamine (0.024g, 0.0d8mmol) is treated with /4-chlorophenylisocyanate (0.014g, 0.09mmol, 1.1eq.) in SNegSig (ml) similarly to the method, given in example 1.10, and compound 59 (0.034g, 0.07mmol, 91905) is obtained as a white solid. RHMS t/z (95)-463 (MAN" VIZSI, 82), 465 (MANNU VISI, 100), 467 (Manu VISI, 29). "H NMR (400 MHz, acetone-dv) 6: 8.24 (s , 1H), 8.17 (s, 1H), 7.65 (dd, 9U-2.5, 8.9Hz, 1), 7.55 (d, 9U-8.6Hz, 2H), 7.49 (c, 1), 7.42 (d, U-2.5Hz, 1H), 7.28 (d, y-8.6Hz, 2H), 4.42-4.52 (m, 1H), 3 .70 (c, ЗН), 1.26 (d, U-6.0Hz, ЗН), 1.11 (d, У-6.0Hz, ЗН).

Example 1.36: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxyphenyl|-3-(4-fluorophenyl)urea (Compound 60) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-isopropoxyphenylamine (0.027g, 0.09mmol) is treated with /4-fluorophenylisocyanate (0.013g, 11.0mmol, 0.1Omol, 1.1eq.) in СНоСі» (Iml) similarly to the method given in example 1.2, and compound 60 (0.015g, 0.0Zmmol, 38905) is obtained as a white solid.

LCMS t/ (95)-447 (MaeH"VHg, 98), 449 (MaNU!VIg, 100). "H NMR (400 MHz, acetone-dv) o: 8.11 (s, 2H), 7.65 ( dd, 92.4, 8.9Hz, 1), 7.54 (dd, 9U-4.9, 8.7Hz, 2H), 7.49 (s, 1H), 7.41 (d, 9-2 .6Hz, 1), 7.12 (d, 9U-8.9Hz, 1H), 7.04 (t, y-8.6Hz, 2H), 4.40-4.52 (m, 1H), 3 .70 (c, ЗН), 1.26 (d, U-6.0Hz, ЗН), 1.11 (d, У-6.0Hz, ЗН).

Example 1.37: Preparation of 4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenylamine

The reaction mixture of 5-(2-benzyloxy-5-nitrophenyl)-4-bromo-1-methyl-1H-pyrazole is reduced in the presence

ZpC12.2HgO, similar to the method given in example 1.1, and 4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenylamine) is obtained (0.079g, 0.22mmol, 3995 in three stages). RHMS t/ (95)-358 (MAN"VI, 98), 360 (MaNUVg, 100). "H NMR (400MHz, SOSIv) 6: 7.45 (s, 1H), 7.15-7.26 ( m, ZN), 7.10 (d, 9-6.6Hz, 2H), 6.83 (d, 928.7Hz, 1), 6.66 (dd, U-2.8, 8.6Hz, 1H ), 6.55 (d, 9U-2.8Hz, 1H), 4.83 (AB quartet, U-12.0, 17.2Hz, 2H), 3.62 (s, zn).

The intermediate 5-(2-benzyloxy-5-nitrophenyl)-4-bromo-1-methyl-1H-pyrazole is obtained as follows:

A. 5-(2-Benzyloxy-5-nitrophenyl)-1-methyl-1H-pyrazole: 2-(2-Methyl-2H-pyrazol-3-yl)-4-nitrophenol (0.124 g, 0.57 mmol) treat Mann (0.049g, 1.13mmol, 2.0eq.) with its benzyl bromide (0.297g, 0.21ml, 1.70mmol,

C,Eq.) in a mixture of DMF/THF (2 ml/4 ml) similarly to the method given in example 1.31 at stage B, and 5-(2-benzyloxy-5-nitrophenyl)-1-methyl-1H-pyrazole is obtained by LCMS t/ l (95)-310 (M.-N). "H NMR (400 MHz,

SOSIz) 6: 8.32 (dd, 9U-2.8, 9.1Hz, 1), 8.24 (d, U-2.8Hz. 1H), 7.59 (d, 9U-1.7Hz, 1H) , 7.22-7.45 (m, 5H), 7.16 (d, 9U-9.1Hz, 1H), 6.37 (d, 9U-1.7Hz, 1H), 5.25 (s, 2H), 3.77 (s, ЗН).

B. 5-(2-Benzyloxy-5-nitrophenyl)-4-bromo-1-methyl-1H-pyrazole: Crude reaction mixture containing 5-(2-benzyloxy-5-nitrophenyl)-1-methyl-1H- pyrazole, treat MV5 (0.113 g, 0.6 mmol, 1.1 equiv.) similarly to the method given in example 1.1 at stage 0, and obtain 5-(2-benzyloxy-5-nitrophenyl)-4-bromo-1-methyl- 1H-pyrazole. RHMS ti/ (95):388 (MeNVg, 100), 390 (M--NU'Vu, 94). "H NMR (400 MHz, SOSIz) 6: 8.36 (dd, 9-28, 9.2 Hz, 1H), 8.23 (d, U9-2.8 Hz, 1H), 7.59 (s, 1H) .

Example 1.38: Preparation of 1-(4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl)-3-(4-chlorophenyl)urea (Compound 61) 4-Benzyloxy-3-( 4-bromo-2-methyl-2H-pyrazole-3-iluphenylamine (0.023g, 0.09mmol) is treated with 4-chlorophenylisocyanate (0.016g, 0.10mmol, 1.1eq) in CH2Cl2 (1ml) similarly to the method , given in example 1.2, and compound 61 (0.019g, 0.04mmol, 42905) is obtained as a white solid. RHMS t/l (90)-511 (MAN"VIZSI, 82), 513 (M.-NUVIZ5SI, 100), 515 (MANU'VIZ"SI, 33). "H NMR (400 MHz, acetone-dv) δ: 8.22 (s, 1H), 8.16 (s, 1H), 7.66 (dd, 9-24, 8.9Hz, 1H), 7.55 (d, U-8.7Hz, 2H), 7.50 (s, 1H), 7.46 (d, 9U-2.5Hz, 1H), 7.28-7.35 (m, 5H), 7.28 (d, 9-8.7 Hz, 2H), 7.22 (d, U-8.9Hz, 1H), 5.13 (AB quartet , U-12.0, 24.3 Hz, 2H), 3.69 (s, ЗН).

Example 1.39: Preparation of 1-(4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl)-3-(4-fluorophenyl)urea (Compound 62) 4-Benzyloxy-3-( 4-bromo-2-methyl-2H-pyrazole-3-iluphenylamine (0.031 g, 0.59 mmol) is treated with 4-fluorophenyl isocyanate (0.013 g, 11.00 μl, 0.1 mmol, 1 Teq) in CH2Cl ( ml) similar to the method given in example 1.2, and compound 62 (0.011g, 0.02mmol, 26905) is obtained as a white solid. LCMS t/27 (96)-511 (MeANVHg, 82), 513 (MeANU!' VIg, 100). "H NMR (400 MHz, acetone-av) 6: 8.12 (s, 2H), 7.66 (dd, 9-26, 8.9 Hz, 1H), 7.54 (dd, 9 -48, 9.0Hz, 2H), 7.50 (s, 1H), 7.47 (d, U-52.6Hz, 1H), 7.25-7.36 (m, 5H), 7.22 (d, U-8.9Hz, 1), 7.04 (t, U-8.6Hz, 2H), 5.13 (AB quartet, U-12.0, 24.4Hz, 2H), 3.69 (c, ZN).

Example 1.40: Preparation of intermediate 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chlorobenzyloxy)phenyl amine

The crude reaction mixture containing 4-bromo-5-(2-(4-chlorobenzyloxy)-5-nitrophenyl|-1-methyl-1H-pyrazole (as described below) is treated with 5pSi»2HgO (0.378, 1.64 mmol , 4.0 equiv.) in EYN (5 ml) similarly to the method given in example 1.1, and aniline 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chlorobenzyloxy)phenylamine is obtained (0.114g, 0.29mmol, 7195 in two stages). RHMS t/z (95): 392 (MAN"VIZ5SI, 70), 394 (MaANU'VIZSI, 100), 396 (MAN VISI, 23). "H NMR (400MHz, SOCIz) 6: 7.54 (s, 1H), 7.28 (d, 9-8.2Hz, 2H), 7.11 (d, u28.2Hz, 2H), 6.90 (d , 9U-8.7Hz, 1H), 6.76 (dd, 922.7, 8.7Hz, 1H), 6.63 (d, 9U-22.7Hz, 1H), 4.86 (AB quartet,

U-12.1, 20.9Hz, 2H), 3.71 (s, ЗН).

Intermediate 4-bromo-5-|(2-(4-chlorobenzyloxy)-5-nitrophenyl)|-1-methyl-1H-pyrazole is obtained as follows:

A. 4-(2-(4-Chlorobenzyloxy)-5-nitrophenyl|-1-methyl-1H-pyrazole: 2-(2-Methyl-2H-pyrazol-3-yl)-4-nitrophenol (0.143g, . similarly to the method given in example 1.31 at stage B, and obtain 5-|2-(4-chlorobenzyloxy)-5-nitrophenyl)-1-methyl-1H-pyrazole (0.142g, 0.41mmol, 6395) in the form of oil. RHMS. t/z (95)-2344 (MANZ5SI, 100), 346 (MNS, 39). "IN NMR (400 MHz, SOSIz) 6: 8.33 (dd, y-2.8, 9.1 Hz, 1), 8.23 (d, 95-9.1 Hz, 1H), 7.58 (d, 9-1.7Hz, 1H), 7.36 (d, U-8.3Hz, 2H), 7.21 (d, U-8.3Hz, 1H), 7.13 (d, 4-9.1Hz , 1H), 6.36 (d, 9-1.7 Hz, 1H), 5.20 (s, 2H), 3.75 (s, ЗН).

B. 4-Bromo-5-(2-(4-chlorobenzyloxy)-5-nitrophenyl|-1-methyl-1H-pyrazole: 5-(2-(4-Chlorobenzyloxy)-5-nitrophenyl|-1-methyl -1H-pyrazole is treated with MV5 (0.082g, 0.45mmol, 1.05eq.) similarly to the method given in example 1.1 at stage O, and 4-bromo-5-I(2-(4-chlorobenzyloxy)-5- nitrophenyl|-1-methyl-1H-pyrazole. LCMS t/2 (95)-422 (MAN"ZVIZ5CI, 85), 424 (MaiNV'VIZ5CI, 100), 426 (Mane VICI, 26). "H NMR ( 400MHz, SOSIz) 6: 8.37 (dd, 922.7, 9.2Hz, 1H), 8.22 (d, 952.7 Hz, 1H), 7.59 (s, 1H), 7.34 (d, 9U-8.3Hz, 2H), 7.21 (d, y-8.3Hz, 2H), 7.16 (d, U-9.2Hz, 1H), 5.20 (AB quartet, U-12, 1, 15.2Hz, 2H), 3.72 (s, ЗН).

Example 1.41: Preparation of /1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chlorobenzyloxy)phenyl|-3-(4-chlorophenyl)urea (Compound 63 ) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chlorobenzyloxy)phenylamine (0.029g, 0.08mmol) is treated with 4-chlorophenylisocyanate (0.014g, O0.09mmol, 1 ,2 equiv.) in CH2Cl" (ml) similarly to the method given in example 1.2, compound 63 (0.027g, 0.05mmol, 65905) is iodinated as a white solid. LCMS t/l (90)-545 (MAN"VIZ5SIZSI , 65). 1H), 8.17 (s, 1H), 7.66 (dd, 9U-2.7, 9.0Hz, 1H), 7.56 (d, U-8.9Hz, 2H), 7.50 (s, 1H), 7.46 (d, 9-2.7Hz, 1), 7.37 (d, 9-8.7Hz, 2H), 7.33 (d, U-8.7Hz, 2H), 7, 28 (d, u-8.9Hz, 2H), 7.22 (d, U-9.0Hz, 1H), 5.14 (AB quartet, U-12.3, 24.8Hz, 2H), 3, 69 (c, ZN).

Example 1.42: Preparation of /1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chlorobenzyloxy)phenyl|-3-(4-fluorophenyl)urea (Compound 64 ) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chlorobenzyloxy)phenylamine (0.032g, 0.08mmol) is treated with 4-fluorophenylisocyanate (0.014g, 11.1μl, 0 ,1Omol, 1.2equiv.) in CH2Cl" (1ml) similarly to the method given in example 1.2, and compound 64 (0.023g, 0.04mmol, 5495) is obtained as a white solid. РХМО t/2 (953-545 (MaAN"VIZ5CI, 65), 547 (MaANUVIZ5, 100), 549 (MN VIZ7CI, 25). "H NMR (400 MHz, acetone-av) 5: 8.13 (s, 2H), 7.66 (dd, 92.7, 9.0Hz, 1H), 7.51-7.56 (m, ЗН), 7.50 (s, 1H), 7.46 (d, 9-22.7Hz, 1), 7, 37 (d, U-8.7Hz, 2H), 7.33 (d, 9U-8.7Hz, 2H), 7.21 (d, 9U-9.0Hz, 1H), 7.05-7.75 (m, 2H), 5.14 (AB quartet, 9U-12.3, 24.8Hz, 2H), 3.69 (s, zn).

Example 1.43: Preparation of intermediate 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxyphenyl amine

The crude reaction mixture, which contains 4-bromo-1-methyl-5-(5-nitro-2-phenethyloxyphenyl)-1H-pyrazole (as described below), is treated with ZpsCl».2iH20O (0.387g, 1.6d8mmol, 4 ,0 equiv.) in EN (5 ml) similarly to the method given in example 1.1, and obtain aniline 3-(4-bromo-2-methyl-2H-pyrazol-3-yl/-4-phenethyloxyphenylamine (0.124 g, 0.3 mmol , 8095 for two stages) in the form of oil. RHMS ti/l (95): 372 (MAN"VHg, 94), 394 (MeNU!Vh, 100).

IN NMR (400MHz, SOSIv) 5: 7.54 (s, 1H), 7.18-7.33 (m. ZN), 7.08 (d, 9-7.7Hz, 2H), 6.85 ( d, U-8.7Hz, 1H), 6.77 (dd, uU-2.7, 8.7Hz, 1H), 6.61 (d, 9U-2.6Hz, 1H), 3.99-4 ,15 (m, 2H), 3.53 (s, ZH), 3.10-3.40 (width, 2H), 2.83-3.00 (m, 2H).

Intermediate 4-bromo-1-methyl-5-(5-nitro-2-phenethyloxyphenyl)-1H-pyrazole is obtained as follows:

A. 1-Methyl-5-(5-nitro-2-phenethyloxyphenyl)-1H-pyrazole: 2-(2-Methyl-2H-pyrazol-3-yl)-4-nitrophenol (0.125g, 0.57mmol) treated with Mann (0.049g, 1.14mmol, 2.0eq) and (2-bromomethyl)benzene (0.323g, 0.24ml, 1.71mmol, 3.0eq) in a mixture of DMF/THF (0.9ml/2 .5ml) similar to the method given in example 1.31 at stage B, and 1-methyl-5-(5-nitro-2-phenethyloxyphenyl)-1H-pyrazole (0.137g, 0.42mmol, 7495) is obtained in the form of oil. RHMS. t/ (95)-324 (MN). "H NMR (400 MHz, SOSIz) 6: 8.31 (dd, yU-2.8, 9.1Hz, 1), 8.17 (d, y-2.6Hz, 1), 7.59 (s, 1H), 7.20-7.36 (m, ЗН), 7.09 (d, 9-7.1Hz, 2H), 7.05 (d, U-9.2Hz, 1H), 6.26 ( s, 1H), 4.33 (t, uU-6.6Hz, 2H), 3.55 (s, ЗН), 3.05 (t, У-6.6Hz, 2H).

B. 4-Bromo-1-methyl-5-(5-nitro-2-phenethyloxyphenyl)-1H-pyrazole: 1-Methyl-5-(5-nitro-2-phenethyloxyphenyl)-1H-pyrazole (0.137g, . nitro-2-phenethyloxyphenyl)-1H-pyrazole. LCMS t/l (95)-402 (MaN"Vg, 100), 404 (MaNU'Vu, 97). "H NMR (400 MHz,

SOSIz) 6: 8.27 (dd, uU-2.8, 9.2Hz, 1H), 8.10 (d, 9U-2.8HzC, 1), 7.52 (s, 1H), 7.16 -7.24 (m, ЗН), 6.94-7.03 (m, ЗН), 4.18-4.28 (m, 2Н), 3.37 (s, ЗН), 2.88-3 ,02 (m, 2H).

Example 1.44. Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxyphenyl|-3-(4-chlorophenyl)urea (Compound 66) 3-(4-Bromo-2- methyl-2H-pyrazol-3-yl)-4-phenethyloxyphenylamine (0.028g, 0.07mmol) is treated with 4-chlorophenylisocyanate (0.014g, 0.09mmol, 1.2eq.) in CH2Cl2 (ml) similarly to the method given in Example 1.10, compound 6b (0.025g, 0.05mmol, 6695) was obtained in the form of a solid film. RHMS t/2 (90)-525 (MAN"VIZSI, 85), 527 (M.-NUVIZ5SI, 100), 529 (MANU'VIZ7SI, 31). "H NMR (400 MHz, acetone-dv) 5: 8.34 (s, 1H), 8.26 (s, 1H), 7.65 (dd, 9U-2.7, 8.9Hz, 1H), 7.56 (d, U-8.9Hz, 2H), 7.53 (s, 1H), 7.43 (d, 922.7 Hz, 1H), 7.16-7 .31 (m, 5H), 7.09-7.16 (m, ЗН), 4.11-4.30 (m, 2Н), 3.51 (s, ЗН), 2.86-3.06 (m, 2H).

Example 1.45: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxyphenyl|-3-(4-fluorophenyl)urea (Compound 65) 3-(4-Bromo -2-methyl-2H-pyrazol-3-yl)-4-phenethyloxyphenylamine (0.029g, 0.08mmol) is treated with 4-

with fluorophenyl isocyanate (0.013g, 11, 0.09mmol, 1.2eq) in CH2Cl2 (ml) similarly to the method given in example 1.10, and compound 65 (0.030g, 0.0bmmol, 7495) is obtained in the form of a solid film . RHMS Ip/2 (90)-509 (MeANVH, 100), 511 (MaН8!Vu, 97). "H NMR (400 MHz, acetone-av) 5: 8.22 (s, 2H), 7.63 (d, 9-8.9 Hz, 1H), 7.48-7.56 (m, ЗН), 7 .41 (s, 1H), 7.15-7.28 (m, ЗН), 7.08-7.16 (m, ЗН), 7.03 (t, U-8.7Hz, 2Н), 4 ,08-4.30 (m, 2H), 3.50 (s, ЗН), 2.86-3.06 (m, 2H).

Example 1.46: Preparation of intermediate 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylaminoethoxy)phenylamine (2-(2-(4-Bromo-2-methyl-2H- pyrazol-3-yl)-4-nitrophenoxy|)ethyl dimethylamine (0.128 g, 0.35 mmol) is treated with 5 psSi".2H 2 gO (0.319 g, 1.39 mmol, 4.0 equiv.) in EN (20 ml) similarly to the method given in the example 1.1, and 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-2-dimethylaminoethoxy)phenylamine (0.067 tg, 0.20 mmol, 5695) is obtained as an oil. LCMS ti/z (95)-339 (MaAN"Vg, 78), 341 (MaNU!'Vu, 100). "H NMR (400 MHz, acetone-iv) o: 7.68 (dd, U-2.5 , 8.9 Hz, 1H), 7.55 (s, 1H), 7.45-7.51 (m, 2H), 4.62-4.82 (m, 2H), 3.76 (s, ЗН ), 3.65-3.76 (m, 2H), 2.87 (s, 6H).

The intermediate 42-(2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|)ethyl-dimethylamine is obtained as follows:

A. Dimethyl2-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxyethyl)amine: /2-(2-Methyl-2H-pyrazol-3-yl)-4-nitrophenol ( . /10 ml) similar to the method given in example 1.31 at stage B, and obtain dimethyl (2-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|ethylamine) (0.280g, 0.9bmmol , 6295) in the form of a yellow solid. RHMSOS t/2 (90)-:291 (MH). "H NMR (400MHz, SOSIz) 6: 8.31 (dd, 92.8, 9.1Hz, 1), 8.18 (d, 952.8Hz, 1H), 7.52 (d, 921.9Hz, 1H), 7.08 (d, -9.1Gu, 1H), 6.30 (d, 9-1, 9HzC, 1H), 4.20 (t, 9-5.7 Hz, 2H), 3.76 (s, ЗН), 2.69 (t, 9-5.7Hz, 2H), 2.22 (s , 6H).

B. (2--2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|ethyl)dimethylamine: To dimethyl2-(2-(2-methyl-2H-pyrazol-3 -yl)-4-nitrophenoxy|ethyl)amine (0.239g, 0.82mmol) in SNeoSi" (10ml) is added dropwise at 0"C

Hg" (47 μl, 0.145 g, 0.91 mmol, 1.1 equiv.) in СНоСі" (3.5 ml) and the mixture is stirred at the specified temperature for 3 hours. Additionally, H2O (40 μl) is added and the mixture is stirred for another 2 hours to allow the remaining starting substances to react. The reaction is quenched by adding a saturated solution

Mag252Oz3, washed with a saturated solution of ManHCO3, and the aqueous phase is extracted with EtOAc. The organic phases are combined, washed with a saturated salt solution, dried over anhydrous Md5O", filtered and evaporated.

The crude reaction mixture was purified by HPLC to give (2-(2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|ethyl)dimethylamine (128 g, 0.35 mmol, 4295). LCMS t /ya (95)-369 (MaAN"Vg, 100), 371 (MaANU'VI, 97). "H NMR (400MHz, SOSIz) 6: 8.45 (dd, uU-2.6, 9.2Hz, 1), 8.21 (d, 9U-2.6Hz, 1H), 7.59 (s, 1H), 7.19 (d, 9-9.2Hz, 1H), 4.34-4.56 ( m, 2H), 3.60 (s, ЗН), 3.23-3.50 (m, 2H), 2.59 (s, 6H).

Example 1.47: Preparation of 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4--2-dimethylaminoethoxy)phenyl|-3-(4-chlorophenyl)urea (Compound 69)

4- chlorophenyl isocyanate (0.017 g, 0.117 mmol, 1.1 equiv.). After the reaction, the solvent is removed and the reaction mixture is purified by HPLC. Pure fractions are collected and CH3SM is evaporated under vacuum. The residue is diluted with EAs and neutralized with a saturated solution of MansSoz; phase

ETAS is washed with a saturated salt solution, dried over anhydrous Ma95O", filtered and evaporated.

Compound 69 was obtained with a yield of 8595. LCMS t/l (95)-492 (MaAN"VIZ5Si, 78), 494 (MANNU VISI, 100), 496 (MaANUVIZ7Si, 28). "H NMR (400 MHz, acetone-dv) 6 : 8.17 (s, 2H), 7.66 (dd, U-2.7, 9.0Hz, 1H), 7.50-7.58 (m, 2H), 7.48 (s, 1H) , 7.43 (d, 9-2.7Hz, 1H), 7.13 (d, U-9.0Hz, 1), 7.04 (t, U-8.8Hz, 2H), 3.98- 4.20 (m, 2H), 3.73 (s, ЗН), 2.49-2.66 (m, 2H), 2.16 (s, 6H).

Example 1.48: Preparation of 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4--2-dimethylaminoethoxy)phenyl|-3-(4-fluorophenyl)urea (Compound 70) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4--2-dimethylaminoethoxy)pheshlamin (0.034 g, 0.1 mmol) is treated with 4-fluorophenyl isocyanate (0.015 g, 12.5 μl, 0.11 mmol) , 1.1 equiv.-) in СНоСи» (2 ml) similarly to the method given in example 1.47, and compound 70 (0.020 g, 0.04 mmol, 4295) is obtained. RHMS t/z (95)-476 (MaANVg, 100), 478 (M.-NU'Vg, 87). "H NMR (400MHz, acetone-av) 6: 8.17 (s, 2H), 7.66 (dd, uU-2.7, 9.0Hz, 1H), 7.50-7.58 (m, 2H), 7.48 (s, 1H), 7.43 (d, 9-2.7Hz, 1H), 7.13 (d, 9U-9.0HzC, 1H), 7.04 (t, U- 8.8Hz, 2H), 3.98-4.20 (m, 2H), 3.73 (s, ЗН), 2.49-2.66 (m, 2H), 2.16 (s, 6H) .

Example 1.49; Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea (Compound 58)

To Compound 1 (see example 1.16) in SNeSi" (1.170g, 2.68mmol) at a temperature of 0"C, slowly add anhydrous AISiS (1.432g, 10.74mmol, 4.0eq.), mix while boiling with reflux in the refrigerator overnight and then the reaction is quenched by adding a saturated solution of MnSOOz. The mixture is extracted with EIHUASc, the organic phases are combined, washed with water and a saturated salt solution, dried over anhydrous MdSO, filtered and evaporated. First, it is purified by column chromatography at 500" (eluent:

EOAc/hexane-from 1/3 to 1/1) and then the main fraction containing compound 58 is purified by HPLC. Clean fractions are neutralized with a saturated solution of Manso»z, extracted with EIOAc and dried over anhydrous Md5O4. The Ma5OH was filtered off and the solvent was removed in vacuo to give compound 58 as a white solid.

RHMS ti/ (965-421 (MaAN" VZSI, 69), 423 (MaNU'VZSI, 100), 425 (Mane VIZ SI, 21). "YAN NMR (400 MHz, acetone-av) 6: 8.47 (s , 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.44 (d, U-8.9Hz, 2H), 7.38-7.43 (m, 1H), 7.35 (s, 1H), 7.26 (d, U5-2.6Hz, 1H), 7.15 (d, U-8.9Hz, 2H), 6.87 (d, U-8.8Hz , 1Н), 3.62 (с, ЗН).

Example 1.50: Preparation of intermediate 4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)/uphenylamine 5-(2-Methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (2.11 g, 9.0bmmol) are treated with 5psSi»2H2O (8.341g, 36.22mmol, 4.0eq.) in EUN (50ml) similarly to the method given in example 1.1, and 4-methoxy-3-(2-methyl-2H-pyrazole -3-iluphenylamine (1.592g, 7.8Zmmol, 8795) in the form of oil. РХМО t/a (96)-204 (MN). "H

NMR (400 MHz, SOSIv) 6: 7.51 (d, 9U-1.8Hz, 1H), 6.83 (d, U9-8.7Hz, 1H), 6.76 (dd, 9U-2.8, 8.7Hz, 1H), 6.62 (d, y-2.6Hz, 1H), 6.22 (d, 9U-1.8HzC, 1H), 3.74 (s, ЗН), 3.73 ( s, ZN), 3.24-3.55 (width s, 2H).

Example 1.51: Preparation of 1-(4-chlorophenyl)-3-(4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea

(Compound 75) 4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine (0.291 g, 1.4 mmol) was treated with 4-chlorophenyl isocyanate (0.247 g, 1.57 mmol, 1.1 equiv.) in СНоСи» (5 ml) similarly to the method given in example 1.2, compound 75 (0.415 g, 1.16 mmol, 81905) is obtained as a white solid. РХМС t/i (90)-357 (MN). "H YAMER (400MHZ, acetone-dv) 6: 8.21 (s, 1H), 8.07 (s, 1H), 7.58 (dd, uU-2.8, 8.9Hz, 1), 7 .56 (d, U-8.8Hz, 2H), 7.44 (d, 9-2.7Hz, 1H), 7.39 (d, 9U-1.8Hz, 1H), 7.28 (d, 9U-8.8Hz, 2H), 7.08 (d, U-8.9Hz, 1), 6.20 (d, U9-1.8Hz, 1H), 3.81 (s, ЗН), 3, 68 (c, ZN).

Example 1.52: Preparation of intermediate 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine 4-Chloro-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H- pyrazole (2.27g, 8.5mmol) is dissolved in dry EUN (150ml) and heated to 75"C. Tin chloride dihydrate (II) (9.6g, 42.5mmol) is added to the hot solution and stirred at 75"C. After three hours, TLC and LCMS control shows that the reaction is complete.

The solvent is removed under reduced pressure. The residue is successively diluted with ETOAc and yin Mmaon, the reaction mixture is neutralized to about 6 or 7. Then the mixture is filtered through celite. The organic phase is separated and the aqueous phase is extracted with E(OAc (2x50 ml). The organic layers are combined, dried over Mag5O", filtered and the solvent is removed under reduced pressure. The residue is then purified by flash chromatography (Vioiade, 50", gradient elution with a mixture of hexane/ E(OAc) and obtain 1.73 g (8695) of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine in the form of a light brown solid. LCMS t/2 (95) -240 (MANUSI, 37), 238 (MANI, 100). "H NMR (400 MHz, SOSI3) o: 7.48 (s, 1H), 6.87 (d, 9-8, 1H), 6.81 (dd, 1-8,

U2х4, 1H), 6.63 (d, 9-4, 1H), 3.72 (s, ЗН), 3.70 (s, ЗН).

Intermediate 4-chloro-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole is obtained as follows: 5-(2-Methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (2 ,37g, 10.17mmol) is dissolved in DMF (100ml). Then the solution is heated to 80"C. M-chlorosuccinimide (1.49 g, 11.immol) is added at a temperature of 80"C in an argon atmosphere. Stir continuously for 2 hours, monitor the course of the reaction by TLC method and

RHMS and establish that the reaction has not ended. An additional aliquot of MOH (0.5 g, 3.7 mmol) is added, after which the reaction ends after 1.5 hours. To precipitate the product from the solution, a portion of water (200 ml) is added while stirring. After the formation of a precipitate, the flask containing the solid substance is heated for 10 minutes. cooled in an ice bath. Then the solid substance is filtered off under vacuum and washed with water, obtaining 2.4 g (8995) of 4-chloro-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole. The obtained substance is used at the next stage without further purification. RHMS ti/ (95)-:267 (M.N). "H NMR (400 MHz,

SOS z) 6: 8.41 (dd, U1-8Hz, 92-24 Hz, 1H), 8.22 (d, U-4HzC, 1H), 7.53 (s, 1H), 7.14 (d , 9-12Hz, 1H), 3.97 (s, ZN), 3.72 (s, ZN).

Example 1.53: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-fluorophenyl)urea (Compound 28) 3-(4-Chloro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (20 mg, 0.0 v8 mmol) was dissolved in anhydrous

SNesi" (150 ml) and treated with 4-fluorophenyl isocyanate, while compound 28 immediately begins to precipitate as a white solid. The reaction mixture is stirred at room temperature for 3 hours.

Then the flask with the solid substance is cooled in an ice bath for 20 min. The solid substance is filtered off under vacuum and washed with СНоСи», obtaining 17.7 mg (2695) of compound 28. LCMS t/ya (95)-377 (MANUССИ, 39), 375 (MANZССИ, 100). Н NMR (400MHz, DMSO-α) 6: 8.95 (s, 1H), 8.93 (s, 1H), 7.86 (s, 1H), 7.81 (dd, U12:9Hz, 9Ua24 Hz, 1H), 7 ... ), 4.01 (s, ZN), 3.86 (s, ZN).

Example 1.54; Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-fluorophenyl)urea (Compound 36) 3-(4-Chloro-2-methyl) -2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3-fluorophenylisocyanate similarly to the method given in example 1.53, and 0.5 mg (195) of compound 36 is obtained. , 375 (Ma-NUZSI, 100). "H NMR (400 MHz, acetone-yv) 6: 8.23 (s, 1H), 7.45 (dt, 51-12, uUe-4, dzh2Hz, 1H), 7.37 (s, 1H), 7 ... .77 (d, U-2Hz, 1H), 6.63 (td, U1-8Hz, 9U2-4Hz, 1H), 3.68 (s, ЗН), 3.52 (s, ЗН).

Example 1.55: Preparation of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl)-3-(2,4-difluorophenyl)urea (Compound 29) 3-(4 -Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 2,4-difluorophenylisocyanate similarly to the method given in example 1.53, and 26.7 mg (3695) of compound 29 are obtained. LCMS t/ (95) -395 (MaANUSI, 35), 393 (MNS, 100). "H NMR (400MHz, DMSO-av) 6: 9.00 (s, 1H), 8.43 (s, 1H), 8.03 (m, U1-12Gu, usch2agtsC, 1), 7.56 (s , 1H), 7.50 (dd, 9U1-:9Hz, U2-4 Hz, 1), 7.34 (d, 9-4 Hz, 1), 7.28 (m, U1-12Hz, 9da2:4 Hz, 1H), 7.12 (d, U Gu, 1H), 7.01 (m, 91-28 Hz, 9dae22HzC, 1), 3.72 (s, ЗН), 3.56 (s, ЗН) .

Example 1.56: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-methoxyphenyl)urea (Compound 30) 3-(4-Chloro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3-methoxyphenyl isocyanate similarly to the method given in example 1.53, and 7.5 mg (27965) of compound 30 is obtained. (Note: the compound does not precipitate. Therefore, CH2Si » is removed under reduced pressure, the residue is dissolved in 5 ml of DMSO and purified by HPLC). LCMS ti/z (95)-389 (Ma-NU"Si, 39), 387 (MANI, 100). "H NMR (400 MHz, acetone-av) 5: 7.99 (s, 1H), 7.49 (dd, 9U12:8Hz, 9h222 Hz, 1H), 7.29 (d, 9-8Hz, 1), 7.28 (s, 1H), 7.12 (t, U-22Hz, 1H), 6, 95 (d, U-52Hz, 1), 6.93 (d, U-4Hz, 1H), 6.81 (dd, U1-8Hz, U2-4 Hz, 1H), 6.37 (dd, U129Hz, 924 Hz, 1H), 3.63 (s, ЗН), 3.57 (s, ЗН), 3.47 (s, ЗН).

Example 1.57: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2-trifluoromethoxyphenyl)urea (Compound 34) 3-(4-Chloro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 2-trifluoromethoxyphenylisocyanate similarly to the method given in example 1.53, and 1.5 mg (395) of compound 34 is obtained. LCMS ti/z (95)-440 (M .-NU"SI, 14), 438 (MANZZSI, 14). "H NMR (400 MHz, acetone-av) 6: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 ( d, U-4Hz, 1), 7.25 (s, 1H), 7.04 (t, 9-12Hz, 2H), 6.99 (dd, U1-8Hz, 9Ua2-2Hz, 1), 6, 75 (d,

U-AgHzC, 1), 6.72 (d, U-4Hz, 1H), 6.66 (d, U-2Hz, 1H), 3.63 (s, ЗН), 3.45 (s, ЗН) .

Example 1.58: Preparation of 1-(3-acetylphenyl)-3-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-

Methoxyphenyl|urea (Compound 35) 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3-acetylphenylisocyanate similarly to the method given in example 1.53, and 3.7 mg (695) are obtained compound 35. (Note: the compound does not precipitate. Therefore, CH2Si" is removed under reduced pressure, the residue is dissolved in 5 ml of DMSO and purified by HPLC). LCMS ti/z (95)-: 401 (MaANUSI, 27), 399 (MANI, 100). s, 1H), 8.23 (s, 1H), 7.84 (d, U-8Hz, 1H), 7.75 (dd, U1212Hz, shU2eZHz, 1H), 7.62 (d, U-vHz, 1H), 7.56 (d, 9-4Hz, 1H), 7.49 (s, 1H), 7.43 (t, U-8Hz, 1), 7.16 (d, U-8Hz, 1H) , 3.84 (s, ZN), 3.69 (s, ZN), 3.42 (s, ZN).

Example 1.59: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chlorophenyl)urea (Compound 26) 3-(4-Chloro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-chlorophenylisocyanate similarly to the method given in example 1.53, and 12 mg (3095) of compound 26 are obtained. LCMS ti/z (95)-393 (MHC, 60 ), 391 (MANI, 100). "H NMR (400 MHz, DMSO-av) 6: 8.80 (s, 1H), 8.71 (s, 1H), 7.62 (s, 1H), 7.57 (dd, U1-8Hz,

У2АЦС, 1), 7.49 (dd, У1-8Hz, 9У2-2Hz, 2Н), 7.39 (d, У-4ХцЦ, 1Н), 7.33 (dd, У1-8Hz, 9Уа2-2Hz, 2Н ), 7.17 (d, U-8Hz, 1H), 3.77 (s, ZN), 3.62 (s, ZN).

Example 1.60: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-isopropylphenyl)urea (Compound 76) 3-(4-Chloro- 2-Methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-isopropylphenylisocyanate similarly to the procedure given in Example 1.53, and 1.3 mg (295) of compound 76 is obtained. (Note: compound 76 does not precipitate. Therefore CH2Si2" is removed under reduced pressure, the residue is dissolved in 5 ml of DMSO and purified by HPLC). РХМСО t/ya (95)-401 (MaNZ"SI, 31), 399 (MANZZSI, 100). "H NMR (400 MHz, acetone-av) o: 8.63 (s, 1H), 8.52 (s , 1H), 7.59 (dd, U12:8Hz, 924 Hz, 1H), 7.41 (d, U52Hz, 1H), 7.37 (dd, U1-12Hz, Ug22Hz, 2H), 7.33 ( s, 1H), 7.17 (dd, U1-:8 Hz, da22Hz, 2H), 7.00 (d, U9U-12HzC, 1), 3.68 (s, ЗН), 3.54 (s, ZN).

Example 1.61: Preparation of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl)-3-(2,4-dichlorophenyl)urea (Compound 77) 3-(4 -Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 2,A4-dichlorophenylisocyanate similarly to the method given in example 1.53, and 16 4 mg (24905) of compound 77 are obtained. (Note: compound 77 does not precipitate Therefore, CH2Si" is removed under reduced pressure, the residue is dissolved in 5 ml of DMSO and purified by HPLC). RHMO ti/a (95)-427 (Ma-NUZ"SI, 72), 425 (MANZSI, 100). "H NMR (400 MHz, acetone-av) o: 8.85 (s, 1Н), 8.26 (dd, U1-12 Hz, Ug4Hz, 1H) 7.90 (s, 1H), 7.59 (dd, U128Hz, 9U2-4 Hz, 1H), 7.38 (d, 9U54Hz, 1H), 7, 36 (s, 1H), 7.36 (s, 1H), 7.24 (dd, 9U1-12Hz, 9Ua24 Hz, 1), 7.05 (d, U-8HzC, 1H), 3.72 (s , ZN), 3.56 (c, ZN).

Example 1.62: Preparation of //- 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-naphthalen-1-ylurea (Compound 78) 3-(4- Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 1-naphthyl isocyanate similarly to the method given in example 1.53, and 21.1 mg (6095) of compound 78 are obtained. LCMS t/a (95)-409 (MaANU"SI, 38), 407 (MaANZZSI, 100). "H NMR (400 MHz, DMSO-dv) 6: 9.02 (s, 1H), 8.71 (s, 1H), 8.10 (d , U-8HzC, 1), 7.96 (d,

UvHz, 1), 7.91 (d, U-8Hz, 1), 7.61 (s, 1H), 7.59 (t, U-4HzC, 1), 7.58 (s, 1H), 7 .56 (t, U-2HzC, 1H), 7.54 (dd,

U-4Hz, 9x2 Hz, 1H), 7.45 (d, U-8HzC, 1H), 7.41 (d, U-4 Hz, 1H), 7.16 (d, 9-8Hz, 1H), 3.75 (s, ZN), 3.60 (s, ZN).

Example 1.63: Preparation of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|)|-3-(4-chloro-2-trifluoromethylphenyl)urea (Compound 79) 3 -(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 2-chloro-2-trifluoromethylphenylisocyanate similarly to the method given in example 1.53. and 4.4 mg (895) of compound 79 are obtained. (Note: compound 79 does not precipitate. Therefore, CH2Si" is removed under reduced pressure, the residue is dissolved in 3 ml of DMSO and purified by HPLC): РХМО p/z (95)-461 (MaNU "SI, 60), 459 (MANZSI, 100).

IN NMR (400 MHz, acetone-dv) 5: 8.99 (s, 1H), 8.30 (s, 1H), 8.16 (dd, U1-8Hz, 9Ua222Hz, 1H), 8.01 (d, U-8Hz, 1), 7.66 (s, 1H), 7.64 (d, U-4Hz, 1H), 7.45 (d, U-4Hz, 1H), 7.43 (s, 1H) , 7.12 (d, U-8Hz, 1H), 3.79 (s, ZN), 3.63 (s, ZN).

Example 1.64: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-trifluoromethylphenyl)urea (Compound 80) 3-(4-Chloro- 2-Methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-trifluoromethylphenylisocyanate similarly to the method given in example 1.53, and 8 mg (1595) of compound 80 is obtained. (Note: compound 80 does not precipitate. Therefore, CH2Si» removed under reduced pressure, the residue was dissolved in 5 ml of DMSO and purified by HPLC): LCMO ti/ (96)-427 (ManZ"Si, 22), 425 (MANSI, 100). "H NMR (400 MHz, acetone-av) about: 8.48 (s, 1H), 8.24 (s, 1H), 7.56 (d, U-8HzC, 2H), 7.50 (dd, U12:8Hz, 9sh:2Hz, 1H), 7, 40 (d, U-8Hz, 1), 7.28 (d, U-4Hz, 1), 7.27 (s, 1H), 6.96 (d, 9-12Hz, 1H), 3.62 ( c, ZN), 3.46 (c, ZN).

Example 1.65: Preparation of 1--4-bromophenyl)-3-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 81) 3-(4-Chloro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-bromophenyl isocyanate similarly to the method given in example 1.53, and 2.3 mg (695) of compound 81 is obtained: РХМО t/2 (96)-437 (МНС , 100), 435 (MANZZSI, 82). "H NMR (400MHz, DMSO-av) 6: 8.97 (d, U-2Hz, 2H), 8.80 (s, 1H), 8.70 (s, 1H), 7.61 (s, 1H ), 7.53 (dd, U1-12Hz, 9U228Hz, 1H), 7.44 (t, Ux4Hz, 2H), 7.35 (d, U-4Hz, 1H), 7.13 (d, U-8Hz , 1), 3.74 (c, ZN), 3.58 (c, ZN).

Example 1.66: Preparation of /1-(3,5-bis-trifluoromethylphenyl)-3-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 82) 3 -(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3,5-bis(trifluoromethyl)phenylisocyanate similarly to the method given in example 1.53, and 21.5 mg (3295) of compound 82 are obtained : LCMS ti/ (95)-495 (M.-NU"SI, 41), 493 (MANZZSI, 100). "H NMR (400 MHz, DMSO-adv) 6: 9.58 (s, 1H), 9, 18 (s, 1H), 8.31 (s, 2H), 7.80 (s, 1H), 7.79 (s, 1H), 7.79 (dd, U128Hz, 92-24 Hz, 1H), 7.59 (d, U22Hz, 1H), 7.36 (d, U-8Hz, 1H), 3.96 (s, ЗН), 3.80 (s, ЗН).

Example 1.67: Preparation of intermediate 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine

To obtain 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine, two reduction methods are used, which are given below:

Reduction method A: To 4-fluoro-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (205 mg, 0.817 mmol) in

Tin (II) chloride dihydrate (626.3mg, 2.45mmol) was added to EUN (25ml) and heated to a temperature of 507C for 12 hours. Allow the reaction mixture to cool to room temperature and add 1095 MOH (10O0ml). Add EAs (50 ml) and separate the organic phase. The aqueous layer is extracted with E(Ac (2 x 50 ml), the organic layers are combined, dried over Na»5O»m, filtered and the solvent is removed under reduced pressure.

The residue was dissolved in DMSO (5 ml) and purified by preparative HPLC, obtaining 85 mg (4795) of 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine as a light brown oil. RHMO t/ (95):222 (MN, 100). "H NMR (400MHz, SOSIv) 6: 7.38 (d, Un,e-:4.8Hz, 1), 6.86 (d, U-8.8Hz, 1H), 6.79 (dd, u1 -8.8Hz, 9U2-:2.8HzC, 1H), 6.64 (d, 9-2.6Hz, 1), 3.75 (s, ZN), 3.69 (s, ZN), 3, 21 (c, 2H). E NMR (376 MHz, SOSI") 6: (175.50 (Chne25, ZHz, 16).

Reduction method B: To 4-fluoro-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (109 mg, 0.434 mmol) in

To EUN (1 Oml) add Ra-C (1095 wt, Oedizza) and bubble Neo gas out of the balloon. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure to give 9Zmg (9795). 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine as a light brown oil. RHMO t/ (95):222 (MN, 100). "H NMR (400MHz, SOSIv) 6: 7.38 (d, Une4.4Hz, 1), 6.86 (d, U-8.8Hz, 1H), 6.78 (dd, U1-8.8Hz, 9U2-:2.8Hz, 1H), 6.63 (d, 9-2.8Hz, 1), 3.74 (s, ЗН), 3.68 (s, ЗН), 3.53 (s, 2Н ). There is NMR (376 MHz, SOSIz) 6: -175.50 (d,

Uneh5, HZ, 1).

Intermediate 4-fluoro-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole, which is used in reduction methods A and B, is obtained as follows: 5-(2-Methoxy-5-nitrophenyl)- 1-Methyl-1H-pyrazole (300.00 mg, 1.29 mol) is dissolved in ACM (15 ml) in a polypropylene tube for scintillation. To the resulting solution is added bBeissiog (913.9mg, 2.58mmol), the mixture is degassed with argon and heated for 2 hours to a temperature of 80°C. The solvent is removed under reduced pressure and the residue is dissolved in 500ml EOAc and 30ml Zn NS. The organic layer is separated and the aqueous layer the layer is extracted with EtOAc (2 x 50 ml). The organic layers are combined, dried over MgCl5Ox, filtered and the solvent is removed under reduced pressure. The residue is purified by flash chromatography (Vioide 500), gradient elution in hexane (0.0195 TEAUEOAc) and 108 mg is obtained (3395) 4-fluoro-5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole in the form of a white solid. LCMS t/2 (95)-5252 (MH, 100). "H NMR (400MHz, SOSIv) 5: 8.39 (d, U-29.2Hz, 1H), 8.22 (s, 1H), 7.44 (d, Uni4, A4HzC, 1), 7.12 (d, 9U-9.2Hz, 1H) 3.98 (s, ZN), 3.77 (s, ZN). E NMR (376 MHz, SOSIz) 6: -175.50 (d, Une5, ZHcC, 1KE).

Example 1.68: Preparation of 1-(4-chlorophenyl)-3-(3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 27) 3-(4-Fluoro -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (49mg, 0.22mmol) was dissolved in 3ml of SNeSig, 4-chlorophenylisocyanate (40mg, 0.27mmol) was added and stirred overnight at room temperature.

The solvent is removed under reduced pressure, the residue is dissolved in DMSO (5ml) and purified by HPLC to give compound 27 as a white solid, 41mg, yield 4995: LCMS t/z (95)5377 (M'-NUZ"SI, 31), 375. -2.6Hz, 1H), 7.60 (d, 9U-9.2Hz, 2H), 7.54 (d, 9U-2.8Hz, 1), 7.38 (d, Unee-4.4Hz, 1). "E NMR (376 MHz, acetone-av) 6: -177.39 (d, Une5.3Hz, 1P).

Example 1.69: Preparation of 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|/|-3-(4-fluorophenyl)urea (Compound 31) 3-(4- Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (45mg, 0.20mmol) was dissolved in 3ml of CHNeSig, treated with 4-fluorophenylisocyanate (29μl, 0.24mmol) and stirred overnight at room temperature. The desired compound precipitates from the solution and is filtered off, washed with NaCl and compound 31 is obtained as a white solid, 56 mg, yield 7795: LCMS t/l (95)-359 (MH, 100). 7N

NMR (400 MHz, acetone-av) 6: 8.12 (s, 1H), 8.08 (s, 1H), 7.63 (ddd, U129.0Hz, 9U2-2.6Hz, 1H), 7.54 (m, 2H), 7.48 (d, u2.8Hz, 1H), 7.38 (d, Une-4.8Hz, 1), 7.13 (d, U-8.8Hz, 1H), 7 .05 (dd, uU1-9.0Hz, 9U2-29.0Hz, 2H), 3.83 (s, ЗН), 3.65 (s, ЗН). NMR (376MHz, acetone-yv) 6: -123.08 (m, 1P), -177.41 (d, Unk5.3Hz, 1).

Example 1.70: Preparation of 1-(3,4-difluorophenyl)-3-(3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 32) 3-(4 -Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3,4-difluorophenylisocyanate similarly to the method given in example 1.69, and 27 mg (yield 6390) of compound 32 are obtained: LCMS t/: (95) -377 (MAN, 100). "H NMR (400MHz, acetone-av) at: 8.28 (s, 1H), 8.12 (s, 1H), 7.74 (ddd, U12:13.5Hz, dg2:7,ZHC, uUz22.5Hz, 1H), 7.63 (ddd, 91-8.8Hz, 9Ua:2.8Hz, 1), 7.47 (d, U-2.8HzC, 1), 7 .38 (d, Unee-: 4.4 Hz, 1), 7.16 (m, ZN), 3.84 (s, ZN), 3.65 (s, ZN). E NMR (376 MHz, acetone-iv ) 6: -138.89 (m, 1P), -148.38 (m, 15), -177.40 (d,

Uneh5, HZ, 1).

Example 1.71: Preparation of 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-fluorophenyl)urea (Compound 33) 3-(4-Fluoro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3-fluorophenylisocyanate similarly to the method given in example 1.68, and 15 mg (yield 5595) of compound 33 is obtained: LCMS t/: (95)-359 (MAN, 100). "H NMR (400 MHz, acetone-av) 6: 8.38 (s, 1H), 8.21 (s, 1H), 7.64 (dd, U1-9.0Hz, d222.6Hz, 1H), 7 .59 (d, 9-12.0Hz, 1), 7.48 (d, 9-22.8Hz, 1H), 7.39 (d, Une4.8HzC, 1H), 7.27 (dd, 9U12: 14.8Hz, Ug:8.0Hz, 1), 7.15 (d, 9U-9.6Hz, 1), 7.12 (s, 1H), 6.72 (dd, uU159.6Hz, 9Ug-: 7.2 Hz, 1H), 3.83 (s, ЗН), 3.65 (s, ЗН). ЕС NMR (376 MHz, acetone-ав) at: -114.00 (m, 1Р), -177.35 (d, Une-3.9Hz, 1B).

Example 1.72: Preparation of 1-(2,4-difluorophenyl)-3-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 37) 3-(4- Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 2,4-difluorophenyl isocyanate similarly to the method given in example 1.68, and 21 mg (yield 5895) of compound 37 is obtained: LCMS t/: (95)- 377 (MAN, 100). "H NMR (400 MHz, acetone-dv) 6: 8.50 (s, 1H), 8.24 (m, 1H), 7.98 (s, 1H), 7.64 (dd, U1-9.0 Hz ,

Ugt2.6Hz, 1), 7.51 (d, U2.4Hz, 1H), 7.38 (d, dne4.8Hz, 1), 7.14 (d, 9U-8.8Hz, 1H), 7, 06 (ddd, 41-11.4Hz,

Ug28.6Hz, oz-2.8Hz, 1), 6.99 (dd, 5U129.6Hz, 9U2-29.6Hz, 1H), 3.83 (s, ZN), 3.65 (s, ZN). "E NMR (376 MHz, acetone-dv) 6: -119.93 (m, 1P), -127.63 (m, 1P) -177.41 (d, Une-4.1HzC, 15).

Example 1.73: Preparation of 1-(3-chlorophenyl)-3-(3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 83) 3-(4-Fluoro) -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3-chlorophenylisocyanate similarly to the procedure given in Example 1.68. Additional purification by flash chromatography (5105, gradient elution in a mixture of hexane/E(Ac)) is required, which gives 10 mg (yield 2795) of compound 83: LCMS ti/z (95)-377 (MHC, 25), 375 (MHC, 100). "H NMR (400Mhz, acetone-av) 6: 8.28 (s, 1H ), 8.16 (s, 1H), 7.80 (s, 1H), 7.64 (dd, U1-8.8Hz, uШ22.8Hz, 1), 7.48 (d, 9U-2.8Hz , 1H), 7.38 (d, Une4, in HC, 1), 7.34 (dd, 9U1-29.2Hz, 9Ug:0.8Hz, 1), 7.26 (dd, 4U1-8.2 ,

Ugt8.2Hz, 1), 7.13 (d, 9U-8.8Hz, 1H), 7.00 (dd, u1-8.8Hz. 9U2-0.8Hz, 1), 3.83 (s, ZN ), 3.65 (c, ZN). TE NMR (376 MHz, acetone-av) at: -177.35 (d, Une4.1 Hz, 1B).

Example 1.74: Preparation of 1--4-bromophenyl)-3-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 85) 3-(4-Fluoro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-bromophenyl isocyanate similarly to the method given in example 1.68, and 27 mg (yield 6095) of compound 85 is obtained: РХMS t/: (95)-421 (MaNU' Hg, 100), 419 (MAN"Hg, 100). "H NMR (400 MHz, acetone-dv) 6: 8.24 (s, 1H), 8.13 (s, 1H), 7.63 (dd, 41-9.0Hz, 9Uan2.6Hz, 1), 7.51 (d, U-8.8Hz, 2H), 7.48 (d, U-2.8Hz, 1H), 7.42 (d, U -8.8Hz, 2H), 7.38 (d,

Une-4, AHC, 1), 7.13 (d, 9U-9.2Hz, 1H), 3.83 (s, ZN), 3.65 (s, ZN). "E NMR (376 MHz, acetone-av) at: -177.39 (d,

Une-5, HZ, 1).

Example 1.75: Preparation of 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-trifluoromethylphenyl)thiourea (Compound 86) 3-(4-Fluoro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-trifluoromethylphenylthioisocyanate similarly to the method given in example 1.69. Additional purification by flash chromatography (Vioitade 500, gradient elution in hexane/EtOAc) was required, which gave Zmg (yield 6895) of compound 86: LCMS t/ (95)-425 (MAN, 100). "H NMR (400 MHz, acetone-iv) 5: 9.32 (d, 9U-20.0Hz, 2H), 7.83 (d, 9-8.4Hz, 2H), 7.67 (d, 9U- 8.8Hz, 2H), 7.61 (dd, U1-8.9Hz, 9U2-2.9Hz, 1H), 7.45 (d, U-52.4Hz, 1H), 7.38 (d, Une4 ,8Hz, 1H), 7.20 (d, 9U-8.8Hz, 1H), 3.88 (s, ZN), 3.67 (s, ZN). ZE NMR (376 MHz, acetone-av) 6: -63.10 (c,

ZE), -176.49 (d, dUne41Hz, 1).

Example 1.76: Preparation of 1-(4-chloro-3-trifluoromethylphenyl)-3-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 84) 3-( 4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-chloro-3-trifluoromethylphenylisocyanate similarly to the method given in example 1.68, and 15 mg (yield 2995) of compound 84 is obtained: LCMS ti/z (95)-445 (M-NU"Si, 34), 443 (MANZSI, 100). "H NMR (400 MHz, acetone-av) δ: 8.69 (s, 1H), 8.39 (s, 1H ), 8.15 (d, U-2.4Hz, 1), 7.74 (dd, uU1-8.6Hz, 9Ua-2.2Hz, 1H), 7.65 (dd, 9129.0Hz, 9a- :2.6Hz, 1), 7.53 (d, 9U-8.8HzC, 1H), 7.49 (d, 922.4HzC, 1H), 7.38 (d, dne4.4Hz, 1), 7 ,14 (d, 959.2 Hz, 1H) 3.83 (s, ЗН), 3.65 (s,

ZN). E NMR (376 Mhz, acetone-dv) 6: -63.75 (s, 3R), -177.40 (d, Uune5, ZHz, 1P).

Example 1.77: Preparation of 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-methoxyphenyl)urea (Compound 87) 3-(4-Fluoro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-methoxyphenylisocyanate similarly to the method given in example 1.68. The residue is additionally washed with SNegSi" and 18 mg (yield 2995) of compound 87 is obtained: LCMS ti/a (95)-371 (MH, 100). "H NMR (400 MHz, acetone-av) at: 8.06 (s, 1H), 7.95 (s, 1H), 7.63 (dd, U1-8.6 Hz, 92-28 Hz, 1H) , 7.49 (d, U-2.8Hz, 1H), 7.42 (d, 9-8.4Hz, 2H), 7.37 (d, Une-4.4Hz, 1H), 7.11 ( d, U-9.2Hz, 1H), 6.85 (d, 9U-9.2Hz, 2H), 3.82 (s, ZN), 3.75 (s, ZN), 3.65 (s, ZN). "E NMR (376 MHz, acetone-dv) 6: - 177.41 (d, Une 41 Hz, 1P).

Example 1.78: Preparation of 1-(3-acetylphenyl)-3-(3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 88) 3-(4-Fluoro -2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3-acetylphenyl isocyanate similarly to the procedure given in Example 1.68. Additional purification by flash chromatography (5 µg, gradient elution in hexane/EthOAc) is required, which gives Zbmg (yield 5395) compound 88: LCMS t/: (953-383 (MAN, 100). "H NMR (400Mhz, acetone-av) o: 8.31 (s, 1H), 8.17 (s, 1H) . 7 Hz, 1H), 7.50 (d, 9U-2.4Hz, 1H), 7.41 (m, ЗН), 7.14 (d, 9-9.2Hz, 1H), 3.84 (s .

Example 1.79: Preparation of 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-trifluoromethylphenyl)urea (Compound 89) 3-(4-Fluoro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 4-trifluoromethylphenylisocyanate similarly to the method given in example 1.69, and 24 mg (yield 4995) of compound 89 is obtained: LCMS t/2 (95)-409 (MAN, 100). "H NMR (400 MHz, acetone-dv) 6: 8.56 (s, 1H), 8.29 (s, 1H), 7.75 (d, 9U-8.8Hz, 2H), 7.65 (dd , .U129.0 Hz, 9U2-2.6Hz, 1), 7.60 (d, U-8.4Hz, 2H), 7.50 (d, U9-2, A4Hz, 1H), 7.38 ( d, Un-4.4HzC, 1H), 7.14 (d, 9U-8.8Hz, 1H), 3.84 (s, ZN), 3.65 (s, ZN). "E NMR (376 MHz, acetone-av) 6: -62.80 (s, ЗР), -177.39 (d, dne4.1Hz, 15).

Example 1.80: Preparation of 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-trifluoromethylphenyl)urea (Compound 90) 3-(4-Fluoro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine is treated with 3-trifluoromethylphenylisocyanate similarly to the method given in example 1.69, and 37 mg (yield 4895) of compound 90 is obtained: LCMS t/: (953-409 (MAN, 100 ). "H NMR (400 MHz, acetone-av) about: 8.50 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.67 (d, 9U-8 ,8Hz, 1H), 7.64 (d, U-2.4HzC, 1H), 7.49 (m, 2H), 7.38 (d, Une-4.8HzC, 1), 7.30 (d , U-8.0Hz, 1), 7.14 (d, uU-8.8Hz, 1), 3.84 (s, ZN), 3.65 (s, ZN). -av) o: -63.85 (c, ZE), -177.42 (d, Unk-4.1 HC, 1).

Example 1.81: Preparation of intermediate 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine

ZpsSi2.2HgO (1.3 g, 5.88mmol) and the mixture is heated to a temperature of 5573 overnight.

Ethanol is evaporated, the residue is dissolved in ethyl acetate (50 ml) and washed with 1096 Mahon (10 ml).

The organic layer was dried over anhydrous Mod5O4 and evaporated to give a light yellow solid.

The crude product was purified by chromatography on Vioiade silica gel (hexane/EOAc, 3/1) to give 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)/-4-methoxyphenylamine (0.38g, 85905) in in the form of a light yellow solid. RHMS ti/z (95)-311 МН (7Vg, 100), (ZVH, 96.5). "H NMR (400MHz, SOSIv) 6: 7.47 (s, 1H), 6.78 (d, 928.08 Gu, 1), 6.72 (dd, 9U1-8.01HzC, 9da-2.78Hz , 1H), 6.54 (d, U-2.78Hz, 1H), 4.14 (m, 1H), 3.63 (s, ЗН), 1.4 (d, uU-6.57 Hz, ZN), 1.23 (d, U-6.57 Hz, ZN).

Intermediate 4-bromo-1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole is obtained as follows:

A. 1-Isopropyl-1H-pyrazole: To a solution of pyrazole (50.0 g, 735.3 mmol) in a solution of sodium hydroxide (123.5 g

Mahon/gbml of water) isopropyl bromide (180.0g, 1470.1mmol) is added and then the mixture is refluxed for 6-7 days. The reaction mixture is cooled and extracted with ethyl acetate (3 x 3 300 ml).

The organic phases are combined and dried over Md5O". Volatile substances are removed in a vacuum and a light yellow oil is obtained, which is distilled using Kideigopg at a temperature of 140"C and a pressure of 10 mm Hg and 1-isopropyl-1H-pyrazole is obtained in the form of a colorless oil (43g, 5395). PHMS t/y (90)-111 MAN" (100).

IN NMR (400MHz, DMSO-iv) 6: 7.72 (d, U22.3Hz, 1H), 7.41 (t, 1H), 6.21 (t, 1H), 4.5 (q., 1H ), 1.41-1.37 (d uzh 111 hGu).

B. 2-Isopropyl-2H-pyrazole-3-boronic acid: p-Vy and (17.46g, 1100ml, 273MM in hexane) for 30 minutes. at a temperature of -78"C, slowly add to a solution of 1-isopropyl-1H-pyrazole in THF (25.0 g, 227 mmol).

The reaction mixture is stirred at a temperature of -78"C for 2 hours. Using a cannula, a solution of cooled triisopropoxyboronate (170.0 g, 909 mmol) is slowly added over 45 minutes. The reaction mixture is allowed to warm to room temperature and stirred overnight. With the help of HCl (1 M, 17 Oml) bring the pH of the reaction mixture to 6-7. The solvent is evaporated to dryness and the resulting residue is triturated in a mixture of 1:11 ethyl acetate:dichloromethane, the suspension is filtered and the solvent is evaporated in a vacuum, obtaining 2-isopropyl-2H-pyrazole-Z-boronic acid in the form white solid (20.0 g, 5895).

Mn" (100). "H NMR (400 MHz, DMSO-α) 6: 8.14 (s, 2H), 7.2 (s, 1H), 6.5 (s, 1H), 5.05 (m , 1H), 1.2 (d y-9.0Gu, vn). b. 1-Isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole: To a mixture of 2-methoxy-5-nitrophenyl ether of trifluoromethanesulfonic acid (4.1 g, 13.6 mmol; see example 1.1, stage B for preparation) , 2-isopropyl-2H-pyrazole-Z3-boronic acid (5.2g, 34.1mmol) and anhydrous С52СО3 (17.7g, 544mmol) in DMF in an argon atmosphere add РО(РРПз)" (0.79g, O, bZmmol) and the mixture is heated to a temperature of 80"C for 16 hours.

The reaction mixture is cooled, filtered through Celite and evaporated to dryness. The residue is dissolved in ethyl acetate and the solution is washed with water. The organic layer was dried over Ma250, evaporated to give the crude product as a brown solid. The crude product was purified by Vioiade silica gel chromatography (hexane/EthOAc, 3/1) to give 1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole (1.88g, 5295) as a colorless solid. RHMS t/2 (95)5261 MN" (100). "YAN NMR (400MHz, SOSIz) o: 8.36 (dd, U1-59.09Hz, 9ae22.5Hz, 1H), 8.18 (d, U -8.18Hz, 1H), 7.65 (s, 1H), 7.09 (d, 9U-8.08Hz, 1H), 6.25 (s, 1H), 4.16 (dd, U1-13 ,14Hz, 9dag-:6.57 Hz, 1H), 3.95 (s, ЗН), 1.45 (d, U-6.82Hz, 6H).

O. 4-Bromo-1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole: To a stirred ice-cooled solution of 1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole (1.0 g, 3.8 mmol) in DMF (100 ml) slowly over 1 h. add MV5 (0.75 g, 4.22 mmol). The reaction mixture is heated to room temperature and stirred for 2 hours. The reaction mixture with vigorous stirring is poured into a mixture of ice and water, while a white solid is formed, which is filtered and washed with cold water until DMF is completely removed. The solid was dried in vacuo to give 4-bromo-1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole (1.25 g, 9695) as a colorless solid. RHMS pt/ (95)-340

Mne (B, 100), 342 (VI, 96.5). IN NMR (400MHz, SOSIz) 6: 8.4 (dd, 9129.09Hz, 9da:2.78Hz, 1H), 8.19 (d, uU-2.78), 7.6 (s, 1H), 7.14 (d, U-9.35HzC, 1H), 4.11 (m, 1H), 3.96 (s, ЗН), 1.49 (d, 9-6.52HzC, ЗН), 1, 36 (d, 9U-6.52Hz, zn).

Example 1.82: Preparation of intermediate 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine

To a solution of 4-chloro-1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole (0.18g, 0.bimol) in ethanol (5.0ml) add ZpsSi».2HgO (0.56g , 2.44 mmol) and the mixture is heated to a temperature of 557C overnight.

Ethanol is evaporated, the residue is dissolved in ethyl acetate (50 ml) and washed with 1096 Mahon (10 ml).

The organic layer was dried over anhydrous Mo95O4 and evaporated to give a light yellow solid.

The crude product is purified chromatographically on Vioiade silica gel (hexane/EIOAc, 3/1) and 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.116 bg, 7595) is obtained as a light - yellow solid. RHMS ti/g (96)-267 MaNU (З5СИ, 100), 269 (37СИ, 28.5). "H NMR (400 MHz, SOSIv) 6: 7.47 (s, 1H), 6.78 (d, --8.08 Hz, 1), 6.72 (dd, 91-8.01 Hz, 922.78 Hz , 1H), 6.54 (d, 9U-2.78Hz, 1H), 4.14 (m, 1H), 3.63 (s, ЗН), 1.4 (d, uU-6.57 Hz, ZN), 1.23 (d, U-6.57 Hz, ZN).

Intermediate 4-chloro-1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole is obtained as follows:

To a stirred ice-cooled solution of 1-isopropyl-5-(2-methoxy-5-nitrophenyl)-1H-pyrazole from Example 1.81, stage C (1.0g, 3.83mmol) in DMF (10ml) for 10min. add MOH (0.56 g, 4.22 mmol). The reaction mixture is heated to room temperature and stirred at 557C for 6 hours. The reaction mixture is cooled and, with vigorous stirring, poured into a mixture of water and ice, while a white solid is formed, which is filtered off and washed with cold water until DMF is completely removed. The solid substance is dried in vacuo to give 4-chloro-1-isopropyl-5-(2-methoxy-

B-nitrophenyl)-1H-pyrazole (1.1 g, 9795). RHMS t/z (95)-5296 МН (З5СИ, 100), 298 (37СИ, 28.5). "H NMR (400MHz,

SOS z) 6: 8.4 (dd, 9U1-9.09Hz, 9Ua2-2.78Hz, 1H), 8.19 (d, 9U-2.8Hz), 7.6 (s, 1H), 7 ... (d, U-6.62Hz, ZN).

Example 1.83: Preparation of intermediate 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine

ZpsSi2.2HgO (1, 97g, 8.74mmol) and the mixture is heated to a temperature of 557°C overnight. Ethanol is evaporated, the residue is dissolved in ethyl acetate (50ml) and washed with 1095

Mahogany (1bml). The organic layer was dried over anhydrous Md5O" and evaporated to give a light yellow solid. The crude product is purified by chromatography on Vioiade silica gel (hexane/EtOAc, 3/1) to give 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.465g, 9495) as a light yellow solid . LCMS ti/ (95)-232 MH" (100). "H NMR (400MHz, SOCI3) 6: 7.47 (s, 1H), 6.78 (d, U-8.08HzC, 1H), 6, 72 (dd, 41-8.01Hz, 9Uan2.78Hz, 1H), 6.54 (d, U-2.78Hz, 1H), 6.25 (s, 1H), 4.14 (m, 1H), 3.63 (s, ZN), 1.4 (d, 926.57 Hz, ZN), 1.23 (d, 9-6.57 Hz, ZN).

Example 1.84: Preparation of 1-(4-chlorophenyl)-3-3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 43)

4-

chlorophenyl isocyanate (0.0733g, 0.47bmmol) and stirred overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 43 is obtained as a colorless solid (0.050 g, 3095). RHMO t/z (95)-386 MN (Z7SI, 26), 395 Mann" (SI, 94). "H NMR (400 MHz, DMSO-yv) 6: 8.84 (width s, 1H), 8.77 (width s, 1H), 7.48 (d, 9U-1.91 Hz, 1), 7 .46 (d, uU-1.84Hz, 1), 7.44 (d, 9-3.65Hz, 1), 7.33 (t, 1H), 7.3 (s, 1H), 7.29 (d, 9-7 .68Hz, 2H), 7.07 (d, 9U-8.9Hz, 2H), 6.13 (d, U9-1.83Hz, 1H), 4.25 (m, 1H) , 3.7 (s, ZN), 1.3 (d, U-6.76Hz, 6H).

Example 1.85: Preparation of 1-(4-fluorophenyl)-3-3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 44)

4-fluorophenylisocyanate (0.0652g, 0.47bmmol) was added to a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.1g, 0.4333mmol) in SiCl2 and stirred overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 44 is obtained as a colorless solid (0.050 g, 3095). RHMS t/ (95)-369 MH" (100). "H NMR (400 MHz,

DMSO-yv) 6: 8.59 (width s, 1H), 8.52 (width s, 1H), 7.42-7.35 (m, 4H), 7.28-7.27 (d . 1.24 (d, U-6.56Hz, 6H).

Example 1.86: Preparation of 1-(3,4-difluorophenyl)-3-I3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 46)

Add

C3,4-difluorophenyl isocyanate (0.067 g, 0.47 mmol) and stirred overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 46 is obtained as a colorless solid (0.078 g, 4295). LCMS t/ (95)-387 МН" (100). "H NMR (400 MHz, acetone-dv) o: 8.45 (width s, 1H), 8.27 (width s, 1H), 7, 65-7.59 (m, ZN), 7.485 (d, 9U-2.56Hz, 1H), 7.228-7.009 (m,

AN), 6.245 (d, 9-1.73 Hz, 1H), 4.36 (m, 1H), 3.82 (s, ZN), 1.418 (d, U-6.61 Hz, 6H).

Example 1.87: Preparation of 1-(3-chloro-4-fluorophenyl)-3-I3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 47)

To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.1g, 0.4333mmol) in СНеСи2, add 3-chloro-4-fluorophenylisocyanate (0.075g, 0.47bmmol) and mix overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 47 is obtained as a colorless solid (0.090 g, 5295). RHMS ti/ya (95)-: 405 Man (З7СИ, 23), 403 МН (35СИ, 60). "H NMR (400Mhz, acetone-dv) 6: 8.3 (width s, 1H), 8.1 (width s, 1H), 7.82-7.796 (dd, U1-: 6.75Hz, 9da -2.58Hz, 1H), 7.536 (d, 9U-2.67Hz, 2H), 7.514 (d, U-2.67Hz, 2H), 7.43 (d, 9U-1.57Hz, 1H), 7.368 (d, U-2.65Hz, 1H), 7.299 (d, y-1.23Hz, 1), 7.136 (t, 1H), 6.079 (d, 9-1 .69Hz, 1H), 4.224 (m, 1H), 3.73 (s, ЗН), 1.308 (d, 9-6.61 Hz, 6H).

Example 1.88: Preparation of 1-(2-chloro-4-trifluoromethylphenyl)-3-(3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 48)

To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.1 g, 0.43 mmol) in СНоСи», add 2-chloro-4-fluoromethylphenylisocyanate (0.106 g, 0.47 mmol) and stir overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 48 is obtained as a colorless solid (0.109g, 5695). РХМС t/z (96): 455 МН (С7СИ, 35), 453 МН (СИ, 100). "H NMR (400Mhz, acetone-ae) b: 8.78 (width s, 1H), 8.48 (d, 958.97 Hz, 1H), 7.99 (width s, 1H), 7.615 ( s, 1H), 7.52-7.46 (m, 1H), 7.375 (d, 9-1.41Hz, 1H), 7.337 (d, U-2.64Hz, 1H), 6.973 (d, y- 8.92Hz, 1H), 6.027 (d, U9-1.63Hz, 1H), 4.151 (m, 1H), 3.676 (s, ЗН), 1.244 (d, U-6.61Hz, 6H).

Example 1.89: Preparation of 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chlorophenyl)urea (Compound 49)

4-Chlorophenylisocyanate (0.041g, 0.263mmol) was added to a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.08g, 0.258mmol) in NaCl and stirred. overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 49 is obtained as a colorless solid (0.052 g, 4295). RHMS t/z (96)-: 463 МН" (7ZVg, З5СИ, 41), 465 MEN" (8'ВИZ5СИ, 88), 467 НУ (89ВИZ7СИ, 21). "H NMR (400MHZ, acetone-iv) 6: 8.30 (width s, 1H), 8.24 (width s, 1H), 7.685 (d, U-2.66 Hz, 1H), 7.577 (d , U9-1.92Hz, 2H), 7.74 (d, U-2.65, 1H), 7.292 (d, 9-1.9Hz, 2H), 7.280 (d, 9U-1.6Hz, 1H) . 61 Hz, ZN).

Example 1.80: Preparation of 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-fluorophenyl)urea (Compound 50)

4-Fluorophenylisocyanate (0.036g, 0.263mmol) is added to a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.08g, 0.258mmol) in СНоСи» and mixed overnight. The precipitate formed is filtered, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum and the compound is obtained as a colorless solid (0.037g, 3295). RHMS t/ya (95)-: 449 MN" (VG, 58), 447 MN" (VI, 63). "H NMR (400 MHz, SOSIz) 5: 7.5 (s, 1H), 7.346 (d, 1.95 Hz, 2H), 7.326 (width s, 1H), 7.151 (d, U-4.77 Hz, 1H), 7.124 (t, 1H), 6.995 (d, 9U-1.87Hz, 2H), 6.869 (d, 9U-5.42Hz, 1H), 6.847 (d, U-4.71Hz, 1H), 4.045 (m, 1H), 3.651 (s,

ZN), 1.333 (d, 9U-6.61 Hz, ZN), 1.160 (d, U-6.61 Hz, ZN).

Example 1.91: Preparation of 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3,4-difluorophenyl)urea (Compound 51)

3,4-difluorophenyl isocyanate (0.041 g, 0.263 mmol) was added to a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.08 g, 0.258 mmol) in СНоСи» and stir overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 51 is obtained as a colorless solid (0.096 g, 8095). RHMS t/z (953-467 M.N (8Vg, 88), 465 Man" (Vu, 95). "H NMR (400 MHz, DMSO-aiv) 6: 8.816 (width s, 1H), 8.681 (width .s, 1H), 7.5 (s, 1H), 7.412 (d, 9-2.51Hz, 2H), 7.389 (d, 9U-2.51Hz, 2H), 7.199 (t, 1H), 7.167 ( s, 1H), 6.983 (t, 1H), 3.989 (m, 1H), 3.596 (s, ZN), 1.225 (d, uU-6.61Hz, ZN), 1.078 (d, U-6.61Hz, ZN ).

Example 1.92: Preparation of / 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-chloro-4-fluorophenyl)urea (Compound 52)

To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.08g, 0.258mmol) in NaCl, add 3-chloro-4-fluorophenylisocyanate (0.045g, 0. 263mmol) and stir overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 52 is obtained as a colorless solid (0.067 g, 5490). RHMS t/7 (90)-485 MN (8'VIZ"Si, 30), 483 MN (VISI, 100), 481. MN (79VIZ5SI, 72). "H NMR (400 MHz, SOSIz) 5: 7 .7 (s, 1H), 7.4 (d, uU-1.6Hz, 1H), 7.3 (d, 9-1.8Hz, 1), 7.25 (s, 1H), 7.1 -6.8 (m, ЗН), 4.2 (m, 1Н), 3.8 (s, ЗН), 1.5 (d, U-6.61Hz, ЗН), 1.3 (d, 5 -6.61 Hz, ZN).

Example 1.93: Preparation of / 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2-chloro-4-trifluoromethylphenyl)urea (Compound 53)

To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.08g, 0.258mmol) in СНоСи» is added 3-chloro-4-trifluoromethylphenylisocyanate (0.059g, 0. 263mmol) and stirred overnight at room temperature. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (17), dried under vacuum and compound 53 is obtained as a colorless solid (0.1 g, 7395). RKHMS t/2 (965)-535 Man" (8VIZ7SI, 39), 533 Man" (8VIZ5SI, 100), 531 Manet (VISI, 63). "H NMR (400 MHz, DMSO-av) 6: 8.582 (width s, 1H), 8.456 (width s, 1H), 7.864 (s, 1H), 7.654 (d, 9U-8.28Hz, 1H), 7.557 (d, U-2.76Hz, 1H), 7.536 (d, y-2.76Hz, 1H), 7.369 (d, 9U-9.13Hz, 1H), 4.133 (m, 1H), 3.752 (s, ZN), 1.375 (d, 9U-6.61Hz, ZN), 1.217 (d, 9U-6.61Hz, zn).

Example 1.94: Preparation of 1-I3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chlorophenyl)urea (Compound 45)

4-Chlorophenylisocyanate (0.073g, 0.47bmmol) is added to a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.1g, 0.43mmol) in SNeSig2 and mixed overnight. The precipitate formed is filtered, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum and the compound is obtained as a colorless solid (0.097g, 5495). RHMO t/ya (95)-: 421 Man (Z7SI, 53), 419 Man (Z35SI, 77). "H NMR (400 MHz, SOSIz) 6: 7.689 (width s, 2H), 7.617 (s, 1H), 7.460 (d, U-2.62Hz, 1H), 7.438 (d, U-22.52Hz, 1H ), 7.22-7.28 (m, ЗН), 6.947 (d, U-8.93Hz, 1Н) 4.245 (m, 1Н), 3.808 (s, ЗН), 1.575 (d, 9У-6.35Hz , ZN), 1.381 (d, u-6.35 Hz, ZN).

Example 1.95: Preparation of 1-I3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-fluorophenyl)urea (Compound 54)

4-fluorophenyl isocyanate (0.065 g, 0.47 mmol) was added to a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.1 g, 0.433 mmol) in SiCl stir overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 54 is obtained as a colorless solid (0.055 g, 323). RHMS t/ya (95)-405 M.N (37SI, 20), 404 Mane (Z5SI, 50). "H NMR (400 MHz, acetone-av) 6: 8.62 (lat.s, 1H), 8.101 (s, 1H), 8.081 (d, U-2.3Hz, 2H). 7.967 (t, 1H), 7.885 (d, 9-2.21Hz, 2H), 7.558 (d, U-8.91HzC, 1H), 7.473 (t, 1H), 4.67 (m, 1H), 4.238 (s, ЗН), 1.873 (d, 9U-6.61Hz, ZN), 1.713 (d, U-6.61Hz, ZN).

Example 1.96: Preparation of 1-I3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3,4-difluorophenyl)urea (Compound 55)

To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.1g, 0.4333mmol) in SiSi" is added 3,4-difluorophenylisocyanate (0.075g, 0.47bmmol ) and stir overnight. The formed precipitate is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum and the compound is obtained as a colorless solid (0.062g, 3595). РХМС t/z (95)-5423 Mann" (37СИ, 23), 421 Manet (З5СИ, 67). "H NMR (400 MHz, acetone-av) about: 8.199 (d, U-22.44 Hz, 1H), 8.181 (d, 9-2.42 Hz, 1H), 8.166 (d, 9-2.37 Hz, 1H ), 8.147 (d, U-2.08Hz, 1H), 8.106 (d, 9U-2.65Hz, 1H), 8.085 (d, U-2.68Hz, 1H), 7.967 (c, 1H), 7.880 ( d, 9-2.61Hz, 1), 7.627 (t, 1H), 7.594 (d, 9U-3.86Hz, 1H) 7.563 (d, U-8.96Hz, 1H), 4.669 (m, 1H), 4.242 (s, ZN), 1.874 (d, U-6.61 Hz,

ZN), 1.713 (d, U-6.61 Hz, ZN).

Example 1.97: Preparation of 1-(3-chloro-4-fluorophenyl)-3-|3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 56)

3-Chloro-4-fluorophenyl isocyanate (0.082g, 0 ,47bmmol) and stir overnight. The precipitate formed was filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 56 was obtained as a colorless solid (0.052 g, 2895). РХМС t/z (95)-439 МН (37СИ, 29), 437 МН (СИ, 46). "H NMR (400 MHz, acetone-av) 6: 8.764 (lat.s, 1H), 8.673 (lat.s, 1H), 8.31-8.28 (m, 1H), 8.110 (d, 9U-2 ,72HzC, 1H), 8.088 (d, 9-2.71Hz, 1H), 7.974 (s, 1H), 7.878 (d, U-2.68HzC, 1H), 7.828-7.788 (m, 1H), 7, 68-7.64 (m, 1H), 7.635-7.563 (m, 1H), 4.668 (m, 1H), 4.246 (s, ЗН), 1.874 (d, 9U-6.61Hz, ЗН), 1.713 (d ,

U-6.61 Hz, ZN).

Example 1.98: Preparation of //- 1-I3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2-chloro-4-trifluoromethylphenyl)urea (Compound 57)

2-Chloro-4-trifluoromethylphenylisocyanate (0.107g, 0 ,47bmmol) and stir overnight. The precipitate formed is filtered off, washed with a mixture of methylene chloride/hexane (1:1), dried in a vacuum, and compound 57 is obtained as a colorless solid (0.085 g, 4095). RHMS t/z (95)-5489 МН (З7СИ, 25), 488 МН (35СИ8'СИ, 25), 487. МН (35СИ, 100). "H NMR (400 MHz, acetone-iodv) 6: 8.88 (width s, 1H), 8.544 (width s, 1H), 8.063 (s, 1H), 7.669 (d, 9U-1.54Hz, 1H ), 7.606 (d, U-2.69Hz, 1H), 7.58 (t, 1H), 7.549 (d, 9U-1.51Hz, 1H), 7.385 (d, 9U-2.68Hz, 1H), 7.68-7.64 (m, 1H), 7.080 (d, U-8.98HzC, 1H), 4.145 (m, 1H), 3.742 (s, ЗН), 1.345 (d, uU-6.61HzC, ZN), 1.188 (d, U-6.61Hz, ZN).

Example 1.99: Preparation of intermediate /3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenylamine

To a stirred solution of 4-bromo-5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.08g, O0.20mmol) in EUN (0.7ml) add zZpsSi» .2NgO (0.18g, 0O.8O0mmol, 4 eq.), the mixture is stirred at reflux for 2 hours and then the EN is removed in vacuo. The resulting solid was dissolved in EtOAc and 1N Mahon was added until the pH reached 6. The mixture was stirred overnight and filtered through celite. The aqueous phase is extracted with E(Ac (3x50ml). The organic phases are combined, dried over anhydrous Mo95O4, filtered and evaporated, obtaining 3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)- 4-Methoxyphenylamine (0.06g, 0.17mmol, yield 9990 in two stages) in the form of a white solid: LCMS t/z (953-350 (MaAN"Vg, 95), 352 (MaANU!'Vg, 100). "H NMR (400MHz, SOSIv) 5:

6.78 (dd, U-14.0, 6.0Hz, 1H), 6.76 (dd, U-8.0, 4.0Hz, 1H), 6.54 (d, U-4.0Hz, 1H), 3.67 (s, ЗН), 3.66 (s, ЗН) 3.36 (width s, 2H).

Intermediate 4-bromo-5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole is obtained as follows:

A. 2-Methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid: 1-methyl-3-trifluoromethyl-1H-pyrazole (1.00 g, 6.6 mmol) is dissolved in THF (25 ml) in dried round-bottomed flask and cooled to -78°C in an acetone/dry ice bath. A 2.5 M solution of n-butyllithium in hexane (3.19 bml, 7.99 mmol) was added dropwise to the stirred solution, and then triisopropylborate (5, 01g, 26.64mmol). The mixture is warmed to room temperature and stirred for 3 hours. The pH of the mixture is adjusted to 6 with 1N NOSI solution and then THF is removed in vacuo. The aqueous layer is extracted with EtOAc (3x100ml).

The organic phases were combined, washed with saturated salt solution, dried over anhydrous M4obax, filtered and evaporated to give 2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid (1.12g, 5.80mmol, yield 8795) in in the form of a white solid: LCMS m/z (95)-195 (MH, 100). "H NMR (400 MHz,

DMSO-yv) 6: 8.37-8.40 (m, 2H), 7.57 (dd, U-54.0Hz, 1H), 4.06 (s, ЗН).

B. 5-(2-Methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole: 2-Methoxy-5-nitrophenyl ether of trifluoromethanesulfonic acid (0.10 g, 0.34 mmol), 2-methyl- 5-trifluoromethyl-2H-pyrazole-3-boronic acid (0.10 g, 0.52 mmol, 1.5 equiv.) and MgSO3 (0.04 g, 0.41 mmol, 1.2 equiv.) are dissolved in a mixture of OME (bml) and NgO (0.bml) in a round-bottomed flask purged with argon. The resulting mixture is degassed with argon for 5 minutes. and then RA(RRPz)4 (0.04g, 0.0Zmmol, 0.01eq) is added. Degas with argon for another 5 minutes. and stirred overnight at a temperature of 70°C. After the reaction is complete, OME is removed in vacuo and the crude reaction mixture is purified by column chromatography at 5 µg (eluent: EtOAc/hexane-from 595 to 3095). Final purification is performed by reversed-phase HPLC C-18 and obtain 5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.05g, 0.17mmol, 4995): LCMS t/l (96):302 (MN, 100). "N

NMR (400MHz, SOSIz) 6: 8.38 (dd, 9U-10.0, 2.0Hz, 1H), 8.19 (d, 9U-54.0Hz, 1H), 7.12 (d, U- 8.0 Hz, 1), 6.57 (s, 1H), 3.98 (s, ZN), 3.78 (s, ZN).

C. 4-Bromo-5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole: At 0"C to a stirred solution of 5-(2-methoxy-5-nitrophenyl)-1 -methyl-3-trifluoromethyl-1H-pyrazole (0.05g, 0.17mmol) in DMF (2/3ml) add MV5 (0.03g, 0.18mmol, 1.1eq.) in DMF (1/3ml) dropwise ).Stir the reaction mixture for 4 hours at 0"C, but TLC shows the absence of reaction products. An additional equivalent amount is added

MV and stir overnight at a temperature of 70°C. The next day, add the second and third equivalent amounts of MV5 and try to complete the reaction. DMF is removed under vacuum, the crude product is diluted with EOAc (50 ml) and washed with a saturated salt solution (3x1i0 ml). The EOAc phase is dried over anhydrous M95O»x, filtered and evaporated, obtaining the partially purified product 4-bromo-5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.08 g) as a light of a yellow solid: LCMS t/ya (95)-380 (Ma-H"Vg, 80), 382 (Ma-NU!VIg, 100). "H NMR (400 MHz, SOSIz) 6: 8.44 (dd, 9U-8.0, 4,OHC, 1), 8.22 (d, 1H), 7.15 (d, U-8.0Hz, 1H), 3.98 (s, ЗН), 3.78 (s, ЗН).

Example 1.100: Preparation of intermediate /3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenylamine

Zpsi2 was added to a stirred solution of 4-chloro-5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.11g, 0.33mmol) in EHN (1.00ml). 2NgO (0.30g, 1.31mmol, 4eq.) and the mixture was stirred at reflux for 2 hours and then the EUN was removed in vacuo. The resulting solid was dissolved in EtOAc and Ying Maon was added until the pH reached 6. The mixture was stirred overnight and filtered through celite. The aqueous phase is extracted with E(Ac (3x50ml). The organic phases are combined, dried over anhydrous M950O:, filtered and evaporated, obtaining 3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl) -4-Methoxyphenylamine (0.067g, 0.22mmol, yield 669o in two stages) in the form of a white solid: LCMS t/l (95)-306 (MaANZSSI, 100), 308 (MaANUSI, 33). "H NMR (400MHz, SOSIv) 56: 6.86 (dd, U-14, 0.6.0Hz, 1H), 6.84 (dd, 8.0, 4.0Hz, 1H), 6.63 (d, U-54.0 Hz, 1H), 3.74 (s, ZN), 3.72 (s, ZN).

Intermediate 4-chloro-5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole is obtained as follows:

MOZ (0.05g, 0.37mmol, 1.1eq.) is dissolved in DMF (2/3ml) and at 0"C is added dropwise to a stirred solution of 5-(2-methoxy-5-nitrophenyl)-1-methyl- of 3-trifluoromethyl-1H-pyrazole, see Example 1.99 (01g, 0.3µmol) in DMF (1 1/µml). The reaction mixture was stirred at 0"C, but TLC showed no reaction products. An additional equivalent amount of MO5 is added and stirred overnight at 80°C, after which the reaction is complete. The DMF is removed in vacuo, the crude product is diluted with EtOAc (50 mL) and washed with saturated salt solution (3x0 mL). The EAc phase is dried over anhydrous Md5O5, filtered and evaporate, obtaining the partially purified product 4-chloro-5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.13 g) in the form of a light yellow solid: LCMS t/2 (95)-2336 (M'aANZ5CI, 100), 382 (MANI, 33). "H NMR (400 MHz, SOCI3) 6: 8.37 (dd, U-8.0, 4.0 Hz, 1H), 8 ...

Example 1.101: Preparation of intermediate //4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)/phenylamine

ZpS".2 of it (0.15 g, 0.6 mmol, 4 equiv.) is added to a stirred solution of 5-(2-methoxy-5-nitrophenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole, see example 1.99 (0.05g, 0.bmol)”) in EN (2.0ml). The mixture is stirred at reflux for 4 hours and the EOH is removed in vacuo.

The resulting solid was dissolved in EtOAc and sodium hydroxide was added until the pH reached 6. The mixture was stirred overnight and filtered through celite. The aqueous phase is extracted with E(Ac (3x5Oml). The organic phases are combined, dried over anhydrous Md5Oa, filtered and evaporated, obtaining 4-methoxy-3-(2-methyl-

B-trifluoromethyl-2H-pyrazole-3-iluphenylamine (0.04g, 0.15mmol, yield 9795): LCMS t/ya (95):272 (MH, 100). 7N

NMR (400MHz, SOS") 6: 6.82 (dd, U-16.0, 4.0Hz, 1H), 6.79 (dd, U-10.0, 2.0Hz, 1H), 6.61 (d, 1H), 6.46 (s, 1H), 3.76 (s, ЗН), 3.74 (s, ЗН).

Example 1.102: Preparation of 1-I3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chlorophenyl)urea (Compound 38)

Urea synthesis for compound 38 (General method for examples 1.103 1.106): To a stirred solution of aniline 3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.03g,

0.Ommol) in SNeoSi" (1 ml) at room temperature add 4-chlorophenyl isocyanate (0.01g, 0.O08mmol, 1.eq.). The white solid was filtered off and washed with cold SNeoSi to give compound 38 (0.02g, 0.04mmol, yield 5095) as a white solid: LCMS t/2 (95)-503 (MaH"Vg, 67), 505 ( mMaNe!Vg, 100). "IN NMR (400MHz, Meon-ya) 5: 7.59 (dd, 9U-6.0, 2.0Hz, 1H), 7.42 (d, 9U-8.0Hz, 2H), 7.38 (d, y-4, OGC, 1H), 7.27 (d, U-8.0Hz, 2H), 7.16 (d, U-8.0HzC, 1H), 3, 84 (c, ZN), 3.75 (c, ZN).

Example 1.103: Preparation of 1-I3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-fluorophenyl)urea (Compound 39) 3-( 4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.03g, 0.08mmol) is treated with 4-fluorophenyl isocyanate (0.01g, 8.99μl, 0.08mmol, 1.1 eq.) in СНоСі" (2.0 ml) similarly to the method given in example 1.102, and compound 39 (0.03 g, 0.05 mmol, yield 6495) is obtained as a white solid: LCMS ti/z (955487 ( Ma-H"Vg, 100), 489 (M.--NU!Vg, 93). "H NMR (400 MHz, MeOHn-y") 5: 7.58 (dd, U-10.0, 2.0 Hz , 1H), 7.42 (dd, U-4.0Hz, 2H), 7.39 (dd, U-10.0, 2.0Hz, 1), 7.16 (d, U-12.0Hz, 1H), 7.03 (dd, y-12.0, 8.0Hz, 2H), 3.84 (s, ЗН), 3.75 (s, ЗН).

Example 1.104: Preparation of 1-I3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-fluorophenyl)urea (Compound 40) 3-( 4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.03g, 0.11mmol) is treated with 4-fluorophenylisocyanate (0.02g, 14.bml, 0.1mmol, 1.2 equiv.-) in СНоСи» (4.0 ml) similar to the method given in example 1.102. The product was then purified by reverse phase HPLC C-18 to give the compound (0.03g, 0.07mmol, yield 6395) as a white solid: LCMS. t/z (95)-443 (MNS, 100), 445 (MANI, 36). "H NMR (400 MHz, Meon-y»ya) 5: 7.58 (dd, U-10.0, 2.0 Hz, 1), 7.42 (dd, U-4.0 Hz, 2H), 7, 40 (dd,

U-8.0, 4.0Hz, 1H), 7.16 (d, U-8.0Hz, 1H), 7.03 (dd, 9U-10.0, 6.0Hz, 2H), 3.84 (c, ZN), 3.74 (c, ZN).

Example 1.105: Preparation of 1-I3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chlorophenyl)urea (Compound 41) 3-( 4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (0.03 g, 0.11 mmol) is treated with 4-chlorophenyl isocyanate (0.02 g, 0.1 mmol, 1.2 equiv. ) in СНоСі" (4.0 ml) similarly to the method given in example 1.102. The product is then purified by reverse phase HPLC C-18 to give compound 41 (0.03g,

O,Obmmol, yield 5695) in the form of a white solid: LCMS pt/y (95)-459 (MANZ5SI, 100), 461 (MaANZSIV"SI, 84), 463 (MAANU"SI, 10). "NMR (400MHz, MeOn-th") 5: 7.59 (dd, uU-8.0, 4.0Hz, 1H), 7.41 (dd, 9U-8.0, 8.O0Hz, 2H), 7.40 (dd, 928.0, 1H), 7.27 (d, U28.0Hz, 2H), 7.17 (d, 9-12.0HzC, 1H), 3.84 (s, ЗН), 3.74 (c, ZN).

Example 1.106: Preparation of 1-(4-chlorophenyl)-3-I(4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl/uphenyl)urea (Compound 42) 4-Methoxy- 3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)phenylamine (0.02g, 0.08mmol) is treated with 4-chlorophenylisocyanate (0.01g, 10.45μl, 0.093mmol, 1.2eq. ) in СНоСі" (3.0 ml) similar to the method given in example 1.102. The product is then purified by HPLC with reverse phase С-18 and compound 42 (0.03 g, 0.07 mmol, yield 8895) is obtained as a white solid: LCMS ti/z (95)-425 (M.-NUSI, 100), 427 (MNS, 34). "H NMR (400 MHz, Meon-y") 5: 7.50 (dd, 9U-10.0, 2 ,0Hz, 1H), 7.42 (dd, 9U-8.0Hz, ZN), 7.27 (dd, 9-6.0, 2.0Hz, 2H), 7.12 (d, U-8, 0HZ, 1H), 3.84 (s, ЗН), 3.76 (s, ЗН).

Example 1.107: Preparation of the intermediate compound 1-(4-chlorophenyl)-3-(4-oxo-4H-chromen-b-yl)urea.

Stage 1: Preparation of 6b-aminochromen-4-one

To a solution of b-nitrochromone (2.0g, 10.5mmol) in a mixture of methanol/ethyl acetate (100ml/20ml), purged with argon, add 59o-ny Ra/C (Oeeedizvza-mei, 0.5g) as a catalyst. Hydrogen is bubbled through the suspension with stirring for 2 hours. LCMS and TLC show the absence of starting substances. The spent palladium catalyst is filtered through celite and the solid is washed with methanol. The filtrate and washings were combined and evaporated to give 6b-aminochromen-4-one as a light yellow solid (1.58g, 9495). RHMS t/l (95)-162 (MAN, 100). "H NMR (400MHz, SOSIz") 6: 7.79-7.81 (d, 95.96Hz, 1H), 7.38 (d, 9U-2.86Hz, 1H), 7.29-7.31 (d, U-8.88Hz, 1H), 7.01-7.04 (dd, U-8.80, 2.8Hz, 1H), 6.26-6.28 (d, -5.96HzC, 1H), 5.299 (c, 2H).

Stage 2: Preparation of 1-(4-chlorophenyl)-3-(4-oxo-4H-chromen-b-yl)urea

4-chlorophenylisocyanate (3.2g, 20.5mmol) was added to a stirred suspension of b-aminochromone (3.0g, 18.mmol) in toluene (200ml) at a temperature of 80°C, and the mixture was refluxed for 18 hours. The reaction mixture was cooled, the precipitate was filtered off and washed with methanol. RHMO t/2 (95)-315 (MNS, 100), 317 (MaANU"SI, 32,2). "H NMR (400MHz, DMSO-dv) 6: 9.098 (width s, 1H), 8.94 (width s, 1H), 8.28-8.30 (d, 9U-5.99Hz, 1H) , 8.20-8.21 (d, U-2.69Hz, 1H), 7.81-7.84 (dd, U-9.0, 2.75Hz, 1H), 7.62-7.64 (d, 9-9.07Hz, 1), 7.52-7.55 (dd, 9U-6.84, 2.16Hz, 2H), 7.35-7.37 (dd, 9U-6.85 , 2.11Hz, 2H), 6.33-6.34 (d, 9-5.98Hz, 1H).

Example 1.108: Preparation of 1-(4-chlorophenyl)-3-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea (Compound 119)

To a cooled and stirred solution of methylhydrazine (1 46g, 31.bmmol) in pyridine for 10 min. a suspension of 1-(4-chlorophenyl)-3-(4-oxo-4H-chromen-b-yl)urea (2.5 g, 7.9 mmol) in pyridine is added. At the same temperature, the reaction mixture is stirred for another 2 hours and then slowly heated to room temperature. After 6 hours, the reaction mixture becomes transparent. The reaction mixture is stirred at the indicated temperature for 18 hours and the pyridine is evaporated. The dark residue is dissolved in DMSO and purified by preparative HPLC of the Magiap system. (Separate the regioisomers. The fractions containing compound 119 are dried in vacuo to give a colorless powder (1.78 g, 47905). 1-(4-Chlorophenyl)-3-14-hydroxy-3-(2-methyl-2H-pyrazole -

Z-yl)phenyl|urea. RHMS. t/z (95)-343 (МН, З5СИ, 100), 345 (МН, 97СИ, 32.5). "H NMR (400 MHz, DMSO-dv) δ: 9.59 (width s, 1H), 8.72 (width s, 1H), 8.48 (width s, 1H), 7.43-7 .46 (dd, U-6.8, 2.07Hz, 2H), 7.A1 (d, 9U-1.83Hz, 1H), 7.28-7.30 (dd, 97.13, 2.09Hz , 2H), 7.26 (d, U-2.72Hz, 1H), 6.88-6.90 (d, 9U-9.36Hz, 1), 6.21 (d, 9U-1.84Hz, 1Н), 3.67 (c, ЗН).

Example 1.109: Preparation of 1-(4-chlorophenyl)-3-(4-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)uphenyl|urea

(Compound 154)

To a cooled and stirred solution of methylhydrazine (1.46 g, 31, mmol) in pyridine for 10 min. a suspension of compound 119 (2.5 g, 7.9 mmol) in pyridine is added. At the same temperature, the reaction mixture is stirred for another 2 hours and then slowly heated to room temperature. After 6 hours, the reaction mixture becomes transparent. The reaction mixture is stirred at the specified temperature for 18 hours. Then the pyridine is evaporated. The dark residue is dissolved in DMSO and purified by preparative HPLC of the Magiap system at a volumetric flow rate of bOml/min. and X-240. (Regioisomers are separated. The fractions containing compound 154 are dried in vacuo to give 1-(4-chlorophenyl)-3-(4-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl|urea ( . ) 6: 10.26 (width s, 1H), 8.73 (width s, 1H), 8.46 (width s, 1H), 7.82 (d, U-:2.32Hz, 1H ), 7.77 (d, 9shEZ, 62Hz, 1), 7.44-7.49 (m, 2H), 7.16-7.19 (dd, U-8.74, 2.62Hz, 1H) .

Example 1.110: Preparation of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|/|-3-(4-chlorophenyl)urea (Compound 121)

M-chlorosuccinimide (0.168 g, 1.2 mmol) was added to a stirred and cooled solution of compound 119 (0.22 g, O0.6 mmol) in DMF (2.0 ml). The reaction mixture is stirred until LCMS shows the absence of starting material (2.5 hours). The reaction mixture was poured into ice-water containing Mg52Oz and Manso', and the solid formed was filtered off, washed with ice-water, and dried in vacuo to give 1-I3-(4-chloro-2-methyl-2H-pyrazole-3 -yl)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea (0.14 g, 5895) as an off-white solid. RHMS t/2 (950)-377 (MN, 9501, 350, 100), 379 (MN, З5СИ, 87СИ, 59.4), 381 (MN, З7С1.37СИ, 10.0). "H NMR (400 MHz, DMSO-av) at: 9.76 (width s, 1H), 8.73 (width s, 1H), 8.56 (width s, 1H), 7.58 (s , 1H), 7.44-7.46 (dd, U-8.6, 2.03Hz, 2H), 7.34-7.37 (dd, 9U-8.79, 2.7Hz, 1H), 7.29 (dd, 9U-8.85, 2.07Hz, ZN), 6.92-6.94 (d, U-6.78Hz, 1H), 3.64 (s, ZN).

Example 1.111: Preparation of 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|-3-(4-chlorophenyl)urea (Compound 128)

To the cooled and stirred solution of compound 119, 1-(4-chlorophenyl)-3-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea (0.1g, 0.2923mmol), of triphenylphosphine (0.291g, 1.1078mmol) and z-dimethylaminopropanol (0.114g, 1.099mmol) in THF (25ml) isopropyl azodicarboxylate (0.224g, 1.104mmol) was slowly added over 10 min. The reaction mixture was allowed to warm to room temperature and stirred at the indicated temperature for 4 hours. THF is evaporated, the resulting syrup is dissolved in DMSO and purified by preparative HPLC at a volumetric flow rate of boml/min and X-240. Fractions containing the product are evaporated. The pink-colored residue is purified twice by flash chromatography at 5iO" (eluent: 190 methanol in OME to 15906 methanol in OME). Fractions containing the product are evaporated to give a colorless solid. M-chlorosuccinimide (0.044g, 0.3215mmol) in methanol is added to a cooled solution of the substance in methanol. The reaction mixture is stirred for 1 h.

The methanol is then evaporated and the residue is purified on silica gel using 1595 methanol in OME as eluent. Fractions containing the product are evaporated in vacuo to give 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|-3-(4-chlorophenyl) urea (0.015g, 1295) in the form of a not quite white solid. RHMS ti/z (95)-462 (МН, З5СИ, 35СИ, 100), 464 (МН, З5СИ, 87СИ, 70.2), 466 (МН, 971, 8701, 11.2). 7N

NMR (400Mhz, acetone-dv) 6: 8.29 (width s, 1H), 8.21 (width s, 1H), 7.61-7.64 (dd, 9U-8.94, 2, 73HzC, 1H), 7.53-7.56 (dd, uU-7.09, 2.09HzC, 2H), 7.46 (s, 1H), 7.43-7.46 (d, U-2 ,7Hz, 1H), 7.26-7.28 (dd, 9U-7.09, 2.07Hz, 2H), 7.11-7.13 (d, --8.98Hz, 1H), 3, 98-41 (m, 2H), 3.67 (s, ЗН), 2.21-2.25 (m, 2H), 2.09 (s, 6H), 1.75-1.79 (m, 2H).

Example 1.112: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|-3-(3,4-difluorophenyl)urea (Compound 148)

M-bromosuccinimide (0.014g, 0.077mmol) was added to the cooled and stirred solution of compound 136 (0.03g, 0.0698mmol) in methanol. The reaction mixture is stirred at this temperature for 10 minutes. and then warmed to room temperature. The methanol is evaporated and the residue is purified on silica gel using gradient elution from 196 MeOH/OME to 1595 MeOH/OME. Fractions containing the product are evaporated in vacuo to obtain 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4--3-dimethylaminopropoxy)phenyl|-3- (3,4 -difluorophenyl)urea (0.014 g, 4095) in the form of a not quite white solid. LCMS t/2 (905)-508 (MAN, "Vg, 100), 510 (MH, Vu, 82.6). "H NMR (400 MHz, acetone-av) 6: 8.69 (width s, 1H ), 8.53 (width, 1H), 7.70-7.76 (m, 1H), 7.59-7.62 (dd, U-8.95, 2.74HZ, 1H), 7 .46 (s, 1H), 7.44 (d, 9-22.7 Hz, 1H), 7.08-7.16 (m, ЗН), 3.98- 4.1 (m, 2H), 3 .67 (c, ЗН), 2.43-2.47 (m, 2H), 2.25 (c, 6H), 1.85-1.91 (m, 2H).

Example 1.113: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|-3-(2-chlorophenyl)urea (Compound 149)

M-bromosuccinimide (0.018g, 0.102mmol) was added to a cooled and stirred solution of compound 140 (0.04g, 0.0936bmmol) in methanol. The reaction mixture is stirred at this temperature for 10 minutes. and then warmed to room temperature. The methanol is evaporated and the residue is purified on silica gel using gradient elution from 19060 MeOH/OME to 1595 MeOH/OME. Fractions containing the product are evaporated in vacuo to give 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4--3-dimethylaminopropoxy)phenyl|-3-(2-chlorophenyl )urea (0.02g, 4295) in the form of a not quite white solid. RHMS t/2 (95)-506 (MH, 79, 35СИ, 83.9), 508 (MAN, 8'Вг, 85СИ, 100), 510 (МН, 81Вг, 37СИ, 30). "H NMR (400 MHz, acetone-yv) 6: 8.59 (width c, 1H), 8.09-9.12 (dd, 9U-9.3, 1.51Hz, 1H) 7.63 (width .s, 1H), 7.43-7.46 (dd, uU1--8.95Hz, 9U2-2.75Hz, 1H), 7.27 (s, 1H), 7.22-7.29 (d , U-2.72Hz, 1H), 7.16-7.18 (dd, U-8.63, 1.4Hz, 1H), 7.05-7.08 (m, 1H), 6.91- 6.93 (d, y-8.98 Hz, 1), 6.77-6.81 (m, 1H), 3.48-3.91 (m, 2H), 3.48 (s, ЗН), 2.01-2.05 (m, 2H), 1.89 (s, 6H), 1.56-1.61 (m, 2H).

Example 1.114: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|-3-(2-fluorophenyl)urea (Compound 150)

M-bromosuccinimide (0.019g, 0.107mmol) was added to the cooled and stirred solution of compound 138 (0.04g, 0.0972mmol) in methanol. The reaction mixture is stirred at this temperature for 10 minutes. and then warmed to room temperature. The methanol is evaporated and the residue is purified on silica gel using gradient elution from 19060 MeOH/OME to 1595 MeOH/OME. Fractions containing the product

evaporated in a vacuum to obtain 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4--3-dimethylaminopropoxy)phenyl|-3-(2-fluorophenyl)urea (0.02g , 4295) in the form of a not quite white solid. RHMS t/ (95)-490 (MH, 7ZVg, 100), 492 (MH, 8'Vu, 99.9). 1H NMR (400 MHZ, acetone-dv) 6: 8.59 (width s, 1H), 8.37 (d, 9-1.57Hz, 1H) 8.1 (width s, 1H), 7 ,72-7.75 (dd, 98.95, 2.75, 1H), 7.57 (s, 1H), 7.52-7.53 (d, 9-22.72Hz, 1H), 7, 18-7.22 (m, ЗН), 7.07 (m, 1Н) 4.07-4.19 (m, 2Н), 3.78 (s, ЗН), 2.3-2.35 (m , 2H), 2.19 (s, 6H), 1.85-1.88 (m, 2H).

Example 1.115: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(2,4-difluorophenyl)urea (Compound 103) 1-I3-( 4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl/|-3-(2,4-difluorophenyl)urea (compound 8, 1.44 g, 3.00 mmol) was dissolved in anhydrous СНоСи" (ZOml). The solution, while stirring, is cooled to 0"С in an ice bath. Stir for 10 minutes. and slowly add AIISiz (1.76g, 13.20mmol). The reaction mixture is stirred for another 20 minutes. and then gradually raise the temperature to 80"C. After one hour, according to TLC and LCMS, the reaction ends. The product is treated with EAs (2x50ml) and a 10956 solution of potassium-sodium tartrate (2x50ml). After the specified treatment, aluminum is removed from the solution. Then the organic phase is dried over Mag5O4, filtered and the solvent is removed under reduced pressure.

HPLC and obtain 1.43 g (10095) of compound 103. LCMS (95)-: 425 (Ma-NU'Vg, 100), 423 (MAN"VI, 88). "H NMR (400 MHz, DMSO-bv) 6: 9.74 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.08-8.03 (m, 1H), 7.58 (s, 1H) , 7.36 (dd, U1-8HZ,

U2АГц, 1), 7.33-7.27 (m, 1Н), 7.28 (d, U-2Hz, 1Н), 7.04-7.01 (m, 1Н), 6.95 (d, U-8Hz, 1H), 3.67 (s, ZN).

Example 1.116: Preparation of 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4--2-dimethylaminoethoxy)phenyl|-3-(2,4-difluorophenyl)urea (Compound 123)

Compound 103 (73.7 mg, 0.17 mmol) was dissolved in anhydrous THF (5 mL). To the solution add РРИз (17Zmg,

0.b4mmol) and 2-dimethylaminoethanol (65.5μl, 0.6mmol) and the reaction mixture is stirred at room temperature. After five minutes, BIAO (disopropyl azodicarboxylate) (127μl, 0.b4mmol) is added dropwise to the reaction mixture. According to TLC and LCMS, the reaction is completely completed within 30 min. The solvent is removed under reduced pressure. The residue was purified twice by flash chromatography (Vioiade, 5 µg, gradient elution in the dichloromethane/methanol system) and twice by HPLC to give 26.4 mg (31965) of compound 123 as a light brown oil: LCMS t/ (95)-496 (Ma- NU'Vg, 100), 494 (MAN"VG, 94). "H NMR (400 MHz, DMSO-α) 6: 8.99 (s, 1H), 8.44 (s, 1H), 8.07- 8.01 (m, 1H), 7.59 (s, 1H), 7.52 (dd, У1-8Гц, уШ2а4гцц, 1), 7.35 (d, 9-4, 1Х), 7.32- 7.26 (m, 1H), 7.17 (d, 3-12Hz, 1), 7.05-7.00 (m, 1H), 4.11 (at, 2H), 3.65 (s,

ЗН), 2.58 (at, 2Н), 2.11 (с, 6Н).)

Example 1.117: Preparation of tert-butyl ether (2-(2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-I3-(2,4-difluorophenyl)ureido|phenoxyethyl)carbamic acid ( Compound 147)

Compound 147 is obtained according to a method similar to that given in example 1.116, using M-Osaminoethanol and OEAO; 25 mg (3995) of compound 147 are obtained. LCMS (95)-566 (MaAN"Vg, 21), 568 (MANU!'VI, 12). "H NMR (400 MHz, DMSO-Aiv) 5: 9.00 ( s, 1H), 8.45 (s, 1H), 8.07-8.00 (m, 1H), 7.59 (s, 1H), 7.51 (dd, U1-8HC, 9sh22 HC, 1H ), 7.35 (d, 9U-4Hz, 1H), 7.32 (m, 1H), 7.16 (d, U-8Hz, 1H), 7.05-7.00 (m, 1H), 6.89-6.87 (m, 1H), 4.03-3.98 (m, 1H), 3.98-3.92 (m, 1H), 3.64 (s, ЗН), 3, 34-3.29 (m, 1H), 3.22-3.17 (m, 1H), 1.36 (s, 9H).

Example 1.118: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea (Compound 58)

Compound 1 (1.56 g, 3.58 mmol) was dissolved in anhydrous NaCl (50 ml). The solution, while stirring, is cooled to 0"C in an ice bath. Stir for 10 min. and slowly add AISIS (1.91 g, 14.32 mmol).

The reaction mixture is stirred for another 20 minutes. and then gradually raise the temperature to 80"C. After one hour, according to TLC and LCMS, the reaction ends. The product is treated with EtOAc (2x5O0ml) and a 1096 solution of potassium-sodium tartrate (2x50ml). After the specified treatment, aluminum is removed from the solution. Then the organic phase is dried over Mag5O4, filtered and the solvent is removed under reduced pressure. The residue is purified by HPLC to give compound 58 (402mg, 2795): РХМО ти/ (95)-423 (Ma-NU"Si, 100), 421 (MANZSI, 98).

NMR (400 MHz, DMSO-α) δ: 9.74 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 7.60 (s, 1H), 7.48 (d, 9-8Hz, 2H), 7.39 (dd,

U18Hz, 924Hz, 1H), 7.32 (d, U:8Hz, 2H), 7.28 (d, 952Hz, 1H), 6.96 (d, U-12Hz, 1H), 3.67 (s , ZN).

Example 1.119; Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-chlorophenyl)urea (Compound 91) 3-(4-Chloro-2-methyl) -2H-pyrazol-3-yl)-4-methoxyphenylamine (30 mg, 0.1 mmol) is treated with 3-chlorophenylisocyanate (17 μl, 0.14 mmol) similarly to the method given in example 1.53, and 25 mg (4695) of compound 91 is obtained: /z (95)-391 (MHC, 100), 393 (M-A-NZ"CI, 70). "H NMR (400 MHz, acetone-av) 6: 8.51 (s, 1H), 8.41 (s, 1H), 7.84 (t, 1H), 7.71 (dd, 91-28 Hz, 9shchae24 Hz, 1), 7.49 (s, 1H), 7.49 (d, Ux2HzC, 1H ), 7.38 (d, U-8Hz, 1H), 7.29 (t, 1H), 7.16 (d, U-8HzC, 1H), 7.01 (d, U-8Hz, 1H), 3.84 (c, ZN), 3.68 (c, ZN).

Example 1.1290: Preparation of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3,4-difluorophenyl)urea (Compound 92) 3-(4- Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (30 mg, 0.1 mmol) is treated with 3,4-difluorophenyl isocyanate (17 μl, 0.14 mmol) similarly to the method given in example 1.53, and 18 is obtained, mg (34965) of compound 92: LCMS ti/ia (95)-393 (M'ANZ5CI, 100), 395 (M--NU"CI, 38). "H NMR (400Mhz, acetone-dv) o: 8, 18 (s, 1H), 8.05 (s, 1H), 7.65 (m, 1H), 7.57 (dd, U1-:8Hz, U2-4Hz, 1H), 7.36 (s, 1H ), 7.33 (d, U22Hz, 1H), 7.09 (d, 9-4Hz, 1H), 7.06 (d, U-2HzC, 1H), 7.04 (d, U-8Hz, 1H ), 3.72 (s, ZN), 3.55 (s, ZN).

Example 1.121: Preparation of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3,5-difluorophenyl)urea (Compound 93) 3-(4- Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (30 mg, 0.1 mmol) is treated with 3,5-difluorophenyl isocyanate (17 μl, 0.14 mmol) similarly to the method given in example 1.53, and 24 is obtained, mg (44965) of compound 93: LCMS ti/ia (95)-393 (MaANZ5Cl, 100), 395 (M--NU"Cl, 47). "H NMR (400Mhz, acetone-dv) o: 8.26 c, 1H), 8.01 (c, 1H), 7.47 (dd, U1-:9Hz, 9222HzC, 1H), 7.26 (c, 1H), 7.22 (d, U-52HzC, 1 ), 7.04 (dd, U1-12Hz, uschgahz, 2H), 6.95 (d, U-8HzC, 1), 6.40 (m, 1H), 3.62 (s, ЗН), 3, 48 (c, ZN).

Example 1.122: Preparation of 1-benzoyl-3-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 95) 3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-methoxyphenylamine (20 mg, 0.08 mmol) is treated with benzyl isocyanate (14 mg, 0.09 mmol) similarly to the method given in example 1.53, and 10 mg is obtained

(3195) compound 95: LCMS of (96)-385 (MaANZSSI, 11), 387 (MaANUSI, 4). "H NMR (400 MHz, SOSIz) 6: 10.85 (s, 1H), 9.15 (s, 1H), 7.88 (d, 9U-12Hz, 2H), 7.58 (dd, U1-8Hz . U-8Hz, 2H), 6.95 (d, U-8Hz, 1H), 3.75 (s, ЗН), 3.64 (s, ЗН).

Example 1.123: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2-fluorophenyl)urea (Compound 97) 3-(4-Chloro- 2-Methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (20 mg, 0.0 mmol) is treated with 2-fluorophenyl isocyanate (1 μmol, 0.09 mmol) similarly to the method given in example 1.53, and 8 μmol (26965) is obtained compound 97: LCMS (95)-:375 (MaANZSI, 100), 377 (MHC, 43). "H NMR (400 MHz, SOCIz) 5: 8.26 (t, 1H), 7.73 (dd, U1-:8Hz, 9da2-:4Hz, 1), 7.69 (s, 1H), 7.36 (t, 1H), 7.35 (d, 9U-4Htsu, 1H), 7.29 (t, 1H), 7.24 (d,

U8Hz, 1), 7.19 (d, U-8Hz, 1H), 7.17 (d, U-8Hz, 1H), 3.97 (s, ЗН), 3.86 (s, ЗН).

Example 1.124: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-cyanophenyl)urea (Compound 109) 3-(4-Chloro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (55 mg, 0.23 mmol) is treated with 3-cyanophenyl isocyanate (37 mg, 0.26 mmol) similarly to the method given in example 1.53, and 57 mg (6595) of compound 109 are obtained : RHMS ti/ (95)-382 (MaANZZSI, 100), 384 (MNS, 38). "H NMR (400MHz, DMSO-dv) 6: 9.02 (s, 1H), 8.85 (s, 1H), 7.98 (t, 1H), 7.68 (d, U58Hz, 1H), 7.62 (s, 1H), 7.59 (dd, U1-12Hz, shU222Hz, 1H), 7.50 (t, 1H), 7.42 (t, 1H), 7.42 (d, U- 4HzC, 1H), 7.18 (d, U-8HzC, 1), 3.78 (s, ZN), 3.62 (s, ZN).

Example 1.125: Preparation of 1-benzyl-3-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea (Compound 105) 3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-methoxyphenylamine (59 mg, 0.25 mmol) is treated with benzyl isocyanate (34 μl, 0.28 mmol) similarly to the method given in example 1.53, and 42.7 mg (46.195) of compound 105 are obtained: PHMS t/ (95):371 (MANI, 100), 373 (Ma-NU"SI, 40). "H NMR (400MHz, DMSO-av) 6: 8.55 (s, 1H), 7.58 (s, 1H ), 7.50 (dd, U1-:8Hz, 9Ua2-:4Hz, 1H), 7.33 (m, 5H), 7.30 (d, 9-4 Hz, 1H), 7.10 (d, 9-12Hz, 1), 6.58 (s, 1H), 4.28 (s, 2H), 3.73 (s, ЗН), 3.58 (s, ЗН).

Example 1.126: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-nitrophenyl)urea (Compound 110) 3-(4-Chloro- 2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (Zbmg, 0.15 mmol) is treated with 3-nitrophenyl isocyanate (28 mg, 0.17 mmol) similarly to the method given in example 1.53, and 8.7 mg (1595 ) PO compounds: LCMS ti/ (965)-402 (MHC, 100), 404 (M.-NU"SI, 38). "H NMR (400 MHz, DMSO-α) 6: 9.22 (s, 1Н) , 8.84 (s, 1H), 8.55 (s, 1H), 7.83 (dd, U12:8Hz, 9da2:4 Hz, 1H), 7.72 (d, U28HzC, 1H), 7, 62 (s, 1H), 7.61 (d, 9-4Hz, 1H), 7.58 (s, 1H), 7.58 (t, 1H), 7.41 (d, U-4HzC, 1H) , 7.19 (d, 9-12 Hz, 1), 3.78 (s, ZN), 3.62 (s, ZN).

Example 1.127: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-I3-(1-hydroxyethyl)phenyl|urea (Compound 94)

Compound 17 (30.2 mg, 0.07 mmol, see example 1.24) was dissolved in ethanol (5 ml). Sodium borohydride (3.1 mg, 0.08 mmol) was added under a stream of argon. The reaction mixture is stirred overnight and the complete completion of the reaction is determined by TLC and TLC. The mixture is treated with NCI (10 ml) and EOAc (2 x 15 ml). The organic layers are combined and washed with water, dried over Ma»5Ox4, filtered and the solvent is removed under reduced pressure. The residue is purified by HPLC and 19.4 mg (6395) of compound 94 are obtained: RHMO ti/ya (95)-: 445 (MAN"VH, 25), 447 (MaANU!Vu, 25). "H NMR (400 MHz, SOSIz) 5 : 7.34 (dd, U128Hz, shda22Hz, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 7.11 (d, 9-8Hz , 1), 7.09 (s, 1H), 7.06 (t, 1H), 6.95 (d, U-4 Gu, 1H), 6.85 (d, U-8Hz, 1H), 6 .76 (d, U-8Hz, 1H), 4.65 (m, 1H), 3.59 (s, ЗН), 3.49 (s, ЗН), 1.27 (d, U-4Hz, ЗН ).

Example 1.128: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-I3-(1-hydroxyiminoethyl)phenyl|urea (Compound 96)

Compound 17 (54 mg, 0.12 mmol, see example 1.24) is dissolved in ethanol (1 Oml). Hydroxylamine hydrochloride (17 mg, 0.24 mmol) was added under an argon stream. Adjust the pH of the solution to 4 with 1N hydrogen chloride solution.

The reaction mixture is stirred overnight at room temperature and the complete completion of the reaction is determined by TLC and LCMS. Ethanol is removed under reduced pressure. The residue is treated with EtOAc (2 x 20 ml) and saturated salt solution. The organic layers were combined, dried over NaCl, filtered and the solvent was removed under reduced pressure. The residue is purified by HPLC and 8.8 mg (16905) of compound 96 are obtained: RHMSO t/: (95)-458 (MAN VG, 96), 460 (M.-NU'Vg, 100). "H NMR (400MHz, SOSIz) 6: 7.78 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.48 (dd, U1-12Hz, 9daeh4 Hz, 1H), 7.42 (s, 1H), 7.41 (dd, U128Hz, 9U2:4 Hz, 1H), 7.39 (d, U-4Hz, 1H), 7.30 (t, 1H), 7.19 (d, U-9Hz, 1), 7.15 (s, 1H), 7.08 (dd, U1-12Hz, 9Ua2-:4Hz, 1H), 6.88 (dd, U1-12Hz, 9Ug2-:8Hz, 1), 3.66 (s, ZN), 3.58 (s,

ZN), 1.99 (c, ZN).

Example 1.129: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-chloro-2-hydroxyphenyl)urea (Compound 107) 3- (4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (bbmg, 0.23 mmol) was dissolved in dichloroethane (1.5 mL). In another flask, 4-nitrophenyl chloroformate was dissolved in dichloroethane (3 mL) and the solution is heated with a hair dryer until it is completely dissolved. The two solutions are mixed with a catalytic amount of pyridine and stirred at room temperature. As soon as the carbamate is formed, the absorber "Zigayuz5rpPegev" is added.

The mixture is vigorously stirred for two hours and filtered. 2-Amino-5-chlorophenol is dissolved in pyridine (ml) and added to the reaction mixture. The reaction mixture is stirred for 5 hours and the complete completion of the reaction is determined by TLC and LCMS. The solvent is removed in vacuo under reduced pressure and the residue is purified

HPLC, yielding 36.5 mg (3595) of compound 107: LCMS, (95)-451 (Mann "Vg, 80), 453 (MNU'Vg, 100). "H NMR (400MHz, SOSI»z) 6: 7 .74 (s, 1H), 7.67 (s, 1H), 7.53 (d, U9-8Hz, 1), 7.28 (s, 1H), 7.28 (d, 9-12Hz, 1 ), 7.12 (d,

UvHcC, 1H), 6.99 (c, 1H), 6.91 (d, U-8HC, 1H), 3.89 (c, ZN), 3.82 (c, ZN).

Example 1.130: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2,2-difluorobenzo|1,3|dioxol-5-yl) truncated (Compound 115) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (bbmg, 0.22 mmol) is combined with 5-amino-2,2-difluoro-1,3 -benzodioxole, similar to the method given in example 1.129, and 32 mg (30905) of compound 115 are obtained: LCMS ti/ya (95)-481 (MaH"Bg, 96), 483 (Ma-NU'Bg, 100). "H NMR (400 MHz, acetone-av) o: 8.42 (s, 1H), 8.28 (s, 1H), 7.76 (d, 9U-4Hz, 1H), 7.70 (dd, U12:8Hz, 9U2-:4Hz, 1H), 7.52 (s, 1H), 7.45 (d, U-2Hz, 1H), 7.19 (d,

U12Hz, 1), 7.16 (d, 9-2 Hz, 1H), 7.14 (d, 9-4Hz, 1H), 3.83 (s, ЗН), 3.70 (s, ЗН).

Example 1.131: Preparation of intermediate 4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)/phenylamine

Stage 1: Preparation of M-I4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl/phenyl|acetamide)

A mixture of M-I4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenylacetamide (2.0g, 8.15mmol) in anhydrous 1,2-dichloroethane (bOml) is cooled to 0"C at ice bath and stir for 10 minutes. Anhydrous aluminum chloride (4.35 g, 32.bmol) is added, the reaction mixture is stirred at 0"C for 20 minutes, then transferred to an oil bath and stirred for 1 hour at a temperature of 80"C. Ethyl acetate is added and washed twice with sodium potassium tartrate (1095). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the crude product, which was purified by preparative HPLC.

The appropriate fractions were collected and lyophilized to give //-M-I4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl|acetamide in 7095% yield as a white solid. РХМС t/ (95)-:232 (MN, 100). "N

NMR (400MHz, DMSO-α) 5: 7.39 (s, 1H), 6.86 (d, U-8.74Hz, 1H), 6.62 (d, 9U-8.70Hz, 1H), 6 .47 (s, 1H), 6.15 (s, 1H), 4.80 (width, s, 2H), 3.87 (t, 9-5.80Hz, 2H), 3.63 (s, ), 2.44 (t, 9-5.80 Hz, 2H), 2.08 (s, 6H).

Stage 2: Preparation of IM-I4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-iluphenyl|acetamide)

Triphenylphosphine (2.91 g, 11, 1 mmol) and 2-dimethylaminoethanol (1.11 mL, 11.1 mmol) and then diisopropyl azodicarboxylate (OIA0) (2.15 mL, 11.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and concentrated to give the crude product, which is purified by preparative HPLC.The appropriate fractions are collected, neutralized with Mahon's solution, and extracted four times with ethyl acetate to give M-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|acetamide in in the form of a solid colorless waxy substance with a yield of 51.296. LCMS t/2 (953-303 (MAN, 100). "H NMR (400 MHz, DMSO-dbv) 5: 9.94 (s, 1H), 7.63 (d, 9U-8.93Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.14 (d, U-8.98Hz, 1H), 6.25 (s, 1H) , 4.07 (t, U-5.82Hz, 2H), 3.69 (s, ЗН), 2.56 (t, U-5.80Hz, 2H), 2.15 (s, 6H), 2 ,05 (c, ZN).

Stage 3: Preparation of 4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine

The compound M-I4--2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazole-3-iluphenyl|acetamide (0.50 g, 1.7 mmol) is dissolved in ethanol (25 ml), sodium hydroxide (1.5 g) is added , granules) in d3ml of water, the reaction mixture is stirred at 80"C overnight and then concentrated. Water and saturated salt solution are added and extracted four times with EIHUASc. The organic phases are combined, washed with water and saturated salt solution, dried over anhydrous Mag25O4 and then the solvent was removed under reduced pressure to give 4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)/uphenylamine in 87.595 yield as a light brown oil. LCMS mp (95) -261 (MH, 100). "H NMR (400 MHz, DMSOO-av) 6: 9.82 (s, 1H), 9.71 (width s, 1H), 7.48-7.45 (m, ZN), 6.93 (d, U-8.74 Hz, 1H), 6.23 (s, 1H), 3.7 (s, ZN), 2.0 (s, ZN).

Example 1.132: Preparation of /1-(4-chlorophenyl)-3-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl)urea (Compound 127)

A solution of /4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine (26.0 mg, 0.0 mmol) in methylene chloride (ml) is treated with 4-chlorophenyl isocyanate (13.3 μl, 0.105 mmol) , the reaction mixture was stirred overnight at room temperature and then concentrated to give an oily residue which was purified by flash chromatography (5102, gradient elution in a mixture of CNeSig/Meon) to give compound 127 as a white solid in 69.895 yield. RHMS. t/a (95)-414 (MaeNZSI, 100), 416 (M-NU"SI, 36). "H NMR (400 MHz, acetone-iv) 6: 8.51 (s, 1H), 8.36 ( s, 1H), 7.62-7.59 (m, ЗН), 7.50 (s, 1H), 7.42 (s, 1H), 7.31 (d, 9U-8.90Hz, 2H) , 7.12 (d, 9U-8.92Hz, 1H), 6.24 (s, 1H), 4.11 (t, U-5.86Hz, 2H), 3.77 (s,

ZN), 2.61 (t, 9-5.85 HZ, 2H), 2.20 (s, 6H).

Example 1.133: Preparation of /- 1-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-iluphenyl|-3-(4-fluorophenyl)urea (Compound 142) 4-(2- Dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine (26.0mg, 0.mmol) is treated with 4-fluorophenylisocyanate (11.3ml, 0.105mmol) similarly to the method given in example 1.2, and obtain with a yield of 66.495 compound 142 as a white solid. LCMS t/: (96)-398 (Mann, 100). "H NMR (40OMHC, acetone-dv) 5: 8.33 (s, 1H), 8.25 (s, 1H), 7.61-7.56 (m, ЗН), 8.49 (s, 1Н), 7.42 (s, 1Н), 7.11-7.04 (m, ЗН), 6.24 (s, 1H), 4.11 (t, 9-5.85Hz, 2H), 3.77 (s, ЗН), 2.62 (t, 9-5.85Hz, 2H), 2, 20 (p. 6H).

Example 1.134: Preparation of 1-(2,4-difluorophenyl)-3-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea (Compound 141) 4-( 2-Dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (26.0 mg, 0.1 mmol) is treated with 2,4-difluorophenyl isocyanate (12.4 μl, 0.105 mmol) similarly to the method given in example 1.2, and compound 141 is obtained with a yield of 73.395 in the form of a white solid. LCMS t/l (95)-416 (MAN, 100). "H NMR (400MHz, DMOSO-av) o: 8.95 (s, 1H ), 8.46 (s, 1H), 8.08-8.02 (m, 1H), 7.45-7.42 (m, 2H), 7.37 (d, 922.7 Hz, 1H) , 7.33-7.27 (m, 1H), 7.12 (d, U-8.95Hz, 1H), 7.05-6.98 (m, 1H), 6.24 (d, 9U- 22.7HzC, 1H), 4.03 (t, U-5.80Hz, 2H), 3.67 (s, ЗН), 2.54 (t, 9-5.73Hz, 2H), 2.12 ( p, 6H).

Example 1.135: Preparation of 1-(3-acetylphenyl)-3-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea (Compound 143) 4-(2- Dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine (26.0mg, 0.mmol) is treated with 3-acetylphenylisocyanate (16.9μl, 0.105mmol) similarly to the method given in example 1.2, and obtain with a yield of 64.395 compound 143 in the form of a colorless waxy solid. LCMS t/2 (90)-422 (MAN, 100). "H NMR (400 MHz, DMSO-α) 6: 8.98 (s, 1H), 8, 73 (s, 1H), 8.10 (s, 1H), 7.52-7.42 (m, 4H), 7.37 (d, y-8.06 Hz, 1H), 7.37 (d, 9U-6.75Hz, 1H), 7.33-7.28 (m, 4H), 7.15 (d, U-8.98Hz, 1H), 6.28 (s, 1H), 4.08 ( t, U-5.80Gu, 2H), 3.71 (s, ЗН), 2.54 (m, 6H), 2.12 (s, 6H).

Example 1.136: Preparation of /- 1-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-(3-methoxyphenyl)urea (Compound 146) 4-( 2-Dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine (26.0 mg, 0./mmol) is treated with 3-methoxyphenyl isocyanate (13.8 μl, 0.105 mmol) similarly to the method given in example 1.2 , and compound 146 was obtained in a yield of 71.195 as a colorless waxy solid. LCMS t/2 (90)-410 (MAN, 100). "H NMR (400 MHz, DMSO-dv) 6: 8.70 (s, 1H) , 8.63 (s, 1H), 7.45-7.42 (m, 2H), 7.37 (d, 9-2.7Hz, 1H),

7.18-7.10 (m, ZN), 6.91 (dd, U-8.02Hz, 1.2Hz, 1H), 6.53 (dd, 9U-7.71Hz, 2.05Hz, 1H), 6.24 (d, U-1.83Hz, 1H), 4.03 (t, 9-5.80Hz, 2H), 3.72 (s, ЗН), 3.67 (s, ЗН) , 2.52 (t, 9-5.80 Hz, 2H), 2.12 (s, 6H).

Example 1.137: Preparation of 1-(2,2-difluorobenzo|1,3|dioxol-5-yl)-3-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl) phenyl|urea (Compound 144)

To a solution of 4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazole-3-iluphenylamine (26.0 mg, 0.mmol) in methylene chloride (ml) was added pyridine (24.µl, 0.mmol) and 4-nitrophenyl chloroformate (20.2 mg, 0.1 mmol) and the mixture was stirred at room temperature for 1 h. 5-amino-2,2-difluoro-1,3-benzodioxole (11.6 μL, 0.1 mmol) was added, the reaction the mixture was stirred at room temperature for 48 hours and concentrated to give an oily residue, which was purified by flash chromatography (500, gradient elution in a mixture of CH2HSig/Meon) to give compound 144 as an off-white solid in a yield of 14.0950. LCMS T/" (95)-460 (MH, 100). "H NMR (400 MHz, DMSOO-av) 6: 10.30 (s, 1H), 7.64 (d, U-8.96Hz, 1H) , 7.53 (s, 1H), 7.42 (s, 1H), 7.40-7.34 (m, 4H), 7.13 (d, U-8.92Hz, 1H), 6.22 (s, 1H), 4.10 (t, 95.56Hz, 2H), 3.65 (s, ЗН), 3.63 (s, 2H), 2.76-2.65 (m, 2H), 2.22 (c, 6H).

Example 1.138: Preparation of 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(2,4-difluorophenyl)urea (Compound 120)

A mixture of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2,4-dichlorophenyl)urea (compound 77, example 1.61) (0.270g, 0 .69 mmol) in anhydrous 1,2-dichloroethane (10 ml) is cooled to 0"C in an ice bath and stirred for 10 minutes. Anhydrous aluminum chloride (0.368g, 2.76 mmol) is added and the reaction mixture is stirred at 0"C for 20 minutes. , then transferred to an oil bath and stirred for 1 hour at a temperature of 80°C. Ethyl acetate was added and washed twice with sodium potassium tartrate (1095). The organic layer was separated, dried over anhydrous Mag5O4, filtered and concentrated, obtaining a crude product that was purified by HPLC. The corresponding fractions were collected and lyophilized to give compound 120 as a white solid in a yield of 7595. РХМО t/l (95)-379 (MaАНЗЗСИ, 100), 381 (Ma-НУССИ, 40). "H NMR (400 MHz,

DMSO-α) about: 9.81 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.12-8.06 (m, 1H), 7.63 ( c, 1H), 7.40-7.31 (m, ЗН), 7.09-7.04 (m, 1H). 6.99 (d, U1-8.72 Hz, 1H), 3.69 (s, ЗН).

Example 1.139: Preparation of 1-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-dimethylaminoethoxy)phenyl|-3-(2,4-difluorophenyl)urea (Compound 132 )

To a solution of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl/|-3-(2,4-difluorophenyl)urea (see above) (0.035g, 009mmol ) in THF (3 ml) add triphenylphosphine (0.071 g, 0.27 mmol) and 2-dimethylaminoethanol (27.1 μl, 0.27 mmol) and then dropwise add diisopropylazodicarboxylate (OIAV) (52.3 μl, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to give the crude product, which was purified by preparative HPLC. The corresponding fractions are collected, neutralized with a solution of NaOH and extracted with ethyl acetate. A second purification by flash chromatography (500, gradient elution in a mixture of СНоСИг/MeОНН) gave compound 132 in a yield of 45.995 as an off-white solid. RHMS t/l (95)-450 (MaNZZSI, 100), 452 (MNS, 32). "H NMR (400 MHz, DMSO-av) 6: 9.11 (s, 1H), 8.56 (s, 1H), 8.06-8.00 (m, 1H), 7.60 (s, 1H ), 7.52 (d, U-8.95HzC, 1), 7.38 (s, 1H), 7.33-7.27 (m, 1H), 7.17 (d, 9U-9.04Hz , 1H), 7.05-6.98 (m, 1H), 4.12-3.95 (m, 2H), 3.65 (s, ЗН), 2.55-2.51 (m, 2H ), 2.10 (c, 6H).

Example 1.140: Preparation of 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|-3-(2,4-difluorophenyl)urea (Compound 133 )

To a solution of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl/|-3-(2,4-difluorophenyl)urea (see above) (0.035g, 009mmol ) in THF (3 mL) add triphenylphosphine (0.071 g, 0.27 mmol) and 3-dimethylaminopropanol (31.6 µL, 0.27 mmol) and then add diisopropyl azodicarboxylate (PIAO) (52 µL, 0.27 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours and concentrated to give the crude product, which was purified by preparative HPLC. The corresponding fractions are collected, neutralized with Mahon's solution and extracted four times with EAs. A second purification by flash chromatography (500, gradient elution in a mixture of СНоСИг/MeОНН) gave compound 133 in a yield of 25.495 as an off-white solid. RKHMS t/l (95)-464 (MNS, 100), 466 (MNS, 39). "H NMR (400 MHz, DMSO-α) 6: 9.02 (s, 1H), 8.47 (s, 1H), 8.07-8.01 (m, 1), 7.62 (s, 1H ), 7.51 (d, 9-8.90HzC, 1), 7.38 (s, 1H), 7.33-7.28 (m, 1H), 7.15 (d, 9U-9.02Hz , 1H), 7.03-6.97 (m, 1H), 4.11-3.94 (m, 2H), 3.63 (s, ЗН), 2.28-2.18 (m, 2H ), 2.11 (s, 6H), 1.78-1.69 (m, 2H).

Example 1.141: Preparation of / 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxyphenyl|-3-(4-chlorophenyl)urea (Compound 108)

Stage A: Preparation of tert-butyl ether (3-bromo-4-trifluoromethoxyphenyl)carbamic acid

A solution of 3-bromo-4-(trifluoromethoxy)aniline (3.84g, 15mmol) in dioxane (15ml) is mixed with di-tert-butyldicarbonate (4.91g, 22.5mmol) and then the reaction mixture is heated overnight at a temperature of 80" C. The solvent was removed under reduced pressure to give an oily residue, which was treated with hexane. The precipitate formed was collected by filtration to give (3-bromo-4-trifluoromethoxyphenyl)carbamic acid tert-butyl ether as a white solid in a yield of 61.095." H NMR (400 MHz, DMSO-av) 6: 9.78 (b, 1H), 7.87 (s, 1H), 7.54-7 43 (m, 2H), 1.51 (s, 9H ).

Stage B: Preparation of tert-butyl ester of 3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxyphenylcarbamic acid

Tert-butyl ether (3-bromo-4-trifluoromethoxyphenyl)carbamic acid (230.0 mg, 0.65 mmol), 1-methylpyrazole-5-boronic acid (392.9 mg, 1, 93mmol), sodium carbonate (137.8mg, 1.hmol), OME (5ml) and water (0.5ml). Tetrakis(triphenylphosphine)palladium (75.1 mg, 0.05 mmol) was added and the reaction mixture was again purged with argon.

The reaction mixture was heated overnight at 80°C and then cooled to room temperature. Ethyl acetate (1 mL) was added and then washed with saturated salt solution and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was subjected to purification by flash chromatography (5102, gradient elution in a mixture of sng:sg/meon), obtaining tert-butyl ether 3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxyphenylcarbamic acid with a yield of 36.595 in the form of not quite white solid.

RHMS ti/i (96)-358 (MAN, 100). "H NMR (400MHz, DMSO-av) o: 9.83 (b, 1H), 7.77 (d, 9-8.95Hz, 1H), 7.69 (s, 1H), 7.63 (c, 1H), 7.57 (d, U-8.84 Hz, 1H), 6.45 (c, 1H), 3.78 (c, ЗН), 1.60 (c, 9H).

The stage of Preparation of 13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxyphenylcarbamic acid tert-butyl ether

M -bromosuccinimide (35.6 mg, 0.2 mmol) and the reaction mixture was stirred overnight at room temperature. The resulting mixture was diluted with ethyl acetate, washed with saturated salt solution and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily the residue, which is purified by flash chromatography (5iO2, gradient elution in a mixture of CHNeSig/mMeon) to give tert-butyl (3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxyphenylcarbamic acid) with a yield of 89.29 in the form of a white solid. LCMS ti/i (95)-5436 (M-AN"Vg, 100), 438 (MANU!'VG, 98). "H NMR (400 MHz, SOzOB) 6: 7.79 (d, U-8.90Hz, 1), 7.613, 1H), 7.55 (s, 1H), 7.43 (d, 9-8.94Hz, 1H), 3.73 (s, ЗН), 1.55 (c, 9Н).

Stage p: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-fluoromethoxyphenyl|-3-(4-chlorophenyl)urea (Compound 108)

Trifluoroacetic acid ( 0.5 ml) and the reaction mixture is stirred at room temperature for 20 minutes.

The solvent is removed under reduced pressure and 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxyphenylamine trifluoroacetate is obtained in quantitative yield as a colorless oil. RHMOS t/2 (95)-336 (MAN"Vg, 100), 338 (MaNU'Vg, 95). The obtained compound is dissolved in methylene chloride (0.8 ml) and then treated with M,M-isopropylethylamine until the pH reaches 7-8. 4-Chlorophenyl isocyanate (8.5 mg, 0.055 mmol) was added, the reaction mixture was stirred overnight, then concentrated to give a residue which was purified by flash chromatography (5102, gradient elution in a mixture of hexane/E(OAc), obtaining from with a yield of 62.095 compound 108 in the form of a white solid. LCMS t/g (95)-489 (MaAN"VIZ5CI, 93), 491 (MAN VIZ5CI, 100), 493 (MANU'VIZ7CI, 34). "H NMR (400 MHz, SOzOB) 6: 7.71 (dd, U-8.98 Hz, 2.72 Hz, 1H), 7.64-7.62 (m, 2H), 7.49-7.45 (m, ЗН), 7.33-7.30 (m, 2H), 3.76 (s, ZN).

Example 1.142: Preparation of /1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4A-trifluoromethoxyphenyl|-3-(2,4-difluorophenyl)urea (Compound 113)

Trifluoroacetic acid ( 0.5 ml) and the reaction mixture is stirred at room temperature for 20 minutes.

The solvent is removed under reduced pressure and 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxyphenylamine trifluoroacetate is obtained in quantitative yield as a colorless oil. RKHMOS vol. 2 (95)-336 (MaANVg, 100), 338 (MaANUVg, 95). The obtained compound is dissolved in methylene chloride (0.8 ml) and then treated with M,M-diisopropylethylamine until the pH reaches 7-8. 2,4-Difluorophenyl isocyanate (8.5 mg, 0.055 mmol) was added, the reaction mixture was stirred overnight, then concentrated to give a residue which was purified by flash chromatography (5i0), gradient elution in a mixture of hexane/E(OAc) to give 46.395 compound 113 as a white solid. LCMS t/2 (95)-491 (MaAN"Vg, 100), 493 (mMANU!'Vg, 98). "H NMR (400MHz, COzOb) 5: 8.06- 8.00 (m, 1H), 7.71 (dd, 9U-9.00Hz, 2.74 Hz, 1), 7.65-7.62 (m, 2H), 7.48 (d, U- 9.00 Hz, 1H), 7.09-7.00 (m, 1H), 6.99-6.94 (m, 1H), 3.76 (s, ZN).

Example 1.143: Preparation of 1-(2,4-difluorophenyl)-3-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazole-

Z-yl)phenyl|urea (Compound 124)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (21.4 mg, 0.078 mmol) in

2,4-difluorophenyl isocyanate (0.10 μl, 0.0 in 4 mmol) is added to SNesi" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (5СХ, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 124 as a colorless solid (30.2 mg, 7395). RHMS t/z (95)-5430 (MNU) (100). "H NMR (400 MHz, DMSO-yv) at: 8.94 (width s, 1H), 8.46 (width s, 1H), 8.09-8.00 (m, 1H), 7.45 (d, 9U-1.80Hz, 1H), 7.42 (dd, y-8.89, 2.72Hz, 1H), 7.34-7.26 (m, 1H), 7.09 (d, U-8.94Hz, 1H), 7.06-6.99 (m, 1H), 6.24 (d, 9U-1.83Hz, 1), 3.97 (t, 9-6.32HzC, 2H ), 3.65 (s, ZN), 2.23 (t, 9-7.07 Hz, 2H), 2.10 (s, 6H), 1.78-1.69 (m, 2H).

Example 1.144: Preparation of 1-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(2-fluorophenyl)urea (Compound 138)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (60 mg, 0.221 mmol) in

2-fluorophenyl isocyanate (0.27 μl, 0.240 mmol) was added to SNeoSi" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried under vacuum to give compound 138 as a colorless solid (85.5 mg, 9195). RHMS t/z (95)-5412 (MNU) (100). "H NMR (400MHz, DMSO-av) 6: 9.36 (width s, 1H), 8.25 (width s, 1H), 8.15 (dd, 9U-8.34, 1.52Hz, 1H), 7.47-7.42 (m, ЗН), 7.40 (d, 9-2.78Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, U-9.09Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, 9-2.02Hz, 1H), 3.98 (t, 9-6.32HzC, 2H ), 3.66 (s, ZN), 2.19 (t, 9-7.07Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).

Example 1.145: Preparation of 1-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4-trifluoromethylphenyl)urea (Compound 137)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (45 mg, 0.167 mmol) in

4-(trifluoromethyl)phenyl isocyanate (0.28 μl, 0.196 mmol) was added to SNesi" (2 ml) and stirred for 2 hours. The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 137 as a colorless solid (25.1 mg, 3390). RHMS t/g (95)-462 (MNU) (100). "H NMR (400MHz, DMSO-dv) 6: 9.11 (width s, 1H), 8.75 (width s, 1H), 7.65 (d, U-9.08Hz, 2H), 7 .62 (d, 99.35Hz, 2H), 7.47 (dd, 9U-9.09, 2.78Hz, 1H), 7.45 (d, 9-1.77Hz, 1H), 7.39 ( d, 9U-2.78Hz, 1H), 7.10 (d, 9U-8.84Hz, 1H), 6.24 (d, 9-1.77Hz, 1H), 3.98 (t, U-6 ,32Hz, 2H), 3.66 (s, ЗН), 2.19 (t, 9-7.07Hz, 2H), 2.07 (s, 6H), 1.77-1.69

(m, 2H).

Example 1.146: Preparation of 1-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(2-fluoro-

B5-methylphenyl)urea (Compound 139)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (43.9 mg, 0.160 mmol) in

2-Fluoro-5-methylphenylisocyanate (0.23 μl, 0.17 mmol) was added to CHneosSi" (2 ml) and stirred for 2 hours. The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 139 as a colorless solid (53.2 mg, 7890). РХМСО t/y (95)-426 (МН) (100). "H NMR (400 MHz, DMSO-aiv) 6: 8.98 (width s, 1H), 8.42 (width s, 1H), 7.96 (dd, 9U-7.89, 1.96 Hz, 1H), 7.45 (d, U-1.82HZ, 1H), 7.44-7.38 (m, 2H), 7.13-7.06 (m, 2H), 6.82-6, 75 (m, 1H), 6.24 (d, 9-1.85Hz, 1H), 3.98 (t, 9-6.35Hz, 2H), 3.66 (s, ЗН), 2.25 ( s, ZN), 2.19 (t, 9-7.03 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

Example 1.147: Preparation of 1-(2-chlorophenyl)-3-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea (Compound 140)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (51.4 mg, 0.184 mmol) in

2-Chlorophenyl isocyanate (0.25 μl, 0.207 mmol) is added to СНоСи" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (5СХ, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 140 as a colorless solid (76.5 mg, 9595). RHMSO t/ (95)-:428 (MNS, 100), 430 (MaANUSI, 37). "H NMR (400MHz, DMSO-dBv) 6: 9.36 (width s, 1H), 8.25 (width s, 1H), 8.15 (dd, U-8.33, 1.48Hz, 1H), 7.48-7.42 (m, ЗН), 7.40 (d, U-2.70Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, U-8.92Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, 9-1.84Hz, 1H), 3.98 (t, U-6.36Hz, 2H ), 3.66 (s, ZN), 2.19 (t, U9-7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).

Example 1.148: Preparation of 1-(33-chlorophenyl)-3-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea (Compound 134)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (47.4 mg, 0.173 mmol) in

3-chlorophenyl isocyanate (0.24 μl, 0.197 mmol) was added to СНоСи" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 134 as a colorless solid (31.0 mg, 4295). RHMS t/" (95)-428 (MaАНЗЗСІ, 100), 430 (MaАНУ"СІ, 39). "H NMR (400MHz, DMSO-dbv) 6: 8.64 (width, 1H), 8.59 (width, 1H), 7.47-7.41 (m, ЗН), 7.45 (d, 9-1.79Hz, 1), 7.37 (d, 9U-2.71Hz, 1) , 7.30-7.23 (m, 2H), 7.09 (d, U-8.97Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, y- 1.85Hz, 1), 3.97 (t, U-6.36Hz, 2H), 3.66 (s, ЗН), 2.19 (t, 9-7.04Hz, 2H), 2.07 ( c, 6H), 1.77-1.69 (m, 2H).

Example 1.149: Preparation of 1-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4-methoxyphenyl)urea (Compound 131)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (38.3 mg, 0.140 mmol) in

4-Methoxyphenyl isocyanate (0.21 μl, 0.162 mmol) was added to SNeSi" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (5СХ, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 131 as a colorless solid (53.1 mg, 9095). RHMS t/a (95)-424 (MNU) (100). "H NMR (400MHz, DMSO-av) 6: 8.49 (width s, 1H), 8.43 (width s, 1H), 7.44 (d, 9U-1.86HzC, 1H), 7 ,42 (dd, 9U-8.92, 2.73Hz, 1H), 7.36 (d, U-2.71Hz, 1), 7.33 (d, 9U-9.09Hz, 2H), 7, 07 (d, U-8.96Hz, 1H), 6.85 (d, U-9.09Hz, 2H), 6.23 (d, y-1.82Hz, 1), 3.96 (t, U -6.35Hz, 2H), 3.71 (s, ЗН), 3.65 (s, ЗН), 2.18 (t, 9-7.05Hz, 2Н), 2.07 (s, 6Н), 1.77-1.69 (m, 2H).

Example 1.150: Preparation of 1-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-paratolylurea (Compound 130)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (45.9 mg, 0.167 mmol) in

4-methylphenyl isocyanate (0.24 μl, 0.191 mmol) was added to SNeosSi" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (5СХ, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 130 as a colorless solid (61.8 mg, 9195). RHMS t/a (95)-408 (MNU) (100). "H NMR (400 MHz, DMSO-av) 6: 8.53 (width s, 1H), 8.52 (width s, 1H), 7.44 (d, 9-1.77 Hz, 1H), 7 ,43 (dd, U-8.91, 2.73Hz, 1H), 7.36 (d, U-2.70Hz, 1H), 7.31 (d, 9U-8.43Hz, 2H), 7, 08 (d, 9U-8.92Hz, 1H), 7.06 (d, U-8.32Hz, 2H), 6.23 (d, y-1.82Hz, 1), 3.96 (t, U -6.36Hz, 2H), 3.65 (s, ЗН), 2.23 (s, ЗН), 2.19 (t, 9-7.05Hz, 2Н), 2.07 (s, 6Н), 1.77-1.69 (m, 2H).

Example 1.151: Preparation of /1-(3-chloro-4-fluorophenyl)-3-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3Z-yl)/uphenyl|urea (Compound 135 )

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (57.3 mg, 0.209 mmol) in

C3-chloro-4-fluorophenyl isocyanate (0.3 µM, 0.241 mmol) was added to the mixture (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (5СХ, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 135 as a colorless solid (66.2 mg, 7195). RHMO t/l (95)-446 (MaNSI, 100), 448 (MaANZ"SI, 35). "H NMR (400 MHz, DMSO-iv) 6: 8.87 (width, 1H), 8.69 (width, 1H), 7.81-7.77 (m, 1H), 7.47-7.42 (m, 2H), 7.37 (d, 9-2.71Hz, 1), 7 .35-7.26 (m, 2H), 7.09 (d, U-8.98Hz, 1), 6.24 (d, 9-1.83Hz, 1H), 3.98 (t, y- 6.36 Hz, 2H), 3.65 (s, ЗН), 2.19 (t, 9-7.04Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m , 2H).

Example 1.152: Preparation of 1-(3,4-difluorophenyl)-3-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazole-

Z-yl)phenyl|urea (Compound 136)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (61.1 mg, 0.223 mmol) in

3,4-difluorophenyl isocyanate (0.30 μl, 0.256 mmol) was added to SNesi" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 136 as a colorless solid (53.3 mg, 5695). RHMS t/l (95)-430 (MN, 100). "H NMR (400 MHz, DMSO-ydv) 6: 8.93 (width s, 1H), 8.72 (width s, 1H), 7.71-7.61 (m, 1H), 7.49 -7.42 (m, 2H), 7.37 (d, y-2.68Hz, 1), 7.35-7.28 (m, 1H), 7.14-7.06 (m, 1H) , 7.09 (d, U-8.96Hz, 1H), 6.23 (d, 9-1.82Hz, 1H), 3.97 (t,

9-6.37 Hz, 2H), 3.65 (s, ЗН), 2.19 (t, 9-7.05Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

Example 1.153: Preparation of 1-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-phenylurea (Compound 145)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (45.6 mg, 0.16 mmol) in

Phenyl isocyanate (0.20 μl, 0.184 mmol) was added to the mixture (2 ml) and stirred for 2 hours. The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1 g), eluting with methanol (Zbml) and then with a 2M solution of МН»z in methanol (ЗОml). Fractions containing MH3 were dried in vacuo to give compound 145 as a colorless solid (45.3 mg, 6995). RHMS t/l (95)-394 (MAN, 100). "H NMR (400 MHz,

DMSO-jav) 6: 8.64 (width s, 1H), 8.59 (width s, 1H), 7.48-7.41 (m, 4H), 7.37 (d, U-52 .71Hz, 1), 7.29-7.23 (m, 2H), 7.09 (d, 9-8.97Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, U-1.85Hz, 1H), 3.97 (t, U-6.36Hz, 2H), 3.66 (s, ZN), 2.19 (t,

U-7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

Example 1.154: Preparation of 1-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4-fluorophenyl)urea (Compound 125)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (24.6 mg. 0.090 mmol) in

4-Fluorophenyl isocyanate (0.12 μl, 0.107 mmol) was added to SNeosSi" (2 ml) and stirred for 2 hours.

The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1g), eluting with methanol (30ml) and then with a 2M solution of MH3 in methanol (30ml). Fractions containing MH3 were dried in vacuo to give compound 125 as a colorless solid (27.0 mg, 7395). RHMS t/l (95)-412 (MAN, 100). "H NMR (400MHz, DMSO-av) 6: 8.67 (lat.s, 1H), 8.58 (lat.s, 1H), 7.48-7 41 (m, 4H), 7.36 ( d, 9-2.70Hz, 1H), 7.14-7.06 (m, ЗН), 6.23 (d, 9-1.82Hz, 1H), 3.97 (t, U-6.34Hz , 2H), 3.65 (s, ЗН), 2.18 (t, 9-7.05Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

Example 1.155: Preparation of 1-(4-chlorobenzyl)-3-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea) (Compound 126)

To a solution of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (20.5 mg, 0.075 mmol) in

4-Chlorobenzyl isocyanate (0.17 μl, 0.128 mmol) was added to SNesi" (2 ml) and stirred overnight. The obtained substance is purified by solid-phase extraction (SSC, cartridge weighing 1g), eluting with methanol (Zbml) and then with a 2M solution of MH3 in methanol (Z0ml). Fractions containing MH3 were dried in vacuo to give compound 126 as a slightly yellowish oil (29.8 mg, 9095). RHMS ti/z (95)-442 (MaANZ5SI, 100), 444 (MNS, 40).

IN NMR (400MHz, DMSO-dv) 6: 8.53 (b, 1H), 7.43 (d, 9-1.81Hz, 1), 7.41-7.36 (m, 4H), 7.34-7.28 (m, ZN), 7.03 (d, 9-8.94Hz, 1H), 6.63 (d, U-6.00HzC, 1H), 6.20 (d, U9 -1.83Hz, 1H), 4.26 (d, 9U-5.96Hz, 2H), 3.94 (t, U-6.36Hz, 2H), 3.63 (s, ЗН), 2.18 (t, 9-7.05 Hz, 2H), 2.06 (s, 6H), 1.77-1.69 (m, 2H).

Example 1.156: Preparation of 1-(2,2-difluorobenzo|1,3|dioxol-5-yl)-3-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea (Compound 129)

To a solution of 4-nitrophenyl chloroformate (55.1 mg, 0.273 mmol) in 1,2-dichloroethane (7 mL) and pyridine (22 μL, 0.272 mmol) was added 5-amino-2,2-difluoro-1,3-benzodioxole (28 μL, 0.241 mmol) and stirred for an hour. Add one spatula of Zigayusrpegez5 RI-OETA resin and continue mixing for another hour. The resulting mixture is filtered (washed with 3 mL of 1,2-dichloroethane) into a flask containing 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine (49.7 mg, 0.181 mmol) and stir overnight. The obtained substance is purified by HPLC. The product was dried in vacuo to give compound 129 as a white solid (29.0 mg, 3495). RKHMS t/» (95)-5474 (MN, 100). "H NMR (400 MHz, DMSO-dv) 6: 8.91 (width s, 1H), 8.61 (width s, 1H), 7.65 (d, 9U-2.09HzC, 1H), 7 ,44 (d, 9U-1.86Hz, 1H), 7.44 (dd, 9U-8.88, 2.82Hz, 1H), 7.37 (d, 9-2.71Gu, 1), 7, 29 (d, 9U-8.75Hz, 1H), 7.09 (d, 9U-8.95Hz, 1H), 7.07 (dd, uU-8.78, 2.18Hz, 1H), 6.23 (d, y-1.81Hz, 1), 3.97 (t, y-6.35Hz, 2H), 3.65 (s, ЗН), 2.19 (t, 9-7.03Hz, 2H) , 2.07 (s, 6H), 1.77-1.67 (m, 2H).

Example 1.157: Preparation of dimethyl(3-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|propyl)amine

Dimethylis-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|propyl)amine is synthesized from 2-(2-methyl-2H-pyrazol-

3-yl)-4-nitrophenol (4.064 g) similarly to the method given in example 1.139. Yellow butter (3.147g, 5690).

РХМС t/: (96)-305 (MN, 100). "H NMR (400MHz, DMSO-yv) 6: 8.35 (dd, 9-9.19, 2.90Hz, 1), 8.10 (d, y-2.88HzC, 1), 7.50 ( d, U-1.86Hz, 1H), 7.39 (d, U-9.26Hz, 1H), 6.37 (d, U9-1.86Hz, 1H), 4.21 (t, U-6 ,40Hz, 2H), 3.67 (s, ЗН), 2.21 (t, U-6.98Hz, 2H), 2.08 (s, 6H), 1.85-1.76 (m. 2H ).

Example 1.158: Preparation of M-I4-pdroxy-3-(2-methyl-2H-trazol-3-yl)uphenyl|Iacetamide

To a suspension of M-(4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)/uphenylacetamide (2.57g, 10.48mmol) in 1,2-dichloroethane (/5ml) add VVgz ( 1Oml) and stir for three hours. The heterogeneous suspension is refluxed for 15 minutes and cooled to room temperature. The reaction is quenched by adding methanol. The resulting substance is purified by HPLC. The product is dried in a vacuum and obtained

M-(4-Hydroxy-3-(2-methyl-2H-pyrazol-3-yl)acetamide as a white solid (508mg, 21905).

RKHMS ti/" (95)-232 (MN, 100). "H NMR (400 MHz, DMSO-av) 5: 9.77 (width s, 1H), 9.66 (width s, 1H), 7.44-7.40 (m, ЗН), 6.89 (d, U-8.85 Hz, 1H), 6.37 (d, 9U-1.81 Hz, 1H), 3.66 (s, ZN), 1.99 (s, ZN).

Example 1.159: Preparation of M-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl/phenyl|acetamide)

M-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)/phenyl|acetamide is synthesized from M-I4-hydroxy-3-(2-methyl-2H-pyrazol-3 -yl/uphenyl|Iiacetamide (489 mg) similarly to the method given in example 1.139.

Colorless oil (375.1mg, 5695). РХМС t/2 (95)-317 (MAN, 100). "YAN NMR (400MHz, DMSO-dv) 6: 9.89 (b, 1H), 7.58 (dd, U-8.92, 2.66Hz, 1H), 7.48 (d, 9U- 2.65HzC, 1H), 7.44 (d, 9U-1.84HzC, 1H), 7.08 (d, 9U-8.98Gu, 1H), 6.21 (d, 9-1.65Hz, 1H ), 3.97 (t, U-6.37 Hz, 2H), 3.63 (s, ЗН), 2.19 (t, U9-7.03Hz, 2H), 2.07 (s, 6H) , 2.01 (c, ZN), 1.77-1.68 (m, 2H).

Example 1.160: Preparation of 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine

Method 1: Within 75 minutes. dimethyl/(3-I(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|propyl)iamine (1.4047g, 4.62mmol) and 59o-ny Ra/C (114mg) are mixed in methanol (40 mL) under 1 atm H. The suspension was filtered through celite and dried in vacuo to give 4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazole-

Z-ylphenylamine in the form of orange oil (1.27 g, 10090).

Method 2: 4-(3-Dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl/phenylamine (375mg, 1.18mmol) and 50965% Mahon in HgO (2.5ml) are boiled with under reflux overnight in methanol (20ml). The resulting substance was purified by HPLC to give an orange oil (230.2mg, 7195). LCMS t/ (95)-:275 (MH, 100). 7Н

NMR (400MHz, DMSO-dv) 6: 7.40 (d, 9U-1.81Hz, 1H), 6.85 (d, U9-8.73Hz, 1H), 6.62 (dd, U-8, 68, 2.82Hz, 1H), 6.47 (d, U-2.80Hz, 1H), 6.15 (d, 9-1.83Hz, 1H), 4.80 (width, 2H), 3.81 (t, 9U-6.35Hz, 2H), 3.62 (s, ЗН), 2.13 (t, 9U-7.04HzC, 2H), 2.05 (s, 6H), 1, 69-1.59 (m, 2H).

Example 1.161: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(4-dimethylaminophenyl)urea (Compound 116)

4-(Dimethylamino)phenyl isocyanate (21 mg, 0.129 mmol) was added to 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenylamine (34.9 mg, 0.124 mmol) in СНоСи" (3 mL). ) and stir for two days. The obtained substance is purified by HPLC. The product was dried in vacuo to give compound 116 as a solid waxy substance (13.5 mg, 2595). RHMS t/g (95)-444 (MaAN"Vg, 100), 446 (MaNU'Vg, 95). "YAN NMR (400 MHz, DMSO-iv) o: 8.51 (width s, 1H), 8 .26 (width c, 1H), 7.61 (c, 1H), 7.53 (dd, U-8.97, 2.71HZ, 1H), 7.34 (d, y-2.70HZ, 1H), 7.24 (d, U-9.03Hz, 2H), 7.12 (d, 9U-9.05Hz, 1H), 6.68 (d, U-9.07Hz, 2H), 3, 75 (s, ZN), 3.63 (s, ZN), 2.82 (s, 6H).

Example 1.162: Preparation of 1-(4-chlorophenyl)-3-I4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea (Compound 122)

Compound 122 is synthesized from compound 119 (79.2 mg, 0.231 mmol) by a method similar to that given in example 1.139. White solid (19.bmg, 2095). RHMS ti/a (95)-428 (MaANZZSI, 100), 430 (Ma-NU"SI, 39).

IN NMR (400 MHz, DMSO-av) 6: 8.80 (width s, 1H), 8.63 (width s, 1H), 7.50-7.42 (m, 4H), 7.36 ( d, 9U-52.71Hz, 1H), 7.31 (d, U-8.90Hz, 2H), 7.09 (d, U-8.96Hz, 1H), 6.23 (d, 9-1 ... , 6H), 1.77-1.68 (m, 2H).

Example 1.163: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|-3-(4-chlorophenyl)urea (Compound 117)

Compound 117 was synthesized from compound 58 (65.1 mg, 0.154 mmol) by a method similar to that given in example 1.139 White solid (41.8 mg, 5395). RHMS t/a (95)-506 (MAN"VG, 100), 508 (MANU!'VI, 81). "N

NMR (400 MHz, DMSO-av) 6: 8.81 (bd.s, 1H), 8.71 (bd.s, 1H), 7.62 (s, 1H), 7.53 (dd, U-8 .96, 2.71Hz, 1H), 7.A7 (d, 5-8.92Hz, 2H), 7.35 (d, U-2.70Hz, 1H), 7.31 (d, U-8, 88Hz, 2H), 7.14 (d, 9U-9.03Hz, 1H), 4.07-3.99 (m, 1H), 3.98-3.89 (m, 1H), 3.64 ( s, ZN), 2.18 (t, U-6.58Hz, 2H), 2.07 (s, 6H), 1.77-1.66 (m, 2H).

Example 1.164; Preparation of 412-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-(4-chlorophenyl)ureido|phenoxyacetic acid (Compound 118) (2-(4-Bromo-2-methyl -2H-pyrazol-3-yl)-4-3-(4-chlorophenyl)ureido|phenoxyacetic acid is synthesized (from compound 58 (125.5mg, 0.298mmol) according to a method similar to that given in example 1.139. The obtained substance is purified by HPLC. The product is dried in vacuo to give ethyl ether as a brown solid containing impurities (99.9 mgHg).

To a solution of ethyl ether in methanol (ml) and THF (5 ml) add 1M HION in HgO (Iml). Through ЗОхв. the obtained substance is purified by HPLC. The product was dried in vacuo to give compound 118 as a white solid (54.Omg, 3895 for two steps). LCMS t/z (95)-479 (MAN"Vgg, 71), 481 (MaNU'Vg, 100). "H NMR (400 MHz, DMSO-ybv) 6: 13.06 (width s, 1H), 8 .80 (width c, 1H), 8.73 (width c, 1H), 7.61 (c, 1H), 7.51 (dd, U-9.02, 2.61HZ, 1), 7 .47 (d, U-8.87 Hz, 2H), 7.38 (d, U-2.67 Hz, 1H), 7.31 (d, U-8.85Hz, 2H), 7.00 ( d, 9U-9.08Hz, 1H), 4.75 (d, 9-16.65Hz, 1H), 4.68 (d, U-16.61Hz, 1H), 3.72 (s, ЗН) .

Example 1.165: Preparation of 1-|3-(4-bromo-2H-pyrazol-3-yl)-4-methoxyphenyl/|-3-(2,4-difluorophenyl)urea (Compound 152)

Stage 1: Preparation of 3-diethylamino-1-(2-hydroxy-5-nitrophenyl)propenone b-Nitrochromone (6.64g, 34.78mmol) is dissolved in pyridine (55ml) when heated to 5570. At a temperature of 557C with stirring in the atmosphere of nitrogen, diethylamine (3.05 g, 41.73 mmol) was added dropwise and the mixture was stirred for 40 min. |RHMSOS shows complete conversion to the reaction product, peak at 265 (MAN). The resulting mixture was cooled to room temperature, the solvent was removed in vacuo and the product was obtained as a yellow solid (8.94 g, 9795). РХМС t/ (95)-265 (MAN, 100). "H NMR (Vhykeg, 400MHz, SOSIz) at: 15.3 (s, 1H), 8.61 (s, 1H), 8.22 (dd, 9U-12.4HzC, 1H), 8.01 (d , U-12Hz, 1H), 6.98 (d,

U8Hz, 1H), 5.85 (d, U-16Hz, 1H), 3.45 (sq., U-8Hz, 4H), 1.31 (t, U-8Hz, 6H).

Stage 2: Preparation of 3-diethylamino-1-(2-methoxy-5-nitrophenyl)propenone

To a stirred solution of 3-diethylamino-1-(2-hydroxy-5-nitrophenyl)propenone (6.5g, 24.6mmol) in acetone (200ml) was added potassium carbonate (6b.8g, 49.2mmol). Through ЗОхв. dimethyl sulfate (3.73 g, 29.5 mmol) was added to the reaction mixture and stirred at room temperature for 20 hours. The suspension was filtered and the filtrate was evaporated to give a yellow solid. The crude product is purified on silica gel (Vioiade) using 3095 ethyl acetate in hexane as eluent. Fractions containing the product were evaporated in vacuo to give a light yellow solid (5.2 g, 76905). RHMS t/z2 (95)-279 (MAN, 100).

IN NMR (Vhykeg, 400 MHz, SOSIz) 6: 8.5 (width s, 1H), 8.23-8.26 (dd, 9-91, 2.1 GHz, 1H), 7.6 (width s , 1H), 6.98-7.01 (d, 9-9.0Hz, 1H), 5.51-5.54 (d, U-12.84Hz, 1H), 3.98 (s, ЗН) , 3.28-3.31 (sq., U-6.95Hz, 4H), 1.31 (t, U-6.68Hz, vn).

Stage 3: Preparation of 1-(5-amino-2-methoxyphenyl)-3-diethylaminopropenone

To an argon-purged solution of 3-diethylamino-1-(2-methoxy-5-nitrophenyl)propenone (0.6 g, 2.1 mmol) in methanol (3 mL) add 5906 Ra-C (Oeeedivzza, 0.25 g). Hydrogen gas (Z3 Ov.) is bubbled through the mixture until LCMS and TLC show complete conversion to the product. The suspension was filtered through celite and the filtrate was evaporated in vacuo to give a yellow solid (0.45g, 8495). РХМС t/2 (95)-249 (Man, 100). "H YAMER (Vhykeg, 400 MHz, SOSIv) 6: 6.9 (width, 1H), 6.76-6.78 (d, 9U-8.6Hz, 1H), 6.67-6.71 ( dd, uU-8.58, 2.61Hz, 2H), 5.64 (width s, 1H), 3.78 (s, ЗН), 3.5 (width s, 1H), 3.28- 3.31 (sq., U-6.95Hz, 4H), 1.22-1.24 (t,

U-6.68Hz, 6H).

Stage 4: Preparation of 1-I3-(3-diethylaminoacryloyl)-4-methoxyphenyl|-3-(2,4-difluorophenyl)urea

To a solution of 1-(5-amino-2-methoxyphenyl)-3-diethylaminopropenone (1.78 g, 7.13 mmol) in methylene chloride (boml) for 1 h. add a solution of 2,3-difluorophenylisocyanate (1.34 g, 8.62 mmol) in methylene chloride (1 Oml). The reaction mixture was stirred at room temperature for 18 hours. The solvent is evaporated and the resulting solid is purified on silica gel (Vioiade) using as eluent a gradient of OSM to 3095 ethyl acetate in OSM. Fractions containing the product were evaporated in vacuo to give a yellow solid (2.7g, 9695). RHMS t/a (95)-404 (MAN, 100). "H NMR (Vhykeg, 400 MHz, DMSO-iv) 6: 8.91 (width s, 1H), 8.41 (width s, 1H), 8.06-8.12 (m, 1H), 7 ,46-7.48 (d, 9U-8.68Hz, 1H), 7.42 (width, 1H), 7.29-7.35 (m, 1H), 7.01-7.08 ( m, 2H), 5.5 (width s, 1H), 3.78 (z, ЗН), 3.27 (width s, 4H), 1.13-1.2 (t, 9U-7, 01Hz, 6N).

Stage 5: Preparation of 1-(2,4-difluorophenyl)-3-(4-methoxy-3-(2H-pyrazol-3-yl)uphenyl|urea

To a solution of 1-3-(3-diethylaminoacryloyl)-4-methoxyphenyl|-3-(2,4-difluorophenyl)urea (1.5 g, 3.72 mmol) in a mixture of methanol/acetic acid (50 ml/2.0 ml) is added hydrazine (0.82 g, 37.22 mmol). The reaction mixture is refluxed at a temperature of 557C for 20 hours. Methanol/acetic acid is evaporated from the reaction mixture and the solid is triturated in an ether/methanol mixture. The solid substance is filtered off and washed with ether. The solid was then dried in vacuo to give a colorless solid (1.0 g, 7695). RHMS t/z (95)-345 (MAN, 100). "H NMR (Vhykeg, 400 MHz, DMSO-iv) 9: 13.0 (width s, 1H), 8.89 (width s, 1H), 8.37 (width s, 1H), 8.09 -810 (d, U-6.05Hz, 1H), 7.74-7.97 (width s, 1H), 7.52-7.64 (width s, 1H), 7.39-7, 40 (d, 9U-5.94 Hz, 1), 7.27-7.32 (m, 2H), 7.01-7.09 (m, 2H), 6.73 (s, 1H), 3, 82 (p.

ZN) (main tautomer).

Stage 6: Preparation of 1-I3-(4-bromo-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2,4-difluorophenyl)urea

To a cooled and stirred solution of /1-(2,4-difluorophenyl)-3-(4-methoxy-3-(2H-pyrazol-3-yl)phenyl|urea (0.6 mg, 1.74 mmol) in DMF (15 ml) ) over 15 min. M-bromosuccinimide (0.37 tg, 2.09 mmol) is added. The reaction mixture is allowed to slowly warm to room temperature and stirred for another 2 hours. The reaction mixture is poured into a well-stirred mixture of ice and water containing

MagSbOz/Mag52O3. The formed precipitate is filtered off and washed with ice water (50 ml). The solid was dried in vacuo to give an off-white solid (0.68g, 9295). RHMS vol. (95)-425 (MaANVg, 100), 427 (MANU!VI, 99). "H NMR (Vhykeg, 400 MHz, DMSO-dv) 6: 8.96 (width s, 1H), 8.44 (width s, 1H), 8.02-8.08 (m, 1H), 7 .48 (width c, 2H), 7.27-7.32 (m, 1H), 6.99-7.08 (m, 2H), 3.73 (c, ЗН) (main tautomer).

Example 2

A. cDNA construction of constitutively active 5-HT2 receptor 1. Human endogenous 5-HT2

The cDNA encoding the human endogenous 5-HTg2c receptor is obtained from the human brain's "RoiU-A" RNA using CT-RSV. The 5'- and 3-primers are obtained from the 5' and 3 untranslated regions and they contain the following sequences: 5B- aASSToOOSASASattastTtTAApASTOaAAdasA-Z (5EOLO.MO 1) 5-ATTTTSTASASAATATOTASSTTatASSSOT-9' (5EOLO.MO:2)

RSE is carried out using either TadRiz"mrhesiviop polymerase (Zigaiadepe) or pip polymerase (Reikip EIteg) with buffer systems supplied by the manufacturers, 0.25 μM of each primer and 0.2 μM of each of the four (4) nucleotides. Cycle conditions: 30 cycles at a temperature of 947 for 1 min., at a temperature of 57"C for 1 min. and at a temperature of 72"C for 2 minutes. With the help of Khpo I and Khra I, RSK-fragments of 1.5 t.p.o. size are cut out and subcloned to the Zai I-Khbva I site from rVipezosgiri.

Determine the primary structures of the obtained cDNA clones and establish that they correspond to the published sequences. 2. KDNA AR-1

The cDNA containing the 5310K mutation (cDNA AP-1) in the third intracellular loop of the human 5-HT2 receptor is constructed by replacing the restriction fragment (in I, containing amino acid 310) with a synthetic double-stranded oligonucleotide that encodes the required mutation. The used sense chain has the following sequence: 5-СТАасСасСАССАТаСАваТстАТтТСААААТОААААААасStТААСпСАААИТТОо-3 (5ЕОО.МО:), and the antisense strand used has the following sequence: 5-САДаСАСТТТСОТТАОСТТТСТТСАТТtТаАТАСССТасАТАстастсс-5 (5ЕО.О.МО:4).

B. cDNA construction of the constitutively active 5-HTga receptor 1. 5-HTgd human (C322K; AR-2)

The cDNA containing the point mutation C322K in the third intracellular loop is constructed using the site 5rpI of the restriction enzyme, which includes amino acid 322. For the RSC procedure, the primer 5-СААДАЧААатАСтасСАТСаТтстстсттост-3 (5ЕОЛО.МО:5), which contains the mutation С322К, is used together with with a primer from the 3' untranslated region ZEO.1O.MO:6. 5-TaSToTAVATTSSASATASITOAAAAASTTO-9" (5BEO.1O.MO:6).

The resulting RSE-fragment is then used to replace the 3'-end of the wild-type 5-HTga cDNA with the zrp I site phosphorylated by T4 polymerase. PCR is carried out using RISH polymerase (5igadepe) with a buffer system supplied by the manufacturer, and 1095 DMSO, 0.25 mM of each primer, 0.5 mM of each of the 4 nucleotides. Cycle conditions: 25 cycles at a temperature of 94"C for 1 minute, at a temperature of 60"C for 1 minute. and at a temperature of 727C for 1 minute. 2. KDNA AR-3

A human 5-HTga cDNA in which the intracellular loop C (IS3) or IS3 and the cytoplasmic tail are replaced by the corresponding human 5-HTa cDNA is constructed using RCE-based mutagenesis. (a) Replacement of the loop IC

The IZ loop of the human 5-HT2 cDNA is first replaced with the corresponding human 5-HT2 cDNA. Two separate RSEK procedures are performed to generate two fragments, fragment A and fragment B, that bind 5-HT2

ISZ loop with transmembrane 6 (TMb) in 5-HTglh. RSOAV-fragment with a size of 237 p.o., fragment A, containing 5-HTos ISZ and the initial 13 p.o. with 5-HTga TMb, amplified using the following primers: 5v-ssastopAaTtASTaASOaSSaASAAAasStTTTalat-zZ (5EO.O.MO:7) 5-SaATaSSSASSASTTTSOSAAasStTTTSsTTTSATTOatTtTO-9 (BEO.IO.MO:8).

Human 5-HTos cDNA is used as a template.

RSV-fragment with a size of 529 p.o., fragment B, containing the C-terminal 13 p.o. ISZ with 5-NT»s, and 3-terminal 5-

NTha, located at the beginning of TMb, is amplified using the following primers: 5B-AAAAISTTSSAAdAaatastasasSAtatststtosst-3 (BEO.LO.MO:9)

5-TaSToTAVATTSSASASATASITOaAAAAASTTOY-3" (5BEO.IO.MO:10).

Human 5-HTg cDNA is used as a template.

The second cycle of RSK is carried out using fragment A and fragment B as common matrices with the sequences 5EO.IO.MO.7 and ZEO.LO.MO:10 (it should be noted that the sequences 5EO.IO.MO:6 and

ZEO.IO.MO:10 match) as primers. The obtained RSE-fragment of 740 bp size, fragment C, contains ISZ3 loop of human 5-HTos, fused with TMb using the end of the cytoplasmic tail of human 5-HTg. RSE is carried out using RIM polymerase (Zigaiadepe) with a buffer system supplied by the manufacturer and 1095 DMSO, 0.25mM of each primer, 0.5mM of each of the four (4) nucleotides. Cycle conditions: 25 cycles at a temperature of 94"C for 1 minute, at a temperature of 5770 (1st cycle of RSEK) or 607C (2nd cycle of RCE) for a minute and at a temperature of 72"C for a minute. (1st cycle

RSEK) or 90 seconds. (2nd cycle of RSK).

To generate an RSOK-fragment containing the fusion region between the human 5-HTgi TM5 and the ISZ loop with 5-

NTga; four (4) primers are used. Two external primers isolated from human 5-HTgd have the following sequences: 5B-SatatSststTosSTtTASTTSA-3' (5BEO.O.MO:11).

Another primer used is the sequence ZEO.1O.Mo:b (see note above re

ZEO.IO.Mo:b and 11). The first internal primer used is an antisense strand containing the initial 13 bp. ISZ with 5-NTos followed by the final 23 base pairs isolated from TM5 in 5-NTha: 5v-tsa,aasasSsAaTASTTTaATAaTTASAAAatAaataAT-Z! (5EOLO.MO 12).

The second internal primer is a sense chain containing the final 14 base pairs isolated from TM5 in 5-HTa, followed by the initial 24 base pairs isolated from ISZ in 5-HTos: 5-TPSTAASTATSAAAatTASTASOaSSaASAADOaStTTTadta-z (5EO.IO. MO:13).

RSEK is carried out using endogenous human 5-HTha and a common matrix, fragment C, in a reaction volume of 30 ml containing buffer 1X rum, 1095 DMSO, 0.5 mM of each of the four (4) nucleotides, 0.25 mM of each of the external primers (ZEO.10.Mo:10 and 11), 0.06 mM of each of the internal primers (ZEO.1O.Mo:12 and 13) and 1.9 units of RISH polymerase (Zigaiadepe). Cycle conditions: 25 cycles at a temperature of 947C for one hour, at a temperature of 52C for one hour and at a temperature of 72C for 2 minutes. and 10 seconds RSK - a product with a size of 1.3 t.p.o. then purified on a gel and cleaved with the help of Pv| and Yesok I. The resulting fragment of Rv I-EsoK I with a size of 1 t.p.o. used to replace the corresponding fragment in the sequence of endogenous human 5-HTgi to generate a mutant sequence of 5-HTga, which encodes the ISZ loop in 5-HTgs. (p) Substitution of the cytoplasmic tail

To replace the cytoplasmic tail in 5-HTgl with the cytoplasmic tail in 5-HTos, PCR is carried out using a sense primer containing the C-terminal 22 bp. from TM7 of human endogenous 5-HTgd followed by the initial 21 base pairs of the cytoplasmic tail of human endogenous 5-HTos: 5-TPSAVSA,STSAASSSSASTAaTSTATASTSTSTOaTTSAASADADAATT-Z (5BEO1O.MO:14).

The antisense primer is isolated from the 3' untranslated region of human endogenous 5-HTos: 5-ATTTTSTASASASATATITASSTTTatASSSOT-9' (5EO.O.MO:15).

The resulting RSC fragment, fragment 0, contains the last 22 base pairs of TM7 of the endogenous 5-

Human HtTgaA, fused to the cytoplasmic tail of endogenous human 5-HTos. The second cycle of ROK is carried out using fragment O, and as a common matrix, endogenous human 5-HTgd is used, which is cleaved in advance with Ass I to avoid unwanted amplifications. The sequence ZEO.IO.Mo:15 is used as an antisense primer (the sequences of ZEO.IO.MoO:15 and 2 coincide), and the used sense primer is isolated from endogenous human 5-HTgi: 5-ATSASSSTATTTSTAASTA-3' (5EO.IO.MO :16).

The conditions for conducting RSC are given in example 2 in section B2(a) for the first cycle of RSE, except that the annealing temperature is 48"С, and the insertion time is 90 seconds. The obtained RSV product containing 710 p.o. is cleaved with Ara I and Xba I and used to replace the corresponding Ara I-Chr I fragments in either (a) endogenous human 5-HTgA or (b) 5-HTgA with 2C IZ to generate (a) endogenous 5-HTgd human with the cytoplasmic tail of human endogenous 5-HTos and (b) AP-3, respectively. 4. AP-4 cDNA

This mutant is obtained by replacing the region of human endogenous 5-HTgl from amino acid 247, the middle of TM5 to the right after Pgo26, to amino acid 337, the middle of TMb immediately before Pgoz38, with the corresponding region of AP-1 cDNA. For convenience, the connection point in TM5 is designated as "2A-2C connection", and the connection point in TMb is designated as "20-2A connection".

Generate three RCE-fragments containing the necessary hybrid connections. A 5'-fragment consisting of 561 base pairs, which contains a 2A-2C junction in TM5, is generated by PCR using endogenous human 5-HTgl as a template, the sequence ZEO.1O.Mo:11 as a sense primer, and antisense primer is isolated from 13 p.o. 5-NT»s, followed by 20 p.o. sequence of 5-H and: 5-SSATAATSITSASOasSaAAATOAAAAATOASASAA-VZ (5EO.IO.MO:17).

The middle fragment with 323 p.o. contains the sequence of endogenous human 5-HTos isolated from the region from the middle of TM5 to the middle of TMb, which is flanked by 13 bp. sequence 5-H Ha from 2A-2C connection to 20-2A connection. This middle fragment is generated using the AP-1 cDNA as a template, a sense primer containing 13 bp. with 5-HTga, followed by 20 p.o. sequence of 5-HTos through 2A-2C connection, and has the following sequence: 5-АТТТТТСАТТОСССТаАСОSATТАТОааTaАТАТАС-Z (5EO.IO.MO:18); and an antisense primer containing 13 p.o. with 5-HTgaA, followed by 20 p.o. sequence of 5-HTos through 26-2A connection, and has the following sequence: 5-TFATOAASAAAaaaySASSASATaATSASSAAASA-Z (5EO.1O.MO:19).

A 487-bp C'-fragment containing a 2C-2A connection is generated by RSK using 5-

Human NTha as a matrix and a sense primer, which has the following sequence from the 2C-2A connection: 5-BATSATATOITaSSTTTTTTSATSASAAAASAT-Z (5BEO.IO.MO:20), and the antisense primer is the sequence of 5EO. IO Mo:6b (see above remarks regarding 5EO.10.Mo:6b and 10).

The two reactions of the second cycle of RCE are carried out separately to bind the 5' and middle fragment (5'M RCE) and the middle and 3'-(fragment (3'M RSC). The common template used in 5'M RSC is the 5' and mid

The RSVA fragment above, the sense primer is the sequence 5EO.IO.MO:III, and the antisense primer is the sequence ZEO.1O.Mo:19. The 5'M RSK procedure gives a RSOK fragment with a size of 857 bp.

In ZM RSK, the middle and Z'M RSOK-fragment described above are used as a common matrix, the sequence ZEO.IO.Mo:18 as a sense primer and the sequence 5EO.IO.Mo:6b (see above remarks regarding 5EO.IO. Mo:6 and 10) as antisense primers, and generate an amplification product with a size of 784 p.p.

The final cycle of RSK is carried out using fragments of size 857 p.o. as a common matrix. and 784 p.o. from the second cycle and the sequence ZEO.1O.Mo:11 and 5EO.1O.Mo:6 (see above remarks regarding 5EO.1O.Mo:6 and 10) as sense and antisense primers, respectively. Amplification product with a size of 1.32 t.p.o. from the last cycle, RSCs are split with the help of Ri I and Eso KI. The obtained fragment of P5i I-Eso KI with a size of 1 t.p.o. used to replace the corresponding fragment in endogenous human 5-HTga to generate a 5-HTga mutant with 5-HTos: 5Z310K/LSZ3. The Ara I-Xra fragment from AP-3 is used to replace the corresponding fragment in the mutant 5-HTgA with 5-HTos: BZTOKLOZ and generate AP-4.

Example C

Receptor expression:

A. rSMM

Although a large number of expression vectors are available in the art, the most preferred vector with both endogenous and non-endogenous receptors discussed herein should be pCMUM. This vector was deposited in the American Type Culture Collection (ATSC) on October 13, 1998. (10801 Opimegeiu Vima., Mapazvzaz, MA 20110-2209 SBA | in accordance with the terms of the Budapest Agreement "InsTegpayopa! Kesodpiiop oi Shte Oerovii oi Misgoogdapizt5 Tog She Rygroze oi Raiepi Rgosedige". The DNA was tested in ATCC and found viable. ATS provided rSMM with the following deposit number: ATOS

Me203351. See Figure 8.

B. Transfection technique

For the general analysis ((5|2TRUZ; example 4) and the analysis of antagonist binding (mesulergin; example 15) transfection of CO5-7 or 2937 cells is carried out using the following technique.

On the first day, 5x1092 CO5-7 cells or 2937 cells are seeded on a 150 mm plate. On the second day, two test tubes are prepared for the reaction (proportions for each test tube are given for one tablet): test tube

A is prepared by mixing 20 μg of DNA (in particular, RSOM vector, RSMM vector of Ar-1 cDNA, etc.) in 12 ml of OMEM (Dulbecco's modified Eagle's medium), which does not contain serum (Igmipe Zsiepis, Irwin,

California); test tube B is prepared by mixing 120 μl of lipofectamine (sirso VK.) in 1.2 ml of OMEM, which does not contain serum. The contents of test tubes A and B are mixed by inversion (several times) and then incubated at room temperature for 30-45 minutes. The mixture is designated as "transfection mixture". Sown cells

СО5-7 are washed with 1X РВ5 (phosphate-buffered saline) and then 10 ml of OMEM, which does not contain serum, is added. Then 2.4 ml of the transfection mixture is added to the cells and incubated for 4 hours at 37"С/5906 СО". Then the transfection mixture is removed by suction and 25 ml of OMEM/1095 fetal calf serum is added. After that, the cells are incubated at 377С/5956 CO". After 72 hours of incubation, the cells are collected and used for analysis.

Example 4

Scintillation proximal analysis of STR membrane binding

The use of (5)24TRUuUZ binding to determine constitutive activation provides the following advantages: (a) G5|2TRUZ binding can generally be used for all receptors bound to protein C; and (p) binding of G5|STRUZ proximal to the membrane surface and, thus, reduces the probability of capturing molecules that affect the intracellular cascade. This assay utilizes the ability of receptors bound to protein C to stimulate the binding of |5|αTRUZ to membranes expressing the corresponding receptors. Thus, the specified analysis can be used for the direct selection of compounds from the serotonin receptors disclosed in this document.

Fig.9 shows the suitability of scintillation proximal analysis for monitoring binding

I5|aTRUS with membranes expressing, in particular, the endogenous human 5-HT2 receptor, which is expressed in CO5 cells. Briefly, the preferred assay technique is as follows: the assay mixture is incubated with 20 mM NERB5, pH 7.4, binding buffer containing 0.3 nM

I5|STRUZ and 12.5 μg of membrane protein, and 1 μM of COP during ZOkhv. Add wheat germ agglutinin balls (25 μl; Ategzpat) and the mixture is incubated at room temperature for another 30 minutes. Then the test tubes are centrifuged at an acceleration of 1500x9d for 5 minutes. at room temperature and count on a scintillation counter. As shown in Fig. 9, serotonin, which as an endogenous ligand activates the 5-HT2c receptor, stimulates the binding of (355|aTRuU5) to membranes depending on the change in concentration.

Stimulated binding completely inhibits ZOmM of mianserin, a compound that is considered a classical 5-HT:s antagonist, but which is also known as a 5-HT»es inverse antagonist.

Although this assay measures agonist-induced (5|STRUZ) binding to membranes and can be used as a standard assay for determining constitutive receptor activity, the cost of wheat germ agglutinin beads can be prohibitively high at this time.

A less expensive but equally useful alternative technique also faces the need for large-scale selection. Umayastm flash chromatography plates and scintillation plates can be used for (55)STRU5 binding assays in a high-throughput format. This technique allows you to control the binding of tritium-labeled ligands to the receptor and simultaneously monitor the efficiency using binding

H5|aTRUV. This is possible because the UmaPas'm beta particle counter allows switching energy pulses to analyze samples containing both tritium and 355 labels.

In addition, this analysis can be used to detect manifestations of other types of membrane activation that are a consequence of receptor activation. For example, the analysis can be used to monitor zgr-phosphorylation of various receptors (including receptors associated with OS-protein and tyrosine kinase receptors). When the membranes are lowered to the bottom of the tablet by centrifugation, connected with

I5|OTRUZ or 32P-phosphorylated receptor activates the scintillator, which is covered with cell walls. This principle is demonstrated by the use of Zsipif (UMaiyas) plates. In addition, the specified assay can be used to determine the binding of ligands to receptors using ligands containing a radioactive label. Similarly, bound ligand containing a radioactive label is omitted by centrifugation to the bottom of the cell, where it also activates the scintillator.Analysis results using

I5|OTRUZ are parallel to the results obtained in traditional receptor assays using repeated messengers.

As shown in Fig. 10, serotonin stimulates the binding of (5|αTRU5 to the endogenous human 5-HT2 receptor, while mianserin inhibits this reaction in return; moreover, mianserin acts as a partial inverse agonist, inhibiting the basic essential binding binding of |55|2TRU5 to membranes expressing the endogenous human 5-HT2 receptor. As expected, no response to the agonist is observed without CPR, since in the absence of CPR there is no exchange for (5|CRU5. This assay system not only demonstrates a response of the native 5-HT2 receptor, but also allows to assess the constitutive activation of other receptors.

Fig. 11A and Fig. 11B show that there is an increase in the binding of I5|2TRUuU5 to membranes obtained from 293T cells expressing only the control vector, the native human 5-HT 2 receptor, or the AP-1 receptor (data not shown). The total concentration of the protein used in the analysis affects the total level of G5|STRUZ binding for each receptor. The difference in the number of pulses per minute between the transfected SMM and the constitutively activated mutant receptor increased from approximately 1000 pulses per minute for 1 µg per well to approximately 6-8000 pulses per minute for a protein concentration of 75 µg per well, as shown in Figure 11.

The AP-1 receptor shows the highest level of constitutive activation, followed by the wild-type receptor, which also shows enhanced binding of |5|2TRUZ compared to baseline. This is consistent with the ability of the human endogenous 5-HT2 receptor to accumulate intracellular IR in the absence of C5HT stimulation (Example 6) and is also consistent with published data showing that the human endogenous 5-HT2 receptor has a high natural basal activity. Thus, the AP-1 receptor demonstrates that constitutive activity can be assessed by proximal binding

І5|сTRUB flowing on the surface of the interface of the membranes.

Example 5

Serotonin receptor agonist/antagonist competitive binding assay:

Membranes are prepared from transfected CO5-7 cells (see example 3) by homogenization in 20 mM

Add 10 mM EDTC, pH 7.4, and centrifuge at 49,000 rpm for 15 minutes. The tablet is resuspended in 20 mM NEREZ and 01 mM EDTC, pH 7.4, and homogenized for 10 seconds. with the help of a Royuiop homogenizer (Vhipktap) at a speed of 5000 rpm. and centrifuged at an acceleration of 49,000 x 9 for 15 minutes. The final tablet is suspended again in 20 mm NEREZB and 10 mm Mass", pH 7.4, and homogenized for 10 seconds. with the help of a Royuigop homogenizer (Vhipktap) at a speed of 5000 rpm.

Analyzes are carried out in three series of parallel experiments in a volume of 200 μl on 96-well tablets.

To dilute the membranes, use a buffer solution for analysis (20 mM NEREZ and 10 mM Masi, pH 7.4), ZN-I. 50, ZN-mesulergin, serotonin (used to determine non-specific binding for

G5O) and mianserin (used to determine non-specific binding for mesulergin). The final concentration during the analysis is 1nM of ZN-I.50 or 1nM of ZN-mesulergin, 500 μg of membrane protein and 100 μM of serotonin or mianserin. Assays with 50 are incubated for 1 hour at 37°C, while assays with mesulergin are incubated for 1 hour at room temperature. Assays are stopped by rapid filtration through Riyeptai Toure B from M/Aias using cold binding buffer and a 5Kaigop cell harvester.Radioactivity is determined using a Umaiyiias 1205 Veiar'agie counter.

Example 6

Analysis of accumulation of intracellular IRz

To analyze the accumulation of intracellular IRz, a transfection technique different from that given in example 3 is used. In the following example, the methods used for days 1-3 differ slightly from the data obtained for Figures 12 and 14 and for Figures 13 and 15; the technique for the 4th day is the same for all conditions.

A. Cells СО5-7 and 293

On the first day, CO5-7 or 293 cells are seeded on 24-well plates, usually 1x10? cells per well or 2x105 cells per well, respectively. On the second day, the cells are transfected, first mixing in one well

0.25 μg of DNA (see example 3) in 10 μl of serum-free OMEM, and then mixing per well 2 μl of lipofectamine in 30 μl of serum-free OMEM. Solutions ("medium for transfection") are carefully mixed and incubated at room temperature for 15-30 minutes. The cells are washed with 0.5 ml of PB5 and then 4000 μl of serum-free medium is mixed with the transfection medium and added to the cells. Then the cells are incubated for 3-4 hours at 377С/595 СО". The transfection medium is then removed and replaced with regular growth medium in the amount of iml per well. On the 3rd day, the medium is removed and the cells are washed with 5 ml of РВ5Z and suctioned. Then add 2 ml of trypsin (0.0595) per tablet. After 20-30 seconds. warm medium 293 is added to the plates, the cells are gently resuspended and the number of cells is counted. A total of 55,000 cells are then mixed into sterile 96b-well microtiter plates treated with poly-U-lysine and the cells are allowed to attach for 6 hours in an incubator. Then the medium is removed by suction and 0.1 ml of the medium that does not contain inositol and does not contain serum (sirso VK/I) is added to each well along with 0.25 µCi of ZN-myoinositol per well and the cells are incubated overnight for 16-18 hours at 377C/ 595 SO". Method A.

V. Cells 293

On the first day, 13 x 1052 cells of 293 are sown on a 150 mm plate. On the second day, add

2ml of Oriiteti serum (Ipigodep Sogrogaiiop) and then add 100ml of lipofectamine and 1bmkg of cDNA. It should be noted that Lipofectamine must be added to Oriyeti and mixed well before it is added.

KDNK. As complexes between lipofectamine and cDNA form, the medium is carefully removed by suction, the cells are gently washed with 5 ml of Oriiteti medium and then gently suctioned. Then, 12 ml of Oriiteti and 2 ml of transfection solution are added to each tablet, then incubated for 5 hours at 37 "C in an incubator containing 595 CO". use. On day 3, cells are treated with 2 ml of 0.0595 trypsin solution for 20-30 sec., then 10 ml of warmed medium is added, gently triturated to dissociate cells, and then an additional 1 ml of warmed medium is carefully added. Cells are counted and then 55,000 of cells are plated on sterile 96-well plates treated with poly-O-lysine.The cells are allowed to attach by incubating them for more than six hours at 37°C in an incubator containing 595°C. Then the medium is carefully aspirated and 100 μl of warm medium that does not contain inositol plus 0.5 μCi of ZN-inositol is added to each well, after which the tablets are incubated for 18-20 hours at 37"C in an incubator containing 595 CO".

On day 4, the medium is carefully removed by suction and 0.1 ml of assay medium containing inositol-free and serum-free medium, 10 μM pargyline, 10 mM lithium chloride, and the indicated concentration of test compound is added. The plates are incubated at 37°C for three hours and then the cells are carefully removed by suction. After that, 200 μl of ice-cold 0.1M formic acid solution is added to each well. At this stage, the plates can be frozen at -80°C until the next use. . The frozen tablets are subsequently thawed within an hour and the contents of the wells (approximately 220 μl) are placed on 400 μl of washed ion-exchange resin (AS 1-X8), which is contained on Miyi 5sgeep filter plates, incubated for 10 minutes. and then vacuum filtered. Then the resin is washed nine times with 200 μl of water, inositol phosphates containing a tritium label are eluted on the receiving plate, adding an additional 200 μl of 1M ammonium formate solution, and additionally incubated for 10 minutes. The eluate is then transferred to 20 ml bottles for scintillation and added

Zml scintillation cocktails ZyiregMmih or Ni-Zaie and bottles are read within 0.5-1 min. with the help of a Umayyas 1414 scintillation counter.

Fig. 12 illustrates the production of IRz from the human 5-HTga receptor, which will be mutated using the same point mutation as proposed by Sazeu, which makes the rat receptor constitutively active.

The results shown in Figure 12 confirm that when a point mutation that has been shown to activate the rat receptor is introduced into the human receptor, the resulting receptor activation is too small to allow appropriate selection of candidate compounds, while the response response only moderately exceeds the response response of the human endogenous 5-HTα receptor. In general, a response that is at least 2 times greater than the endogenous response is predominant.

Fig. 13 illustrates a comparison of IR3 production from the endogenous 5-HTα receptor and the AP4 mutation. The results shown in Fig. 13 confirm that when using the new mutation disclosed in this description, a reliable reaction is obtained in response to a significant accumulation of IRZ (in particular, more than 2 times the value for the endogenous receptor).

Fig. 14 illustrates the products of IRZ from ARZ. The results shown in Fig. 14 confirm that when using the new mutation disclosed in this description, a reliable reaction is obtained in response to a significant accumulation of IRZ.

In Fig. 15, a histogram is used to compare the accumulation of IRZ between the human endogenous 5-HT2 receptor and AR-1. It should be noted that the endogenous receptor has a high degree of natural constitutive activity, compared to control transfected SMM cells (ie, the endogenous receptor is constitutively activated).

Example 7:

It was possible to bind the 5-HTα receptor

Animals

Animals (Zrgadoe-Oamzhmieu rats) are killed, brains are quickly removed and frozen in isopentane at a temperature of -42"C. Horizontal sections are prepared in a cryostat and kept at a temperature of -2076.

Substitution method I 50

Lysergic acid diethylamide (50) is an active 5-HTga receptor and a ligand for the O2 dopamine receptor.

Indications for the selectivity of the compounds in relation to any or both of the specified receptors is the replacement of bound I 50 containing a radioactive label in pre-treated brain slices. To carry out the specified studies, I-I 50, which contains a radioactive label, is used (MEM Tsite bsiepsev,

Boston, Massachusetts, catalog number МЭХ-199); also use spiperon (KVI, Natik,

Massachusetts, catalog number 5-128), which is an antagonist of the 5-HTα-receptor and the Y2-receptor of dopamine.

The buffer solution is 50 nM TKI5-NSI, pH 74.

Brain slices are incubated in (a) buffer solution plus 1nM 1251-50; (b) buffer solution plus TnM 1251-

And 50 and 1mM spiperone; or a buffer solution plus 1nM 7251-50 and 1mM of the compound of formula (I) during ZOkhv. at room temperature. Then the sections are washed 2x1Okhv. in a buffer solution at a temperature of 4"C and then with distilled water for 20 seconds. Then the preparations are dried in air.

After drying, the sections are placed on X-ray film (Kodak Nurepiit) and exposed for 4 days.

Analysis:

In Fig. 16A-C, autoradiographic sections from the conducted research are presented in gradation of the gray scale.

In Fig. 16A, darker bands (derived from 7221-50 binding) are observed, mainly both in the fourth layer of the cerebral cortex (mainly 5-HTGd receptors) and in the caudate nuclei (mainly Y2 receptors dopamine and a certain amount of 5-HTα receptors). As can be seen from Figure 168, spiperone, which is an antagonist of the 5-HTga receptor and the O2 dopamine receptor, replaces 725I-Y50 in receptors both in the cerebral cortex and in the caudate nuclei. As can be seen further from Figure 16C, the compound 5-1610, 4-methoxyphenyl ether (3-(4-bromo-2-methyl-2H-pyrazole-3-isophenyl)carbamic acid, is able to selectively replace 1251-50 in the cerebral cortex (5- NTgga), but not to the caudate nucleus (02 dopamine).

Example 7a

Selection of compounds known to have antagonistic activity against 5-HTos against the non-endogenous, constitutively activated human serotonin receptor: AP-1

The final concentration of 12.5 μg of membranes obtained from CO57 cells (see example 3), transiently expressing the constitutively activated human 5-HT2 receptor AP-1, is incubated together with the binding buffer (20 mM NERB, pH 7.4, 100mM Masi, 20mM Masi», 6bNgo, 0.290 saponin and 0.2mM ascobate), OPOR (µm) and the compound in the format of a 96-well tablet for 20 min. at ambient temperature. Then the tablets are centrifuged at a speed of 4000 rpm. within 15 minutes, the reaction medium is removed by suction and counting is carried out during their hours. using a scintillation counter for UmaPastm MisgoWeiga tablets. It was established that a number of compounds, which, as is known from the reports, possess antagonistic activity in relation to 5-HT»:c, are active in the binding assay of (5)|24TRUZ using AR-1. For these commercially available compounds (BVI, Natik,

Massachusetts) determined values of ISvo-Results are shown in Table 5. For each of the determinations, three series of studies are conducted in parallel for eight concentrations of the tested compounds. The negative control in these experiments is the AP-1 receptor without the addition of the tested compounds, and the positive control is 12.5 μg per well of the membranes of CO57 cells expressing the SMM promoter without the expressed AP-1 receptor.

Table 5

The results of determination of ISvo confirm that the tested compounds show antagonistic activity in relation to the AP-1 receptor.

Example 8

Analysis of receptor binding

In addition to the methods discussed above in this description, another means of evaluating the compound being tested is the determination of binding affinity to the 5-HTga receptor. This type of assay usually requires the use of a 5-HTα receptor ligand that contains a radioactive label. In the absence of known ligands for the 5-HTgd-receptor and their derivatives, which contain a radioactive label, it is possible to introduce a radioisotope label into the compounds according to the present invention and use them in the analysis to assess the affinity of the tested compounds to the 5-HTga-receptor.

A compound of formula (I), which contains a radioactive label of 5-HTga, can be used in screening for identification or evaluation of compounds. In general terms, a newly synthesized or identified compound (ie, a test compound) can be evaluated for its ability to reduce the binding of a "compound of formula (I) containing a radioactive label" to the 5-HTα receptor. Thus, the ability to compete with a "radiolabeled compound of formula (I)" and a "radiolabeled 5-HTgdl ligand" for binding to the 5-HTα receptor directly correlates with the binding affinity of the compound that tested, to the 5-HTgA receptor.

Analysis method for determination of receptor binding for 5-HTg

A. Preparation of 5-HTgda receptor

293 cells (human kidney, ATCC), transiently transfected with 10 μg of human 5-HTgda receptor and 1 μg of Lipofectamine (per 15 mm dish) are grown in a dish for 24 hours (confluence 7595), the medium is removed and replaced with Nere5-EDTC buffer solution (20mM Nerez5-10mM EDTC, 7.4) at 1TOml per cup. Cells are centrifuged on a Vesktap Soshneg centrifuge for 20 minutes. at a speed of 17000 rpm./min. (UA-25.50 rotor). Then, after centrifugation, the precipitate is resuspended in 20 mM Nerez-1 mM

EDTC, 7.4, is homogenized in a UOotspse homogenizer with a volume of 5 Oml and then centrifuged again. After removal of the liquid above the sediment, the sediment from centrifugation is stored until use in the binding assay at a temperature of -80°C. When used in the assay, the membranes are thawed on ice for 2 hours and then 10 ml of incubation buffer (20 mM Nerevz, 1 mM Maosi, 100 mM mass, pH 7.4).The membranes are vigorously stirred to resuspend the crude sediment from the membranes and homogenized in a homogenizer

VIPktapp RT-3100 Roiuiop within 15 seconds. in mode 6. The concentration of the membrane protein is determined using the VE protein assay. Wgaatoga

B. Binding analysis

For general binding, appropriately diluted membranes (diluted with a buffer solution for analysis containing 50 mM Ttgiz NOSI (pH 7.4), 10 mM Maosi" and 1 mM EDTC; 5-50 μg of protein) with a total volume of 5 Ω are introduced into the microtiter 96- well tablets made of polypropylene and then additionally mix 100 μl of buffer solution for analysis and 5 μl of the ligand 5-HTgl, which contains a radioactive label. For non-specific binding, instead of 100 μl, add 50 μl of buffer solution for the analysis and additionally add 50 μl of 1 μM cold 5-HTga before adding 5 μl of the ligand 5-HTgl, which contains a radioactive label. Then the tablets are incubated at room temperature for 60-120 minutes. The binding reaction is determined by filtering the analyzed tablets through a filter tablet ZR/C Opitneg of Misgoriaie UOemise5 using a 96-well tablet harvester Vgapaiei. and then washed with a cold 50 mM solution of Ttgiz HCl with pH 7.4, which contains 0.995 Mass. Then the lower part of the filter tablet is sealed, 50 μl of Oriirpase Zyreptih is added to each well, the upper part of the tablets is sealed and the tablets are read in a Tych Misgoveia scintillation counter. When conducting competitive studies for compounds, instead of adding 100 μl of the buffer solution for the analysis, 100 μl of the appropriately diluted test compound is added to the corresponding well, and then 5O0 μl of the ligand 5-

HtTgA containing a radioactive label.

S. Calculations

Test compounds are first tested at concentrations of 1 and 0.µM and then a range of concentrations is chosen such that the average dose causes approximately 5095-fold inhibition of ligand binding 5-

NTga, which contain a radioactive label, (ie ISvo). Specific binding in the absence of test compound (B0) is the difference between total binding (W) and non-specific binding (M5B), and similarly, specific binding (in the presence of test compound) (B) is the difference between substitution binding (B0) and nonspecific binding (M5B). The value of ISvo is determined from the curve of inhibition of the reaction in response to Iodine-I0d in axes of 95 V/Vo against the concentration of the tested compound.

The value of K; determined, for example, using the Cheng and Proustoff transformation:

K-ISvo(I4(CyCo), where (| means the concentration of the 5-HTga ligand used in the analysis, which contains a radioactive label, and Ko means the dissociation constant of the 5-HTga ligand, which contains a radioactive label, which is determined independently under the same conditions binding

Example 9

Activity of the compounds according to the present invention in the analysis of the accumulation of IRz

Some compounds of the present invention and their corresponding activity in the IR accumulation assay are given in

Tables 6.

Table 6 accumulation of IRz (NM) 607 77777711111mo7 " Average values obtained from at least two tests are given

Most of the other compounds in the examples have been tested at least once and have shown value

ISvo activity in the 5-HTga IR3 accumulation assay, which is at least approximately 10μM.

Example 10

Efficacy of compounds according to the present invention in attenuating BO!-induced decrease in locomotor activity in rats

In this example, compounds of the present invention, such as compound 1 and compound 26, are tested for inverse agonist activity by determining whether said compounds are able to attenuate BO!-induced reduction in motility in rats in a novel environment. BOI is an active agonist of the 5HTgd/ho-receptor, which is able to overcome the blood-brain barrier.

Animals:

Male Brgadse-Oam/eu rats (Nagiap, Diego,

California) weighing 200-300 grams. Rats are placed 3-4 individuals in one cage. These rats have not previously been used in experimental studies and have not been used for drug testing.

Rats are maintained for one to three days prior to testing to allow them to acclimate to the experimental conditions. Rats are not given food the night before testing.

Compounds: (2-00 NS (SchiNiv!MO».CARRIERS) are obtained from the Zidpa-AIgisp company and dissolved in 0.995 physiological solution. The compounds according to this invention are synthesized in Agepa RPaptaseshis!5 Ips. and they are dissolved in 10095 RES 400. BOY is administered as a subcutaneous injection in the amount of Tml/kg, and the compounds of this invention are administered orally in the amount of 2ml/kg.

Method:

Moyog Mopyog (Natiykop-Kipaeg, Poway, CA) was used to measure activity. This device allows you to register movements using infrared rays.

Research on motor activity is carried out during daylight hours (0630-1830) between 9 am and 4 pm. Before starting the test, the rats are allowed to acclimatize in the room for ZOhv.

To determine the effect of compounds according to the present invention on OO!-induced reduction of locomotor activity, animals are first injected with a carrier or compounds according to the present invention (50 μmol/kg) in the cages where they are kept. In another 6bOkhv. an injection of physiological solution or IV (0.Zmg/kg in the form of salt) is administered. After 10 minutes after the introduction of BOI, the animals are stirred in the device for recording activity and the movement activity is measured for 1 Okhv.

Statistics and results:

The results (the total number of movements during 10Okhv.) are analyzed using the criterion

Student (I-test). A value of Р«е0.05 is taken as significant. As shown in Figure 22, compound 1 attenuates the OO1-induced decrease in locomotor activity in rats. In addition, as shown in Figure 23, compound 26 also attenuates the OO!-induced decrease in locomotor activity in rats.

Example 11

Study of the degree of occupation of the 5-HTga-serotonin receptor in monkeys

In this example, the degree of occupation of the 5-HTα receptor by the compound according to the present invention, compound 1, is determined. Research is carried out on rhesus macaques using the PET method and "E-altanserin.

Radioligand:

The PET radioligand used in studies of the degree of occupation is /UB-altanserin. Radiosynthesis makes it possible to obtain "E-altanserin with high specific activity, which is suitable for injection by injecting a radioactive label into 5-HTga receptors | see Biaieu ei ai., Mysi. Mea.

VioI., 28: 271-279 (2001) and the references given there). Issues related to quality control (chemical and radiochemical purity, specific activity, stability, etc.) and appropriate radioligand binding are checked on rabbit brain slices before conducting PET experiments.

Drug doses and compositions:

Briefly, the radiopharmaceutical is dissolved in a sterile 0.9956 saline solution with a pH of approximately 6-7. The compounds according to the present invention (compound 1) are dissolved in a mixture of 6095 RES-4400/4095 sterile physiological solution on the day of the PET experiment.

Reports on conducting a study on the degree of 5-HTgd serotonin occupancy in humans are given for the compound M100907 |Sgapadeg ei ai., Mepgorzusporpagtasoioudu, 17: 175-185 (1997) and Taimik-Goyi ei ai.,

Rzusporpagtaso!odu, 148: 400-403 (2000)). A significant degree of occupation of 5HTα receptors is reported for various oral doses (the range of doses studied is from 6 to 20 mg). For example, an occupancy rate of 29,095 is reported for a 20mg dose (Taymik-I oi eyii a!., see above), corresponding to approximately 0.28mg/kg.

It can therefore be expected that an intravenous dose of 0.1-0.2 mg/kg of compound M100907 should cause a higher degree of receptor occupancy. In the described studies, a dose of compound 1 is used, which is 0.5 mg/kg.

PET experiments:

Monkeys are anesthetized with ketamine (1Omg/kg) and maintained using 0.7-1.2595 isoflurane. Usually, monkeys use two intravenous lines, one in each upper limb. One intravenous line is used to administer the radioligand, and the second line is used to collect blood samples for pharmacokinetic studies of radioligands as well as unlabeled drugs. In the general case, blood samples are taken quickly immediately after the introduction of the radioligand, the concentration of which is then weakened as the scans are carried out. At each moment of time, a volume of blood of approximately 1 ml is taken, which is centrifuged, and the plasma is used to measure radioactivity in the blood.

A primary control study is performed to determine baseline values of receptor density.

PET scans of monkeys are done at intervals of at least two weeks. A non-medicinal drug that does not contain a label (compound 1) is administered intravenously as a solution in a mixture of 8090 РЕС 400:4095 sterile saline.

Analysis of PET data

PET data analysis is performed by selecting the cerebellum as a comparison area and using the method of volume distribution area (OM). The specified method is used for the analysis of PET data for "P-altanserin" in the study of non-human primates and in the study of humans (tiy ei a!I., zZuparze, 30: 380-392 (1998)|.

The values of the degree of occupation of 5-HTga (experimental methods are carried out on rhesus macaques) for compound 1 are shown in Fig. 24-27. Results are presented for both 8-hour and 24-hour studies.

The tested compound is administered by intravenous infusion in 5.0 ml of 80956 solution in RES 400. During an 8-hour study, venous blood samples are taken after 5 minutes. after the introduction of compound 1 and in 15 min. before conducting a PET scan. During a 24-hour study, venous blood samples are taken after 5 minutes. after the introduction of compound 1 and in 10 min. before conducting a PET scan.

The results show that the degree of occupation of the 5-HTα receptor by compound 1 at a dose of 0.5 mg/kg 8 hours after drug administration is approximately 9095 in the cerebral cortex, which is a region with a high density of 5-HTα receptors. The indicated degree of occupancy falls to approximately 8095 24 hours after injection, although no detectable concentrations of the drug are detected in plasma samples after 8 hours.

Example 12

Effect of compounds of this invention and zolpidem on delta energy in rats

In this example, the effects of compounds of this invention, such as compound 1 and compound 26, on sleep and wakefulness are compared with zolpidem, which is used as a comparator drug. Medicines are administered in the middle of the light period (inactivity period).

Briefly, four compounds of the present invention, including compound 1 (1.00 mg/kg) and compound 26 (1.4 mg/kg), are being investigated for their ability to influence sleep parameters and compared with zolpidem (5.0 mg/kg, zZidta , St. Louis, MO) and the vehicle used as a control (8095 Tmeep, Zidta, St. Louis,

Missouri). A series of repeated measurements is carried out, in which each rat received several separate doses by oral gavage. The first and seventh doses represent the vehicle, and the second to sixth doses represent the test compound and zolpidem administered in a counterbalanced order. Since all dosages are administered at the moment when the rats are connected to the recording device, in the process of feeding through a stomach tube, to create a light sedative effect, a gas environment of bod СО2/4095 О is used. Rats recover completely through bosek. after the procedure is completed. The intervals between dosing are at least three days. In order to study the effect of the compound on strengthening sleep, dosing is carried out in the middle of the normally inactive period of rats (a few hours after turning on the light).

Dosing is usually done between 13:15 and 13:45 on a 24-hour time scale. All dosing solutions are prepared fresh on the day of dosing. After each dosage, the animal is continuously observed until the light is turned off the next day (-30 hours).

Animal observation and surgical operations:

Animals are housed in a temperature-controlled room with a 12/12 light/dark cycle (lights on at 7:00 a.m.) and given ad libitum food and water. Room temperature (24--2"C), humidity (50--2095), and lighting conditions are continuously monitored by computer. Drugs are administered by gavage as described above, with a minimum interval of three days between doses. Animals are examined daily in accordance with the recommendations of the National Institute of Hygiene (NIH).

Eight male Muiztag rats (300425 g; Spavez Kimeg, Wilmington, MA) are prepared and implanted with permanent recording implants for continuous electroencephalography

(EES, EEG) and electromyography (EMO, EMG). Under anesthesia using isoflurane (1-495), the hair is removed from the upper part of the skull and the skin is disinfected with betadine and alcohol. A dorsal median incision is made, the temporal muscle is pulled back, and the skull is cauterized and thoroughly cleaned with a 2956 solution of hydrogen peroxide. Steel screws (2000), which serve as epidural electrodes, are implanted in the skull. EEG electrodes are placed bilaterally at a distance of 42.0 mm AR from bregma and 2.0 mm MI, as well as -6.0 AR and 3.00 mm MI. Multi-core twisted wire electrodes made of stainless steel are sewn bilaterally into the neck muscles for recording EMO . Electrodes for EMG and EEE are soldered to the main connector, which is fixed to the skull with dental acrylic cement. The incisions are closed with a suture (silk 4-0) and local antibiotic treatment is carried out. Pain is stopped with a long-acting pain reliever (buprenorphine), which is administered intramuscularly once after the operation. After the operation, each animal is moved into a clean cage and observed until registration begins. Animals are allowed to rehabilitate after surgery for at least one week before conducting research.

To record sleep, animals were connected to a Meszgodaia model 15 data acquisition system (Sgaz5-Teigasiog, West Warwick, Island) using a cable and a balancing switch. Before the start of the experiment, the animals are allowed to acclimatize for at least 48 hours and then for the entire period of the experiment, except for the need to replace damaged cables, they are connected to the recording device. Amplified EEG and EMG signals were digitized and stored in a computer using 5ieerzidp software (Kizzei, Irvine, CA).

Data analysis:

EEG and EMG data are visually recorded at intervals of 10 seconds. for the period of wakefulness and phases of KEM-sleep and

MAEM-sleep. The collected data is analyzed and expressed in the form of time spent on each stage within half an hour. The duration of sleep episodes and the number of episodes of each state are counted with accumulation every hour. "Episodes" consist of at least two consecutive periods of a given condition. EEG delta energy (0.5-3.5Hz) in the MKEM-sleep phase is also analyzed with accumulation every hour. EEG spectra during MKEM-sleep are obtained offline using the fast Fourier transform algorithm for all periods when no artifacts were observed. Delta energy is normalized with respect to the average delta energy in the MKEM-sleep phase between 11:00 PM and 1:00 AM, a time period when delta energy is typically at a minimum.

The data is analyzed by repeated measurements by the AMOMA method. Data for the light phase and the dark phase are analyzed separately. Both the treatment effect for each rat and the duration of the treatment effect for each rat are analyzed. Since two comparisons are made, a minimum value of Ре0.025 is required for re-analysis. In the event that the results of AMOMA show statistical significance, I-tests are conducted to compare all compounds with the carrier, as well as the tested compounds with zolpidem.

Results:

Three rats managed to completely exhaust the methodology of 7 dosage regimens. The other 5 animals completed only 3-6 of the 7 dosing regimens, mainly due to implant loss. However, all drug administration regimens were tested on a minimum of 5 rats.

Although the duration of effect varied for each compound tested, delta energy increased significantly (p<0.05) immediately after dosing for all compounds tested compared to vehicle (see Figure 28). For all compounds, there was a trend, which for some modes was statistically significant, to increase the duration of MCEM-sleep episodes, while the number of wake episodes and the number of MCEM-sleep episodes were reduced, compared to vehicle. No significant effect was found on the duration of wake episodes, the duration of FEM sleep episodes, and the number of episodes or total time spent in each state.

The obtained results show that the compounds according to the present invention contribute to the strengthening of sleep in rats during the period during their circadian cycle when their sleep is usually fragmentary. This conclusion is supported by the tendency for all compounds to increase the duration of MEEM-sleep episodes, while the number of waking episodes and MKEM-sleep episodes is reduced. Delta energy during MKEM sleep increases during the same period when sleep consolidation is observed, suggesting that these compounds promote "deeper" sleep as well as sleep consolidation. Thus, the compounds of the present invention may be effective in the treatment of sleep disorders.

No significant difference was found between treatments for wakefulness, MEEM sleep, or CEM sleep. However, delta energy during MEEM sleep is significantly different from drug or vehicle control regimens. Compound 1 and compound 26 significantly increased delta energy during the second hour after dosing (15:00).

No significant effect was found on both the duration of wakefulness episodes and the number of these episodes. However, a significant difference is observed in the duration of both MEEM-sleep and KEM-sleep. Compound 1 significantly increases the duration of MCEM sleep episodes during the second hour. The number of episodes of MKEM-sleep is not of great importance. The duration of CEM-sleep bouts is significantly increased by compound 1 and compound 26 during the fourth hour. The number of CEM-sleep attacks is not of great importance.

It will be apparent to those skilled in the art that various modifications, additions, substitutions, and variations may be made to the illustrative examples presented that do not conflict with the spirit of the invention and should therefore be considered to be within the scope of this invention. All of the above documents, including, but not limited to, published documents, as well as prior and normal patent publications, are incorporated herein by reference in their entirety.

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Fig. 70

In CI

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Java 1 (ZV) groves

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Attenuation of VOI-induced decrease in motor activity in shuriken.

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N N i I AME N t: N Neo N

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Claims (95)

1. A compound selected from the compounds of formula (1): Ka Kk, Kv schy X bi Kos Kk, Kv yo what or its pharmaceutically acceptable salt, hydrate or solvate; where Ki is aryl or heteroaryl, each of which is optionally substituted with Co, Co, K1, Ki", Kis, Kyl1Ki5, each of which is independently selected from the group consisting of: C-c-acyl, C-c- Acyloxy, C-C-Alkenyl, C-C-Alkoxy, C-C-Alkyl, C-C-Alkylcarboxamide, C-C-Alkynyl, C-C-Alkylsulfonamide, C-C6-Alkylsulfinyl, C-6-Alkylsulfonyl, C -C6-alkylthio, C1-C6-alkylureyl, amino, C1-C6-alkylamino, Co-8-dialkylamino, C1-C6-alkylimino, carbo-C1-6-Alkoxy, carboxamide, carboxy, cyano, C3-;"- cycloalkyl, C-8-dialkylcarboxamide, C-6-dialkylsulfonamide, halogen, C-6-haloalkyl, C-6-haloalkyl, C-6-haloalkylsulfinyl, C-6-haloalkylsulfonyl, C-6-haloalkylthio, heterocyclyl, hydroxyl, thiol . necessarily substituted by atoms -E, -СИ or -Вг; and where C 6 -alkenyl, C 6 -alkyl, C 6 -6 alkynyl, C 6 -alkylamino, C 6 -alkylimino, C 8 -dialkylamino, heterocyclyl and phenyl are each optionally substituted with 1- 5 substituents independently selected from the group consisting of: C-C-acyl, C-C-acyloxy, C-C-alkenyl, C-C-Alkoxy, C-C-Alkyl, C-C-Alkylcarboxamide, C-C- alkynyl, C-6-alkylsulfonamide, C-6-alkylsulfinyl, C-6-alkylsulfonyl, C-6-alkylthio, C-6-alkylureyl, amino, C-6-alkylamino, C-6-dialkylamino, carbo-Ci- alkoxy, carboxamide, carboxy, cyano, C3-7-cycloalkyl, C10-8-dialkylcarboxamide, halogen, C1-6-halogenalkoxy, C1-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C1-6 -haloalkylthio, hydroxyl, thiol m1 nitro; Co is selected from the group including: -H, C1-6-alkyl, Co-6-alkenyl, Co-6-alkynyl, 1 C3-7-cycloalkyl; Kz is selected from the group consisting of: -H, C1-6-alkenyl, C1-6-alkyl, C1-6-alkylcarboxamide, C1-6-alkynyl, C1-6-alkylsulfonamide, carbo-C1-6- alkoxy, carboxamide , carboxy, cyano, C3-7-cycloalkyl, C3-5-dialkylcarboxamide, halogen, heteroaryl and phenyl; and where each of the specified C0-6-alkenyl, C1-6-alkyl, C0-6-alkynyl, C1-6-alkylsulfonamide, C3-7-cycloalkyl, heteroaryl and phenyl groups may be optionally substituted with 1-5 substituents independently selected from the group including: C-c-acyl, C-c-acyloxy, C-6-alkenyl, C-4-alkoxy, C-6-alkyl, C-6-alkylamino, C-8-dialkylamino, C- - -alkylcarboxamide, So v-alkynyl, Si. 4-alkylsulfonamide, C1-4-alkylsulfinyl, C1-4-alkylsulfonyl, C1-4-alkylthio, C1-4-alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6e-cycloalkyl, Co-v-dialkylcarboxamide, halogen, C-4-halogenalkoxy, Si. 4-haloalkyl, Ci-4-haloalkylsulfinyl, Ci-4-haloalkylsulfonyl, Ci-4-haloalkylthio, hydroxyl, nitro-1 sulfonamide; Ky is selected from the group consisting of: -H, C-C-acyl, C-C-acyloxy, C-C-Alkenyl, C-C-Alkoxy, C-C-Alkyl, C-C-Alkylcarboxamide, C-C-6-alkynyl, C-C -alkylsulfonamide, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, C1-6-alkylthio, C1-6-alkylureyl, amino, C1-6-alkylamino, C10-8-dialkylamino, carbo-C1-6-alkoxy, carboxamide , carboxy, cyano, C3-7-cycloalkyl, C1-6-dialkylcarboxamide, C10-8-dialkylsulfonamide, halogen, /C1-6-halogenalkoxy, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, Si1-6 - haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; K" is chosen from the group that includes: C-C-acyl, C-C-acyloxy, C-C-alkenyl, C-C-Alkoxy, C-C-Alkyl, C-C-Alkylcarboxamide, C-C-Alkynyl, C-C-Alkylsulfonamide, C-C6 -alkylsulfinyl, C-6-alkylsulfonyl, C-6-alkylthio, C-6-alkylureyl, amino, C-6-alkylamino, C-6-dialkylamino, carbo-C6-alkyl, carboxamide, carboxy, cyano, C3-7 - cycloalkyl, C10-8-dialkylcarboxamide, C10-8-dialkylsulfonamide, halogen, C1-6-haloalkyloxy, C1-6-haloalkyl, C1-6-haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C1-6-haloalkylthio, hydroxyl, thiol, nitro-1 sulfonamide, where the indicated C-C-Alkoxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of: C-acyl, C-acyloxy, C-C-alkenyl, Su- Alkoxy, C-C-Alkyl, Amino, C-C-Alkylamino, C2.8-Dialkylamino, C-4-Alkylcarboxamide, C-C-Alkynyl, C-4-Alkylsulfonamide, C-4-Alkylsulfinyl, C-4-Alkylsulfonyl, C-4-alkylthio, C-C-alkylureyl, amino, carbo-Ci-C-Alkoxy, carboxamide, carboxy, cyano, C3-E-cycloalkyl, C0-6-dialkylcarboxamide, halogen, C and -4-haloalkyl, C1-4-haloalkyl, C1-4-haloalkylsulfinyl, C1-4-haloalkylsulfonyl, C1-4-haloalkylthio, hydroxyl, nitro and phenyl, and where amino and phenyl substituents are indicated, each is optionally substituted 1-5 additional substituents selected from the group consisting of halogen and carbo-Ci-6-alkoxy; Kwa, Co 1 Cos, each, independently selected from the group consisting of: -H, C-C-acyl, C-C-Acyloxy, C-C-Alkenyl, C-C-Alkyl, C-C-Alkyl, C-C-Alkylcarboxamide . -Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-cycloalkyl, C1-6-dialkylcarboxamide, C10-8-dialkylsulfonamide, halogen, /Ci-6- haloalkoxy, C1-6-haloalkyl, C-6- haloalkylsulfinyl, C1-6-haloalkylsulfonyl, C1-6-haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; EC; and Ez independently mean -H or C1-6-alkyl; X means O or 5; 1 O means Ci-3-alkylene, optionally substituted with 1-4 substituents selected from the group consisting of Ci-3-alkyl, Ci-4-alkoxy, carboxy, cyano, Ci-3-haloalkyl, halogen 1 oxo group; or O means connection; where "Ci-c-acyl" means a Ci-c-alkyl radical attached to a carbonyl; "aryl" means an aromatic ring radical containing 6-10 carbon atoms; "Carbo-Ci-6-Alkoxy" means a C-6-alkyl ester of a carboxylic acid; "heterocyclyl" means a non-aromatic carbon ring where one, two or three carbon atoms of the ring are replaced by a heteroatom selected from 0, 5 or M, where M is optionally substituted by H, C1-4-acyl or C1-6-alkyl, and the carbon atoms of the ring are optionally substituted with oxo or thioxo, and the heterocyclic group is a 3-, 4-, 5-, 6-, or 7-membered ring; "heteroaryl" means an aromatic ring system which may have one ring, two fused rings or three fused rings, where at least one ring carbon is replaced by a heteroatom selected from O, 5 or M, where M is optionally substituted with -H, Si- acyl or C-6-alkyl. 2. A compound according to claim 1, where Ki is phenyl or naphthyl, each of which is optionally substituted with Co, Co, Ky, Ki", Kis, Ki4 1 Ki, each of which is independently selected from the group consisting of: Ci-v -acyl, C-C-Alkoxy, C-C-Alkyl, C-6E-alkylsulfonyl, amino, C-6-Alkylamino, C-C-dialkylamino, C1-C-alkylimino, carbo-Ci-C-Alkoxy, carboxamide, carboxy, cyano, C3-cycloalkyl, halogen, C-6-haloalkyl, C-6-haloalkyl, heterocycle, hydroxyl, nitro and phenyl, or two adjacent substituents Co, Kio, Ky, Ki», Kis, Kia 1 Kis together with atoms , to which they are attached, form a C»7-cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an -E atom; and wherein C 1-6 alkyl, C 1-6 alkylimino, and heterocycle are each optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 acyl, C 1-6 alkoxy, C 6 -alkyl, C1-6-alkylsulfonyl, amino, C1-6-alkylamino, C10-8-dialkylamino, carboxamide, cyano, C3-7-cycloalkyl, halogen, C1-6-haloalkyl, C1-6-haloalkyl 1 hydroxyl . 3. The compound according to claim 1, where Ki is phenyl or naphthyl, each of which is optionally substituted Co, Co, Ky, Ki", Kis, Ki4 1 Ki, each of which is independently selected from the group consisting of: C1-6-acyl, C1-6-alkyl, C1-6-alkyl, amino, C1-6-alkylamino, C o c-dialkylamino, C-6-alkylimino, cyano, halogen, C-6e-haloalkoxy, C-6-haloalkyl, heterocycle, hydroxyl, nitro 1 phenyl, or two adjacent substituents Co, Kio, K1, Ki", Kis, Ki 1 Kis, together with the atoms to which they are attached, form a C»7-cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an -E atom; and wherein C 1-6 alkyl, C 1-6 alkylamino and heterocycle are each optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 alkyl, amino, C 1-6 alkylamino, Co 2-8 - dialkylamino and hydroxyl. 4. A compound according to claim 1, where Ki is phenyl or naphthyl, each of which is optionally substituted with Co, Co, Ky, Ki", Kis, Ki4 1 Ki, each of which is independently selected from the group consisting of: -СО) CH», -ОСН», -СН3, -«СН(СН33», -СН(ОН)СН», -М(СН3)», (2-dimethylaminoethyl)methylamino, (3-dimethylaminopropyl)methylamino, -С(- MONISN», cyano, -E, -SI, -W, -OSE», -SIEZ, 4-methylpiperazin-1-1l, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro 1-phenyl. 5. The compound according to claim 1, where Ki is phenyl or naphthyl, each of which is optionally substituted with Co, Co, Ky, Ki», Kis, Kia 1 Kis, each of which is independently selected from the group consisting of: -OSN» , -СН», cyano, -Е, -СИ, -Вг, -ОСЕ 1 -СЕ.. 6. The compound according to claim 1, where Ki means heteroaryl, optionally substituted with Ko, Kio, Ky, Ki? 1 Kiz, each of which is independently selected from the group consisting of: C 1 -C 6 -acyl, C 1 -C 6 -Alkoxy, C 1 -C 6 -Alkyl, Amino, C 6 -C 6 -Alkylamino, C 1 -C 8 -Dialkylamino, C 1 -C 6 -Alkylimine . attached, form a C»7-cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an -E atom; and wherein C 1-6 alkyl, C 1-6 alkylimino and heterocycle are each optionally substituted with 1-5 substituents independently selected from the group consisting of: C 1-6 alkyl, amino, C 6-alkylamino, Co-85-dialkylamino and hydroxyl. 7. The compound according to claim 1, where Ki means heteroaryl, optionally substituted with Ko, Kio, K1, Ki? 1 Goats, each of which is independently selected from the group including: -СО)СН», -ОСН», -СН3, -«СН(СН3)», -«СН(ОН)СН», -М(СН3)» , (2-dimethylaminoethyl)methylamino, (3-dimethylaminopropyl)methylamino, -С(-МОН)СН3, cyano, -Е, -СИ,. -Wt, -OSEz, -SEz, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, hydroxyl, nitro-1-phenyl. 8. The compound according to claim 1, where Ki means heteroaryl, optionally substituted with Ko, Kio, Ky, Ki? 1 Goats, each of which is independently selected from the group including: -ОСН», -СН», cyano, -Е, -СИ, -Вг, -ОСЕ 1 -СЕ.. 9. A compound according to any one of claims 1-8, where Co" means H or C1-6-alkyl. 10. The compound according to any one of claims 1-8, where Co is selected from the group including -CH3, -СОСН», - СсН(СН3)», -ССНОСН», -ССН(СНЗ)» 1 -СНОСНоСНоСН». 11. A compound according to any of claims 1-8, where Co means -СН3 or -"СН(СН3)". 12. The compound according to any of claims 1-8, where Co means -H. 13. The compound according to any one of claims 1-12, where Kz means -H or halogen. 14. A compound according to any of claims 1-12, where Kz means -Н, -Е, -СИ or -Вг. 15. A compound according to any one of claims 1-14, where Ka is selected from the group consisting of -H, C1-6-alkyl or Si. β-haloalkyl. 16. The compound according to any one of claims 1-14, where Ka means -H or -SEz. 17. A compound according to any one of claims 1-16, where Co is selected from the group consisting of: C 1 -C 6 -alkylthio, C 1 -C 6 -alkylthio, amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, halogen, C 6 -haloalkyl and hydroxyl, where the indicated C-C-Alkoxy group may be optionally substituted with 1-5 substituents independently selected from the group consisting of: amino, Si. β-alkylamino, C0-85-dialkylamino, carbo-Ci-β-alkoxy, carboxamide, carboxy, cyano, halogen 1 phenyl, and where indicated amino 1 phenyl substituents are each optionally substituted with 1-5 additional substituents selected from groups including halogen and carbo-Si-6-alkoxy. 18. The compound according to any one of claims 1-16, where Co is selected from the group consisting of: C-C-Alkoxy, C-C-C-Alkoxy and hydroxyl, where the specified C-C-Alkoxy group can be optionally substituted by 1 -5 substituents independently selected from the group consisting of: amino, C0-6-dialkylamino, carboxy, and phenyl, and where amino and phenyl are each optionally substituted with 1-5 additional substituents selected from the group consisting of halogen and carbo-Ci1-6-alkoxy. 19. The compound according to any one of claims 1-16, where Co is selected from the group including: -OSH3, -OSNOCH», -OSH(CH3)», -OSE», hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, carboxymethoxy 1 2-tert-butoxycarbonylaminoethoxy. 20. The compound according to any of claims 1-16, where Ko means -OSN". 21. A compound according to any one of claims 1-20, where Kwa, Co» 1 Kos, each, are independently selected from the group consisting of: -H, C-C-Alkoxy, C-C-Alkyl, amino, C- β-alkylamino, C»o-β8-dialkylamino, cyano, halogen, C-6-haloalkyl, C-6-haloalkyl, hydroxyl and nitro. 22. A compound according to any of claims 1-20, where Kwa, Co» 1 Cos, each, are independently selected from the group including: -H, -ОСН», -СН3, -М(СН3)», cyano, -E, -SI, -W, -OSE", hydroxyl and nitro. 23. A compound according to any of claims 1-20, where Kwa, Ke 1 Kes all mean -H. 24. The compound according to any of claims 1-23, where K7 means -Н. 25. The compound according to any of claims 1-24, where Kv means -Н. 26. The compound according to any one of claims 1-25, where X means 0. 27. The compound according to any one of claims 1-25, where X means 5. 28. The compound according to any of claims 1-27, where ОО means -С(О).-. 29. The compound according to any one of claims 1-27, where O means -СНо-. 30. The compound according to any one of claims 1-27, where O is a bond. 31. The compound according to claim 1, selected from compounds of the formula (Pa): Ka Kk, y Kv Hra r ros! to scha Kos Kk Kk Kt , (on) and their pharmaceutically acceptable salts, hydrates and solvates; where Ki is phenyl or naphthyl optionally substituted with Co, Co, K11, Ki", Kis, Ki4 1 Kis, EACH of which is independently selected from the group consisting of: C1-6-acyl, C1-6-Alkoxy, C1-6 -alkyl, amino, C 6 -alkylamino, C 6 -dialkylamino, C 6 -alkylimino, cyano, halogen, C 6 -haloalkyl, C 6 -haloalkyl, heterocycle, hydroxyl, nitro 1 phenyl, or two adjacent substituents Ko, Kio, Ky, Ki", Kis, Kia 1 Kis, together with the atoms to which they are attached, form a C»7-cycloalkyl group or a heterocyclic group, each of which is optionally substituted by an -E atom; and wherein C 1-6 alkyl, C 1-6 alkylimino, and heterocycle are each optionally substituted with 1-5 substituents independently selected from the group consisting of: C 1-6 alkyl, amino, C 1-6 alkylamino, Co-5-dialkylamino and hydroxyl; KE" means C1-6-alkyl; Ez means -H or halogen; Ka is selected from the group consisting of H, Si -6-alkyl 1 Si 6-haloalkyl; K" is selected from the group consisting of: C-C-Alkoxy, C-C-6-Halo-Alkoxy, 1-hydroxyl, where the specified C-C-Alkoxy group may be optionally substituted with 1-5 additional substituents independently selected from the group consisting of: amino, C 6 -dialkylamino, carboxy 1 phenyl, and where the amino group and phenyl are indicated, each optionally substituted with 1-5 additional substituents selected from the group consisting of halogen and carbo-Ci-C 6-Alkoxy; Kwa Ke 1 Kos, each, independently selected from the group consisting of: -H, C1-6-alkyl, C1-6-alkyl, amino, C1-6-alkylamino, C10-6-dialkylamino, cyano, halogen, C-6-halogenalkoxy, C-6-haloalkyl, hydroxyl and nitro; Ki Evz both mean -H; X stands for O; 1 O means connection. 32. The compound according to claim 1, selected from the compounds of the formula (Pa): Ka Kk, and Ka X i; Also Kos Kk, Ka Kt (na) and their pharmaceutically acceptable salts, hydrates and solvates; where Ki is phenyl or naphthyl optionally substituted with Co, Co, K11, Ki", Kis, Ki4 1 Kis, EACH of which is independently selected from the group consisting of: -CO)CH", -OSH", -CH3, -"CH(CH3z", -CH(OH)CH", -M(CH3)", (2-dimethylaminoethyl)methylamino, (3- dimethylaminopropyl)methylamino, -C(-MONICH", cyano, -E, -SI . ; Kz means -H, -E, -CI or -Bg; Ka means -H or -SEZ; K" is selected from the group including: -ОСН3, -ОСНОСН», -ОСН(СНЗ)», -ОСЕ» hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, carboxymethoxy 1 2-tert-butoxycarbonylaminoethoxy; Kwa Ke 1 Kos, each independently selected from the group consisting of -H, -OSH»z, -CHz , -M(CH3)", cyano, -E, -CI, -Bg, -OSE;", hydroxyl and nitro; K and Ez both mean -H; X means O; 1 O means bond. 33. The compound according to claim 1, selected from the compounds of the formula (Pa): Ka Kk, Kk Ka Hra r ros! hi Ge Ks Kk, Ka Kt , (on) and their pharmaceutically acceptable salts, hydrates and solvates; where Ki stands for phenyl, optionally substituted with Ko, Kio, Kiyi, Ki? 1 Goats, each of which is independently selected from the group including: -СО)СН», -ОСН», -СН3, -СН(СН3з», -СН(ОН)СН», -М(СН3)», ( 2-dimethylaminoethyl)methylamino, (3- dimethylaminopropyl)methylamino, -С(-MONISN», cyano, -Е, -СИ, -Вт, -ОСЕ», -СИЕз, 4-methylpiperazine-1-1l, morpholine-4- yl, 4-methylpiperidin-1-yl, hydroxyl, nitro 1 phenyl; Ko means -CH3 or -CH(CH3)"; Kz means -H, -E, -CI or -Hg; Ka means -H or -CE" ; K5 is selected from the group including -ОСН3, -ОСНоСН»3, -ОСН(СН3)», -ОСЕ», hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, carboxymethoxy and 2-tert -butoxycarbonylaminoethoxy; Kwa Ke 1 Kos, each, independently selected from the group consisting of -H, -OSH»z, -CHz, -M(CHz)", cyano, -E, -SI, -Bg, -OSE;" , hydroxyl and nitro; Ki and Evs both mean -H; X means O; 1 O means bond. 34. The compound according to claim 1, selected from the compounds of the formula (Pa): B. in , (on) and their pharmaceutically acceptable salts, hydrates and solvates; where Ki stands for phenyl, optionally substituted with Ko, Kio, Kiyi, Ki? 1 Goats, each of which is independently selected from the group consisting of: -С(ФО)СН», -ОСН», -СН3, -СН(СНЗ)», -М(СНЗ)», cyano, -Е, -СИ , -Vg, -OSE", -SI, hydroxyl and nitro; EC stands for -СН3; Kz means -Н, -Е, -СИ or -Вг; Ku means -H; K» is selected from the group including: -ОСН3, -ОСНОСН», -ОСН(СН3)», -ОСЕ», hydroxyl, benzyloxy, 4-chlorobenzyloxy, phenethyloxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, carboxymethoxy 1 2-tert - butoxycarbonylaminoethoxy; Kva, Ko 1 Kos each means -H; Ki Evz both mean -H; X stands for O; 1 O means connection. 35. The compound according to claim 1, where the compound is selected from the group consisting of: (1) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-( 4-chlorophenyl )urea; (2) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-fluorophenyl )urea; (3) 1 -I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(2,4-dichlorophenyl)urea; (4) 1-(3-(4-bromo- 2-methyl-2H-pyrazole-3-1l)-4-methoxyphenyl |-3-(4-methoxyphenyl)urea; (5) 1-I(3-(4-bromo-2-methyl-2H-pyrazole-3 -1l)-4-methoxyphenyl |-3-(4-bromophenyl)urea; (6) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3 -(4-chloro-3-trifluoromethylphenyl)urea; (7) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(3,5-difluorophenyl )urea; (8) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(2,4-difluorophenyl)urea; (9) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-chloro-2- trifluoromethylphenyl)urea; (10) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(3,4-difluorophenyl)urea; (11) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(3-trifluoromethylphenyl)urea; (12) 1-I(3- (4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4--rifluoromethylphenyl)urea; (13)1-(3,5-bis-trifluoromethylphenyl)-3- |3-(4-bromo-2-methyl-2H-pyrazole-3-1l)-4-methoxyphenyl |urea; (14) 1-I(3-(4-bromo-2-methyl-2H-pyrazole-3 -1l)-4-methoxyphenyl|-3-naphthalen-2-ylurea; (15) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(3-nitrophenyl)urea; (16) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-fluoro-3-nitrophenyl)urea; (17) 1- (acetylphenyl)-3-I3-(4-bromo-2-methyl-2H-pyrazol-3-1yl)-4-methoxyphenyl |urea; (18) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(3-fluorophenyl)urea; (19) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4--riftomethoxyphenyl)urea; (20) 1-I(3 -(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(3-chlorophenyl)urea; (21) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(3-cyanophenyl)urea; (22) 1-biphenyl-2-yl-3-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl urea; (23) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(4-isopropylphenyl)urea; (24) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-naphthalen-1-ylurea; (25) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(2-fluorophenyl)urea; (26) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(4-chlorophenyl)urea; (27) 1-(4-chlorophenyl)-3-I3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |urea; (28) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(4-fluorophenyl)urea; (29) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(2,4-difluorophenyl)urea; (30) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(3-methoxyphenyl)urea; (31) 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(4-fluorophenyl)urea; (32) 1-(3,4-difluorophenyl)-3-|3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea; (33) 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(3-fluorophenyl)urea; (34) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(2-trifluoromethoxyphenyl)urea; (35) 1-(3-acetylphenyl )-3-|3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |urea; (36) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(3-fluorophenyl)urea; (37) 1-(2,4-difluorophenyl)-3-|3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea; (38) 1-I(3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4- chlorophenyl)urea; (39) 1-I(3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(4-fluorophenyl)urea; (40) 1-(3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(4-fluorophenyl)urea; (41) 1-I(3-(4-chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4- chlorophenyl)urea; (42) 1-(4-chlorophenyl)-3-|(4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-1l)phenyl |urea; (43) 1-(3- chlorophenyl)-3-|3-(2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl |urea; (44) 1-(4-fluorophenyl)-3-|3-(2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl|urea; (45) 1-(3-(4-chlorophenyl-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(4-chlorophenyl)urea; (46) 1-(3,4- difluorophenyl)-3-|3-(2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl |urea; (47) 14(3-chloro-4-fluorophenyl)-3-|3-(2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl|urea; (48) 1-(2-chloro-4-trifluoromethylphenyl)-3-|3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea; (49) 1-I(3-(4-bromo-2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(4-chlorophenyl)urea; (50) 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-fluorophenyl)urea; (51) 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(3,4-difluorophenyl)urea; (52) 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(3-chloro-4-fluorophenyl)urea; (53) 1-I3-(4-bromo-2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(2-chloro-4- trifluoromethylphenyl)urea; (54) 1-I(3-(4-chloro-2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-fluorophenyl)urea; (55) 1-I3-(4 -chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(3,4-difluorophenyl)urea; (56) 1-(3-chloro-4-fluorophenyl)-3-| 3-(4-chloro-2-isopropyl-2H-pyrazol-3-1l)-4-methoxyphenyl |urea; (57) 1-I3-(4-chloro-2-isopropyl-2H-pyrazole-3-1l) -4-methoxyphenyl |-3-(2-chloro-4-trifluoromethylphenyl)urea; (58) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-hydroxyphenyl |-3 -(4-chlorophenyl)urea; (59) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-isopropoxyphenyl|-3-(4-chlorophenyl)urea; ( 60) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-isopropoxyphenyl |-3-(4-fluorophenyl)urea; (61) 1-(4-benzyloxy- 3-(4-bromo-2-methyl-2H-pyrazol-3-1l)phenyl|-3-(4-chlorophenyl)urea; (62) 1-(4-benzyloxy-3-(4-bromo-2- methyl-2H-pyrazol-3-yl)phenyl |-3-(4-fluorophenyl)urea; (63) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4 -(4-chlorobenzyloxy)phenyl |-3-(4-chlorophenyl)urea; (64) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(4- chlorobenzyloxy)phenyl |-3-(4-fluorophenyl)urea; (65) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-phenethyloxyphenyl |-3-(4-fluorophenyl)urea; (66) 1-I(3- (4-bromo-2-methyl-2H-pyrazol-3-1l)-4-phenethyloxyphenyl |-3-(4-chlorophenyl)urea; (67) 1-I(3-(4-bromo-2-methyl- 2H-pyrazol-3-1l)-4-ethoxyphenyl |-3-(4-chlorophenyl)urea; (68) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)- 4-ethoxyphenyl |-3-(4-fluorophenyl)urea; (69) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(2-dimethylaminoethoxy)phenyl | -3-(4-chlorophenyl)urea; (70) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(2-dimethylaminoethoxy)phenyl |-3-( 4-fluorophenyl)urea; (71) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(4-chlorophenyl)thiourea; (72) 1- I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(3-methoxyphenyl)urea; (75) 1-(4-chlorophenyl)-3-| (4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea; (76) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)) -4-methoxyphenyl |-3-(4-isopropylphenyl)urea; (77) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-( 2,4-dichlorophenyl)urea; (78) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-naphthalen-1-ylurea; (79) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(4-chloro-2-trifluoromethylphenyl)urea; (80) 1- (3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4--rifluoromethylphenyl)urea; (81) 1-(4-bromophenyl)-3-| 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |urea; (82) 1-(3,5-bis-trifluoromethylphenyl)-3-|3-(4-chloro -2-methyl-2H-pyrazole-3-1l)-4-methoxyphenyl|urea; (83) 1-(3Z-chlorophenyl)-3-I3-(4-fluoro-2-methyl-2H-pyrazole-3- 1l)-4-methoxyphenyl |urea; (84) 1-(4-chloro-3-trifluoromethylphenyl)-3-|3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)-4- methoxyphenyl |urea; (85) 1-(4-bromophenyl)-3-|3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |urea; (86) 1-I3- (4-fluoro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-t-rifluoromethylphenyl)thiourea; (87) 1-I3-(4-fluoro-2-methyl- 2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(4-methoxyphenyl)urea; (88) 1-(3-acetylphenyl)-3-|3-(4-fluoro-2-methyl-2H- pyrazol-3-yl)-4-methoxyphenyl |urea; (89) 1-I3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(4A-t- reef tormethylphenyl)urea; (90) 1-I(3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-(3-trifluoromethylphenyl)urea, and their pharmaceutically acceptable salts, hydrates and solvates . 36. The compound according to claim 1, where the compound is selected from the group including: (91) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-( 3-chlorophenyl)urea; (92) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(3,4-difluorophenyl)urea; (93 ) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(3,5-difluorophenyl)urea; (94) 1-I(3- (4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl |-3-I3-(1-hydroxyethyl)phenyl |urea; (96) 1-I3-(4-bromo-2- methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-|3-(1- hydroxyiminoethyl)phenyl |urea; (97) 1-I(3-(4-chloro-2-methyl-2H- pyrazole-3-1l)-4-methoxyphenyl|-3-(2-fluorophenyl)urea; (98) 1-(4-chlorophenyl)-3-|3-(2-methyl-2H-pyrazol-3-yl)-4-t-rifluoromethoxyphenyl|urea; (99) 1-(-2,4-difluorophenyl)-3-|3-(2-methyl-2H-pyrazol-3-yl)-4--rifluoromethoxyphenyl|urea; (100) 1-(4-fluorophenyl)-3-|3-(2-methyl-2H-pyrazol-3-1l)-4-trifluoromethoxyphenyl|urea; (101) 1-(3-(2-methyl-2H-pyrazol-3-1l)-4-trifluoromethoxyphenyl |-3-(4--rifluoromethylphenyl)urea; (102) 1-(3-(4-bromo- 2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-|(4-chloro-2-(4-methylpiperazin-1-yl)phenyl |urea; (103) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-hydroxyphenyl|-3-(2,4-difluorophenyl)urea; (104) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(4-chloro-2-morpholin-4-ylphenyl)urea; (106) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-chloro-2-(4-methylpiperidin-1-yl)phenyl) |urea; (107) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-chloro-2-hydroxyphenyl)urea; (108) 1-( 3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-rifluoromethoxyphenyl |-3-(4-chlorophenyl)urea; (109) 1-(3-(4-chloro-2- methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(3-cyanophenyl)urea; (110) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(3-nitrophenyl)urea; (111) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3- | 4-chloro-2-|(2-dimethylaminoethyl)methylamino |phenyl | urea; (112) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3- | 4-chloro-2-|(3-dimethylaminopropyl)methylamino |phenyl ) urea; (113) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4--rifluoromethoxyphenyl |-3-(2,4-difluorophenyl)urea; (114) 1-(3 -acetylphenyl)-3-|3-(2-methyl-2H-pyrazol-3-yl)-4--rifluoromethoxyphenyl |urea; (115) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(2,2-difluorobenzo| 1,3 |dioxol-5-yl) )urea; (116) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-dimethylaminophenyl)urea; (117) 1-I(3-( 4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(4- chlorophenyl)urea; (118) 12-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-|3-(4-chlorophenyl)ureido|phenoxy)acetic acid; (119) 1-(4-chlorophenyl)-3-|4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea; (120) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-hydroxyphenyl|-3-(2,4-difluorophenyl)urea; (121) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea; (122) 1-(4-chlorophenyl)-3-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea; (123) 1-(3-( 4-bromo-2-methyl-2H-pyrazol-3-1l)-4--2-dimethylaminoethoxy)phenyl |-3-(2,4-difluorophenyl)urea; (124) 1-(2.4-difluorophenyl)-3-I(4--3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazole-3- yl)phenyl |urea; (125) 1-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-1yl)phenyl|-3-(4-fluorophenyl)urea; (127) 1-(4-chlorophenyl )-3-(4--2-dimethylaminoethoxy )-3-(2-methyl-2H-pyrazol-3-1l)phenyl |urea; (128) 1-(3-(4-chloro-2-methyl-2H) -pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl | -3-(4- chlorophenyl)urea; (129) 1-(2,2-difluorobenzo|1,3|dioxol-5-1l)-3-I4--3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl | urea; (130) 1-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-1l)phenyl|-3-paratolylurea; (131) 1--4--"3-dimethylaminopropoxy) -3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4-methoxyphenyl)urea; (132) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(2-dimethylaminoethoxy)phenyl |-3-(2,4-difluorophenyl)urea; (133) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(2,4-difluorophenyl)urea; (134) 1-(3-chlorophenyl)-3-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea; (135) 1-(3-chloro -4-fluorophenyl)-3-I(4--3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazole-3- yl)phenyl |urea; (136) 1-(3,4-difluorophenyl)-3-I(4--3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea; (137) 1--4--"3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |-3-(4-trifluoromethylphenyl)urea; (138) 1-(4- (3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-1l)phenyl |-3-(2-fluorophenyl)urea; (139) 1-(4-(3-dimethylaminopropoxy)-3-( 2-methyl-2H-pyrazol-3-1l)phenyl|-3-(2-fluoro-5-methylphenyl)urea; (140) 1-(2-chlorophenyl)-3-(4-(3-dimethylaminopropoxy)- 3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea; (141) 1--2,4-difluorophenyl)-3-(4-(-2-dimethylaminoethoxy)-3-(2-methyl -2H-pyrazol-3-yl)phenyl |urea; (142) 1-(4-(2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-1l)phenyl |-3-(4- fluorophenyl)urea; (143) 1-(3-acetylphenyl)-3-(4-(-2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-1l)phenyl |urea; (144). Urea (145) 1-(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-1yl)phenyl|-3-phenylurea; (146) 1-(4-(-2-dimethylaminoethoxy) )-3-(2-methyl-2H-pyrazol-3-yl)phenyl |-3-(3-methoxyphen il) urea; (147) tert-butyl ether (2-12-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-|3-(2,4-difluorophenyl)ureido|phenoxy)ethyl)carbamic acid ; (148) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(2,4-difluorophenyl)urea; (149) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(2-chlorophenyl)urea; (150) 1-(3- (4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(2-fluorophenyl)urea; (151) 1-(4-chlorophenyl)-3- (4-methoxy-3-(2H-pyrazol-3-yl)phenyl |urea; (152) 1-I(3-(4-bromo-2H-pyrazol-3-yl)-4-methoxyphenyl |-3- (2,4-difluorophenyl)urea; (153) 1--2,4-difluorophenyl)-3-|4-methoxy-3-(2H-pyrazol-3-1yl)phenyl |urea; (154) 1-( 4-chlorophenyl)-3-|(4-hydroxy-3-(1-methyl-1H-pyrazol-3-1l)phenyl|urea, and their pharmaceutically acceptable salts, hydrates and solvates. 37. The compound according to claim 1, where the compound is selected from the group including: (73) 1-benzoyl-3-|3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl | urea; (74) 1-benzyl-3-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl urea, and their pharmaceutically acceptable salts, hydrates and solvates. 38. The compound according to claim 1, where the compound is selected from the group consisting of: (95) 1-benzoyl-3-|3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl | urea; (105) 1-benzyl-3-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|urea; (126) 1-(4-chlorobenzyl)-3-I4--3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-1l)phenyl urea, and their pharmaceutically acceptable salts, hydrates and solvates. 39. The compound according to claim 1, where the compound is selected from the group consisting of: (155) 1-(4-chlorophenyl)-3-(4--2-dimethylaminoethoxy)-3-(4-fluoro-2-methyl-2H) -pyrazol-3-yl)phenyl |urea; (156) 1-(4--2-dimethylaminoethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)phenyl|-3-(4-fluorophenyl)urea; (157) 1--2,4-difluorophenyl)-3-(4--2-dimethylaminoethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)phenyl|urea; (158) 1-(4-chloro-2-hydroxyphenyl)-3-I(4--2-dimethylaminoethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)phenyl|urea; (159) 1-(4-2-dimethylaminoethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)phenyl |-3-(4-fluoro-2-hydroxyphenyl)urea; (160) 1-(4-chloro-3-hydroxyphenyl)-3-I(4--2-dimethylaminoethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)phenyl |urea; (161) 1--4-9-dimethylaminoethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)phenyl |-3-(4-fluoro-3- hydroxyphenyl)urea; (162) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4--2-dimethylaminoethoxy)phenyl|-3-(4-chlorophenyl)urea; (163) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(2-dimethylaminoethoxy)phenyl|-3-(4-fluorophenyl)urea; (164) 1-(4-chloro-2-hydroxyphenyl)-3-13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylaminoethoxy)phenyl|urea; (165) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(2-dimethylaminoethoxy)phenyl|-3-(4-fluoro-2-hydroxyphenyl)urea; (166) 1-(4-chloro-3-hydroxyphenyl)-3-|3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(2-dimethylaminoethoxy)phenyl|urea; (167) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-dimethylaminoethoxy)phenyl |-3-(4-fluoro-3-hydroxyphenyl)urea; (168) 1-(4-chloro-2-hydroxyphenyl)-3-I(4--2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea; (169) 1-(4-2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4-fluoro-2-hydroxyphenyl)urea; (170) 1-(4-chloro-3-hydroxyphenyl)-3-I(4-(-2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea; (171) 1--4-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4-fluoro-3-hydroxyphenyl)urea; (172) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4--2-dimethylaminoethoxy)phenyl |-3-(4-chloro-2-hydroxyphenyl)urea; (173) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4--2-dimethylaminoethoxy)phenyl |-3-(4-fluoro-2-hydroxyphenyl)urea; (174) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4--2-dimethylaminoethoxy)phenyl |-3-(4-chloro-3-hydroxyphenyl)urea; (175) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4--2-dimethylaminoethoxy)phenyl |-3-(4-fluoro-3-hydroxyphenyl)urea; (176) 1-(4-chlorophenyl)-3-(4-(3-dimethylaminopropoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)phenyl urea; (177) 1--4--"3-dimethylaminopropoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)phenyl |-3-(4-fluorophenyl)urea; (178) 1--2,4-difluorophenyl)-3-(4-(3-dimethylaminopropoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)phenyl |urea; (179) 1-(4-chloro-2-hydroxyphenyl)-3-I(4--3-dimethylaminopropoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)phenyl |urea; (180) 1-(4-(3-dimethylaminopropoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)phenyl|-3-(4-fluoro-2-hydroxyphenyl)urea; (181) 1-(4-chloro-3-hydroxyphenyl)-3-14-(3-dimethylaminopropoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)phenyl|urea; (182) 1--4-"3-dimethylaminopropoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-1l)phenyl|-3-(4-fluoro-3-hydroxyphenyl)urea; (183) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl|-3-(4-fluorophenyl)urea; (184) 1-(4-chloro-2-hydroxyphenyl)-3-13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl|urea; (185) 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl|-3-(4-fluoro-2-hydroxyphenyl)urea; (186) 1-(4-chloro-3-hydroxyphenyl)-3-|3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl|urea; (187) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylaminopropoxy)phenyl |-3-(4-fluoro-3-hydroxyphenyl)urea; (188) 1-(4-chloro-2-hydroxyphenyl)-3-I(4--3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea; (189) 1 -(4-(3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-1l)phenyl |-3-(4-fluoro-2-hydroxyphenyl)urea; (190) 1-(4-chloro -3-hydroxyphenyl)-3-I(4--3-dimethylaminopropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |urea; (191) 1--4--"3-dimethylaminopropoxy )-3-(2-methyl-2H-pyrazol-3-yl)phenyl |-3-(4-fluoro-3-hydroxyphenyl)urea; (192) 1-I(3-(4-bromo-2-methyl -2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(4-fluorophenyl)urea; (193) 1-(3-(4-bromo-2-methyl-2H-pyrazole- 3-1l)-4-(3-dimethylaminopropoxy)phenyl|-3-(4-chloro-2-hydroxyphenyl)urea; (194) 1-(3-(4-bromo-2-methyl-2H-pyrazole-3 -1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(4-fluoro-2-hydroxyphenyl)urea; (195) 1-(3-(4-bromo-2-methyl-2H-pyrazole-3- 1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(4-chloro-3-hydroxyphenyl)urea ovine, (196) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(3-dimethylaminopropoxy)phenyl |-3-(4-fluoro-3-hydroxyphenyl)urea , and their pharmaceutically acceptable salts, hydrates and solvates. 40. The compound according to claim 1, which is (1) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(4-chlorophenyl)urea or a pharmaceutically acceptable salt, solvate or hydrate thereof. 41. The compound according to claim 1, which is (8) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(2,4-difluorophenyl )urea or its pharmaceutically acceptable salt, solvate or hydrate. 42. The compound according to claim 1, which is (26) 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl|-3-(4-chlorophenyl)urea or a pharmaceutically acceptable salt, solvate or hydrate thereof. 43. The compound according to claim 1, which is (56) 1-(3-chloro-4-fluorophenyl)-3-I|3-(4-chloro-2-isopropyl-2H-pyrazol-3-1l)-4 -methoxyphenyl urea or its pharmaceutically acceptable salt, solvate or hydrate. 44. The compound according to claim 1, which is (62) 1-(4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-1l)phenyl |-3-(4-fluorophenyl)urea or a pharmaceutically acceptable salt, solvate or hydrate thereof. 45. The compound according to claim 1, which is (66) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-phenethyloxyphenyl|-3-(4-chlorophenyl)urea or a pharmaceutically acceptable salt, solvate or hydrate thereof. 46. The compound according to claim 1, which is (98) 1-(4-chlorophenyl)-3-|3-(2-methyl-2H-pyrazol-3-1l)-4-t-rifluoromethoxyphenyl|urea or its pharmaceutical an acceptable salt, solvate or hydrate. 47. The compound according to claim 1, which is (111) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3- | 4-chloro-2- |(2-dimethylaminoethyl)methylamino|phenyl|urea or its pharmaceutically acceptable salt, solvate or hydrate. 48. The compound according to claim 1, which is (115) 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl |-3-(2,2-difluorobenzo | 1,3 |dioxol-5-yl)urea or its pharmaceutically acceptable salt, solvate or hydrate. 49. The compound according to claim 1, which is (123) 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4--2-dimethylaminoethoxy)phenyl|-3-(2,4-difluorophenyl)urea or its pharmaceutically acceptable salt, solvate or hydrate. 50. The compound according to claim 1, which is (74) 1-benzyl-3-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-methoxyphenyl urea or its pharmaceutically acceptable salt, solvate or hydrate. 51. The compound according to claim 1, which is (169) 1-(4--2-dimethylaminoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl |-3-(4-fluoro-2 - hydroxyphenylurea or its pharmaceutically acceptable salt, solvate or hydrate. 52. A pharmaceutical composition containing a compound according to any one of claims 1-51 in a pharmaceutically acceptable carrier. 53. The method of obtaining the composition according to claim 52, in which the stage of mixing the compound according to any of claims 1-51 with 1 pharmaceutically acceptable carrier is carried out. 54. Compound according to any of claims 1-51! for use in a method of treating a person or an animal by means of therapy. 55. A compound according to any one of claims 1-51 for use in a method of prevention or treatment by means of therapy of a disorder mediated by the action of 5-HT»a in a person or an animal. 56. The compound according to any one of claims 1-51 for use in a method of prevention or treatment by means of therapy of a sleep disorder in a person or an animal. 57. A compound according to any one of claims 1-51 for use in a method of prevention or treatment by therapy of a sleep disorder in a human or animal by promoting sleep enhancement. 58. A compound according to any one of claims 1-51 for use in a method of prevention or treatment by therapy of a sleep disorder in a human or animal by increasing delta energy. 59. The compound according to any one of claims 56-58, wherein said sleep disorder comprises a fragmented sleep pattern. 60. The compound according to any one of claims 56-58, wherein said sleep disorder is dyssomnia. 61. The compound according to claim 60, where the indicated dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep pattern perception disorder, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement syndrome, restless legs syndrome eating or drinking, sleep disorder caused by sleeping pills, sleep disorder caused by stimulant use, sleep disorder caused by alcohol consumption, sleep disorder caused by toxic exposure, jet lag syndrome, sleep disorder caused by shift work, irregular sleep mode - wakefulness, sy sleep phase delay syndrome, early sleep phase syndrome, and sleep disorder caused by a non-24-hour sleep-wake cycle. 62. The compound according to any one of claims 56-58, wherein said sleep disorder is a parasomnia. 63. The compound according to claim 62, wherein said parasomnia is selected from the group consisting of confusion upon awakening, sleepwalking and night terrors, rhythmic movement disorder, sleep tremors, sleep talking, and nocturnal leg cramps. 64. The compound according to any of claims 56-58, wherein said sleep disorder is associated with an organic or psychiatric disorder. 65. A compound according to any one of claims 1-51 for use in a method of prevention or treatment with platelet aggregation therapy in a human or animal. 66. The compound according to any one of claims 1-51 for use in a method of prevention or treatment of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke 1 of atrial fibrillation. 67. The compound according to any one of claims 1-51 for use in a method of preventing or treating the formation of blood clots during angioplasty or coronary bypass surgery in an individual. 68. A compound according to any one of claims 1-51 for use in a method of preventing or treating the formation of blood clots in an individual suffering from atrial fibrillation. 69. Use of a compound according to any one of claims 1-51 for the preparation of a medicinal product for the prevention or treatment of a disorder mediated by the action of 5-HTaA. 70. Use of a compound according to any one of claims 1-51 for obtaining a medicinal product for the prevention or treatment of a sleep disorder. 71. Use of a compound according to any one of claims 1-51 for the preparation of a medicinal product for the prevention or treatment of a sleep disorder by promoting sleep enhancement. 72. Use of a compound according to any one of claims 1-51 for the preparation of a medicinal product for the prevention or treatment of a sleep disorder by increasing delta energy. 73. Use according to any one of claims 70-72, wherein said sleep disorder includes a fragmented sleep structure. 74. Use according to any one of claims 70-72, wherein said sleep disorder is dyssomnia. 75. Application according to claim 74, where the indicated dyssomnia is selected from the group including psychophysiological insomnia, sleep structure perception disorder, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement syndrome, restless legs syndrome eating or drinking, sleep disorder caused by sleeping pills, sleep disorder caused by stimulant use, sleep disorder caused by alcohol consumption, sleep disorder caused by toxic exposure, jet lag syndrome, sleep disorder caused by shift work, irregular sleep mode - awake I, delayed sleep phase syndrome, early sleep phase syndrome, and sleep disorder due to non-24-hour sleep-wake cycle. 76. Use according to any one of claims 70-72, wherein said sleep disorder is a parasomnia. 77. The application of claim 76, wherein said parasomnia is selected from the group consisting of confusion upon awakening, sleepwalking and night terrors, rhythmic movement disorder, tremors during sleep, sleep talking, and night leg cramps. 78. Use according to any one of claims 70-72, where said sleep disorder is associated with an organic or psychiatric disorder. 79. Use of a compound according to any of claims 1-51 for the preparation of a medicinal product for the prevention or treatment of platelet aggregation. 80. Use of a compound according to any one of claims 1-51 for obtaining a medicinal product for the prevention or treatment of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke 1 of atrial fibrillation. 81. Use of a compound according to any one of claims 1-51 for the preparation of a medicinal product for the prevention or treatment of the formation of blood clots during angioplasty or coronary bypass surgery in an individual. 82. Use of a compound according to any one of claims 1-51 for the preparation of a medicament for the prevention or treatment of blood clot formation in an individual suffering from atrial fibrillation. 83. A method of preventing or treating platelet aggregation in an individual, in which a therapeutically effective amount of the compound according to any one of claims 1-51 is administered to said individual in need thereof. 84. A method of preventing or treating a condition selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, and atrial fibrillation in an individual, comprising administering to said individual in need thereof a therapeutically effective amount of a compound of any of claims 1-51. 85. A method of prevention or treatment for reducing the risk of blood clot formation during angioplasty or coronary bypass surgery of an individual, in which a therapeutically effective amount of the compound according to any one of claims 1-51 is administered to said individual in need thereof. 86. A method of prevention or treatment for reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, wherein a therapeutically effective amount of the compound according to any one of claims 1-51 is administered to said individual in need thereof. 87. A method of preventing or treating a sleep disorder in an individual, in which a therapeutically effective amount of the compound according to any one of claims 1-51 is administered to said individual in need thereof. 88. The method according to claim 87, wherein said sleep disorder includes a fragmented sleep structure. 89. The method according to claim 87, wherein the indicated effective amount of the specified compound contributes to strengthening sleep. 90. The method of claim 87, wherein the effective amount of said compound increases delta energy. 91. The method according to claim 87, wherein said sleep disorder is dyssomnia. 92. The method according to claim 91, where the specified dyssomnia is selected from the group that includes psychophysiological insomnia, sleep structure perception disorder, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement syndrome, restless legs, sleep disorder caused by poor sleep hygiene, sleep disorder caused by environmental factors, high-altitude insomnia, sleep disorder caused by adaptive reactions, insufficient sleep syndrome, sleep disorder caused by disturbed bedtime routine, associative sleep disorder, nocturnal syndrome eating or drinking, sleep disorder caused by sleeping pills, sleep disorder caused by stimulant use, sleep disorder caused by alcohol consumption, sleep disorder caused by toxic exposure, jet lag syndrome, sleep disorder caused by shift work, irregular sleep-wake mode, syndrome with sleep phase delay, early sleep phase syndrome 1 sleep disorder caused by a non-24-hour sleep-wake cycle. 93. The method according to claim 87, wherein the indicated sleep disorder is parasomnia. 94. The method of claim 93, wherein said parasomnia is selected from the group consisting of confusion upon awakening, sleepwalking and night terrors, rhythmic movement disorder, tremors during sleep, sleep talking, and night leg cramps. 95. The method according to claim 87, where the specified sleep disorder is associated with an organic or psychiatric disorder.