UA91350C2 - 3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT-2a SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO - Google Patents

Abstract

The present invention relates to certain 3-phenyl-pyrazole derivatives of Formula (Ia) 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 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, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HTserotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

Description

The present invention relates to some C3-phenylpyrazole derivatives of formula (Ia) and their pharmaceutical compositions that modulate the activity of the 5-HTgl serotonin receptor. The compounds and their pharmaceutical compositions are directed to methods useful in the treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, atrial fibrillation, reducing the risk of blood clots, asthma or symptoms thereof, anxiety or a symptom thereof , behavioral disorders, drug psychosis, excitability psychosis, Tourette's syndrome, manic disorders, organic or

MOB psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, MO5 schizophrenia and related disorders, sleep disorder, diabetes-related disorders, progressive multifocal leukoencephalopathy, etc.

The present invention also relates to methods of treating 5-HTgli serotonin receptor mediated disorders in combination with other pharmaceutical agents administered alone or together.

C protein-related receptors

β protein-related receptors share a common structural motif. All these receptors have seven sequences of 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane. The transmembrane helices are connected by chains of amino acids that have a larger loop between transmembrane helices four and five on the extracellular side of the membrane. Another larger loop, composed primarily of hydrophilic amino acids, connects transmembrane helices five and six on the intracellular side of the membrane. The carboxy terminus of the receptor is located inside the cell, while the amino terminus is located in the extracellular space. It is believed that the loop that connects helices five and six, as well as the carboxy terminus, interacts with protein C. Currently, C proteins 4, 05, and and so have been identified.

Under physiological conditions, C protein-coupled receptors exist in the cell membrane in equilibrium between two different states or conformations: an "inactive" state and an "active" state. In an inactive state, the receptor is unable to communicate with the intracellular transduction pathway to produce a biological response. Changing the conformation of the receptor to an active state enables communication with the transduction pathway and produces a biological response.

The receptor can be stabilized in the active state with the help of an endogenous ligand or an exogenous agonistic ligand. Recent discoveries, including, but not limited to, modifications of the amino acid sequence of the receptor, provide means other than ligands to stabilize the active conformation. 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-independent means is called "constitutive activation of the receptor."

Serotonin receptors

Receptors for serotonin (5-hydroxytryptamine, 5-HT) are a class of protein-coupled receptors, which is important. Serotonin is believed to play a role in processes related to recall and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behavior, appetite, neurodegenerative regulation, and biological rhythms. Not surprisingly, serotonin is associated with pathophysiological conditions such as anxiety, depression, obsessive-compulsive disorder, schizophrenia, suicide, autism, migraine, vomiting, alcoholism, and neurodegenerative disorders. With respect to anti-psychotic treatment approaches focused on serotonin receptors, these types of therapeutics can be broadly divided into two classes: "typical" and "atypical." Both have anti-psychotic effects, but typical agents also include associated side effects related to motor function (extrapyramidal syndromes, such as lip smacking, tongue protrusion, locomotor movement, etc.). Such side effects are believed to be related to compounds that interact with other receptors, such as the human dopamine O2 receptor, in the nigrostriatal pathway. Therefore, atypical treatment is preferred. Haloperidol is considered a typical antipsychotic and clozapine is considered an atypical antipsychotic.

Serotonin receptors are divided into seven subfamilies, which denote from 5-NTI to 5-NIT7, inclusive. These subfamilies are further subdivided into subtypes. For example, the 5-HT" subfamily is divided into three subtypes of receptors: 5-HTga, 5-HT"2b and 5-HTos. The human 5-HT2 receptor was first isolated and cloned in 1987, and the human 5-HT1 receptor was first isolated and cloned in 1990. It is believed that these two receptors are the site of action of hallucinogenic drugs. In addition, it is believed that antagonists of 5-HTaA and 5-

NTes receptors are useful in the treatment of depression, anxiety, psychosis and eating disorders.

US patent Me4985352 describes the isolation, identification and expression of a functional cDNA clone encoding the entire human 5-HTis receptor (now known as the 5-HTis receptor). US Patent Nos. 5,661,024 and 6,541,209 describe the isolation, identification, and expression of a functional cDNA clone encoding the entire human 5-HT A receptor.

It was reported that mutations of the endogenous forms of rat 5-HTgaA and 5-HTa receptors lead to constitutive activation of these receptors (5-HTga: Sazeu, S. Yei ai. (1996) Bosieiu g Meshcygozsiepse Arzigasib5, 22:699.10, hereinafter - "Saseu" ; 5-NTos: Nepisk-Oamiv, K., apa Tesheg, M. (1996) Zosieiu g Meitsgozsiepse Arzigasiv, 22:699.18, hereinafter - "Negtisk-Oamiv 1"; and Negtisk-Oamiv5, K. ei ai. (1997 ) U. Meyhospetivighu 69(3): 1138, hereinafter - "Negtisk-Oamiv-2"). Sazeu describes a mutation of the cysteine residue at position 322 of the rat 5-HTgdi receptor to lysine (C322K), glutamine (C32209), and arginine (C322K), which was reported to result in constitutive activation. Ne!tisk-Oami5 1 and

Neittisk-Oami5 2 describe mutations of the serine residue at position 312 of the rat 5-HT 2 receptor to phenylalanine (5312) and lysine (5312K), which were reported to result in constitutive activation.

One aspect of the present invention encompasses certain 3-phenylpyrazole derivatives represented by formula (Ia):

-In c

Kv M vu Shko Suk e te Y Kz vo or their pharmaceutically acceptable salts, hydrates or solvates; where:

M represents O, 5, 5(50), 5(2O)" or MECHO;

MU is a Ci-4 alkylene optionally substituted with 1-8 substituents independently selected from the group consisting of Ci-3 alkyl, Ci-4 alkyl, carboxy, cyano, Ci-3 haloalkyl, halogen and oxo; or M/ absent;

X is C(:O), C(-5) or absent;

M represents 0, ME or absent; 7 is C-4 alkylene or C3-e cycloalkylene, each optionally substituted with 1-8 substituents independently selected from the group consisting of C1-3 alkyl, C1-4 alkoxy, carboxy, cyano, C1-3 haloalkyl, halogen , hydroxyl and oxo; or 2 is absent;

B is selected from the group consisting of H, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl and C3-7 cycloalkyl;

AB2 is selected from the group consisting of H, C1-C acyl, C1-C acyloxy, C1-C alkenyl, C1-C alkoxy, C1-C alkyl, C1-C alkylcarboxamide, C1-C alkynyl, C1-C alkylsulfonamide, C1-C alkylsulfinyl, C-e alkylsulfonyl, C-e alkylthio, C1-6 alkylureyl, amino, C-e alkylamino, C2-e dialkylamino, carbo-Ci-e-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, Cg2- in dialkylcarboxamide, C1-2 dialkylsulfonamide, halogen, C1-e haloalkoxy, C1-6e haloalkyl, C1-e haloalkylsulfinyl, C1-e haloalkylsulfonyl, C1-e haloalkylthio, hydroxyl, thiol, nitro and sulfonamide;

Az is selected from the group consisting of H, C2-alkenyl, C1-alkyl, C1-alkylcarboxamide, C1-6 alkynyl, C1-6 alkylsulfonamide, carbo-C1-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C1-C dialkylcarboxamide, halogen, heteroaryl and phenyl; and where each of the specified Co2-e alkenyl, C-e alkyl, Co-e alkynyl, C1-6 alkylsulfonamide, C3-7 cycloalkyl, heteroaryl and phenyl groups is optionally substituted with 1-5 substituents independently selected from the group, which includes C1-5 acyl, C1-5 acyloxy, C2-e alkenyl, C1-4 alkoxy, C1-8 alkyl, C1-8 alkylamino, C2-z dialkylamino, C1-4 alkylcarboxamide, C1-4 alkynyl, C1-4 alkylsulfonamide, C-4 alkylsulfinyl, C1-4 alkylsulfonyl, C-4 alkylthio, C-4 alkylureyl, amino, carbo-Ci--alkoxy, carboxamide, carboxy, cyano, C3-e cycloalkyl, C2-e dialkylcarboxamide, halogen, C-4 haloalkoxy, C-4 haloalkyl, C1-4 haloalkylsulfinyl, C1-4 haloalkylsulfonyl, C-4 haloalkylthio, hydroxyl, nitro and sulfonamide;

Ah represents a heterobicyclic group, a heterocyclic group, or a heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-12 acyloxy, C1-4 alkenyl, C1-4 alkoxy, C1-4 alkoxycarbonylamino, C-e alkyl, C-e alkylamino, C-2-c dialkylamino, C-4 alkylcarboxamide, C-2-6 alkynyl, C-4 alkylsulfonamide, C-4 alkylsulfinyl, C-4 alkylsulfonyl, C-4 alkylthio, C-4 alkylureyl, amino, carbo-Si-alkoxy, carboxamide, carboxy, cyano, C3-cycloalkyl, C3-7 cycloalkylcarbonyl, C2-6 dialkylcarboxamide, formyl, halogen, C-4 haloalkyl, C-4 haloalkyl, C-4 haloalkylsulfinyl, C1-4 haloalkylsulfonyl , C-4 haloalkylthio, heteroaryl, hydroxyl, nitro, phenyl and sulfonamide; where indicated

C1-5 acyl, C1-5 acyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 alkylcarboxamide, amino, carbo-C1-6 alkoxy and heteroaryl, each optionally substituted with substituents independently selected from the group, including C1-6 alkyl, C1-5 acyl,

Ci-4 alkoxy, Ci-e alkylamino, Ci-e alkylamino, Ci-e dialkylamino, Ci-4 alkylcarboxamide, Ci-4 alkylsulfonyl, amino, carbo-Ci-6- alkoxy, carboxamide, carboxy, cyano, Ci-e cycloalkyl, halogen, Ci- 4 haloalkoxy, C-1 haloalkyl, hydroxyl and phenyl;

A5, Hb, and C7, each independently selected from the group consisting of H, C3-is acyl, C1-is acyloxy, C8-is alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, Co- alkynyl, C-e alkylsulfonamide, C-e alkylsulfinyl, C-e alkylsulfonyl, C-e alkylthio, C-e alkylureyl, amino, C-e alkylamino, C-e dialkylamino, C-e alkylimino, carbo-C1-6- alkoxy , carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-in dialkylcarboxamide, C1-in dialkylsulfonamide, halogen, C-e haloalkyl, C-e haloalkyl, C-e haloalkylsulfinyl, C-e haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic group, hydroxyl, thiol, nitro, phenoxy and phenyl;

Ag is C1-6 alkyl, C1-6 alkenyl, aryl, C3-7 cycloalkyl or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C1-6 alkenyl . , C1-C dialkylamino, C1-C alkylimino, carbo-C1-6- alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C dialkylcarboxamide, C1-C dialkylsulfonamide, halogen, C1-C1-6-alkyloxy, C1-C1-C1 haloalkyl, Ci-e haloalkylsulfinyl, Ci-e haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic group, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent substituents together with the specified aryl or specified heteroaryl form C5-7 cycloalkyl, which optionally includes 1-2 oxygen atoms and optionally substituted PE, SI or HG; and where indicated Cg is alkenyl, Cg is alkyl, Cg is alkynyl, C1-6 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-e acyloxy, C1-e alkenyl, C1-e alkoxy, C1-6 alkyl, C1-e alkylcarboxamide, C1-e alkynyl, C1-e alkylsulfonamide, C1-e alkylsulfinyl , C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C2 alkylamino, C2 dialkylamino, carbo-C1-alkoxy, carboxamide, carboxy, cyano, C3 cycloalkyl, C2 dialkylcarboxamide, halogen, C-e haloalkyl, C-haloalkyl, C-6 haloalkylsulfinyl, C1-e haloalkylsulfonyl, C-b haloalkylthio, hydroxyl, thiol and nitro; and

B", Vo, and Vi, each independently, represents H or C3-C alkyl; provided that the compound is different from N-(4-oxiranylmethoxy-3-(2H-pyrazol-3-yl)phenyl|acetamide).

One aspect of the present invention encompasses pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention encompasses methods of modulating the activity of the 5-HTgl serotonin receptor by contacting the receptor with a compound according to any of the embodiments of the invention described in this application, or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods of treating 5-HTgda-mediated disorders in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or its pharmaceutical composition.

One aspect of the present invention encompasses methods of treating platelet aggregation in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition thereof. It should be understood that the treatment of platelet aggregation refers to any reduction in platelet aggregation that results in amelioration of the pathophysiological condition associated with platelet aggregation.

One aspect of the present invention encompasses methods of treating one or more conditions associated with platelet aggregation in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the embodiments described herein , or its pharmaceutical composition.

One aspect of the present invention encompasses methods of treating 5-HTα-mediated disorders selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, and atrial fibrillation in a subject comprising administering to the subject, who needs it, a therapeutically effective amount of the compound according to any of the embodiments of the invention described in this application, or its pharmaceutical composition.

One aspect of the present invention encompasses methods of reducing the risk of blood clot formation following angioplasty or coronary artery bypass grafting in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the invention described herein, or its pharmaceutical composition.

One aspect of the present invention encompasses methods of reducing the risk of blood clot formation in a subject suffering from atrial fibrillation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein application, or its pharmaceutical composition.

One aspect of the present invention encompasses methods of treating asthma in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods of treating asthma symptoms in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods of treating anxiety arousal or symptoms thereof in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the invention described herein, or a pharmaceutical composition thereof . In some embodiments of the invention, the subject is a cognitively intact elderly subject.

One aspect of the present invention encompasses methods of treating anxiety agitation or a symptom thereof in a subject suffering from dementia, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the invention described herein , or its pharmaceutical composition. In some embodiments of the invention, dementia is the result of a degenerative disease of the nervous system. In some embodiments, the dementia is Alzheimer's disease with Lewy bodies, Parkinson's disease, or Huntington's disease. In some embodiments of the invention, dementia is the result of diseases affecting blood vessels. In some embodiments, the dementia results from stroke or multi-infarct dementia.

One aspect of the present invention encompasses methods of treating a subject suffering from at least one of the indications selected from the group consisting of behavioral disorders, drug-induced psychosis, excitability psychosis,

Tourette's, manic disorders, organic or MOB psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, and MO5 schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of a dopamine OO" receptor antagonist and a compound of any of variants of the embodiment of the invention described in this application, or its pharmaceutical composition. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods of treating a subject suffering from childhood autism, Huntington's chorea, or chemotherapy-induced nausea and vomiting or chemotherapeutic antibodies, comprising administering to the subject in need thereof a therapeutically effective amount of a dopamine O2 receptor antagonist and a compound of any which of the variants of the embodiment of the invention described in this application, or its pharmaceutical composition. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods of treating schizophrenia in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a dopamine JO2 receptor antagonist and a compound according to any of the embodiments of the invention described herein, or a pharmaceutical formulation thereof compositions.

In some embodiments of the invention, the dopamine Og receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods of treating negative symptoms of schizophrenia caused by the administration of haloperidol to a subject suffering from schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein application, or its pharmaceutical composition. In some embodiments of the invention, the dopamine Y2 receptor antagonist or haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms. In some embodiments, the dopamine O2 receptor antagonist or haloperidol and the compound or pharmaceutical composition are administered in a single dosage form.

One aspect of the present invention encompasses methods of treating a sleep disorder in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition thereof. In some embodiments of the invention, the sleep disorder is dyssomnia. In some embodiments of the invention, dyssomnia is selected from the group that includes psychophysiological insomnia, abnormal sleep state perception, idiopathic insomnia, obstructive sleep apnea syndrome, general sleep apnea syndrome, general alveolar hypoventilation syndrome, periodic limb movement, tired legs syndrome, disorders sleep hygiene, environmental sleep disorder, altitude insomnia, sleep dysregulation, sleep deprivation syndrome, sleep restriction disorder, sleep onset association disorder, nocturnal eating or drinking syndrome, sleep disorders , hypnotic-dependent sleep disorders, stimulant-dependent sleep disorders, alcohol-dependent sleep disorders, toxin-induced sleep disorders, jet lag syndrome (rapid jet lag), transition-related sleep disorders working hours, irregular sleep-wake pattern, delayed sleep phase syndrome, premature sleep phase syndrome and violation of 24 -hourly sleep-wake mode. In some embodiments of the invention, the sleep disorder is a parasomnia. In some embodiments, the parasomnia is selected from the group consisting of disordered awakenings, sleepwalking and sleep terrors, rhythmic movement disorders, sleep tremors, sleep talking, and nocturnal leg cramps. In some embodiments of the invention, the sleep disorder is associated with medical or psychiatric disorders. In some embodiments of the invention, the medical or psychiatric disorder is selected from the group consisting of psychoses, mood disorders, anxiety, panic disorders, alcoholism, cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, narcolepsy, electro-epileptic sleep, headaches during sleep apnea, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, asthma attacks during sleep, gastroesophageal reflux during sleep, peptic ulcer, fibrotic syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia, and sleep disorders after surgery.

One aspect of the present invention encompasses methods of treating diabetes-related disorders in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the embodiments of the invention described herein, or a pharmaceutical formulation thereof compositions. In some embodiments of the invention, the diabetes-related disorder is diabetic peripheral neuropathy. In some embodiments of the invention, the diabetes-related disorder is diabetic nephropathy. In some embodiments of the invention, the diabetes-related disorder is diabetic retinopathy.

One aspect of the present invention encompasses methods of treating progressive multifocal leukoencephalopathy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition thereof. In some embodiments of the invention, the subject in need suffers from a lymphoproliferative disorder. In some embodiments of the invention, the subject in need suffers from carcinomatosis. In some embodiments of the invention, the subject in need is immunocompromised. In some embodiments of the invention, the subject in need is HIV-infected.

In some embodiments of the invention, the HIV-infected subject has a number of CO4- cells equal to x 200/mm3. In some embodiments of the invention, the HIV-infected subject has AIDS. In some embodiments of the invention

An HIV-infected subject has the AIDS complex (ACS). In some embodiments, the subject in need thereof receives a course of immunosuppressive therapy. In some embodiments of the invention, the subject who needs it undergoes a course of immunosuppressive therapy after organ transplantation.

One aspect of the present invention encompasses methods of treating hypertension in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods of treating pain in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition thereof.

One aspect of the present invention encompasses methods of preparing a composition comprising mixing a compound according to any of the embodiments of the invention described herein with a pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound of the present invention for the preparation of a medicament for use in the treatment of 5-HTα-mediated disorders.

One embodiment of this invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTga-mediated disorders, where the disorder is platelet aggregation.

One variant of the embodiment of this invention is the use of the compound to obtain a medicinal product for use in the treatment of one or more conditions associated with platelet aggregation.

One embodiment of the present invention is the use of a compound for the preparation of a medicament for use in the treatment of 5-HTGDL-mediated disorders, wherein the disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, and atrial fibrillation. .

One embodiment of the present invention is the use of the compound for the preparation of a drug for use in the treatment of 5-HTgda-mediated disorders, where the disorder is the formation of a blood clot during angioplasty or coronary bypass surgery in a subject.

One embodiment of this invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTgda-mediated disorders, where the disorder is the formation of a blood clot in a subject suffering from atrial fibrillation.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the treatment of a sleep disorder such as the above.

One variant of the embodiment of this invention is the use of the compound to obtain a medicinal product for use in the treatment of dyssomnia.

One variant of the embodiment of this invention is the use of the compound to obtain a medicinal product for use in the treatment of parasomnias.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the treatment of diabetes-related disorders.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTGDL-mediated disorders, where the disorder is asthma.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTGDL-mediated disorders, where the disorder is a symptom of asthma.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, where the disorder is an anxiety disorder or a symptom thereof in a subject. In some embodiments, the subject is a cognitively intact elderly subject.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, where the disorder is anxiety agitation or a symptom thereof in a subject suffering from dementia. In some embodiments of the invention, dementia is the result of a degenerative disease of the nervous system. In some embodiments, the dementia is Alzheimer's disease with Lewy bodies, Parkinson's disease, or

Huntington. In some embodiments of the invention, dementia is the result of diseases affecting blood vessels. In some embodiments, the dementia is the result of stroke or multi-infarct dementia.

One embodiment of the present invention is the use of a compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, in addition to including a dopamine O2 receptor antagonist, where the disorder is selected from the group consisting of behavioral disorders, drug-induced psychosis, psychosis excitability, Tourette syndrome, manic disorders, organic or MOB psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia and MO5 schizophrenia. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, other than those involving a dopamine O2 receptor antagonist, where the disorder is childhood autism, Huntington's chorea, or chemotherapy-induced nausea and vomiting. or chemotherapeutic antibodies. In some embodiments, the invention is a dopamine antagonist

Or" of the receptor is haloperidol.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTga-mediated disorders, other than those involving a dopamine Y receptor antagonist, where the disorder is schizophrenia. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTHD-mediated disorders, where the disorder is a negative symptom or symptoms of schizophrenia caused by the administration of haloperidol.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTgda-mediated disorders, where haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTgda-mediated disorders, where haloperidol and the compound or pharmaceutical composition are administered in a single dosage form.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, where the disorder is progressive multifocal leukoencephalopathy.

One variant of the embodiment of this invention is the use of the compound to obtain a medicinal product for use in the treatment of hypertension.

One variant of the embodiment of this invention is the use of the compound to obtain a medicinal product for use in the treatment of pain.

One aspect of the present invention relates to compounds according to any of the embodiments of the invention described herein for use in a method of treating a human or animal by therapy.

One aspect of the present invention relates to compounds according to any of the embodiments of the invention described herein for use in a method of treating 5-HTga-mediated disorders described herein in a human or animal by therapy.

One aspect of the present invention relates to compounds according to any of the embodiments described herein for use in a method of treating a sleep disorder described herein in a human or animal by therapy.

One aspect of the present invention relates to compounds according to any of the embodiments of the invention described herein for use in a method of treating platelet aggregation in a human or animal by therapy.

One aspect of the present invention relates to compounds according to any of the embodiments of the invention described herein for use in a method of treating one or more conditions associated with platelet aggregation in a human or animal by therapy.

One aspect of the present invention relates to compounds according to any of the embodiments of the invention described herein for use in a method of treating progressive multifocal leukoencephalopathy in a human or animal by therapy.

One aspect of the present invention relates to compounds according to any of the embodiments described herein for use in a method of therapeutically treating hypertension in a human or animal.

One aspect of the present invention relates to compounds according to any of the embodiments described herein for use in a method of therapeutically treating pain in a human or animal.

These and other aspects of the present invention disclosed in this application are described in more detail below.

Fig. 1 presents a general synthesis scheme for obtaining intermediate compounds according to the present invention. Figure 1 shows a general method of combining pyrazoleboronic acid and aryl triflate, it should be understood that similar methods of combination known in the art can also be used, and a halogen compound such as I, Bg or CI can be used instead of the triflate.

Fig. 2 presents a general synthesis scheme for obtaining intermediate compounds according to the present invention, where "U" represents oxygen. Fig. 2 shows a general method of combining pyrazoleboronic acid and phenyl halide using methods of combination known from the state of the art, such as the combination reaction

Suzuki, etc. Figure 2 also shows the use of orthogonal protecting groups for oxygen (M-O) and nitrogen.

After the coupling reaction, the phenol protecting group is removed, and various -M/-Ba groups can be introduced. The alkylamide protecting group can then be hydrolyzed to give the amine intermediate of the present invention.

Fig. 3 presents a general synthesis scheme for obtaining intermediate compounds according to the present invention. Figure 3 shows a general method of combining 2-substituted pyrazole-3-ylboronic acid and an aryl triflate, it should be understood that similar methods of combination known in the art can also be used, and a halogen compound such as I, H or C , can be used instead of triflate.

Fig. A4 presents a general synthesis scheme for obtaining intermediate compounds according to the present invention. Figure 4 shows the general reaction of hydrazines with substituted chromen-4-ones to obtain some 2-(pyrazol-3-yl)phenols. In addition, Fig. 4 presents general alkylation reactions for the introduction of the M/-Ba group.

Fig. 5 presents a general synthesis scheme for obtaining intermediate compounds according to the present invention. Figure 5 illustrates general methods of introducing various halogens into the compounds of the present invention. It should be understood that these halogenation reactions can also be carried out at subsequent stages of the synthesis, for example, as a final stage.

Fig. b6 represents a general synthesis scheme for obtaining intermediate compounds according to the present invention. Figure b shows general reactions such as alkylation reactions and Mitsunobu-type reactions for the introduction of the M/-Ba group.

Fig. 7 presents a general synthesis scheme for obtaining compounds according to the present invention. Fig. 7 shows the general reaction of the combination of an aniline intermediate with various electrophiles, such as carboxylic acids, acyl halides, isocyanates, isothiocyanates, haloformates, etc.

Fig. 8 presents a general synthesis scheme for obtaining intermediate compounds and compounds according to the present invention.

Fig.9 represents the general reaction for obtaining diarylamines and heteroaryl-arylamines. Figure 9 shows the combination of an aniline intermediate with a heteroarylhalogen compound or an arylhalogen compound to produce diarylamines and heteroaryl-arylamines according to the present invention.

Fig. 10 represents a general synthesis scheme for obtaining compounds according to the present invention, where the M/-Ba group is introduced at the last stage(s). Figure 10 shows general reactions such as alkylation reactions and Mitsunobu-type reactions for the introduction of M/-Na groups.

Fig. 11 presents a general synthesis scheme for obtaining compounds according to the present invention, where M is 5 or Mo, and the M/-Ba4 group is introduced at the last stage(s). Figure 11 shows general reactions, such as alkylation reactions, for the introduction of M/-Na groups, where M is 5 or ME-O.

Fig. 12 represents a general synthesis scheme for obtaining compounds according to the present invention, where M is 5(O) or 5(O)".

Definition

In the scientific and technical literature that deals in any way with receptors, different terms are used to refer to ligands that have different effects on the receptors. For clarity and consistency, the following definitions are used throughout this patent document.

Agonists mean groups that interact with and activate a receptor, such as the 5-HTgld receptor, and initiate a physiological or pharmacological response typical of that receptor. For example, when groups activate an intracellular response when binding to a receptor or enhance binding of STRs to membranes.

The term antagonists refers to groups 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 may thus inhibit intracellular responses, caused by agonists or partial agonists. Antagonists do not reduce the baseline intracellular response in the absence of agonist or partial agonist.

Chemical group, fragment or radical:

The term "C 1 acyl" means a C 1 -alkyl radical attached to a carbonyl, wherein alkyl has the meaning defined 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 "C1-12 acdcyloxy" means an acyl radical attached to an oxygen atom, where acyl has the meaning defined herein; in some embodiments of the invention acyloxy is C-11 acyloxy, in some embodiments of the invention acyloxy is C-10 acyloxy, in some embodiments of the invention acyloxy is C-1 acyloxy, in some embodiments of the invention acyloxy is C-6 acyloxy, in some embodiments of the invention acyloxy is C-5 acyloxy, in some embodiments of the invention acyloxy is C-4 acyloxy, in some embodiments of the invention acyloxy is Cio-2 acyloxy, in some embodiments of the invention acyloxy is Sv -o acyloxy. Some examples include, but are not limited to, acetyloxy, propionyloxy, butanoyloxy, isobutanoyloxy, sec-butanoyloxy, tert-butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanyloxy, undecanoyloxy, dodecanoyloxy, tridecanoyloxy, and the like.

The term "Cg-v alkenyl" means a radical containing 2-6 carbon atoms, where at least one carbon-carbon double bond is present, in some embodiments 2-4 carbon atoms, in some embodiments 2-3 atoms of carbon, and some variants contain 2 carbon atoms. The term "alkenyl" covers both E and 7 isomers. Moreover, the term "alkenyl" includes di- and tri-alkenyl. Accordingly, if more than one double bond is present, then all bonds may be E or 7 or mixtures of E and 7. Examples of alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl, etc.

The term "C 1-6 alkoxy" as used herein means an alkyl radical, as defined herein, attached directly to an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, and the like.

The term "Ci-e alkoxycarbonylamino" means a group represented by the formula: sioyannn to (c) where Ci-alkyl has the meaning defined in this application. Examples of C 1 -Alkoxycarbonylamino include methoxycarbonylamino, ethoxycarbonylamino, isopropoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino, butoxycarbonylamino, and the like.

The term "C 1-6 alkyl" means a linear or branched carbon radical containing from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, in some embodiments from 1 to 3 carbon atoms, and in some embodiments 1 or 2 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo-pentyl, 1-methylbutyl ie -

СснН(СН3)СнН.НеснН with, 2-methylbutyl (i.e. -"СНгСН(СН3)СНесСнН and, 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 is as defined herein. C1i-e alkylcarboxamido can be represented by the following formulas: ) o au ut shi bo, -v alkyl

Nn N

Examples include, but are not limited to, M-methylcarboxamide, M-ethylcarboxamide, /M-M-propylcarboxamide, M-iIsopropylcarboxamide, M-M-butylcarboxamide, M-tert-butylcarboxamide, M-isobutylcarboxamide, M-tert-butylcarboxamide, etc. .p.

The term "Ci-4 alkylene" refers to a C1-4 divalent linear carbon group containing from 1 to 4 carbon atoms, in some embodiments from 1 to 3 carbon atoms, in some embodiments from 1 to 2 carbon atoms. In some embodiments, alkylene means, for example, -СНео-, -СНаСНео-, -СНаСНоСНе-, -

SnNsSnNNesnNe-, 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 meaning defined in this application. 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-6 alkylsulfonamide" refers to the groups presented below: chuk Ky and zu db alkyl Mov alkyl nn n n where Ci-v alkyl has the meaning defined in this application.

The term "C 1 -C alkylsulfonyl" means a C 1 -alkyl radical attached to a sulfonic radical of the formula: -5(0)2-, where the alkyl radical has the meaning defined in this application. 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-C6 alkylthio" means a C1-6 alkyl radical attached to a sulfide of the formula: -5-, where alkyl radical is as defined herein Examples include, but are not limited to, methylsulfanyl (ie, CH35-), ethylsulfanyl, n-propylsulfanil, isopropylsulfanil, n-butylsulfanil, sec-butylsulfanil, isobutylsulfanil, tert-butylsulfanil, etc.

The term "Ci-e alkylthiocarboxamide" means a thioamide having the following formulas: 5 pu srlbnentn boron alkyl where Ci-4" alkyl has the meaning defined in this application.

The term "Ci-e alkylureyl" means a group of the formula: -MS(O)M-, where one or both nitrogen atoms are replaced by the same or different Ci-e alkyl groups, where alkyl has the meaning defined in this application. Examples of alkyl ureas include, but are not limited to, CH3MnHCe(O)MH-, MHgC(OMCH3-, (Snag4Me(omnH-, (CH325-MOe(O)MH-, (CH3)g2/MS(O)MeH3-, SnzaSnaMne ()mMn-, SNzaSnNaMnOe(OMeNz-, etc.

The term "C2-b alkynyl" means a radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, in some embodiments 2-4 carbon atoms, in some embodiments 2-3 carbon atoms , and some variants contain 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 tri-ynes.

The term "amino" means the group -MH".

The term "C 1-6 alkylamino" means one alkyl radical attached to an amino radical, wherein the alkyl radical is as defined herein. Some examples include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, t-butylamino, isobutylamino, tert-butylamino, and the like. In some embodiments, "Ci-2 alkylamino".

The term "aryl" means an aromatic ring radical containing from 6 to 10 ring carbon atoms.

Examples include phenyl and naphthyl.

The term "arylalkyl" means a C1i-C4 alkylene such as -CHe-, -CHNaCHnoe-, etc., which, in addition, is substituted with an aryl group. Examples of "arylalkyl" include benzyl, phenethylene, and the like.

The term "arylcarboxamido" means one aryl group attached to the nitrogen of the amide group, where aryl is as defined herein. An example is M-phenylcarboxamide.

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

The term "benzyl" means the group -"СНеСеНв5".

The term "bicyclic" refers to two C4-7 cycloalkyl groups with two ring carbon atoms in common, thus forming either a fused or bridged ring. Examples of bicyclic groups include, but are not limited to, bicyclo(1.1.1|Ipentyl, bicyclo[2.1.1Ihexyl, bicyclo(2.2.1|)heptyl, bicyclo(|2.2.2|octyl, bicyclo[3.1.1|heptyl, bicycloi|3.2.1|octyl, etc.

The term "carbo-Ci-C-Alkoxy" refers to a C-C-C alkyl ester of a carboxylic acid, wherein the alkyl group has the meaning defined herein. Examples include, but are not limited to, carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbo-t-butoxy, carbo-isobutoxy, carbo-tert-butoxy, carbo-M-pentoxy, carbo-isopentoxy, carbo-tert-pentoxy, carbo-neo-pentoxy, carbo-M-hexyloxy, etc.

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

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

The term "cyano" means the -CM group.

The term "C4-7 cycloalkenyl" means a non-aromatic ring radical containing from 4 to 7 ring carbon atoms and at least one double bond; some variants contain from 4 to 6 carbon atoms; some variants contain 4 to 5 carbon atoms; some variants contain 4 carbon atoms. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

The term "C3-7 cycloalkyl" means a saturated ring radical containing from 3 to 7 carbon atoms; some variants contain from 3 to 6 carbon atoms; some variants contain from 3 to 5 carbon atoms; some variants contain from 5 to 7 carbon atoms; some variants contain from 3 to 4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "C3-7 cycloalkylcarbonyl" means a C3-7 cycloalkyl group described in this application bonded to a carbon of a carbonyl group (ie, -C(-0)-). Examples of the C3-7 cycloalkylcarbonyl group include, but are not limited to, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and the like.

The term "C3-e cycloalkylene" refers to a divalent cycloalkyl radical, wherein cycloalkyl is as defined herein, containing from 3 to 6 carbon atoms; some embodiments contain from 3 to 5 carbon atoms; some embodiments contain from 3 to 4 carbon atoms In some variants of the embodiment of the invention, the C3-6 cycloalkylene group contains two linking groups on the same ring carbon atom, for example: 1,1-cyclopropyl

In some embodiments of the invention, the C3 cycloalkylene group contains two linking groups on different ring carbon atoms. It should be understood that when two C3-e cycloalkylene groups are located on different ring carbon atoms, they may be cis or trans or a mixture thereof relative to one another.

The term "C1-C dialkylamino" means an amino substituted by two identical or different C1-4 alkyl radicals, where the alkyl radical has the meaning defined in this application. Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino, and the like. In some embodiments, "Sg.4" is dialkylamino.

The term "C 1-8 dialkylcarboxamido" or "C 1-8 dialkylcarboxamide" means two alkyl radicals, which are the same or different from each other, attached to an amide group, where alkyl has the meaning defined herein. C 1-8 dialkylcarboxamido may be represented by by the following groups: (F) (9) pu o ulocant and alkyl

Si dalkyl Si.dalkyl de Sil has the meaning defined in this application. Examples of 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 "C2-C dialkylsulfonamide" refers to one of the following groups:

WOULD 5 FOR

Ka we 1-4alkyl go to Sta alkyl

Cdalkyl Cdalkyl where C-4 has the meaning defined in this application, for example, but not limited to, methyl, ethyl, n-

propyl, isopropyl, etc.

The term "C 1-6 dialkylthiocarboxamido" or "C 1-6 dialkylthiocarboxamide" means two alkyl radicals, which are the same or different from each other, attached to a thioamide group, where alkyl is as defined herein. C2-in dialkylthiocarboxamido or C2-in dialkylthiocarboxamide can be represented by the following groups:

C. dalkyl Si-"alkyl

Examples of dialkylthiocarboxamide include, but are not limited to, M,M-dimethylthiocarboxamide, M-methyl-M-ethylthiocarboxamide, and the like.

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

The term "C 1-6 haloalkyl" means C 1-6 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 "C 1-6 haloalkyl" means a C 1-6 alkyl group as defined herein, wherein the alkyl is substituted by one halogen to fully substituted, and the fully substituted C 1-6 haloalkyl may be represented by the formula Spi gpy, where I is a halogen and " n" has the value 1, 2, 3, 4, 5 or 6; when more than one halogen is present, then they may be the same or different from each other, and may be selected from the group consisting of E, CI, Bg and I, preferably PE. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

The term "Ci-C haloalkylcarboxamide" means a C-C alkylcarboxamide group, as defined in this application, where alkyl is substituted by one halogen to fully substituted, represented by the formula Spi, where Y is halogen and "n" has the value 1, 2, 3, 4, 5 or 6. When more than one halogen is present, then they can be the same or different from each other, and can be selected from the group consisting of BE, SI, Bg 1, preferably P.

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

The term "C 1-6 haloalkylthio" means a C 1-6 haloalkyl radical directly attached to sulfur, wherein haloalkyl has the meaning defined herein. Examples include, but are not limited to, trifluoromethylthio (ie, CE35-, also called trifluoromethylsulfanyl), 1,1-difluoroethylthio, 2,2,2-trifluoroethylthio, and the like. The term "halogen" or "halo" means a fluorine, chlorine, bromine or iodine group.

The term "heteroaryl" means an aromatic ring system, which may be one ring, two fused rings, or three fused rings, wherein at least one ring carbon atom is replaced by a heteroatom selected from, but not limited to, the group consisting of 0, 5 and M, where M can optionally be replaced by H, C-4 acyl or C-4 alkyl. Examples of heteroaryl groups include, but are not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and the like. In some embodiments, the heteroatom is selected from, but not limited to, the group consisting of O, IM, where M is substituted with H (ie, MH), examples include, but are not limited to, pyrrolyl, indolyl, 1H-benzoimidazole-2 - mud, etc. Other examples include, but are not limited to, the compounds listed in Table 1, Table 2, etc.

The term "teterobicyclic" means a non-aromatic bicyclic ring as described herein wherein 1, 2, or C ring carbon atoms are replaced by a heteroatom selected from, but not limited to, consisting of

О, 5, 5(-0), 5(-0)", and MH, where nitrogen may optionally be substituted, and 1 or 2 ring carbon atoms may optionally be substituted by oxo or thiooxo, thus forming together a carbonyl or thiocarbonyl group, respectively. Examples of the heterobicyclic group include, but are not limited to, 2,5-diazabicyclo(2.2.1|hept-2-yl, 7-azabicyclo(2.2.1|hept-7-yl, etc.

The term "heterocyclic" means a non-aromatic carbon ring (ie, C3-7 cycloalkyl or Ca4-7 cycloalkenyl as defined herein) wherein one, two, or three ring carbon atoms are replaced by a heteroatom selected from, but not limited to, consisting of O , 5, 5(50), 5(50)2, МН, where M, optionally, can be substituted as described in this application, in some embodiments of the invention, nitrogen is optionally substituted by C-4 acyl or Si. 4 alkyl, and the ring carbon atoms are optionally substituted with oxo or thiooxo, thus forming a carbonyl or thiocarbonyl group. The heterocyclic group can be attached/bonded to any available ring atom, for example, a ring carbon atom, a ring nitrogen atom, etc. A heterocyclic group is a 3-, 4-, 5-, 6-, or 7-membered ring. Examples of a heterocyclic group include, but are not limited to, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-2- yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-Z-yl, morpholin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-Z-yl, piperazin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, (1,3|-dioxolan-2-yl, thiomorpholin-4-yl, (|1,4|oxazepan- 4-yl, 1,1-dioxo-1/6-thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, etc.

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

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

As it is used in this application, the term "oxo" refers to the substituent -O, respectively, when the carbon is replaced by an oxo group, the new group formed by the carbon together with the oxo is a carbonyl group.

The term "phenoxy" refers to the group SeHzO-.

The term "phenyl" refers to the group SviH5-.

The term "sulfonic acid" refers to the -5OZN group.

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

A composition means a substance that contains at least two compounds or two components; for example, and without limitation, a pharmaceutical composition is a composition containing a compound of the present invention and a pharmaceutically acceptable carrier.

Contact or contacting means bringing these fragments into contact, either in the ip mio system or in the ip mimo system. Thus, "contacting" a 5-HT1 receptor with a compound of the present invention includes administering a compound of the present invention to a subject, preferably a human, having a 5-HT1 receptor, as well as, for example, administering a compound of the present invention to a sample containing cellular or more purified drug containing 5-HTα receptor.

In need of treatment, as used herein, refers to the judgment of an observer (e.g., physician, nurse practitioner, nurse practitioner, etc., in the case of a human; veterinarian, in the case of an animal, including mammals, exceptional from a human) that the subject or animal needs treatment or will benefit from treatment. Such judgment is based on various factors that are within the expert knowledge of the observer, but which include the understanding that the subject or animal is, or will be, diseased as a result of a disease, condition, or disorder treatable by the compound this invention. Accordingly, the compounds of the present invention can be used as protective or prophylactic agents; or compounds of the present invention can be used to ameliorate, inhibit or reduce the severity of a disease, condition or disorder.

Subject, as used herein, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans .

Inhibit or inhibition, as used in the term "response", means that the response is reduced or prevented in the presence of the compound as compared to that which occurs in the absence of the compound.

Inverse agonists mean fragments that bind to the endogenous form of the receptor or to the constitutively activated form of the receptor and that inhibit the basal intracellular response initiated by the active form of the receptor below the normal basal activity level observed in the absence of agonists or partial agonists, or reduce the binding of STR with membranes. Preferably, the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 3095, more preferably by at least 5095, and most preferably by at least 7595, compared to the baseline response in the absence of the inverse agonist.

As used herein, the terms MODULATE or THAT MODULATE mean an increase or decrease in the amount, quality, response, or effect of a particular activity, function, or molecule.

Pharmaceutical composition means a composition that includes at least one active ingredient; including, but not limited to, salts, solvates and hydrates of compounds of formula (Ia); thus, the composition is suitable for studies of a defined effective outcome in a mammal (eg, without limitation, a human). Techniques suitable for determining whether an active ingredient provides the desired effective result sought by the skilled artisan should be readily apparent to those of ordinary skill in the art.

A therapeutically effective amount, as the term is used herein, refers to the amount of an active compound or pharmaceutical agent that produces a biological or medical response in a tissue, system, animal, subject, or human being that a researcher, veterinarian, physician, or other person seeks to achieve. clinician, including one or more of the following: (1) Disease prevention; for example, the prevention of a disease, condition or disorder in a subject who may be susceptible to the disease, condition or disorder but who does not experience or exhibit the pathology or symptomatology of that disease, (2) Inhibition of the disease; for example, inhibiting a disease, condition, or disorder in a subject experiencing or exhibiting the pathology or symptomatology of that disease, condition, or disorder (ie, stopping further development of the pathology and/or symptomatology), and (3) Attenuating the disease; for example, amelioration of a disease, condition or disorder in a subject who experiences or exhibits the pathology or symptomatology of that disease, condition or disorder (ie, reversal of the pathology and/or symptomatology).

Compounds according to this invention:

One aspect of the present invention covers certain 3-phenylpyrazole derivatives represented by formula (Ia):

Kv M 7 Xx vo (Ia) ve Zu7 tv C ih te and Kz Ro or their pharmaceutically acceptable salts, hydrates or solvates; where Ki, РН», Nz, Ba, H5, Nv, B7, Nv, Vo, M, M, X, M and 27 have the values defined in this application, above and below, provided that the compound is not M-I4 -oxiranylmethoxy-3-(2H-pyrazol-3-yl)/uphenylacetamide:

then (c) about n

AJ M

M M

H X /

In some embodiments, the present invention relates to the compounds of formula (Ia) described in this application, or their pharmaceutically acceptable salts, hydrates, solvates or M-oxides.

In some embodiments, the present invention relates to compounds where the Ka group contains an M-oxide.

In some embodiments, the present invention relates to some C-phenylpyrazole derivatives represented by formula (Ia): or their pharmaceutically acceptable salts; where:

M represents O, 5, 5(50), 5(2O)" or MECHO;

MU is a Ci-4 alkylene optionally substituted with 1-8 substituents independently selected from the group consisting of Ci-3 alkyl, Ci-4 alkyl, carboxy, cyano, Ci-3 haloalkyl, halogen and oxo; or M/ absent;

X is C(:O), C(-5) or absent;

M represents 0, ME or absent; 7 represents C-4 alkylene, optionally substituted with 1-8 substituents independently selected from the group consisting of C-3 alkyl, C-4 alkyl, carboxy, cyano, C-3 haloalkyl, halogen and oxo; or 727 is missing;

B is selected from the group consisting of H, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl and C3-7 cycloalkyl;

AB2 is selected from the group consisting of H, C1-C acyl, C1-C acyloxy, C1-C alkenyl, C1-C alkoxy, C1-C alkyl, C1-C alkylcarboxamide, C1-C alkynyl, C1-C alkylsulfonamide, C1-C alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-c dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2- in dialkylcarboxamide, C1-c dialkylsulfonamide, halogen, C1-e haloalkyl, C1-e haloalkyl, C1-e haloalkylsulfinyl, C1-e haloalkylsulfonyl, C1-e haloalkylthio, hydroxyl, thiol, nitro and sulfonamide;

Az 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, C1-C dialkylcarboxamide, halogen, heteroaryl and phenyl; and where each of the Cov alkenyl, Ci-e alkyl, Co2-v alkynyl, Ci-6 alkylsulfonamide, C3-7 cycloalkyl, heteroaryl and phenyl groups is optionally substituted with 1-5 substituents independently selected from the group consisting of Ci1- 5 acyl, C-5 acyloxy, C2-e alkenyl, C-4 alkoxy, C1-8 alkyl, C- alkylamino, C2-z dialkylamino, C1-4 alkylcarboxamide, C-alkynyl, C-4 alkylsulfonamide, C-4 alkylsulfinyl . 4 haloalkyl, C1-4 haloalkylsulfinyl, C1-4 haloalkylsulfonyl, C1-4 haloalkylthio, hydroxyl, nitro and sulfonamide;

Aha is a heterocyclic or heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of C1-e acyl, C1-2 acyloxy, C1-e alkenyl, C1-4 alkoxy, C1-6 alkyl, C1-6 alkylamino, C-4 dialkylamino, C-4" alkylcarboxamide, C-4 alkynyl, C-4 alkylsulfonamide, C-4 alkylsulfinyl, C-4 alkylsulfonyl, C-4 alkylthio, C-4 alkylureyl, amino, carbo-C1i-- alkoxy, carboxamide, carboxy, cyano, C3-6 cycloalkyl, C3-e dialkylcarboxamide, halogen, C-4 haloalkyl, C-4 haloalkyl, C-4 haloalkylsulfinyl,

C-1 haloalkylsulfonyl, C-4 haloalkylthio, hydroxyl, nitro and sulfonamide; wherein C1-6 acyl, C1-5 acyloxy, C1-6 alkyl, C1-4 alkylcarboxamide, and carbo-C1-6-alkyloxy are each optionally substituted with substituents independently selected from the group consisting of C3-5 acyl, C1-6 -4 alkoxy, C-4 alkylamino, C-4 dialkylamino, C-4 alkylcarboxamide,

Ci-4 alkylsulfonyl, amino, carbo-Ci-4-alkoxy, carboxamide, carboxy, cyano, C3-i cycloalkyl, halogen, Ci-4 haloalkyl, Ci-4 haloalkyl, hydroxyl and phenyl;

A5, Hb, and K7, each independently selected from the group consisting of H, C1-e acyl, C1-e acyloxy, C1-e alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-e alkylcarboxamide, Co- alkynyl, C-e alkylsulfonamide, C-e alkylsulfinyl, C-e alkylsulfonyl, C-e alkylthio, C-e alkylureyl, amino, C-e alkylamino, C-e dialkylamino, C-e alkylimino, carbo-C1-6- alkoxy , carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-in dialkylcarboxamide, C1-in dialkylsulfonamide, halogen, C-e haloalkyl, C-e haloalkyl, C-e haloalkylsulfinyl, C-e haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic group, hydroxyl, thiol, nitro, phenoxy and phenyl;

Ag is C3-C alkyl, C0-C alkenyl, aryl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-C acyl, C1-C acyloxy, C1-C6 alkenyl, C1-C6 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, C2-6 dialkylamino, Ci-e alkylimino, carbo-Ci-c-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, Cg-c dialkylcarboxamide, Cg-z dialkylsulfonamide, halogen, Ci-e haloalkoxy, C1-6 haloalkyl, C1i- is haloalkylsulfinyl, C-e haloalkylsulfonyl, C-e haloalkylthio, heterocyclic group, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent substituents together with aryl or heteroaryl form C-7 cycloalkyl, which optionally includes from 1 to 2 of oxygen atoms, which is optionally substituted by RE,

Si or Vg; and where C 1 -alkenyl, C 1 -alkyl, C 1 -alkynyl, C 1 -alkylamino, C 1 -alkylimino, C 2 -dialkylamino, a heterocyclic group and phenyl are each optionally substituted with 1-5 substituents independently selected from the group consisting of C3-c acyl, C1-e acyloxy, C1-e alkenyl, C1-e alkoxy, C1-e alkyl, C1-e alkylcarboxamide, C1-6 alkynyl, C1-6 alkylsulfonamide, C1-e alkylsulfinyl, C1-e alkylsulfonyl, C-is alkylthio, C1i-is alkylureyl, amino, C-is alkylamino,

C2-C dialkylamino, carbo-C1-E-Alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-C dialkylcarboxamide, halogen, C1-E haloalkyl, C1-E haloalkyl, C1-E haloalkylsulfinyl, C1-E haloalkylsulfonyl , C1-6 haloalkylthio, hydroxyl, thiol and nitro; and

B", Vo, and Vi, each independently, represents H or C3-C alkyl;

provided that the compound is different from N-(4-oxiranylmethoxy-3-(2H-pyrazol-3-yl)uphenyl|acetamide).

It should be understood that some features of the present invention, which, for clarity, are described in the context of individual embodiments of the invention, may also be presented in combination in one embodiment. | conversely, the various features of the present invention, which, for the sake of brevity, are described in the context of one embodiment of the invention, may also be presented individually or in any suitable subcombination. All combinations of variants of the embodiment of the invention relating to chemical groups represented by variables (for example, Ki, P", Az, Ba, X, Y, 2, etc.) falling under the general chemical formulas described in this application (for example (Ia), (Ic), (Ie), etc., are specifically encompassed by the present invention as if they had been fully disclosed, to the extent that such combinations encompass compounds that yield stable compounds (i.e., compounds that can be isolated, identified, and tested for biological activity.) Furthermore, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of the uses and medical indications described herein, are also specifically encompassed by the present invention, as if each of such subcombinations of chemical groups and subcombinations of uses and medical indications were fully disclosed herein.

As used herein, "substituted" indicates that at least one hydrogen atom of a chemical group is replaced by a non-hydrogen substituent or group, wherein said non-hydrogen substituent or group may be monovalent or divalent. When a substituent or group is divalent, then it should be understood that this group is additionally substituted by another substituent or group. When a chemical group in this application is "substituted", it may be fully substituted in valency; for example, a methyl group can be substituted with 1, 2 or C substituents, a methylene group can be substituted with 1 or 2 substituents, a phenyl group can be substituted with 1, 2, 3, 4 or 5 substituents, a naphthyl group can be substituted with 1, 2, 3 , 4, 5, 6 or 7 substituents, etc. Similarly, "substituted with one or more substituents" refers to the substitution of a group with from one to the total number of substituents physically possible for a given group. Also, when a group is substituted by more than one group, these groups may be the same or different from each other.

The compounds of the present invention may also include tautomeric forms such as keto-enol tautomers and the like. The tautomeric forms may be in equilibrium or may be spatially locked into one form by suitable substitution. It should be understood that various tautomeric forms are encompassed by the compounds of the present invention.

The compounds of the present invention may also include all isotopes of atoms present in intermediate compounds 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 obvious that the compounds of the present invention may have one or more chiral centers and therefore may exist as enantiomers and/or diastereomers. It is understood that the invention extends to and encompasses all such enantiomers, diastereomers and mixtures thereof, including, but not limited to, racemates. Accordingly, some embodiments of the present invention relate to the compounds of the present invention, which are E enantiomers. In addition, some embodiments of the present invention relate to the compounds of the present invention, which are 5 enantiomers. In examples where more than one chiral center is present, some embodiments of the present invention include compounds that are 5 or 5E enantiomers. In other embodiments of the present invention, the compounds of the present invention are EE or 55 enantiomers. It is to be understood that the compounds of the present invention are intended to represent all possible individual enantiomers and mixtures thereof, as if each were individually named with its structure, unless otherwise indicated or shown.

Some embodiments of the present invention include some 3-phenylpyrazole derivatives represented by the following formula (Ic):

IN

In m 7

Rv U vi rylo M (is)

VE X M X M

AND

Ka Kk;

Kz g

Some embodiments of the present invention include some 3-phenylpyrazole derivatives represented by the formula (is):

IN.

After all,

Ve M vit 2 AB (Ie)

Kv Kk; --

Kz o

se)

In some embodiments, M is 0.

Some embodiments of the present invention include some 3-phenylpyrazole derivatives represented by formula (Id):

ra

University of

Ev oh v, also ov)

VE tuh "M in M

AND

Co

Ez ho where each variable in the formula (Id) has the value defined in this application, above and below.

In some embodiments of the invention, M/ is C3-4 alkylene, optionally substituted oxo.

In some variants of the embodiment of the invention, UM is -СНе-, -СНаСНе-, -СН2б(-0)-, -СНаСНеоСнН»-, -

С(СН3)»с(-0)-, -СНСН(СнН3)-, -СН(СН3)СНе-, -С(СН3)265СНе- or -СНоС(СнН3)2-.

In some variants of the embodiment of the invention, M/ represents -СНе-, -СНаСНе-, -"СН2С(-0)-" or -"СНаСНоСН"-.

In some variants of the embodiment of the invention, M represents -СН2СНео-.

In some variants of the embodiment of the invention, the MU is absent.

In some embodiments of the invention, X is C(:0).

In some variants of the embodiment of the invention X is absent.

In some embodiments of the invention, Y is MH, O or absent.

In some embodiments of the invention, U represents MH or is absent.

In some variants of the embodiment of the invention, U is MH.

In some embodiments of the invention, U is 0.

In some variants of the embodiment of the invention, U is absent.

In some embodiments of the invention, 7 is C1-4 alkylene or C3-e cycloalkylene, optionally substituted with 1, 2, C or 4 substituents independently selected from the group consisting of C'-C alkyl, halogen and oxo.

In some variants of the embodiment of the invention, 7 is absent, or is -СНе-, -СН(ОН)-, Сгг-, -С(СН3)2-, 1,1- cyclopropyl, СНаСНе-, -СНа.СНоСнНе-, - СН(СНЗ3)- or -С(-0)-.

In some variants of the embodiment of the invention, 72 is absent or is -CH2- or -CH(OH)-.

In some variants of the embodiment of the invention, 2 is absent or is -CHnoeo-.

In some variants of the embodiment of the invention, 2 is absent.

In some embodiments of the invention, Ki is C 1 -alkyl.

In some embodiments of the invention, Ki is -CH3.

In some variants of the embodiment of the invention, Ki is N.

It should be understood that when Ki is H, then tautomers are possible. It is well known and understood in the art that pyrazoles can exist in various tautomeric forms. Two possible tautomeric forms are illustrated below: "In "Ka

V y Av U v M Ve MN --- 1

That's what Ke b vo ho o a"

It should also be understood that the tautomeric forms may also have an appropriate nomenclature for each tautomer represented, for example the pyrazole-3-yl groups in formula (II) and formula (II) may be represented by the general chemical names 1H-pyrazole-3-yl and 2H-pyrazol-3-yl, respectively. Therefore, the present invention includes all tautomers and various nomenclature names.

In some variants of the embodiment of the invention, Kg is H.

In some embodiments of the invention, Kz is H or halogen.

In some embodiments of the invention, Kz is H, E, Si or HG.

In some variants of the embodiment of the invention, Kz is H, SI or Hg.

In some variants of the embodiment of the invention, Kz is H.

In some embodiments of the invention, Ka is a group different from the oxyranyl group.

In some embodiments, Ka represents a heterobicyclic group, a heterocyclic group, or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of

C-in acyl, C-i2 acyloxy, C-i-e alkenyl, C-i-4 alkoxy, C-i-e alkoxycarbonylamino, C-i-e alkyl, C-i-e alkylamino, C-i-i dialkylamino, C-i-e alkylcarboxamide, C-i-e alkynyl, C1i-4 alkylsulfonamide, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl,

C-4 alkylthio, C-4 alkylureyl, amino, carbo-Ci--alkyl, carboxamide, carboxy, cyano, C3-e cycloalkyl, C2-dialkylcarboxamide, formyl, halogen, C-4 haloalkyl, C-4 haloalkyl, C- 4 haloalkylsulfinyl, C1-4 haloalkylsulfonyl, C-4 haloalkylthio, heteroaryl, hydroxyl, nitro, phenyl and sulfonamide; where indicated

C1-5 acyl, C1-5 acyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 alkylcarboxamide, amino, carbo-C1-6 alkoxy and heteroaryl, each optionally substituted with substituents independently selected from the group, including C1-6 alkyl, C1-5 acyl,

Ci-4 alkoxy, Ci-e alkylamino, Ci-e alkylamino, Ci-e dialkylamino, Ci-4 alkylcarboxamide, Ci-4 alkylsulfonyl, amino, carbo-Ci-6- alkoxy, carboxamide, carboxy, cyano, Ci-e cycloalkyl, halogen, Ci- 4 haloalkoxy, C-1 haloalkyl, hydroxyl and phenyl.

In some embodiments, Ka represents a heterobicyclic group, a heterocyclic group, or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of

C-in acyl, C-i2 acyloxy, C-4 alkoxy, C1i-e alkoxycarbonylamino, C-i alkyl, C-i alkylamino, Cg-i dialkylamino,

C-4 alkylcarboxamide, C-4 alkylsulfonamide, C-4 alkylsulfonyl, C-4 alkylureyl, amino, carbo-Ci-C-alkoxy, carboxamide, carboxy, cyano, C3-is cycloalkyl, C3-is dialkylcarboxamide, formyl, halogen, C-4 haloalkyl, C1-4 haloalkyl, heteroaryl, hydroxyl and phenyl; where C-5 acyl, C-5 acyloxy, C-4-alkyl, C-6 alkyl, C-1-4 alkylcarboxamide, amino, carbo-Ci-6-alkyloxy and heteroaryl, each optionally substituted with substituents, are indicated,

independently selected from the group consisting of C1-6 alkyl, C1-6 acyl, C1-4 alkoxy, C1-6 alkylamino, C1-6 dialkylamino,

C-4 alkylcarboxamide, C1-4 alkylsulfonyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-e cycloalkyl, halogen, C1-4 haloalkyl, C1-4 haloalkyl, hydroxyl and phenyl.

In some variants of the embodiment of the invention KK. represents a heterobicyclic group, a heterocyclic group, or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of

C-4 acyl, C-4 acyloxy, C-4 alkoxycarbonylamino, C-4 alkoxy, C-4 alkyl, C-4 alkylcarboxamide, C-4 alkylsulfonamide, C-4 alkylsulfonyl, C-4 alkylureyl, amino, carbo-C-4- alkoxy, carboxamide, carboxy, C2-6 dialkylcarboxamide, formyl, halogen, C1-" haloalkyl, heteroaryl, hydroxyl and phenyl; where C-5 acyl is indicated,

C 1-6 acyloxy, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkylcarboxamide, amino, carbo-C 1-6 alkoxy, and heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C 1-6 alkyl, carbo -Ci1-6- alkoxy, carboxy and phenyl.

In some embodiments of the invention, Ka represents a heterocyclic group or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of C1-e acyl, C1-12 acyloxy, C1-4 alkoxy, C1-6 alkyl, C1-4 is alkylamino, C1-4 dialkylamino, C1-4 alkylcarboxamide, C1-4 alkylsulfonyl, C1-4 alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-4 cycloalkyl, halogen, C1-4 haloalkoxy , C1-4 haloalkyl and hydroxyl; where Ci-x acyl, Ci-z acyloxy, Ci-e alkyl, Ci-e-4 alkylcarboxamide and carbo-Ci-c-alkoxy, each optionally substituted with Ci-x acyl, Ci-o-alkoxy, Ci-e alkylamino, C2- in dialkylamino, C-4 alkylcarboxamide, C-4 alkylsulfonyl, amino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-cycloalkyl, halogen, C-4 haloalkyl, C-4 haloalkyl, hydroxyl and phenyl.

In some embodiments of the invention, Ka is a heterocyclic group or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of C1-4 acyl, C1-12 acyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 4-alkylcarboxamide, C-4 alkylureyl, amino, carbo-Ci1-vei-alkoxy, carboxy, and hydroxyl; where C1-acyl, C1-acyloxy, C1-6 alkyl, C1-4 alkylcarboxamide and carbo-C1-6-alkoxy are each optionally substituted with carbo-C1-6-alkoxy, carboxy and phenyl.

In some embodiments of the invention, the heteroaryl is a 5-membered heteroaryl, for example, the 5-membered heteroaryl shown in Table 1:

TABLE 1 ge Ge ge C (C (Ce 7 47 M z Mn z o -x Z , z n z z z z 2

Metn M-t M-ane 0 Mevn 0 m-n lo s KUKN Malo o, a"

Met l, M -- V--oz yno, mete

МВ Ма, и МН Май Мт, и мы where the 5-membered heteroaryl is bound at any available position in the ring, for example, the imidazolyl ring can be bound by one of the ring nitrogen atoms (i.e. the imidazol-1-yl group) or one ring carbon atom each (ie imidazol-2-yl, imidazol-4-yl or imidazol-5-yl group).

In some embodiments of the invention, the heteroaryl is a b-membered heteroaryl, for example, a 6-membered heteroaryl presented in Table 2:

TABLE 2 a shk in I not I tes sh m

A A, where the heteroaryl group is bonded to any ring carbon atom.

In some variants of the embodiment of the invention Ka. selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl 2,5-diazabicyclo(|(2.2.1|heptyl, (1,oxazepanyl, 1,1-dioxo-1L6-thiomorpholinyl, azepanyl, and 3-oxopiperazinyl, azabicyclo(2.2.1|heptyl and imidazolyl), each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-12 acyloxy, C1-4 alkoxy, C1-6 alkoxycarbonylamino, C1-6 alkyl , C-4 alkylcarboxamide, C-4 alkylsulfonamide, C-4 alkylsulfonyl, C-4 alkylureyl, amino, carbo-Ci-e-alkoxy, carboxamide, carboxy, C2-e dialkylcarboxamide, formyl, halogen, C.« haloalkyl, heteroaryl , hydroxyl and phenyl; where indicated is C-5 acyl, C-5 acyloxy, C1-4 alkoxy, C1-4 alkyl, C1-alkylcarboxamide, amino, carbo-C1-e-alukoxy and heteroaryl, each optionally substituted with substituents, independently selected from the group consisting of C 1-6 alkyl, carbo-C 1-6 alkoxy, carboxy and phenyl.

In some variants of the embodiment of the invention Ka. selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl, 2,5-diazabicyclo|2.2.1|heptyl, 1,4oxazepanyl, 1,1-dioxo-1/6-thiomorpholinyl, azepanyl, 3-oxopiperazinyl, 7-azabicyclo(2.2.1|hept-7-yl) and imidazolyl, each optionally substituted with substituents independently selected from the group consisting of CH3, C(-O0)O-tert-butyl,

С(-ОЙН, Сб(-0)0ОБ5 МНО(-0О)О-tert-butyl, ОН, С(хО)МНОСНС(-О)ОСНИ, 0 МНОТ-О)СнНС(-FOOSН», с(-ОМНОеНоС) (-FOON, МНОес-Оо)сСнго-ООН, С(-OOSN», ОоС(-О0)СНаСНоС(-О)ОСН 5,

OoF(-0)SNaSnH.snNSNgsN with, SnHS(-FOOSNoCH 5, Osn", Сsno(-FOOH, OoS(-O0)SNaSNoS(-O)OSN 5,

SnNaSnHgS(-FOSsH», C(-0)CHz, C(-O)OSHn-phenyl, C(-O)СНаСНоС(-ОСН», С(-O)СНаСНоС(-ООН, BE, phenyl,

СнасС(-Ф0)ОСНзи, 51-0)2СНз, OSНо-phenyl, СНо-phenyl, С(-О)МН:, СНО, -МН, МНОС(-О)СНз, С(-О)М(СНвз) ",

МНО(-О)2СнНавз, -СЕз, З-methyl-(1,2,4|oxadiazol-5-yl and СН(СНЗ3)»).

In some variants of the embodiment of the invention Ka. selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin- 3-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl, 2,5-diazabicyclo(2.2.1|hept-2-yl, (1,oxazepan-4-yl, 1,1-dioxo-1l6-thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl, pyrrolidin-3-yl, 3-oxopiperazin-1-yl, 1 - azabicyclo(2.2.1|hept-7-yl and imidazol-1-yl, each optionally substituted with substituents independently selected from the group consisting of CH3, C(-O0)O-tert-butyl, C(I- O)OH, C(-O)OEI, MNO(-O)O-tert-butyl, OH,

С(-ОМНОоНхС(-ФО)ОССНИ, МНО(-0СНхС(-FOСН3, С(-О)МНОННГО(-О)OH, МНОе(-О)СнНаС(-ООН, С(-Ф0О0ОСН 5,

ОоС(-О0)СНаСНоС(-О)ОСН 5, ОоФб(-0)СнНаснН.снННСнН 5, СнНС(-ФОСНоСН 5, Osn», Ссно(-ФОН,

OS(-0)SNa.SnNoS(-O)OSNiI, СNoСНgС(-O)СН:i, С(-О0)СН3, and С(хООСНо-phenyl,8 С(-O)СНаСНС(-ФО)ОСН5,

ФС(-О)СНа.СНоС(-ООН, PE, phenyl, СН»С(-О)ОСН», 5(-0)2СН3, OSНg-phenyl, СНg-phenyl, С(-О)МН», СНО , -MN",

МНОТ(-О)СН3, С(-О)М(СН3)», МНО(-О)2СН3, -СЕ3, 3-methyl-(1,2,4|oxadiazol-5-yl and CH(СН33)» .

In some variants of the embodiment of the invention Ka. selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl and 2,5-diazabicyclo(2.2.1)heptyl, optionally substituted with substituents independently selected from the group consisting of C-5 acyl C-5 acyloxy, C-4 alkoxy, C1-6 alkyl, C-4 alkylcarboxamide, C1-4 alkylureyl, amino, carbo-Ci-6-alkoxy, carboxy and hydroxyl; where C1-5 acyl, C1-5 acyloxy, C1-6 alkyl, C1-4 alkylcarboxamide, and carbo-C1-6-alkoxy are each optionally substituted with carbo-C1-6-alkoxy, carboxy, and phenyl.

In some variants of the embodiment of the invention Ka. selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl and 2,5-diazabicyclo(2.2.1)heptyl, optionally substituted with substituents independently selected from the group consisting of CH3, C(- O)O-tert-butyl, С(хООН,

C(-OOBEiY, MNO(-O)O-tert-butyl, OH, C(O)MNONhO(-O)OSN", MNO(-O0)SSN-O)OSsH", C(-O)MNON»C (-OJUN,

МНне(-ОосСнис(-ООюН, С(-ФООсСН), ОС(-О0)СНаСНнгС(-ФО)ОсСНзи, ОС(-О)СНа.СНа.СНгсСНгсН», СНоо(-О)ОСНоСН 5,

Osn», СНг.о(-ООН, OS(-О0)СНаСНо(-О)ОСН», СНаСнНго(-О)ОСН», С(-О)СН3 and С(-О)OSNeg-phenyl.

In some variants of the embodiment of the invention Ka. selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin- 3-yl, pyridin-2-yl, pyridin-4-yl, azetidin-yl, thiomorpholin-4-yl and 2,5-diazabicyclo|(2.2.1|)heptyl optionally substituted with substituents independently selected from the group including CH3, C(-O0)O-tert-butyl, C(I-O)OH, C(-O)OBE, MHO(-O)O-tert-butyl, OH, C(O) МНОСНоС(-ФО)ОСНИ, МНОТ(-О)СНгС(-О)ОСН3, С(-ОМНОоНнНгС(-ООН), MNOe(-ОСНИС(-ООН),

Фс(-0ОсСН»з, ОС(-0)СНа.СнНхС(-О)ОСНии, ОС(-О0)СНа.СнНасСНосСНосСНз, СНаС(-Ф0)ОСНасСН:И, ОСН3, СНоС(-ООН,

OoC(-0)SNaSnHgS(-FO)OSN», СNaSnHgS(-O)OSH»z, C(-O)CHz and C(-O)OSNeg-phenyl.

In some embodiments of the invention, Ka is selected from the group consisting of morpholin-4-yl, piperazin-1-yl, and 7-azabicyclo(2.2.1|hept-7-yl), and the piperazin-1-yl is substituted or C(xO )СН3, or С(ХО)МН».

In some embodiments of the invention, Ka is 4-acetylpiperazin-1-yl, morpholin-4-yl, piperidin-4-yl or pyrrolidin-1-yl.

In some embodiments of the invention, K5, Hv and K7 are all H.

In some variants of the embodiment of the invention, K5 is H.

In some variants of the embodiment of the invention, Kaye is N.

In some variants of the embodiment of the invention, K7 is H.

In some embodiments of the invention, Kz is C1-6 alkyl, C1-6 alkenyl, aryl, C3-7 cycloalkyl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-6 alkoxy Ci - is haloalkyl, heterocyclic group, hydroxyl, nitro and phenyl, or two adjacent substituents together with aryl or heteroaryl form C5-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and optionally substituted PE.

In some embodiments of the invention, Kz is C3-6 alkyl, C1-6 alkenyl, aryl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-6 alkoxy, C1-6 alkyl . is haloalkyl, heterocyclic group, hydroxyl, nitro and phenyl, or two adjacent substituents together with aryl or heteroaryl form C5-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and optionally substituted PE.

In some embodiments of the invention, Kz is C1-6 alkyl, C1-6 alkenyl, aryl, C3-7 cycloalkyl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-6 alkoxy , C-e alkyl, cyano, halogen, C-e haloalkyl, C-e haloalkyl and hydroxyl, or two adjacent substituents together with aryl or heteroaryl form C5-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and optionally necessarily substituted RE.

In some embodiments of the invention, Kz is C3-6 alkyl, C1-6 alkenyl, aryl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-6 alkoxy, C1-6 alkyl , halogen, C-e haloalkyl and hydroxyl, or two adjacent substituents together with aryl or heteroaryl form C-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and is optionally substituted by P.

In some embodiments of the invention, Kz is C1-6 alkyl, C1-6 alkenyl, aryl, C3-7 cycloalkyl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of

FS(-O)CH3, OSnH»3, CH, E, Si, Vg, CE3, hydroxyl, OSE3 and CM, or two adjacent substituents together with aryl or heteroaryl form C-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and optionally substituted R.

In some embodiments of the invention, Kz is C3-6 alkyl, Co is alkenyl, aryl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C(xO)CH3, OSnH3, CH, E, SI,

Bg, Cez and hydroxyl, or two adjacent substituents together with aryl or heteroaryl form C5-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and optionally substituted PE.

In some embodiments, Ka" is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, 3-methylbutyl, phenyl, naphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridinyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, thienyl, furanyl, benzothienyl, thiazolyl, isoxazolyl and pyridin-4-yl, each optionally substituted with substituents independently selected from the group consisting of C(xO)CH3, OCH»3,

CHz, B, SI, VI, SEz, hydroxyl, OSEz, and CM, or two adjacent substituents together with phenyl form C5 cycloalkyl, which includes 2 oxygen atoms and optionally substituted PE.

In some embodiments, Kz is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, phenyl, pyridinyl, benzoimidazolyl, benzooxazolyl, and benzothiazolyl, each optionally substituted with substituents independently selected from groups including C(xO)CH3, OSnH3, CH, E, SI,

Bg, CEz and hydroxyl, or two adjacent substituents together with phenyl form C5 cycloalkyl, which includes 2 oxygen atoms and optionally substituted PE.

In some embodiments of the invention, Kz is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, phenyl, naphthalen-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, pyridin-2-yl, pyridin-3-yl, IN-benzoimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, benzothiophen-2-yl, thiazol-2-yl, isoxazol-3-yl and pyridin-4-yl, each optionally substituted with substituents independently selected from the group consisting of C(xO)CH3, OSH3, CH, E, SI, VI, CE3, hydroxyl, OSE3, and CM, or two adjacent substituents, together with phenyl, form Св cycloalkyl, which includes 2 oxygen atoms and optionally substituted P.

In some embodiments of the invention, Kz is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, phenyl, pyridin-2-yl, pyridin-3-yl, 1H-benzoimidazol-2- yl, benzooxazol-2-yl and benzothiazol-2-yl, each optionally substituted with substituents independently selected from the group consisting of

C(-O)CH3, OSnH»3, CH, E, SI, BG, CE3 and hydroxyl, or two adjacent substituents together with phenyl form C5 cycloalkyl, which includes 2 oxygen atoms and optionally substituted PE.

In some embodiments of the invention, Ka is selected from the group including 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzoi|1,3|dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3-methoxyphenyl, 3-acetylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 4-chloro-2-trifluoromethylphenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2 ,6-difluorophenyl, naphthalene-1-yl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-fluorophenyl, 2,3-difluorophenyl, 2,4,5-trifluorophenyl, 2,3,4 -trifluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, /2-fluoro-4-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 2,6-dichlorophenyl, 4-cyanophenyl and 2,5-dichlorophenyl.

In some embodiments of the invention, Ka is selected from the group including 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzoi|1,3|dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3-methoxyphenyl, 3-acetylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 4-chloro-2-trifluoromethylphenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2, 6-difluorophenyl, naphthalene-1-yl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-fluorophenyl, 2,3-difluorophenyl, 2,4,5-trifluorophenyl, 2,3,4- trifluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, /2-fluoro-4-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, Z -fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 2,6-dichlorophenyl, 4-cyanophenyl, 2,5-dichlorophenyl and benzo|1 ,3|dioxol-

B-il.

In some embodiments of the invention, Ka is selected from the group including 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzoi|1,3|dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3-methoxyphenyl, 3-acetylphenyl, 4-methylphenyl and "3-trifluoromethylphenyl.

In some embodiments of the invention, Kz is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, 3-methylbutyl, cyclopropyl, cyclobutyl and cyclopentyl.

In some embodiments of the invention, Kz is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl and 2-methylpropenyl.

In some embodiments of the invention, Ka is a 5-membered heteroaryl selected from the group presented in Table 1.

In some embodiments of the invention, Ka is a b-membered heteroaryl selected from the group presented in Table 2.

In some embodiments of the invention, Hv is selected from the group including pyridine-3-yl, b6-trifluoromethylpyridin-3-yl, 3-hydroxypyridin-2-yl, b-methylpyridin-3-yl, b-hydroxypyridin-3-yl, 1n- benzoimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, 5-chlorothiophen-2-yl, benzothiophen-2-yl, thiazol-2- yl, 5-methylisoxazol-3-yl and pyridin-4-yl.

In some embodiments of the invention, Ke is selected from the group consisting of pyridine-3-yl, b6-trifluoromethylpyridin-3-yl, 3-hydroxypyridin-2-yl, b-methylpyridin-3-yl, b-hydroxypyridin-3-yl, 1n-benzoimidazol-2-yl, benzooxazol-2-yl and benzothiazol-2-yl.

In some variants of the embodiment of the invention, Ko" is N.

In some embodiments, K is Si. from alkyl

In some variants of the embodiment of the invention, Ko is N.

In some embodiments of the invention, Co is C3-C6 alkyl.

In some variants of the embodiment of the invention, Ki is N.

In some embodiments of the invention, Ki1 is C3-C6 alkyl.

Some embodiments of the invention include some 3-phenylpyrazole derivatives represented by the formula (IC):

we

What Ik vyti o What 8 N M i

Kz or their pharmaceutically acceptable salts; where:

MU is -СНе-, -СН»аСНе-, -СН2гб(-0)-, -СНаСНеаСНе-, -С(СН3)250(-0)-, -СНаСН(СнНЗ)-, -СН(СН3) СНе-, -

С(Снзз»сн»- or -СНС(СНЗз)»2-; or UM is absent;

X is C(:O) or absent;

M represents MH, O or absent; 2 is absent, or is -СНео-, -СН(ОН)-, -Сиб2-, -С(СН3)2-, 1,1-cyclopropyl, -СНаСНе-, -СНаСНеСнНе-, -

СН(Снз)- or -С(-0)-;

B is C-C alkyl;

Az is H or halogen;

Ba is a heterobicyclic group, a heterocyclic group or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-12 acyloxy, C1-4 alkoxy, C1-6 alkoxycarbonylamino, C1-6 alkyl , C-4 alkylcarboxamide, C-4 alkylsulfonamide, C-4 alkylsulfonyl, C-4 alkylureyl, amino, carbo-Ci-e-alkoxy, carboxamide, carboxy, C2-e dialkylcarboxamide, formyl, halogen, C-4 haloalkyl, heteroaryl, hydroxyl and phenyl; where indicated is C-5 acyl, C-5 acyloxy, C-4-4 alkoxy, C-6 alkyl, C 1-4 alkylcarboxamide, amino, carbo-C 1-6 -alkoxy and heteroaryl, each optionally substituted with substituents, regardless of selected from the group consisting of C-C alkyl, carbo-Ci-C-Alkoxy, carboxy and phenyl; and

Ag is C1-6 alkyl, C1-6 alkenyl, aryl, C3-7 cycloalkyl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-6 alkoxy, C1-6 alkyl , C1-6 alkylsulfonyl, amino, C1-6 alkylamino, C1-z dialkylamino, C1-e alkylimino, carbo-Ci-v-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, halogen, C1-e haloalkoxy, C1- is haloalkyl, heterocyclic group, hydroxyl, nitro and phenyl, or two adjacent substituents together with aryl or heteroaryl form C5-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and optionally substituted PE.

Some embodiments of the invention include some 3-phenylpyrazole derivatives represented by formula Ic), above, or their pharmaceutically acceptable salts; where:

УU is -СНе-, -СНаСНе-, -СНаС(-0)-, -СНаСНесСнНе-, or MU is absent;

X is C(:O) or absent;

M represents MH, O or absent; 7 represents -СНе-, - ССН(ОН)- or absent;

B is C-C alkyl;

Az is H or halogen;

Ba is a heterocyclic group or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-12 acyloxy, C1-4-alkyl, C1-6 alkyl, C1-6 alkylamino, C2 -b8 dialkylamino, C1-4 alkylcarboxamide, C1-4 alkylsulfonyl, C1-4 alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-e cycloalkyl, halogen, C1-4 haloalkoxy, C1-4 haloalkyl and hydroxyl; where C1-5 acyl, C1-5 acyloxy, C1-5 alkyl, C1-4 alkylcarboxamide, and carbo-C1-6-alkoxy, each optionally substituted with C1-5 acyl,

C-4 Alkoxy, C-C alkylamino, C-C dialkylamino, C1-4 alkylcarboxamide, C-4 alkylsulfonyl, amino, carbo-C1-c-Alkoxy, carboxamide, carboxy, cyano, C3-C cycloalkyl, halogen, C- 4 haloalkyl, C-4 haloalkyl, hydroxyl and phenyl; and

Ag is C3-6 alkyl, C1-6 alkenyl, aryl, or heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylsulfonyl , amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 alkylimino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7t cycloalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkyl, heterocyclic group, hydroxyl, nitro and phenyl, or two adjacent substituents together with aryl or heteroaryl form C5-7 cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and optionally substituted PE.

Some embodiments of the invention include some C-phenylpyrazole derivatives represented by the formula (IC), above, or their pharmaceutically acceptable salts; where:

MU is -СНе-, -СН»аСНе-, -СН2гб(-0)-, -СНаСНеаСНе-, -С(СН3)250(-0)-, -СНаСН(СнНЗ)-, -СН(СН3) СНе-, -

С(СН3)»СнН»- or -СНоС(СН3)2-; or UM is missing;

X is C(:O) or absent;

M represents MH, O or absent; 7 absent, -СНе-, -СН(ОН)-, -СЕ2-, -С(СН3)2-, 1,1-cyclopropyl, -СНаСНе-, -СНа.СНаСНе»-, -СН(СН3)- or -

F(-0)-;

B is C-C alkyl;

Az is H or halogen;

Ba is a heterobicyclic group, a heterocyclic group or a heteroaryl group, each optionally substituted with substituents independently selected from the group consisting of C1-6 acyl, C1-12 acyloxy, C1-4 alkoxy, C1-6 alkoxycarbonylamino, C1-6 alkyl , C-4 alkylcarboxamide, C-4 alkylsulfonamide, C-4 alkylsulfonyl, C-4 alkylureyl, amino, carbo-Ci-e-alkoxy, carboxamide, carboxy, C2-e dialkylcarboxamide, formyl, halogen, C-4 haloalkyl, heteroaryl, hydroxyl and phenyl; where C1-5 acyl, C1-5 acyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 alkylcarboxamide, amino, carbo-C1-6-alkyloxy and heteroaryl, each optionally substituted with substituents, are indicated, independently selected from the group consisting of C 1 -C 6 alkyl, carbo-C 1 -C 6 -alkyl, carboxy and phenyl; and

Av is selected from the group consisting of 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzo|1,3|dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2 -hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3-methoxyphenyl, Z -acetylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 4-chloro-2-trifluoromethylphenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, naphthalene -1-yl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-fluorophenyl, 2,3-difluorophenyl, 2,4,5--riftophenyl, 2,3,4--riftophenyl, 3 ...

3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 2,6-dichlorophenyl, 4-cyanophenyl, 2,5-dichlorophenyl and benzo| 1,3|dioxol-5-yl.

Some embodiments of the invention include some C3-phenylpyrazole derivatives represented by the formula (It): la

Y Shchi (t) trya Zh M. y y

Ez or their pharmaceutically acceptable salts; where:

MU is -СНе-, -СНаСНе-, -СНаб(-0)-, -СНаСНеСнНе-, -С(СН3)2-С(-0)-, -СНg.СН(СнН3)-, -СН (СН3)СНе-, -

С(СН3)»СнН»- or -СНоС(СН3)2-; or UM is missing;

M represents MH, O or absent; 2 is absent, or is -СНе-, -СН(ОН)-, -СЕ»-, -С(СН3)2-, 1,1-cyclopropyl, -СНаСНе-, -СНаСНеСнН»-, -

СН(Снз)- or -С(-0)-;

B is C-C alkyl;

Az is H or halogen;

You are selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl 2,5-diazabicyclo|(2.2.1Heptyl, (1,4)oxazepanyl, 1,1-dioxo-1A9-thiomorpholinyl, azepanyl and 3-oxopiperazinyl, azabicyclo|2.2.1|heptyl and imidazolyl, each optionally substituted with substituents independently selected from the group consisting of C 1-4 acyl, C 1-12 acyloxy, C 1-6 alkoxy, C 1-4 alkyl, C 4 alkylcarboxamide, C 1-4 alkylsulfonamide , C 1-4 alkylsulfonyl, C 1-4 alkylureyl, amino, carbo-C 1-6 alkoxy, carboxamide, carboxy, C 2-e dialkylcarboxamide, formyl, halogen, C 4 haloalkyl, heteroaryl, hydroxyl and phenyl; where C 5 acyl is indicated, C-5 acyloxy, C-4 alkoxy, C-6 alkyl, C-4 alkylcarboxamide, amino, carbo-C1-6- alkoxy and heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C-4 alkyl, carbo-Ci-C-Alkoxy, carboxy and phenyl; and

Av is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, 3-methylbutyl, phenyl, naphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridinyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, thienyl, furanyl , benzothienyl, thiazolyl, isoxazolyl, and pyridin-4-yl, each optionally substituted with substituents independently selected from the group consisting of C(xO)CH3, OSnH3, CH, E, SI,

Bg, CEz, hydroxyl, OSEz, and CM, or two adjacent substituents together with phenyl form C5 cycloalkyl, which includes 2 oxygen atoms and optionally substituted PE.

Some embodiments of the invention include some C-phenylpyrazole derivatives represented by formula (It), above, or their pharmaceutically acceptable salts; where:

УU is -СНе-, -СНаСНе-, -СНаС(-0)-, -СНаСНесСнНе-, or MU is absent;

M represents MH, O or absent; 2 is absent, or is -CHneg- or -CH(OH)-;

B is C-C alkyl;

Az is H or halogen;

Ba is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridinyl, azetidinyl, thiomorpholinyl, and 2,5-diazabicyclo(2.2.1|heptyl, optionally substituted with substituents independently selected from the group consisting of Ci acyl, Ci -5 acyloxy, C1-4 alkoxy, C1-4 alkyl, C1-4 alkylcarboxamide, C1-4 alkylureyl, amino, carbo-C1-6 alkoxy, carboxy, and hydroxyl; where C1-4 acyl, C1-4 acyloxy, C -C 4 alkyl, C 4 alkylcarboxamide, and carbo-C 4 -C 6 -alkoxy, each optionally substituted with carbo-C 1 -C 6 -C 6 -alkyl, carboxy, and phenyl; and

Ar is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, phenyl, pyridin-2-yl, pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2 -yl and benzothiazol-2-yl, each optionally substituted with substituents independently selected from the group consisting of C(:O)CH3, OCH3, CH3, E, CI, BG, CE3 and hydroxyl, or two adjacent substituents together with with phenyl they form C5 cycloalkyl, which includes 2 oxygen atoms and optionally substituted PE.

Some embodiments of the invention include some C-phenylpyrazole derivatives represented by formula (It), above, or their pharmaceutically acceptable salts; where:

MU is -СНе-, -СНаСНе-, -СНаб(-0)-, -СНаСНеСнНе-, -С(СН3)2-С(-0)-, -СНg.СН(СнН3)-, -СН (СН3)СНе-, -

С(СН3)»СнН»- or -СНоС(СН3)2-; or UM is missing;

M represents MH, O or absent; 2 is absent, or is -СНео-, -СН(ОН)-, -Сиб2-, -С(СН3)2-, 1,1-cyclopropyl, -СНаСНе-, -СНаСНеСнНе-, -

СН(Снз)- or -С(-0)-;

B is C-C alkyl;

Az is H or halogen;

Ba is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-yl-1-yl, pyridine -Z-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl, 2,5-diazabicyclo|2.2.1|hept-2-yl . -azabicyclo(2.2.1|hept-7-yl and imidazol-1-yl, each optionally substituted with substituents independently selected from the group consisting of CH3, C(-O0)O-tert-butyl,

С(-ОЮН, Сб(-О0Б, МНО(-О)О-tert-butyl, ОН, С(хО)МНОСНС(-О)ОСНИ, 0 МНОТ-О)СнНС(-FOOSN», с(-ОМНенНгС( -ОюН, МНОес-Оо)сСнго-ООН, С(-OOСН», ОоС(-О0)СНаСНоС(-О)ОСН 5,

ОоФ(-0)СНаСнН.снНСНгснН with, СнНго(-ООСНоСН .», Osn», Сснго(-ФОН, OоФ(-О)СН.СНаС(-ООСН»,

Сн nНС(-ФОХССН», С(-О)СН», and С(-ФОСН»-phenyl, С(И-О)СНаСНС(-ОСН), С(-О0)СНаСНоС(ООН, PE, phenyl,

СнасС(-Ф0)ОСНзи, 51-0)2СНз, OSНо-phenyl, СНо-phenyl, С(-О)МН:, СНО, -МН, МНОС(-О)СНз, С(-О)М(СНвз) ",

MHO(-O)2CHbz, -SEz, 3-methyl-(1,2,4|oxadiazol-5-yl and CH(CH3z)"; and

Av is selected from the group consisting of 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzo|1,3|dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2 -hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3-methoxyphenyl, Z -acetylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 4-chloro-2-trifluoromethylphenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, naphthalene -1-yl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-fluorophenyl, 2,3-difluorophenyl, 2,4,5--riftophenyl, 2,3,4--riftophenyl, 3 ...

3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 2,6-dichlorophenyl, 4-cyanophenyl and 2,5-dichlorophenyl.

Some embodiments of the invention include some C-phenylpyrazole derivatives represented by formula (It), above, or their pharmaceutically acceptable salts; where:

УU is -СНе-, -СНаСНе-, -СНаС(-0)-, -СНаСНесСнНе-, or MU is absent;

M represents MH, O or absent; 2 is absent, or is -CHneg- or -CH(OH)-;

B is C-C alkyl;

Az is H or halogen;

Ba is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridine -Z-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl and 2,5-diazabicyclo(2.2.1|heptyl, each optionally substituted with substituents independently selected from the group including CH3, С(-О0)О-tert-butyl, С(ХО)ОН, С(-О)OBEI, МНОС(-О)О-tert-butyl, ОН, С(О)МНОСНгС( -O) OSN 5,

МНес-ОосСниС-ФоюснН», С(-О)МНОнНго(-ОЮН, МНОТ(-О0)СНо(-О)ОН, С(-ФО)ОСНз, OS(-О)СНаСнНхС(-О)ОСН»,

ОоФ(-0)СНаСнН.снНСНгснН with, СнНго(-ООСНоСН .», Osn», Сснго(-ФОН, OоФ(-О)СН.СНаС(-ООСН»,

SnNaSnHC(-FO)OsCH", C(-O)CH3 and C(-FOOSN"-phenyl; and

Av is selected from the group consisting of 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzo|1,3|dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2 -hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3-methoxyphenyl, Z -acetylphenyl, 4-methylphenyl and 3-trifluoromethylphenyl.

Some embodiments of the invention include some 3-phenylpyrazole derivatives represented by formula (It), above, or their pharmaceutically acceptable salts; where:

MU is -СНе-, -СНаСНе-, -СНаб(-0)-, -СНаСНеСнНе-, -С(СН3)2-С(-0)-, -СНg.СН(СнН3)-, -СН (СН3)СНе-, -

С(СН3)»СнН»- or -СНоС(СН3)2-; or UM is missing;

M represents MH, O or absent; 2 is absent, or is -СНе-, -СН(ОН)-, -СЕ»-, -С(СН3)2-, 1,1-cyclopropyl, -СНаСНе-, -СНаСНеСнН»-, -

СН(Снз)- or -С(-0)-;

B is C-C alkyl;

Az is H or halogen;

Ba is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-yl-1-yl, pyridine -Z-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl, 2,5-diazabicyclo|2.2.1|hept-2-yl , 1,oxazepan-4-yl, 1,1-dioxo-1l6-thiomorpholin-4-yl, piperidin-2-yl, azepan-yl, pyrrolidin-3-yl, 3-oxopiperazin-yl, 7 -azabicyclo(2.2.1|hept-7-yl and imidazol-1-yl, each optionally substituted with substituents independently selected from the group consisting of CH3, C(-O0)O-tert-butyl,

С(-ОЮН, Сб(-О0Б МНО(-0О)О-tert-butyl, ОН, С(хО)МНОСНС(-О)ОСНИ, 0 МНОТ-О)СнНС(-FOOSN», с(-ОМНенНгС(- OyuN, MNOes-Oo)sSngo-OON, C(-OOSN", OoS(-O0)СНаСНоС(-О)ОСН 5,

ОоФ(-0)СНаСнН.снНСНгснН with, СнНго(-ООСНоСН .», Osn», Сснго(-ФОН, OоФ(-О)СН.СНаС(-ООСН»,

Сн nНС(-ФОХССН», С(-О)СН», and С(-ФОСН»-phenyl, С(И-О)СНаСНС(-ОСН), С(-О0)СНаСНоС(ООН, PE, phenyl,

СнасС(-Ф0)ОСНзи, 51-0)2СНз, OSНо-phenyl, СНо-phenyl, С(-О)МН:, СНО, -МН, МНОС(-О)СНз, С(-О)М(СНвз) ",

MHO(-O)2CHbz, -SEz, 3-methyl-(1,2,4|oxadiazol-5-yl and CH(CH3z)"; and

Av is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, 3-methylbutyl, cyclopropyl, cyclobutyl and cyclopentyl.

Some embodiments of the invention include some C-phenylpyrazole derivatives represented by formula (It), above, or their pharmaceutically acceptable salts; where:

УU is -СНе-, -СНаСНе-, -СНаС(-0)-, -СНаСНесСнНе-, or MU is absent;

M represents MH, O or absent; 2 is absent, or is -CHneg- or -CH(OH)-;

B is C-C alkyl;

Az is H or halogen;

Ba is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridine -Z-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl and 2,5-diazabicyclo(2.2.1|heptyl, each optionally substituted with substituents independently selected from the group including CH3, С(-О0)О-tert-butyl, С(ХО)ОН, С(-О)OBEI, МНОС(-О)О-tert-butyl, ОН, С(О)МНОСНгС( -O) OSN 5,

МНес-ОосСниС-ФоюснН», С(-О)МНОнНго(-ОЮН, МНОТ(-О0)СНо(-О)ОН, С(-ФО)ОСНз, OS(-О)СНаСнНхС(-О)ОСН»,

ОоФ(-0)СНаСнН.снНСНгснН with, СнНС(-ФОСНоСН 5, Osn», Сснго(-ФООН, ОоФ(-О)СН.СНаС(-OOSN),

СнНаСнНС(-FOЮСсН», С(-О)СН3, and С(-OOСН»-phenyl; and

Ag is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl and 2-methylpropenyl.

Some embodiments of the invention include some 3-phenylpyrazole derivatives represented by formula (It), above, or their pharmaceutically acceptable salts; where:

MU represents -СНаСНо-; MU is MN or absent; Bi is CH3; Va is 4-acetylpiperazin-1-yl, morpholin-4-yl, piperidin-4-yl or pyrrolidin-1-yl; and

Av is phenyl or C3-7 cycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C(xO)CH3, OCH33, CHNuv, E, CI, Bg, CE3, and hydroxyl .

Some embodiments of the invention include some 3-phenylpyrazole derivatives represented by the formula (IC), above, or their pharmaceutically acceptable salts; where:

MU is -СНе-, -СНаСНе-, -СНаб(-0)-, -СНаСНеСнНе-, -С(СН3)2-С(-0)-, -СНg.СН(СнН3)-, -СН (СН3)СНе-, -

С(Снзз»сн»- or -СНоС(СНЗз)»2-; or UM is absent;

X is C(:O) or absent;

M represents MH, O or absent; 2 is absent, or is -СНе-, -СН(ОН)-, -СЕ»-, -С(СН3)2-, 1,1-cyclopropyl, -СНаСНе-, -СНаСНеСнН»-, -

СН(Снз)- or -С(-0)-;

B is C-C alkyl;

Az is H or halogen;

Ba is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-yl-1-yl, pyridine -Z-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl, 2,5-diazabicyclo(/2.2.1|hept-2- yl, 1,Aoxazepan-4-yl, 1,1-dioxo-1l6-thiomorpholin-4-yl, piperidin-2-yl, azepan-yl, pyrrolidin-3-yl, 3-oxopiperazin-yl, 7-azabicyclo(2.2.1|hept-7-yl and imidazol-1-yl, each optionally substituted with substituents independently selected from the group consisting of CH3, C(-O0)O-tert-butyl,

С(-ОЮН, Сб(-О0Б МНО(-0О)О-tert-butyl, ОН, С(хО)МНОСНС(-О)ОСНИ, 0 МНОТ-О)СнНС(-FOOSN», с(-ОМНенНгС(- OyuN, MNOes-Oo)sSngo-OON, C(-OOSN", OoS(-O0)СНаСНоС(-О)ОСН 5,

ОоФ(-0)СНаСнН.снНСНгснН with, СнНС(-ФОСНоСН 5, Osn», Сснго(-ФООН, ОоФ(-О)СН.СНаС(-OOSN),

Сн nНС(-ФОХССН», С(-О)СН», and С(-ФОСН»-phenyl, С(И-О)СНаСНС(-ОСН), С(-О0)СНаСНоС(ООН, PE, phenyl,

СнасС(-Ф0)ОСНзи, 51-0)2СНз, OSНо-phenyl, СНо-phenyl, С(-О)МН:, СНО, -МН, МНОС(-О)СНз, С(-О)М(СНвз) ",

MHO(-O)2CHbz, -SEz, 3-methyl-(1,2,4|oxadiazol-5-yl and CH(CH3z)"; and

Ag is selected from the group consisting of pyridin-3-yl, b-trifluoromethylpyridin-3-yl, 3-hydroxypyridin-2-yl, 6-methylpyridin-3-yl, b-hydroxypyridin-3-yl, 1H-benzoimidazol-2 -yl, benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, 5-chlorothiophen-2-yl, benzothiophen-2-yl, thiazol-2-yl, 5-methylisoxazole -Z-yl and pyridin-4-yl.

Some embodiments of the invention include some C-phenylpyrazole derivatives represented by the formula (IC), above, or their pharmaceutically acceptable salts; where:

УU is -СНе-, -СНаСНе-, -СНаС(-0)-, -СНаСНесСнНе-, or MU is absent;

X is C(:O) or absent;

M represents MH, O or absent; 2 is absent, or is -CHneg- or -CH(OH)-;

B is C-C alkyl;

Az is H or halogen;

Ba is pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl , pyridin-2-yl or pyridin-4-yl, each optionally substituted with substituents independently selected from the group consisting of CH3, C(-O0)O-tert-butyl, C(I-O)OH, C( -O)OEI,. МНО(-О)О-tert-butyl, ОН, С(О)МНОН»С(-О)ОСН3, МНО(-0)СН»С(-ФО)ОСН3, С(-О)МНОСнНгС(-ООН, МНОе(-О)СнНхС(-ООН, с(-ФОСнН), ОС(-О0)СНаСНнгС(-О0)ОсСНзи, ОС(-О)СНа.СнНа.сСНосSNасН»з, СНгС(-ОСНаСНз, ОСН3, СНо( -UN,

ОоФ(-О)СН.СНаго(-О)ОСН», СНаСНгС(-О)ОсСН», С(-О)СН3 and С(-О)ОСН»-phenyl; and

Ag is selected from the group consisting of pyridin-3-yl, b-trifluoromethylpyridin-3-yl, 3-hydroxypyridin-2-yl, 6-methylpyridin-3-yl, b-hydroxypyridin-3-yl, 1H-benzoimidazol- 2-yl, benzooxazol-2-yl and benzothiazol-2-yl.

Some variants of the embodiment of the invention include some 3-phenylpyrazole derivatives represented by the formula (Io): and (9) in

VV KHID, (Io)

M M

H u z or their pharmaceutically acceptable salts;

where:

MU is -СНе-, -СНаСНе- or -СН2С(-0)-;

B is C-C alkyl;

Az is H or halogen;

Ba is pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl , pyridin-2-yl or pyridin-4-yl, each optionally substituted with substituents independently selected from the group consisting of CH3, C(-O)O-tert-butyl, C(-O)OH, C(- OE МНО(-О)О-tert-butyl, ОН, С(О)МНОН»С(-О)ОСН3, МНО(-0)СН»С(-ФО)ОСН3, С(-О)МНОСнНгС(-ООН . (-UN,

ОоФ(-О)СН.СНаго(-О)ОСН», СНаСНгС(-О)ОсСН», С(-О)СН3 and С(-О)ОСН»-phenyl; and

Ag is selected from the group consisting of 1H-benzoimidazol-2-yl, benzooxazol-2-yl and benzothiazol-2-yl.

Some embodiments of the invention include any combination of one or more compounds selected from the following group, where the number in bold immediately preceding the chemical name denotes the compound number used throughout this disclosure:

I: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; y2: 1-

13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; 23: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; 44: 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|urea; 45: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,4-difluorophenyl)urea; b: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-(2,4-difluorophenyl)urea; Z7 : isopropyl ether (|3-(4-bromo-2-methyl-2IN-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|carbamic acid; 8: /1-(4-chlorophenyl )-3-I3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|urea; o: 1--3-(4-bromo-2-methyl -2H-pyrazol-3-yl)-4-(2-(4- methylpiperazin-1-yl ethoxy|phenyl)-3-(4-chlorophenyl)urea; H10: 1-I(3-(4-bromo-2 -methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenyl|-3-(4-chlorophenyl)urea; 1: 1-(3-(4-bromo-2-methyl-2H) -pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(2,4-difluorophenyl)urea; Z12: isopropyl ether (|3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylcarbamic acid; 13: 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4- (2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,4-difluorophenyl)urea; Z14: 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4- (2-piperidin-1-ylethoxy)phenyl|-3-(2,4-difluorophenyl)urea; Ж15: 1-13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4- methylpiperazin-1-yluethoxy|phenyl)-3-(2,4-difluorophenyl) urea; H16: 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(2,4-difluorophenyl) 17: 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; Z18: 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; o: 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; 20: M-( 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|acetamide; I21: 1-3-(4-bromo-2-methyl-2H-pyrazol- 3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-fluorophenyl)urea; 22: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl )-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(3-chlorophenyl)urea; 23: 13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4 isobutyl ether -(2-pyrrolidin-1-ylethoxy)phenyl|carbamic acid; NA. 1-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy) phenyl|-3-(2, 2-difluorobenzoi|1,3|dioxol-5-yl)serine; Z25: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-hydroxyphenyl)urea; 26: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-chloro-2-hydroxyphenyl)urea; 27: 1-(2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|urea; 528: 1-( 2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)phenyl|urea; 29: 1-(2,4-difluorophenyl)- 3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-3-ylmethoxy)phenyl|urea; 30: isopropyl ether 3-(2-methyl-2H-pyrazol-3-yl) -4-(pyridin-3-ylmethoxy)phenylcarbamic acid; ZZ1: tert-butyl ether (K)-3-I4-I3-(2,4-difluorophenyl)ureidoI|-2-(2-methyl-2H-pyrazole- 3-Iluphenoxy|pyrrolidine-1-carboxylic acid; 32: /M-133-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|iacetamide; Ж33: isopropyl ether (|13-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|carbamic acid; Z34: isobutyl ether (3-(2-methyl-2H-pyrazole -3-yl)-4-(2-piperid in-1-ylethoxy)phenyl|carbamic acid; 35: M-III-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-2-phenylacetamide; 36: tert-butyl ether of 4-(4-acetylamino-2-(2-methyl-2H-pyrazol-3-yl)phenoxymethyl|piperidine-1-carboxylic acid; 237: tert-butyl ether (K)-3-( 4-isopropoxycarbonylamino-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|pyrrolidine-1-carboxylic acid; ZH38: tert-butyl ether (5)-3-I(4-I(3-(4 - fluorophenyl)ureido!|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|pyrrolidine-1-carboxylic acid; Z39: tert-butyl ether (5)-3-I4-(3-(4-chlorophenyl) )ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|pyrrolidine-1-carboxylic acid; 40: tert-butyl ether (5)-2-I4-I(3-(2,4-difluorophenyl )ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxymethyl|pyrrolidine-1-carboxylic acid; 41: tert-butyl ether (5)-2-I4--3--4-fluorophenyl)ureido| -2-(2-methyl-2H-pyrazol-3-yl)phenoxymethyl|pyrrolidine-1-carboxylic acid; 242: tert-butyl ether (K)-2-I4-I3-(4-chlorophenyl)ureido|-2 - (2-methyl-2H-pyrazol-3-yl)uphenoxymethyl|pyrrolidin-1-carboxylic acid; 43: 2-(4-chlorophenyl)-M-I3-(2-methyl-2H-pyrazol-3-yl) -4-(2-piperidin-1-ylethoxy)phenylacetamide; A. 1-benz yl-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; 45: 1-(4-chlorobenzyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; nab: 1-(4-fluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; AT. 1-(3 -fluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; 48: tert-butyl ether 4-I4-I3- (4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)phenoxy-methyl|piperidine-1-carboxylic acid; 249: tert-butyl ether 4-(4-(3-(4 -fluorophenyl)ureido1|-2-(2-methyl-2H-pyrazole-3-ylphenoxymethyl|piperidine-1-carboxylic acid; 15O: tert-butyl ether 4-(4-13-(2,4-difluorophenyl)ureido| -2-(2-methyl-2H-pyrazole-3-ylphenoxymethyl|piperidine-1-carboxylic acid; Z51: 1-(2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazole-3- yl)-4-(pyridin-4-ylmethoxy)phenyl|urea; 252: 1-(4-chlorophenyl)-3-|3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin- 4-ylmethoxy)phenyl|urea: 1-(4-fluorophenyl)-3-(3-(-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenyl| urea; 54: 1-(2,4-difluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenyl|urea; and55: 1- (2,4-difluorophenyl)-3-I3-(2-methyl-2 N-pyrazol-3-yl)-4-((5)-pyrrolidin-3-yloxy)phenyl|urea; 56: 1-(4-fluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-pyrrolidin-3-

yloxy)phenyl|urea; y57: 1-(4-chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-pyrrolidin-3-yloxy)phenyl|urea; y58: 1- (2,4-difluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-1-pyrrolidin-2-ylmethoxy)phenyl|urea; 59: 1- -4-fluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-1-pyrrolidin-2-ylmethoxy)phenyl|urea; for: 1-(4 -chlorophenyl)-3-3-(2-methyl-2H-pyrazol-3-yl)-4-((8)-1-pyrrolidin-2-ylmethoxy)phenyl|urea; 261: 1-tert-butyl ether ( 2K,4)-4-I4-I3-(2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|pyrrolidine-1,2-dicarboxylic acid; 62: ( 2K,4k)-4-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|pyrrolidine-1,2-dicarboxylic acid; ib3: (2E, 4)-4-I4-I3-(-2,4-difluorophenyl)ureido1|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|pyrrolidine-2-carboxylic acid; Zb4: (22.4K )-4-I4-I(3-(4-chlorophenyl)ureido!-2-(2-methyl-2H-pyrazole-3-ylphenoxy|pyrrolidine-2-carboxylic acid; H65: 1-(2-fluorophenyl)- 3-I3-(2-methyl-2H-pyrazole-

3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; about: 1-(3-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; yb7/: 0 1-(2-chlorophenyl)-3-13-(-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; 68: 1-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-phenylurea; and 69: 0 1-(4-bromophenyl)- 3-|3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; Z70: /1-(3,5-difluorophenyl)-3-I3 -(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; 1: 1-(4-methoxyphenyl)-3-I3-(2-methyl-2H -pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; 72: 1-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin- 1-ylethoxy)phenyl|-3-(4-trifluoromethylphenyl)urea; 3: 1-(3,5-bis-trifluoromethylphenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4- (2-piperidin-1-ylethoxy)phenyl|urea; Ж74: 1-(2-fluoro-5-methylphenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2 -piperidin-1-ylethoxy)phenyl|urea; Ж75: 1-(3-methoxyphenyl)-3-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy) phenyl|urea; Z76: 1-(3-acetylphenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; 77: 1 -tert-butyl ether (25,45)-4-I4-I3-(2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|pyrrolidin- 1,2-dicarboxylic acid; Ж78: 1-tert-butyl ether (25,45)-4-14-3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|pyrrolidin-1,2 - dicarboxylic acid; 9: (25,45)-4-14-3-(2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)phenoxy|pyrrolidine-2-carboxylic acid; Zh80: 1-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-

C-p-tolylurea; 81: 1-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-(3-trifluoromethylphenyl)urea; 82: (25,45)-4-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)phenoxy|pyrrolidine-2-carboxylic acid; 2483: 1-(4-(2-azetidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|- 3-(4-fluorophenyl)urea; 84: 1-(4 -(2-azetidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-iluphenyl|-3-(4-chlorophenyl)urea; 85: 1-(4-chlorophenyl)-3-I4- (1-methylpiperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea; 86: 1-(4-(2-azetidin-1-ylethoxy)-3-(2 -methyl-2H-pyrazol-3-yl)phenyl/|-3-(2,4-difluorophenyl)urea; 87: 1-(4-(2-azetidin-1-ylethoxy)-3-(2-methyl- 2H-pyrazole-Z3-iluphenyl|-3-(2,2-difluorobenzo|1,Z|dioxol-5-yl)retinate; 288: 1-(4-chlorophenyl)-3-I4-(2-(4- methylpiperazin-1-yl)-2-oxoethoxy|-3-(2- methyl-2H-pyrazol-3-yl/phenyl|urea; 289: tert-butyl ether 4-(4-(2-(4-chlorophenyl) acetylamino|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxymethyl|piperidine-1-carboxylic acid; 90: tert-butyl ether 4-|d- isobutoxycarbonylamino-2-(2-methyl-2H-pyrazole -3-ylphenoxymethyl|piperidine-1-carboxylic acid; Ж91: tert-butyl ether of 4-I(ID-isopropoxycarbonylamino-2-(2-methyl-2H-pyrazole-33-ylphenoxy-methyl|piperidine-1-carboxylic acid) slots; 92: isopropyl ester of 3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenyl|carbamic acid; 93: 2-(4-chlorophenyl)-N-13-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenyl|acetamide; 94; 13-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenylcarbamic acid isobutyl ether; 95: 2-(4-chlorophenyl)-2-hydroxy-N-13-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|acetamide; 96: 3-methyl-N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|butyramide; 97: 1-(4-chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; Z98: ethyl ether // 1-(2-I4--3--4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)phenoxy|ethyl)piperidine-4-carboxylic acid; 299: tert-butyl ether (1-2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperidin-4-yl)ucarbamic acid ; Zh100: 1-(4-chlorophenyl)-3-I4-(2-((5)-

3-Hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea; YAZH101: 1-(2,4-difluorophenyl)-3-|3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|urea; og: 1-(4-fluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|urea; 103: 1-(2-I(4-(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperidine-4-carboxylic acid; I104: 1-(4-(2-(4-aminopiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4-chlorophenyl)urea; i.e.: M -(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; compound: I3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|iamide of 3-methylbut-2-enoic acid; Z107: methyl ether ((1-(2-I4-3-(4- chlorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)piperidine-4-carbonyl)amino|acetic acid; 4108: methyl ether M-(1-(2-

Malonic acid I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidin-4-yl)umonamide; o9: (1-12-(4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)piperidine-4-carbonyl)amino|acetic acid; 10: Malonic acid M-(1-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)ipiperidin-4-ylmonoamide; 111: methyl ether ( 5)-1-12-I4-(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethylpiperidine-3-carboxylic acid; 112: 1-I(3- (2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-trifluoromethylphenyl)urea; 2113: isopropyl ether (3-(2-methyl-2H -pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylcarbamic acid; Х114: (5)-1-(2-І4-І3-(4-chlorophenyl)ureido|-2-(2- methyl-2H-pyrazole-3-ylphenoxy|ethylpiperidine-3-carboxylic acid; 115: 1-(3-chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-( 2-morpholin-4-ylethoxy)phenyl|urea; 4116: 1-(3-fluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4- 117: 2-(4-chlorophenyl)-M-3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenylacetamide; 118: methyl I(5)-1-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethylpiperidine-3-carbonyl)amino|acetic acid ester; 2119:

I(5)-1-2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperidine-3-carbonyl)amino|acetic acid ; 120: 1-(4-chlorophenyl)-3-(4-(2-(4-hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea; 21 : 1-(2-2-(2-methyl-2H-pyrazol-3-yl)-4-((pyridin-3-carbonyl)amino|phenoxy)ethyl)piperidine-4-carboxylic acid ethyl ester; 122: ethyl 1-(2-I4-(3-methylbutyrylamino)-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidine-4-carboxylic acid ester; Ж123: 1-2-(4-butyrylamino) ethyl ether -2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidine-4-carboxylic acid; 4124: 1-(2-(2-(2-methyl-2H-pyrazol-3-yl)-4 -pentanoylamino-phenoxy|ethyl)piperidine-4-carboxylic acid; Ж125: methyl ether 1-(2-I4-3-(2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3- yl)uphenoxy|ethyl)ipyrrolidine-2-carboxylic acid; 26: 1-(2-14-3-(2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl) ethyl ether )uphenoxy|ethyl)piperidine-2-carboxylic acid; 27. tert-butyl ether 4-I4-I3-(2,2-difluorobenzo|1,3|dioxol-5-yl)ureido|-2-(2-methyl -2H-pyrazole-3-ylphenoxymethyl|piperidine-1-carboxylic acid 128: 1-(4-chlorophen 1)-3-14-(2-(4-methylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|urea; 129: 1-(2,4-difluorophenyl)-3-14-(2-(4-methylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea); Х130: 1-(4-fluorophenyl)-3-14-(2-(4-methylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|urea; Х131: /1 -(4-chlorobenzyl)-3-(4-(2-(4-methylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea; 132: 1- (2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenyl|urea; 133: 1-(4-chlorophenyl) -3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenyl|urea; Ж134: ethyl ether 1-(2-2-(2-methyl -2H-pyrazol-3-yl)-4-((b-trifluoromethylpyridine-3-carbonyl)amino|phenoxy)ethyl)piperidine-4-carboxylic acid; 2135: 1-(2-I4-(3-(4- chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperidin-4-yl ester of succinic acid, methyl ether; 2136: 1-2-I4-I(3-(4 -chlorophenyl)ureido|-2-(2-methyl-2H-pyrazole-

C-yl)phenoxy|ethyl)piperidin-4-yl ester of hexanoic acid; 2137: 1-(2,4-difluorophenyl)-3-(3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|urea; Ж138: (1-12-14-(3-(4-chlorophenyl)ureido-2-(2-methyl-2H-pyrazol-3-yl)phenoxy|ethyl)piperidin-4-yl)acetic acid ethyl ester; 2139 : 1-(2,2-difluorobenzo|1 Z|dioxol-

B-yl)-3-3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenyl|urea; 2140: 1-(2,4-difluorophenyl)-3-14-(2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea; 141: 1-(4-chlorophenyl)-3-I4-(2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea; 42: (1-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)ipiperidin-4-yl)acetic acid; /-Ж143: 1- (4-chlorophenyl)-3-(4-(2-(3-hydroxyazetidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|urea; Ж144: M-(3- (4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-methylbutyramide; 145: 1-(3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; 146: 1-I3-(4-bromo-2-methyl-2IN - pyrazol-3-yl)-4-(2-piperidin-4-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; Ж147: isobutyl ether (3-(4-chloro-2-methyl-2H-pyrazole -3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|carbamic acid; 48: (5)-1-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2- methyl-2H-pyrazol-3-ylphenoxy|ethylpiperidin-3-yl ester of succinic acid, methyl ether; 149: 1- (2,4-difluorophenyl)-3-I4-(2-(3-hydroxyazetidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/phenyl|urea; 50: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-methylbutyramide; 51: methyl ether 3-( 1-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidin-4-yl)propionic acid; Z152: 1-(2, 4-difluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|urea; 153: 1-(4-chlorophenyl)-3 -I3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|urea; 2154: I3-(2-methyl-2H-pyrazol-3-yl) isopropyl ether )-4-(3-morpholin-4-ylpropoxy)phenyl Icarbamic acid; Z155: isobutyl ether (3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl| carbamic acid; 156: 1-(4-chlorophenyl)-3-14-(2-(3-hydroxypyrrolidin-1-yl)ethoxy1|-3-(2-methyl-2H-pyrazol-3-yl)/phenyl| urea; Z157: (1-2-14-(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperidin-3-yl)acetic acid acids; Z158: tert-butyl ether //4-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethylpiperazine-1-carbono your acids; Z159: 1-(4-chlorophenyl)-3-I(4-(2-((5)-3-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl) /uphenyl|urea; 160: 2-(4-fluorophenyl)-N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; Z161: 2-(4-Methoxyphenyl)-

M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; Z162: 1-(2,4-difluorophenyl)-3-I4- (2-(4-methylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea; Z163: 1-(2,4-difluorophenyl)-3-I4- (2-(3-methylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea; 164: 1-(4-chlorophenyl)-3-I4-(2 -((A)-3-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/uphenyl|urea; 165: 2-(2,4-difluorophenyl)-IM -(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; 2166: M-I4-(2-(25,68)-2, 6-dimethylmorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenylacetamide; Z167: 1-14-(2-(4-acetylpiperazin-1-yl)ethoxy|-3 -(2-methyl-2H-pyrazol-3-iluphenyl|-3-(4-chlorophenyl)urea; 168: |3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-( Pentanoic acid 2-morpholin-4-ylethoxy)phenyl|amide; 69: 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|amide 3-hydroxypyridine-2-carboxylic acid; 170: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)pheny 11-b6-trifluoromethylnicotinamide; Ж171: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-b-methylnicotinamide; 2172: tert-butyl ether 5 -(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)-2,5-diazabicyclo(2.2.1|heptane-2-carboxylic acid 173: Benzyl ether of /2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxymethyl|morpholine-4-carboxylic acid;

I174: (1-13-2-methyl-2H-pyrazol-3-yl)-4-(morpholin-2-ylmethoxy)phenyl|3-phenylurea; 175: (1-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidin-3-yl)acetic acid; Z176: methyl ether 4-(4-(2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperazin-1-yl)-4-oxobutyric acid 77: 1-(4-chlorophenyl)-3-(4-(2-(2,5-diazabicyclo(2.2.1|hept-2-yl)ethoxy|-3-(2-methyl-2H-pyrazol- 3-yl)/phenyl|urea; 78: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl)|-6 - hydroxynicotinamide; 2179: 43-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-hydroxypiperidin-1-yl)ethoxy|phenylamide of pentanoic acid; Z180: (3- Pentanoic acid (4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-hydroxypiperidin-1-yl)ethoxy|phenyl)iamide; Ж181: M-(3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-hydroxypiperidin-1-yl)ethoxy|phenyl)-6-methylnicotinamide; 182: 1-(2,4-difluorophenyl)- 3-I4-I(2-(28,65)-2,6-dimethylmorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/uphenyl|urea; 183: 1 -I4-I(2-(28,65)-2,6-dimethylmorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl) )/phenyl|-3-(4-fluorophenyl)urea; Ж184: 1-(4-chlorophenyl)-3-I4-I-2-(28,65)-2,6-dimethylmorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3- yl)uphenyl|urea; 185: 1-2-(2-(2-methyl-2H-pyrazol-3-yl)-4-pentanoylaminophenoxy|ethyl)ipiperidine-4-carboxylic acid; 186: 4-chloro-M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; Z187: methyl ether of 4- (5-2-(4--3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)-2,5-diazabicyclo((2.2.1|hept- 2-yl)-4-oxobutyric acid; 188: 1-(4-chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-ylethoxy) phenyl|urea; 189: 1-I4-(2-(28,65)-2,6-

dimethylmorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|-3-(3-fluorophenyl)urea; 90: 2-(4-chlorophenyl)-M-(4-( 2-(28,65)-2,6-dimethylmorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/phenylacetamide; 2191: 4-(4-(2-I4) -I(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperazin-1-yl)-4-oxobutyric acid; 92: 1-(2 ,4-difluorophenyl)-3-(4-(1-methylpiperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea; 193: isopropyl ether (4-(2- (25,68)-2,6-dimethylmorpholin-4-yl ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|carbamic acid; ЖЖ194: methyl ether /(((1-2-( 2-(2-methyl-2H-pyrazol-3-yl)-4-pentanoylamino-phenoxy|ethyl)piperidine-4-carbonyl)amino|acetic acid; 2195: ((1-42-(2-(2-methyl -2H-pyrazole-

C-yl)-4-pentanoylaminophenoxy|ethyl)piperidine-4-carbonyl)amino|acetic acid; Zh196: (1H-benzoimidazol-2-yl)-

13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine; 97: 1-2-(I4-(benzooxazol-2-ylamino)-2-(2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)piperidine-4-carboxylic acid; Z198: benzothiazol-2-yl-( 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine; Ж199: benzooxazol-2-yl-13-(4-bromo- 2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|iamine; Z200: methyl ether ((1-(2-(4-(benzooxazol-2-ylamino)- 2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidine-4-carbonyl)amino|acetic acid; Х201: ethyl ether 1-(2-(4-(benzooxazol-2-ylamino)-2- (2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)piperidine-4-carboxylic acid; 202: I1-2-4-(benzooxazol-2-ylamino)-2-(2-methyl-2H-pyrazole-Z -yl)uphenoxy|ethyl)piperidine-4-carbonyl)amino|acetic acid; 203: I4-(2-(4-hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3- yl/phenyl|pentanoic acid amide; 204: 3-(4-(2-(2-(2-methyl-2H-pyrazol-3-yl)-4-pentanoylaminophenoxy|ethyl)piperazin-1-yl)propionic ethyl ester acids; Ж205: 1-(2,4-difluorophenyl)-3-I(I3-(2-methyl-2H-pyrazol-3-yl)-4-(pyrrolidin-2- ylmethoxy)phenyl|urea; 206: (4--2--2-(2-methyl-2H-pyrazol-3-yl)-4-pentanoylaminophenoxy|ethyl)piperazin-1-yl)acetic acid; 207: 3-(4-(2-(2-(2-methyl-2H-pyrazol-3-yl)-4-pentanoylaminophenoxy|ethyl/)piperazin-1-yl)propionic acid; 208: -I4-(2 -(4-hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-6-trifluoromethylnicotinamide; Z209: methyl ether (4-(2-I4-I3-( 4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperazin-1-yl)acetic acid; 210: 4-(5-(2-I4-(3- (4 -chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)-2,5-diazabicycloyl|2.2.1|hept-2-yl)-4-oxobutyric acid; i211: 3-(1-2-(4-3--4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)piperidin-4-yl)propionic acid; 212: (4 2213: (4-( 2-(3-methanesulfonylpyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|Iamide of pentanoic acid; Ж214: isopropyl ether (|3-(2-methyl-2H-pyrazole- 3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenylcarbamic acid; 2215: isopropyl ether (3-(2-methyl-2H-pyrazol-3-yl)-4-( 2-1 "oxazepan-4-ylethoxy)phenyl|carbamic acid; 2216: 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-

I1,oxazepan-4-ylethoxy)phenyl|urea; 217: 1-(2,4-difluorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-

1,4oxazepan-4-ylethoxy)phenyl|urea; 1Z218: 1-(4-chlorophenyl)-3-14-(2-imidazol-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl)/uphenyl|urea; 219: 1-(2,4-difluorophenyl)-3-I4-(2-imidazol-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-ylphenyl|urea; 220: 1-(2, 4-difluorophenyl)-3-I4-(2-(1,1-dioxo-126-thiomorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|urea; 221 : 3-methyl-M-(3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|butyramide; 222: M-I4-(2-(З -methoxyazetidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|acetamide; 25223: "3-(4-bromo-2-methyl-2H-pyrazol-3-yl )-4-I(2-(4-hydroxypiperidin-1-yl)ethoxy|phenyl)amide of 4-methylpentanoic acid; 224: 1-(4-chlorophenyl)-3-I4-(2-(3-methoxyazetidin-1 -yl)ethoxy|-3-(2-methyl-2H-pyrazole-

Z-yl)phenyl|urea; 2225: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4,4-difluoropiperidin-1-yl)ethoxy|phenyl)y-

C-trifluoromethylbenzamide; 226: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-phenylpiperidin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; 227: 1 -(2,4-difluorophenyl)-3-I4-I(2-(3-methoxyazetidin-1-yl)ethoxy|-3- (2-methyl-2H-pyrazole-3-iluphenyl|urea; iZh228: 2- (4-Chlorophenyl)-M-I4-(2-(3-Methoxyazetidin-1-yl)ethoxy|-3-(2- methyl-2H-pyrazol-3-yl)phenyl|acetamide; 229: 1-IZ- (4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-fluorophenyl)urea; 230: 1-IZ-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(2-fluorophenyl)urea; 231: 1-IZ-(4-chloro-2 -methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-chlorophenyl)urea; 232: 1-I3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-phenylurea; 233: 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl) )-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3,5-difluorophenyl)urea; 234: 1-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl )-4-(2-morpholin-4-ylethoxy)phenyl|-3-(2,4-dichlorophenyl)urea; 235: 1-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl )-4-(2-morpholin-4-ylet si)phenyl|-3-(4-chloro-2-fluoromethylphenyl)urea; 236: 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-p-tolylurea; 5237: 1-(I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|- 3-(4-methoxyphenyl)urea; 238: methyl ester of (1--2--2-(2-methyl-2H-pyrazol-3-yl)-4-pentanoylaminophenoxy|ethyl)piperidin-4-yl)acetic acid; 239: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-methanesulfonylpiperazin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; 2240: ( 1-42-(2-(2-methyl-2H-pyrazol-3-yl)-4-pentanoylaminophenoxy|ethyl)piperidin-4-yl)acetic acid; 241: M-I3-(4-bromo-2-methyl -2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|acetamide; H242: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)- 4-(2-piperidin-1-ylethoxy)phenyl|acetamide; 5243: isopropyl ether (4-(2-(4-methylpiperazin-1-yl)ethoxy)|-3-(2-methyl-2H-pyrazol-3- yl)phenyl|carbamic acid; 244: butyl ether (|4-(2-(4-methylpiperazin-1-yluethoxy|-3-(2-methyl-2IN-pyrazol-3-yl))/phenylIcarbamic acid; 2245: 1 -(3-fluorophenyl)-3-(4-(1-methylpiperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)/uphenyl|urea; 246: 1-(2-fluorophenyl )-3-(4-(1-methylpiperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea; YANA: 1-(4-methoxyphenyl)-3-I4- (1-methylpiperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)/phenyl|urea; 248: 1-(3-chlorophenyl)-3-14-(1-methylpiperidin-4 -yloxy)-3-(2-methyl-2H-p irazol-3-yl)/phenyl|urea; Ж249: M-I(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-/1,4|oxazepan-4-ylethoxy)phenyl|acetamide; 2250: 1-(4-chlorophenyl )-3-I4-(2-(1,1-dioxo-156-thiomorpholin-4-yl)ethoxy1|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|urea; 251: 1- (4-(2-(1,1-dioxo-125-thiomorpholin-4-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl)|-3-(4-fluorophenyl)urea 252: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; 2253: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenyl|-3-(2,4-difluorophenyl)urea; 254: 1-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(1,1-dioxo-156-thiomorpholin-4-yl)ethoxy|phenyl)-3-( 4-chlorophenyl)urea; 255: 1-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(1,1-dioxo-1x6-thiomorpholin-4-yl) ethoxy|phenyl)-3-(2,4-difluorophenyl)urea; 2256: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(-2-I1 Aoxazepan-

4-ylethoxy)phenyl|-3-(4-chlorophenyl)urea; 257: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-M1,Aoxazepan-4-ylethoxy)phenyl|-3-(2,4-difluorophenyl) urea; 258: 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3,4-difluorophenyl)urea 259: 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-fluoromethylphenyl)urea; 260 : 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-methoxyphenyl)urea; 2261: 1 -(3-acetylphenyl)-3-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|urea; 262: 1-I3 -(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(2,5-difluorophenyl)urea; 263: 1-I3- (4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|-3-(2,6-difluorophenyl)urea; 264: 1-(3 ,5-bis-trifluoromethylphenyl)-3-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|urea; 265: 1- 13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-naphthalen-1-ylurea; 266: M-(3-( 4-bromo-2-methyl-2H-pyrazole-3- yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenylacetamide; 267: 1--3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl)-3-(4-chlorophenyl) )urea; 2268: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl)-3-(2,4 -difluorophenyl)urea; 2269: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl)-2 -(4-chlorophenyl)acetamide; 270: 1-13-(4-bromo-2-methyl-2H-pyrazole-

C-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl)-3-(4-fluorophenyl)urea; 2271: (3-(4-chloro-2-methyl-2H-pyrazole-

C-yl)-4-(2D-morpholin-4-ylethoxy)phenyl|Iamide of cyclopropanecarboxylic acid; 272: Thiophene-2-carboxylic acid (|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|amide; Zh273: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-4-fluorobenzamide; Z274: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-(4-chlorophenyl)acetamide; 215: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-methylbutyramide; 2276: M-I4-(2-( 4-acetylpiperazin-1-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl|-3-methylbutyramide; 2. M-(3-(4-bromo-2 -methyl-2H-pyrazol-3-yl)-4-(2-(4-hydroxypiperidin-1-yl)ethoxy|phenyl-3-methylbutyramide; 278: /-M-(3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-(2-(3-hydroxyazetidin-1-yl)ethoxy|phenyl)acetamide; 219: 1--3-(4-bromo-2-methyl-2H-pyrazole -3-yl)-4-(2-(3- hydroxyazetidin-1-yl)ethoxy|phenyl)-3-(4-chlorophenyl)urea; 280: 4-fluoro-M-I3-(2-methyl-2H -pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; 281: 2,4-difluoro-M-|3-(2-methyl-2H-pyrazol-3-yl)- 4--2-morpholin-4-ylethoxy)phenyl|benzamide; 282: M-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4 - trifluoromethyl-benzamide; 283: M-(3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl)|-4-trifluoromethoxybenzamide; 284: 1-3 -(4-b Rom-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-hydroxyazetidin-1-yl)ethoxy|phenyl)-3-(2,4-difluorophenyl)urea; 285: 1-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-hydroxyazetidin-1-yl)ethoxy|phenyl)-3-(4-fluorophenyl) urea; 2286: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-hydroxyazetidin-1-yl)ethoxy|phenyl)-3-(2-fluorophenyl) )urea; 5287: Furan-2-carboxylic acid 13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|Iamide; 2288: M- (3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-fluorobenzamide; 289: /- M-I3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|-3-fluorobenzamide; 290: 1-I4-(1-methylpiperidin-4-yloxy)- 3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-p-tolylurea; 291: 1-(3-cyanophenyl)-3-14-(1-methylpiperidin-4-yloxy)-3- (2-methyl-2H-pyrazol-3-yl)phenyl|urea; 292: 1-(2-fluoro-5-methylphenyl)-3-(4-(1-methylpiperidin-4-yloxy)-3-(2 -methyl-2H-pyrazol-3-yl)/phenyl|urea; 293: M-I4--2-(28,65)-2,6-dimethylpiperidin-1-yl)ethoxy|-3-(2-methyl -2H-pyrazol-3-yl/phenyl|acetamide; 294: 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|cyclopropanecarboxylic acid amide; 295: |3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|amide thiophene-2-carbon acids; 2296: Furan-2-carboxylic acid (3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|iamide; 297: 4-fluoro-M-I( 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 298: 1-(3-(4-chloro-2-methyl-2H-pyrazole) -3-yl)-4-I(2-(3-hydroxyazetidin-1-yl)ethoxy|phenyl)-3-(4-chlorophenyl)urea; 299: 1-(3-(4-chloro-2-methyl) -2H-pyrazol-3-yl)-4-I(2-(3-hydroxyazetidin-1-yluethoxy|phenyl)-3-(2,4-difluorophenyl)urea; 2300: methyl ether (1-(2-( 2-(2-methyl-2H-pyrazol-3-yl)-4-((b-trifluoromethylpyridine-3-carbonyl)amino|phenoxy)ethyl)piperidin-4-yl|acetic acid; YAZO1: /(1-( 2-(2-(2-methyl-2H-pyrazol-3-yl)-4-((6-trifluoromethylpyridine-3-carbonyl)amino|phenoxy)ethyl)piperidin-4-yl|acetic acid; 302: 3- fluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; ZH303: 2-fluoro-M-|3-(2- methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 304: 1-(2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazole -3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea; y305: 3-(4-chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-(4-chlorophenyl)amine; 306: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-cyclopropylacetamide; 307: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-cyclopentylacetamide; z308: cyclopropanecarboxylic acid 13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|amide; 2309: Cyclobutanecarboxylic acid (3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|iamide; 2310: I(3-(4-bromo Cyclopentanecarboxylic acid -2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|iamide; 311: 1-(4-chlorophenyl)-3-(3-(2-methyl) -2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethylamino)phenyl|urea; - Z312: 1-(2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazole -3-yl)-4-(2-morpholin-4-ylethylamino)phenyl|urea; Ж313: 2-(4-chlorophenyl)-2,2-difluoro-M-I3-(2-methyl-2H-pyrazole- 3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; 314: 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidine -1-ylethoxy)phenyl|-3-(4-fluorophenyl)urea; 315: 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1- ylethoxy)phenyl|-3-(4-methoxyphenyl)urea; /-Ж316: 1--4-bromophenyl)-3-(4-(1-methylpiperidin-4-yloxy)-3-(2- methyl-2H- pyrazol-3-yl)phenyl|urea; y317: 1-(4-(1-methylpiperidin-4-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-(2- -rifluoromethoxyphenyl)urea; ZH318: 1-I4-(1-methylpiperidin-4-yloxy)-3-(2-methyl -2H-pyrazol-3-yl)/phenyl|-3-(4-fluoromethylphenyl)urea; Zh319: 1-(4-chlorophenyl)-3-I4-I2-(25,6H8)-2,6-dimethylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl) phenyl|urea; 320: 1-(2,4-difluorophenyl)-3-(4-(2-(25,68)-2,6-dimethylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole- 3-iluphenyl|urea; 321: 1-(4-(2-(25,68)-2,6-dimethylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl| -3-(4-fluorophenyl)urea; 322: tert-butyl ether 4-(2-(2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(I3-(4- chlorophenyl)ureido|phenoxy)ethyl)piperidine-1-carboxylic acid; 323: tert-butyl ether 4-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-(4 - chlorophenyl)ureido|phenoxymethyl)piperidine-1-carboxylic acid; 2324: 1-I4-I2-(28,65)-2,6-dimethylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H- pyrazol-3-iluphenyl|-3-(4-methoxyphenyl)urea; 325: 2-(4-chlorophenyl)-M-I(4-(2-

(25,68)-2,6-dimethylpiperidin-1-yl)ethoxy-3-(2-methyl-2H-pyrazol-3-yl)phenylacetamide; 326: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl-3-methylbutyramide; Z327: | Thiophene-2-carboxylic acid 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-11,oxazepan-4-ylethoxy)phenyl|amide; 2328: 2-(4-chlorophenyl)-2 ,2-difluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-1,4|oxazepan-4-ylethoxy)phenyl|iacetamide; Z329: 1-(4- chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-(1-methylpyrrolidin-2-yl ethoxy|phenylurea; Z330: 3-methyl-M-(3-( 2-methyl-2H-pyrazol-3-yl)-4-(2-(1-methylpyrrolidin-2-ylethoxy|phenylbutyramide; 331: tert-butyl ether (K)-2-(2-I4-I3-(4 - chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethylpiperidine-1-carboxylic acid; 332: tert-butyl ether 4-2-(2-methyl-2H-pyrazol-3-yl )-4-(thiophene-2-carbonyl)amino|phenoxymethyl/)piperidine-1-carboxylic acid; 333: I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2 -morpholin-4-ylethoxy)phenyl|iamide -:5-chlorothiophene-2-carboxylic acid; Z334: 1-I4-(1-acetylpiperidin-4-ylmethoxy)-3-(4-bromo-2-methyl-2H- pyrazol-3-yl/uphenyl|-3-(4-x lorphenyl)urea; 335: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-ylmethoxy)phenyl|-3-(4-chlorophenyl)urea; 336: Thiophene-2-carboxylic acid 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl]amide; 337: (|4-(2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|iamide of thiophene-2-carboxylic acid; 338: (| Thiophene-2-carboxylic acid 3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenylamide; 2339: 1-(4-chlorophenyl)-3-(3- (2-methyl-2H-pyrazol-3-yl)-4-((A)-2-piperidin-2-ylethoxy)phenyl|urea; Ж340: 1-(4-chlorophenyl)-3-(4-(1 ,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea; Z341: M-(3-(4-bromo-2 -methyl-2H-pyrazol-3-yl)-4-(2-(3-hydroxyazetidin-1-yl)ethoxy|phenyl)-2-(4-chlorophenyl)acetamide; 342: M-III-(4-chloro -2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-2-(4-chlorophenyl)-2,2-difluoroacetamide; Z343: M-IZ-(2 -methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-trifluoromethylbenzamide; (piperidin-4-ylmethoxy)phenyl|thiophene-2-carboxylic acid 2345: (3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy) )phenyl|thiophene-2-carboxylic acid amide; 2346: 1-I3-(4-chloro-2-methyl-2H-n irazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,5-difluorophenyl)urea; 347: Thiophen-2-carboxylic acid 13-(2D-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|amide; 2348: Thiophene-2-carboxylic acid (3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|amide; 349: ethyl ether (K )-4-benzyloxy-2-(2-|4-I3-(4-fluorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)pyrrolidine-1-carboxylic acid; ZhZ50: 1-|4-(2-azepan-1-ylethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenyl|-3-(4-chlorophenyl)urea; ZH351: 1- |(4-(2-azepan-1-ylethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl|-3-(2,4-difluorophenyl)urea; 2352: isopropyl (4-(2-Azepan-1-ylethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl|carbamic acid ester; 353: 1-(4-chlorophenyl)-3-

14-(2-(A8)-1-methylpiperidin-2-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/phenyl|urea; Zh354: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl)-2-(4-chlorophenyl) )-2,2-difluoroacetamide; urea; 356: 1-(4-chloro-2-fluorophenyl)-3-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy) phenyl|urea; 357: 14-(1-methylpiperidin-4-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-iluphenyl|thiophene-2-carboxylic acid amide; 2358: 1-(2,4- difluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylpropoxy)phenyl|urea; 359: 1-(4-fluorophenyl)-3-(3 -(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylpropoxy)phenyl|urea; Ж360: / M-I3-(4-bromo-2-methyl-2H-pyrazol- 3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-fluorobenzamide; 361: M-I3-(4-bromo-2-methyl-2IN-pyrazol-3-yl)-4-( 2-pyrrolidin-1-ylethoxy)phenyl|-2-(4-chlorophenyl)acetamide; Z362: M-(3-(4-bromo-2-methyl-2H-pyrazole-

C-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-2-cyclopentylacetamide; Zh363: 1-(4-chlorophenyl)-3-14-(1-methylpiperidin-4-ylmethoxy)-3-(2-methyl-2H-pyrazole-3-iluphenyl|urea; 364: tert-butyl ether (K) -3-I4-(2-(4-chlorophenyl)-2-hydroxyacetylamino|-2-(2-methyl-2H-pyrazole-3-ylphenoxy|pyrrolidine-1-carboxylic acid; 2365: tert-butyl ether (K) -3-I4-3-(4-fluorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3-ylphenoxy|pyrrolidine-1-carboxylic acid; 366: tert-butyl ether (K)-3-( 2-(2-methyl-2H-pyrazol-3-yl)-4--4-fluoromethylbenzoylamino)phenoxy|pyrrolidine-1-carboxylic acid; 367: 2-(4-chlorophenyl)-M-I3-(2- methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylpropoxy)phenyl|acetamide; Z368: 2-(4-chlorophenyl)-2,2-difluoro-M-(3-(2- methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylpropoxy)phenyl|acetamide; Z369: 2-(4-chlorophenyl)-M-I4-(1-methylpiperidin-4-ylmethoxy)- 3-(2-methyl-2H-pyrazole-

Z-yl)phenyl|acetamide; 370: 1-(4-chlorophenyl)-3-14-(1-methyl-2-morpholin-4-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea; y371: 2 -(4-chlorophenyl)-2-hydroxy-N-3-(2-methyl-2H-pyrazol-3-yl)-4-((B)-pyrrolidin-3-yloxy)phenyl|acetamide; 372: 1- (4-fluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(A)-pyrrolidin-3-yloxy)phenyl|urea; 373: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(A)-pyrrolidin-3-yloxy)phenyl|-4-trifluoromethylbenzamide; ЖЖ374: tert-butyl ether of 4-(4-acetylamino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenoxymethyl|piperidine-1-carboxylic acid; 375: 1-(2,4- difluorophenyl)-3-(4-(1-methyl-2-morpholin-4-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea; 376: 2-(4-chlorophenyl) -Im-I4-(1-methyl-2-morpholin-4-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|acetamide; Z377: M-(3-(4-chloro- 2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-2-(4-chlorophenyl)acetamide; 378: 1-3-(4-bromo-2-methyl) -2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-3-(4-chlorophenyl)urea; 379: 1-3-(4-chloro-2-methyl-2H-pyrazol- 3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,3-difluorophenyl)urea; 380: I3-(4-bromo-2-methyl-2H-pyrazol-3-yl )-4-(piperidin-4-ylmethoxy)phenyl|amide of thiophene-2-carboxylic acid; 2381: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin- 4-ylmethoxy)phenyl|-2-(4-chlorophenyl)acetamide; 382: |3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-ylmethoxy) phenyl|thiophene-2-carboxylic acid amide; Z383: /M-I3-(4-bromo-2-methyl-2H-pyra zol-3-yl)-4-(1-methylpiperidin-4-ylmethoxy)phenyl|-2-(4-chlorophenyl)acetamide; Zh384: 1-I(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,4,5-trifluorophenyl) )urea; Z385: 1-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,3,4 -trifluorophenyl)urea; 2386: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((B)-pyrrolidin-3-yloxy)phenyl|-4-trifluoromethylbenzamide; 387 : M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((B)-pyrrolidin-3-yloxy)phenyl|-4-chlorobenzamide; 388: M-I3- (4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((A)-pyrrolidin-3-yloxy)phenyl|-4-fluorobenzamide; Z389: M-I3-(4-bromo-2 -methyl-2H-pyrazol-3-yl)-4-((A)-pyrrolidin-3-yloxy)phenyl|)|-2,4-difluorobenzamide; 390: 4-chloro-M-|3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; 391: 1-I3-(4-bromo-2-methyl-2H-pyrazole-3 -yl)-4-(A)-pyrrolidine-3-yloxy)phenyl|-3-(4-chlorophenyl)urea; Zh392: 1-

13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((A)-pyrrolidin-3-yloxy)phenyl|-3-(-2,4-difluorophenyl)urea; Z393: 1-(4-chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|urea; 394: 1-I3-(4 -bromo-2-methyl-2H-

pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-3-(4-fluorophenyl)urea; Zh395: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-4-chlorobenzamide; 396: /M-I(I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-4-fluorobenzamide; 397: M-I3-( 4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-2,4-difluorobenzamide; 398: M-I3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-2-(4-fluorophenyl)-2-hydroxyacetamide; 2399: 4-fluoro-M-I3-(4-fluoro-2- methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; I400: 2-(4-chlorophenyl)-M-(3-(4-fluoro-2-methyl- 2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; 401: 1-(4-chlorophenyl)-3-(4-(1,1-dimethyl-2-pyrrolidine- 1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea; 402: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin- 3-yloxy)phenyl|-4-trifluoromethylbenzamide; 403: 1-14-(1,1-dimethyl-2-pyrrolidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl| -3-(4-fluorophenyl)urea; 404: 2-(4-chlorophenyl)-M-|4-(1,1-dimethyl-2-pyrrolidin-1-ylethoxy)-3-(2-methyl-2H- pyrazol-3-yl/uphenyl|iacetamide; 405: 1-I4-(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3-(2-methyl-2H-pyrazole-Z3 -yl)uphenyl|-3-(4-hl orphenyl)urea; 406: 1-|4-I(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3- (4-fluorophenyl)urea; 407: 1-(2,4-difluorophenyl)-3-I4-(1,1-dimethyl-2-pyrrolidin-1-ylethoxy)-3-(2-methyl-2H-pyrazole- 3-yl)uphenyl|urea; 54408: 3,4-difluoro-M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 409 : 2,4-dichloro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 410: 3,4-dichloro-M -I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; Z411: / 3-fluoro-M-I3-(2-methyl-2H- pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-4-trifluoromethylbenzamide; JA12: 5-fluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)- 4-(2-piperidin-1-ylethoxy)phenyl|-2--rifluoromethylbenzamide; 413: 3,5-difluoro-M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2- piperidin-1-ylethoxy)phenyl|benzamide; IA14: M-13-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|/|-4-trifluoromethylbenzamide; IA15: 2-(4-Chlorophenyl)-1N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylisobutyramide; 416: |3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|iamide of 1-(4-chlorophenyl)-cyclopropanecarboxylic acid; 417: M-13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-2-(4-chlorophenyl)isobutyramide; IA18: 1-(4-chlorophenyl)cyclopropanecarboxylic acid N3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylamide; 2419: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-2-(4-chlorophenyl)-2-hydroxyacetamide; 420: 1-14-(8)-1-benzylpyrrolidin-3-yloxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-(4-chlorophenyl)urea; 21: 1-(4-chlorophenyl)-3-(4-(2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl |urea; 422: 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-((B)-piperidin-3-yloxy)phenyl|urea; 423: 2-(4-chlorophenyl)-M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(A)-piperidin-3-yloxy)phenyl|acetamide; 24: 2,4-difluoro- M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 425: M-(3-(2-methyl-2H-pyrazol- 3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 426: M-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin- 1-ylethoxy)phenyl|-2-trifluoromethylbenzamide; 427: M-I4-(2-(7-azabicyclo|2.2 1|hept-7-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3- yl)phenyl|-2-(4-chlorophenyl)acetamide; 428: 1-I4-(2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(2-methyl-2H- pyrazol-3-yl)phenyl|-3-(2,4-difluorophenyl)urea; 429: 1-I4-(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3- (2-methyl-2H-pyrazol-3-yl/uphenyl|-3-(2,5-difluorophenyl)urea; 430: M-I(4-(2-(7-azabicyclo|2.2.1|hept-7 -yl)ethoxy|-3-(2-methyl-2IN-pyrazol-3-yl)/ phenyl|-4-chlorobenzamide; 431: M-I4-(2-(7-azabicyclo(2.2.1)hept-7-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-fluorobenzamide; 432 : 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|amide of benzo(b|thiophene-2-carboxylic acid; 433: 2-(4-chlorophenyl )-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-piperidin-3-yloxy)phenyl|acetamide; Aza; 2-(4-chlorophenyl)-2- hydroxy-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-piperidin-3-yloxy)phenyl|acetamide; 435: M-3-(2-methyl-2H -pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 436: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-( 2-piperidin-1-ylethoxy)phenyl|-2-thiophen-2-ylacetamide; 437: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin- 1-ylethoxy)phenyl/|-3-(4-fluorophenyl)propionamide; 438: 1-(2,4-difluorophenyl)-3-3-(2-methyl-2H-pyrazol-3-yl)-4-( piperidin-4-yloxy)phenyl|urea; 439: 1-(4-chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)phenyl| urea; A: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-trifluoromethylbenzamide; A. M-( 3-(4 -chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3,4-difluorobenzamide; ON: 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-ylpropoxy)phenyl|urea; y443: 2-(4-chlorophenyl)-N-13-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-ylpropoxy)phenyl|acetamide; Ada: 3,4-difluoro-N-3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)phenyl|benzamide; 445: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)phenyl|-4-trifluoromethylbenzamide; 446: /M-3-(2-methyl-2H) -pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-ylpropoxy)phenyl|-4-trifluoromethylbenzamide; 447: /M-(3-(4-bromo-2-methyl-2H-pyrazole) -3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-2-(4-fluorophenyl)-2-hydroxyacetamide; 448: M-I3-(4-bromo-2-methyl-2H-pyrazole -3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-2-(2-chlorophenyl)-2-hydroxyacetamide; 2449: M-I3-(4-bromo-2-methyl-2H-pyrazole -3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-4-fluorobenzamide; 450: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4- (2-piperidin-1-ylethoxy)phenyl|-3-fluorobenzamide; NAABI: 00M-14-(2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(2-methyl- 2H-pyrazol-3-yl)uphenyl|-4-trifluoromethylbenzamide; iaB2: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy) phenyl|-4-trifluoromethylbenzamide; 453:

M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3,4-difluorobenzamide; 454: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-trifluoromethylbenzamide; Х455: M-I3-( 4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-fluorobenzamide; 456: M-I3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3,4-difluorobenzamide; 457: M-(4-(2-(2-methylpiperidin-1-yl)ethoxy) -3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-fluoromethylbenzamide; -3-(2- methyl-2H-pyrazol-3-yl/uphenyl|benzamide; 2459: 3,4-difluoro-M-(4-(2-(2-methylpiperidin-1-yl)ethoxy|-3- (2-methyl-2IN-pyrazol-3-yl)/phenyl|benzamide; 460: 1-(4-chlorophenyl)-3-(4-(2-(2-methylpiperidin-1-yl)ethoxy|-3- (2-methyl-2H-pyrazol-3-yl)/uphenyl|urea; 461: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1 -ylethoxy)phenyl|-3-(4-chlorophenyl)propionamide; 462: M-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy) phenyl|-3-(2,4-dichlorophenyl)propionamide; 463: M-13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl |-3- those azol-2-ylpropionamide; 464: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-pyridin-

Z-ylpropionamide; 465: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-hydroxyphenyl)propionamide; 466: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-

methoxyphenyl)propionamide; Av: 2-(4-chlorophenyl)-M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-yloxy)phenyl|acetamide; t468: 2,4-difluoro-M-1|3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; 469: 3,4-dichloro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; ZHA70: /M-(4- (2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-trifluoromethylbenzamide; 471: /-M-(4- (2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; 472: M-(4-(2 -((5)-3-fluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-methylbenzamide; 473: 3-fluoro-M-I4-I (2-(5)-3-fluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|benzamide; 474: M-(3-(4-bromo-2 -methyl-2H-pyrazol-3-yl)-4-(2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|phenyl)-4-fluorobenzamide; y475: M-(3-(4-bromo) -2-methyl-2H-pyrazol-3-yl)-4-(2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|phenyl)-3-fluorobenzamide; 2476: 4-chloro-M-| 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-pyrrolidin-1-ylpropoxy)phenyl|benzamide; IA77: 2-fluoro-M-(3-(2-methyl -2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-trifluoromethylbenzamide; 478: 1-

13-(2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|-3-(4-trifluoromethylphenyl)urea; 479: 4-chloro-

M-I3-(2d-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; Zh480: M-|3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 481: -I4-(2-(4-fluoropiperidin-1-yl)ethoxy |-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|-4-trifluoromethylbenzamide; 2482: M-I4-(2 -(4-fluoropiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; 483: 3,4-difluoro-M-IZ3-(2- methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; new: 3-chloro-4-fluoro-M-I3-(2-methyl-2H-pyrazol-3 -yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; 485: 4-fluoro-M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin- 1-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 486: 4-fluoro-3-methyl-m-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy) phenyl|benzamide; 487: 3-fluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-trifluoromethylbenzamide; 488: C -fluoro-4-methyl-M-1|3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; 489: 4-chloro-M- (3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; 490: 3,4-dichloro-M-|3-(2-methyl- 2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|benzamide; 491: 4-fluoro-M-|3-(2-methyl-2H-pyrazol- 3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 492: M-(4-I(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-Z- trifluoromethylbenzamide; 493: 3-chloro-4-fluoro-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 2494: 4- fluoro-M-(3-(2-methyl-2IN-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 5495: 3-fluoro-4-methyl-M -I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 496: 4-fluoro-33-methyl-M-(3-(2- methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|Ibenzamide; H497: /- M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl) )-4-(2-pyrrolidin-1-ylethoxy)phenyl|-2,4-difluorobenzamide; 498: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2 -pyrrolidin-1-ylethoxy)phenyl|-4-chlorobenzamide; 499: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl |-4-methylbenzamide; Y500: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-trifluoromethylbenzamide; Z501: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-chlorobenzamide; Ж502: M-|3-(4- b Rom-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; Z503: M-|3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-2,4-difluorobenzamide; 504: /M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-4-chlorobenzamide; y505: M-I3- (4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-4-methylbenzamide; Z506: M-I3-(4-bromo-2-methyl) -2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-trifluoromethylbenzamide; Z507: /M-(3-(4-bromo-2-methyl-2H-pyrazole-3 -yl)-4-(2-piperidin-1-ylethoxy)phenyl|-3-chlorobenzamide; Z508: 0 M-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4 -(2-piperidin-1-ylethoxy)phenyl|benzamide; 509: 4-fluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy) phenyl|benzamide;

I510: 4-methyl-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; Z511: M-I3-(2- methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-trifluoromethoxybenzamide; 512: 3-chloro-M-(3-(2-methyl-2H-pyrazol-3 -yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; 1-ylethoxy)phenyl|benzamide; Z514: 1-(4-chlorophenyl)-3-(4-(2-methyl-2-morpholin-4-ylpropoxy)-3-(2-methyl-2H-pyrazole-3- yl)uphenyl|urea; y515: M-(4-(2-methyl-2-morpholin-4-ylpropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; y516 : M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-33-fluorobenzamide; 517: M-(3-(4 -bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-fluorobenzamide; y518: M-(4-(2-methyl-2-morpholin- 4-ylpropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-trifluoromethylbenzamide; y519: 4-chloro-3-fluoro-N-(3-(2-methyl-2H-pyrazole) -3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 2520: 4-chloro-M-I3-(4-chloro-2-methyl-2H-pyrazole -3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-fluorobenzamide; 521: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(4-fluorophenyl)propionamide; 522: M-III-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-fluorophenyl)propionamide; 523: M-III -(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(4-chlorophenyl)propionamide; 524. M-(3-( 4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl)-2,4-difluorobenzamide; 525: 3,4-dichloro-M-3- (4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; 2526: 3-chloro-M-I3-(4-chloro-2- methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-fluorobenzamide; y52: M-(3-(4-chloro-2-methyl-2H-pyrazol-3 -yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 528: 3-chloro-M-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)- 4-(2-morpholin-4-ylethoxy)phenyl|benzamide; 529: M-III-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy) phenyl|-3-methylbenzamide; 530: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-trifluoromethoxybenzamide; y531: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|-4-methoxybenzamide; 532: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-methylbenzamide; y533: M-(3- (2-methyl-2H-pyrazol-3-yl)-4-(2-(1-methylpyrrolidin-2-yl)ethoxy|phenyl)-3-trifluoromethylbenzamide; 534: 2,4-difluoro-M-(3- (2-methyl-2H-pyrazol-3-yl)-4-(2-(1-methylpyrrolidin-2-yl)ethoxy|phenyl)benzamide; y535: 3-chloro-4-fluoro-M-(3-( 2-methyl-2H-pyrazol-3-yl)-4-(2-(1-methylpyrrolidin-2-yl)ethoxy|phenylbenzamide; Ж536: M-(4-(2-(3,3-difluoropyrrolidin-1- yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-trifluoromethylbenzamide; 537: 4-fluoro-M-(4-(2-(4-fluoropiperidin-1-yl) ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-

C-methylbenzamide; y538: 3-Chloro-4-fluoro-N-I4-(2-(4-fluoropiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|benzamide; y539: M-I3-(d-methyl-2H-pyrazol-3-yl)-4-((5)-1-methylpyrrolidin-2-ylmethoxy)phenyl|-3-trifluoromethylbenzamide; y540: 3-chloro-4-fluoro- M-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-1-methylpyrrolidin-2-

ylmethoxy)phenyl|benzamide; z: 4-chloro-3-fluoro-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide; 542: M-(3 -(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-pyridin-3-ylpropionamide; Z543: M-(3-(4 -chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-thiophen-2-ylpropionamide; 544: M-(3-(4-chloro- 2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-3-thiazol-2-ylpropionamide; 545: 3-chloro-M-(4-(2-( 3,3-difluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|-4-fluorobenzamide; 546: /-M-(4-(2-(3,3- difluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-4-fluoro-3-methylbenzamide; 54: 4-fluoro-3-methyl-M-I3-( 2-methyl-2H-pyrazol-3-yl)-4-((5)-1-methylpyrrolidin-2-ylmethoxy)phenyl|benzamide; 548: /M-I3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|)|-2,4-difluorobenzamide; 549: I3-(4-bromo-2-methyl-2H-pyrazol-3-yl )-4-(2-morpholin-4-ylethoxy)phenyl|5-methylisoxazole-3-carboxylic acid amide; 550: M-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4 -(2-morpholine-4- i ethoxy)phenyl|-3-(2,4-dichlorophenyl)propionamide; 551: M-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(2-chlorophenyl)propionamide; 552: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(2,6-dichlorophenyl)propionamide; 553: M-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(4-methoxyphenyl)propionamide; 554: M -(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(4-hydroxyphenyl)propionamide; Z555: M-IZ -(2-methyl-2H-pyrazol-3-yl)-4-((2)-1-methylpyrrolidin-3-yloxy)phenyl|-3-trifluoromethylbenzamide; y556: 3-chloro-4-fluoro-M-( 3-(2-methyl-2H-pyrazol-3-yl)-4-((A)-1-methylpyrrolidin-3-yloxy)phenyl|benzamide; y557: 3-(2-methyl-2H-pyrazol-3- yl)-4-(A)-1-methylpyrrolidin-3-yloxy)phenyl|amide of 5-methylisoxazole-3-carboxylic acid; 558: M-I3-(4-chloro-2-methyl-2H-pyrazole-3- yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-fluoro-4-trifluoromethylbenzamide; 2559: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)- 4-(2-morpholin-4-ylethoxy)phenyl|-3-fluoro-4-methylbenzamide; 560: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-( 2-morpholin-4-ylethoxy)phenyl|-4-fluoro-3-trifluoromethylbenzamide; 561: M-(3-(4-chloro-2-methyl-2H-pyrazole-3 -yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-fluoro-3-methylbenzamide; 562: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylisonicotinamide; y563: M-III-(4-chloro-2 -methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|nicotinamide; y564: M-3-(4-chloro-2-methyl-2H-pyrazol-3-yl) -4-(2-morpholin-4-ylethoxy)phenyl|benzamide; 565: M-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4- ylethoxy)phenyl|-4-cyanobenzamide; 566: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-/1 4|oxazepan-4-ylethoxy)phenyl|-4- trifluoromethylbenzamide; 567: M-13-(2-methyl-2H-pyrazol-3-yl)-4-(2-1,4oxazepan-4-ylethoxy)phenyl|/|-4-trifluoromethoxybenzamide; y568: M-(Z -(2-methyl-2H-pyrazol-3-yl)-4-(2-/1Aoxazepan-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 569: 3,4-difluoro-M-|3-(2 -methyl-2H-pyrazol-3-yl)-4-(2-1,oxazepan-4-ylethoxy)phenyl|benzamide; y570: 4-fluoro-M-I3-(2-methyl-2H-pyrazol-3- yl)-4-(2-Y14|oxazepan-4-ylethoxy)phenyl|benzamide; y571: 4-fluoro-3-methyl-N-3-(2-methyl-2H-pyrazol-3-yl)-4 -(2-1 4|oxazepan-4-ylethoxy)phenyl|benzamide; 572: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpyr) olidin-1-yl)ethoxy|phenyl)-3-trifluoromethylbenzamide; 573: M-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-fluoro-4-trifluoromethylbenzamide; 574: M-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(4-trifluoromethylphenyl)propionamide; 575: M-I4-42-((5)-3-hydroxypyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; Ж576: 3-chloro-4-fluoro-M-I4-(2-(5)-3-hydroxypyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/phenyl| benzamide; 577: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-I(2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|phenyl)-2 ,4-difluorobenzamide; 578: 3-chloro-4-fluoro-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpyrrolidin-1-yl)ethoxy| phenylbenzamide; 579: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpyrrolidin-1-yl ethoxy|phenyl)-3,4-difluorobenzamide; 580: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpyrrolidin-1-yl)ethoxy|phenyl)-2,4-difluorobenzamide; Ж581: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; 582: 4-fluoro-M-I4-(2-( 4-Methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; Z583: /-M-(3-(4-bromo-2-methyl) -2H-pyrazol-3-yl)-4-((H)-1-methylpyrrolidin-3-yloxy)phenyl|-2,4-difluorobenzamide; Z584: M-I(4-(2-(A)-3 -hydroxypyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; Ж585: /- M-(3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-((H)-1-methylpyrrolidin-3-yloxy)phenyl|-3,4-difluorobenzamide; Z586: M-I4-(2-(5)-3-hydroxypyrrolidine- 1-yl)ethoxy|-3-(2-m ethyl-2H-pyrazol-3-yl)phenyl|-4-trifluoromethylbenzamide; y587: /-M-I4-((5)-4-benzylmorpholin-3-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; 588: M-I(4-(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2IN-pyrazol-3-yl)/ uphenyl|-3-trifluoromethylbenzamide; Z589: M-I4-(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy)|-3-(4-bromo-2-methyl-2H-pyrazole -3-yl/uphenyl|-4-trifluoromethylbenzamide; -3-(4--rifluoromethylphenyl)urea; Z591: /1-14-(2-(2-methylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl)|-3 -(3-trifluoromethylphenyl)urea; 592: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-1-morpholin-3-ylmethoxy)phenyl|-3-trifluoromethylbenzamide 2593: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-((8)-1-morpholin-

3-ylmethoxy)phenyl|-3-trifluoromethylbenzamide; 594: M-I4-(8)-4-benzylmorpholin-3-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)/uphenyl|-3-trifluoromethylbenzamide; Zh595: -M-I4-(2-(7-azabicyclo(|(2.2.1|hept-7-yl)ethoxy)|-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl| -4-fluorobenzamide; 596: M-(4-(2-(7-azabicyclo|2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazole-3- isophenyl|-3-fluorobenzamide; 4-trifluoromethylbenzamide; 598: 3,4-difluoro-M-I4-(2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|benzamide; 599: M-(4-(2-(7-azabicyclo(|(2.2.1|hept-7-yl)ethoxy|-3-(4- bromo-2-methyl-2H-pyrazole-3-iluphenyl)|-2- (4-chlorophenyl)acetamide; Z600: M-(4-(2-(4-methoxypiperidin-1-yl)ethoxy |-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-trifluoromethylbenzamide) YabO1: M-(4-(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)/ phenyl|-4-chlorobenzamide; 602: M-(4-(2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2- methyl-2H-pyrazol-3-yl/uphenyl|-3-trifluoromethylbenzamide) ; YabBOZ: M-(4-(2-(7-azabicyclo(2.2 1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl|-Z- chlorbenzamide; b og: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-1'oxazepan-4-ylethoxy)phenyl|-4-trifluoromethylbenzamide; ЖЖбО5: 0 M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-1'oxazepan-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide; bean: /M -(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-1'oxazepan-4-ylethoxy)phenyl|-3-fluoro-4-trifluoromethylbenzamide; Z6O7: M- I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-1,4|oxazepan-4-ylethoxy)phenyl|-4-fluoro-3-methylbenzamide; Z608: M- I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-1'oxazepan-4-ylethoxy)phenyl|-4-fluoro-3-trifluoromethylbenzamide; 609: M-I3- (4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenyl|-4-trifluoromethylbenzamide; Yab610: M-I3-(4-bromo-2-methyl -2H-pyrazol-3-yl)-4-(2-

thiomorpholin-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 611: 1-(4-(2-(4-methoxypiperidin-1-yl)ethoxy1|-3-(2-methyl-2H-pyrazole-3-iluphenyl)|-3-(4-trifluoromethylphenyl)urea; 2612: M -I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(r-thiomorpholin-4-ylethoxy)phenyl|-3-fluoro-4-trifluoromethylbenzamide; 613: 1-(4- (2-(4-Methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl)-3-(3-trifluoromethylphenyl)urea; I614: M-I3-(4-bromo -2-methyl-2IN-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenyl|-4-fluoro-3-trifluoromethylbenzamide; Yab15: M-(3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-I(2-((5)-3-hydroxypyrrolidin-1-yl)ethoxy|phenyl Ii-2,4-difluorobenzamide; bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-((5)-3-hydroxypyrrolidin-1-yl)ethoxy|phenyl)-4-chlorobenzamide; 617: 1-I4-(8 )-4-benzylmorpholin-3-ylmethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-(4-chlorophenyl)urea; 2618: 4-chloro-M-I4-(2 - (A)-3-hydroxypyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/uphenyl|benzamide; Z619: 2-(4-chlorophenyl)-M-I4- (2-(A)-3-Hydroxypyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|acetamide ; 620: -(4-(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenyl|- 3-fluoro-4-trifluoromethylbenzamide; Java: M-I4-(2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol- 3-yl)uphenyl|-4-fluoro-3-trifluoromethylbenzamide; phenyl)-3-trifluoromethylbenzamide; yab23: 2-(4-chlorophenyl)-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-(3-oxopiperazin-1-yl) ethoxy|phenyl)acetamide; nb24.: 4-fluoro-3-methyl-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-(3Z-oxopiperazin-1-yl) ethoxy|phenylbenzamide; 625: M-(4-(2-(4-hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-trifluoromethylbenzamide; 626: M-I(4-(2-(4-hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-4-trifluoromethylbenzamide; 627: M-I4-( 2-(4-(3-methyl-(1,2,4|oxadiazol-5-yl)piperidin-1-yl|ethoxy)-3-(2-methyl-2IN-pyrazol-3-yl)/uphenyl| -4-trifluoromethylbenzamide; 628: 2-(4-chlorophenyl)-M-(4-(2-(4-(3-methyl-(1,2,4|oxadiazol-5-yl)-piperidin-1-yl) Here xy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|acetamide; 629: 4-fluoro-3-methyl-M-(4-(2-I4-(3-methyl-

1,2,4|oxadiazol-5-yl)-piperidin-1-yl|ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|benzamide; 4630: 2-(4-chlorophenyl)-

M-I(I4-(2-(4-Methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|Iacetamide; 631: 1-(4-chlorobenzyl)- 3-

I4-(2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea; 632: 1-(4-fluorobenzyl)-3-(4 - (2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/phenyl|urea; Ж633: M-13-(4-chloro-2-methyl -2H-pyrazol-3-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy|phenyl)-4-trifluoromethylbenzamide; 634: M-(3-(4-chloro-2-methyl-2H) -pyrazol-3-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; ib35: /-M-(3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy|phenyl)-3,4-difluorobenzamide; 636: M-(3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy|phenyl-4-fluorobenzamide; y637: M-(3-(4-bromo-2-methyl-2H-pyrazol-3 -yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy|phenyl)-3-fluorobenzamide; 638: -(4-(2-(7-azabicyclo(|2.2.1|hept-7- yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenyl|-2,4-difluorobenzamide; 639: M-I4-(2-(7-azabicyclo(2.2.1 |hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl|-3,4-dichlorobenzamide; 640: M-(3-(4-chloro- 2-methyl-2H-pyra zol-3-yl)-4-(2-(2-methylpiperidin-1-yl)ethoxy|phenyl-4-trifluoromethylbenzamide; 641: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpiperidin-1-yl)/ethoxy|phenyl)-3,4-difluorobenzamide 642: 1-(4-chlorobenzyl)-3-13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpiperidin-1-yl)ethoxy|phenyl )urea; 643: 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpiperidin-1-yl)ethoxy|phenyl)y-3- (4-fluorobenzyl)urea; ib44:

M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(2d-methylpiperidin-1-yl)ethoxy|phenyl-4-trifluoromethylbenzamide; yaba45: M-( 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2--2-methylpiperidin-1-yl)ethoxy|phenyl)-3,4-difluorobenzamide; bab: 1-3 -(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpiperidin-1-yl)ethoxy|phenyl)-3-(4-fluorobenzyl)urea; nbvA: 4 -chloro-M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-oxopiperazin-1-yl)ethoxy|phenyl)-benzamide; nb48: 1 -(4-chlorobenzyl)-3-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|urea; 649: 1-I3- (4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-3-(4-fluorobenzyl)urea; 650: 1-I3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-fluorobenzyl)urea; ib51: ethyl ether 4-(2-(2- (2-methyl-2H-pyrazol-3-yl)-4-(4-trifluoromethylbenzoyl-amino)phenoxy|ethylpiperazine-1-carboxylic acid; ib52: /M-(3-(4-chloro-2-methyl-2H) -pyrazol-3-yl)-4-I(2-(3-oxopiperazin-1-yl)ethoxy|phenyl-4-fluorobenzamide; 2653: ethyl ether 4-(2-I4-(3- fluorobenzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)ipiperazine-1-carboxylic acid; 654: ethyl ether of //4-2-14-13-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethylpiperazine-1-carboxylic acid; Ж655: tert-butyl ether (1-42-I4-(3-fluorobenzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperidin-4-yl)ucarbamic acid; 656: tert-butyl ether (1-(2-(2-(2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxy|ethyl)piperidin-4-yl)ucarbamic acid; 25657 : tert-butyl ether (1-(2-14-2-(4-chlorophenyl)acetylamino)-2-(2-methyl-2H-pyrazol-3-ylphenoxy)ethyl)piperidin-4-yl)ucarbamic acid; 658: 1-(4-(2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl)|-3- benzylurea; 659: M-(4-(2-(4-acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3- trifluoromethylbenzamide; ybbO: M- (4--2-(4-acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-fluorobenzamide; 661: M-(4-(2- (4-Acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-2-(4-chlorophenyl)acetamide; I6b2: ethyl ether (1-(2-I4 -(3-fluorobenzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)phenoxy|ethyl)piperidin-4-yl)ucarbamic acid; 5663: ethyl ether (1-42-(2-(2- methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoyl-amino)phenoxy|ethyl)piperidin-4-yl-carbamic acid; - pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|-3-(4-trifluoromethyl-phenyl)urea; 665: /1-3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|-3-(3-trifluoromethylphenyl)urea; 666: 1-(4-chlorobenzyl)-3-

13-(2D-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|urea; 667: 2-(4-chlorophenyl)-N-|3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|acetamide; 668: M-3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|-4-trifluoromethylbenzamide; 669: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|-3-trifluoromethylbenzamide; 670: M-(3-(4-bromo) -2-methyl-2H-pyrazol-3-yl)-4-(2-(3-oxopiperazin-1-yluethoxy|phenyl-3-chlorobenzamide; 671: 00 1-(3-fluorobenzyl)-3-(3- (2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|urea; iab72: 4-chloro-M-I3-(2-methyl-2H-pyrazol-3- yl)-4-(3-morpholin-4-ylpropoxy)phenyl|benzamide; 673: 3,4-difluoro-M-3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholine -4-ylpropoxy)phenyl|benzamide; 674: M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-oxopiperazin-1-yl)ethoxy| phenyl-3-trifluoromethylbenzamide; 675: 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-oxopiperazin-1-yl)ethoxy|phenyl)- 3-(4-chlorophenyl)urea; 676: 1-(4-fluorobenzyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(3-

morpholin-4-ylpropoxy)phenyl|urea; Jab77: /M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-oxopiperazin-1-yl)ethoxy|phenyl-3-fluorobenzamide; Jab78: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-methyl-3-oxopiperazin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; 79 : M-3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-ylpropoxy)phenyl|-4-trifluoromethylbenzamide; 680: M-3-(2-methyl-2H- pyrazol-3-yl)-4-(3-pyrrolidin-1-ylpropoxy)phenyl|-3-trifluoromethylbenzamide; 681: 4-chloro-M-I3-(2-methyl-2H-pyrazol-3-yl)-4 -(3-pyrrolidin-1-ylpropoxy)phenyl|benzamide; 682: 3,4-difluoro-M-3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-ylpropoxy) )phenyl|benzamide; 683: 2-(4-chlorophenyl)-N-I3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-ylpropoxy)phenyl|acetamide; new: 1-(2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-ylpropoxy)phenyl|urea; 685: 1-(4- chlorophenyl)-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-ylpropoxy)phenyl|urea; 686: 1-(4-chlorobenzyl)-3-I3 -(2-methyl-2H-pyrazol-3-yl)-4-(3-pyrrolidin-1-ylpropoxy)phenyl|urea; 687: M-(3- (4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-oxopiperazin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; no88: M-(4-(3-imidazol-1-ylpropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-trifluoromethylbenzamide; ib89: M-I4-(3-imidazol- 1-ylpropoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; 690: 2-(4-chlorophenyl)-M-I4-(3-imidazol-1-ylpropoxy) -3-(2-methyl-2H-pyrazol-3-yl/phenyl|acetamide; oo 1: 1-(4-chlorophenyl)-3-I4-(3-imidazol-1-ylpropoxy)-3-(2- methyl-2H-pyrazol-3-yl)phenyl|urea; 692: 1-I4-((5)-4-benzylmorpholin-3-ylmethoxy)-3-(4-chloro-2-methyl-2H-pyrazole-3 -yl)phenyl|-3-(4-fluorophenyl)urea; 693: 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-((5)-1-morpholin- 3-ylmethoxy)phenyl|-3-(4-fluorophenyl)urea; 694: M-(4-((5)-4-benzylmorpholin-3-ylmethoxy)-3-(4-chloro-2-methyl-2H- pyrazole-3-iluphenyl|-

C-trifluoromethylbenzamide; 695: 3-chloro-N-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-methyl-3-oxopiperazin-1-yl)ethoxy|phenylbenzamide ; JabOb6: /M-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-((5)-1-morpholin-3-ylmethoxy)phenyl|-3-trifluoromethylbenzamide; 697: 4-(2-(2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxy|ethyl)-4-methylmorpholin-4-yl; 698: 1- 4--2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl|-3-(2-fluorobenzyl) urea; 699: 1-I4-(2-(7-azabicyclo(|2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenyl) |-3-(3-fluorobenzyl)urea; Z700: 1-

I4-I2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl|-3-(4-fluorobenzyl)urea iTo1: 1-(4--2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl|-3 -(2,4-dichlorobenzyl)urea; Ж702: 1-I4-(2-(7-azabicyclo|2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H- pyrazol-3-ylphenyl|-3-(1-phenylethyl)urea; Ж703: M-(4-(2-(4-acetylpiperazin-1-yl)ethoxy|-3-(4-chloro-2-methyl-2H) -pyrazole-

C-yl)/phenyl|-C-trifluoromethylbenzamide; then: M-I4-(2-(4-acetylpiperazin-1-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)/phenyl|-3-fluorobenzamide; andTO5: -(4-(2-(4-acetylpiperazin-1-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)/uphenyl|-3-chlorobenzamide; Z706: 0/ 0 M-I4-(2-(4-acetylpiperazin-1-yluethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-chloro-4-fluorobenzamide; yTO07: -(4- (2-(4-acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4--fluoromethylbenzamide; 708: -I4-(2-(4-acetylpiperazine) -1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-chlorobenzamide; Z709: 1-I4-(2-(7-azabicyclo|2.2.1|)hept -7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl|-3-(4--rifluoromethylbenzyl)urea; Z710: 1-(4-(2- (7-azabicyclo|2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazole-3-iluphenyl|-3-(3-trifluoromethylbenzyl)urea; 4711: 1 -(4-(2-(4-acetylpiperazin-1-yl)ethoxy|- 3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-(4-fluorophenyl)urea; Z712: 1- I4-(2-(7-azabicyclo(2.2.1|)hept-7-yl)ethoxy|- 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenyl|-3-(4 -chlorobenzyl)urea and; Zh713: (5)-1-(2-(2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxy|ethyl)pyrrolidine-2-carboxylic acid amide 2714: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-formylpiperazin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; 715: 1-(2-(2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoyl-amino)phenoxy|ethyl)piperidine-4-carboxylic acid amide; 716: amide 4-(2-(2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxy|ethyl)piperazine-1-carboxylic acid; Ж717: M- 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|acetamide; 2718: tert-butyl ether (1-(2-(2- (4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxy|ethyl)piperidin-4-yl)-carbamic acid; Ж719: M-

14-(2-(4-aminopiperidin-1-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)uphenyl|-3-trifluoromethylbenzamide; 720: -(4-( 2-(4-acetylaminopiperidin-1-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl|-3-trifluoromethylbenzamide; Z721: 1-I4-(2-( 7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)/phenyl|-3-(2-chlorobenzyl)urea; 2722 : 1-I4-(2-(7-azabicyclo(2.2.1)hept-7-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/phenyl|-3-(2- fluorobenzyl)urea; 123: 4-(2-(2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxy|ethyl)piperazine-1-carboxylic acid dimethylamide y724: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-isopropylpiperazin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; Х725: -M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy|phenyl-3-trifluoromethylbenzamide; 726: M-

13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-3-trifluoromethylbenzamide; 727: 3-chloro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; 728: M-(3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-ylmethoxy)phenyl|-3-trifluoromethylbenzamide; 2729: 3-fluoro-M-|3-(2-methyl-2H - pyrazol-3-yl)-4-2-morpholin-4-ylethoxy)phenyl|benzamide; 730: 3,4-difluoro-M-I3-(2-methyl-2H-pyrazol-3-yl)-4 -(2-morpholin-4-ylethoxy)phenyl|benzamide; yl)phenyl|-2,4-difluorobenzamide; 132: 3-fluoro-4-methyl-N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy) phenyl|benzamide; 733: 3-methoxy-M-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; 734: 0 1-I4- (2-(7-azabicyclo(2.2.1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl|-3-(2,4- difluorobenzyl)urea; 2735: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-I(2-(3,3-difluoroazetidin-1-yluethoxy|phenyl-3- trifluoromethylbenzamide; Z736: /1-I4-(2-(7-azabicyclo|2.2.1|hept-7-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazole-3-iluphenyl|- 3-(3-fluorobene zyl)urea; 737: 1-(4-(2-(7-azabicyclo(|(2.2.1|hept-7-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)uphenyl) |-3-(2-fluorobenzyl)urea; 38: 1-I4-(2-(7-azabicyclo|2.2.1|hept-7-yl)ethoxy|-3-(4-chloro-2-methyl-2H -pyrazol-3-yl)uphenyl|-3-(4-fluorobenzyl)urea; 2739: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidine) -4-yloxy)phenyl|-4-fluorobenzamide; Ж740: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl| -3-fluorobenzamide; ZTA1.: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-2-fluorobenzamide; яТ42 M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-3-methoxybenzamide; 4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-

methylpiperidin-4-yloxy)phenyl|-4-methylbenzamide; HORROR. M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-3-fluoro-4-methylbenzamide; 745: /- M -I(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-4-fluoro-3-methylbenzamide; Z746: 1-| 4-(2-(7-azabicyclo(|2.2.1|)hept-7-yl)ethoxy|-3- (4-chloro-2-methyl-2H-pyrazol-3-yl/uphenyl|-3-benzylurea ; 747: amide of 1-2-I4-(3-fluorobenzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)ipiperidine-4-carboxylic acid; 748: amide of 4-(2- 14-(3-fluorobenzoylamino)-2-(2-methyl-2H-pyrazole-3-ylphenoxy|ethyl)piperazine-1-carboxylic acid; 749: 1-(4-(2-(7-azabicyclo(|2.2. 1|hept-7-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)uphenyl|-3-benzoylurea; Ж750:. M-(4-(2-(7 -azabicyclo|2.2.1|hept-7-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)/uphenyl|benzamide; Ж751: M-(3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-methylpiperazin-1-yl)-2-oxo-ethoxy|phenyl-3-trifluoromethylbenzamide; y52: 3-fluoro-M- (4-(2-(4-formylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|benzamide; 153: 3-fluoro-M-( 4-(2-(4-methanesulfonylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)/uphenyl|benzamide; Z754: 3-fluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-I(2-(4-trifluoromethylpiperidin-1-yl)ethoxy|phenylbenzamide; Z755: M-I4- (2-(4-acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|-3-methoxybenzamide; Z756: M-|3-(4-chloro-2-methyl -2H-pyrazol-3-yl)-4-(2-oxo-2-piperazin-1-ylethoxy)phenyl|-3-trifluoromethylbenzamide; 757: M-(3-(4-chloro-2-methyl-2H- pyrazol-3-yl)-4-(2-(4-methanesulfonylamino-piperidin-1-yl)ethoxy|phenyl)-3-trifluoromethylbenzamide; Ж758: /- M-(4-(2-(4-acetyl- 1 ,4Idiazepan-1-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)uphenyl|-2,4-difluorobenzamide; 759: 2,5-difluoro-M-I| 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide; Ж760: 3,5-dimethoxy-M-|3-(2-methyl-2H - pyrazol-3-yl)-4-2-morpholin-4-ylethoxy)phenyl|benzamide; 761: 3,5-difluoro-M-I3-(2-methyl-2H-pyrazol-3-yl)-4 -(2-morpholin-4-ylethoxy)phenyl|benzamide; 762: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2 - phenylacetamide; Z763: 2-(2-chlorophenyl)-M-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|a cetamide; java: M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-(2-trifluoromethylphenyl)acetamide; Zh765: 2-(2-methoxyphenyl)-1N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; 166: 2-(3-fluorophenyl)-N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; Zh767: 2-(3Z-chlorophenyl)-M-

13-(2D-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; Ж768: M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-(3-trifluoromethylphenyl)acetamide; Ж769: /2-( 3-methoxyphenyl)-1N-3-(2-methyl-2H-pyrazol-3-yl)-4-2-morpholin-4-ylethoxy)phenylacetamide; Ж770: M-I(I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-m-tolylacetamide; Ж771: M-IZ-(2 -methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-p-tolylacetamide; yt2: 2-benzo|1,3|dioxol-5-yl-M- (3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; sh13: M-(3-(2-methyl-2H-pyrazol-3-yl) yl)-4-2-morpholin-4-ylethoxy)phenyl|-2-o-tolylacetamide, and M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4- (2-1,4|diazepan-1-ylethoxy)phenyl|-2,4-difluorobenzamide; Ж775: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-( 2-(4-methyl-(1 4|diazepan-1-yl)ethoxy|phenyl)-2,4-difluorobenzamide; Ж776: M-I4--2-(4-acetylpiperazin-1-yl)ethoxy|-3 -(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl/|-2,4-difluorobenzamide; I: 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl) )-4-(2-morpholin-4-ylethoxy)phenyl|-3-(3-fluorobenzyl)urea; 778: 0 M-I4-(2-(4,4-difluoropiperidin-1-yl)ethoxy|-3 -(2-methyl-2H-pyrazol-3-yl)phenyl|-3-fluorobenzamide; Z779: (|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2- morpholine-4-ylethoxy)phenyl|iamide of cyclobutane-carbonic acid lots; 180: Cyclopentanecarboxylic acid 13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamide; 2781: Cyclohexanecarboxylic acid (3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|amide; Z782: M-(3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-formyl-(/1,4|diazepan-1-yl)ethoxy|phenyl)-2,4-difluorobenzamide; 183: 1-(4-(2-(4-acetylpiperazin-1-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl|-3-(3-fluorobenzyl)urea 84: M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-2,4-difluorobenzamide; 185: M- (3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-3-methylbenzamide; 786: amide 4-(2-I4-- 2,4-difluorobenzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperazine-1-carboxylic acid; Z787: M-(4-(2-(4-acetylpiperazine-1- yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl/phenyl|-2-fluorobenzamide; Z788: amide 1-(2-(2-(4-chloro-2-methyl) -2H-pyrazol-3-yl)-4-(2-fluorobenzoylamino)phenoxy|ethylpiperidine-4-carboxylic acid; Z789: 3-methoxy-M-(3-(2-methyl-2H-pyrazol-3-yl) -4--2-(4-trifluoromethylpiperidin-1-yl)ethoxy|phenylbenzamide; Ж790: M-(3-(4-chloro- 2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-ylethoxy)phenyl|-2,4-difluorobenzamide; 791: amide of 4-(2-(4-(3-methoxybenzoylamino)-2-(2-methyl-2IN-pyrazol-3-yl)uphenoxy|ethyl)piperazine-1-carboxylic acid; 2792: M-I3-( 2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|-2-pyridin-3-ylacetamide; Z793: 2-(2-fluorophenyl)-M-III- (2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide; yT94: M-(3-(2-methyl-2H-pyrazol-3-yl)- 4--2-morpholin-4-ylethoxy)phenyl|-2-(4-trifluoromethylphenyl)acetamide; Ж795: M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin- 4-ylethoxy)phenyl|-2-thiophen-2-ylacetamide; 2796: 3-fluoro-N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-ylethoxy) phenyl|benzamide; Z797: M-I(4-(2- (4-cyclopropanecarbonylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-fluorobenzamide; Z798 : C3-fluoro-

M-I(4-(2-(4-isobutyrylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl/phenyl|benzamide; 799: M-|Z-(2- methyl-2IN-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-2-pyridin-2-ylacetamide; -methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxy|ethyl)pyrrolidine-2-carboxylic acid; 2801: amide (K)-1-(2-

I4-(3-chloro-4-fluorobenzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethylpyrrolidine-2-carboxylic acid; 802: amide (5)-1-22-(2-(2-methyl-2H-pyrazol-3-yl)-4--4-trifluoromethylbenzoyl-amino)phenoxy|ethyl)pyrrolidine-2-carboxylic acid; 803: (5)-1-(2-14-(3-chloro-4-fluorobenzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)phenoxy|ethyl)pyrrolidine-2-carboxylic acid amide; y804: (5)-1-2-(2-(-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethylbenzoylamino)phenoxyethyl)pyrrolidine-2-carboxylic acid amide; 805: M-I4-(2-(4-aminopiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazole-3-iluphenyl|-3-fluorobenzamide; Ж806: M-(4-(2 -(4-aminopiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|-3-trifluoromethylbenzamide; 2807: M-I(4-(2-(4-aminopiperidine -1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-2-(4-chlorophenyl)acetamide; 2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-(4-trifluoromethylphenyl)amine; 809: I3-(4-bromo-2-methyl-2H-pyrazol-3-yl) )-4-(2-pyrrolidin-1-ylethoxy)phenyl|-(4-chlorophenyl)amine; 810: I|3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-( 2-pyrrolidin-1-ylethoxy)phenyl|-(4-fluorophenyl)amine; 811: I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy) )phenyl|-(3-fluorophenyl)amine; 812: I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-(4- trifluoromethylphenyl)amine; 813: 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-(4-fluorophenyl)amine; 814: | 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-(3-chlorophenyl)amine;

I815: |3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|-(3-fluorophenyl)amine; 2816: (3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-(3,4-difluorophenyl)amine; 817: |3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-(4-trifluoromethoxyphenyl)amine; 818: 13-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|pyridin-3-yl-amine; Zh819: 1-13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(1-methylpiperidin-4-yl)ethoxy|phenyl)-3-(4-chlorophenyl) urea; 5820: Thiophene-2-carboxylic acid (3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|iamide; 2821: M-I3- (4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-fluorobenzamide; 822: M-I3-(4-bromo-2-methyl -2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-2-(4-chlorophenyl)acetamide; 2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|benzamide; 924: M-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidine -1-ylethoxy)phenyl|/|-4-trifluoromethylbenzamide; 925: M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl |-3-fluorobenzamide; 826: 4-fluoro-M-(4--2-(4-methoxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-iluphenyl|-3- trifluoromethylbenzamide; 5827: M-I4-(2-(8-acetyl-3,8-diazabicyclo/|3.2.1|oct-3-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl) )phenyl|-33-fluorobenzamide; Z828: M-(4-(2-(3-acetyl-3,8-diazabicyclo/3.2.1|oct-8-yl)ethoxy|-3-(2-methyl-2H) -pyrazole-

C-yl)phenyl|-3-fluorobenzamide; 829: M-I(4-(2-(8-acetyl-3,8-diazabicycloi|3.2.1|oct-3-yl)ethoxy|-3-(2-methyl-2IN-pyrazol-3-yl) /uphenyl|-3-methoxybenzamide; Z830: /M-I4--2-(3-acetyl-3,8-diazabicyclo|3.2.1|oct-8-yl)ethoxy|-3-(2- methyl-2H -pyrazole-3-iluphenyl|-3-methoxybenzamide; 831: tert-butyl ether (5)-3-14-3-(2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3 -yl)uphenoxy|pyrrolidine-1-carboxylic acid; 2832: tert-butyl ether (K)-3-14-13-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl )uphenoxy|pyrrolidine-1-carboxylic acid; 2833: tert-butyl ether (K)-2-I4-I3-(-2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3- yl)uphenoxy-methyl|pyrrolidine-1-carboxylic acid; 834: tert-butyl ether (K)-2-I4-3-(4-fluorophenyl)ureido|-2-(2-methyl-2H-pyrazole-3- yl)phenoxymethyl|pyrrolidine-1-carboxylic acid; 835: 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-((B)-pyrrolidine-3- yloxy)phenyl|urea; and 836: 1-(4-fluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-1-pyrrolidin-2-ylmethoxy) phenyl|urea.

In addition, individual compounds and chemical species of the present invention, such as compounds of Formula (a) and related Formulas, include all pharmaceutically acceptable salts, solvates and especially hydrates of such compounds.

It is to be understood that the present invention encompasses each diastereomer, each enantiomer, and mixtures thereof of each compound and general Formula disclosed in this application, as if they were, each individually, disclosed with a specific stereochemical designation for each chiral atom, e.g., carbon.

Compounds of formula (Ia) according to the present invention can be obtained according to the general synthesis schemes presented in Fig. 1-12, as well as according to the relevant procedures known from publications used by specialists in this field. Examples of reagents and procedures for these reactions are presented below in the Working Examples. Protection and deprotection can be performed using procedures well known in the art (see, for example, Sgeyepe, T. MU. apa UMshi5, R. 0. M., Rgoyesiime Sgoyr5 ip Ogdapis BZupipeviv, 39

Europe, 1999 (MYPeu)|; incorporated into this application by reference in its entirety).

The present invention also encompasses diastereomers, as well as optical isomers, for example, mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers, which are formed as a result of structural asymmetry in some compounds of the present invention. Separation of individual isomers (such as chiral

HPLC, recrystallization of a diastereomeric mixture, etc.) or selective synthesis (such as selective synthesis of enantiomers, etc.) of individual isomers is carried out in various ways, which are well known to those skilled in the art who carry out practical work.

Indications and methods of treatment

In addition to the above useful uses of the 5-HTgl receptor activity modulators disclosed herein, the compounds disclosed herein are believed to be useful in the treatment of certain other diseases and disorders and to alleviate their symptoms. Without limitation, such uses include the following: 1. Anti-platelet Aggregation Therapeutics (Platelet Aggregation-Related Conditions):

Agents against platelet aggregation (antiplatelet) are prescribed for various conditions. For example, in coronary artery disease, they are used to prevent myocardial infarction or stroke in patients at risk of developing obstructive blood clots (for example, coronary thrombosis).

In a myocardial infarction (heart attack), the heart muscle does not receive enough oxygen-enriched blood as a result of a blockage in the coronary blood vessels. When taken during an attack or immediately after an attack (preferably within 30 minutes), antiplatelet agents can reduce heart damage.

A transient ischemic attack ("TIA" or "micro-stroke") is a short-term interruption of oxygen to the brain due to a decrease in the amount of blood flowing through the arteries, usually due to an obstructing blood clot. Antiplatelet agents have been found to be effective in preventing TIA.

Angina is a temporary and often recurring pain in the chest area, pressure or discomfort caused by insufficient flow of oxygen-enriched blood (ischemia) to some areas of the heart. In patients with angina, antiplatelet agents can reduce the effects of angina and the risk of myocardial infarction.

A stroke is a phenomenon in which the brain does not receive a sufficient amount of oxygen-enriched blood, usually due to a blockage of blood vessels in the brain by a blood clot. In patients at high risk of the disease, regular use of antiplatelet agents has been found to prevent the formation of blood clots that cause the first or subsequent strokes.

Angioplasty is a catheter-based procedure used to open arteries blocked by a blood clot. Regardless of whether a stent is inserted immediately after this procedure to keep the artery open, antiplatelet agents can reduce the risk of additional blood clots after the procedure (procedure).

Coronary artery bypass grafting is a surgical procedure in which an artery or vein is taken from some part of the body and implanted into a blocked coronary artery, directing blood flow around the blockage and through the newly attached vessel. After such a procedure, antiplatelet agents can reduce the risk of repeated blood clots.

Atrial fibrillation is the most common type of slow, irregular heart rhythm (arrhythmia). Atrial fibrillation affects approximately two million Americans each year. In atrial fibrillation, the atria (the upper parts of the heart) rapidly fire electrical signals that cause them to quiver instead of contracting normally. The result is an abnormally fast and extremely irregular heartbeat. When taken after an episode of atrial fibrillation, antiplatelet agents can reduce the risk of blood clots forming in the heart and traveling to the brain (embolism). 5-HTα receptors are expressed on the smooth muscles of blood vessels, and 5-HT secreted as a result of platelet activation causes vasoconstriction and the activation of additional platelets in the process of clot formation. This provides evidence that a 5-HTgl inverse agonist will inhibit platelet aggregation and thus is a potential therapeutic agent as an antiplatelet agent (see Zayitiga, K, et al.,

Siip Saga! 2002 add. 25 (1):28-32; MLizop, N.Sei ai., Tygoto Nayetovi 1991 Ber 2;66(3):355-60).

5-HTα inverse agonists can be used to treat, for example, intermittent claudication or peripheral arterial disease, as well as cardiovascular complications (see Rev.

Mea. 9. 298: 424-430, 1989), arterial thrombosis (see, Ramlak, O. ei am. Tpgotro5i5 Kezeagsp 90: 259-270, 1998), atherosclerosis (see, Nauazpi, T. ei aI. Agtegossiegozi5 168: 23-31, 2003), serotonin-induced vasoconstriction (see Etsimaga, T. apa Sira, 5. Choshta!oi Sagaiiomassshag RPaptasoiodo 26: 503-510, 1995), arterial restenosis after angioplasty or stenting (see, Etska, M. ei aI. At Neai -. 145:e16 2003). They may also be used alone or in combination with thrombolytic therapy, such as IRA (see

Uatavzniia, T. eh ai. Naetozvyaviv 30:321-332, 2000), to provide cardioprotection after MI or postischemic myocardial dysfunction (see, My, T. ei aiI. Moi. SeiI. Viospet. 272: 119-132, 2005) or protection against ischemic damage in the process of percutaneous intervention in coronary vessels (see, Nogire, E. Sigsshayop Kezeagsp 68:68-72, 2004), etc., including complications as a result of the above. 5-HTα inverse antagonists can increase circulating adiponectin in patients, suggesting that they may also be useful in protecting patients against adiponectin-related indications, such as myocardial ischemia reperfusion injury and arteriosclerosis (see Motyga, zpozaky, Viosa Soadshaiyop apa Ribhypoiuziz 2005, 16, 423-428).

The 5-HTα inverse agonists disclosed herein provide beneficial improvement of microcirculation in patients in need of antiplatelet therapy by antagonizing vasoconstrictor products of aggregating platelets, such as, but not limited to, the indications described above.

Accordingly, in some embodiments, the present invention provides methods of reducing platelet aggregation in a patient in need thereof, comprising administering to the patient a composition comprising a 5- inverse agonist

NTga disclosed in this application. In other embodiments, the present invention provides methods of treating coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, atrial fibrillation, or symptoms of any of the foregoing in a patient in need thereof, comprising administering to the patient a composition that includes the 5-HTga inverse agonist disclosed in this application.

In other embodiments, the present invention provides methods of reducing the risk of blood clot formation in a patient following angioplasty or coronary artery bypass grafting or in a patient suffering from atrial fibrillation, comprising administering to the patient a composition that includes a 5-HTga inverse agonist disclosed herein, during the existence of such risk. 2. Asthma 5-HT (5-hydroxytryptamine) is associated with the pathophysiology of acute asthma (see Sa;2oYa, M. apa Maiega, M.6.,

TIRB, 2000, 21, 13; apa Oe Vie, 9.9. Yeyi a!yi., Viyeyp u). Rpagpt., 1998, 124, 857-864). The compounds of the present invention disclosed herein are useful in the treatment of asthma and its symptoms. Accordingly, in some embodiments, the present invention provides methods of treating asthma in a patient in need thereof, comprising administering to the patient a composition that includes a 5-HTga inverse agonist disclosed herein. In other embodiments of the invention, methods of treating asthma symptoms in a patient in need of such treatment are provided, which include administering to the patient a composition that includes a 5-HTga inverse agonist disclosed in this application. 3. Anxious excitement

Anxiety arousal is a well-known behavioral syndrome with a variety of symptoms including hostility, high arousal, low impulse control, tension, and uncooperativeness (see Sopep-MapwiyeYiy U, apa Wiyid, M., (1986), Adiageya Vepamioge ip She I. Sopsershai!

We will In At Sepaig os 34(10): 711-721).

Anxious agitation is common in the elderly and is often associated with dementia, such as dementia caused by Alzheimer's disease with Lewy bodies, Parkinson's disease, and Alzheimer's disease.

Huntington's, which are degenerative diseases of the nervous system, and diseases that affect blood vessels, such as stroke, or multi-infarct dementia, which is the result of multiple strokes in the brain, can also cause dementia. Alzheimer's disease accounts for approximately 50 to 70,905 of all cases of dementia (see Ko55 E, ei ai!., (1997), Azzezzipo racegp5 oi Adigynop ip AI2gpeiteg5 aizease rayepiv m/p se Sopep-Mapviieii Adiganop Ipimepiog. Te AIg2peiitegz Oizease Sooregaime Zschau. AI2Ppeiteg Oiv Avzos bivoga 11(v!irri 2):545-550).

An estimated 5 percent of people age 65 and older and up to 20 percent of people age 80 and older have dementia; of these, about half exhibit behavioral disturbances such as anxious agitation, incoherent speech, and violent outbursts.

Excited behavior can also occur in cognitively intact older adults and in people with psychiatric disorders other than dementia.

Anxiety agitation is often treated with antipsychotic medications such as haloperidol in home care and other appropriate treatment settings. There is convincing evidence that agents that act on 5-HTgl receptors in the brain have effects in reducing anxiety in patients,

including Alzheimer's dementia (see Kail, I.K., et al., In Siip Rzuspiaigu 1999 Reb., 60(2):107-115; apa 5igevi,

U.5., egai., Agsp Sep Rzuspianu 2000 Osi., 57(10):968-976).

The compounds of the present invention disclosed in this application are useful in the treatment of anxiety agitation and its symptoms. Thus, in some embodiments, the present invention provides methods of treating anxiety in a patient in need of such treatment, comprising administering to the patient a composition that includes a 5-HTα inverse agonist disclosed herein. In some embodiments, the anxious arousal is the result of a psychiatric disorder other than dementia. In some embodiments, the present invention provides methods of treating anxiety or a symptom thereof in a patient suffering from dementia, comprising administering to the patient a composition that includes a 5-HTga inverse agonist disclosed herein. In some embodiments of such methods, the dementia results from a degenerative disease of the nervous system, such as, but not limited to, Alzheimer's disease with Lewy bodies, Parkinson's disease, and Huntington's disease, or the dementia results from diseases that affect blood vessels, including, without limitation, stroke and multi-infarct dementia. In some embodiments, the invention provides methods of treating anxiety or a symptom thereof in a patient in need of such treatment, where the patient is a cognitively intact elderly patient, comprising administering to the patient a composition that includes a 5-HTga inverse agonist disclosed herein. 4. Adjunctive therapy added to haloperidol for the treatment of schizophrenia and other disorders:

Schizophrenia is a psychopathic disorder of unknown origin that usually first appears in early puberty and is characterized by various signs, psychotic symptoms, progression, phase development, and deterioration of social behavior and professional ability below the highest level ever achieved. Characteristic psychotic symptoms are disorders of thinking (scattered, fragmented, incoherent, implausible or simply false thoughts, or obsessions) and mental abilities (loss of mental connection, flight of imagination, incoherence to the point of incomprehensibility), as well as disorders of the ability to perceive (hallucinations), emotions (excessive or inadequate emotions), sense of self, intentions and motives, human relationships, and finally psychomotor disorders (such as catatonia). Other symptoms are also associated with this disorder. (See, Ategisap 5iaiiziisa! apa Oiadpoviis Naparook).

Haloperidol (haldol) is a strong antagonist of the dopamine OG2 receptor. It is often prescribed for acute schizophrenic symptoms 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 dysfunction. According to some methods of the present invention, the addition of a 5-HTgl inverse agonist concurrently with galdol will provide beneficial effects, including the ability to use lower doses of galdol without losing its effect on positive symptoms, while reducing or eliminating its induced effects on negative symptoms and prolonging the duration occurrence of the next attack of schizophrenia in the patient.

Haloperidol is used to treat various behavioral disorders, drug psychosis, excitability psychosis, Tourette's syndrome, manic disorders, psychosis (organic and MOB), psychotic disorders, psychosis, schizophrenia (acute, chronic and MOB). In addition, the field of application includes the treatment of childhood autism, Huntington's chorea and nausea and vomiting from chemotherapy and chemotherapeutic antibodies. Administration of the 5-HTgl inverse agonists disclosed herein with haloperidol will also provide benefit in these indications.

In some embodiments, the present invention provides methods of treating behavioral disorders, drug psychosis, excitability psychosis, Tourette's syndrome, manic disorders, psychosis (organic and

MOB), psychotic disorders, psychosis, schizophrenia (acute, chronic and MO5), which include administration to the patient of the dopamine O" receptor antagonist and the 5-HTga inverse agonist disclosed in this application.

In some embodiments, the present invention provides methods of treating behavioral disorders, drug psychosis, excitability psychosis, Tourette's syndrome, manic disorders, psychosis (organic and

MO5), psychotic disorders, psychosis, schizophrenia (acute, chronic and MO5), which include the administration of haloperidol and the 5-HTga inverse agonist disclosed in this application to the patient.

In some embodiments, this invention provides methods of treating childhood autism, chorea

Huntington's or nausea and vomiting from chemotherapy or chemotherapeutic antibodies, including administration to the patient of the dopamine O2 receptor antagonist and the 5-HTgaA inverse agonist disclosed in this application.

In some embodiments, this invention provides methods of treating childhood autism, chorea

Huntington's or nausea and vomiting from chemotherapy or chemotherapeutic antibodies, including the administration to the patient of haloperidol and the 5-HTga inverse agonist disclosed in this application.

In other embodiments, the present invention provides methods of treating schizophrenia in a patient in need of such treatment, which include administering to the patient a dopamine O2 receptor antagonist and a 5-HTga inverse agonist disclosed in this application. Preferably, the dopamine Og2 receptor antagonist is haloperidol.

The administration of the dopamine O2 receptor antagonist can be simultaneous with the administration of the 5-HTga inverse agonist, or they can be administered at different times. One skilled in the art will be able to readily determine the appropriate administration schedule to most effectively reduce or eliminate the adverse effects of haloperidol. In some embodiments of the invention, haloperidol and the inverse agonist 5-HTga are administered in one dosage form, and in other embodiments, they are administered in 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 schizophrenia, comprising administering to the patient a 5-HTga inverse agonist disclosed herein. 5. Sleep disorders

In Maiyopa! Bier Eoipadaiopje 2002 Zijer Ip Ategisa Royi reported that more than half of the adults surveyed (5,895) reported experiencing one or more symptoms of insomnia at least several nights per week in the past year. In addition, approximately three in ten (3,595) reported

that they experienced insomnia-like symptoms every night or almost every night.

The normal sleep cycle and sleep structure can be interrupted by various organic causes, as well as the influence of environmental conditions. According to the International Classification of Sleep Disorders, there are more than 80 recognized sleep disorders. Of these disorders, the compounds of the present invention are effective, for example, in one or more of the following sleep disorders (IS5O - Ipiegpayopa! Siazviysayop oii bier Oizogaegv: Oiadpoviis apa Sodipd Mappia).

Oiadpoziis Siazviysayop bieegipd Sotticeye, Ategisap bier Oizogayege Avzosiaiop, 1990):

A. Dysomnias a. Intrinsic sleep disorders: psychophysiological insomnia, abnormal sense of sleep state, idiopathic insomnia, obstructive sleep apnea syndrome, general sleep apnea syndrome, general alveolar hypoventilation syndrome, periodic limb movement, tired legs syndrome, and internal sleep disorder MO5. r. External sleep disorders: sleep hygiene disorder, sleep disorder related to environmental conditions, insomnia in conditions of altitude, sleep regulation disorder, insufficient sleep syndrome, disorder related to established sleep restriction, sleep onset association disorder, reception syndrome eating (drinking) at night, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced sleep disorder, and external sleep disorder MOB. with. Sleep disorders associated with the circadian rhythm: syndrome of changing the time zone (rapid time shift), sleep disorders associated with changing working hours, irregular sleep-wake pattern, delayed sleep phase syndrome, premature sleep phase syndrome, 24 - hourly sleep-wake regime and sleep disorders caused by circadian rhythm disturbances

MO5.

B. Parasomnias a. Arousal disorders: disordered awakenings, sleepwalking, and sleep terrors. p. Disorders of the sleep-wake transition state: disturbance of rhythmic movements, twitching during sleep, talking during sleep and night leg cramps.

C. Sleep disorders associated with medical/psychiatric disorders a. Associated with disorders of mental activity: psychoses, mood disorders, anxiety, panic disorders and alcoholism. p. Associated with neurological disorders: cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, narcolepsy, electro-epileptic sleep and headaches during sleep. with. Associated with other medical disorders: sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, asthma attacks during sleep, gastroesophageal reflux during sleep, peptic ulcer, fibrotic syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia, and post-surgery operations

The effects of sleep loss are more than excessive daytime sleepiness. Sufferers of chronic insomnia report increased levels of stress, anxiety, depression, and medical illness (Myopia!

Ipziishevz oi Neatsi, Maiiopai Neagi, I ipod, apa Viosa Ipziishe, Ipsotpia Rasi5 Zpeei, Osi. 1995). Preliminary evidence suggests that sleep disorders leading to significant sleep loss may contribute to a greater susceptibility to infections through immunosuppression, cardiovascular complications such as hypertension, cardiac arrhythmias, stroke and myocardial infarction, increased risk of glucose tolerance, severe obesity and metabolic syndrome.

The compounds of the present invention are useful in preventing or alleviating such complications by improving sleep quality.

The most widely used class of drugs for most of these sleep disorders are benzodiazepines, the adverse effect profiles of benzodiazepines include daytime sedation, decreased motor coordination, and cognitive impairment. Moreover, at the conference held in 1984 in Maiopai!

Ipviyshez oi Neayip Sopzepsiv, for the problems of hypnotics and insomnia, instructions were adopted that warn against the use of such sedative-hypnotic agents for more than 4-6 weeks, because there are fears related to the incorrect use of drugs, addiction, withdrawal syndrome and caused them insomnia. Therefore, it would be desirable to have a pharmacological agent for the treatment of insomnia that would be more effective and/or have fewer side effects than currently used agents. In addition, benzodiazepines are used to induce sleep, but they have little or no effect on sleep maintenance, sleep consolidation, or slow-wave sleep. Therefore, sleep disorders are not well treated nowadays.

Clinical studies using agents with the same mechanism of action as the compounds of the present invention have shown a significant improvement in objective and subjective sleep parameters in normal healthy volunteers, as well as in patients with sleep disorders and mood disorders (Zpagrieu AG , ей аЙ. Ziom/ Umame Ziver ip

Nitapzvg: Noie 5-NTga apa 5NTos Neseriog5. Meigorpaptasoiiodu, 1994, Moi. 33(3/4):467-71; Mipokyg A, ei aI. Asshe

EnNesiv oi Mipagaripe op biyer Sopiipiyu apa bier Agspiiyesishge ip Oergezzei Raiiepiv: A Riioi 5schshaw. boss oh Vio!

Rzusi, 2000, Moi. 48:75-78; apa Iapdoiy NR, ei aiYi. Zegoiopip-2 Keseriog5 and Nytap 5Bieer: EpPesi oi ZeiIesiime

Apiadopizi op EESH Rozheg Bresiga. MeigorzusporPpagtaso!odu, 1999, Moi. 21(3):455-66).

Certain sleep disorders are sometimes found in association with other conditions and, accordingly, such conditions can be treated with the compounds of formula (Ia). For example, but not limited to, patients suffering from a mood disorder typically suffer from a sleep disorder that can be treated with the compounds of formula (Ia). When there is one pharmacologic agent that treats two or more existing or potential conditions, as in the case of the present invention, this results in cost savings, better treatment acceptance, and fewer side effects compared to when two or more agents are taken.

The purpose of this invention is to provide a therapeutic agent for use in the treatment of a sleep disorder.

Another object of this invention is to provide a single pharmaceutical agent that can be useful in the treatment of two or more conditions, where one of the conditions is a sleep disorder. The compounds of this invention described in this application can be used alone or in combination with a mild hypnotic (ie, antihistamine).

Form of sleep:

Sleep includes two physiological states: non-REM sleep (REM) and REM sleep (REM). MKEM sleep includes four stages, each of which is characterized by a progressively slower picture of the electroencephalogram, where slower pictures indicate deeper sleep. The so-called delta 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, patients' sleep patterns are described as fragmented, meaning that the patient spends a lot of time alternating between stages! and 2 (half-awake) and upon awakening and spends very little time in deep sleep. As used herein, the term "fragmentary sleep pattern" means that a subject, such as a patient with a sleep disorder, spends the majority of his sleep time in MEEM sleep, stages 1 and 2, the lighter periods of sleep from which the subject the subject can easily wake up to a state of insomnia under the influence of limited external stimuli. As a result, the subject goes through frequent bouts of light sleep interrupted by frequent awakenings throughout the sleep period.

Many sleep disorders are characterized by a fragmented sleep structure. For example, many elderly patients who complain of sleep problems have difficulty achieving a prolonged state of deep refreshing sleep (MEEM stages C and 4) and instead spend most of their sleep in stages 1 and 2 of MEEM sleep

In contrast to "fragmented sleep structure" as used in this application, the term "sleep consolidation" refers to a condition in which the number of onsets of the MCEM sleep state, specifically stages C and 4, and the duration of such emerging sleep states increases, while the number and the duration of insomnia decreases. Essentially, the patient's disrupted sleep pattern consolidates into a sleep state with increased sleep periods and fewer awakenings during the night, and more time spent in slow-wave sleep (Stages C and 4) with less sleep oscillation stages 1 and 2. Compounds of the present invention can be effective in producing a pattern of sleep consolidation so that a patient with previously fragmented sleep can now achieve restorative, delta sleep for longer, more consistent periods of time.

As sleep progresses from stage 1 to later stages, heart rate and blood pressure drop, metabolic rate and glucose consumption drop, and muscles relax. With a normal sleep structure

MEEM sleep is up to about 7595 of the total sleep time; stage 1 - 5-1095 of total sleep time, stage 2 - about 45-5095, stage C - about 1295 and stage 4 - 13-1595. Approximately 90 minutes after sleep onset, MCEM is initially replaced by the first nocturnal episode of sleep CMEM. KEM is 2595 of the total sleep time. Unlike MKEM sleep, KEM sleep is characterized by a rapid pulse, breathing, and high blood pressure, as well as other physiological patterns that are similar to what can be observed in an active waking state. Thus, REM sleep is also known as "paradoxical sleep." The onset of sleep occurs in the process

MEEM sleep, and in young healthy people it takes 10-20 minutes. The four stages of MKEM sleep together with the KEM phase make up a complete sleep cycle, which is repeated during the entire sleep, usually four or five times. The cyclical nature of sleep is regular and reliable; A CEM period occurs every 90 minutes during the night. However, the first CEM period is usually the shortest, often lasting less than 10 minutes, while subsequent CEM periods can last as long as 40 minutes. With age, the time between bedtime and sleep onset increases, and the total amount of nightly sleep decreases due to changes in sleep patterns, as sleep maintenance and sleep quality become poorer. Both MKEM (specifically, stages C and 4) and KEM sleep decrease. However, stage 1 MKEM sleep, which is the lightest sleep, increases with age.

As used in this application, the term "delta power" refers to the measurement of the duration of EEG activity in the range of 0.5 to 3.5 Hz during MEEM sleep and is considered an indicator of deeper, longer sleep.

Delta force is hypothetically an indicator of a theoretical process called Process 5, and is believed to be inversely related to the amount of sleep that the subject has during a certain period of sleep. Sleep is controlled by homeostatic mechanisms; therefore, the less the subject sleeps, the more he wants to sleep. It is believed that Process 5 is built during the entire period of wakefulness and is most effectively manifested during delta sleep. Delta force is an indicator of the magnitude of Process 5 before the sleep period. The longer the subject remains awake, the greater the Process 5 or sleep drive and thus the greater the delta power during MEEM sleep. However, subjects with sleep disorders have problems achieving and maintaining delta sleep, and thus have a large accumulation of Process 5 with limited ability to release this accumulation during sleep. 5-HTgd agonists that have passed preclinical and clinical trials mimic the effect of delta power sleep loss, suggesting that subjects with sleep disorders treated with a 5-HTgl inverse agonist or antagonist may be able to achieve deeper , more refreshing sleep. Such effects have not been observed for currently available commercial pharmacotherapeutic agents. In addition, commercially available pharmacotherapeutic sleep aids have side effects such as "hangover" or addictive effects related to the GABA receptor. 5-HTgaA inverse agonists do not target the GABA receptor, and therefore there is no problem with such side effects.

Subjective and objective definition of sleep disorder:

There are many ways to determine whether there is a worsening or improvement in the onset, duration, or quality of sleep (eg, non-restorative or restorative sleep). One method is a subjective determination by the patients themselves, for example, whether they feel sleepy or rested upon awakening. Other methods are observation of the patient by another person during sleep, for example, how long it takes the patient to fall asleep, how many times the patient wakes up during the night, how restless the patient is during sleep, etc. Another method is an objective measurement stages of sleep using polysomnography.

Polysomnography is the monitoring of several electrophysiological parameters during sleep. It, as a rule, includes measurements of EEG activity, electroculographic activity and electromyographic activity, as well as other measurements. These results, together with observations, can be used to measure not only sleep latency (the amount of time it takes to fall asleep), but also sleep duration (the overall balance of sleep and wakefulness) and sleep consolidation (the percentage of sleep time that is in delta sleep or restorative sleep), which can be an indicator of sleep quality.

There are five distinct stages of sleep that can be measured by polysomnography: REM sleep (REM) and four stages of REM sleep (REM) (Stages 1, 2, C, and 4). Stage 1 MEEM sleep represents the transition from wakefulness to sleep and takes about 595 of the time spent asleep in healthy adults. Stage 2 of MKEM sleep, characterized by a specific EEG pattern (sleep spindles and K complexes), takes about 50905 of the time spent in sleep. Stages 3 and 4 of MEKEM sleep (which are also generally called slow-wave sleep and delta sleep) represent the deepest levels of sleep and occupy about 10-2095 of the time spent in sleep. FEM sleep, during which the main part of lucid dreams occurs, takes about 20-2595 of the total sleep time.

These stages of sleep have a characteristic temporal organization during the night. Stages C and 4 MKEM occur in the first third - the first half of the night period, and their length increases in response to sleep interruption. REM sleep occurs cyclically throughout the night. Alternating with MKEM sleep approximately every 80-100 minutes, periods of KEM sleep increase until morning. A person's sleep also typically changes throughout life. After relative stability with more REM sleep in childhood and early adolescence, sleep duration and depth decline with age in adults. This deterioration is manifested in more frequent cases of awakening and stage 1 sleep and a decrease in stages C and 4 sleep.

In addition, the compounds of the present invention may be useful in the treatment of sleep disorders characterized by excessive daytime sleepiness, such as narcolepsy. Inverse agonists of the serotonin 5-HTga receptor improve the quality of sleep at night, which can reduce excessive daytime sleepiness.

Accordingly, 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 of the present invention are potent inverse agonists of the serotonin 5-HTα receptor and may be effective in the treatment of a sleep disorder by promoting one or more of the following: a reduction in sleep latency (a measure of sleep induction), a reduction in the number of nighttime awakenings, and a prolongation of sleep stay in delta sleep (indicator of improved sleep quality and sleep consolidation), without affecting KEM sleep. In addition, the compounds of the present invention may be effective either as monotherapy or in combination with hypnotics, such as, but not limited to, antihistamines.

Diseases associated with diabetes:

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), the increased concentration of serotonin in the plasma of diabetic patients also plays a role in the development of the disease (Rieigaz2ek, M.N ., ei ai. Tpgotrovziz Nez. 1992, 66(6), 765-74; apa Apagge|emvKa-Vysako .), ei a)i., Kiip Osgpa. 1996; 98(2), 101-4). Serotonin is believed to play a role in vasospasm and increased platelet aggregation. Improving microvascular blood flow may be beneficial in diabetic complications.

Recently conducted studies, Sategop apa Sotseg, Mashpup Zsptiederegd5 Ahosp Rpagtasoi. 2003 Oip; 367(6):607-14, included the use as a 5-HTgl antagonist of the experimental drug AT-1015 and other non-specific 5-HTgl antagonists, including ritanserin and sarpogrelate. These studies showed that all three drugs were able to provide the indicated correction (82.6-99.790) of 19,895 sciatic nerve conduction deficits in diabetic rats. Similarly, 44,7905 and 14990 reductions in sciatic endoneurial blood flow and sensory conduction velocity in the saphenous vein of the leg were fully restored.

In a separate patient study, sarogrelate was evaluated for its effect in preventing the development or progression of diabetic nephropathy (Takapazpi, T., ei ai!., Oiareitez Kez Siip Rgasi. 2002 Mom; 58(2):123-9). In trials involving treatment for 24 months, sarpogrelate significantly reduced urinary albumin excretion. 7. Glaucoma

Local ocular introduction of 5-HT2 receptor antagonists leads to a decrease in intraocular pressure (IOP) in monkeys (Spapo ei ai., U. Osy! Rpagtasoi 1:137-147 (1985)) and man (Mazhigorazdpa ei a!., Asta Orpipa! so! zsapa

Zirri 224:24-25 (1997)), indicating the utility of similar compounds such as 5-HTgD inverse agonists for the treatment of glaucoma associated with ocular hypertension. The 5-HT2 receptor antagonist ketanserin (Mazigorazdtsa, supra) and sarpogrelate (Takepaka et al., Ipmevid Orpiipaito!i Mi5 Zsi 36:5734 (1995)) have been shown to significantly reduce IOR in glaucoma patients. 8. Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by an opportunistic viral infection of oligodendrocytes. in immunocompromised patients. The cause is the US virus, a ubiquitous papovavirus that infects most of the population before puberty and creates a latent infection in the kidney. In immunocompromised hosts, the virus can reactivate and productively infect oligodendrocytes. This previously rare condition, which until 1984 was reported mainly in subjects with lymphoproliferative disorders, has now become more common and occurs in 495 patients with AIDS. Patients usually have progressive local neurologic deficits that do not abate, such as hemiparesis or visual field deficits, or changes in mental status. One or more white matter lesions are present in the brain with ME; they are hyperintense on T2-weighted images and hypointense on T1-weighted images. There is no mass effect and contrast enhancement is sparse. The diagnosis can be confirmed by a brain biopsy, with the demonstration of the virus by IP 5sh hybridization or by immunocytochemistry. Amplification of sequences

Viral PCR using polymerase chain reaction from CE can confirm the diagnosis without the need for biopsy (see, for example, Apiipogi ei a!., Meigoiodu (1997) 48:687-694; Vegdeg apa Mayog, Zetipage ip Meigoiodu (1999) 19: 193-200; Apa Ropediev, Yei Ai., Eig U. Meshgoi. (2004) 11:297-304|. Currently, there is no effective therapy.

In patients with AIDS, the survival period after diagnosis is approximately 3 to 5 months.

US virus enters the cell by receptor-mediated clathrin-dependent endocytosis.

C virus binding to human glial cells (eg, oligodendrocytes) induces an intracellular signal that is critical for entry and infection through a ligand-induced clathrin-dependent mechanism (Ochegrev et al., U Migoiodu (2004) 78:250-256 Recently it was shown that 5-

HTα is a receptor on human glial cells that mediates the penetration of US virus infection with the help of clathrin-dependent endocytosis (Eirpisk ei a!., 5siepse (2004) 306:1380-1383|. 5-NTha antagonists, including ketanserin and ritanserin, inhibit US virus infection of human glial cells Ketanserin and ritanserin have 5-HT ha inverse agonist activity.

5-HTα antagonists, including inverse agonists, are considered useful in the treatment of PMI. G(EIrpisk ei ai.,

Zsiepse (2004) 306:1380-1383). Prophylactic treatment of HIV-infected patients with antagonists 5-

NTga is intended to prevent the spread of the US virus to the central nervous system and the development of PM.

Aggressive therapeutic treatment of patients with RMI. it is supposed to reduce the spread of the virus in the central nervous system and prevent additional episodes of demyelination.

In some embodiments, the invention provides methods of treating progressive multifocal leukoencephalopathy in a patient in need of such treatment, comprising administering to the patient a composition that includes a 5-HTga inverse agonist disclosed herein. 9. Hypertension

Observations have shown that serotonin plays an important role in the regulation of vascular tone, vasoconstriction and pulmonary hypertension (see, beispag, o. ei aI. Ryit. Rpaptasoi!. TNeg. 18(1):23-31. 2005; apa Magsoz, E. ei a). Sigs.

Transportation 94(9):1263-70 2004). Ketanserin, a 5-HTga inverse agonist, has been shown to protect against circulatory shock, intracranial hypertension, and cerebral ischemia in heat stroke (see, Spapo, S. ei ai. ZNosk 24(4): 336-340 2005); and stabilizes blood pressure in spontaneously hypertensive rats (see Miao, S. Siip.

Ex. RPaptasoi. Rpuvioi 30(3): 189-193). Mainserin, a 5-HTgA inverse agonist, has been shown to prevent OOCA-salt-induced hypertension in rats (see 5iima, A. Yeig, U. Rpagtasoi. 518(2-3): 152-7 2005). 10. Pain

5-HTγi inverse agonists are also effective in treating pain. Sarpogrelate was observed to provide significant analgesic effects on both thermo-induced pain in rats following intraperitoneal administration and inflammatory pain in rats following either subcutaneous or intraperitoneal administration (see Mizpiuata, T. Eig. U. Rpagtasoi. 516: 18-22 2005). The same 5-HTα inverse agonist in humans has been shown to be effective in the treatment of low back pain, leg pain, and numbness associated with sciatica caused by a herniated lumbar disc (see Kapauata, M. et al. in Meigozygud: Zripe 2:441-446 2005).

Representative methods of the present invention:

One aspect of this invention includes methods of modulating the activity of the serotonin 5-HTgl receptor by contacting the receptor with a compound according to any of the embodiments of the invention described in this application or a pharmaceutical composition.

One aspect of the present invention encompasses methods of treating platelet aggregation in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition.

One aspect of the present invention encompasses methods of treating an indication selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, and atrial fibrillation in a subject comprising administering to the subject in need thereof a therapeutically effective the amount of the compound according to any of the variants of the embodiment of the invention described in this application, or the pharmaceutical composition.

One aspect of the present invention encompasses methods of treatment for reducing the risk of blood clot formation in a subject following angioplasty or coronary bypass surgery, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described in this application, or a pharmaceutical composition.

One aspect of the present invention encompasses methods of treatment for reducing the risk of blood clot formation in a subject suffering from atrial fibrillation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the invention, described in this application, or a pharmaceutical composition.

One aspect of the present invention encompasses methods of treating asthma in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition.

One aspect of the present invention encompasses methods of treating an asthma symptom in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition.

One aspect of the present invention encompasses methods of treating an anxiety disorder or symptom thereof in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein, or a pharmaceutical composition . In some embodiments of the invention, the subject is a cognitively intact elderly subject.

One aspect of the present invention encompasses methods of treating anxiety agitation or a symptom thereof in a subject suffering from dementia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein applications, or pharmaceutical compositions. In some embodiments of the invention, dementia is the result of a degenerative disease of the nervous system. In some embodiments of the invention, the dementia is Alzheimer's disease with Lewy bodies, Parkinson's disease, or Huntington's disease. In some embodiments of the invention, dementia is the result of diseases affecting blood vessels. In some embodiments, the dementia is the result of stroke or multi-infarct dementia.

One aspect of the present invention encompasses methods of treating a subject suffering from at least one of the indications selected from the group consisting of behavioral disorders, drug-induced psychosis, excitability psychosis,

Tourette's, manic disorders, organic or MOB psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia and MO5 schizophrenia comprising administering to a subject in need thereof a therapeutically effective amount of a dopamine Y receptor antagonist and a compound according to any from the variants of the embodiment of the invention described in this application, or the pharmaceutical composition. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods of treating a subject with childhood autism, Huntington's chorea, or chemotherapy-induced nausea and vomiting or chemotherapeutic antibodies, comprising administering to a subject in need thereof a therapeutically effective amount of a dopamine OO receptor antagonist and a compound according to any which of the variants of the embodiment of the invention described in this application, or the pharmaceutical composition. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods of treating schizophrenia in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a dopamine O2 receptor antagonist and a compound according to any of the embodiments of the invention described herein, or pharmaceutical compositions. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods of treatment for alleviating negative symptoms of schizophrenia caused by the administration of haloperidol to a subject suffering from schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention, described in this application, or a pharmaceutical composition. In some embodiments of the invention, haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms. In some embodiments of the invention, haloperidol and the compound or pharmaceutical composition are administered in the same dosage form.

One aspect of the present invention encompasses methods of treating a sleep disorder in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the embodiments described herein, or a pharmaceutical composition.

In some embodiments of the invention, the sleep disorder is dyssomnia. In some embodiments of the invention, dyssomnia is selected from the group that includes psychophysiological insomnia, abnormal sleep state perception, idiopathic insomnia, obstructive sleep apnea syndrome, general sleep apnea syndrome, general alveolar hypoventilation syndrome, periodic limb movement, tired legs syndrome, disorders sleep hygiene, environmental sleep disorder, altitude insomnia, sleep regulation disorder, sleep deprivation syndrome, sleep restriction disorder, sleep onset association disorder, night eating or drinking syndrome, disorders hypnotic-dependent sleep disorders, stimulant-dependent sleep disorders, alcohol-dependent sleep disorders, toxin-induced sleep disorders, jet lag syndrome (rapid time shift), sleep disorders associated with change in working hours, irregular sleep-wake cycle, delayed sleep phase syndrome, premature sleep phase syndrome and disorders 24-hour sleep-wake mode.

In some embodiments of the invention, the sleep disorder is a parasomnia. In some embodiments, the parasomnia is selected from the group consisting of disordered awakenings, sleepwalking and sleep terrors, rhythmic movement disorders, sleep tremors, sleep talking, and nocturnal leg cramps. In some embodiments of the invention, the sleep disorder is characterized by excessive daytime sleepiness, such as narcolepsy.

In some embodiments of the invention, the sleep disorder is associated with a medical or psychiatric disorder. In some embodiments of the invention, the medical or psychiatric disorder is selected from the group consisting of psychoses, mood disorders, anxiety, panic disorders, alcoholism, cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, narcolepsy, electro-epileptic sleep, headaches during sleep apnea, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, asthma attacks during sleep, gastroesophageal reflux during sleep, peptic ulcer, fibrotic syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia, and sleep disorders after surgery.

One aspect of the present invention encompasses methods of treating diabetes-related disorders in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical compositions.

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

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

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

One aspect of the present invention encompasses methods of treating glaucoma or other eye diseases with abnormal intraocular pressure.

One aspect of the present invention encompasses methods of treating progressive multifocal leukoencephalopathy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments of the invention described herein, or a pharmaceutical composition.

In some embodiments of the invention, the subject in need suffers from a lymphoproliferative disorder. In some embodiments of the invention, the lymphoproliferative disorder is leukemia or lymphoma. In some embodiments of the invention, leukemia or lymphoma is chronic lymphocytic leukemia, Hodgkin's disease, or the like.

In some embodiments of the invention, the subject in need suffers from a myeloproliferative disorder.

In some embodiments of the invention, the subject in need suffers from carcinomatosis.

In some embodiments of the invention, the subject in need suffers from granulomatosis or an inflammatory disease. In some embodiments of the invention, the granulomatosis or inflammatory disease is tuberculosis or sarcoidosis.

In some embodiments of the invention, the subject in need is immunocompromised. In some embodiments of the invention, an immunocompromised subject has impaired cellular immunity. In some embodiments of the invention, impaired cellular immunity includes impaired T-cell immunity.

In some embodiments of the invention, the subject in need is HIV-infected. In some variants of the embodiment of the invention, the HIV-infected subject has a number of CO4- cells "x200/mm3. In some embodiments of the invention, the HIV-infected subject has AIDS. In some embodiments of the invention, the HIV-infected subject has

AIDS-associated complex (ACS). In some variants of the embodiment of the invention, AKS is defined as the presence of two consecutive readings of the number of СО4 cells below 200/mm! and at least two of the following signs or symptoms: hairy leukoplakia of the oral cavity, recurrent candidal stomatitis, weight loss of at least 2.5 kg or 1095 of body weight in the last six months, multidermatomal shingles, temperature above 38.52C for more than than 14 consecutive days or more than 15 days in a 30-day period or diarrhea where there are loose stools more than three times a day for at least 30 days

See, for example, Khatada ei ai., Siip. Oiadp. Migoi (1993) 1:245-256).

In some embodiments of the invention, the subject who needs it undergoes a course of immunosuppressive therapy. In some embodiments of the invention, immunosuppressive therapy includes the administration of immunosuppressive agents (see, e.g., MieiIeg, App Tpogas Zygu (2004) 77:354-362; Kpedeg apa Etgeje, Rediaig Tgaperiapiayop (2004) 8:594-599), In some embodiments embodiment of the invention, immunosuppressive therapy includes administration of an immunosuppressive agent selected from the group including: corticosteroids (for example, prednisone, etc.), calcineurin inhibitors (for example, cyclosporine, tacrolimus, etc.), antiproliferative agents (for example, azathioprine , mycophenolate mofetil, sirolimus, everolimus, etc.), agents that reduce the level of T cells (for example, OKTUZ3 monoclonal antibody (tAB), anti-POZ immunotoxin EM18-SVMO, Satraip-1H (anti-

CO52) tAB, anti-CO4 tA, anti-T-cell receptor tAB, etc.), tAB against receptor 1-2 (CO25) (for example, basiliximab, daclizumab, etc.), co-stimulation inhibitors (for example . and its analogues (for example, leflunomide EK778, EK779, etc.), ETU720, anti-alpha-4-integrin monoclonal antibody and anti-CO45 KV monoclonal antibody. In some embodiments of the invention, the immunosuppressive agent and the specified compound or pharmaceutical composition are administered in separate dosage forms. In some embodiments of the invention, the immunosuppressive agent and the specified compound or pharmaceutical composition are administered in one dosage form.

In some embodiments of the invention, the subject who needs it undergoes a course of immunosuppressive therapy after organ transplantation. In some embodiments of the invention, the organ is a liver, kidney, lung, heart, or the like. (see, for example, Zipdp ei ai!., Tgapzriapiayop (2000) 69:467-472).

In some embodiments of the invention, the subject who needs it undergoes a course of treatment for a rheumatic disease. In some embodiments of the invention, the rheumatic disease is systemic lupus erythematosus or the like.

In some embodiments of the invention, the compound or pharmaceutical composition inhibits US viral infection of human glial cells.

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

One aspect of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders.

One embodiment of this invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTga-mediated disorders, where the disorder is platelet aggregation.

One embodiment of the present invention is the use of a compound for the preparation of a medicament for use in the treatment of 5-HTGDL-mediated disorders, wherein the disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, and atrial fibrillation. .

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTgda-mediated disorders, where the disorder is the formation of a blood clot in a subject after angioplasty or coronary bypass surgery.

One embodiment of this invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTgda-mediated disorders, where the disorder is the formation of a blood clot in a subject suffering from atrial fibrillation.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTGDL-mediated disorders, where the disorder is asthma.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTGDL-mediated disorders, where the disorder is a symptom of asthma.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, where the disorder is an anxiety disorder or a symptom thereof in a subject. In some embodiments of the invention, the subject is a cognitively intact elderly subject.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, where the disorder is anxiety agitation or a symptom thereof in a subject suffering from dementia. In some embodiments of the invention, dementia is the result of a degenerative disease of the nervous system. In some embodiments, the dementia is Alzheimer's disease with Lewy bodies, Parkinson's disease, or

Huntington. In some embodiments of the invention, dementia is the result of diseases affecting blood vessels. In some embodiments, the dementia is the result of stroke or multi-infarct dementia.

One embodiment of the present invention is the use of a compound for the preparation of a medicament for use in the treatment of 5-HTgl-mediated disorders, further comprising a dopamine O2 receptor antagonist, wherein the disorder is selected from the group consisting of behavioral disorders, drug-induced psychosis, psychosis excitability, Tourette syndrome, manic disorders, organic or MO5 psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia and MO5 schizophrenia. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for the preparation of a medicament for use in the treatment of 5-HTgl-mediated disorders, further comprising a dopamine O2 receptor antagonist, where the disorder is childhood autism, Huntington's chorea, or chemotherapy-induced nausea and vomiting or chemotherapeutic antibodies. In some embodiments, the invention is a dopamine antagonist

Or" of the receptor is haloperidol.

One embodiment of this invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTgl-mediated disorders, which includes, in addition, an antagonist of the dopamine Y" receptor, where the disorder is schizophrenia. In some embodiments of the invention, the dopamine O2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTHD-mediated disorders, where the disorder is a negative symptom or symptoms of schizophrenia caused by the administration of haloperidol.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTgda-mediated disorders, where haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of the compound for the preparation of a medicinal product for use in the treatment of 5-HTgda-mediated disorders, where haloperidol and the compound or pharmaceutical composition are administered in a single dosage form.

One embodiment of the present invention is the use of the compound for the preparation of a medicament for use in the treatment of 5-HTga-mediated disorders, where the disorder is progressive multifocal leukoencephalopathy.

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

One aspect of the present invention is a compound according to any of the embodiments of the invention described herein for use in a method of treating 5-HTα-mediated disorders described herein in a human or animal by therapy.

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

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

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

Pharmaceutical compositions

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

Some embodiments of the invention include a method of preparing a pharmaceutical composition that includes mixing at least one compound according to any embodiment of the invention disclosed in this application and a pharmaceutically acceptable carrier.

The compositions may be prepared in any suitable manner, typically by homogeneously mixing the active compound(s) with liquid or finely divided solid carriers, or both, in the required proportions, and then, if necessary, shaping the resulting mixture into the desired shape .

Conventional excipients such as binders, fillers, acceptable wetting agents, tableting lubricants and disintegrants can be used in tablets and capsules for oral administration. 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 liquid carrier prior to administration. Additional impurities such as suspending agents or emulsifiers, non-aqueous carriers (including edible oils), preservatives, fragrances and 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 and sterilizing the solution by filtration before filling it into a suitable vial or ampoule and sealing it. These are just a few examples of a number of suitable methods well known in the art for preparing dosage forms.

The compounds of this invention can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmaceutically acceptable carriers, in addition to those specified in this application, are known from the state of the art; for example, see Ketipdiop, Tne Zsiepse apa Rgasiise oi Rpagtasu, 2017 Eayop, 2000, Prripsoi M/Shiatv 8; MLIKipv, (Ediyuge: Seppago, A. V., ей а1.).

Although it is possible, for therapeutic use, to administer the compounds of the present invention, in alternative uses, in crude form or in the form of a pure chemical compound, it is preferred that the compound or active ingredient be presented in a pharmaceutical composition or a composition that additionally includes a pharmaceutically acceptable carrier .

Thus, the present invention also provides pharmaceutical compositions containing a compound of the present invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense that it must be compatible with the other ingredients of the composition and not unduly harmful to the recipient.

Pharmaceutical compositions include compositions suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or compositions in a form suitable for administration by inhalation, insufflation or with a transdermal patch. Transdermal patches distribute drug at a controlled rate, effectively providing drug for absorption with minimal drug degradation. Typically, transdermal patches include an impermeable base layer, one pressure-sensitive adhesive, and a removable protective layer with liner paper. Techniques suitable for making the desired effective transdermal patch as needed should be readily apparent to those skilled in the art.

The compounds of the present invention, together with a conventional adjuvant, carrier or diluent, can thus be prepared in the form of pharmaceutical compositions and unit dosage forms thereof, and in such form they can be used in solid form, for example in the form of tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with them, all intended for oral use, in the form of suppositories for rectal administration; or in the form of sterile solutions for injections for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may include conventional ingredients in conventional proportions, with or without additional active compounds or active ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dose limits to be use.

For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions or in liquid form. The pharmaceutical composition is preferably obtained in a single dosage form containing a certain amount of the active ingredient. Examples of such dosage forms are capsules, tablets, powders, granules or suspensions, with traditional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatins; with leavening agents such as corn starch, potato starch or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection in the form of a composition where, for example, saline, dextrose or water can be used as a suitable pharmaceutically acceptable carrier.

The compounds of the present invention or their solvates or physiologically functional derivatives can be used as active ingredients in pharmaceutical compositions, specifically, as modulators of the 5-HTγi receptor. The term "active ingredient" is defined in the context of a "pharmaceutical composition" and means a component of a pharmaceutical composition that provides the main pharmacological effect, in contrast to "inactive ingredients that should mainly be considered as providing a pharmaceutical benefit."

The dose when using the compounds according to this invention can vary widely, as is generally accepted and known to doctors, it should be selected according to the condition of the subject in each individual case. It depends, for example, on the nature and severity of the disease to be treated, on the condition of the patient, on the compound used, or on whether the acute or chronic form of the disease is to be treated, or to be prophylactic, or whether other active compounds are administered in addition to compounds according to the present invention. Representative dosages according to the present invention include, but are not limited to, from about 0.001mg to about 5000mg, from about 0.001mg to about 2500mg, from about 0.001mg to about 100Omg, from 0.001mg to about 500mg, from 0.001mg to about 250mg , from about 0.001 mg to about 10 Ω, from about 0.001 mg to about 5 Ω, and from about 0.001 mg to about 25 mg. Several doses can be administered during the day, especially when it is considered necessary to administer relatively larger amounts, such as 2, 3 or 4 doses. Depending on the subject and if the physician or caregiver deems it appropriate for the patient, it may be necessary to deviate from the indicated doses in a higher or lower direction.

The amount of active ingredient or active salt or derivative thereof required to be used in treatment varies not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and is ultimately determined by doctor or clinician. Typically, one of ordinary skill in the art knows how to extrapolate data obtained in a model system, typically an animal model, to another subject, such as a human. In some circumstances, such extrapolations may be based simply on the weight of the animal model compared to another subject, such as a mammal, preferably a human, but more often such extrapolations are based on more than just weight, but include various factors. Representative factors include the patient's species, age, weight, sex, nutritional status and medical condition, disease severity, route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicological profiles of the particular compound used, whether a drug delivery system is used, or from whether the acute or chronic form of the disease is treated or prevented, or whether other active compounds are administered in addition to the compounds according to the present invention and as part of a combination of drugs. The administration regimen for the treatment of a disease state with the compounds and/or compositions of the present invention is selected according to the various factors listed above. Thus, the actual administration schedule used may vary widely and therefore may deviate from the preferred administration schedule, and one of ordinary skill in the art should be aware that doses and dosing schedules outside the specified typical limits may be tried and, if appropriate, may be used in the methods of the present invention.

The required dose may conveniently be presented as a single dose or as several separate doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose, in turn, can be further divided, for example, into several separate, time-separated administrations. Especially when it is considered that it is necessary to enter a large amount, the daily dose can be divided into several, for example, 2, 3 or 4 parts for administration. If it is suitable, depending on the behavior of the subject, it may be necessary to deviate from the indicated dose in a larger or smaller direction.

The compounds of the present invention can be administered in various oral and parenteral dosage forms.

It should be apparent to one skilled in the art 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.

For the preparation of pharmaceutical compositions from the compounds of the present invention, a suitable pharmaceutically acceptable carrier can be a solid, liquid or a mixture of such substances. Solid preparations include powders, tablets, pills, capsules, sachets, suppositories and dispersible granules. The solid carrier can be one or more substances that can also act as diluents, perfumes, solubilizers, lubricants, suspending agents, binders, preservatives, disintegrants for tablets or encapsulating substances.

In powders, the carrier is a finely divided solid substance mixed with a finely divided active component.

In tablets, the active component is mixed with a carrier that has the necessary binding capacity, in suitable proportions, and compressed to obtain the desired shape and size.

Powders and tablets may contain different percentages of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, one skilled in the art should know when quantities outside these limits are required. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc. The term "preparation" includes the composition of an active compound with an encapsulating substance as a carrier to form a capsule in which the active ingredient, with or without carriers, is surrounded by a carrier, which is thus in association with it.

Similarly, sachets and cakes are included. Tablets, powders, capsules, pills, sachets and cakes can be used as solid forms suitable for oral administration.

To obtain suppositories, a low-melting wax, such as with an admixture of glycerides of fatty acids or cocoa butter, is first melted and the active component is homogeneously dispersed in this mixture, for example, by stirring. The molten homogeneous mixture is then poured into molds of convenient size, allowed to cool and thus harden.

Compositions suitable for vaginal administration may 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 to be suitable for such purposes.

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

The compounds of the present invention may thus be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and may be presented in unit dosage forms in ampoules, prefilled syringes, small infusion volumes or in multi-dose containers with an added preservative. Pharmaceutical compositions can also be in such forms as suspensions, solutions or emulsions in oil or water carriers and can contain agents for forming the composition, such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization from solution, for reconstitution with a suitable carrier, such as sterile pyrogen-free water, prior to use.

Aqueous compositions suitable for oral administration can be prepared by dissolving or suspending the active ingredient in water and adding suitable dyes, fragrances, stabilizers and thickeners, if desired.

Aqueous suspensions suitable for oral use can be obtained by dispersing the finely divided active ingredient in water with a viscosity agent such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agents.

Also included are solid preparations that are intended to be converted into liquid preparations for oral administration before use. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, dyes, fragrances, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

For local application to the epidermis, the compounds of the present invention can be formulated as ointments, creams or lotions or as a transdermal patch.

Ointments and creams can, for example, be formulated using an aqueous or oil base with the addition of a suitable thickener and/or gelling agent. Lotions can be formulated using an aqueous or oil base and typically also contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickeners, or coloring agents.

Compositions suitable for topical administration in the mouth include lozenges comprising an active ingredient in a base which contains fragrances, typically sucrose and gum arabic or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly into the nasal cavity by traditional means, for example using a dropper, pipette or spray. The compositions may be provided in single-dose or multi-dose form. In the latter case, when using a dropper or pipette, this is achieved by introducing a suitable, pre-measured volume of solution or suspension to the patient. In the case of a spray, this is achieved, for example, by means of a metering pump for spraying with a spray.

Inhalation is also achieved by aerosol formulations in which the active ingredient is provided in a pressurized package with a suitable propellant. If the compounds of the present invention or pharmaceutical compositions comprising such compounds are administered in the form of aerosols, for example, in the form of nasal sprays or by inhalation, this can be done, for example, using a spray, a nebulizer or a pump atomizer, an inhalation device, a metered dose inhaler or dry powder inhaler. Pharmaceutical forms for the administration of the compounds of the present invention in the form of an aerosol can be obtained by methods well known to those skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable physiological solutions can be used with the use of common additives, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, solubilizing agents, dispersants, etc., and, if appropriate, conventional propellants, which include, for example, carbon dioxide, SES, such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; etc. It is also convenient when the aerosol contains a surfactant such as lecithin. The dose of the drug can be controlled by providing a metering valve.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound usually has a small particle size, for example, about 10 microns or less. This particle size can be obtained by means known in the art, for example by grinding in a micron colloid mill. If desired, compositions intended for slow release of the active ingredient can be used.

Alternatively, the active ingredients may be provided in dry powder form, for example a powdered mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP). It is convenient when the powdered carrier will form a gel in the nasal cavity. The powder compositions can be provided in a standard dosage form, for example, in capsules or cartridges, for example, gelatin, or in a blister pack, from which the powder can be administered by means of an inhaler.

Pharmaceutical preparations are mainly available in single dosage forms. In this form, the drug is divided into unit doses, which contain 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, for example, packaged tablets, capsules and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, sachet or cake as such, or may be suitable amounts of any of the above in a packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.

The compounds of this invention may optionally exist in the form of pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts derived from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Representative 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, malic, mandelic, methanesulfonic, mucilage , nitrogen, oxalic, pamoic, pantothenic, phosphoric, amber, sulfuric, tartaric, oxalic, p-toluenesulfonic, etc., such pharmaceutically acceptable salts as listed in Chotsgpa! oh RPpaptaseshisa! Zsiepse, 66, 2 (1977); included in this application by reference in its entirety.

Acid addition salts can be obtained as direct products of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing a suitable acid with isolation of the salt by evaporation of the solvent or by separation of the salt and solvent. The compounds of the present invention can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

The compounds of this invention can be converted into "prodrugs". The term "prodrugs" refers to compounds that have been modified with specific chemical groups known in the art, and when administered to a subject, these groups undergo biotransformation to form the parent compound. Prodrugs, therefore, can be considered as compounds of the present invention containing one or more special non-toxic protecting groups used temporarily to change or eliminate a defined property of the compound. In one general aspect, a "prodrug" approach is used to facilitate oral absorption. A detailed discussion is presented in T. Nidispa apa M. EgeiPa, "Rgodgyd5 az Mome! Oeiiimegu Zuzietv5," Moi. 14 oi She A.S.5. 5utrozit zegie5; and also in Vioghemegzirie Saggieg5 ip Ogyd Oevidp, ed. Edulhaga V. Kospe, Ategisap Rpagtaseshisa! Av5zosiayop apa Regdatop Rgez5, 1987, both of these documents are incorporated into this application by reference in their entirety.

Some embodiments of the present invention include a method of preparing a pharmaceutical composition for "combination therapy" that includes mixing at least one compound according to any embodiment of the compounds disclosed in this application together with at least one known pharmaceutical agent described in this application, and a pharmaceutically acceptable carrier.

It should be noted that when 5-HT2i receptor modulators are used as active ingredients in a pharmaceutical composition, they are not only intended for human use, but also for other non-human mammals. Indeed, recent advances in the field of animal therapy indicate that attention should be paid to the use of active agents such as 5-HTγ1 receptor modulators for the treatment of 5-HTgA-mediated diseases or disorders in domestic animals (e.g., cats and dogs) and other domestic animals (for example, such as cows, chickens, fish, etc.). Those skilled in the art will readily appreciate the applicability of such compounds in the art.

Combined therapy:

Although the compounds of the present invention may be administered as a single active pharmaceutical agent (ie, monotherapy), they may also be used in combination with other pharmaceutical agents (ie, combination therapy) to treat the diseases/conditions/disorders described herein. Accordingly, another aspect of the present invention includes methods of treating 5-HTgl serotonin receptor mediated disorders and diseases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention in combination with one or more additional pharmaceutical agents described in this application.

Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include other antiplatelet, antithrombotic drugs or anticoagulants, antiarrhythmic agents, cholesteryl ester transfer protein (CET) inhibitors, niacin or niacin analogs, adenosine or adenosine analogs, nitroglycerin or nitrates, prothrombolytic agents, etc. Other pharmaceutical agents, including the agents described below, are well known or will be apparent in light of this disclosure to those skilled in the art.

The compounds of the present invention may also be used in combination with other antiplatelet, antithrombotic drugs, or anticoagulants, such as thrombin inhibitors, platelet aggregation inhibitors such as aspirin, clopidogrel (Riamixb)), ticlopidine, or C5-747 (ie, 5-(2 -cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl|-4,5,6,7-tetrahydro-thienoYZ3,2-c|Ipyridin-2-yl ester of acetic acid and its active metabolite k-99224, (2 )-2-(1--(2-cyclopropyl-1(5)-(2-fluorophenyl)-2-oxoethyl|-4(A)-sulfanyl-piperidin-3-ylideneoacetic acid), abciximab (KeoRgoF), eptifibatit (IpiedgiipF), tirofiban (Addagvsiant), warfarin, low molecular weight heparins (such as HOMEMOX), SRIIB/OR Sha blockers, RAI!-1 inhibitors such as ХК-330 (ie (32,62)-3-benzylidene-6- (4-Methoxybenzylidene)-1-methylpiperazine-2,5-diones and tert-686 (ie, C(E)-benzylidene-4(E)-(3,4,5-trimethoxybenzylidene)pyrrolidine-2,5-dione| , inhibitors of α-2-antiplasmin, such as antibody against α-2-antiplasmin and thromboxane antagonists new receptor antagonists (such as ifetroban), prostacyclin mimetics, phosphodiesterase (POE) inhibitors such as dipyridamole (Rezapiipe?F) or cilostazol, POE inhibitors in combination with thromboxane receptor antagonists/thromboxane A synthetase inhibitors (such as picotamide), serotonin antagonists 2-receptors (such as ketanserin), fibrinogen receptor antagonists, lipid-lowering agents such as NMO-CoA reductase inhibitors, such as pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, A24522, and itavastatin (Mizzap/Coma); microsomal triglyceride transport protein inhibitors (such as those disclosed in US Patent Nos. 5,739,135, 5,712,279, and 5,760,246), hypotensive agents such as angiotensin-converting enzyme inhibitors (eg, captopril, lisinopril, or fosinopril); angiotensin-I receptor antagonists! (eg, irbesartan, losartan, or valsartan); and/or inhibitors

ACE/MER (eg, omapatrilat and hemopatrilat); B-blockers (such as propranolol, nadolol, and carvedilol), ROE inhibitors in combination with aspirin, ifetroban, picotamide, ketanserin, or clopidogrel (RiamixF)), etc.

The compounds of the present invention may also be used in combination with antiarrhythmic agents, such as antiarrhythmic agents such as amiodarone or dofetilide.

The compounds of the present invention can also be used in combination with cholesteryl ester transfer protein (CET) inhibitors for dyslipidemia and atherosclerosis, niacin or niacin analogs for dyslipidemia and atherosclerosis, adenosine or adenosine analogs for vasodilation, nitroglycerin or nitrates for vasodilation.

The compounds of the present invention can be used in combination with prothrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, isolated complex of streptokinase and plasminogen activator (A5RAS), animal salivary gland plasminogen activators etc. The compounds of the present invention can also be used in combination with β-adrenergic agonists such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pilbuterol or fenoterol; anticholinergic agents such as ipratropium bromide; anti-inflammatory corticosteroids such as beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide or dexamethasone; and anti-inflammatory agents such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast, monteleukast, and pranleukast.

Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include antiretroviral agents |see, eg, Tigrip, Ehreg Kem Apii Iptesi Tpeg (2003) 1:97-1281. Some embodiments of the present invention include methods of treating progressive multifocal leukoencephalopathy described herein, comprising administering to a subject in need of such treatment a therapeutically effective amount or dose of a compound of the present invention in combination with at least one pharmaceutical agent selected from groups that include: inhibitors of nucleoside reverse transcriptase (for example, Reigomige, Erimi?, Sotbimig?, Nimid?, midehe, Tgig2mige, 7epb, Ladepe, Mmigea?, Emtricitabine, OARO, etc.), inhibitors of non-nucleoside reverse transcriptase (for example, Migattipe-, Vezsgiro!ye, bivyimaye, SMU687,

ORSOV8FZ3, TMOS 125, Emivirin, Capavirin, WMO 561390, 0С-781 and other oxathiincarboxyanilides, 5-3366,

Alkenyldiarylmethane (ABAM), Trivirapine, Calanolide A, NVU097, Loviride, derivatives of the NERT family, TIVO derivatives, etc.), protease inhibitors (for example, Eroghiomaze?-, Ipmigaze?, Momi?, Sihimape, Migaser", Aderegaze", Kaiegga?,

Atazanavir, Tipranavir, OMRA50O, etc.), inhibitors of HIV-cell interaction (for example, soluble CO4, toxin-conjugated CO4, monoclonal antibody to CO4 or dr120, RKO 542, dextran sulfate, Rersobene, ER-23199, Cyanovirin- M, Zintevir (730177, AK177), I -chicoric acid and derivatives, etc.), ligands, co-receptor inhibitors (for example, K5, X4, modified ligands (5), modified ligands (X4), etc. .), XA co-receptor inhibitors (for example, 122, T134, AI X40-4C, AMOZ3100, bicyclam derivatives, etc.), co-receptor 5 inhibitors (for example, TAK-779, 5СН-С (5СН-351125 ), 5СН-О (5202Н-350634), MZS 651016, OMO RPagtaseshchiisa!, Megsk, etc.), fusion inhibitors (for example, Rygeop? (T-20, ОР 178, enfuvritide) trimeris, T-1249, TMS125 etc.), integrase inhibitors (for example, 5SITER, I.731,988, I 708,906, I -870,812, 5-1360, etc.), inhibitors of 27p fingers of MSr? nucleocapsid (for example, MOVA, OIVA, ddithyans, PO-161374, pyridiniumalkanoylthioethers (RATEZ5), azodicarbonamide (AbBA), cyclic 2,2 dithiobisbenzamide, etc.), EMase H inhibitors (for example, VVNM, SRNM PO-26388, etc. .p.), Tai inhibitors (for example, dominant negative mutants, Ko24-7429, No5-3335, etc.), Kem inhibitors (for example, dominant negative mutants, Leptomycin B, RKERO50-638, etc.), transcription inhibitors (eg

Temacrazine, K-12 and K-37, EM2487, etc.), HIV assembly/maturation inhibitors (eg, SAR-1 and SAR-2, etc.) and pharmaceuticals targeting cellular anti-HIV targets (for example, G8B6-8275 and HEM1275, sake inhibitors, etc.).

In some embodiments, a compound of the present invention can be used in combination with highly active antiretroviral therapy (HAART). When antiretroviral drugs are used in combination with three or four drugs, the treatment is called NAACT (see, for example,

Rogiediezv, ei ai., Eig. U. Meishgoi. (2004) 11:297-304).

According to the present invention, a combination of a compound of the present invention and a pharmaceutical agent can be prepared by mixing the respective active ingredients, either together or independently, with a pharmaceutically acceptable carrier, excipient, binder, diluent, etc., as described herein , with the introduction of a mixture or mixtures either orally or in another way in the form of a pharmaceutical composition (compositions). When a compound or a mixture of compounds of formula (Ia) is administered as a combination therapy with another active compound, each of them can be formulated as separate pharmaceutical compositions that are administered simultaneously or at different times. Alternatively, in some embodiments, the pharmaceutical compositions of the present invention include a compound or mixture of compounds of formula (Ia) and a pharmaceutical agent(s) in the form of a single pharmaceutical composition.

Other applications

Another object of the present invention relates to the radiolabeled compounds of the present invention, which may be useful not only for radioimaging, but also in assays, both ip mygo and ip mimo, to determine the localization and quantification of 5-HTα receptors in tissue samples that include human tissues, and to identify ligands of 5-HTα receptors by inhibiting the binding of a radiolabeled compound. Another goal of this invention is to develop new assays for the 5-HTgl receptor that include such radiolabeled compounds.

The present invention encompasses the isotopically labeled compounds of the present invention. "Isotopically" or "radiolabeled" compounds are those compounds which are identical to the compounds disclosed in this application, but have one or more atoms replaced or replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number that naturally exist in nature, (that is, natural). Suitable radionuclides that may be incorporated into the compounds of the present invention include, but are not limited to, "H (which is also denoted as

O - deuterium), ZN (which is also denoted as T - tritium), C, 130, 140, 13M, 15M, 150, 170), 180), 18rg, 5555, 36С|, 82Vu, t5Vg, "VH, 77Vg, 128), 124), 125) | 191), The radionuclide that is included in the radiolabeled compounds according to the present invention depends on the specific application of this compound. For example, for ip migo labeling of the 5-HTgla receptor and competitive assays of compounds that include ZH, 17 . or "VG.

It should be understood that "radiolabeled" or "labeled compound" is a compound of formula (Ia), which includes at least one radionuclide; in some variants of the embodiment of the invention, the radionuclide is selected from the group including ZN, 17C, 125), 355 and 82Vg,

Certain isotopically labeled compounds of the present invention are useful in assays of compound and/or substrate tissue distribution. In some embodiments of the invention, the radionuclide isotopes Zn and/or "Sb" are useful for these studies. In addition, substitution with heavier isotopes such as deuterium (i.e., ?H) may provide some therapeutic advantages due to better metabolic stability (eg, increased half-life (i.e. mimo or reduced doses) and therefore may be preferred in some circumstances. The isotopically labeled compounds of the present invention may generally be prepared by the following procedures similar to those disclosed in the Schemes above and in the Examples below , by substituting an isotopically labeled reagent for an unlabeled reagent. Other synthetic methods that are useful are discussed below. Furthermore, it should be understood that the atoms represented in the compounds of the present invention may be either the most abundant isotope of such an atom, or a rarer radioisotope or a non-radioactive isotope.

Synthesis methods for incorporating radioisotopes into organic compounds are applicable to the compounds of this invention and are well known in the art. These synthesis methods, for example, to incorporate tritium activity levels into target molecules, are as follows:

A. Catalytic reduction with gaseous tritium - this procedure usually gives high specific activity products and requires halogenated or unsaturated precursors.

B. Reduction with sodium borohydride (NO) - this procedure is quite cheap and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, etc.

C. Reduction with lithium aluminum hydride (NH | - this procedure offers products with almost theoretical specific activity. It also requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, etc.

Or. Labeling under the influence of gaseous tritium - this procedure involves exposure to precursors containing exchangeable protons with gaseous tritium in the presence of a suitable catalyst.

E. M-methylation using methyl iodide (NO - this procedure is usually used to obtain O-methyl- or M-methyl-containing (HN) products by treating suitable precursors with methyl iodide (HN), which has a high specific activity. This method, as as a rule, it allows to obtain a higher specific activity, for example, about 70-90 Ki/mmol.

Synthesis methods for inclusion of activity levels 122| target molecules include:

A. Zapateueg Reactions and the like - this procedure converts an aryl or heteroarylamine into a diazonium salt, such as a tetrafluoroborate salt, and then into a 725-labeled compound with the help of Ma!zI. A representative procedure is described in p, O.-5. apa so-zhoiKkegz ip U. Ogud. Spent 2002, 67, 943-948.

V. Ortho "5-iodination of phenols - this procedure makes it possible to incorporate "2zI in the ortho position of phenol, as reported by Soieg, T. .. apa so-mogkKegz ip u). And areed Sotra Raadiorpagt. 1999, 42, 5264-5266.

S. Exchange of aryl and heteroaryl bromide with 125| - this method, as a rule, is a two-stage method.

The first step is the conversion of an aryl- or heteroaryl bromide into the corresponding trialkyltin intermediate using, for example, a reaction catalyzed by Pa (i.e., Pa(RPzP)4| or through an aryl- or heteroaryllithium, in the presence of a trialkyltin halide or a hexaalkyldiol (e.g. , (СНз)з5pop(СНЗзи)зи.

A representative procedure is described by Vaz, M.-O. apa so-mogkKegz ip .). And abeyed Sotra Nadiornaghtt. 2001, 44, 5280-5282.

The radiolabeled 5-HTgl receptor and the compound of formula (Ia) can be used in a screening assay to identify/evaluate the compounds. In general, newly synthesized or identified compounds (ie, test compounds) can be evaluated for their ability to reduce the binding of a "radiolabeled compound of formula (Ia)" to the 5-HTg receptor. Accordingly, the ability of the tested compound to compete with the "radiolabeled compound of formula (Ia)" for binding to the 5-HTgl receptor is directly correlated with its binding affinity.

Labeled compounds according to the present invention bind to the 5-HTgla receptor. In one embodiment of the invention, the labeled compound has an ICoo of less than about 500 µM, in another embodiment of the invention, the labeled compound has an IC of less than about 100 µM, in yet another embodiment of the invention, the labeled compound has an IC of less than about 10 µM, in the next embodiment of the invention, the labeled compound has an IC of less than about 1 µM, and in yet another embodiment of the invention, the labeled compound has an IC of less than about 0.1 µM.

Other applications of the disclosed receptors and methods should be apparent to those skilled in the art based on, among other things, a review of this disclosure.

It should be understood that the steps of the methods of the present invention need not be performed any particular number of times or in any particular sequence. Additional objects, advantages and novel features of the present invention will become apparent to those skilled in the art upon careful consideration of the examples, which are intended to illustrate and not to limit the invention.

Examples

Example 1: Synthesis of compounds according to the present invention.

Illustrated methods for synthesizing compounds of the present invention are presented in Figures 1-12, where symbols have the meanings used in this disclosure.

The compounds of this invention and their synthesis are illustrated in more detail by means of the following examples. The following examples are intended to further describe the present invention, but are not intended to limit the present invention to the specifics of these examples. The compounds described in this application, above and below, are named in accordance with C5 Spet Ogam/ Shyga Megsiop 7.0.1 or AshoMot 2000. In some cases, common names are used and it is intended that these common names should be understood by those skilled in the art .

Chemistry: Proton nuclear magnetic resonance ("H NMR) spectra were recorded on a Magiap Megsig Mkh-400 equipped with a 4-nucleus auto-switching probe and 2-gradient, or on a VgykKeg Amapse-400 or 500 МН2 equipped with an OMR (Otsai Mysieyiz Rgore) or VVI (Vgoai Vapa Ipmegze) and a 2-gradient.Chemical shifts are presented in parts per million (ppm) with the residual solvent signal used as a standard.

The following NMR abbreviations are used: c-:singlet, d-doublet, dd-doublet, dt-doublet, t-triplet, q-quartet, m-multiplet, wide-extended. Microwave irradiation was carried out using Etgu5 Zupipezigeg (Regzopa! Spezigeg). Thin-layer chromatography (TLC) was performed on silica gel 60 Roz. (Megsk), preparative thin-layer chromatography (prep TLC) was carried out on 1 mm plates 60 A from silica gel RKbE (U/paytap), and column chromatography was carried out on a column with silica gel using Kieseide! 60, 0.063-0.200mm (Megsk). Evaporation was carried out in vacuum on a Vysp rotary evaporator. Seiye 5455) was used in palladium filtration.

Conditions of RHMS: 1) ROS: HPLC-pumps: I S-10A0O MR, ZPPitaid2y Ips.; HPLC system controller: ZSI-10A MR,

Zpitayd7y Ips; UV detector: BRO-10A MUR, Zpitaidy Ips; Automatic sampler: STO NT5, RAI, I ear

Zsiepiis; Mass spectrometer: АРИ 150ЭХ with a source of turbo ion sputtering, AV/MO5 5Zsieh; Program: Apaiusi 1.2. 2) Mass: HPLC-pumps: I S-8A MUR, ZPPpPitayd2y Ips; controller of the HPLC system: 5СИ-10А MR, ZPitayd»2y Ips. UV detector: ZRO-1I0A MR, 5Ppitai?y IPS; Automatic sampler: 215 Hidtsid Napayeg, Siizop Ips; Mass spectrometer: АРИ 150ЭХ with a source of turbo ion sputtering, AB/MO5 5sieh; Program: Mazzspgot 1.5.2.

Example 1.1: Preparation of /1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|)|-3-(2,4- difluorophenyl)urea (Compound 13).

Stage 1.1a: Preparation of the intermediate compound 1-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(2,4-difluorophenyl)urea. Method A

Me

I E he e o o o / ie -6---- di, in NN a that Y p

A mixture of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl|-3-(2,4-difluorophenyl)urea (0.270g,

0.b9mmol) in anhydrous 1,2-dichloroethane (1LOml) was cooled to 02C in an ice bath and stirred for 10 minutes. Anhydrous aluminum chloride (0.368 g, 2.76 mmol) was added and the reaction mixture was stirred at 02C for 20 minutes, then transferred to an oil bath and stirred at 802C for 1 hour.

Ethyl acetate was added and washed with sodium potassium tartrate (1095) twice. The organic layer was separated, dried over anhydrous Ma»5O, filtered and concentrated to obtain a crude product, which was purified by HPLC. The required fractions were collected and lyophilized to obtain 1-I3-(4-chloro-2-methyl-2IN-pyrazol-3-yl)-4-hydroxyphenyl|-3-(2,4-difluorophenyl)urea in the form of a white solid with with an output of 75.0905.

RHMS ti/z (95)-379 (MAN Z5SI, 100), 381 (MAN Z7SI, 40). "H NMR (400 MHz, OM5O-dv) b: 9.81 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.12-8.06 (m, 1H ), 7.63 (s, 1H), 7.40-7.31 (m, ЗН), 7.09-7.04 (m, 1H), 6.99 (d, uU1-8.72Hz, 1H ), 3.69 (s,

ZN).

Stage 1.16: Preparation of /1-I(I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,4- difluorophenyl)urea (Compound 13). Method B

Um oh he, "and 2 Shk B; deno - there are more of them

To a solution of 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl)|-3-(2,4-difluorophenyl)urea (0.35 g, 00.09 mmol) in triphenylphosphine (70.8mg, 0.27mmol) and 1-(2-hydroxyethyl)pyrrolidine (0.032ml, 0.27mmol) were added to anhydrous THF (2ml), followed by the dropwise addition of diisopropylazodicarboxylate (O1AO) (0.052ml, 0.27mmol) . The reaction mixture was stirred at room temperature for 2 hours, concentrated to obtain the crude product, which was purified by preparative HPLC. The required fractions were collected, neutralized with Mahon ions and extracted with EtOAc four times.

The solution was evaporated under reduced pressure to give Compound 13 as an off-white solid in a yield of 52.895. RHMS t/ (96)-476 (MN SI, 100), 478 (MAN Z'"SI, 40). "H NMR (400 MHz, OM5O-dbv) 6: 9.10 (s, 1H), 8.55 (s, 1H), 8.17-8.09 (m, 1H), 7.69 (s, 1H), 7.61 (dd, 58.97 and 2.72Hz, 1H), 7.47 (d , 922.70 Hz, 1H), 7.43-7.36 (m, 1H), 7.26 (d, 9U-9.04Hz, 1H), 7.16-7.09 (m, 1H), 4.25-4.08 (m, 2H), 3.73 (s, ЗН), 2.58-2.45 (m, 2H), 2.45-2.29 (m, 4H), 1, 75-1.69 (m, 4H).

Example 1.2: Preparation of the intermediate compound 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine. Method C

M M

IF

M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|acetamide (1.0 g, 2.92 mmol) was dissolved in ethanol (15 mL), then aqueous sodium hydroxide solution (2.5 mL, 5095 wt/wt) was added and the reaction mixture was stirred at 802C overnight, then concentrated. Water and saturated saline were added, then extracted with EAs three times. The organic layers were combined, dried over anhydrous Mag50O », then the solvent was removed under reduced pressure to obtain 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine as a brown oil with a yield of 97.195. (90)-:301 (M--H, 100).

Example 1.3: Preparation of isopropyl ester of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylcarbamic acid (Compound 33). Method O

M M

GO izsy r M

To a solution of /3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine (30.00 mg, 0 mmol) in methylene chloride (1 ml) was added pyridine (24.3 μl , 0,Zmmol). The mixture was treated with isopropyl chloroformate (13.3 µl, 0.1 mmol), then the reaction mixture was stirred at room temperature overnight and concentrated to give an oily residue, which was purified by flash chromatography (5

Snow/Meon gradient elution) to give Compound 33 as an off-white waxy solid in 90.695 yield. РХМС t/ (90)-387 (MN, 100).

Example 1.4: Preparation of M-III-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|-2-phenylacetamide (Compound 35). Method E

M M

It's bad

Pyridine (17.0 μl) was added to a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine (21.0 mg, 0.07 mmol) in methylene chloride (1 ml) , 0,Zmmol). The mixture was treated with phenylacetyl chloride (10.bml, 0.8mmol), then the reaction mixture was stirred at room temperature overnight and concentrated to give an oily residue, which was purified by flash chromatography (5µl).

SngsSig/Meon gradient elution) to give Compound 35 as an off-white solid in 81.295 yield. RHMS t/ (95)-419 (MAN, 100).

Example 1.5: Preparation of 1-benzyl-3-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea

(Compound 44). The method is the same

A solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine (21.0 mg, 0.07 mmol) in methylene chloride (1 mL) was treated with benzyl isocyanate (9.1 μL, 0.074 mmol), then the reaction mixture was stirred at room temperature overnight and concentrated to give an oily residue, which was purified by flash chromatography (5105, CNaSig/MeOH gradient elution) to give Compound 44 as an off-white solid in a yield of 51.495. RHMS t/l (90)-434 (MAN, 100). "H NMR (400 MHz,

Acetone-yv) 6: 8.04 (s, 1H), 7.57 (dd, uU-8.88 and 2.70 Hz, 1H), 7.48 (d, 9U-52.67 Hz, 1H), 7 ,42-7.27 (m, 6H), 7.07 (d, y-8.91Hz, 1H), 6.26 (width c, 1H), 6.23 (d, 9U-1.6 Hz . (m, 2H), 2.52-2.А41 (m, 4H), 1.58-1.51 (m, 4H), 1.46-1.38 (m, 2H).

Example 1.6: Preparation of 1-(2-14-I3-(-2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)pyrrolidin-2-carboxylic acid methyl ester acid (Compound 125).

Stage 1.ba: Preparation of methyl ester of 1-2-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|ethyl)pyrrolidine-2-carboxylic acid. The method of

Saint 7 1 --- (' - 5 J «« t r (9)

M what about IM-M

OIEA was added to 5-(2-(2-bromo-ethoxy)-5-nitrophenyl|-1-methyl-1H-pyrazole (200.00 mg, 0.1 bimol) in acetonitrile (3 ml) followed by the addition of H-OI-Pho -OMe. The reaction mixture was heated by microwave heating at 1709C for 20 minutes, then purified by preparative HPLC. The required fractions were collected and lyophilized to obtain methyl ether 1-(2-(2-(2-methyl-2H-pyrazole- 3-yl)-4-nitrophenoxy|ethyl)ipyrrolidine-2-carboxylic acid, in the form of a salt of trifluoroacetic acid, in the form of a light brown oil with a yield of 84.295.

Stage 1.6r: Preparation of methyl ester of 1-2-(4-amino-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)pyrrolidine-2-carboxylic acid. Method H -0, o - o th i oh gop Ge! 00 A-K Yum

Methyl ester of 1-(2-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|ethyl)ipyrrolidine-2-carboxylic acid (150.0 mg) in methanol (15 ml) was treated with a catalytic amount of palladium on activated carbon (1095 mass,

Redizza), degassed with argon, then bubbled with hydrogen from a cylinder through the suspension at room temperature overnight. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and dried to obtain the methyl ester of 1-2-|4-amino-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)pyrrolidine-2-carboxylic acid, in the form of a trifluoroacetic acid salt acid, in the form of a brown oil with a yield of 9295. LCMS t/ (95)-345 (MH, 100).

Stage 1.bs: Preparation of methyl ether 1-(2-I4-I3-(2,4-difluorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)pyrrolidin-2- carboxylic acid (Compound 125). -9, 80 -9, 0 and 2

Ot o "o Yi ak u

The title compound was prepared in the same manner as described in Method P to give a colorless oil. RHMS t/ (903-500 (MAN, 100).

Example 1.7: Preparation of (1H-benzoimidazol-2-yl)-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine (Compound 196). Method I

M M

GO OSzhsbiU nd, i

Hg Hg

To a mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine (0.105g, 0.28mmol) and 2-chlorobenzimidazole (0.057g, 0.3 mmol) in ethanol (ml) and two drops of 1N HCl were added. The reaction mixture was heated by microwave heating at 1809C for 1 hour, concentrated, then purified by preparative HPLC. The required fractions were collected and lyophilized to give Compound 196 as an off-white solid in a yield of 17.195. RHMS t/z (95)-:495 (MN "Vi, 100), 497 (MAN 81Vu, 90).

Example 1.8: Preparation of methyl ether 3-(1-2-I4-(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl)piperidin-4-yl )upropionic acid (Compound 151). Method in

And hm si o u shvi i dubu" ono Ko

A mixture of 1-I4-(2-chloroethoxy)-3-(2-methyl-2H-pyrazol-3-iluphenyl|-3-(4-chlorophenyl)urea (0.104g, 0.257 mmol), 3-piperidine-4 methyl ester -ylpropionic acid (0.108g, 0.631mmol) and potassium carbonate (0.143, 1.03mmol) in OMA (4.5ml) was heated by microwave irradiation at 1507C for 1 hour.

The crude mixture was purified by HPLC to give Compound 151 as an oil (TEA salt, 0.030Gg, 1895). The exact mass calculated for SgvNzaSIM5O4 is 539.23, found to be 540.4 (MNU). "H NMR (400MHz, chloroform-dv) 6: 10.70 (s, 1H), 8.24-8.30 (m, 2H), 7.61-7.62 (m, 1H), 7.57 (width c, 1H), 7.34-7.36 (m, 2H), 7.20-7 22 (m, 2H), 7.14-7.16 (m, 1H), 6.70- 6.71 (m, 1H), 6.23 (s, 1H), 4.27 (s, 2H), 3.71 (s, ЗН), 3.67 (s, ЗН), 3.24-3 .31 (m, 2H), 3.51-3.57 (m, 2H), 2.24-2.28 (t, 9-7.33Hz, 2H), 1.40-1.75 (m, 8H).

Example 1.9: Preparation of (1-(2-I4-I(I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)phenoxy|ethyl)piperidin-3-yl)acetic acid (Compound 175). Method K

Ov o she o GO zd o SS

To a stirred solution of ethyl ether (1-2-14-(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidin-3-yl)/acetic acid ( TPA salt, 0.038g, 0.058mmol) in a mixture of THF (0.9ml), MEeOH (0.3ml) and HgO (0.3ml) was added lithium hydroxide, monohydrate (0.044g, 1.05mmol) at room temperature and the mixture stirred for 45 min.The crude mixture was purified by HPLC to give

Compound 175 in the form of oil (TRA salt, 0.024g, 6695). The exact mass calculated for Cg2vNzoSiIM5O4 is 511.2, found to be 512.3 (MN). "H NMR (400 MHz, methanol-dial) 5: 7.39-7.42 (m, 2H), 7.29-7.32 (m, 3H), 7.13-7.15 (m, 2H) , 7.01-7.03 (m, 1H), 6.23 (s, 1H), 4.23-4.24 (m, 2H), 3.36 (s, 2H), 3.30 (s , 1H), 3.18 (s, ЗН), 2.58-2.64 (m, 2H), 2.46-2.52 (m, 2H), 2.10-2.15 (m, 2H ), 2.03-2.06 (m, 1H), 1.71 (width, 2H), 1.54-1.57 (m, 1H), 1.01-1.04 (m, 1H ).

Example 1.10: Preparation of methyl ether 4-(4-(2-I4-I(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl/)piperazin- 1-yl)-4-oxobutyric acid (Compound 176). Method I.

AND

OM, -- di, ry

To a stirred solution of 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-ylethoxy)phenyl|urea (HCl salt, 0.033g, 0.067mmol) and SIEA (0.035g, 4bmcl, 0.26bmmol) in THF (5ml) was added methyl 4-chloro-4-oxobutyrate (0.011g, 4bmcl, 1.05mmol) at 09С. The mixture was heated to room temperature and stirred for 45 minutes. The crude mixture was purified by HPLC to give Compound 176 as an oil (TRA salt, 0.024g, 5295). The exact mass calculated for Сг8вНззСИМвО5 568.22 was found to be 569.5 (МН). "H NMR (400 MHz, methanol-diaa) 6: 7.50 (s, 1H), 7.42-7.45 (m, 1H), 7.32-7.36 (m, ЗН), 7.15 -7.18 (m, 2H), 7.05-7.07 (m, 1H), 6.28 (s, 1H), 4.29-4.30 (m, 2H), 3.64 (s , 5H), 3.46-3.47 (m, 2H), 3.11-3.13 (m, 2H), 3.01-3.13 (m, 4H), 2.58-2.59 (m, 2H), 2.53-2.55 (m, 2H), 1.26-1.28 (m, 5H).

Example 1.11: Preparation of 1-(4-chlorophenyl)-3-I4-(2-(2,5-diazabicyclo(2,2,1|hept-2-yl)ethoxy|-3-(2-methyl-2H- pyrazol-3-yl)/phenyl|urea (Compound 177). Method M

M - 6 6 -- Chn

Oh t Oh

A suspension of tert-butyl ether 5-(2-I4-I(3--4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)-2,5-diazabicycloi(2, 2,1|heptane-2-carboxylic acid (TRA salt, 0.042g, 0.062mmol) and 4M HCl in dioxane (2 mL) were stirred at room temperature overnight.The mixture was dried in vacuo to give Compound 177 as an oil (HCl salt, 0.046g, 10095). The exact mass calculated for Сг2гаНо27СИМвО» 466.19, found 467.5 (MNU).

Example 1.12: Preparation of methyl ether (4-(2-I4-(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)uphenoxy|ethyl/)piperazin-1-yl ) of acetic acid (Compound 209).

And K nn I

To a stirred solution of 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperazin-1-ylethoxy)phenyl|urea (TRA salt, 0.063 g, 0.11mmol) and OIEA (0.572g, 77μl, 0.44mmol) in THF (3ml) was added methyl bromoacetate (0.019g, 12μl, 0.121mmol) at 09Сb. The mixture was heated to room temperature and stirred for 20 hours. The crude mixture was purified by HPLC to give Compound 209 as an oil (TEA salt, 0.053g, 7495). The exact mass calculated for SgvNziSiMeOa4 is 526.21, found to be 527.5 (MNU).

IN NMR (400 MHz, acetonitrile-d3z) 6: 7.78-7.89 (m, 2H), 7.77 (s, 1H), 7.54-7.77 (m, 1H), 7.43- 7.48 (m, ZN), 7.25-7.29 (m, 2H), 7.06-7.08 (m, 1H), 6.49 (s, 1H), 4.33-4, 35 (t, 9U-4.55, 4.80Hz, 2H), 3.84 (s, 2H), 3.80 (s, ZN), 3.75 (s, ZN), 3.46-3, 48 (t, U-4.55Hz, 2H), 3.39-3.41 (m, 8H).

Example 1.13: Preparation of /1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea ( Compound 17). Method O - Includes Stages 1.13a-1.13c, with the production of phenol.

Stage 1.1Za: Preparation of b-aminochromen-4-one.

at. | Go) o C 7 sew NoM o (c) (c)

To a solution of b-nitrochromone (2.0g, 10.5mmol) in methanol/ethyl acetate (100ml/20ml), which was purged with argon, a catalyst of 595Ra/s (Oedizza, wet weight 0.5g) was added. Hydrogen gas was bubbled through the suspension with stirring until (2 hours) HPLC and TLC showed complete conversion of starting materials to product. The spent palladium catalyst was filtered through celite and the solid was washed with methanol. The combined filtrate and washings were evaporated to give b-aminochromen-4-one (1.58g, 9495) as a light yellow solid. LCMS ti/a (95)-162 (MH, 100), "H NMR (400MHz, SOSIv) b: 7.79 (d, 9U-5.96Hz, 1H), 7.38 (d, 9U-2, 86Hz, 1H), 7.29 (d, U-8.88HzC, 1H), 7.01 (dd, U-8,v0Hz, 2.8Hz, 1H), 6.26 (d, 95.96HzC, 1H), 5.29 (s, 2H).

Stage 1.13r: Preparation of 1-(4-chlorophenyl)-3-(4-oxo-4H-chromen-b-yl)urea. o si o o still -60--idod OO (o non o

To a suspension, which is stirred and heated (807), of b-aminochromone (3.0 g, 18.6 mmol) in toluene (200 ml) was added 4-chlorophenyl isocyanate (3.2 g, 20.5 mmol) and the mixture was refluxed for another within 18 hours. The reaction mixture was cooled and the precipitate was filtered off and washed with methanol. The residue was dried under vacuum to obtain 1-(4-chlorophenyl)-3-(4-oxo-4H-chromen-b-yl)urea (5.8 g, 9995) as a yellow powder. RHMS ti/ya (95)2315 (MAN З5СИ, 100), 317 (MAN 97СИ, 32.2), "Н NMR (400 MHz, ОМ5О-dv) b: 9.09 (width s, 1Н), 8, 94 (width c, 1H), 8.29 (d, 9U-5.99HZ, 1), 8.20 (d, 9U-2.69HZ, 1H), 7.81 (dd, 9U-9.0 , 2.75Hz, 1H), 7.62 (d, 929.07 Hz, 1H), 7.52 (dd, uU-6.84, 2.16 Hz, 2H), 7.35 (dd, 9U- 6.85, 2.11Hz, 2H), 6.33 (d, 9U-5.98Hz, 1H).

Stage 1.13c: Preparation of 1-(4-chlorophenyl)-3-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-iluphenyl)urea.

A suspension of 1-(4-chlorophenyl)-3-(4-oxo-4H-chromen-b-yl)urea (2.5g, 7.9mmol) was added to a stirred and ice-cooled solution of methylhydrazine (146g, 31 mmol) in pyridine ) in pyridine for 10 minutes.

The reaction mixture was again stirred at this temperature for 2 hours and then allowed to slowly warm to ambient temperature. After 6 hours, the reaction mixture became clear. The reaction mixture was stirred at this temperature for 18 hours. The pyridine was evaporated and the formed dark residue was dissolved in OM5O and purified using a Magiap preparative HPLC system (2Oml/min, A-240, 0.190

TEA/HgO: 0.195 TEA/CH3SM). The two regioisomers were separated. Fractions containing the product were concentrated and dried under vacuum to obtain (1.78 g, 4795) a colorless powder. RHMS t/l (95)-343 (МН З5СИ, 100), 345 (MAN "СИ, 32.5). "Н NMR (400MHz, ОМ50О-ав) b: 9.59 (width s, 1Н), 8.72 (width c, 1H), 8.48 (width c, 1H), 7.43 (dd, 9-68, 2.07Hz, 2H), 7.A1 (d, 9-1.83Hz , 1), 7.28 (dd, 9-7.13, 2.09Hz, 2H), 7.26 (d, 9U-52.72Gu, 1H), 6.89 (d, 9U-9.36Hz, 1), 6.21 (d, U9-1.84HZ, 1H), 3.67 (s, ZN).

Stage 1.13a: Preparation of 1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|urea. "o ri on, Fi o o;

To a stirred and ice-cooled solution of 1-(4-chlorophenyl)-3-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl/phenyl|urea (0.1g, 0.2923mmol)), triphenylphosphine (0.291g, 1.1078mmol) and 1-(2-hydroxyethyl)pyrrolidine (0.127g, 1.099mmol) in THF (25ml) was slowly added diisopropylazodicarboxylate (0.224g, 1.104mmol) over 10 minutes. The reaction mixture was allowed to warm to room temperature environment and stirred for another 4 hours at this temperature. The THF was evaporated and the resulting syrup was dissolved in OM5O and purified using a preparative HPLC system o Magap (flow rate bOml/min and /X-240 0.195 TEA/NgO:0.195 TEA/CHzSM ). Fractions containing the product were evaporated. The bright pink residue was subjected to 2MU purification using 500" flash chromatography (eluent: 1906 methanol in OSM -" 1595 methanol in

OSM). Fractions containing the product were evaporated to obtain a colorless solid, which was directly used in the next step.

Stage 1.136e: Preparation of / 1-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea . "I oh go "ah oh a; si

To a solution of /1-(4-chlorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|urea -:-in cold methanol was added a solution of M-chlorosuccinimide (0.044 g, 0.3215 mmol) in methanol. The reaction mixture was stirred for 60 minutes. Then the methanol was evaporated and the residue was purified by flash chromatography on silica gel using 1595 methanol in OSM as eluent. Fractions containing the product were evaporated and dried under vacuum to obtain /1-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|- 3-(4-chlorophenyl)urea (Compound 17) (0.05g, 3895) as an off-white solid.

РХМС tu/ (95)-474 (MAN 8501 3501, 100), 476 (MAN 8501 87СИ, 81.7), 478 (MAN 8701 37С1, 11.2). "H NMR (400 MHz,

OM50-yv) 6: 8.83 (width s, 1H), 8.73 (width s, 1H), 7.61 (s, 1H), 7.54 (dd, 9U-2.65, 2 ... 2H), 7.16 (d, --9.03Hz, 1H), 4.2-4.0 (width m, 2H), 3.65 (s, ЗН), 2.7-2.5 ( width m, 2H), 2.4-2.3 (width m, 4H), 1.7-1.5 (width m, 4H).

Example 1.14: Preparation of 1-(2,4-difluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)phenyl|urea (Compound 28).

Stage 1.14a: Preparation of 2-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxymethyl|pyridine. Method P 7 me - e -- B «2 - - - - u o g r - c) A-M oo (c) ek

A mixture of /2-(2-methyl-2H-pyrazol-3-yl)y-4-nitrophenol (100 mg, 0.46 mmol), hydrobromide salt of /2-bromomethylpyridine (140 mg, 0.55 mmol) and potassium carbonate (158 mg, 1 .15 mmol) in OM 5 O (4 mL) was stirred at 100 °C overnight. The crude product was purified by HPLC to give the title compound as a brown solid (158mg, 8195). The exact mass calculated for Sib6Ni«MaOz 310.1 was found to be 311.2 (MNU).

Stage 1.14p0: Preparation of 3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)phenylamine. Way

F | M z Her hv) spon o oo Ki 1 NM ih o -K 2 | m

Zinc dust ( 192mg, 2.96mmol) at 02C. The mixture was stirred at the indicated temperature for 15 min and then filtered through celite. The solution was concentrated in vacuo to give the title compound as a solid (150mg, 10095). The exact mass calculated for SivNiveMm4O 280 ,1, found 281.4 (MNU).

Stage 1.14c: Preparation of 1-(2,4-difluorophenyl)-3-3-(2-methyl-2H-pyrazol-3-yl)-4-(pyridin-2-ylmethoxy)phenyl|urea (Compound 28) . va A -- - - - - - яяЮЯ -yeyak (v, y OKH nam Sya NN U,

The title compound was prepared in the same manner as described in the EP method to give an off-white solid. "H NMR (0M50-av, 400 MHz) b: 3.68 (s, ЗН), 5.20 (s, 2H), 6.31 (d, 9-2.02Hz, 1H), 7.04-7 .06 (m, 1H), 7.18 (d, 9U-8.34Hz, 1), 7.27-7.34 (m, 2H), 7.37-7.47 (m, AN), 7 .87 (dt, U-2.02, 8.08Hz, 1H), 8.00-8.07 (m, 1H), 8.48 (s, 1H), 8.59-8.60 (m, 1H), 8.98-8.99 (m, 1H). The exact mass calculated for SgzNioR»M5O» 435.2, found 436.4 (MNU).

Example 1.15: Preparation of /2-(4-chlorophenyl)-2-hydroxy-N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylacetamide (Compound 95 ). Method B

Mho sovs (--- ditches

M M,

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylamine (10mg, 0.35mmol), 4-chloromandelic acid (98mg, 0.525mmol), NATIi ( 200mg, 0.525mmol) and triethylamine (O0.5ml) in DMF (bml) were heated at 502C overnight. The crude product was purified by HPLC to give the title compound as a semi-solid (24mg, 1595). "H NMR (0M50-av, 400 MHz) b: 1.60-1.73 (m, 2H), 1.84-1.91 (m, 2H), 2.80-2.90 (m, 2H) , 3.22-3.30 (m, 4H), 3.65 (s, ЗН), 4.25 (t, 9-5.05Hz, 2H), 6.26 (d, 9-1.77Hz , 1H), 7.17 (d, 9-9.09HzC, 1H), 7.39-7.46 (m, 2H), 7.51-7.53 (m, ЗН), 7.67 (d , U-2.53Hz, 1H), 7.80 (dd, 9U-2.78, 8.84Hz, 1H), 9.50 (with width, 1H), 10.0 (s, 1H). Accurate mass calculated for SgaH27SIMAOz 454.2, found 455.4 (MNU).

Example 1.16: Preparation of 3-methylbut-2-enoic acid (3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylamide (Compound 106). Method 5 of this CO is SK o-- AH y

AL MV (

3-methyl-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|butyramide (20 mg, 0.054 mmol) was treated with MV5 (10 mg, 0.054 mmol) in DMF (2 ml) at room temperature for 2 hours.

The crude product was purified by HPLC to give the title compound as an off-white solid (bmg, 2595). The exact mass calculated for С21иН27ВИМаО» 446.1, found 447.2 (MNU).

Example 1.17: Preparation of 4-bromo-5-(2-(2-bromo-ethoxy)-5-nitrophenyl)|-1-methyl-1H-pyrazole. Method T

Вг Вг г тя Ве

Go7h nya 7. I go Sov c) MM Io) MM

A mixture of 5-(2-(2-bromo-ethoxy)-5-nitrophenyl|-1-methyl-1H-pyrazole (200 mg, 0.bimol) and M-bromosuccinimide (0.6 mmol, 1.0 equiv.) in 2 gml DMF stirred at 1002 C for 10 minutes in a microwave oven. The mixture was quenched with water, extracted with ethyl acetate and dried in vacuo to give the title compound as a yellow solid (200 mg, 8195). "IN NMR (400 MHz, SOCI3) 5 3, 53-3.64 (m, 2H), 3.78 (s, ЗН), 4.38-4.49 (m, 2H), 7.11 (d, 1H), 7.57 (s, 1H) , 8.23 (s, 1H), 8.39 (d, 1H). The exact mass calculated for

Si2NiVg2MzOz 402.9, found 406.1 (MNU).

Example 1.18: Preparation of pentanoic acid 13-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-I(2-(4-hydroxypiperidin-1-yl)ethoxy|phenyl)amide (Compound 179) . Method in

M M oche pen nn tnnnnnse Ha! oh ovi - ho im Vg

A mixture of 1-(2-(4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenoxy|ethylpiperidin-4-ol (5O0mg, 0.126mmol), valeric anhydride (28mg, 0 .15 mmol) and triethylamine (0.1 mL) in DMF (mL) was heated by microwave heating at 802 C for 10 minutes. The crude product was purified by HPLC to give the title compound as a yellow solid (27 mg, 4595). NMR (0M5O-av, 40MHz) 6: 0.90 (t, 9-7.33Hz, ZN), 1.33 (quart., U9-7.58Hz, 2H), 1.47-1.51 (m , 1H), 1.57 (quint., U-7.58Hz, 2H), 1.68-1.90 (m, 2H), 2.30 (t, 9-7.33Hz, 2H), 2, 75-3.30 (m, 6H), 3.40-3.43 (m, 2H), 3.70-3.71 (m, ЗН), 3.85-3.90 (m, 1H), 4.22- 4.50 (m, 2H), 7.22 (d, 9-9.35Hz, 1H), 7.53 (d, U-2.53Hz, 1H), 7.64 (d, 9U -8.84Hz, 1H), 7.76 (dd, 9U-2.53, 9.09Hz, 1H), 9.37 (with width, 1H), 9.98 (s, 1H). Exact mass, calculated for SgoNziVgMaOz 478.2, found 479.3 (MNU).

Example 1.19: Preparation of (|4-(2-(4-hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-iluphenyl)|pentanoic acid amide (Compound 203).

Stage 1.19a: Preparation of 4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine. The method of M vg r o sonia Ge

AH m y y y NM i y

A mixture of M-I4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|Iacetamide (450mg, 1.33mmol), concentrated

NOSI (0.9ml) in THF (4ml) was heated by microwave irradiation at 1502C for 30 minutes.

The crude product was concentrated in vacuo to give the title compound as a brown oil. The exact mass calculated for Si2Ni«SIM2O is 251.1, found to be 252.0 (MNU). This product was used without purification in the next step.

Stage 1.19r: Preparation of (4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|pentanoic acid amide. si Y b, OO o 7,

ISH N We

The title compound was prepared in the same manner as described in Method 2 to give a white solid. "H NMR (SOSIz, 400MHz) b: 0.95 (t, 9U-7.33Hz, ZN), 1.43 (quart., 9U-7.58Hz, 2H), 1.72 (quint., 9U- 7.60Hz, 2H), 2.40 (t, 9-7.58Hz, 2H), 3.72 (t, U9-5.31HzC, 2H), 4.04 (s, ЗН), 4.25 ( t, 2H), 6.25 (d, 1H), 6.98-7.00 (m, 1H), 7.44 (s, width, 1H), 7.59-7.60 (m, 1H ), 7.64-7.66 (m, 1H), 7.81 (d, U-2.53Hz, 1H). The exact mass calculated for

Si17Ng2SIM3Oz 335.1, found 336.3 (MH).

Stage 1.19c: Preparation of pentanoic acid (|4-(2-(4-hydroxypiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl))amide (Compound 203) U and M o o, o OO ky M, prare M, "S, Mo,

A mixture of (4-(2-chloro-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)pentanoic acid amide (50 mg, 0.15 mmol), 4-hydroxypiperidine (18 mg, 0.18 mmol) , potassium carbonate (Zimg, 0.225 mmol) and a catalytic amount of tetrabutylammonium iodide in DMF (ml) was heated by microwave heating at 1002 C for 2.5 hours. The crude product was purified by HPLC to give the title compound as a sticky solid ( 51 mg, 8595). IN NMR (0M50O-ivye, 400MHz) b: 0.89 (t, 9U-7.33Hz, ZN), 1.30 (quart., y-7.58Hz, 2H), 1.40 -1.48 (m, 1H), 1.54 (quint., U-7.58Hz, 2H), 1.66-1.82 (m, 2H), 2.28 (t, 9-7.33Hz , 2H), 2.82-2.89 (m, 1H), 3.05-3.09 (m, 2H), 3.19-3.22 (m, 1H), 3.39-3.45 (m, 2H), 3.64 (d, 9U-2.53Hz, ZN), 3.85 (s, 1H), 4.11-4.18 (m, 4H), 6.25 (dd, U -2.02, 5.05Hz, 1H), 7.16 (d, U-9.09Hz, 1H), 7.45 (dd, 9U-52.02, 5.31Hz, 1H), 7.55 (d, U-52.78Hz, 1H), 7.66 (dd, 92.53, 9.09HzC, 1H), 9.23 (s, lat., 1H), 9.91 (s, 1H). The exact mass calculated for Сg2Нз2Маоз 400.2 was found at 401.3 (MNU).

Example 1.20: General chlorination procedure. Preparation of the intermediate compound 5-(2-(2-bromomethoxy)-5-nitrophenyl|-4-chloro-1-methyl-1H-pyrazole. Method X

Go Ve GVe o O p

And renew ok o o, ovi o- V-k o MM

A mixture of 5-I(2-(2-bromo-ethoxy)-5-nitrophenyl|-1-methyl-1H-pyrazole (470 mg, 1.44 mmol) and M-chlorosuccinimide (1.44 mmol, 1.0 equiv.) in 2 gml DMF was stirred at 1002 C for 20 minutes in a microwave oven. The mixture was quenched with water, extracted with ethyl acetate and dried in vacuo to give the title compound as a yellow solid (462 mg, 8995). "IN NMR (400 MHz, SOCI3) 6 3 .61 (t, 2H), 3.78 (s, ЗН), 4.44 (t, 2H), 7.13 (d, 1H), 7.57 (s, 1), 8.23 (s, 1H), 8.40 (d, 1H). The exact mass calculated for

SigNy8'VgSIMzOz 359.0, found 362.0 (MN).

Example 1.21: Preparation of 1-(4-(2-azetidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-(2,2-difluorobenzo|1,3| dioxol-5-yl)urea (Compound 87). Method U ko.

To a solution of 4-nitrophenyl chloroformate (51.5 mg, 0.255 mmol) in 1,2-dichloroethane (4 mL) and pyridine (5 µM) was added 5-amino-2,2-difluoro-1,3-benzodioxole (32 µL, 0.275 mmol). After 1 hour, 4-(2-azetidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-ylphenylamine) (47.4 mg, 0.147 mmol) in 1,2-dichloroethane (5 mL) was added and stirring was continued. overnight. The resulting substance was purified by HPLC. The product was dried in vacuo to give Compound 87 as a white solid (40.7 mg, 5095). LCMS t/ (95)-472 (MH, 100), "H NMR (400 MHz . 41 (m, 2H), 7.36 (d, y-2.71Hz, 1), 7.30 (d, 9U-8.74 Hz, 1H), 7.10-7.02 (m, 2H) . ,92Hz, AN), 2.60 (t, 9U-5.47 Hz, 2H), 1.86 (quintet, U-6.90Hz, 2H).

Example 1.22: Preparation of /1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-hydroxyphenyl)urea ( Compound 25). Method 7. ,/ g s beige o us (077 triphosen M K

Vg 2. TVA Ve

4-(tert-butyldimethylsilanyloxy)phenylamine (48.4 mg, 0.217 mmol) was added to a solution of triphosgene (19.7 mg, 0.Obbmmol) in tgF (dml). After 1 hour, 3-(4-bromo-2-methyl-2IN-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylamine (62.3 mg, 0.171 mmol) in THF (5 mL) was added ), and after another 30 minutes, triethylamine (100 μl) was added and stirring was continued overnight. The obtained substance was purified by HPLC. The isolated oil (8mg) was dissolved in THF (15ml). TVAE (0.165 ml of a 1.0 M solution in THF, 0.165 mmol) was added to this solution. The reaction mixture was concentrated to give an oil, which was purified by column chromatography at 5 µg (eluent: 2095 methanol/8095 dichloromethane) to give

Compound 25 as a white solid (57.2 mg, 6795). RHMS t/l (95)-500 (MAN "Vi, 100), 502 (MAN 8'Vu, 89), "H NMR (400 MHz, OM50O-yv) b: 9.03 (s, 1H), 8, 59 (width c, 1H), 8.35 (width c, 1H), 7.59 (c, 1H), 7.51 (dd, 98.97, 2.71HZ, 1H), 7.33 ( d, 9U-2.70Hz, 1H), 7.20 (d, U-8.86 Hz, 1H), 7.12 (d, 9U-9.04Hz, 1H), 6.67 (d, U- 8.85Hz, 1H), 4.13-4.04 (m, 1H), 4.04-3.95 (m, 1H), 3.66 (s, ЗН), 2.77-2.66 ( m, 1H), 2.66-2.57 (m, 1H), 2.41-2.30 (m, 4H), 1.65-1.55 (m, 4H).

Example 1.23: Preparation of 2-(tert-butyldiphenylsilanilox)-4-chlorophenylamine. Method AA si SI dz - - ho no (c)

2-amino-5-chlorophenol (0.949g, 6.61mmol), tert-butylchlorodiphenylsilane (2.50ml, 9.61mmol) and imidazole (1.335g, 19bmmol) were dissolved in THF (50ml). After a few days, the reaction mixture was concentrated to obtain an oil, which was purified by column chromatography at 5% (eluent: 4595 dichloromethane/5595 hexane).

The product was dried in vacuo to give 2-(tert-butyldiphenylsilanyloxy)-4-chlorophenylamine as a yellow oil (784.2mg, 3195). "H NMR (400 MHz, OM5O-av) 6: 7.72-7.64 (m, AN), 7.55-7.43 (m, 6H), 6.71 (d, U-8.45 Hz, 1H), 6.65 (dd, 9U-8.46,2.27Hz, 1H), 6.10 (d, 9-2.26Hz, 1), 1.05 (s, 9H).

Example 1.24: Preparation of intermediate compound 5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole. Method AB 1. l-butyllithium bt 2. zinc chloride

Zh.-B .- 6:-- 7 I 35 -- 2 3. Om! what

Ome

A solution of M-methylpyrazole (5.12g, 624mmol) in THF (100ml) was cooled to 782C and 2.5M n-butyllithium in hexane (27.5ml, 68.dmol) was added. After stirring for 30 minutes at the specified temperature, 0.5 M zinc chloride in THF (107 mL, 53.5 mmol) and 1 M zinc chloride in diethyl ether (15.3 mL, 15.2 mmol) were added. The mixture was allowed to warm to room temperature and 2-iodo-4-nitroanisole (17 4g, 62.4mmol) was added, followed by the addition of tetrakis(triphenylphosphine)palladium (3.6bg, 3.1mmol). After stirring at 609C for 20 hours, the black solution was concentrated using a rotary evaporator and extracted with ethyl acetate and saturated saline. The combined organic layers were dried over magnesium sulfate, filtered, and partially concentrated until a solid precipitated. Hexane was added, the precipitate was filtered off and washed with a cold mixture of 3:1 hexane/ethyl acetate to give 5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (8.6g, 3b, Ummol, 5995) as a yellowish - brown solid. РХМС ti/ (95)-:234 (МН, 100). "H NMR (400MHz, SOS) 6: 8.34 (dd, U-2.8, 9.2Hz, 1H), 8.19 (d, 9-2.8Hz, 1H), 7.56 (d, U-2.0HzC, 1), 7.08 (d, 9U-9.2Hz, 1H), 6.31 (d, U9-1.6Hz, 1H), 3.96 (s, ЗН), 3, 74 (c, ZN).

Example 1.25: Preparation of the intermediate compound 4-methoxy-3-(2-methyl-2H-pyrazole-3-iluphenylamine. Method AS that -- - I

M voi o

Ge) IM-M Y

Zinc dust (11.7g, 179mmol) was added portionwise to a solution of 5-(2-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (7.95g, 34.1mmol) in acetic acid (250ml) cooling in an ice bath for 10 minutes.

After stirring for 30 minutes at room temperature, the solids were filtered through celite. The filtrate was concentrated and the residue was purified by column chromatography at 50° (eluent: methylene chloride/methanol 20:11) to give 4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenylamine (4.34g, 21 ,4mmol, 6295) in the form of oil. LCMS t/z (95)-204 (M.N). "H NMR (400MHz, SOSIz) 6: 7.51 (d, 9U-1.8Hz, 1H), 6 .83 (d, 9-8.7 Hz, 1H), 6.76 (dd, uU-2.8, 8.7Hz, 1H), 6.62 (d, 9U-2.8Hz, 1H), 6 ,22 (d, 9U-1.8HzC, 1), 3.74 (s, ZN), 3.73 (s,

ZN), 3.24-3.55 (width c, 2H).

Example 1.26: Preparation of intermediate compound 1-(3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea. Method it nn and in

Tribromoborane ( 1Oml, 10bmmol). The mixtures were allowed to warm to room temperature. After stirring over the weekend, the mixture was cooled in an ice bath and a mixture of ice-cooled ammonium hydroxide and water (1OO0ml) was slowly added. The mixture was transferred to a separatory funnel and extracted with methylene chloride and water. The solid in the aqueous phase was filtered off and washed with water to give 1-I3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea as a white solid (4, 92 g, 9095 rige, 12.7 mmol, 7195). The combined organic phases were dried over Md50O", filtered and concentrated to obtain an additional amount of 1-I3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea in the form of a white solid (1.7 g, 4.99 mmol, 2895). Total yield: 9995. RHMS t/2 (95)-343.1 (MAN). "H NMR (400 MHz, SOSIz) 6: 9.60 (width s, 1H), 8.78 (s, 1H), 8.53 (s, 1H), 7.48-7.42 (m, ЗН ), 7.32-7.27 (m, 4H), 6.91-6.89 (m, 1H), 6.21 (d, 9-1.8Hz, 1H), 3.68 (s, ЗН ).

Example 1.27: Preparation of 1-I(3-(2-methyl-2H-pyrazol-3-yl)-4-smorpholin-2-ylmethoxy)phenyl|-3-phenylurea (Compound 174). AE method

SH. o ta) o ra si o z) now o o !

To a solution of 2-I4-I3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-yl)phenoxymethylimorpholine-4-carboxylic acid benzyl ether (30 mg, 0.052 mmol) in methanol (5 ml) , added Ra on carbon (1095, 50905 NgO, 5Omg, 0.024 mmol) and the mixture was stirred in a hydrogen atmosphere (balloon) at room temperature for 2 hours. The solids were filtered through celite and the mixture was purified by HPLC to give Compound 174 as a white solid (TRA salt, 9.8mg, 0.0176mmol, 3690). RHMO t/2 (95)-408.5 (MAN). "H NMR (400MHz, Meon-a»z) 5: 7.43-7.38 (m, 2H), 7.32-7.30 (m, ЗН), 7.20-7.16 (m, 2H), 7.00 (d, y-8.9Hz, 1H), 6.99-6.90 (m, 1H), 6.23 (s, 1H), 4.01-3.98 (m, ЗН), 3.88-3.85 (m, 1Н), 3.72-3.69 (m, 1Н), 3.65 (с, ЗН), 3.14-3.09 (m, 2Н) , 2.98-2.92 (m, 1H), 2.79-2.73 (m, 1H).

Example 1.28: Amination using boronic acid and copper (II) acetate, obtaining (3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl| -(4-Chlorophenyl)amine (Compound 305). in, "sh le nu SCSSHHOAS)o! TEA / SNASYI. Y tr si si

A mixture of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenylamine (0.050g, 0.15mmol), 4-chlorophenylboronic acid (0.035 g, 0.23 mmol), copper (II) acetate (0.0273 g, 0.15 mmol) and triethylamine (0.042 ml,

O,Zmmol) in methylene chloride (Zml) was stirred at room temperature for 48 hours. The reaction mixture was concentrated to obtain a crude product, which was subjected to purification using a preparative

TOP. The corresponding fractions were collected and lyophilized to obtain the TEA salt of compound 305 as a gray solid with a yield of 21.395. RHMS: Exact mass calculated for SgoNgasSi»MaO» 446.13, found t/2-447.1 (M.--N).

Example 1.29: Reductive amination, obtaining 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-ylmethoxy)phenyl|-3-(4-chlorophenyl) urea (Compound 335). The method of AS ro nsNno o), a o o, Mav) o o,

OH OSE oh

Wh Vh

A mixture of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-4-ylmethoxy)phenyl|-3-(4-chlorophenyl)urea (0.030g, O, 00bmmol) and formaldehyde (3795 aqueous solution, 0.015ml, 0.18mmol) in 1,2-dichloroethane (2ml) was treated with sodium triacetoxyborohydride (0.025g, 0.12mmol). The mixture was stirred at room temperature under an argon atmosphere overnight, diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified using

TOP. The corresponding fractions were collected and lyophilized to obtain the TEA salt of compound 335 as a white solid with a yield of 54.7956. RHMS: Exact mass calculated for SgaH27VgSIM5O» 531.10, found t/2-532.2 (MAN).

Example 1.30: Preparation of M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2--4-methanesulfonylaminopiperidin-1-yl)ethoxy|phenyl-3-trifluoromethyl-benzamide (Compound 757). Method AN

M M

E o se kA Ge) poh

M and M of the M. council of Shch, M for V.M

M-I(4-(2-(4-aminopiperidin-1-yl)ethoxy|-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)uphenyl|-3-trifluoromethylbenzamide) (0.038g, . extracted using

EUAs (2x20ml). The organic extracts were dried (Mag5054), filtered, concentrated and purified by preparative HPLC to give the title compound (0.016g, 0.02bmmol, 3595, TEA salt) as a white solid. LCMS ti/z (95)-600 (MaNZZSI, 100), 602 (MANZ"SI, 36). "H NMR (400 MHz, OM5O-dv) 6: 10.54 (s, 1H), 9.30 (s , 1H), 8.30 (s, 1H), 8.26 (d, U-8.0HzC, 1), 7.97 (m, 2H), 7.80 (m, 1H), 7.72 ( d, 9U-2.6Hz, 1H), 7.68 (s, 1H), 7.31 (m, 1H), 4.40 (m, 1H), 4.32 (m, 1H), 3.69 (s, ЗН), 3.50-2.90 (m, 7Н), 2.95 (s, ЗН), 2.00-1.50 (m, 4Н).

Example 1.31: Preparation of 1-(4-chlorophenyl)-3-I4-(2-(A)-1-methylpiperidin-2-yl)ethoxy|-3-(2-methyl-2H-pyrazole-

Z-yl)/phenyl|urea (Compound 353). Method A! n Bos N Me

M. M tert-Butyl ether of 2-2-(4-(3-(4-chlorophenyl)ureido|-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)piperidine-1-carboxylic acid) (240 mg , 0.434mmol) was added to a solution of 1M HyAl in THF (3.472ml, 3.472mmol) and THF (1Oml) at 02C. The reaction mixture was heated to reflux at 7520 for 8 hours. The crude reaction mixture was quenched with water at 02C with stirring and Ma»bOx was added to the crude mixture and then stirred at room temperature for another 30 minutes.The resulting solid was filtered, washed with ethyl acetate and the supernatant was concentrated and dried in vacuo.

The crude product was purified by HPLC to give the title compound as a pale pink solid as the TPA salt. The exact mass, calculated for С25СИНзоМ5О» 467 2, was found to be 468.5 (MN).

Example 1.32: Preparation of M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy|phenyl-3-fluorobenzamide (Compound 637).

M M

GO sold Sun out

Vg Ve

To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy)benzeneamine (0.024g, 0.06Ommol) in СНесСи» (0.9ml) was added 3-fluorobenzoyl chloride (0.0086bml, 0.0714mmol) and triethylamine (0.011ml, 0.077mmol). The reaction mixture was stirred for 1 hour, concentrated and purified using Z3f-

TOP. Lyophilization gave the TEA salt as a brown oil (0.027g, 5695). RHMS t/": (953-531 (MaAN"VI, 94), 533 (MANU!'VI, 100). "H NMR (400 MHz, OM5O-dyv) 6: 10.42 (s, 1H), 7, 95 (dd, 9-21, 8.5Hz, 1H), 7.82 (d, 9-7.9Hz, 1H), 7.79-7.75 (m, 1H), 7.74-7.72 (m, 1H), 7.68 (d, U-8.6Hz, 1H), 7.63-7.57 (m, 1H), 7.45 (dt, 9U-2.6, 8.3Hz, 1H), 7.29 (dd, 923.7, 9.1Hz, 1H), 4.47-4.38 (m, 1H), 4.35-4.28 (m, 1H), 3.69 ( s, ЗН), 3.27 (s, ЗН), 3.53-1.37 (m, 11Н).

Example 1.33: Preparation of M-|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-fluoro-4-methylbenzamide (Compound 559).

M M go prede: si si

To a solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamine (0.040 g, 0.12 mmol) in

3-fluoro-4-methylbenzoyl chloride (0.025 ml, 0.14 mmol) and triethylamine (0.022 ml, 0.15 mmol) were added to СНоСИ" (1.9 ml). The reaction mixture was stirred for 1 hour, concentrated and purified using ZF-

TOP. Lyophilization gave the TPA salt as a brown oil (0.0096g, 1495). RHMSO t/ya (95)-473 (MAN Z5SI, 100), 475 (MAN 97SI, 27). "H NMR (400MHz, OM5O-av) 6: 10.31 (s, 1H), 7.96 (dd, 9-26, 11.6Hz, 1), 7.76-7.72 (m,

ZN), 7.67 (s, 1H), 7.49-7.44 (m, 1H), 7.30 (d, 9U-9.1Hz, 1H), 4.48-4.44 (m, 1H), 4.38-4.30 (m, 1H), 3.66 (s, ЗН), 4.00-2.90 (m, 1OH), 2.32 (s, ЗН).

Example 1.34: Preparation of 1-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)-3-(3-chlorophenyl)urea (Compound 231) . (about; M

СО о и и --- Х M nam и; NN Gl s (0).

A solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenylamine (0.040g, 0.12mmol) in

СНоСи»g (ml) was treated with 3-chlorophenylisocyanate (0.015 ml, 0.125 mmol). The reaction mixture was stirred overnight, concentrated and purified by 3F-HPLC. Lyophilization gave the TEA salt as a brown solid (0.016g, 2795). RHMS t/l (95)-490 (MAN Z5SI Z5SI, 100), 492 (MAN Z5SI 97SI, 76), 494 (MAN SI 87SI, 15). "H NMR (400 MHz, OM5O-yv) b: 8.92 (s, 1H), 8.79 (s, 1H), 7.74 (t, 9-2.0Hz, 1H), 7.70-7 .63 (m, 1H), 7.57 (dd, 92.7, 6.3 Hz, 1), 7.41 (d, 9U-22.7 Hz, 1H), 7.36-7.28 (m, 2H), 7.21 (d, 9U-9.0Gu, 1), 7.04 (dt, 9U-1.9, 7, AHC, 1H), 4.22-4.15 (m, 1H), 4.11-4.05 (m, 1H), 3.70 (s, ZN), 3.56-3.51 (m, AN), 2.66-2.48 (m, 2H), 2, 42-2.30 (m, AN).

Example 1.35: Preparation of 1-(4-chlorobenzyl)-3-|3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-ylpropoxy)phenyl|urea (Compound 666). that's what

GO) S oi, nom M. M o

As Vo IVIe;

A solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(3-morpholinopropoxy)benzeneamine (0.025g, 0.079mmol) in NaCl (0.bml) was treated with 4-chlorobenzylisocyanate (0.012ml, 0. 08Z3mmol). The reaction mixture was stirred for 1 hour, concentrated and purified by ZF-HPLC. Lyophilization gave the TPA salt as a white solid (0.037g, 7895). RHMS t/z (95)-484 (MN Z5SI, 100), 486 (MAN 97SI, 38). "H NMR (400MHz, OM50-av) b: 9.60 (s, 1H), 8.63 (s, 1H), 7.46 (d, 9U-1.8Hz, 1H), 7.43 (dd , 22.6, 8.9Hz, 1H), 7.40-7.29 (m, 4H), 7.07 (d, U-29.0Hz, 1), 6.75-6.70 (m, 1H), 6.25 (d, 9-1.6 Hz, 1H), 4.26 (d, U9-5.8Hz, 2H), 4.02-3.90 (m, 4H), 3.65 (c, ЗН), 3.58 (t, U-12.0Hz, 2Н), 3.34 (d, 9У-12.4Hz, 2Н), 3.09-2.92 (m, 4Н), 2 .06-1.97 (m, 2H).

Example 1.36: Preparation of 3-chloro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|benzamide (Compound 512). ,

To a solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzeneamine (0.029 g, 0.1 mmol) in SNeaSig" (1.5 ml) was added C-chlorobenzoyl chloride (0.015 ml, 0.12 mmol) and triethylamine (0.018 ml, 0.1 mmol). The reaction mixture was stirred for 1 hour, concentrated and purified using 3F-HPLC. Lyophilization gave

TRA salt in the form of brown oil (0.037g, 8795). RHMS t/l (95)-425 (MN SI, 100), 427 (MAN USI, 42). 7 TN

NMR (400MHz, OM5O-yv) 6: 10.40 (s, 1H), 8.01-8.00 (m, 1H), 7.94-7.87 (m, 2H), 7.72 (d , 9U-2.6Hz, 1H), 7.70-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.49 (d, 9-1.8Hz, 1H) , 7.25 (d, U-9.0Hz, 1H), 6.31 (d, 9U-1.8HzC, 1H), 4.32-4.28 (m, 2H), 3.69 (s,

ZN), 3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.95-2.82 (m, 2H), 1.95-1.85 ( m, 2H), 1.78-1.68 (m, 2H).

Example 1.37: Preparation of // 3-fluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-trifluoromethylbenzamide (Compound 487) .

I will sell it

Ez

To a solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzeneamine (0.029 g, 0.1 mmol) in SNeaSig" (1.5 ml) was added 3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.018 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.1 mmol). The reaction mixture was stirred for 1 hour, concentrated and purified using ZF-

TOP. Lyophilization gave the TEA salt as a brown oil (0.042g, 8895). Rkhmso t/z (95)-477 (MN, 100).

IN NMR (400MHz, OM50O-dv) b: 10.55 (s, 1H), 8.07-7.95 (m, ZN), 7.88 (dd, 9U-2.6, 9.0Hz, 1H ), 7.73 (d, 9U-2.6Hz, 1H), 7.49 (d, 9-1.6HzC, 1H), 7.27 (d, U-9.0Hz, 1H), 6.31 (d, 9U-1.8HzC, 1H), 4.33-4.29 (m, 2H), 3.69 (s, ЗН), 3.58-3.52 (m, 2H), 3.35 -3.25 (m, 2H), 2.92-2.81 (m, 2H), 1.95-1.85 (m, 2H), 1.80-1.69 (m, 2H).

Example 1.38: Preparation of 1-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-hydroxyazetidin-1-yl)ethoxy|phenyl)u- 3-( 4-chlorophenyl)urea (Compound 298).

SI SI

4-Chlorophenyl isocyanate (19.0 mg, 0.124 mmol) was added to a solution of 1-(2-(4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)azetidin-3-ol) (40.0mg, 0.124mmol) in dichloromethane (2.0ml) and DMF (0.1ml) and the mixture was stirred at room temperature overnight.The solution was concentrated and purified using Zf-

TOP. The collected fractions were concentrated and a 1295 solution of sodium hydroxide (aq.) (0.2 ml) was added with the pH adjusted to 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to obtain a white solid (28 mg, 4795) . RHMS t/l (95)-476 (MAN 8501100), 478 (MAN 97SI ,67). "H NMR (400 MHz, OM50-av) b: 8.81 (width s, 1H), 8.71 (width s, 1H), 7.60 (s, 1H), 7.53-7.50 (m, 1H), 7.47 (d, 9-2.08HzC, 1H), 7.46 (d, U-210HzC, 1), 7.36 (d, 9U-2.71HzC, 1H), 7 .32 (d, 9U-52.11Hz, 1H), 7.30 (d, 9-2.04Hz, 1H)U, 7.11 (d, 9-9.06Hz, 1H), 5.19 (d , U-8.00Hz, 1H), 4.10-4.00 (m, 1H), 3.99-3.85 (m, 2H), 3.65 (s, ЗН), 3.40-3 .30 (m, 2H), 2.70-2.55 (m, 4H).

Example 1.39: Preparation of 1-(4-(-2-(7-azabicyclo(2,2,1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3- yl)/phenyl|-3-(3-trifluoromethyl-benzyl)urea (Compound 710).

z z o o ", esuty

4-(2-(7-Azabicycloyl|2,2,1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenylamine ( 50.0 mg, 0.13 mmol) was added to a solution of 4-nitrophenyl chloroformate (26.0 mg, 0.1 mmol) in 1,2-dichloroethane (4.0 mL) and the mixture was stirred at room temperature for 1 hour. To the resulting precipitate was added 3- trifluoromethylbenzylamine (0.022 mL, 0.15 mmol) and M,M-diisopropylethylamine (0.030 mL, 0.17 mmol) and the mixture was stirred for another 1 hour. The mixture was concentrated and purified by ZF-HPLC. The collected fractions were concentrated and 1295 sodium hydroxide solution was added (aq.) (0.2 ml) with pH adjusted to 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give a white solid (49 mg, 6595). MH "Vi, 100), 594 (MAN 8'Vg, 67). "H NMR (400MHz, OM5O-ye) 6: 8.67 (lat. s, 1H), 7.67 (lat. s, 1H) , 7.65-7.59 (m, 4H), 7.53-7.50 (m, 1), 7.33 (d, u2.69HZ, 1), 7.12 (d, U-59, 04 Hz, 1), 6.7 7-6.74 (m, 1H), 4.40 (d, 9U- 4.0Hz, 2H), 4.08-3.98 (m, 2H), 3.67 (s, ЗН), 3.12 (m, 2H), 2.59-2.55 (m, 2H) , 1.56-1.54 (m, 4H), 1.17-1.15 (m, 4H).

Example 1.40: Preparation of 1-(4-(-2-(7-azabicyclo(2,2,1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3- yl)/phenyl|-3-(2,4-difluorobenzyl)urea (Compound 734).

U is o I -- - - zh - -ye eE o o / no dir

Bg e Be 4-(2-(7-Azabicycloyl|2,2,1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenylamine (50 .0mg, 0.1Zmmol) was added to a solution of 4-nitrophenyl chloroformate (26.0mg, 0.1Zmmol) in 1,2-dichloroethane (4.0ml) and the mixture was stirred at room temperature for 1 hour. To the resulting precipitate was added 2.4 - difluorobenzylamine (0.03Oml, 0.25mmol) and M,M-diisopropylethylamine (0.03Oml, 0.17mmol) and the mixture was stirred for another 1 hour. The mixture was concentrated and purified using ZF-HPLC. The collected fractions were concentrated and added 1295 sodium hydroxide solution (aq.) (0.2 ml) with pH adjusted to 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give a white solid (62 mg, 8795). 95560 (Man "Vu, 100), 562 (M.N 8!Vg, 91). "H NMR (400 MHz,

OM50-ав) b: 8.59 (width s, 1H), 7.58 (width s, 1H), 7.48-7.38 (m, 2H), 7.29 (width s, 1H ), 7.24-7.18 (m, 1H), 7.10-7.04 (m, 2H), 6.60-5.59 (m, 1H), 4.29 (d, 9U-4 ... ), 1.54-1.52 (m, 4H), 1.15-1.13 (m, 4H).

Example 1.41: Preparation of 4-fluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide (Compound 281).

Stage 1.41a: General Mitsunobu Procedure. Preparation of /-4-(2-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|ethylmorpholine).

SY in 0o, o rt Sov in) AM-M

A mixture of triphenylphosphine (7.5 g, 1.8 eq.) and diisopropylazodicarboxylate (5.6 bml, 1.9 eq.) in 500 ml of TGgFffF was stirred at 02C for 10 minutes, then 2-(2-methyl-2H-pyrazole) was added to the mixture at 02C -3-yl)-4-nitrophenol (3.5 g, 15.9 mmol) and 2-morpholin-4-ylethanol (3.6 bml, 1.8 eq.). The reaction mixture was stirred at room temperature for another 1 hour. The mixture was purified by HPLC to give the title compound as a yellow resinous solid (9.436 bg, 8995). The exact mass calculated for

SivNgoMmaO»5 332.2, found 333.3 (MN).

Stage 1.41p: Preparation of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamine.

M M

SO h o A-M and ! th

To a solution of /4-2-(2-(2-methyl-2H-pyrazol-3-yl)-4-nitrophenoxy|ethylmorpholine (1.913g, 2.88mmol) in a saturated solution of ammonium chloride (bml), water (bml) and THF (12 mL) was added zinc dust (1.123 g, bq.) at 02 C. The mixture was stirred at room temperature for 1 hour and then filtered through celite.

The solution was dried in vacuo to give the title compound as a yellow resinous solid (1.87g, 9995). The exact mass calculated for SivNgg2MaO» 302.2, found 303.4 (MN).

Stage 1.41c: Preparation of 2,4-difluoro-M-(3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenylbenzamide. (Compound 281).

M M

M, M,

This is what we have

A mixture of //3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenylamine (200mg, 0.ppmmol), 2,4-

difluorobenzoyl chloride (14 mg, 1.2 eq.) and triethylamine (0.2 ml, 2 eq.) in 3 ml of THF were stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (99mg, 3495). "H NMR (Acetone-ae, 400 MHz) b: 2.92-3.06 (m, 2H), 3.13-3.17 (m, 2H), 3.50-3.58 (m, 4H) , 3.68 (s, ZN), 3.82-3.85 (m, 2H), 4.36 (t, 2H), 6.29 (s, 1H), 7.24 (d, U-9 ... .

Example 1.42: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-4-trifluoromethylbenzamide (Compound 282).

M ro prodo: -ozh ik,

easy

A solution of NATO (98.0mg, 0.260mmol), triethylamine (55.7μl, 0.40000mmol) and 4-trifluoromethylbenzoic acid (49.0mg, 0.2600mmol) in THF (1.0ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamine (60, 00 mg, 0.200 mmol) was added and the mixture was stirred at 1002C for 10 minutes in the device with microwave heating. The mixture was purified by HPLC to give the title compound as a white solid (TRA salt, 27mg, 2895). "H NMR (0M50O-ydv, 400 MHz) b: 2.96-3.10 (m, 2H), 3.16-3.19 (m, 2H), 3.52-3.60 (m, 4H) . 1H), 7.28 (d, 9U-9.09Hz, 1H), 7.51 (d, 9-1.77Hz, 1H), 7.75 (d, 9U-2.78Hz, 1H), 7, 94 (d, 9U-8.34Hz, 2H), 8.16 (d, U-8.84Hz, 2H), 8.89 (s, 1H), 10.5 (s, 1H). Exact mass, calculated for SgaNozEziMaOz 474 2, found 475.4 (Mn.

Example 1.43: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-trifluoromethylbenzamide (Compound 435). STU,

A solution of NATI (113 mg, 0.0 mmol), triethylamine (55.7 μl, 0.400 mmol) and 3-trifluoromethylbenzoic acid (57 mg, 0.0 mmol) in DMF (1.0 mL) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylamine (57.0 mg, 0.200 mmol) was added and the mixture was stirred at 100°C for 10 minutes in the device with microwave heating. The mixture was purified by HPLC to give the title compound as a red wine-colored oil (TEA salt, 42 mg, yield 4695). The exact mass calculated for SgaNozEziMaO» 458.2, found 459.4 (MN).

Example 1.44: Preparation of M-I(4-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-fluoro-3Z -methylbenzamide (Compound 546).

ME

M.

IS

A mixture of 4-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl/uphenylamine) (b4mg, 0.20mmol), 4-fluoro-3- methylbenzoyl chloride (52 mg, 0.3 mmol) and triethylamine (56.5 μL, 0.40 mmol) in 1 mL of THF were stirred at room temperature for 10 min. The mixture was purified by HPLC to give the title compound as a white solid (TRA salt, 29mg, output 3295).Exact mass calculated for

SgaNgbEzMaO" 458.2, found 459.3 (MN).

Example 1.45: Preparation of /4-fluoro-3-methyl-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-((5)-1-methylpyrrolidin-2-ylmethoxy)phenyl|benzamide (Compound 547). ra; (o;

Yi x

IS

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(1-methylpyrrolidin-2-ylmethoxy)phenylamine (b4mg, 0.233mmol), 4-fluoro-

C-methylbenzoyl chloride (bOmg, 0.35 mmol) and triethylamine (63.4 μl, 0.4 mmol) in 1 ml of THF were stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TRA salt, 92 mg, yield 9595). The exact mass calculated for

SgaH2?7EMaO" 422.2, found 423.2 (MH).

Example 1.46: Preparation of M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpyrrolidin-1-yl)ethoxy|phenyl)-3,4- Difluorobenzamide (Compound 579).

E Ve

A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(2-methylpyrrolidin-1-yl)ethoxy|phenylamine (95 mg, 0.25 mmol), 3,4- difluorobenzoyl chloride (40 µL, 0.301 mmol) and triethylamine (70.2 µL, 0.501 mmol) in 1 mL of THF were stirred at room temperature for 10 min. The mixture was purified by HPLC to afford the title compound as a white solid (TRA salt, bOmg, output 4695). IN NMR (0M50-yv, 400MGu) 6: 1.22 (dd, 9U-19.71, 6.57 Hz, ZN), 1.45-1.53 (m, 1H), 1, 72-1.89 (m, 2H), 2.07-2.14 (m, 1H), 2.79-2.98 (m, 1H), 3.08-3.15 (m, 1H), 3.31-3.44 (m, 2H), 3.59-3.65 (m, 1H), 3.68 (d, U-4.80Hz, ZN), 4.21-4.46 (m , 2H), 7.29 (dd, 9U-9.85Hz, 6.82Hz, 1H), 7.60-7.67 (m, 1H), 7.66 (s, 1H), 7.70-7 .72 (m, 1H), 7.84-7.88 (m, 1H), 7.94 (dt, U-9.09, 2.78, 2.53HZ, 1H), 8.01-8, 06 (m, 1H), 9.22-9.48 (m, 1H from TRA), 10.4 (s, MH). The exact mass calculated for SgaNov'"VigB2MaO?", 518.1, found 519, 3, 521.5 (MNU).

Example 1.47: Preparation of M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((H8)-1-methylpyrrolidin-3-yloxy)phenyl|-3,4-difluorobenzamide (Compound 585).

Hmm what U Hm

Vg R Ve

A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-((8)-1-methylpyrrolidin-3-yloxy)phenylamine (88 mg, 0.25 mmol), 3,4-difluorobenzoyl chloride (40 μl, 0.0 mmol) and triethylamine (7 μl, 0.5 mmol) in 1 ml of THF were stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TRA salt, 24 mg, release 1995). IN NMR (COzO0, 400 MHz) 6: 2.17-2.31 (m, 1H), 2.71-2.84 (m, 2H), 2.87-2.97 (m, 2H), 3, 14-3.25 (m, 1H), 3.38-3.48 (m, 1H), 3.72-3.79 (m, 1H), 3.75 (s, ЗН), 3.89- 3.97 (m, 1H), 5.17-5.24 (m, 1H), 7.17-7.30 (m, 1H), 7.41-7.47 (m, 1H), 7, 56-7.62 (m, 1H), 7.63-7.69 (m, 1H), 7.78-89 (m, 1H), 7.88-7.93 (m, 2H). The exact mass calculated for Cg2VgNa1B2MaO»2 490.1, found 491.5, 493.5 (МН).

Example 1.48: Preparation of M-I4-(2-((5)-3-hydroxypyrrolidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-4-trifluoromethylbenzamide (Compound 586).

Shchi Mov Ko,

A solution of NATIi (183mg, 0.482mmol), triethylamine (100μl, 0.741mmol) and 4-trifluoromethylbenzoic acid (92mg, 0.482mmol) in THF (1.0ml) was stirred at room temperature. After 15 minutes, (5)-1-(2-(4-amino-2-(2-methyl-2H-pyrazol-3-ylphenoxy|ethyl)pyrrolidin-3-ol) (112 mg, 0.370 mmol) was added and the mixture was stirred at 1009C for 10 min in a microwave oven. The mixture was purified by HPLC to afford the title compound as a white solid (TRA salt, 58 mg, yield 3395). "H

NMR (0M50-av, 400 MHz) 56: 1.67-1.74 (m, 1H), 1.78-1.90 (m, 1H), 2.09-2.18 (m, 1H), 2 .88-2.97 (m, 1H), 3.31-3.37 (m, 1H), 3.47-3.61 (m, 2H), 3.69 (s, ЗН), 4.31 -4.36 (m, 4H), 6.31 (s, 1H), 7.24-7.28 (m, 1H), 7.50 (s, 1H), 7.75 (s, 1H), 7.90 (d, 9-8.84Hz, 1H), 7.94 (d, 9U-8.34Hz, 2H), 8.16 (d, 9U-8.34Hz, 2H), 9.93-10 ,11 (m, 1H), 10.5 (s, 1H). The exact mass calculated for SgaNozEziMaOz 474 2 was found to be 475.3 (Mn.

Example 1.49: Preparation of 3-fluoro-M-(4--2-(4-formylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|benzamide (Compound 752) .

With (9) ! Sotro e M. M. n u i

A mixture of /N-(4-(2-bromomethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl)-3-fluorobenzamide (8 mg, 0.198 mmol) and piperazine-1-carbaldehyde (27 mg, 0.238 mmol) and K2CO3 (110mg, 0.794mmol) in 2ml DMF were stirred at 1202C for 20 minutes in a microwave oven. The mixture was purified by HPLC to afford the title compound as a white solid as the TEA salt. The exact mass calcd. for SgaENheM5Oz 451.2, found 452.2 (MNU), "H NMR (SOZzSM, 400MHz) b: 3.15-3.32 (m, 4H), 3.66-3.71 (m, 4H), 3.71-3.76 (m, 2H), 3.74 (s, ЗН), 4.60 (t, U-4.80Hz, 2H), 6.30 (d, 9U-1.77 Hz, 1H), 7.23 (d, U-8.84Hz, 1), 7.37 (dd, U-8.59, 2.78Hz, 1H), 7.50 (d, 91.77Hz, 1) , 7.54-7.61 (m, 1H), 7.73-7.77 (m, 1H), 7.81 (d, U-52.53Hz, 1H), 7.85 (d, 9- 7.83Hz, 1H), 7.94 (dd, U-9.09, 2.53Hz, 1H), 8.08 (s, 1H), 9.68 (s, MH).

Example 1.50: Preparation of /M-I4-(2-(4-acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-methoxybenzamide (Compound 755).

Stage 1.50a: Preparation of 4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenylamine.

Bg Vg prov

M

Aha, what

Sulfuric acid (2 ,2ml, 42mmol, 4.78eq.) at 02C with stirring. The reaction mixture was refluxed at 909C for 1 hour and 20 minutes. The crude mixture was quenched with water, neutralized with saturated sodium hydroxide solution until pH 8, extracted with ethyl acetate, and then concentrated in vacuo to give the title compound as a solid (2.6 g, 9995). The exact mass, calculated for C1i2Ni«V/MzO 295.0, was found to be 296.1 (MAN "Vi, 100), 298.2 (m-H UVU, 98).

Stage 1.50r: Preparation of M-I4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-iluphenyl|-3-methoxybenzamide).

at 7 o'clock AD

Nam Gh A IF g

A mixture of 4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazole-3-iluphenylamine (1.012g, 3.417mmol), 3-methoxybenzoyl chloride (700mg, 1.2eq.) and triethylamine (1.0ml , 2 eq) in 5 mL of THF was stirred at room temperature for 10 min. The mixture was purified by HPLC to afford the title compound as a white solid (957 mg, 5290). Exact mass calcd for SgoNgoVIMzOz 429.1, found 430, 3 (MAN "Vi, 100), 432.5 (MAN 8'Vg, 98).

Stage 1.50c: Obtaining /- M-I4--2-(4-acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-iluphenyl|-3-methoxybenzamide).

Hg

M o g Ge still purely, they

A mixture of M-(4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-methoxybenzamide (90 mg, 0.21 mmol) and 1-piperazine-1-ylethanone (32 mg, 1.2 equiv) and KgCO3 (116 mg, 4.0 equiv) in ml of DMF were stirred at 1202 C for minutes in a microwave oven.The mixture was purified by HPLC to afford the title compound as a white solid in the form TRA salt (97 mg, 97905). IN NMR (Acetone, 400 MHz) 6: 2.07 (s, ZN), 3.30 (s, lat., 4H), 3.71 (t, U-4, 80Hz, 2H), 3.75 (s, ЗН), 3.79 (s, width, 2Н), 3.87 (s, ЗН), 4.60 (t, U-4.80Hz, 2Н), 4.99 (s, width, 2H), 6.32 (s, 1H), 7.13 (d, U-8.08Hz, 1), 7.23 (d, 9U-9.09Hz, 1H) , 7.42 (t, 98.08, 1), 7.53 (m, 2H), 7.56 (d, 9U-7.83Hz, 1H), 7.82 (s, 1H), 7.94 (dd, U- 8.84, 2.53 Hz, 1H), 9.56 (s, MH). The exact mass calculated for SovNziM5Ox4 is 477.2, found to be 478.3 (MH).

Example 1.51: Preparation of M-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-phenylacetamide (Compound 762).

M M i -olotsia

M. oh oh

A solution of NATI (57.Omg, 0.150 mmol), triethylamine (41.8 μl, 0.300 mmol) and phenylacetic acid (20.4 mg,

0.150 mmol) in DMF (0.3 ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)aniline (30.2 mg, 0.100 mmol) was added and the mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by Z3F-HPLC and lyophilized to give the TEA salt as a yellow oil (49mg, 9295). RHMS t/a (95)-421.3 (MAN 100). "H NMR (500MHz, Meon-aa) b: 2.96-3.26 (m, 4H) 3.51-3.55 (m, 2H) 3.55- 3.97 (m, 4H) 3 .67 (s, 2H) 3.70 (s, ЗН) 4.36-4.41 (m, 2H) 6.32 (d, 9-1.89Hz, 1H) 7.14 (d, 9U-8 ,83Hz, 1H) 7.21-7 26 (m, 1H) 7.29-7.36 (m, 4H) 7.53 (d, U-1.89Hz, 1H) 7.56 (d, U- 2.52Hz, 1H) 7.66 (dd, U-8.83, 2.52Hz, 1H).

Example 1.52: Preparation of 2-(3-fluorophenyl)-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide (Compound 766).

M E nd what

A solution of NATI (57.0 mg, 0.150 mmol), triethylamine (41.8 μL, 0.300 mmol) and 3-fluorophenylacetic acid (23.1 mg, 0.150 mmol) in DMF (0.3 mL) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)aniline (30.2 mg, 0.1000 mmol) was added and the mixture was stirred at room temperature overnight . The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness.

The crude product was purified by ZF-HPLC and lyophilized to give the TEA salt as a yellow oil (39mg, 7195). RHMS ti/ (95)-439.5 (MAN 100). "H NMR (500 MHz, Meon-dy") b: 2.92-3.28 (m, 2H), 3.50-3.57 (m, 2H), 3.59-3.95 (m, 2H ), 3.69 (s, 2H), 3.71 (s, ЗН), 4.37-4.43 (m, 2H), 6.32 (d, 9-2.21Hz, 1H), 6, 96-7.02 (m, 1H), 7.07-7.13 (m, 1H), 7.13-7.18 (m, 2H), 7.29-7.36 (m, 1H), 7.52 (d, U-1.89Hz, 1H), 7.56 (d, U-2.84Hz, 1H), 7.67 (dd, y-8.99, 2.68Hz, 1H).

Example 1.53: Preparation of 2-(3-chlorophenyl)-M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide (Compound 767).

M si ch - vu ny, o

A solution of NATI (57.0mg, 0.150mmol), triethylamine (41.μl, 0.300mmol) and 3-chlorophenylacetic acid (25.bmg, 0.150mmol) in DMF (0.3ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)aniline (30.2 mg, 0.1000 mmol) was added and the mixture was stirred at room temperature overnight . The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness.

The crude product was purified by ZF-HPLC and lyophilized to obtain the TEA salt as a yellow oil (ZZmg, 5895). RHMS t/ (95)-:455.3 (MAN 100). "H NMR (500 MHz, Meon-a"x) b: 2.95-3.28 (m, 2H), 3.50-3.56 (m, 2H), 3.57-4.05 (m, 2H), 3.68 (s, 2H), 3.71 (s, ЗН), 4.37-4.42 (m, 2H), 6.32 (d, 9U-1.89Hz, 1H), 7 ,15 (d, 9U-8.83Hz,

1H), 7.24-7.33 (m, ЗН), 7.37-7.39 (m, 1H), 7.52 (d, U9-1.89ГЦ, 1H), 7.56 (d, 9U-2.84Hz, 1H), 7.67 (dd, U-8.99, 2.68Hz,

Example 1.54: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-(3-trifluoromethylphenyl)acetamide (Compound 768).

M se, that blu

But what?

A solution of NATI (57.0mg, 0.150mmol), triethylamine (41.8μl, 0.300mmol) and 3-trifluoromethylphenylacetic acid (30.bmg, 0.150mmol) in DMF (0.3ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)aniline (302 mg, 0.0000 mmol) was added and the mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by ZF-HPLC and lyophilized to obtain the TEA salt as a yellow oil (Zbmg, 6095). LCMS ti/ (95)-489.3 (MaH 100). "H NMR (500 MHz, MeOon-a") 5: 2.96-3.27 (m, 2H), 3.51-3.56 (m, 2H), 3.58-3.98 (m, 2H ), 3.71(s, 2H), 3.789 (s, ZN), 4.37-4.43 (m, 2H), 6.32 (d, 9U-1.89HZ, 1), 7.16 ( d, 9U-9.14Hz, 1H), 7.49-7.59 (m, 4H), 7.61 (d, 9-7.57Hz, 1H), 7.65-7.70 (m, 2H ).

Example 1.55: Preparation of 2-(3-methoxyphenyl)-1N-3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide (Compound 769).

M OME glo ne

M.

A solution of NATI (57.0mg, 0.150mmol), triethylamine (41.8µl, 0.300mmol) and 3-methoxyphenylacetic acid (249mg, 0.150mmol) in DMF (0.3ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)aniline (30.2 mg, 0.1000 mmol) was added and the mixture was stirred at room temperature overnight . The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness.

The crude product was purified by ZF-HPLC and lyophilized to give the TEA salt as a yellow oil (57mg, 8095). RHMS t/ (95)-451.2 (MAN 100). "H NMR (500 MHz, Meon-a") b: 2.91-3.27 (m, 4H), 3.50-3.55 (m, 2H), 3.57-3.99 (m, 4H ), 3.64 (s, 2H), 3.70 (s, ZN), 3.77 (s, ZN), 4.35-4.42 (m, 2H), 6.31 (d, U- 1.89Hz, 1H), 6.79-6.85 (m, 1H), 6.89-6.95 (m, 2H), 7.14 (d, 9U-8.83Hz, 1H), 7, 22 (t, 9-8.20 Hz, 1H), 7.52 (d, 9U-1.89 Hz, 1H), 7.56 (d, U-2.84 Hz, 1H), 7.67 (dd, U-8.98, 2.68Hz, 1H).

Example 1.56: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-2-m-tolylacetamide (Compound 770).

M o: ee o o

A solution of NATI (57.0mg, 0.150mmol), triethylamine (41.8μl, 0.300mmol) and m-tolylacetic acid (22.5mMgH,

0.150 mmol) in DMF (0.3 ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)aniline (30.2 mg, 0.100 mmol) was added and the mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by Z3F-HPLC and lyophilized to give the TEA salt as a yellow oil (49mg, 8995). RHMO t/z (95)-435.3 (MAN 100). "H NMR (500 MHz, Meon-a") 6: 2.31 (s, 3H), 2.89-3.27 (m, 2H), 3.47-3.54 (m, 2H), 3, 58-4.00 (m, 2H), 3.63 (s, 2H), 3.70 (s, ЗН), 4.36-4.41 (m, 2H), 6.31 (d, U- 1.89Hz, 1H), 7.04-7.08 (m, 1H), 7.10-7.22 (m, 4H), 7.52 (d, 9U-1.89Hz, 1H), 7, 56 (d, U-2.52Hz, 1H), 7.66 (dd, U-8.83, 2.52Hz, 1H).

Example 1.57: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenyl|-2-p-tolylacetamide (Compound 771).

Z s du t Ov nm M. M M, 2 Shchy N Shchy

A solution of NATI (57.Omg, 0.150 mmol), triethylamine (41.8 μl, 0.300 mmol) and p-tolylacetic acid (22.5 mg,

0.150 mmol) in DMF (0.3 ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)aniline (30.2 mg, 0.100 mmol) was added and the mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by Z3F-HPLC and lyophilized to give the TEA salt as a yellow oil (5O0mg, 9195). RHMS ti/i (95)-435.3 (MAN 100). "H NMR (500MHz, MeOon-y") b: 2.31 (s, ЗН), 3.01-3.23 (m, 2Н), 3.49-4.00 (m, 2Н), 3, 51-3.57 (m, 2H), 3.62 (s, 2H), 3.71 (s, ЗН), 4.35-4.42 (m, 2H), 6.31 (d, 9- 1.89Hz, 1H), 7.12-7.18 (m, ЗН), 7.22 (d, y-8.20Hz, 2H), 7.52 (d, 9U-1.89Hz, 1H), 7.53 (d, U-2.84Hz, 1H), 7.69 (dd, U-8.98, 2.68Hz, 1H).

Example 1.58: Preparation of 2-benzo|1,3|dioxol-5-yl-M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl| acetamide (Compound 772).

A solution of NATI (57.0mg, 0.150mmol), triethylamine (41.8μl, 0.300mmol) and 3,4-methylenedioxyphenylacetic acid (27.0mg, 0.150mmol) in DMF (0.3ml) was stirred at room temperature. After 15 minutes, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)aniline (302 mg, 0.0000 mmol) was added and the mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by ZF-HPLC and lyophilized to give the TEA salt as a yellow oil (48 mg, 8395). LCMS ti/ (95)-465.4 (MaH 100). "H NMR (500 MHz, Meon-y") 6: 2.94-3.24 (m, 2H), 3.48-4.05 (m, 2H), 3.51-3.56 (m, 2H ), 3.58 (s, 2H), 3.71 (s, ЗН), 4.35-4.43 (m, 2H), 5.92 (s, 2H), 6.32 (d, y- 1.89HuC, 1), 6.74-6.83 (m, 2H), 6.83-6.87 (m, 1H), 7.16 (d, U-8.83Hz, 1), 7, 52-7.54 (m, ZN), 7.69 (dd, 9U-8.98, 2.68HZ, 1H).

Example 1.59: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-2-(4-trifluoromethylphenyl)acetamide (Compound 794).

GO ve a: (77 -- skh I

Cyclic 1-propanephosphonic acid anhydride (5095 in EtOAc, 10 bml, 0.20 mmol) was added to 3-(2-methyl-2H-pyrazol-3-yl)-4-2-morpholin-4-ylethoxy)aniline (30, 2 mg, 0.1 mmol), 4-trifluoromethylphenylacetic acid (18 mg, 0.09 mmol) and triethylamine (123 μl, 0.9 mmol) in ethyl acetate (0.1 ml) and the mixture was stirred at room temperature. After 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate solution and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in methanol (0.5 ml), a solution of acetyl chloride (1 µl, 0.2 mmol) in methanol was added and the solution was evaporated to dryness. The residue was redissolved in methanol and evaporated. The residue was dissolved in water and lyophilized to obtain the NCI salt as a white solid (17mg, 3695). RHMS ti/ (95)-489.3 (MAN 100). "H NMR (500 MHz, MeOn-y") b: 3.05-3.14 (m, 2H), 3.21-3.28 (m, 2H), 3.56-3.61 (m, 2H ), 3.65-3.74 (m, 2H), 3.79 (s, ЗН), 3.81 (s, 2H), 3.90-3.98 (m, 2H), 4.42- 4.49 (m, 2H), 6.47 (d, y-2.21 HZ, 1), 7.22 (d, 9-9.14 HZ, 1H), 7.57 (d, У-8, 20Hz, 2H), 7.64 (d, U-2.84Hz, 1H), 7.66 (d, 9U-7.88Hz, 2H), 7.70-7.14 (m, 2H).

Example 1.60: Preparation of /-M-I3-(2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|-2-thiophen-2-ylacetamide (Compound 795). o: west E

With Ya

What

Cyclic 1-propanephosphonic acid anhydride (5095 in EtOAc, 10 bml, 0.20 mmol) was added to 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)aniline (30, 2mg, 0.1Omol), 2-thienylacetic acid (13ZmgH,

0.09 mmol) and triethylamine (123 μl, 0.9 mmol) in ethyl acetate (0.1 ml) and the mixture was stirred at room temperature. After 1 hour, the reaction was quenched with saturated sodium bicarbonate solution and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in methanol (0.5 ml), a solution of acetyl chloride (1 µl, 0.2 mmol) in methanol was added and the solution was evaporated to dryness. The residue was redissolved in methanol and evaporated. The residue was dissolved in water and lyophilized to obtain the NCI salt as a yellow solid (22mg, 5495). RHMS ti/ (95)-427.2 (MAN 100). "H NMR (500 MHz, MeOn-y") b: 3.06-3.15 (m, 2H), 3.25-3.31 (m, 2H), 3.56-3.61 (m, 2H ), 3.67-3.75 (m, 2H), 3.82 (s, ЗН), 3.92 (s, 2H), 3.95 (dd, 9U-12.61, 2.52Hz, 2H ), 4.45-4.50 (m, 2H), 6.52 (d, U-2.21Hz, 1H), 6.99 (d, 9U-3.47Hz, 1H), 7.00 ( d, 9-3.47 Hz, 1H), 7.01-7.04 (m, 1H), 7.24 (d, U-9.14 Hz, 1H), 7.31 (dd, 95.04 , 1.26Hz, 1H), 7.66 (d, 9U-52.52Hz, 1H), 7.71 (dd, U-8.99, 2.68Hz, 1H), 7.80 (d, 9- 52.21 Hz, 1H).

Example 1.61: Preparation of 1-(4-(2-azetidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl/|-3-(2,4-difluorophenyl)urea (Compound 86).

M is Z points ha

M, Fe M

To a solution of 4-(2-(azetidin-1-yl)ethoxy)-3-(1-methyl-1H-pyrazol-5-yl)benzeneamine (40 mg, 0.147 mmol) in

2,4-difluorophenyl isocyanate (18 μl, 0.152 mmol) was added to SNesi" (2 ml) and stirred for two hours.

The crude reaction mixture was purified by column chromatography at 500° (eluent: methanol/CHg2gSi2-1/6) to give the title compound (50.4 mg, 8095). RHMS t/2 (95)-428 (MN", 100), "H NMR (400MHz, OM50O-dv) b: 8.96 (width s, 1H), 8.47 (width s, 1H), 8.09-7.98 (m, 1H), 7.45-7.39 (m, 2H), 7.36 (d, U-2.71Hz, 1H), 7.34-7.26 (m , 1H), 7.06 (d, U-8.94 Hz, 1H), 7.06-6.98 (m, 1H), 6.23 (d, 9U-1.85Hz, 1H), 3, 89 (t, 95.49Hz, 2H), 3.67 (s, ZN), 2.98 (t, U-6.92Hz, AN), 2.60 (t, 9U-5.47Hz, 2H) , 1.86 (quintet, U-6.99Hz, 2H).

Example 1.62: Preparation of 1-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl)- 3-(4 -chlorophenyl)urea (Compound 267).

M M go, toi o - nd, breath,

In Vg

To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzeneamine (39.2 mgH, 0O.1O0Zmmol) in SNeSi 4-chlorophenyl isocyanate (18.0 mg) was added to (4 ml) and stirred for two hours.

The obtained substance was purified by HPLC. The product was dried in vacuo to give the title compound as a white solid (50.7 mg, 9295). RHMS ti/ (96):534 (MAN "Vi, 74), 536 (MAN 81Vg, 100). "H NMR (400 MHz, OM5O-av) b: 8.79 (width s, 1H), 8.70 (width c, 1H), 7.60 (c, 1H), 7.52 (dd, uU-8.95,

2.11Hz, 1), 7.47 (d, U-8.94HzC, 2H), 7.35 (d, U-:2.70Hz, 1H), 7.31 (d, 9-8.91Hz, 2H), 7.09 (d, 9-9.03Hz, 1H), 4.02-3.86 (m, 2H), 3.83 (quint., U-5.80Hz, 1H), 3.66 (c, ЗН), 3.35-3.29 (m, 1Н), 3.27-3.18 (m, 1Н), 3.08 (с, ЗН), 2.74-2.56 (m , Academy of Sciences).

Example 1.63: Preparation of M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy|phenyl)-

Z-methylbutyramide (Compound 326).

M M g shk ro u, what niy, i

VG vg

To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzeneamine (40 mg, 0.107 mmol) and pyridine ( Isovaleryl chloride (15 µl, 0.122) was added to 35 µl) in СНоСиг" (2 ml) and stirred for two hours. The obtained substance was purified by HPLC. The product was dried in vacuo to give the title compound as a white solid (36.0 mg, 7390). LCMS ti/z (90)-465 (men "Vu, 75), 467 (MAN 8'Vg, 90). "H NMR (400MHz, OM5O-yv) 6: 10.00 (width s, 1H), 7.69 (dd, 9U-8.99, 2.65Hz, 1H), 7.60 (s, 1H), 7.48 (d, U-2.63Hz, 1H), 7.09 (d, 9U -9.06Hz, 1H), 4.03-3.86 (m, 2H), 3.82 (quint., U-5.76Hz, 1H), 3.65 (s, ЗН), 3.35- 3.28 (m, 1H), 3.24-3.17 (m, 1H), 3.08 (s, ЗН), 2.73-2.55 (m, 4H), 2.16 (d, U-6.96Hz, 2H), 2.12-2.00 (m, 1H), 0.92 (d, U-6.55Hz, 6H).

Example 1.64: Preparation of benzoxazol-2-yl-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|amine (Compound 199).

M M dO St. "Yes, I,

Hg Hg

To a mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine (0.034g, 0.09mmol) and 2-chlorobenzoxazole (0.016g, 0.11 mmol) in isopropanol (Iml) was added OIEA (0.031 ml, 0.18 mmol). The reaction mixture was heated at 60C for 4 days, concentrated, then purified by preparative HPLC. The corresponding fractions were collected and lyophilized to give Compound 199 (TRA salt) as an off-white solid with a yield of 18.495. RHMS t/ (96)-496 (MN "Vi, 90), 498 (MAN UVG, 100). "N

NMR (400 MHz, Acetone-iv) 6: 11.80 (lat. s, 1H), 8.04 (dd, U-2.8, 9.0H2, 1H), 7.91 (d, 9U-2, 9Hz, 1H), 7.61 (s, 1H), 7.48-7.42 (m, 2H), 7.36 (d, 9U-9.0Hz, 1), 7.27 (dt, 9U- 1.0, 7.6Hz, 1H), 7.18 (dt, 9-1.2, 7.8Hz, 1H), 4.72-4.63 (m, 1H), 4.60-4.5 (m, 1H), 3.80 (s, ZN), 3.81-3.42 (m, AN and water), 2.95-2.82 (m, 2H), 1.95-1.80 (m, 4H), 1.55-1.30 (m, 2H).

Example 1.65: Preparation of (|3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4-ylethoxy)phenyl|iamide of 5-chlorothiophene-2-carboxylic acid (Compound 333).

M M go prodo nd, ory,

Si Si

To a mixture of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamine (0.100g, 0.1 mmol), 5-chlorothiophene-2-carbon acid (0.049 g, 0.0 mmol) and NATIi (0.114 g, 0.0 mmol) in DMF (4 ml) was added OIEA (0.157 ml, 0.9 mmol), then the reaction mixture was stirred at room temperature overnight.

The crude product was purified by preparative HPLC. The corresponding fractions were collected and lyophilized to obtain the TEA salt of compound 333 as a brown solid with a yield of 15.195. RHMS t/: (o5)-481.2 (MAN, 100). "H NMR (400 MHz, OM50O-av) 6: 10.41 (s, 1H), 9.95 (lat. s, 1H), 7.90-7.87 (m, 2H), 7.66 (s , 1H), 7.63 (d, 9U-2.6HzC, 1H), 7.31-7.23 (m, 2H), 4.48-4.27 (m, 2H), 3.66 (s , ZN), 3.81-2.87 (m, 10OH and water).

Example 1.66: Preparation of 3,4-difluoro-M-I4-(2-(2-methylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|benzamide (Compound 459 ). go go o -- : 5" (e) o y in M nm Hm water. Food

A mixture of 4-(2-(2-methylpiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)uphenylamine (0.031 g, 0.1 mmol), 3,4-difluorobenzoyl chloride (0.015 ml, 0.12 mmol) and triethylamine (0.018 ml, 0.133 mmol) in methylene chloride (1.5 ml) were stirred at room temperature overnight and concentrated to give the crude product, which was purified by preparative HPLC. The appropriate fractions were collected and lyophilized from by obtaining the TEA salt of compound 459 as a white solid with a yield of 88.295.

Example 1.67: Preparation of M-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenyl|-4-fluoro-33-methylbenzamide (Compound 745 ). o Z (o) --I-- zh -ye o y ich nam Im su Im

SI eE si

A mixture of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methylpiperidin-4-yloxy)phenylamine (0.040g, 0.12mmol), 4-fluoro-3-methylbenzoyl chloride ( 0.026g, 0.12mmol) and triethylamine (0.01bml, 0.1zmmol) in methylene chloride (1.5ml) were stirred at room temperature overnight and concentrated to give crude product, which was purified by preparative HPLC. The corresponding fractions were collected and lyophilized to give the TEA salt of Compound 745 as a white solid with a yield of 57.095. RHMSO t/2 (95)-457.4 (MAN, 100).

Example 1.68: Preparation of 1-(2-fluorophenyl)-3-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenyl|urea (Compound 65). th CO 55525 OKH

MN; m aa;

A solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-ylethoxy)phenylamine (21.0mg, 0.07mmol) in methylene chloride (1ml) was treated with 2-fluorophenylisocyanate (0.074mmol ), then the reaction mixture was stirred at room temperature overnight and concentrated to give an oily residue, which was purified by flash chromatography (5105, CNaSig/MeH gradient elution) to give Compound 65 as a white solid in a yield of 45.195. RHMS t/l (95)-438.4 (MH, 100). "H NMR (400 MHz, OM5O-yv) 6: 8.52 (lat. s, 1H), 8.32-8.28 (m, 1H), 8.02 (lat. s, 1H), 7.57 (dd, uU22.7, 8.9Hz, 1H), 7.48 (d, 922.7Hz, 1H), 7.39 (d, 9-1.8Hz, 1), 7.18-7.06( m, ZN), 7.00-6.92 (m, 1H), 6.22 (d, 9U-1.8HzC, 1H), 4.11-4.08 (m, 2H), 3.75 ( c, ZN), 2.67-2.60 (m, 2H), 2.42-2.31 (m, 4H), 1.52-1.43 (m, 4H), 1.40-1, 32 (m, 2H).

Example 1.69: Preparation of //- M-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-fluorobenzamide (Compound 455).

VG Vg

A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylamine (0.036g, 0.Tmmol), 3-fluorobenzoyl chloride (14, bmcl, 0.12mmol) and triethylamine (18.1µl, 0.1mmol) in methylene chloride (2ml) were stirred at room temperature overnight and concentrated to give the crude product, which was purified by preparative HPLC. The corresponding fractions were collected and lyophilized to give the TEA salt of Compound 455 as a yellowish-brown solid with a yield of 85.495. RHMS t/2 (95)-487 (MAN "Vi, 97), 489 (MAN 8'Vg, 100). "H NMR (400 MHz, OM5O-dv) 6: 10.42 (s, 1H), 9, 71 (width s, 1H), 7.96 (d, U-9.0Hz, 1H), 7.83-7.73 (m, ЗН), 7.66 (s, 1H), 7.63- 7.57 (m, 1H), 7.46 (t, U-8.7 Hz, 1H), 7.30 (d, 9-9.1Hz, 1H), 4.45-4.21 (m, 2H), 3.68 (c, ZN), 3.51-3.42 (m, 2H and water), 3.43-3.20 (m, 2H), 2.93-2.60 (m, 2H), 1.97-1.68 (m, 4H).

Example 1.70: Preparation of cyclopentanecarboxylic acid (|3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamide (Compound 310).

M M o shrozhe "Chr, sly

In VG

A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamine (7mg, 0.2mmol), cyclopentylcarboxylic acid (27mg, 0, 24mmol), NATI (99mg, 0.26mmol) and triethylamine (0.3ml) in DMF (2ml) were heated in a microwave oven at 100°C for 30 minutes. The crude product was purified by HPLC to give the title compound ( 20 mg, 2195) in the form of a brown solid in the form of a TRA salt. "H NMR (COzZSM, 400 MHz) b: 1.66-1.95 (m, 8H), 2.70-2.80 (m, 1H), 2.85-3.02 (m, 2H), 3.13-3.27 (m, 2H), 3.43 (t, 2H), 3.73 (s, ЗН), 3.74-3, 80 (m, 2H), 3.82-3.90 (m, 2H), 4.34-4.48 (m, 2H), 7.13 (d, 929.09Hz, 1), 7.55 ( d, U-2.53Hz, 1H), 7.57 (s, 1H), 7.76 (dd, uU-2.78, 9.35Hz, 1H), 8.38 (s, 1H). The exact mass calculated for Sg2Nho"ZVIMaOz 476 1 was found to be 477.3 (MAN "Vu, 100), 479.3 (MAN 8'VI, 98).

Example 1.71: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-trifluoromethylbenzamide (Compound 343).

M

GO and what?

M M

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenylamine (57mg, 0.2mmol), 4-trifluoromethylbenzoic acid (42mg, 0.22mmol), NATI (91mg, 0.24mmol) and triethylamine (O0.3ml) in DMF (2ml) were heated in a microwave oven at 1002C for 15 minutes. The crude product was purified by HPLC to give the title compound (b5mg, 71905) as a brown solid as the TPA salt. "H NMR (0OM5O-iv, 400 MHz) 5 1.73-1.76 (m, 2H), 1.87-1.92 (m, 2H), 2.85-2.90 (m, 2H), 3.29-3.32 (m, 2H), 3.53-3.57 (m, 2H), 3.69 (s, ЗН), 4.32 (t, U-4.80Hz, 2H), 6.32 (d, 9U-2.02Hz, 1H), 7.26 (d, y-8.59Hz, 1), 7.50 (d, 9-1.78Hz, 1H), 7.75 (d , U-2.53 Hz, 1H), 7.88-7.94 (m, ЗН), 8.15 (d, U-8.84 Hz, 2H), 9.81 (s, 1H), 10, 5 (s, 1H). The exact mass calculated for SgaNozEzMaO» 458.2, found 459.4 (MN).

Example 1.72: Preparation of M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|phenyl-Z -fluorobenzamide (Compound 475).

In Vg

A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-((5)-3-fluoropyrrolidin-1-yl)ethoxy|phenylamine (7 mg, 0.2 mmol), 3-fluorobenzoyl chloride (32 mg, 0.22 mmol), triethylamine (0.3 mL) in THF (2 mL) was stirred at room temperature for 20 min. The solvent was concentrated in vacuo and the crude product was purified by HPLC to afford the title compound (40 mg, 4095) in the form of a yellow solid in the form of a TRA salt. "H NMR (0M50-av, 400 MHz) 6: 1.98-2.10 (m, 2H), 2.90-3.45 (m, 6H), 3.68 (c, ZN), 4.28-4.30 (m, 1H), 4.39-4.42 (m, 1H), 5.28-5.42 (m, 1H), 7, 28-7.31 (m, 1H), 7.44-7.49 (m, 1H), 7.57-7.63 (m, 1H), 7.67 (d, 1H), 7.73- 7.82 (m, ЗН), 7.94 (dd, 1Н), 10.4 (s, 2Н). The exact mass calculated for СгзНгзВгР2МаО» 5041, found 505.5/507.5 (МНУ).

Example 1.73: Preparation of 3-chloro-4-fluoro-M-I4-(2-(4-fluoropiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|benzamide ( Compound 538).

M M or "bitch,

IS

A mixture of 4-(2-(4-fluoropiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl/uphenylamine (8Omg, 0.25mmol), 4-fluoro-

C-chlorobenzoyl chloride (48 mg, 0.25 mmol) and triethylamine (0.3 mL) in THF (3 mL) were stirred at room temperature for 10 minutes. The solvent was concentrated in vacuo and the crude product was purified by HPLC to give the title compound (58mg, 5095) as a white solid as the TPA salt. "H NMR (acetone-dv, 400 MHz) b: 2.02-2.24 (m, 4H), 3.08-3.18 (m, 2H), 3.32-3.42 (m, 2H) , 3.63 (t, y-4.55Hz, 2H), 3.80 (s, ЗН), 4.59 (t, 9U-4.55Hz, 2H), 4.91-5.03 (m, 1H), 6.30 (d, 9-1.77 Hz, 1), 7.23 (d, U-8.84 Hz, 1H), 7.43-7.51 (m, 2H), 7.81 (t, 9-2.27 Hz, 1H), 7.91-7.97 (m, 1H), 8.02-8.08 (m, 1H), 8.18 (dd, 9U-2.53 , 7.33 Hz, 1H), 9.71 (s, 1H). The exact mass calculated for SgaNo5SIR2MaO» 503.1, found 5041/5061 (МН).

Example 1.74: Preparation of M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-4-fluorobenzamide (Compound 396).

Stage 1.74a: Preparation of 3-(2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluorobenzoylamino)phenoxy|piperidine-1-carboxylic acid tert-butyl ether.

Ge) ' z» o o !

M a sur

Ve e Vs

A mixture of tert-butyl ether of 3-(4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenoxy|piperidine-1-carboxylic acid (900 mg, 0.2 mmol), 4-fluorobenzoic acid acid (34mg, 0.24mmol), NaCl (99mg, 0.26mmol) and triethylamine (0.3ml) in DMF (2ml) was heated in a microwave oven at 100°C for 15 minutes.

The crude product was purified by HPLC to give 3-(2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluorobenzoylamino)phenoxy|piperidine-1-carboxylic acid tert-butyl ester (Zbmg, 3295) as a white solid.M5 found, 573.5 and 575.5.

Stage 1.746r: Preparation of M-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)phenyl|-4-fluorobenzamide (Compound 396). that "b o br y Sho lenation; DU

E vg e vg

To the tert-butyl ether of 3-(2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluorobenzoylamino)phenoxy|piperidine-1-carboxylic acid (Zbmg) was added NS in dioxane (4 M, 1 ml), the mixture was stirred at room temperature for several hours. The solvent was concentrated in vacuo to give the title compound (Zbmg) in the form of the HCI salt. "H NMR (0M50O0-dv, 400MHz) 6: 1.42- 2.08 (m, 4H), 2.72-3.38 (m, 4H), 3.73 (d, ЗН), 4.45 (m, 1H), 7.33-7.39 (m, ЗН), 7.65 (d, U-2.53Hz, 1Н), 7.74 (t, 9-3.03HzС, 1Н), 7.90-7.95 (m, 1Н), 8.03- 8.07 (m, 2H), 8.85-9.02 (m, 1H), 9.15-9.30 (m, 1H), 10.4 (s, 1H). The exact mass calculated for Cg2Hg2VIEMaO » 472.1, found 473.3/475.3 (MNU.

Example 1.75: Preparation of /M-I4-(2-(4-acetylpiperazin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-fluorobenzamide (Compound 660).

Hg

M o I nshi o de

Kk M and M M.

Si, Si,

A mixture of M-I4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-33-fluorobenzamide (105 mg, 0.251 mmol), 1-acetylpiperazine (34 mg, 0.264 mmol) and potassium carbonate (42 mg, 0.301 mmol) in DMF (3 mL) was heated in a microwave oven at 120°C for 20 min. The mixture was purified by HPLC to give the title compound (75 mg, 6495) as a white solid in in the form of the TRA salt. "H NMR (SOZSM, 40OMHutz) 5: 2.09 (s, ЗН), 3.32-3.38 (m, 6Н), 3.48 (t, 9У-5.05Hz, 4Н) . 09Hz, 1H), 7.40 (dt, U-2.78, 8.59HzC, 1H), 7.57-7.63 (m, 2H), 7.70-7.74 (m, 2H), 7.80-7.82 (m, 1H), 7.85 (dd, 9U-2.78, 9.09Hz, 1H), 8.93 (s, 1H). The exact mass, calculated for С25НгвЕМ5Оз 465.2, was found to be 466.4 (МН).

Example 1.76: Preparation of M-I(4-(2-(4,4-difluoropiperidin-1-yl)ethoxy|-3-(2-methyl-2H-pyrazol-3-yl)phenyl|-3-fluorobenzamide (Compound 778). chapter Ou iy "Tires and E

SK, sly

A mixture of //M-(4-(-2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|-3-fluorobenzamide (104 mg, 0.25 mmol), hydrochloride 4.4 -difluoropiperidine (43 mg, 0.275 mmol) and potassium carbonate (10 mg, 0.75 mmol) in DMF (2 mL) were heated in a microwave oven at 1207°C for 20 minutes. The crude product was purified by HPLC to give the title compound ( 20 mg, 1890) in the form of a white solid in the form of a TRA salt." ), 3.57 (t, 2H), 3.68 (s, ЗН), 4.37 (t, 2H), 6.30 (d, 1H), 7.25 (d, 1H), 7.45 (dt, 1H), 7.50 (d, 1H), 7.57-7.62 (m, 1H), 7.72 (d, 1H), 7.74-7.82 (m, 2H), 7.89 (dd, 1H), 10.3 (s, 1H). The exact mass calculated for SgaNo5EzMaO» 458.2, found 459.4 (MNU).

Example 1.77: Preparation of /1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea ( Compound 1). 7 th sia, si SOU vid, - uh

Vg nn Shchy

Hg

To o solution / 1-(3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(4-chlorophenyl)urea (44.Zmg,

0.105 mmol) in THF (5 ml) was added triphenylphosphine (66.2 mg, 0.252 mmol) and 1-(2-hydroxyethyl)pyrrolidine (28.0 mg, 0.243 mmol) followed by the dropwise addition of diisopropyl azodicarboxylate (OI1AB) (5 Oml, 0.258 mmol) ).

After 1 hour, LC/MS analysis showed only partial conversion, so additional triphenylphosphine (36b, 9mg, 0.141mmol) and 1-(2-hydroxyethyl)pyrrolidine (17μl, 0.145mmol) were added, followed by dropwise addition of diisopropylazodicarboxylate (0IAO) ( 27 μl, 0.139 mmol). The reaction mixture was stirred at room temperature for another 1 hour and then concentrated. The obtained substance was purified by HPLC. The product was dried in vacuo to give the title compound as a light brown solid (31.Zmg, 5795). RHMS ti/z (95)-520 (MaNV!'Vg, 100), 518 (MAAN"ZVI, 73),

IN NMR (400MHz, OM50-av) b: 8.81 (width s, 1H), 8.71 (width s, 1H), 7.60 (s, 1H), 7.53 (dd, 9U- 8.98, 2.72Hz, 1H), 7.A7 (d, U-8.95Hz, 2H), 7.35 (d, U-2.71Hz, 1), 7.31 (d, U-8 ,90Hz, 2H), 7.15 (d, 9U-9.05Hz, 1H), 4.15-4.07 (m, 1H), 4.06-3.98 (m, 1H), 3.66 (c, ZN), 2.80-2.69 (m, 1H), 2.69-2.58 (m, 1H), 2.42-2.31 (m, 4H), 1.66-1 .55 (m, 4H).

Example 1.78: Preparation of 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-3-(2,4-difluorophenyl)urea (Compound 5).

M th V th

Nam t p-O-----she xx X M ? and YIV sh;

Hg Hg

2,4 -difluorophenyl isocyanate (0.42 g, 2.71 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with OM5O and purified using Zf-

TOP. Fractions containing the product were collected and evaporated to a small volume. The aqueous solution was neutralized with Tn Mason to pH 0.0 and the product was extracted with ethyl acetate (2x, 500ml). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to obtain 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-ylethoxy)phenyl|- 3-(2,4-difluorophenyl)urea in the form of a colorless solid with a yield of 5995. LCMS ti/z (95)-520 (MH "Bg, 100), 522 (M--H 8!VIg, 98)." H NMR (400 MHz OM50O-av) 6: 9.03 (lat. s, 1H), 8.49 (lat. s, 1H), 8.01-8.1 (m, 1H), 7.61 ( s, 1H), 7.51 (dd, uU-8.96 and 2.73Hz, 1H), 7.35 (d, 952.72Hz, 1H), 7.27-7.33 (m, 1H), 7.15 (d, 9U-9.04Hz, 1), 7.04-7.09 (m, 1H), 4.01-4.11 (m, 2H), 3.67 (s, ЗН), 2.51-2.73 (m, 2H), 2.34-2.38 (lat. s, AN), 1.59-1.63 (lat. s, 4H).

Example 1.79: Preparation of / 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-ylethoxy)phenyl|-3-(4-chlorophenyl)urea ( Compound 145). here and there:

Os "br so as lich pi

Ve nn what

Hg

To a solution of 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl|-3-(4-chlorophenyl)urea (0.1 g, 0.24 mmol), 4 -(2-hydroxyethyl)pyridine (0.0443g, 0.5 mmol) and triphenylphosphine (0.0944g, 0.5 mmol) in 100 ml of anhydrous THF was added diisopropyl azodicarboxylate (0.0728 g, 0.3 mmol) at ambient temperature. The mixture was stirred for 2 hours. Then an additional amount of triphenylphosphine (0.0944 g, 0.5 mmol), 4-(2-hydroxyethyl)pyridine (0.0443 g, 0.5 mmol) and isopropyl azodicarboxylate was added to the reaction mixture, followed by stirring at room temperature overnight.

The solvent from the reaction mixture was evaporated and the crude residue was dissolved in 5.0 ml of OM5O and purified by ZF-HPLC. The required fractions were collected and concentrated to 75% volume. The aqueous solution was neutralized with 1N ammonium chloride and extracted with ethyl acetate (2x, 59ml). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to obtain 1-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-ylethoxy)phenyl |-3-(4-chlorophenyl)urea in the form of a brown solid with a yield of 4495. LCMS t/2 (95)-526 (MAN "Vy, 100), 528 (MAN 81VI, 67). "H NMR (0М50- av) b: 9.33 (width c, 1H), 9.24 (width c, 1H), 8.39 (dd, 94.44 and 1.48Hz, 2H), 7.63 (d, 9U -7.28Hz, 1), 7.59 (s, 1H), 7.56 (dd, U-8.94 and 2.71Hz, 2H), 7.48 (m, 1H), 7.34 (d , 92.67, 1H), 7.31 (d, 922.67, 1H), 7.28 (dd, 9U-6.8811 4.87 Hz, 2H), 7.14 (d, U29.05Hz, 1H), 7.09 (d, U25.93Hz, 1H), 4.01-4.2 (m, 2H), 3.48 (s, ЗН), 2.96-2.91 (m, 2H) .

Example 1.80: Preparation of /- 1-(2,4-difluorophenyl)-3-(4-(2-imidazol-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenyl|urea ( Compound 219).

Xia eE Som so OSS

NM Y M Y Y M Y M

2,4-Difluorophenylisocyanate was added to a solution of 4-(2-imidazol-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl/uphenylamine (0.08 g, 0.25 mmol) in 2.00 ml of dichloromethane (0.042g, O0.280mmol) and the mixture was stirred at ambient temperature overnight. UOSM was evaporated from the reaction mixture, the crude residue was dissolved in 5.0ml of UM5O and purified by ZF-HPLC. The required fractions were collected and lyophilized to give 1-( 2,4-difluorophenyl)-3-(4-(2-imidazol-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-yl)uphenyl|Urea -: In the form of a not quite white solid with yield 7595. LCMS t/z (95)-439 (MAN). "H NMR (400 MHz, Acetone-dv) 6: 8.46 (width s, 1H), 7.96-8.02 (m, 1H ), 7.48 (dd, 928.9 and 2.72Hz, 1H), 7.39-7.41 (m, 2H), 7.31 (d, 9-1.81Hz, 1H), 7.17 (t, 9U1.42Hz, 1H), 6.94 (d, U-8.94Hz, 1H), 6.7-6.8 (m, 2H), 6.01 (d, 9U-1.78Hz, 1H), 4.62 (t, U-4.74Hz, 2H), 4.33 (t, 9-5.07Hz, 2H), 3.48 (s, ZN).

Example 1.81: Preparation of isopropyl ether (|4-(2-azepan-1-ylethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenylcarbamic acid (Compound 352).

CO oh

Oh! oh oh and "Ar, li,

Vs Vg

Isopropyl chloroformate was added to a solution of 4-(2-azepan-1-ylethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)uphenylamine (0.06g, 0.1539mmol) in 2.0ml of OMA (0.021g, 0.1687mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 ml with OM5O and purified by Z3F-HPLC. The required fractions were collected and evaporated to 75% of the volume, and the aqueous fraction was neutralized with Mahon's solution to pH-9.0. Then the product was extracted with ethyl acetate (2x, 30ml).

The collected organic layer was dried with sodium sulfate, filtered and evaporated to dryness to obtain isopropyl ether I(4-(2-azepan-1-ylethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl) phenyl|carbamic acid in the form of a colorless solid with a yield of 6995. РХМСО t/ (90) 5478 (MAN 7zVg, 100), 480 (MAN UVU, 98). "H NMR (400 MHz, OM5O-yv) b: 8.79 (width c, 1H), 8.69 (width c, 1H), 7.59 (c, 1H), 7.34 (d, U-2.62Hz, 1H), 7.21-7.31 (m, 1H), 7.14 (d, 9-9.04Hz, 1H), 4.02-4.12 (m, 1H), 3.92-4.12 (m, 2H), 3.67 (с, ЗН), 2.69-2.78 (m, 2Н), 2.53-2.59 (m, 2Н), 1.4-1.58 (width с, 8Н), 1.26 (d, 9-6.82Hz, 6H).

Example 1.82: Preparation of M-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1]oxazepan-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide (Compound 568). Ka U kE 09 o ko no, gu

OIEA ( 0.057g, 0.443mmol) followed by the addition of m-trifluoromethylbenzoyl chloride (0.056g, 0.26bmmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 ml with OM5O and purified by ZF-HPLC. The required fractions were collected and lyophilized to obtain /-M-I3-(2-methyl-2H-pyrazol-3-yl)-4-(2-(1,4|oxazepan-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide in in the form of a not quite white semi-solid substance with a yield of 87905.

РХМС t/i (965)-489 (MAN, 100). "H NMR (400MHz, OM5O-av) b: 10.5 (lat. s, 1H), 8.29 (s, 1H), 8.26 (d, 9-7.94Hz, 1H), 7.98 (d, U-7.83Hz, 1H), 7.89 (dd, U 8.93 and 2.55Hz, 1), 7.79 (t, 9U-27.82Hz, 1H), 7.72 (d , 9U-2.53Hz, 1H), 7.49 (s, 1H), 7.26 (d, U-9.14Hz, 1H), 6.31 (d, U9-1.79Hz, 1H), 4 ,29-4.43 (m, 2H), 3.69 (s, ЗН), 3.55-3.64 (m, 5H), 3.01-3.18 (m,

B5H), 1.8-21 (m, 2H).

Example 1.83: Preparation of M-(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-Y1,4Aoxazepan-4-ylethoxy)phenyl|-3-fluoro-4-trifluoromethylbenzamide (Compound 606).

M M go pre, (9 s--yaoi in ; nm Hm oi (w

Ve E E Ve

To a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-1,4oxazepan-4-ylethoxy)phenylamine (0.06g, 0.152mmol) and M,M-isopropylethylamine (0.0529ml, 0.304mmol) in 3.0ml OMA was slowly added 3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.0278ml, 0.182mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 ml with OM5O and purified by 3F-HPLC. The required fractions were collected and lyophilized to obtain M-I(3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-I1,Aoxazepan-4-ylethoxy)phenyl|-3-fluoro -4-trifluoromethylbenzamide in the form of a not quite white semi-solid substance with a yield of 5395. LCMS ti/z (953-585 (MAN "Vi, 100), 587 (М--Н 81Вг, 98). 1Н

NMR (400MHz, OM50O-yv) 6: 10.3 (lat. s, 1H), 8.06 (d, 9-11.27 Hu, 1H), 7.95-8.01 (m, ЗН), 7.72 (d, 9-2.60Hz, 1), 7.68 (d, 9U-2.36Hz, 1H), 7.91 (d, 9U-9.48Hz, 1H), 4.35-4 .44 (m, 2H), 3.5-3.9 (m, TON), 2.51-2.69 (m, 5H).

Example 1.84: Preparation of isopropyl ether (|3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenylcarbamic acid (Compound 214).

M M glo pe

M tet X M -o (v; o

To a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenylamine (0.14 g, 0.44 mmol) in a mixture of 2.0 ml/1.0 ml OSM/ pyridine was added isopropyl chloroformate (0.06g, 0.487mmol) and the reaction mixture was stirred at room temperature overnight. The OSM/pyridine mixture was evaporated to give a brown residue.

The residue was dissolved in 5.0 ml of OM5O and purified by ZF-HPLC. The required fractions were collected and lyophilized to obtain 13-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-ylethoxy)phenylcarbamic acid isopropyl ether as a solid with a yield of 8495. (90)-405 (MAN, 100).

IN NMR (400MHz, Acetone-av) 6: 8.58 (width s, 1H), 7.66 (dd, 9-8.4 and 2.6Hz, 1H), 7.55 (s, 1H), 7.47 (d, 9U-1.81H2, 1H), 7.28 (d, U9-1.8Hz, 1), 7.16 (d, U-8.9Hz, 1H), 6.05 (d , 9-1.86Hz, 1H), 4.92-4.98, (m, 1H), 4.53 (t, U-4.3Hz, 2H), 3.72 (s,

ЗН), 3.59 (dd, U-9.63 and 4.86Hz, 2H), 3.28-3.42 (m, 4H), 2.93-2.99 (m, 4H), 1, 25 (d, U-6.12Hz, 6H).

Example 1.85: Preparation of isopropyl ether (3-(2-methyl-2H-pyrazol-3-yl)-4-(2-1,4|oxazepan-4-ylethoxy)phenylcarbamic acid (Compound 215).

M go go / re i ,;/7-0 nom td o s

Isopropyl chloroformate (0.034 g, 0.278 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted to 5.0 ml with HOM5O and purified by Z3F-HPLC. The required fractions were collected and lyophilized to obtain isopropyl ether (3-(2-methyl-2H-pyrazol-3-yl)-4-(2-I1,Aoxazepan-4-ylethoxy)phenyl|carbamic acid in the form of a not quite white semi-solid substance with a yield of 8095. RHMS t/ (95)-403 (MAN, 100). "H NMR (400 MHz, Acetone-iv) b: 8.35 (width p. 1H), 7.45 (dd, 9-84 and 2.6 Hz, 1H), 7.33 (s, 1H), 7.23 (d, 9U-1.8Hz, 1H), 6.94 (d, 9U-8.95Hz, 1H), 6.05 (d, y-1.82Hz, 1H), 4.69-4.76, (m, 1H), 4.31 (t, U-4.36Hz, 2H), 3.52 (s, ЗН), 3.A1 (t, U-4.93Hz, 2H), 3.10-3.30 (m, AN), 2.71- 2.80 (m, 4H), 1.05 (d, U-6 , 12Hz, 6H).

Example 1.86: Preparation of //- M-I3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|-3-trifluoromethylbenzamide (Compound 527) .

GO widely: but, they

SI SI

To a clear solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamine (60.1 g, 17 mmol) in a mixture of n-propanol/ethyl acetate ( 600/200ml) at 30-352С, 3-trifluoromethylbenzoyl chloride was slowly added with stirring. The reaction mixture initially became cloudy, and after stirring the mixture at ambient temperature for 3 to 5 hours, separation of solids occurred.

The solids were filtered off, washed with n-propanol and dried under vacuum at 409C overnight to give M-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4--2-morpholin-4- ylethoxy)phenyl|-3-trifluoromethylbenzamide in the form of a white solid with a yield of 7295 (in the form of the NCI salt). RHMS ti/a (953-509 (MN Z5SI, 100), 511 (MAN

З7СЙ, 33), "H NMR (400 MHz, OM5O-dbv) 6: 10.7 (width s, 1H), 8.39-8.44 (m, 2H), 8.01 (d, 9-2 ,61Hz, 1H), 7.98 (s, 1H), 7.75-1.83 (m, 2H), 7.69 (s, 1H), 7.35 (d, U-9.01, 1H ), 4.45-4.65 (m, 2H), 3.79-3.89 (m, 4H), 3.69 (s, ЗН), 3.36-3.53 (m,

AN with water), 3.05-3.25 (m, 2H), 2.99-3.05 (m, 2H).

Example 1.87: Preparation of M-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)cyclopropanecarboxamide (Compound 271).

With M pa ATO

M t---3--- Sun, Lu, s SI

To a solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(-2-morpholin-4-ylethoxy)phenylamine (0.20g, 0.bommol) in

Cyclopropane carbonyl chloride (0.075 ml, 0.72 mmol) and pyridine (0.061 ml, 0.78 mmol) were added to SNesi" (14.0 ml).

The reaction mixture was stirred for 20 minutes, concentrated and purified using 3ZF-HPLC.

Lyophilization gave the TPA salt of the title compound as a brown oil (0.027g, 5690). RHMS t/2 (95)-405 (MANZ5SI, 100), 407 (M-ANZ'SI, 38). "H NMR (400MHz, OM5O-yv) 6: 10.28 (s, 1H), 7.74 (dd, 9-26, 9.0Hz, 1), 7.65 (s, 1H), 7.54 (d, 9U-2.6Hz, 1H), 7.23 (d, U9-9.0Hz, 1H), 4.43-4.37 (m, 1H), 4.32-4.25 (m, 1H), 3.63 (s,

ZN), 3.92-2.92 (m, 1OH), 1.78-1.70 (m, 1H), 0.78 (d, U-6.3Hz, 4H).

Example 1.88: Preparation of 3-methoxy-N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl)benzamide (Compound 733). oh - oh ---- -- what the hell

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenylamine (120 mg, 0.40 mmol), 3-methoxybenzoyl chloride (81 mg, 0.48 mmol) and triethylamine ( 0.uml, 0.79mmol) in 5ml of THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TRA salt, 88mg, 5195). "H NMR (Acetone-av, 400MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, U-4.80Hz, 2H) , 3.75 (s, ЗН), 3.85 (s, ЗН), 3.79-3.89 (m, 4Н), 4.58 (t, 9-4 80Hz, 2Н), 6.29 ( d, 922.02 Hz 1), 7.13 (dd, U-8.34, 2.53Hz, 1), 7.22 (d, 9-8.84Hz, 1), 7.42 (t, 9 -7.83Hz, 1), 7.47 (d, 9-1.77Hz, 1), 7.52 (t, 9-1.77Hz, 1H), 7.56 (d, 9U-7.07Hz, 1H), 7.80-7.83 (m, 1H), 7.91-7.96 (m, 1H), 9.54 (s, MH).

The exact mass calculated for SgaNgviMaOl4 436.2, found 437.5 (MNU).

Example 1.89: Analytical data for additional compounds of the present invention.

Certain compounds of the present invention have been prepared in the same manner as described in this application. General methods of synthesis and analytical data for these compounds are presented in the tables below, the calculated mass (i.e.,

Mass calc.) represents MN".

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Some synthesis methods and analytical data for additional compounds are presented in the table below, the calculated mass (ie, Calc. Mass) is MN".

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Example 2

Expression of the receptor

A. rSMM

Although various expression vectors are available to those of skill in the art, it is preferred that the vector used is pCoMU. This vector was deposited in Ategisap Toure Siyige SoPesip (ATSS) on 13 October 1998 (10801

Opimegeiu Vima., Mapavzzaz, MA 20110-2209 OBA), in accordance with the Budapest Treaty on the International Recognition of Deposited Microorganisms for Patenting Purposes. The DNA was tested by ATCC and determined to be viable. RSMM was deposited in ATSS under the following depository number:

ATSOSS yag2o3351.

B. Transfection procedure

For the analysis of IR accumulation (Example 3), HEK293 cells were transfected, while for the analysis of swarm binding (Example 4), CO57 cells were transfected. Several protocols well known in the art can be used to transfect cells. The following protocol is representative of the transfection procedures used in this application for CO57 or HEK293 cells.

On day one CO57 cells were seeded in 24-well plates, usually at a density of 1x105 cells/well or 2x105 cells/well, respectively. On day two, cells were transfected by first mixing 0.25 µg cDNA in 50 µl serum-free OMEM/well and then 2 µl lipofectamine in 50 µl serum-free OMEM/well. The solutions ("transfection medium") were gently mixed and incubated for 15-30 minutes at room temperature. The cells were washed with 0.5 ml of PB5 and then 400 μl of serum-free medium was mixed with the medium for transfection and added to the cells. The cells were then incubated for 3-4 hours at 3720/595002. Then the medium for transfection was removed and replaced with 7 ml/well of normal nutrient medium.

For NEK293 cells, on day one 13x109 NEK293 cells were seeded on 150 mm plates. On day two, 2 ml of serum Oriiteti (Ipimygodep Sogrogayop) was added to the plate, followed by the addition of bomcl of lipofectamine and 100 mg of cDNA. It should be noted that lipofectamine must be added to Oriiteti and thoroughly mixed before adding the cDNA. While the formation of complexes between lipofectamine and cDNA was taking place, the medium was carefully aspirated and the cells were carefully washed with 5 ml of Oriiteti medium followed by careful aspiration. Then 12ml of Orieteti medium was added to each plate and 2ml of transfection solution was added followed by 5 hours of incubation at 37°C in a 595°C incubator. The contents of the plates were then carefully aspirated and 25ml of Complete Medium was added to each plate and the cells were then incubated until their use .

Example C

Inositol phosphate (IP) accumulation analysis

A. 5-HTga receptor

The compounds of the present invention were tested for their ability to activate the 5-HTgl receptor clone using an IR accumulation assay. Briefly, NEK293 cells were transiently transfected with a pOMU expression vector containing the human 5-HTα receptor (for the receptor sequence, see US Pat. Meb6541209, 5EO IO

MO:24), as described in Example 2. Analysis of IR accumulation was performed as described below. In this assay, some compounds of the present invention had activity values ranging from about 75 µM to about 0.bnM.

B. Constitutively active 5-HTgal receptor

The compounds of the present invention were tested for their ability to inhibit constitutively active clone 5-

NTgA receptor by means of IR accumulation analysis. Briefly, NEK293 cells were transiently transfected with a pOMUM expression vector containing a constitutively active human 5-HTαi receptor (for the receptor sequence, see US Patent Mob541209, 5EO 10 MO:30), as described in Example 2. Constitutively active 5-

The human HTα receptor contained the human 5-HTαi receptor described in part A, except that the intracellular loop C (IC3) and the cytoplasmic process were replaced by the corresponding cDNA IM! 5-HT2C of a person. Analysis of IR accumulation was performed as described below. In this assay, some compounds of the present invention had activity values ranging from about 10 µM to about 0.1 nM.

S. Protocol of IR accumulation analysis

On the day after transfection, the medium was removed and the cells were washed with 5 ml of PB5 followed by gentle suction. The cells were then trypsinized with 2ml of 0.0595 trypsin for 20-30 seconds followed by the addition of 1Oml of heated medium, gently triturated to dissociate the cells, and another 13ml of heated medium was carefully added. Cells were then counted and 55,000 cells were added to 96-well sterile plates treated with poly-O-lysine. The cells were allowed to attach during a six-hour incubation at 372°C in a 595°C incubator. The medium was then carefully aspirated and 100 μl of warm medium, which does not label inositol, plus 0.5 μCi of ZN-inositol was added to each well, and the plates were incubated for 18-20 hours at 372C in a 595 CO" incubator.

The next day, the medium was carefully aspirated and then 0.1 ml of medium for analysis was added, containing medium without inositol/serum, 10 μM pargyline, 10 mM lithium chloride and the test compound at the specified concentration. The plates were then incubated for three hours at 372C and then the wells were gently aspirated. Then, 200 μl of ice-cooled 0.1M formic acid was added to each well. The tablets can then be frozen at this point at -802C until further processing. The frozen plates were then thawed for one hour and the contents of the wells (approximately 220μl) were placed on 400μl of washed ion exchange resin (Ac 1-X8) contained in a Mi5sgeep filter plate and incubated for 10 minutes followed by filtration under vacuum conditions. The resin was then washed nine times with 200 μl of water and then the powdered inositol phosphates (IR, IR2, and IRZ) were eluted into a tablet for collection by adding 200 μl of 1M ammonium formate and an additional 10-minute incubation. The eluate was then transferred to 20 ml scintillation vials and added

Zml of scintillation cocktail BiregMih or Ni-Zaiye and the vials were counted for 0.5-1 minute in a scintillation counter UmaiYias 1414.

Example 4

Binding assays

The compounds of the present invention were tested for their ability to bind to a membrane preparation of a 5-HTga receptor clone using a radioligand binding assay. Briefly, CO5 cells were transiently transfected with the expression vector РЕСМУ, containing the human 5-HTgl receptor (for the receptor sequence, see US patent Mob6541209, 5EO IO MO:24), as described in example 2.

A. Preparation of crude membrane preparations for radioligand binding assays

CO57 cells transfected with recombinant human 5-HTgal receptors were cultured for 48 hours after transfection, harvested, washed with ice-cold phosphate-buffered saline, pH 7.4 (PB5B), and then centrifuged at 48,000x9d for 20 minutes. at 42C. The cell pellet after centrifugation was then resuspended in a washing buffer containing 20 mM HERE5, pH74 and 01 mM

EOTA, homogenized on ice using a Vhipktap polytron and centrifuged again at 48,000x9 for minutes at 42C. The obtained sediment was then resuspended in 20 mm NEREZ5, pH7.4, homogenized on ice and centrifuged (48,000 rpm for 20 min at 42C). Crude membrane sediments after centrifugation were stored at -802C until use in radioligand binding assays.

B. Analysis of the binding of I?TsOOI radioligand

Radioligand binding assays for the human 5-HTγ receptor were performed using the 5-HT2 agonist (H25DSHCOII) as a radioligand. To determine non-specific binding, 10 μM ОЙ was used for all analyses. To study competitive binding, 0.5 nM | 5ЦООЙII and compounds were used were analyzed in the range of concentrations from 0.01nM to 10μM. Analyzes were carried out in the total volume

200 μl in 96-well filter plates Regkeep EITeg CPE/C in buffer for analysis (5X0MM Tris-HCl, riH7 4, 0.5MM EOTA, 5mM Mac" and 10μM pargyline). Incubations were carried out for 60 minutes at room temperature and were stopped by rapid filtration under vacuum conditions of the reaction mixture through glass fiber filters U/paytap

SR/C, pre-impregnated in 0.595 REI, using Vgapaei| cell collector. The filters were then washed several times with ice-cooled washing buffer (50 mM Tris-HCI, rin7.4). The tablets were then dried at room temperature and counted in a TesgoWeia UmaIas scintillation counter. Some of the compounds of the present invention and their respective activity indices are presented in the table below.

ICoo obtained in the analysis

Some other compounds of the present invention had activity values ranging from about 10 µM to about

About 1 NM in this analysis.

Example 5

Ip Miigo analyzes of aggregation of human platelets

The compounds of this invention were tested for their ability to aggregate human platelets. Aggregation analyzes were carried out using an optical aggregometer Spgopo-I from Todaei! 410. Human blood (-100 ml), taken from donors, was collected in glass vacuum tubes containing 3.895 sodium citrate (light blue upper part) at room temperature. Platelet-enriched plasma (PEP) was separated by centrifugation at 1009 for 15 minutes at room temperature. After removal of the aqueous RKR layer, plasma with a low content of platelets (PPP) was obtained by high-speed centrifugation at 24009 for 20 minutes. Platelets were counted and their concentration was set at the level of 250,000 cells/μl by dilution with PP. Aggregation analyzes were performed according to the manufacturer's instructions. Briefly, a suspension of 450 μl of PEP was stirred in a glass cuvette (1200°6/min.) and after the baseline was established, 1 μM AOR was added followed by the addition of either saline or iM 5HT and the compound of interest (at the desired concentrations), and the corresponding reaction was recorded aggregation Concentration used

AOR causes approximately 10-2095 of maximum aggregation. The concentration of 5-HT corresponded to the concentration that provided maximum potentiation. The percentage of inhibition of aggregation was calculated from the maximum decrease in optical density of control samples and samples containing inhibitors. Only the synergistic effect was evaluated. In this assay, some other compounds of the present invention had activity values ranging from about 80 µM to about 1 nM. Other compounds of the present invention in this assay had activity values ranging from about 8 µM to about 2 nM.

Example 6

Efficacy of the compounds of the present invention to attenuate OO!-induced hypolocomotion in rats.

In this example, compounds of the present invention were tested for their inverse agonist activity by determining whether these compounds could attenuate OI!-induced hypolocomotion in rats in a novel environment. SOY is a strong agonist of the 5-HTgd/2se receptor that passes through the blood-brain barrier.

The standard protocol used is briefly described below.

Animals:

For all tests, male Zrgadoe-Obauleu rats with a body weight of 200-300 g were used. Rats were placed in cages of three to four individuals each. These rats had not previously been subjected to experimental tests and drug treatment. The rats were habituated to the manipulations for one to three days, as is done in the experiment. Rats were fasted overnight before testing.

Compounds: (2)-BOI NS (Sy NivIMO: NOI) can be obtained from the Zidta-Aiagisp company, and this compound is dissolved in 0.995 physiological solution. Compounds according to this invention are synthesized at Agepa RPpagptaseshis!5 ps. and dissolve in 10095 RES400. BOYs are administered by subcutaneous injection in a volume of 1 ml/kg, while the compounds of the present invention are administered orally in a volume of 2 ml/kg.

Procedure:

"Moyog Mopyog" (Natipkop-Kipdeg, Rozhchau, SA) is used to measure activity. This device registers the movements of body parts using infrared light rays.

Locomotor activity tests were performed during the light cycle (0630-1830) from 9:00 a.m. to 4:00 p.m. Animals were allowed to acclimate for 30 min in the test room before testing.

When determining the effect of the compounds of the present invention on OO|-induced hypoactivity, animals were first injected with a carrier or a compound of the present invention (50 μmol/kg) in the cages where they were kept. Sixty minutes later, physiological solution or saline solution (0.Zmg/kg, salt) was administered by injection.

10 minutes after the introduction of SOY, the animals were placed in the apparatus for measuring activity and the activity of movement of body parts was measured for 10 minutes.

Statistics and results:

The results (total number of movements of body parts during 10 minutes) were analyzed using the 1-criterion. A value of P<0.05 was considered significant.

Example 7

It was able to bind to the 5-HTgl receptor

Animals:

Animals (Zrhadne-bbamieu rats) were killed and the brains were quickly excised and frozen in isopentane,

maintained at a temperature of -4220. Horizontal sections were obtained at Sguoviai and maintained at -2026.

Protocol of displacement I 50:

Lysergic acid diethylamide (50) is a strong ligand of the 5-HTα receptor and the dopamine O2 receptor.

Demonstration of the selectivity of compounds for either or both of these receptors involves displacement of radiolabeled 50 from pretreated brain slices. For these studies, you can use radiolabeled 1251-50 (MEM Ge Zsiepse5, Voviop, Mazv5., Sagaiyudie pitreg MEH-199); it is also possible to use spiperone (VI, MaiyskK, Mav5., Saiaiodne pitbreg 5-128), an antagonist of the 5-HTGD receptor and the dopamine O2 receptor. The buffer consists of 50 nmol. tris-NSI, pH7.4.

Brain slices were incubated in (a) Buffer plus Inmol. 7251-50; (b) Buffers plus Inmol. 1251-50 and 1 μmol. spiperone; or Buffers plus Inmol. 1251-50 and imkmol. of the compound of interest for 30 minutes at room temperature. Sections were then washed 2 x 10 minutes at 42C in Buffer and then 20 seconds in distilled NgO. Then the microscopic preparations were air-dried.

After drying, the sections were placed on X-ray film (Kodak Nuregiit) and exposed for 4 days.

Example 8

Studies of binding to the serotonin 5-HTga receptor in monkeys

In this example, the degree of binding of the compound of the present invention to the 5-HTgla receptor can be measured.

Research can be carried out on monkeys treated with PET and ZR-altanserin.

Radioligand:

PET radioligand used for binding studies is "ZE-altanserine. Radiosynthesis of 18e-altanserine is achieved at high specific activities and is suitable for radiolabeling of 5-HTgd receptors and mimo (see aieu eii ai., Mysi. Med. Vio !., 28:271-279 (2001 and references therein).

Quality control parameters (chemical and radiochemical purity, specific activity, stability, etc.) and corresponding radioligand binding were checked in rat brain slices prior to use in PET experiments.

Doses and compositions of the medicinal product:

Briefly, the radiolabeled pharmaceutical agent was dissolved in sterile 0.995 physiological saline, pH approximately 6-7. The compounds according to the present invention were dissolved in 6095 RES 4400-4095 sterile physiological solution on the same day when the PET experiment was performed.

Studies of the degree of binding to serotonin 5-HTgd in humans have been described for M100,907 (Ogipaeg et al., Mepgorzusporpaptaso!odu, 17:175-185 (1997), and Taimik-Goyi et al., Rzusporpaptasiodu, 148:400 -403 (2000).

A high degree of binding to 5-HTgla receptors was reported for various oral doses (the studied doses ranged from 6 to 20 mg). For example, the degree of binding of »9095 was reported for doses of 20 mg (Taymik-

Goli ei aI., above), which is approximately 0.28mg/kg. Therefore, it can be assumed that intravenous doses

M100,907 from 0.1 to 0.2 mg/kg should provide a high degree of receptor binding. In these studies, a dose of the compound according to the present invention of 0.5 mg/kg can be used.

PET experiments:

The monkey was anesthetized with ketamine (1Omg/kg) and maintained in this state with 0.7-1.2590 isoflurane. Typically, monkeys use two IV systems, one in each arm. One IV system is used to administer the radioligand, while the other system is used to collect blood samples to determine pharmacokinetic data for the radioligand as well as unlabeled drugs. Usually, blood samples are quickly taken immediately after the introduction of the radioligand, which are then nullified until the end of the observation. Approximately, at each moment of blood sampling, a volume of 1 ml is taken, which is subjected to centrifugation, and part of the plasma is used to count the radioactivity in the blood.

The initial control study is carried out to determine the initial density of receptors. PET scanning of a monkey is performed with a break of at least two weeks. The unlabeled compound of the present invention, which is administered intravenously, was dissolved in 8095 RES 400:4095 of sterile saline.

Analysis of PET data:

PET data were analyzed using the cerebellum as a control area and using the area volume distribution (OM) method. This method was used to analyze ZE-altanserin PET data in non-human primate and human studies (Ztiy ei ai!., Zuparze, 30:380-392 (1998)).

Example 9

Effect of compounds according to the present invention and zolpidem (2oIridet) on delta force in rats

In this example, the effect of the compounds of the present invention on sleep and wakefulness can be compared with the control drug zolpidem. Medicines are administered in the middle of the light period (inactive period).

Briefly, the compounds of the present invention are tested for their effect on sleep parameters and compared with zolpidem (5.0 mg/kg, Zidta, Z. Gotsi5, MO) and the vehicle used as a control (8095 Tmeep 80, Zidta, 51.

Gotzyz, Moscow State). The method of repeated measurements is used, in which each rat is administered seven separate doses orally. The first and seventh administrations are the vehicle, and the second to sixth administrations are the test compounds and zolpidem, which are administered alternately. Since all doses are administered while the rats are attached to the recording apparatus, a mixture of gaseous 6095 CO2/4095 O2 is used for mild sedation during oral administration. Rats fully recover within 60 seconds after such a procedure.

The interval between injections is at least three days. To test the effect of the compounds on the consolidation of sleep, the introduction was carried out in the middle of the normal inactive period in rats (b hours after the start of the light period). Usually, the entry is made between 13:15 and 13:45 using the 24-hour system. All solutions administered are freshly obtained on the day of administration. After each injection, the animals' behavior is continuously recorded until the light is turned off the next day (-30 hours).

Recording of animal behavior and surgical procedures:

Animals are housed in a temperature-controlled observation room with a 12/12 light/dark cycle (lights on at 7:00 AM) and receive food and water ad libitum. Room temperature (244-222), humidity (50-2095 relative humidity) and lighting conditions are constantly monitored by computer. Medicines are administered orally, as described above, with a break between administrations of at least three days. Animals are examined daily in accordance with the instructions of the Ministry of Health.

Eight male Umiziag rats (300425 g; Spazez Kimeg, Umitipdiop, MA) were prepared by implanting permanent recording devices for continuous recording of electroencephalographic (EEG) and electromyographic (EMG) readings. Under anesthesia with isoflurane (1-495), the hair is shaved from the upper part of the skull and the skin is disinfected with betadine and alcohol. An incision is made along the dorsal midline and the temporalis muscle is pushed aside, a catheter is inserted into the skull and thoroughly washed with 295% hydrogen peroxide solution. Stainless steel screws (2000), which serve as epidural electrodes, are implanted in the skull. EEG electrodes are placed bilaterally 12.0 mm AR from bregma and 2.0 mm MI. and -6.0 mm AR and Z.0 mm MI... Electrodes made of twisted stainless steel wire are sewn bilaterally into the neck muscles for EMG recording. EMG and EEG electrodes are soldered to the connecting clamp, which is attached to the skull with dental acrylic adhesive. The incisions are closed with a suture (silk 4-0) and antibiotics are administered locally. Pain is alleviated with a long-acting analgesic (Buprenorphine), which is administered intramuscularly immediately after surgery. After surgery, each animal is placed in a clean cage and observed until recovery. Animals are allowed at least one week to recover from surgery before starting the study.

For sleep recordings, animals were connected via a cable and a balanced switch to a Meigodaia tode! 15 (Sgaz5-TeIetasiog, Umezi UMagmysk, KI). The animals were allowed an acclimatization period of at least 48 hours before the start of the experiment and were connected to a recording device for continuous recording throughout the experiment, except when damaged cables had to be replaced. Amplified EEG and EMG signals were converted into digital and stored in a computer using the Zierzidp program (Kizzeii Sotges, Igmipe SA).

Data analysis:

EEG and EMG data were evaluated visually with 10-second periods of wakefulness (M/), KEM5, MKEM5. The evaluated data were analyzed and expressed as the time spent in each state, per Х» hours. The duration of sleep periods and the number of cases of each condition were counted in hours. "Case" consists of at least two consecutive periods of this condition. EEG delta power (0.5-3.5Hz) within MKEM5 was also analyzed. EEG spectra in the MKEM5 process were obtained autonomously with the fast Fourier transform algorithm for all periods without a random false result. The delta power was normalized to the average delta power in MKEM5 between 11:00 PM and 1:00 AM, a time when delta power is usually at a minimum.

Data were analyzed using repeated measurements of AMOMA. Light phase data and dark phase data were analyzed separately. Both the treatment effect for each rat and the duration of the treatment effect for each rat were analyzed. Since two comparisons were made, a minimum value of Ре0.025 is required for the analysis. After determining statistical significance using AMOMA analyses, I-criteria were used to compare all compounds with vehicle and test compounds with zolpidem.

Example 10

Efficacy of the compounds of the present invention to inhibit C virus infection of human glial cells

A compound of the present invention inhibits US virus infection of human glial cells, as can be shown using an IP migo model of EIRPISC. (zsiepse (2004) 306:1380-1383), essentially as briefly described below.

Cells and US virus

For these experiments, the human glial cell line 5MO (or its suitable subclone, such as ZHMO-A) is used. ZMO is a human glial cell line established by transforming human fetal glial cells with a previously defective 5M40 mutant (Mayog eyi a!., Rgos. Mai). Asai. 5bi.

O5A (1985) 82:1257-1261). 5MO cells are cultured in Igla's minimal basic medium (Meaiatesi Ips.,

Negpdop, MA), supplemented with 1095 heat-activated fetal bovine serum, and stored in a humidified incubator at 372С, 595 СО".

For these experiments, the Maa-1/5MEA strain of the US virus is used |Masapei et al., Migoiodu (1989) 170:353-3611. While the host range of the US virus is usually limited to growth in human fetal glial cells, the host range of Madi -1/5EA extends to human kidney and monkey cell types. Mada-1/5MEA is widespread in NEK cells. The titer of the virus is measured by hemagglutination of human erythrocytes of type O.

Assay of inhibition of US viral infection 5MO cells grown on coverslips were pre-incubated at 372C for 45 minutes without a compound of the present invention or with a compound diluted in a medium containing 290 EC5. By way of illustration, but without limitation, a compound of the present invention is used at a concentration of about 1NM to about 100μM, at a concentration of about 10NM to about 100μM, at a concentration of about 1NM to about 10μM, or at a concentration of about 10nM to about 10μM.

US virus (Mad-1/5MEA) was then added at MO!1-1.0 and the cells were incubated for 1 hour at 372C in the constant presence of the compound of this invention. The cells were then washed with 3x in PB5 and nutrient medium containing the compound of the present invention was added. Seventy-two hours after M challenge, antigen-positive cells were counted by indirect immunofluorescence (see below). Controls included the addition of a compound of the present invention at 24 and 48 hours post-infection. The percentage of infected cells in untreated cultures was taken as 10095.

Indirect immunofluorescence

For indirect immunofluorescence analysis of M antigen 5MO expression, cells grown on coverslips were fixed in ice-cooled acetone. To determine the expression of the M antigen, the cells were then incubated for 30 minutes at 372C with a 1:10 dilution of the hybridoma supernatant from RAV597. The RAV597 hybridoma produced a monoclonal antibody against MP1 of the 5M40 capsid protein, which was shown to cross-react with US virus MP1. Cells were then washed and incubated with goat anti-mouse secondary antibody AiYeha Rishog 488 for another 30 minutes. After final washing, the cells were counterstained with 0.0595 Evans blue, mounted on glass slides using 9095 glycerol in PB5, and visually observed using a Micop E800 epifluorescence microscope. The pictures were taken with Natataiva's digital camera and using the Itrgomiviop program.

Example 11

Ip Miigo analysis of dog platelet aggregation

Approximately 50 ml of blood was collected from male beagle dogs. The protocol for analyzing the effect of the compounds on platelet aggregation was the same as that used for human platelets (see Example 5, above), except that 5 μM AR Her 2 μM 5-HT was used to stimulate increased platelet aggregation.

Results: ICho curves were constructed for each test compound ranging from about 2nM to greater than about 10μM.

Example 12

Eh-Mimo aggregation of whole dog blood

One hour after oral administration of the test compound, whole blood was collected from male beagle dogs in 5 ml vacuum tubes with exogenous heparin (5 U/ml) added to the vacuum tubes.

Aggregation studies were carried out using an aggregometer for whole blood (Spgopoiod Sogr.). Briefly, whole blood (400 μl) was added to a physiological solution (b0Omcl) with constant stirring and activated with the help of 5 μg of collagen (Sphopoiod Sogr.). The serotonin response was obtained by adding 5-HT (Zidta) to a final concentration of 2.5 µM. Results: Selected compounds were tested for antiplatelet aggregation activity following a single bolus oral administration. The dose that provided maximum inhibition of 5-HT-enhanced platelet aggregation was determined and used for comparison. Some compounds demonstrated significant inhibition of 5-HT and collagen-enhanced platelet aggregation at concentrations ranging from 0.1 mg/kg to 5 mg/kg.

Example 12

IP Mimo analysis of thrombosis, bleeding, aggregation, RK in rats

Formation of thrombosis and duration of bleeding:

This model simultaneously measures thrombus formation, bleeding time, platelet aggregation, and drug exposure in a single-dose live rat. The tested compounds were administered to male rats (body weight 250-350g) by p/o injection in various concentrations, depending on the activity of the compound, in the range of 1trk-100tk. The animals were then anesthetized with Nembutal approximately 30 minutes after administration.

After the animal was fully anesthetized using accepted surgical techniques, the animal's right femoral artery was dissected in two different sections approximately 4 mm in length, one to accommodate the probe and the other to accommodate the ferric chloride stain. The artery was then allowed to stabilize, allowing her to recover from the surgery. In the process of stabilization, the animal was then subjected to intubation and connected to a breathing apparatus (Nagmaga Arragaishv5, Ips.) at 75 beats/min. with a volume of 2.5 cm3. After intubation and after stabilization, a microarterial probe (Tgapzopis Zuvietv, Ips) was then inserted into the distal divided femoral artery. After the introduction of the probe, the flow was monitored using the recording system Romzhepar (A Ipzigitepiv5) to track the speed of the pulsating flow. A small piece of filter paper soaked in a 3095 ferric chloride solution was placed over the area of the artery above the probe for 10 minutes. After 5 minutes after application of ferric chloride stain, the last Zmm of the rat's tail were removed. The tail was then placed in a glass vial filled with physiological solution at a temperature of 37"C and the time required for the bleeding to stop was recorded.

After removal of the ferric chloride stain, flow control data were recorded until arterial occlusion occurred, and the time required for occlusion was recorded.

Aggregation of whole blood and RK:

After measurement of bleeding and occlusion time, 5 ml of blood was obtained for ex-mmo analysis of aggregation by cardiac puncture in heparin (5 Units/ml). Another 500 μl of blood was collected in a separate vacuum tube for LC analysis (plasma concentration of the medicinal product). Ex-mimo studies of aggregation were carried out using an aggregometer for whole blood (Spgopoiosd Sogr.). Briefly, whole blood (400 μl) was added to physiological solution (b0Omcl) with constant stirring and activated with the help of 2.55 μg of collagen (Sphopoiod Sogr.).

The serotonin response was obtained by adding 5-HT (Zidta) to a final concentration of 2.5 μM. Results:

Test compounds or control compounds with acceptable levels of binding to rat 5-HTgl receptors were evaluated for the effect of thrombus formation, bleeding and platelet activity in one model. This made it possible to most accurately demonstrate the separation of the effects of the test compound on platelet-mediated thrombus formation and the effects on bleeding. For example, the EO determined for Compound 5 for occlusion time and bleeding time in this model showed a -7-fold division (I0d zsaie) in this therapeutic index.

It should be clear to those skilled in the art that various modifications, additions, substitutions and variants of the illustrative examples set forth in this application are possible without departing from the essence of this invention, which are therefore considered to be within the scope of this invention. All documents referenced above, including, but not limited to, printed publications and provisional and formal patent applications, are incorporated herein by reference in their entirety.

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Claims (80)

1. A compound selected from the compounds of formula (Ia): Vo V. M y o i Kk, y v. (Iz) , 1 its pharmaceutically acceptable salts, hydrates or solvates; where: MU is 0; MU/ is C1-alkylene, optionally substituted with 1-8 substituents independently selected from C1-alkyl, C1-allkoxy, carboxy, cyano, C1-haloalkyl, halogen and oxo; or M is missing; X is C(-O), C(-5) or absent; U is O, MKi1 or absent; 7, is Silalkylene or C3-C6cycloalkylene, each optionally substituted with 1-8 substituents independently selected from C1-alkyl, Silalkyl, carboxy, cyano, C3-haloalkyl, halogen, hydroxyl and oxo; or 7, absent; Ki is selected from H, Ci-alkyl, Co-valkenyl, Co-valkynyl, and C3-ucycloalkyl; Co is selected from H, C1-vacyl, C1-acyloxy, C1-valkenyl, C1-valoxy, C1-alkyl, C1-alkylcarboxamide, C1-alkylcarboxamide, C1-alkylsulfonamide, C1-alkylsulfinyl, /-(C1-alkylsulfonyl, C1-valkythio, C 1 -alkylureyl, amino, C 1 -alkylamino, C 1 -dialkylamino, carbo-C 1 -alkoxy, carboxamide, carboxy, cyano, C 3 -dichloroalkyl, C 1 -dialkylcarboxamide, C 1 -dialkylsulfonamide, halogen, C 1 -haloalkyl, C 1 -haloalkyl, C-vhaloalkylsulfinyl, C-vhalogenalkylsulfonyl, C-vhaloalkylthio, hydroxyl, thiol, nitro and sulfonamide; Kz is selected from H, C-valkenyl, C-alkyl, C-alkylcarboxamide, C-valkynyl, C-valkylsulfonamide, carbo-Ci -alkoxy, carboxamide, carboxy, cyano, C3-1cycloalkyl, C3-1dialkylcarboxamide, halogen, heteroaryl and phenyl; where each of the specified C»valkenyl, C-alkyl, subalkynyl, /C-alkylsulfonamide, C3-.lcycloalkyl, heteroaryl and phenyl groups is non-obvious necessarily substituted with 1-5 substituents independently selected from C-zacyl y, C 3 -zacyloxy, C 3 -valkenyl, C 3 -c 4 alkoxy, C 3 -balkyl, C 3 -alkylamino, C 3 -dialkylamino, C 4 alkylcarboxamide, C 4 -valkynyl, C 3 -c 4 alkylsulfonamide, C 3 -alkylsulfinyl, C 4 -alkylsulfonyl, C 4 -alkylthio, C -4-alkylureyl, amino, carbo-C 1-6 alkoxy, carboxamide, carboxy, cyano, C 6-cycloalkyl, /C 2 -dialkylcarboxamide, halogen, C 4-haloalkyl, C 4-haloalkyl, C- 4haloalkylsulfinyl, C-4haloalkylsulfonyl, C-4haloalkylthio, hydroxyl, nitro 1 sulfonamide; Ki is a heterobicyclic group, a heterocyclic group, or a heteroaryl group, each optionally substituted with substituents independently selected from C-vacyl, C-ylacyloxy, C-valkenyl, Sialoxy, C-valkoxycarbonylamino, C-alkyl, C-valkyamino, C- vdialkylamino, C1-alkylcarboxamide, Sovalkynyl, Silalkylsulfonamide, /-(C1-34alkylsulfinyl, C1-alkylsulfonyl, C1-alkylthio, C1-alkylureyl, amino, carbo-C1-6- alkoxy, carboxamide, carboxy, cyano, C3-ecycloalkyl, C3 -IIcycloalkylcarbonyl, C-dialkylcarboxamide, formyl, halogen, C-haloalkyl, C-haloalkyl, C-haloalkylsulfinyl, C-4haloalkylsulfonyl, C-4haloalkylthio, heteroaryl, hydroxyl, nitro, phenyl and sulfonamide; where C-vacyl, C-alkyloxy, C-alkyl, C-alkyl .Silalkylsulfonyl, amino, carbo-Ci-Alkoxy, carboxamide, carboxy, cyano, C3-ecycloalkyl, halogen, Si. 4-haloalkyl, C-4haloalkyl, hydroxyl and phenyl; K»5, Kv 1 K7, each independently selected from H, C1-vacyl, C1-acyloxy, C1-valkenyl, C1-valkoxy, Sialkyl, Sialkylcarboxamide, Subalkynyl, C1-alkylsulfonamide, /C1-alkylsulfinyl, C1-alkylsulfonyl, Si -valkylthio, C-alkylureyl, amino, C-valkylamino, C-zdialkylamino, C-alkylimino, carbo-Ci-alkyl, carboxamide, carboxy, cyano, C3-tychloalkyl, Czdialkylcarboxamide, Czdialkylsulfonamide, halogen, Si. halogenalkoxy, Si. haloalkyl, C1-haloalkylsulfinyl, C1-haloalkylsulfonyl, C1-haloalkylthio, heterocyclic group, hydroxyl, thiol, nitro, phenoxy and phenyl; Kz" is C1-6alkyl, C1-6alkyl, aryl, C3-11cycloalkyl, or heteroaryl, each optionally substituted with substituents independently selected from C1-vacyl, C1-6acyloxy, C2-valkenyl, C1-6alkyloxy, C1-6alkyl, C1-6alkylcarboxamide , So-valkinilu, Si. alkylsulfonamide, C1-alkylsulfinyl, C1-alkylsulfonyl, C1-valkythio, C1-valkyureyl, amino, C1-alkylamino, C10-dialkylamino, C1-alkylimino, carbo-C1-alkyl, carboxamide, carboxy, cyano, C3-ucycloalkyl , C0-vdialkylcarboxamide, C0-vdialkylsulfonamide, halogen, C1-vhaloalkyl, C1-vhaloalkyl, C1-vhaloalkylsulfinyl, -: C1-vhaloalkylsulfonyl, Cv-haloalkylthio, heterocyclic group, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent substituents together with the indicated aryl or the indicated heteroaryl form C5cycloalkyl, which optionally includes from 1 to 2 oxygen atoms and is optionally substituted by E, Ci or Bg; wherein Sovalkenyl, Sivalkyl, Sovalkynyl, C 1 -alkylamino, Sivalkylimino, C 2 -dialkylamino, heterocycle and phenyl are each optionally substituted with 1-5 substituents independently selected from C-vacyl, Sivacyloxy, C-valkenyl, C-valoxy, C1-alkyl, C1-alkylcarboxamide, Sovalkynyl, C1-alkylsulfonamide, C1-alkylsulfinyl, /-(C1-alkylsulfonyl, C1-alkylthio, C1-6alkylureyl, amino, C1-alkylamino, C1-dialkylamino, carbo-C1-6-alkyl, carboxamide, carboxy, cyano, C3/ucycloalkyl, C10-dialkylcarboxamide, halogen, C1-whaloalkyl, C1-whaloalkyl, C1-whaloalkylsulfinyl, -: C1-whaloalkylsulfonyl, Cw-haloalkylthio, hydroxyl, thiol and nitro; 1 Ko, Kb 1 Ki , each independently, represents H or C 1 -alkyl, provided that Ka represents a group other than an oxiranyl group. 2. The compound according to claim 1, selected from the compounds of the formula (Ic), 1 and its pharmaceutically acceptable salts, hydrates and solvates: V. M her I Kk, / V, as 3. The compound according to item I or claim 2, where U/ represents -СНо-, -СНСН»о-, -СНоС(-О)-, - СТСНсНо-, -КСНз»С(-О0)-, -« СТСН(СНЗ)-, -СН(ИСНИ)СНо-, -Ч(СНИ»СН»о- or -СНОС(СНЗ)»-. 4. Compound according to claim 1 or claim 2, where M is absent. 5. The compound according to any of claims 1-4, where X is C(-0O). 6. The compound according to any of claims 1-4, where X is absent. 7. The compound according to any of claims 1-6, where U is MH, O or absent. 8. The compound according to any of claims 1-7, where 7 is absent or represents -СНо-, -СН(ОН)-, - Се-, -КСНЗ)»-, 1,1-cyclopropyl, -СНаСН »o-, -СНАСНСН»о-, -СН(СНЗ)- or -С(-0)-. 9. The compound according to any one of claims 1-8, where Ki is CH3. 10. The compound according to any of claims 1-9, where Co is H. 11. A compound according to any of claims 1-10, where Kz is H, E, Si or Vg. 12. The compound according to any of claims 1-11, where Ki. represents a heterobicyclic group, a heterocyclic group or a heteroaryl group, each optionally substituted with substituents independently selected from C1-vacyl, C1-acyloxy, C1-alkoxycarbonylamino, Silalkyloxy, C1-alkyl, C1-alkylcarboxamide, C1-3alkylsulfonamide, C1-alkylsulfonyl, Silalkylureyl, amino, carbo-C1-6- alkoxy, carboxamide, carboxy, Co-dialkylcarboxamide, formyl, halogen, Sihaloalkyl, heteroaryl, hydroxyl 1-phenyl; wherein C 1 -vacyl, Silgazyloxy, Silalkyloxy, C 1 -alkyl, C 1 -alkylcarboxamide, amino, carbo-C 1 -C 1 alkyl, heteroaryl, each optionally substituted with substituents independently selected from the group consisting of C 1 -alkyl, carbo-C 6b-Alkoxy, carboxyl 1 phenyl; provided that Ka represents a group other than an oxiranyl group. 13. The compound according to any one of claims 1-11, where Ka is selected from: pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin- 4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl, 2,5- diazabicyclo|2,2,1 |hept-2-yl, |1,4|oxazepan-4-yl, 1,1-dioxo-1IA-thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl , pyrrolidin-33-yl, 3-oxopiperazin-1-yl, 7-azabicyclo!|2,2,1|hept-7-yl and imidazol-1-1yl, each optionally substituted with substituents independently selected from CH3, C(-O)O- of tert-butyl, SI-UOH, C(-OXE:, MNST(-O)O-tert-butyl, OH, C(-O)MNHSNOS(-O)OSN", MNSTc-O )СсНносС(-О)СНИ, С(-О)МНСНоС(-ОЙН, МНне-ОснтеСОоонН, 0 С(-«О)ОСН;», ООС-О)СТСНоС(-О)ОСНИ, OS(-О)СТСНСНоСНоСНИ . phenyl, C(-O)SOSNOS(I-O)OSN, C(-O)SOSNOS(I-O)OH, E, phenyl,, CH»C(-O)OSN;», 5(-02»СН3 , OSNo-phenyl, СНо-phenyl, SI-О)МН»о, СНО, -МН», МН OS-O)CHz, SI-OM(CHz)», МНВ(-О»CH», -CE, 3-methyl-|1,2,4 |oxadiazol-5-yl and CH(CHZ)». 14. The compound according to any of claims 1-13, where K5, Kb 1 K7 are all H. 15. The compound according to any one of claims 1-14, where Kv represents C1-alkyl, C1-valkenyl, aryl, C3-cycloalkyl or heteroaryl, each optionally substituted with substituents independently selected from C1-vacyl, C1-alkyloxy . C3.1cycloalkyl, optionally including from I1 to 2 oxygen atoms and optionally substituted IS. 16. A compound according to any one of claims 1-14, where Ke is selected from the group consisting of methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, phenyl, naphthalene-1-yl, cyclopropyl, cyclobutyl , cyclopentyl, pyridin-2-yl, pyridin-3-1l, I1H-benzimidazol-2-yl, benzoxazol-2-yl, benzthiazol-2-yl, thiophene-2-yl, furan-2-yl, benzthiophene-2 -yl, thiazol-2-1l, isoxazol-3-yl 1 pyridin-4-1l, each optionally substituted with substituents independently selected from C(-O)CH»z, OSN;,, CH», E, SI . 17. The compound according to any one of claims 1-14, where Ka" is selected from: 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzo| 1,3 |dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3, 5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3Z-methoxyphenyl, 3-acetylphenyl, 4-methylphenyl, 3Z-trifluoromethylphenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 4-chloro-2-trifluoromethylphenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, naphthalene-1-yl, 4--rifluoromethoxyphenyl, 3-cyanophenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-fluorophenyl, 2,3-difluorophenyl , 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 2-fluoro -4-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-t-rifluoromethylphenyl, 3-chloro-4-fluorophenyl, 2,b -dichlorophenyl, 4-cyanophenyl, 2,5-dichlorophenyl 1 benzo| 1,3|dioxol-5-yl. 18. A compound according to any of claims 1-14, where Ka" is selected from: methyl, isopropyl, isobutyl, n-propyl, n-butyl, 2-methylpropenyl, 3-methylbutyl, cyclopropyl, cyclobutyl and cyclopentyl. 19. The compound according to any of claims 1-14, where Ka" is selected from: pyridin-3-yl, b-trifluoromethylpyridin-3-yl, 3-hydroxypyridin-2-yl, b-methylpyridin-3-yl, b -hydroxypyridin-3-yl, 1H-benzimidazol-2-yl, benzoxazol-2-yl, benzthiazol-2-yl, thiophen-2-yl, furan-2-yl, 5-chlorothiophen-2-yl, benzthiophen-2 -yl, thiazol-2-yl, 5-methylisoxazol-3-yl and pyridin-4-yl. 20. The compound according to any of claims 1-19, where Co is N. 21. The compound according to any of claims 1-20, where Ki1 is H. 22. The compound according to claim 1, selected from the compounds of the formula (IC): мя о І in se du Н Х / І ; (IR) 1 its pharmaceutically acceptable salts, hydrates and solvates; where: UM represents -СНо-, -СНаСН»о-, -СНоС(-0)-, -ССНСНо-, -ССНз»С(-О)-, - СсТСН(СН3)-, -СН(СНи) СНо-, -(СН3)»СНо- or -«СНоС(СН3)2-; or M is absent; X is C(-O) or absent; U represents MH, O or absent; 7, is absent or represents -СНо-, -СН(ОН)-, -СЕ-, -С(СН3)»-, 1,1-cyclopropyl, - СсСНо-, СНССІСН»о-, -СН(СН3)- or -С(-0)-; Ki is Si -alkyl; Kz represents H or halogen; Ki is a heterobicyclic group, a heterocyclic group, or a heteroaryl group, each optionally substituted with substituents independently selected from C1-vacyl, C1-acyloxy, C1-alkyloxy, C1-C1-alkoxycarbonylamino, C1-alkyl, C1-C6-alkylcarboxamide, C1-3C4alkylsulfonamide, C1- alkylsulfonyl, silalkylureyl, amino, carbo-Ci-6-alkoxy, carboxamide, carboxy, C-dialkylcarboxamide, formyl, halogen, Sihaloalkyl, heteroaryl, hydroxyl 1-phenyl; where indicated is C1-vacyl, Silgazyloxy, Silalkyloxy, C1-alkyl, C1-C1-alkylcarboxamide, amino, carbo-C1-C1-alkoxy 1 heteroaryl, each optionally substituted with substituents independently selected from C1-alkyl, carbo-C1-6e-Alkoxy , carboxyl 1 phenyl; 1 Kz is C 1 -alkyl, C 1 -alkenyl, aryl, C 3 -cycloalkyl or heteroaryl, each optionally substituted with substituents independently selected from C 1 -vacyl, C 1 -alkyloxy, C 1 -alkyl, C 1 -alkylsulfonyl, amino, C 1 - alkylamino, C10-dialkylamino, C1-alkylimino, carbo-C1-6-alkyl, carboxamide, carboxy, cyano, C3-cycloalkyl, halogen, C1-6haloalkyl, C1-6haloalkyl, heterocyclic group, hydroxyl, nitro and phenyl, or two adjacent substituents together with the indicated aryl or the indicated heteroaryl form C»5.lcycloalkyl, which optionally includes from 1 to 2 oxygen atoms and is optionally substituted by E; provided that Ka represents a group other than an oxiranyl group. 23. The compound according to claim 1, selected from the compounds of the formula (IC): tak ov 1 VI kanvy, n / Y ; (IR) and its pharmaceutically acceptable salts, hydrates and solvates; where: UM represents -СНо-, -СНаСН»о-, -СНоС(-0)-, -ССНСНо-, -ССНз»С(-О)-, - СсТСН(СН3)-, -СН(СНи) СНо-, -(СН3)»СНо- or -«СНоС(СН3)2-; or M is absent; X is C(-O) or absent; U represents MH, O or absent; 7, is absent or represents -СНо-, -СН(ОН)-, -СЕ-, -С(СН3)»-, 1,1-cyclopropyl, - СсСНо-, СНССІСН»о-, -СН(СН3)- or -С(-0)-; Ki is Si -alkyl; Kz represents H or halogen; Ki is a heterobicyclic group, a heterocyclic group, or a heteroaryl group, each optionally substituted with substituents independently selected from C1-vacyl, C1-acyloxy, C1-alkyloxy, C1-C1-alkoxycarbonylamino, C1-alkyl, C1-C6-alkylcarboxamide, C1-3C4alkylsulfonamide, C1- alkylsulfonyl, silalkylureyl, amino, carbo-Ci-6-alkoxy, carboxamide, carboxy, C-dialkylcarboxamide, formyl, halogen, Sihaloalkyl, heteroaryl, hydroxyl 1-phenyl; where indicated is C1-vacyl, Silgazyloxy, Silalkyloxy, C1-alkyl, C1-C1-alkylcarboxamide, amino, carbo-C1-C1-alkoxy 1 heteroaryl, each optionally substituted with substituents independently selected from C1-alkyl, carbo-C1-6e-Alkoxy , carboxyl 1 phenyl; 1 K selected from 4-chlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2,2-difluorobenzo| 1,3 |dioxol-5-yl, 4-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, /(4-trifluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, 3-methoxyphenyl, 3-acetylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 4-chloro-2- trifluoromethylphenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, naphthalene-1-yl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-fluorophenyl, 2,3- difluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 2- fluoro-4-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 2,6- dichlorophenyl, 4-cyanophenyl, 2,5-dichlorophenyl 1-benzo|1,3|dioxol-5-yl, provided that Cal is a group other than an oxiranyl group. 24. The compound according to claim 1, selected from the compounds of formula (10): raki i c) i o M N X / i ; Po) and its pharmaceutically acceptable salts, hydrates and solvates; where: MU represents -СНо-, -СНоСН»о- or -СНоС(-О)-; Ki is Si -alkyl; Kz represents H or halogen; Ka is pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl , pyridine-2-1l or pyridine-4-1l, each optionally substituted with substituents independently selected from CH3, C(-O)O- tert-butyl, SI-UOH, C(-OXE:, MNST(-O )O-tert-butyl, OH, C(-O)MNSNOS(-O)OSN", MNOI-O)SnosS(-O)OSNI, C(-O)MNSNOS(-ОЙН, МНнеТеСс-OsnНс(-ООН, 0 С(-О)ОСН;», ООС-О)СТСНоС(-О)ОСНИ, OS(-О)СТСНСНоСНоСНИ, СНоС(-О)ОСТоСН», 0 OSсН;», СспО-ОН, оС-О)СТСНС -O)OSNI, SVSNoS(I-O)OSNI, C(-O)CHni 1 C-O)OSNo- phenyl; and Kz" selected from IN-benzimidazol-2-yl, benzoxazol-2-yl and benzthiazol-2-1yl. 25. The compound according to item I, selected from the following compounds and their pharmaceutically acceptable salts, hydrates and solvates: (A) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-( 2-pyrrolidine-1-ylethoxy)phenyl|-3-(4-chlorophenyl)urea (Compound 1); (A2) M-(3-(4-chloro-1-methyl-IN-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)cyclopropanecarboxamide (Compound 271); (Az). M-13-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-|(2-(4-methoxypiperidine-1-1l)ethoxy|phenyl)-3-fluorobenzamide (Compound 637); (A4) M-I3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl |-3-fluoro-4-methylbenzamide (Compound 559) ; (A5) 1-(3-(4-chloro-1-methyl-IN-pyrazol-5-1l)-4-(-2-morpholinoethoxy)phenyl)-3-(3-chlorophenyl)urea (Compound 231) ; (Ab) 1-(4-chlorobenzyl)-3-I|3-(2-methyl-2H-pyrazol-3-1l)-4-(3-morpholin-4-ylpropoxy)phenyl|urea (Compound 666); (AT) 3-chloro-M-I3-(2-methyl-2H-pyrazol-3-1l)-4-(2-pyrrolidine-1-ylethoxy)phenyl|benzamide (Compound 512); (Av) 3-fluoro-M-|3-(2-methyl-2H-pyrazol-3-1l)-4-(2-pyrrolidin-1-ylethoxy)phenyl|-4-trifluoromethylbenzamide (Compound 487); (AZ9). 1-13-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-I2-(3-hydroxyazetidin-1-1l)ethoxy |phenyl )-3-(4-chlorophenyl)urea (Compound 298); (A10) 1-I4-(2-(7-azabicyclo|2,2,1|hept-7-yl)ethoxy|-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl |-3-(3-trifluoromethylbenzyl)urea (Compound 710); (A11) 1-I4-(2-(7-azabicyclo|2,2,1 |hept-7-yl)ethoxy |-3-(4- bromo-2-methyl-2H-pyrazol-3-yl)phenyl |-3-(2,4-difluorobenzyl)urea (Compound 734); (A12) 4-fluoro-M-|3-(2-methyl-2H -pyrazole-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide (Compound 280); (A13) M-Y3-(2-methyl-2H-pyrazol-3-1l)-4- (2-morpholin-4-ylethoxy)phenyl |-4-trifluoromethylbenzamide (Compound 282); (A14) M-I3-(2-methyl-2H-pyrazol-3-1l)-4-(2-pyrrolidine-1- ylethoxy)phenyl |-3-trifluoromethylbenzamide (Compound 435); (A15) M-I4-I(2-(3,3-difluoropyrrolidine-1-1l)ethoxy |-3-(2-methyl-2H-pyrazole-3 -1yl)phenyl |-4-fluoro-3-methylbenzamide (Compound 546); (A16) 4-fluoro-3-methyl-M-|3-(2-methyl-2H-pyrazol-3-1l)-4- (1-methylpyrrolidin-2-ylmethoxy)phenyl|benzamide (Compound 547); (A17). M-13-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-I2-(2- methylpyrrolidin-1-yl)ethoxy|phenyl|-3,4-difluorobenzamide (Compound 579); (A18) M-I3-(4-bromo-2-me ethyl-2H-pyrazol-3-1l)-4-(1-methylpyrrolidin-3-yloxy)phenyl|-3,4-difluorobenzamide (Compound 585); (A19) M-I4-(2-(3-hydroxypyrrolidine-1-1l)ethoxy |-3-(2-methyl-2H-pyrazol-3-1yl)phenyl |-4-trifluoromethylbenzamide (Compound 586); (A20 ) 3-fluoro-M-I4-(2-(4-formylpiperazine-1-1l)ethoxy |-3-(2-methyl-2H-pyrazol-3-yl)phenyl |benzamide (Compound 752); (A21) M-I4-(2-(4-acetylpiperazin-1-yl)ethoxy |-3-(2-methyl-2H-pyrazol-3-1l)phenyl |-3-methoxybenzamide (Compound 755); (A22) M- 13-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl |-2-phenylacetamide (Compound 762); (A23) 2-(3-fluorophenyl)-M -|3-(2-methyl-2H-pyrazol-3-1l)-4-(-2-morpholin-4-ylethoxy)phenyl|acetamide (Compound 766); (A24) 2-(3-chlorophenyl)-M -I|3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide (Compound 767); (A25) M-II3-(2-methyl- 2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl|-2-(3-trifluoromethylphenyl)acetamide (Compound 768); (A26) 2-(3-methoxyphenyl)-M-|3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholine-4- ylethoxy)phenyl|acetamide (Compound 769); (A27) M-I3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl |-2-M-tolylacetamide (Compound 770); (A28) M-I3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl |-2-p-tolylacetamide (Compound 771); (A29) 2-benzo| 1,3|dioxol-5-1l-M-|3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl|acetamide (Compound 772); (AZO) M-I3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl |-2-(4-trifluoromethylphenyl)acetamide (Compound 794); (AZ1) M-II3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl |-2-thiophen-2-ylacetamide (Compound 795); (AZ2) 1-(4-(2-azetidin-1-ylethoxy)-3-(2-methyl-2H-pyrazol-3-1l)phenyl |-3-(2,4-difluorophenyl)urea (Compound 86) ; (AZ33) 1-13-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(|(2-(3-methoxyazetidine-1-1l)ethoxy |phenyl )-3-(4 -chlorophenyl)urea (Compound 267); (AZ4) 0 M-13-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(|12-(3-methoxyazetidin-1-1l)ethoxy |phenyl )-3-methylbutyramide ( Compound 326); (AZ5) benzoxazol-2-1l-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(2-piperidin-1-ylethoxy)phenylamine (Compound 199); (AZb) |3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl|amide of 5-chlorothiophene-2-carboxylic acid (Compound 333) ; (AZ37) 3,4-difluoro-M-|4-(2-(2-methylpiperidin-1-1l)ethoxy |-3-(2-methyl-2H-pyrazol-3-yl)phenyl |benzamide (Compound 459 ); (AZ8). M-|3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-(1-methylpiperidin-4-1yloxy)phenyl|-4-fluoro-3-methylbenzamide (Compound 745); (AZ9) 1-(2-fluorophenyl)-3-|3-(2-methyl-2H-pyrazol-3-1l)-4-(2-piperidine-1- ylethoxy)phenyl|urea (Compound 65); (A40) M-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(2-pyrrolidin-1-ylethoxy)phenyl |-3-fluorobenzamide (Compound 455); (A41) cyclopentanecarboxylic acid 3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl amide (Compound 310); (A42) M-I3-(2-methyl-2H-pyrazol-3-1l)-4-(2-pyrrolidin-1-ylethoxy)phenyl |-4-trifluoromethylbenzamide (Compound 343); (A43) M-13-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-I2-(3-fluoropyrrolidin-1-yl)ethoxy |phenyl )-3-fluorobenzamide (Compound 475) ; (A44) 3-chloro-4-fluoro-M-(4-(2-(4-fluoropiperidin-1-1l)ethoxy |-3-(2-methyl-2H-pyrazol-3-yl)phenyl |benzamide ( Compound 538); (A45) /M-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(piperidin-3-yloxy)phenyl |-4-fluorobenzamide (Compound 396); (A46) M-I4-(2-(4-acetylpiperazin-1-yl)ethoxy |-3-(2-methyl-2H-pyrazol-3-1l)phenyl |-3-fluorobenzamide (Compound 660); (A47) M-I4-(2-(4,4-difluoropiperidine-1-1l)ethoxy |-3-(2-methyl-2H-pyrazol-3-yl)phenyl |-3-fluorobenzamide (Compound 778); (A48) 3-fluoro-M-|3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide (Compound 729); (A49) 3-methoxy-N-|3-(2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide (Compound 733); (OR) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(2-pyrrolidin-1-ylethoxy)phenyl |-3-(2,4-difluorophenyl)urea ( Compound 5); (A5I) 1-I3-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(-2-pyridin-4-ylethoxy)phenyl |-3-(4-chlorophenyl)urea (Compound 145); (A52) 1-02,4-difluorophenyl)-3-(4-(2-imidazol-1-ylethoxy)-3-(2-methyl-2H-pyrazole-3- yl)phenyl|urea (Compound 219); (A53) isopropyl ether (4-(2-azepan-1-ylethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenyl]carbamic acid (Compound 352); (A54) M -I3-(2-methyl-2H-pyrazol-3-1l)-4-(2-11,4 |oxazepan-4-ylethoxy)phenyl |-3-trifluoromethylbenzamide (Compound 568); (A55). M-I3 -(4-bromo-2-methyl-2H-pyrazol-3-1l)-4-(2-(1,4|oxazepan-4-ylethoxy)phenyl|-3-fluoro-4-trifluoromethylbenzamide (Compound 606); (A5b) isopropyl ether |3-(2-methyl-2H-pyrazol-3-1l)-4-(2-thiomorpholin-4-ylethoxy)phenyl |carbamic acid (Compound 214); (A57) isopropyl ether |3- (2-methyl-2H-pyrazol-3-1l)-4-(2-|11,4|oxazepan-4-ylethoxy)phenyl|carbamic acid (Compound 215); (A58) M-I3-(4-chloro -2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl |-3-trifluoromethylbenzamide (Compound 527); (A59) 2,4-difluoro-M-|3- (2-methyl-2H-pyrazol-3-1l)-4-(2-morpholin-4-ylethoxy)phenyl|benzamide (Compound 281); (Or) 1-I3-(4-chloro-2-methyl-2H -pyrazol-3-1l)-4-(-2-morpholine-4-ylethoxy)phenyl |-3-(2,4- difluorophenyl)urea (Compound 16) 1 (Abvb1) /M-13-(4-bromo - 2nd tyl-2H-pyrazol-3-1l)-4-(|(2-(3-methoxyazetidin-1-1l)ethoxy |phenyl)-2-(4-chlorophenyl)acetamide (Compound 269), 26. The compound according to item I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: what, SI c) c) re; Mr. Yi in Vg o 27. The compound according to item I, selected from the following compound 1, its pharmaceutically acceptable salts, hydrates and solvates: (A2) M-(3-(4-chloro-1-methyl-IN-pyrazol-5-yl)-4- (2-morpholinoethoxy)phenyl)cyclopropanecarboxamide (Compound 271). 28. The compound according to item I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: what, o c) in 1/ H Y xx CE; 29. The compound according to item I, selected from the following compound 1, its pharmaceutically acceptable salts, hydrates and solvates: C Su oo Sh 30. The compound according to item I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: shk y to (c) M "8y- 31. The compound according to point I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: СО Е (c) c) о с МОМ М пон | m R Y in . 32. The compound according to item I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: V Ge! about So and / N | m 7 SI o 33. The compound according to item I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: scha c) schu. / M. H. E. E 34. The compound according to item I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: (Or) 1-I3-(4-chloro-2-methyl-2H-pyrazol-3-1l)-4-( -2-morpholin-4-ylethoxy)phenyl |-3-(2,4-difluorophenyl)urea (Compound 16). 35. The compound according to item I, selected from the following compound and its pharmaceutically acceptable salts, hydrates and solvates: (Ab1) /M-13-(4-bromo-2-methyl-2H-pyrazol-3-1l)-4- (2-(3-methoxyazetidine-1-1l)ethoxy |phenyl)-2-(4-chlorophenyl)acetamide (Compound 269), 36. A pharmaceutical composition containing a compound according to any one of claims 1-35 and a pharmaceutically acceptable carrier. 37. A method of preparing a composition in which the compound according to any of claims 1-351 is mixed with a pharmaceutically acceptable carrier. 38. A method of treating 5-HT3-mediated disorders in a subject, wherein a therapeutically effective amount of a compound according to any of claims 1-35 or a pharmaceutical composition according to claim 36 is administered to said subject in need thereof. 39. The method of claim 38, wherein said 5-NOx-mediated disorder is selected from coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, and atrial fibrillation. 40. A method of treating a condition associated with platelet aggregation in a subject, wherein a therapeutically effective amount of a compound according to any one of claims 1-35 or a pharmaceutical composition according to claim 36 is administered to said subject in need thereof. 41. A method of reducing the risk of blood clot formation during angioplasty or coronary bypass surgery in a subject, in which a therapeutically effective amount of the compound according to any 3 claims 1-35 or the pharmaceutical composition according to claim 36 is administered to the indicated subject in need thereof. 42. A method of reducing the risk of blood clot formation in a subject suffering from atrial fibrillation, wherein a therapeutically effective amount of a compound according to any one of claims 1-35 or a pharmaceutical composition according to claim is administered to said subject in need thereof 36. 43. A method of treating a sleep disorder in a subject, wherein a therapeutically effective amount of a compound according to any one of claims 1-35 or a pharmaceutical composition according to claim 36 is administered to said subject in need thereof. 44. The method according to claim 43, where the specified sleep disorder is dyssomnia. 45. The method according to claim 43, where the specified sleep disorder is a parasomnia. 46. A method of treating diabetes-related disorders in a subject, wherein a therapeutically effective amount of a compound according to any one of claims 1-35 or a pharmaceutical composition according to claim 36 is administered to said subject in need thereof. 47. A method of treating progressive multifocal leukoencephalopathy in a subject, wherein a therapeutically effective amount of a compound according to any one of claims 1-35 or a pharmaceutical composition according to claim 36 is administered to said subject in need thereof. 48. A method of treating hypertension in a subject, wherein a therapeutically effective amount of a compound according to any one of claims 1-35 or a pharmaceutical composition according to claim 36 is administered to a subject in need thereof. 49. A method of treating pain in a subject, wherein a therapeutically effective amount of a compound according to any one of claims 1-35 or a pharmaceutical composition according to claim 36 is administered to a subject in need thereof. 50. A compound according to any one of claims 1-35 for use in a method of treating a human or an animal by means of therapy. 51. A compound according to any one of claims 1-35 for use in a method of treating 5-HT3A-mediated disorders in humans or animals by means of therapy. 52. A compound according to any one of claims 1-35 for use in a method of treating 5-HT2a-mediated disorders selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke and atrial fibrillation. 53. A compound according to any one of claims 1-35 for use in a method of treating a condition associated with platelet aggregation. 54. A compound according to any one of claims 1-35 for use in a method of reducing the risk of blood clot formation during angioplasty or coronary bypass surgery in a subject. 55. A compound according to any one of claims 1-35 for use in a method of reducing the risk of blood clot formation in a subject. 56. A compound according to any one of claims 1-35 for use in a method of reducing the risk of blood clot formation in a subject suffering from atrial fibrillation. 57. A compound according to any one of claims 1-35 for use in a method of treating a sleep disorder in a human or animal by means of therapy. 58. A compound according to any one of claims 1-35 for use in a method of treating dyssomnia. 59. A compound according to any one of claims 1-35 for use in a method of treating parasomnias. 60. A compound according to any one of claims 1-35 for use in a method of treating a diabetes-related disorder in a human or animal by therapy. 61. A compound according to any one of claims 1-35 for use in a method of treating progressive multifocal leukoencephalopathy in a human or animal by therapy. 62. A compound according to any one of claims 1-35 for use in a method of treating hypertension. 63. A compound according to any one of claims 1-35 for use in a method of treating pain. 64. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for use in the treatment of 5-HTd-mediated disorders. 65. Use of a compound according to any one of claims 1-35 for the preparation of a medicament for use in the treatment of 5-HTzd-mediated disorders selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, atrial fibrillation atrial arrhythmia. 66. Use of a compound according to any one of claims 1-35 for the preparation of a medicament for use in the treatment of a condition associated with platelet aggregation. 67. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for reducing the risk of blood clot formation during angioplasty or coronary bypass surgery in a subject. 68. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for reducing the risk of blood clot formation in a subject. 69. Use of a compound according to any one of claims 1-35 for the preparation of a medicament for reducing the risk of blood clot formation in a subject suffering from atrial fibrillation. 70. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for use in the treatment of a sleep disorder. 71. Use of a compound according to any one of claims 1-35 for obtaining a medicinal product for use in the treatment of dyssomnia. 72. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for use in the treatment of parasomnia. 73. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for use in the treatment of diabetes-related disorders. 74. Use of a compound according to any one of claims 1-35 for obtaining a medicinal product for use in the treatment of progressive multifocal leukoencephalopathy. 75. Use of a compound according to any one of claims 1-35 for obtaining a medicinal product for use in the treatment of hypertension. 76. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for use in the treatment of pain. 77. A compound according to any one of claims 1-35 for use in a method of treating migraine. 78. A compound according to any one of claims 1-35 for use in a method of treating intermittent claudication or peripheral artery disease. 79. Use of a compound according to any of claims 1-35 for the preparation of a medicinal product for use in the treatment of migraine. 80. Use of a compound according to any one of claims 1-35 for the preparation of a medicinal product for use in the treatment of intermittent claudication or peripheral artery disease.