TW201326134A - Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands - Google Patents

Abstract

The invention relates to substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

Description

a substituted vanazolylamine-containing ligand and a urea derivative containing a phenyl group substituted with a nitrogen-containing group as a ligand for the vanilloid receptor

The present invention relates to a ligand containing a substituted vanazolylamine and a urea derivative containing a phenyl group substituted with a nitrogen-containing group as a vanilloid receptor, and contains such a compound. Pharmaceutical dosage forms, and the use of such compounds to treat and/or prevent pain and other diseases and/or disorders.

Pain management, especially neuropathic pain, is extremely important in the medical community. There is a need in the world for effective treatment of pain. The urgent need for patient-centered and goal-oriented treatment for patients with chronic and non-chronic pain is considered to be a successful and effective way to treat pain in patients. It is also documented in many scientific studies and has recently appeared in pain relief. Basic research areas for drug application or pain.

The vanilloid receptor subtype 1 (VR1/TRPV1), also commonly known as the capsaicin receptor, is a suitable starting point for the treatment of pain, especially from acute pain, chronic pain, neuropathic pain and visceral pain. A group of types. In particular, the receptor is stimulated by vanilloids such as capsaicin, and by heat and protons, and plays a central role in the formation of pain. In addition, the receptor is extremely important for many other physiological and pathological processes, and is suitable for the treatment of many other diseases, such as migraine, depression, neurodegenerative diseases, cognitive disorders, anxiety, epilepsy Cough, diarrhea, itching, inflammation, cardiovascular disease, eating disorders, drug dependence, drug abuse, and urinary incontinence.

Compounds having an affinity for vanilloid receptor subtype 1 (VR1/TRPV1) are known, for example, from WO 2010/127855-A2 and WO 2010/127856-A2.

In addition to the compounds themselves (potency and efficacy) which require affinity for the vanilloid receptor 1 (VR1/TRPV1 receptor), other compounds having comparable or better properties are also required.

Therefore, it is advantageous to improve the metabolic stability of the compound and the solubility or permeability of the aqueous medium. These factors are beneficial for oral bioavailability, or may improve the condition of pharmacokinetic/pharmacodynamic (PK/PD); for example, it may lead to a more favorable potency period.

The phenomenon of weak or no interaction with transport molecules involved in the absorption and metabolism of pharmaceutical dosage forms can also be seen as an indication of improved bioavailability and minimal interaction with pharmaceutical dosage forms. In addition, the interaction between the enzymes involved in the decomposition and metabolism of the pharmaceutical dosage form should be minimized, so that the test results show that the lowest or no interaction between the pharmaceutical dosage form and the pharmaceutical dosage form is expected.

Accordingly, it is an object of the present invention to provide novel compounds which are preferred over those of the prior art. In particular, the compound is suitable as a pharmacologically active ingredient of a pharmaceutical dosage form for the treatment and/or prevention of a pharmaceutical dosage form which is at least partially mediated by the vanilloid receptor 1 (VR1/TRPV1 receptor) disorder or disease.

This goal has been achieved by the subject matter described herein.

It has been unexpectedly found that the substituted compound of the formula (R) shown below has a strong affinity for the vanilloid receptor subtype 1 (VR1/TRPV1) and is therefore particularly suitable for the prevention and/or treatment of at least a part. A disorder or disease mediated by vanilloid receptor 1 (VR1/TRPV1).

Particularly suitable are the substituted compounds of the general formula (R) which, in addition to their activity on the VR1-receptor, have one or more other advantageous properties, for example, appropriate potency, appropriate potency, and no increase in body temperature. And/or thermal pain threshold; suitable solubility in biologically relevant media, such as aqueous media, especially aqueous media with physiologically acceptable pH, such as phosphate buffered buffer systems; appropriate metabolic stability And diversity (for example, sufficient oxidative capacity for liver enzymes such as cytochrome P450 (CYP) enzymes, and sufficient for metabolic elimination by these enzymes Meta-), and similar activities.

Accordingly, the present invention relates to a substituted compound of the formula (R), R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ CH ₂ —OH, CH ₂ - OCH ₃ , CH ₂ CH ₂ -OCH ₃ , OCFH ₂ , OCF ₂ H, OCF ₃ , OH, NH ₂ , mono C _1-4 alkyl, mono OC _1-4 alkyl, mono NH-C _1-4 alkane a group consisting of a group of N(C _1-4 alkyl) ₂ wherein the C _1-4 alkyl group is unsubstituted in each case, and R ² represents CF ₃ and an unsubstituted C _1-4 An alkyl group or an unsubstituted C _3-6 cycloalkyl group, R ⁷ and R ⁹ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, OH, OCF _3, a C _1-4 alkyl group and a group consisting of OC _1-4 alkyl, wherein C _1-4 alkyl in each of the embodiments based unsubstituted, a representative of N, CH or C (CH ₃₎ , q represents 0, 1 or 2, and R ¹¹² represents H or a C _1-4 alkyl group which is unsubstituted or is selected from 1, 2 or 3 independently from F, Cl, Br, OH, a group monosubstituted, disubstituted or trisubstituted with a substituent such as O and OCH ₃ , and R ¹¹³ represents H, S(=O) ₂ -NH ₂ , a C _1-4 alkyl or an S(=O) _2- C _1-4 alkyl, wherein the C _1-4 alkyl group is unsubstituted in each case Or mono-, di- or tri-substituted with 1, 2 or 3 groups independently selected from the group consisting of substituents such as F, Cl, Br, OH, =0 and OCH ₃ , or - premise q ≠ 0-R ¹¹² and R ¹¹³ together with the nitrogen atom to which they are bonded form a 3- to 6-membered heterocyclic group which is unsubstituted or is independently selected from F, Cl, Br by 1, 2 or 3 , CN, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , tertiary butyl, cyclopropyl, OH, =O, OCH ₃ , OCF ₃ , NH ₂ , NH(CH ₃ ) and a group monosubstituted, disubstituted or trisubstituted, consisting of a substituent such as N(CH ₃ ) ₂ , optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or a physiology An acceptable salt form, and/or a physiologically acceptable solvate thereof.

For the purposes of the present invention, the term "single stereoisomer" is preferred to mean a single enantiomer or diastereomer. For the purposes of the present invention, the term "mixture of stereoisomers" refers to an enantiomer and/or mixture of diastereomers of the racemate with any mixing ratio.

For the purposes of the present invention, the term "physiologically acceptable salt" is preferably included to include a salt having at least one compound according to the invention and at least one physiologically acceptable acid or base.

In the meaning of the present invention, at least one compound according to the invention and at least one physiologically acceptable salt such as a physiologically acceptable acid, to mean a physiologically acceptable salt, to contain at least one inorganic or organic At least one salt of a compound according to the invention is preferred - especially when used in humans and/or mammals. Examples of physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, crotonic acid. , maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid (monomethylsebacic acid), 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl Benzoic acid, α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid, aspartic acid. Citric acid and hydrochloric acid are preferred. Therefore, hydrochloride and citrate are particularly excellent salts.

In the meaning of the present invention, at least one physiologically acceptable salt of the compound according to the invention and at least one physiologically acceptable base, preferably means at least one physiologically acceptable salt of the compound according to the invention, An anion containing at least one inorganic cation, preferably when used in humans and/or mammals. Particularly preferred are alkali metal and alkaline earth metal salts, but may also be ammonium salts [NH _x R _4-x ] ⁺ , where x = 0, 1, 2, 3 or 4, and R represents a chain or a non-support Chain C _1-4 alkyl residue, especially a salt such as (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium.

In the sense of the present invention, "alkyl (alkyl)" and "C _1-4 alkyl (C _1-4 alkyl)," the words, to include the acyclic saturated aliphatic hydrocarbon residue preferred, which may be based, respectively, Branched or unbranched, and may be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted, disubstituted or trisubstituted, and containing from 1 to 4 carbon atoms, ie 1, 2, 3 or 4 carbons An atom, a C _1-4 aliphatic residue, ie a C _1-4 alkyl group. Preferred C _1-4 alkyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, secondary butyl and tertiary butyl.

In the sense of the present invention, associated with the "alkyl (alkyl)" and "C _1-4 alkyl (C _1-4 alkyl)" the words "mono- (monosubstituted)" or "poly-substituted by (polysubstituted)" For example, a di- or tri-substituted group, with respect to its corresponding residue or group, means that one or more hydrogen atoms are independently or independently substituted with at least one substituent, for example, di- or tri-substituted. And the polysubstituted substituents and groups, such as disubstituted or trisubstituted residues and groups, the term "polysubstituted", such as disubstituted or trisubstituted, including the residue and The group is polysubstituted on the same or different atoms, for example in the case of the same carbon atom being trisubstituted, as in the case of CF ₃ or CH ₂ CF ₃ , or at different points, such as CH(OH)-CH ₂ CH ₂ -CHCl ₂ case. Multiple substitutions can be made with the same or different substituents.

For the purposes of the present invention, "cycloalkyl (cycloalkyl)" and "C _3-6 cycloalkyl (C _3-6 cycloalkyl)," and the like terms, refers to aliphatic ring containing 5 or 6 carbon atoms The cycloaliphatic hydrocarbon group is preferably a C _3-6 cycloaliphatic residue wherein the hydrocarbon group is saturated and may be unsubstituted or monosubstituted or polysubstituted, for example, mono-, di- or tri-substituted. The cycloalkyl group can be bonded to the corresponding superordinate general structure via any desired or possible ring member on the cycloalkyl residue. Preferably, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; more preferably, it is selected from the group consisting of cyclopropyl and cyclobutyl. A particularly preferred cycloalkyl group is a cyclopropyl group.

In the meaning of the present invention, the terms "heterocyclyl" and "3 to 6 membered heterocyclyl" are used to include 3 to 6 ring members, namely 3, 4, 5 Or a saturated aliphatic heterocycloalkyl group of 6 ring members, that is, a 3- to 6-membered heterocyclic group having at least one carbon atom, if appropriate, two or three carbon atoms, independently of each other a group substitution consisting of a hetero atom or a hetero atom group selected from O, S, S(=O), S(=O) ₂ , N, NH and N(C _1-8 alkyl), etc., wherein The ring member can be unsubstituted or mono- or poly-substituted, such as mono-, di- or tri-substituted. Therefore, a heterocyclic group is a heterocyclic aliphatic residue. The heterocyclic group according to the present invention is formed by a radical of R ¹¹² and R ¹¹³ and a nitrogen atom to which it is bonded, that is, it contains at least one nitrogen as a ring member. The heterocyclic residue is selected from the group consisting of azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dihydropyridinyl, imidazole. Iridazolidinyl, isoxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidine a group consisting of piperidinyl, pyrazolidinyl, tetrahydropyrrolyl, tetrahydropyridinyl, thiazolidinyl, and thiomorpholinyl good.

In the sense of the present invention, and "cycloalkyl (cycloalkyl)", "C _3-6 cycloalkyl (C _3-6 cycloalkyl)", "heterocyclic (heterocyclyl) group" and "3-6 member heterocyclyl (3 to 6 membered heterocyclyl)" or the like, "monosubstituted" or "polysubstituted", such as disubstituted or trisubstituted, with respect to its corresponding residue or group, One or more hydrogen atoms are independently or independently substituted with at least one substituent, such as disubstituted or trisubstituted. And the polysubstituted substituents and groups, such as disubstituted or trisubstituted residues and groups, the term "polysubstituted", such as disubstituted or trisubstituted, including the residue and The group is polysubstituted on the same or different atoms, for example, in the case where the same carbon atom is disubstituted, such as 1,1-difluorocyclohexyl, or substituted at a different point, such as 1-chloro-3-fluorocyclo The situation of hexyl. Multiple substitutions can be made with the same or different substituents.

Within the scope of the present invention, This symbol for the chemical formula represents a residue linked to its corresponding superior overall structure.

In a preferred embodiment of the compound according to the invention, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and A group consisting of N(CH ₃ ) ₂ .

Preferably, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , a group consisting of OH, CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ .

More preferably, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O- A group consisting of CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) ₂ .

Still more preferably, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from the group consisting of H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ A group consisting of CH ₃ .

Even more preferably, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from the group consisting of H, F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ .

Particularly preferably, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ .

Still more particularly, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from the group consisting of H, F, Cl and O-CH ₃ .

In a preferred embodiment of the compound according to the invention, at least one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ is ≠H.

According to a further preferred compound of the present invention embodiments, one of R ^101, R ¹⁰² and R ^103, or wherein two to R ¹⁰² and / or the preferred R ^103, represents H.

In still another preferred embodiment of the compound according to the invention, one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ represents H, and R ¹⁰³ represents H is preferred.

In another preferred embodiment of the compound according to the invention, R ¹⁰¹ and R ¹⁰² are independently selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH , CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N ( CH ₃ ) ₂ groups of groups, and R ¹⁰³ represents H.

Preferably, R ¹⁰¹ and R ¹⁰² are independently selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH _{, CH 3, O-CH 3} , O-CH 2 CH 3, NH 2, NH (CH 3) and the group consisting of N (CH _{3) 2;} mutually independently selected from H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) _{2 are} better grouped; More preferably, the group consisting of H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH ₃ is more preferably selected from each other independently More preferably, the group consisting of H, F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH _{3 is} further selected from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ independently of each other; Particularly preferred; groups selected from the group consisting of H, F, Cl and O-CH ₃ are particularly preferred; and R ¹⁰³ represents H.

In still another preferred embodiment of the compound according to the invention, R ¹⁰¹ is independently selected from the group consisting of F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ Groups, and R ¹⁰² and R ¹⁰³ represent H.

Preferably, R ¹⁰¹ is selected from the group consisting of F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , O-CH ₃ a group consisting of O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; selected from the group consisting of F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ - More preferably, OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) ₂ are grouped; selected from F, Cl, CFH ₂ , CF ₂ H, CF ₃ More preferably, the group consisting of OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 is selected} from the group consisting of F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ and still more preferably; selected from the group consisting of at F, Cl, CF ₃ and the group consisting of O-CH ₃ particularly preferred; selected from the group consisting of at F, Cl and O-CH ₃ group consisting of particularly preferred; and R ¹⁰² and R ¹⁰³ are Represents H.

In still another preferred embodiment of the compound according to the invention, R ¹⁰² is selected from the group consisting of F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF _a group consisting of ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ , and R ¹⁰¹ and R ^{103 both} represent H.

Preferably, R ¹⁰² is selected from the group consisting of F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , O-CH ₃ a group consisting of O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; selected from the group consisting of F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ - More preferably, OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) ₂ are grouped; selected from F, Cl, CFH ₂ , CF ₂ H, CF ₃ More preferably, the group consisting of OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 is selected} from the group consisting of F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ More preferably; preferably selected from the group consisting of F, Cl, CF ₃ and O-CH ₃ ; particularly preferred from the group consisting of F, Cl and O-CH ₃ ; and R ¹⁰¹ and R ¹⁰³ Represents H.

In still another preferred embodiment of the compound according to the invention, R ¹⁰¹ is selected from the group consisting of F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF _a group consisting of ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ R ¹⁰² is selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ are grouped, and R ¹⁰³ represents H.

Preferably, R ¹⁰¹ is selected from the group consisting of F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , O-CH ₃ a group consisting of O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; selected from the group consisting of F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ - More preferably, OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) ₂ are grouped; selected from F, Cl, CFH ₂ , CF ₂ H, CF ₃ More preferably, the group consisting of OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 is selected} from the group consisting of F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ More preferably; it is particularly preferred to be selected from the group consisting of F, Cl, CF ₃ and O-CH ₃ , and is particularly preferred from the group consisting of F, Cl and O-CH ₃ ; R ¹⁰² is selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , a group consisting of NH(CH ₃ ) and N(CH ₃ ) ₂ ; selected from the group consisting of H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N (CH ₃ ) ₂ composition group is better; selected from H, F, Cl, C More preferably, the group consisting of FH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 is selected} from the group consisting of H, F, Cl, CF ₃ , OCF ₃ , More preferably, the group consisting of CH ₃ and O-CH ₃ ; preferably selected from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ ; selected from the group consisting of H, F, Cl and O-CH ₃ groups are particularly preferred; and R ¹⁰³ stands for H.

In still another preferred embodiment of the compound according to the invention, R ¹⁰¹ is selected from the group consisting of F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , a group consisting of OH, CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; selected from F, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) _{2 are more} preferably grouped; selected from F, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 are} more preferably grouped; consisting of selected from F, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ More preferably; the group is particularly preferred; the group selected from the group consisting of F, CF ₃ and O-CH _{3 is} particularly preferred; the group selected from the group consisting of F and O-CH _{3 is} particularly preferred; and R ¹⁰² and R ^{103 are both} representative. H.

In still another preferred embodiment of the compound according to the invention, R ¹⁰¹ is selected from the group consisting of F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , a group consisting of OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ , R ¹⁰² is selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH ( _{CH 3) 2, O-CH} 3, O-CH 2 CH 3, NH 2, NH (CH 3) and N (CH group consisting of _{3) 2,} and R ¹⁰³ represents H.

Preferably, R ¹⁰¹ is selected from the group consisting of F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , O-CH ₃ , O a group consisting of -CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; selected from F, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) _{2 are more} preferably grouped; selected from F, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ More preferably, the group consisting of O-CH ₃ and O-CH ₂ CH ₃ is more preferably; it is more preferably selected from the group consisting of F, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ ; The group consisting of CF ₃ and O-CH _{3 is} particularly preferred; it is particularly preferred to be selected from the group consisting of F and O-CH ₃ ; R ¹⁰² is selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H , CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ a group of ₂ ; selected from the group consisting of H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH _{3 is} better with the group of N(CH ₃ ) ₂ ; selected from H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 are} more preferably grouped; group selected from the group consisting of H, F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ More preferably; it is particularly preferred from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ ; it is particularly preferred in the group selected from the group consisting of H, F, Cl and O-CH ₃ .

In another particularly preferred embodiment according to the present invention, a partial structure (RS2) Is selected from the group consisting of the following groups: In particular, when q represents 0, 1, or 2, and A represents N.

Particularly good, part of the structure (RS2) Is selected from the group consisting of the following groups: In particular, when q represents 0, 1 or 2 and A represents N.

Optimally, part of the structure (RS2) Is selected from the group consisting of the following groups: In particular, when q represents 0, 1 or 2 and A represents N, it is preferred to select a group consisting of the following groups: In particular, when q represents 0, 1 or 2 and A represents N.

According to another particularly preferred embodiment of the present invention, a partial structure (RS2) Is selected from the group consisting of the following groups: In particular, when q represents 1 or 2 and A represents CH or C(CH ₃ ).

Even better, part of the structure (RS2) Is selected from the group consisting of the following groups: Especially when q represents 1 or 2 and A represents CH or C(CH ₃ ).

Optimally, part of the structure (RS2) Is selected from the group consisting of the following groups: Particularly when q represents 1 or 2 and A represents CH or C(CH ₃ ), it is preferably selected from the group consisting of the following groups: Especially when q represents 1 or 2 and A represents CH or C(CH ₃ ).

In another preferred embodiment of the compound according to the invention, R ² represents CF ₃ , methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, secondary butyl, tri Butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Preferably, R ² represents CF ₃ , 2-propyl, n-butyl, isobutyl, secondary butyl, tert-butyl, cyclopropyl or cyclobutyl.

More preferably, R ² represents CF ₃ , a tertiary butyl group or a cyclopropyl group.

In a particularly preferred embodiment of one of the compounds according to the invention, R ² represents CF ₃ .

In another particularly preferred embodiment of the compound according to the invention, R ² represents a tertiary butyl group.

In another particularly preferred embodiment of the compound according to the invention, R ² represents a cyclopropyl group.

In a more preferred embodiment of one of the compounds according to the invention, R ⁷ and R ⁹ are independently selected from H, F, Cl, Br, CF ₃ , CN, OH, OCF ₃ , CH ₃ , CH ₂ CH _3. A group consisting of CH(CH ₃ ) ₂ , O-CH ₃ and O-CH ₂ CH ₃ .

Preferably, R ⁷ and R ⁹ are independently selected from the group consisting of H, F, Cl, CF ₃ , CN, OH, OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH ₃ .

More preferably, R ⁷ and R ⁹ are independently selected from the group consisting of H, F, Cl, CF ₃ , O-CH ₃ and O-CH ₂ CH ₃ .

Still more preferably, R ⁷ and R ⁹ are independently selected from the group consisting of H, F, Cl and O-CH ₃ , and are further preferably selected from the group consisting of H, F and Cl independently of each other.

In still another more specific embodiment of the compound according to the invention, at least one of R ⁷ and R ⁹ is ≠H.

In yet another particularly preferred embodiment of the compound according to the invention, R ⁹ represents H.

In still another preferred embodiment of the compound according to the invention, R ⁷ is selected from the group consisting of F, Cl, Br, CF ₃ , CN, OH, OCF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) _a group consisting of O-CH ₃ and O-CH ₂ CH _{3 ;} consisting of selected from the group consisting of F, Cl, CF ₃ , CN, OH, OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH ₃ Preferably, the group is selected from the group consisting of F, Cl, CF ₃ , O-CH ₃ and O-CH ₂ CH ₃ ; and is selected from the group consisting of F, Cl and O-CH ₃ More preferably; it is more preferably selected from the group consisting of F and Cl; and R ⁹ represents H.

In another preferred embodiment of the compound according to the invention, A represents N or C(CH ₃ ).

In a particularly preferred embodiment of one of the compounds according to the invention, A represents N.

In the embodiment, A represents C (CH ₃₎ According to another particularly preferred compound of specific embodiments of the present invention.

In another preferred embodiment of the compound according to the invention, q represents 1 or 2 to represent 1 is preferred.

In still another preferred embodiment of the compound according to the invention, A represents N, and R ¹¹² represents H or a C _1-4 alkyl group which is unsubstituted or is selected in 1, 2 or 3 a group of mono-, di- or tri-substituted groups of substituents such as F, Cl, Br, OH, =0, and OCH ₃ ; preferably represented by H or a C _1-4 alkyl group, which is unsubstituted; And R ¹¹³ represents H, S(=O) ₂ -NH ₂ , a C _1-4 alkyl or an S(=O) ₂ -C _1-4 alkyl group, wherein the C _1-4 alkyl group is in each case The middle system is unsubstituted or monosubstituted, disubstituted or trisubstituted with 1, 2 or 3 groups selected from substituents such as F, Cl, Br, OH, =0 and OCH ₃ ; S(=O) ₂ -NH ₂ , a C _1-4 alkyl group or a S(=O) ₂ -C _1-4 alkyl group is preferred, wherein the C _1-4 alkyl group is not in each case. Substituting; or - presuppose that q≠0-R ¹¹² and R ¹¹³ together with the nitrogen atom to which they are bonded form a 3- to 6-membered heterocyclic group which is unsubstituted or is independent of 1, 2 or 3 Selected from F, Cl, Br, CN, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , tertiary butyl, cyclopropyl, OH, =0, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ) and a group monosubstituted, disubstituted or trisubstituted with a substituent such as N(CH ₃ ) ₂ ; preferably a 3- to 6-membered heterocyclic group formed together with a nitrogen atom, which is unsubstituted; or A represents CH or C(CH ₃ ), and R ¹¹² represents H or a C _1-4 alkyl group which is unsubstituted or one, two or three selected from the group consisting of F, Cl, Br, OH, =0 and OCH ₃ a group consisting of a mono-, di- or tri-substituted group of substituents; preferably represented by H or a C _1-4 alkyl group, which is unsubstituted; and R ¹¹³ represents H, S(=O) ₂ -NH ₂ , a C _1-4 alkyl group, which is unsubstituted or monosubstituted by 1, 2 or 3 groups selected from the group consisting of substituents such as F, Cl, Br, OH, =0 and OCH ₃ Substituted or trisubstituted; preferably H, S(=O) ₂ -NH ₂ or a C _1-4 alkyl group, which is unsubstituted; or - presupposes q≠0-R ¹¹² and R ¹¹³ and The linked nitrogen atoms together form a 3- to 6-membered heterocyclic group which is unsubstituted or which is independently selected from 1, 2 or 3 independently from F, Cl, Br, CN, CF ₃ , CH ₃ , CH Substituent groups such as ₂ CH ₃ , CH(CH ₃ ) ₂ , tert-butyl, cyclopropyl, OH, =O, OCH ₃ , OCF ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ The group formed is mono-, di- or tri-substituted; it is preferred to form a 3- to 6-membered heterocyclic group with a nitrogen atom to which it is bonded, which is unsubstituted.

In another preferred embodiment of the compound according to the invention, q represents 0, 1 or 2, preferably 1 or 2, preferably 1 is preferred, A represents N, and R ¹⁰¹ is selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH _a group consisting of O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; selected from the group consisting of H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, Preferably, the group consisting of CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH ₂ CH ₃ and N(CH ₃ ) ₂ is selected from H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 are more} preferably grouped; selected from H, F, Cl, CF ₃ , OCF ₃ , CH ₃ and O- The group of CH _{3 is} more preferably; it is more preferably selected from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ ; and is selected from the group consisting of H, F, Cl and O-CH ₃ More preferably, the group is further preferably represented by F or Cl; and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH , CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) a group consisting of ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; independently selected from H, F, Cl, CFH _{2 , CF 2 H, CF 3,} CN, CH 2 -OCH 3, OCF 3, CH 3, O-CH 3, O-CH 2 CH 3 and N (CH _{3) 2} is preferably the group consisting of; independently of each other More preferably selected from the group consisting of H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH ₃ ; More preferably, the group consisting of F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH _{3 is further selected} from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ independently of each other. More preferably; selected from the group consisting of H, F, Cl and O-CH ₃ independently of each other; preferably selected from the group consisting of F or Cl independently of each other; or q represents 1 or 2, Representative 1 is preferred, A represents CH or C(CH ₃ ), preferably represents C(CH ₃ ), and R ¹⁰¹ is selected from H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N (CH _{3) 2} group consisting of; selected from the group consisting in H, F, CFH _{2 CF 2 H, CF 3, CN} , CH 2 -OCH 3, OCF 3, CH 3, O-CH 3, O-CH 2 CH 3 and the group consisting of N (CH _{3) 2} preferred; selected from the group consisting in H More preferably, the group consisting of F, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH _{3 is selected} from the group consisting of H, F, CF ₃ , OCF ₃ , and the group consisting of CH ₃ O-CH ₃ and preferably; selected from the group consisting in H, F, CF ₃ and further more preferably the group consisting of O-CH _3; selected from the group consisting in H, F and O-CH ₃ composed of Groups are particularly preferred; representative of F is optimal; and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) _a group of ₂ ; independently selected from H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OCH ₃ , OCF ₃ , CH ₃ , O-CH ₃ , O-CH _{a group of 2} CH ₃ and N(CH ₃ ) _{2 is} preferred; and is independently selected from H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and The group of O-CH ₂ CH _{3 is more} preferably; independently selected from H, F, Cl, CF ₃ a group of OCF ₃ , CH ₃ and O-CH ₃ is more preferably; more preferably selected from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ independently; It is particularly preferred to select a group consisting of H, F, Cl and O-CH ₃ ; it is most preferably selected from the group consisting of F or Cl independently of each other.

In a more specific embodiment of the compound according to the invention, part of the structure (RS1) Representative part structure (PR1) Wherein R ¹¹⁴ represents NH ₂ or an unsubstituted C _1-4 alkyl group; preferably represents NH ₂ , CH ₃ or CH ₂ CH _{3 ,} preferably represents NH ₂ or CH ₃ to represent CH ₃ Good; or represent partial structure (PR2-a) or (PR2-b) Wherein the C _1-4 alkyl group is unsubstituted in the partial structure (PR2-b) or monosubstituted with =0 or OH, which is preferably unsubstituted, and wherein the C _1-4 alkyl group is partially The structure (PR2-b) is preferably selected from the group consisting of a methyl group and an ethyl group, or represents a part of the structure below. Preferably, part of the structure (RS1) Representative part structure (PR1) Wherein R ¹¹⁴ represents NH ₂ or an unsubstituted C _1-4 alkyl group; preferably represents NH ₂ , CH ₃ or CH ₂ CH ₃ to represent NH ₂ or CH _{3 more} preferably to represent CH ₃ good. In a particularly preferred embodiment of the invention, A represents N, and R ¹⁰¹ is selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ groups of groups, and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF _a group consisting of ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ Preferably, wherein R ¹⁰¹ , R ¹⁰² and R ^{103 are} at least one of ≠H, or A represents CH or C(CH ₃ ) to represent C(CH ₃ ), and R ¹⁰¹ is selected from H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O a group consisting of -CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ , and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br , CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , C a group consisting of H ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; preferably, wherein R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are at least one of ≠H, R ² represents CF ₃ , a tertiary butyl or a cyclopropyl group, and R ⁷ and R ⁹ are independently selected from H, F, Cl, Br, a group consisting of CF ₃ , CN, OH, OCF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ and O-CH ₂ CH ₃ , preferably, wherein R ⁷ is At least one of R ⁹ is ≠H, part of the structure (RS1) Representative part structure (PR1) Wherein R ¹¹⁴ represents NH ₂ , CH ₃ or CH ₂ CH ₃ .

In another particularly preferred embodiment according to the present invention, R ¹⁰¹ is selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , a group consisting of OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ And R ¹⁰² and R ¹⁰³ are independently selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , OH, Preferably, the group consisting of CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) _{2 is} preferably Wherein R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are at least one of ≠H, R ² represents CF ₃ , a tertiary butyl or a cyclopropyl group, and R ⁷ and R ⁹ are independently selected from H, F, and Cl. a group of Br, CF ₃ , CN, OH, OCF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ and O-CH ₂ CH ₃ , preferably, wherein At least one of R ⁷ and R ^{9 is} H, A represents N, and R ¹¹² represents H or a C _1-4 alkyl group which is unsubstituted to represent H, CH ₃ or CH ₂ CH _{3 is} preferred. To represent H or CH _{3 is} better, to represent H special, R ¹¹³ represents H, S(=O) ₂ -NH ₂ , a C _1-4 alkyl group or an S(=O) ₂ -C _1-4 alkyl group, wherein the C _1-4 alkyl group is not in each case Substituted to represent S(=O) ₂ -NH ₂ preferably, or an unsubstituted S(=O) ₂ -C _1-4 alkyl group, to represent S(=O) ₂ -NH ₂ , S(( =O) ₂ -CH ₃ or S(=O) ₂ -CH ₂ CH _{3 is more} preferred to represent S(=O) ₂ -NH ₂ or S(=O) ₂ -CH ₃ is more preferably represented by S (=O) ₂ -CH _{3 is} particularly preferred, or A represents CH or C(CH ₃ ), preferably represents C(CH ₃ ), and R ¹¹² represents H or a C _1-4 alkyl group, which is unsubstituted Preferably, H, CH ₃ or CH ₂ CH _{3 is} preferred to represent H or CH ₃ to represent H, and R ¹¹³ represents H, S(=O) ₂ -NH ₂ or a C _1-4 The alkyl group, which is unsubstituted, is preferably represented by S(=O) ₂ -NH ₂ .

Preferred embodiments of the compound of the formula (R) according to the invention contain the formula (R0-a) and/or (R0-b): In particular, specific free radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and their preferred embodiments.

Other preferred embodiments of the compounds of formula (R) according to the invention contain formula (R1-a), (R1-a-1) and/or (R1-a-2): In particular, specific free radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and their preferred embodiments.

Further, preferred embodiments of the compound of the formula (R) according to the invention contain the formula (R1-b), (R1-b-1) and/or (R1-b-2): In particular, specific free radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and their preferred embodiments.

Further, preferred embodiments of the compound of the formula (R) according to the present invention contain the formula (R1-c), (R1-c-1) and/or (R1-c-2): In particular, specific free radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and their preferred embodiments.

A more preferred embodiment of the compound of the formula (R) according to the invention contains the formula (R1-d), (R1-d-1) and/or (R1-d-2): In particular, specific free radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and their preferred embodiments.

A more preferred embodiment of the compound of the formula (R) according to the invention contains the formula (R1-e), (R1-e-1) and/or (R1-e-2): In particular, specific free radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and their preferred embodiments.

Further, a more preferred embodiment of the compound of the formula (R) according to the present invention contains the formula (R1-f), (R1-f-1) and/or (R1-f-2): In particular, specific free radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and their preferred embodiments.

In a particularly preferred embodiment according to the invention, R ^{101 is} freely based on the formulae (R), (R1-a), (R1-a-1), (R1-b), (R1-b-1), Compounds such as (R1-c), (R1-c-1), (R1-d) and/or (R1-d-1) represent F, Cl, CF ₃ or O-CH ₃ to represent F or Cl Preferably, it is preferred to represent Cl - when R ¹⁰³ is and R ¹⁰² represents H, F, Cl, CF ₃ or OCH ₃ , preferably when R ¹⁰³ is H and R ^{102 is} H, F or Cl Preferably, it is preferred that both R ¹⁰² and R ¹⁰³ represent H, and the remaining specific free radicals, variables and indices have the meanings described herein, and are more relevant in relation to the compounds according to the invention and their preferred embodiments. .

In a particularly preferred embodiment according to the invention, R ^{101 is} freely based on the formulae (R), (R1-a), (R1-a-2), (R1-b), (R1-b-2), Among the compounds (R1-c), (R1-c-2), (R1-d) and/or (R1-d-2), F, CF ₃ or O-CH is represented to represent F or OCH _{3 .} , to represent F is optimal - preferably when R ¹⁰³ is H and R ¹⁰² represents H, F, Cl, CF ₃ or OCH ₃ , preferably when R ¹⁰³ is H and R ^{102 is} H, F or Cl More preferably, when R ¹⁰² and R ^{103 both} represent H, and the remaining specific free radicals, variables and indices are further described herein, and the meanings associated with the compounds according to the invention and their preferred embodiments are further preferred.

In a particularly preferred embodiment according to the invention, R ^{101 is} free based on the general formulae (R1-e), (R1-e-1), (R1-e-2), (R1-f), (R1-f -1) and / or (R1-f-2) and other compounds representing F, Cl, CF ₃ or O-CH ₃ to represent F or Cl is preferred to represent Cl is optimal - when R ¹⁰³ is H And R ¹⁰² represents H, F, Cl, CF ₃ or OCH ₃ preferably, when R ¹⁰³ is H and R ¹⁰² represents H, F or Cl, so that when both R ¹⁰² and R ¹⁰³ represent H, More preferably, the remaining specific free radicals, variables and indices are further described herein and are more relevant in relation to the compounds according to the invention and their preferred embodiments.

A particularly preferred compound according to the invention is selected from the group consisting of B1 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl ]-2-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B2 N-[[2-(3-chloro-4-fluoro-phenyl)- 5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamide ; B3 N-[[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4 -(Methanesulfonylamino-methyl)-phenyl]-propanamine; B4 N-[[2-(3-chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl] -methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B5 N-[[2-(3-chlorophenyl)-5- (trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B6 N-[[ 5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-phenyl] -propanamide; B7 2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-propanamine; B8 2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[ 5-(Trifluoromethyl)-2-[3-(trifluoromethyl)phenyl]- 2H-pyrazol-3-yl]-methyl]-propanamine; B9 N-[[5-trit-butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]- Methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B10 N-[[5-tert-butyl-2-(3,4) -difluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamide; B11 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl )-3-methoxy-phenyl]-urea; B12 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl ]-3-[4-(Methanesulfonylamino-methyl)-3-methoxy-phenyl]-urea; B13 N-[[5-tert-butyl-2-(3-chlorophenyl) -2H-pyrazol-3-yl]-methyl]-2-[3-chloro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B14 1-[[2 -(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylamino-methyl)-phenyl]- Urea; B15 2-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2-(3-methoxyphenyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-propanamide; B16 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl ]-Methyl]-2-[4-[[(ethylsulfonyl)amino]-methyl]-3-fluoro-benzene Benzylamine; B17 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4- [[(ethanesulfonyl)amino]-methyl]-3-fluoro-phenyl]-propanamine; B18 N-[[2-(4-chlorophenyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamide; B19 N-[[2- (3,4-difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino) -Methyl)-phenyl]-propanin; B20 N-[[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2 -[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B21 N-[[5-tert-butyl-2-(4-fluorophenyl)-2H -pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B22 2-[3-chloro-4 -(Methanesulfonylamino-methyl)-phenyl]-N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]- Benzylamine; B23 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3- Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-acetamide; B24 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyridyl Zyrid-3-yl]-methyl]-3-[4-(ethylamine-methyl)-3-fluoro-phenyl]-urea; B25 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(ethylamine-methyl)-3- Fluoro-phenyl]-urea; B26 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro -4-(Methanesulfonylamino-methyl)-phenyl]-acetamide; B27 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazole -3-yl]-methyl]-3-[3,5-difluoro-4-(methylsulfonylamino-methyl)-phenyl]-urea; B28 1-[[5-tertiary butyl -2-(3-Chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-phenyl]-urea; B29 N- [[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[(methyl-A) Sulfonium-amino)-methyl]-phenyl]-propanamine; B30 N-[[5-trit-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl] -methyl]-2-[3-fluoro-4-[(methyl-methylsulfonyl-amino)-methyl]-phenyl]-propanamine; B31 1-[[5-tertiary butyl -2-(3-Chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-urea ; B32 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3,5-difluoro-4-( Methanesulfonamide-methyl)-phenyl] -urea ; B33 N-[[4-[[[2-(3-chlorophenyl)-5-) (trifluoromethyl)-2H-pyrazol-3-yl]-methyl-aminomethylindenyl]amino]-2-fluoro-phenyl]-methyl]-acetamide; B34 N-[ [4-[[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl-aminomethylindenyl]amino]-2-fluoro- Phenyl]-methyl]-acetamide; B35 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]- 3-[4-[(Aminosulfonyl)-methyl]-phenyl] -urea ; B36 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazole 3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl] -urea ; B37 2-[3-fluoro-4-(methylsulfonylamino) -methyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-acetamide; B38 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(dimethylaminomethyl) )-3-fluoro-phenyl] -urea ; B39 1-[4-(aminomethyl)-3-fluoro-phenyl]-3-[[2-(3-chlorophenyl)-5-(three Fluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; B40 1-[4-(aminomethyl)-3-fluoro-phenyl]-3-[[5-tridecyl) Benzyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl] -urea ; B41 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl) )-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(amine sulfonamide) )-methyl]-phenyl]-urea; B42 2-[4-(aminomethyl)-3-fluoro-phenyl]-N-[[2-(3-chlorophenyl)-5-(three Fluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B43 N-[[5-trit-butyl-2-[3-(trifluoromethyl)phenyl]- 2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B44 1-[[2-( 3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-phenyl]- Urea; B45 1-[[5-tert-butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino)- Methyl)-phenyl] -urea ; B46 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3 -fluoro-4-[(amine sulfonylamino)-methyl]-phenyl] -urea ; B47 2-[4-(aminomethyl)-3-fluoro-phenyl]-N-[[5- Tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B48 1-[3-fluoro-4-(methylsulfonylamino)- Methyl)-phenyl]-3-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B49 1- [[2-(3,4-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(A sulfonic amino - methyl) - phenyl] - urea; B50 1 - [[5- three-butyl-2- (3- Phenyl) -2H- pyrazol-3-yl] - methyl] -3- [3-fluoro-4- (methanesulfonyl amino acyl - methyl) - phenyl] - urea; B51 1 - [[5 -Tributyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino) -methyl)-phenyl] -urea ; B52 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3 -[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl] -urea ; B53 1-[[5-tert-butyl-2-(4-fluorophenyl)-2H-pyridyl Zyrid-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl] -urea ; B54 1-[[5-tertiary butyl-2 -[3-(Trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl ]-Urea; B55 1-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-3-[[5-(trifluoromethyl)-2-[3-(trifluoro Methyl)phenyl]-2H-pyrazol-3-yl]-methyl]-urea; B56 1-[[5-tert-butyl-2-(3-fluorophenyl)-2H-pyrazole- 3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl]-urea; B57 1-[[2-(3,4-difluoro-phenyl) -5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl] -urea ; B58 1-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-3-[[2 -(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B59 1-[[5-tert-butyl-2- (3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(aminosulfonylamino)-methyl]-phenyl]-urea; B60 1-[[2-(3-Fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(amine Sulfonamide)-methyl]-phenyl] -urea ; B61 1-[[2-(3-chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl] -3-[3-Fluoro-4-[(amine sulfonylamino)-methyl]-phenyl] -urea ; B62 1-[[2-(3,4-difluoro-phenyl)-5- (trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(aminesulfonylamino)-methyl]-phenyl] -urea ; B63 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylamine-methyl) )-phenyl]-propanin; B64 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4 -(dimethylaminomethyl)-3-fluoro-phenyl]-propanamine; B65 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazole -3-yl]-methyl]-2-[4-(dimethylaminomethyl)-3-fluoro-phenyl]-propanamine; B66 2-[4-(ethylamino-methyl) )-3-fluoro-phenyl]-N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazole- 3-yl]-methyl]-propanamine; B67 2-[4-(ethylamino-methyl)-3-fluoro-phenyl]-N-[[5-tert-butyl-2- (3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B68 2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl] -N-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B69 1-[[5-tri-butyl 2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(aminesulfonylamino)-methyl ]-phenyl]-urea; B70 1-[[2-(3-chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -3-[3-Fluoro-4-[(Aminosulfonylamino)-methyl]-phenyl]-urea; B71 1-[3-Fluoro-4-[(Aminosulfonylamino)-methyl ]-phenyl]-3-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B72 1- [[5-tert-butyl-2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonate) Amino-methyl)-phenyl]-urea; B73 1-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-3-[[2-(3-isopropyl) -phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; B74 1-[[5-tri-butyl-2-(3,4-di) Fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminesulfonylamino)- Yl] - phenyl] - urea; B75 1 - [[2- ( 3- chlorophenyl) -5-cyclopropyl -2H- pyrazol-3-yl] - methyl] -3- [4- [ (amine sulfonamide)-methyl]-phenyl] -urea ; B76 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl ]-Methyl]-2-[4-(methylsulfonylamino-methyl)-3-methoxy-phenyl]-propanamine; B77 1-[[2-(3-fluorophenyl) -5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl] -urea ; B78 1 -[[2-(3-chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(amine sulfonate) Amidino)-methyl]-phenyl] -urea ; B79 1-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl ]-Methyl]-3-[4-[(Aminosulfonylamino)-methyl]-phenyl] -urea ; B80 1-[3-Fluoro-4-[(Aminosulfonylamino)-A ]]-phenyl]-3-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B81 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl B) 2-phenyl] -urea ; B82 2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2-(3-isopropyl-phenyl) -5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamide; B 83 1-[[2-(3-Isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonate) Amino-methyl)-phenyl]-urea; B84 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -3-[4-[[(ethylsulfonyl)amino]-methyl]-phenyl] -urea ; B85 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H -pyrazol-3-yl]-methyl]-3-[4-[[(ethylsulfonyl)amino]-methyl]-phenyl] -urea ; B86 1-[4-(methylsulfonamide) -methyl)-3-methoxy-phenyl]-3-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] - urea; B87 1-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-3-[[2-(m-tolyl)-5-(trifluoromethyl)-2H -pyrazol-3-yl]-methyl]-urea; B88 N-[[5-trit-butyl-2-(m-tolyl)-2H-pyrazol-3-yl]-methyl]-2 -[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B89 1-[4-(methylsulfonylamino-methyl)-phenyl]-3- [[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; B90 1-[[5-tert-butyl-2-( M-tolyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-phenyl] -urea ; B91 1-[4-[[( Ethylsulfonyl)amino]-methyl]-phenyl]-3- [[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; B92 1-[[5-tert-butyl-2-( M-tolyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[[(ethylsulfonyl)amino]-methyl]-phenyl] -urea ; B93 N-[[ 5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[(amine sulfonamide)-A ]]-phenyl]-propanin; B94 2-[3-fluoro-4-[(amine sulfonylamino)-methyl]-phenyl]-N-[[2-(3-isopropyl) -phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B95 N-[[2-(3-chlorophenyl)-5-cyclo Propyl-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[(amine sulfonylamino)-methyl]-phenyl]-propanamide; B96 N- [[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[(amine Sulfonamide)-methyl]-phenyl]-propanamine; B97 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl ]-Methyl]-2-[3-fluoro-4-[( Aminosulfonylamino )-methyl]-phenyl] -propanamine ; B98 N-[[5-tert-butyl-2- (3-Chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-3-methoxy-phenyl]-propanoid amine; B99 1 - [[2- ( 3- chlorophenyl) -5- (trifluoromethyl) -2H- pyrazol-3 ] - methyl] -3- [4- (slightly-1-yl - methyl) - phenyl] - urea; B100 1 - [[2- ( 3- chlorophenyl) -5- (trifluoromethyl -2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(piperidin-1-yl-methyl)-phenyl]-urea; B101 1-[[5 - Tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(rhodin-1-yl-methyl) -phenyl] -urea ; B102 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4- [(Aminosulfonylamino)-methyl]-phenyl]-propanamine; B103 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazole-3- Methyl]-methyl]-2-[4-[( aminosulfonylamino )-methyl]-phenyl] -propanamine ; B104 N-[[2-(3-fluorophenyl)-5- (trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B105 1-[[ 2-(3-Fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-3 -methoxy-phenyl] -urea ; B106 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2 -[4-(Methanesulfonylamino-methyl)-3-methyl-phenyl]-propanamide; and B107 N-[[5-tert-butyl-2-(3-chlorophenyl) -2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-3- Yl - phenyl] - propan-acyl amine; optionally in the form of a single stereoisomer or mixture of stereoisomers, in the form of a free compound and / or a physiologically acceptable salt thereof or the form.

In addition, in the fluorescence imaging plate reader (FLIPR) assay performed with CHO K1 cells, the compound according to the present invention having a concentration of 100 nM is preferably capable of causing a 50% displacement of capsaicin, and is used for CHO K1 assay. The cell line is transfected with less than 2,000 nM of human VR1 gene, preferably less than 1,000 nM, more preferably less than 300 nM, more preferably less than 100 nM, more preferably less than 75 nM, less It is better at 50 nM and best at less than 10 nM.

In this method, the calcium ion influx is supplemented by a calcium ion sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, The Netherlands) with a fluorescence imaging plate reader (FLIPR, Molecular Devices). , Sunnyvale, USA) Verification, which is described below.

The substituted compound, the corresponding stereoisomer thereof and the corresponding acid, base, salt and solvate thereof according to the present invention are toxicologically safe, and therefore, are suitable as pharmaceutical activities in pharmaceutical dosage forms. ingredient.

The invention therefore further relates to a pharmaceutical dosage form containing at least one compound according to the invention, which, if appropriate, is one of the pure stereoisomers in each case, in particular enantiomers or diastereomers , in the form of a racemate or a mixture of stereoisomers, particularly in any desired mixing ratio enantiomers and/or diastereomers, or in the form of their respective salts, or Separately in the form of their corresponding solvates, and if appropriate, one or more pharmacologically compatible auxiliaries.

The pharmaceutical dosage form according to the invention is particularly suitable for the regulation of vanilloid receptor 1 (VR1/TRPV1) for the inhibition of vanilloid receptor 1 (VR1/TRPV1) and/or for the stimulation of vanilloid receptor 1 ( VR1/TRPV1) is better, that is, it has stimulating or antagonizing effect.

Likewise, the pharmaceutical dosage form according to the invention is particularly suitable for the prevention and/or treatment of disorders or diseases which are at least partially mediated by the vanilloid receptor 1 .

The pharmaceutical dosage form according to the invention is suitable for administration to adults and children, including preschool children and infants.

The pharmaceutical dosage form according to the invention may be in the form of a liquid, semi-solid or solid pharmaceutical dosage form, for example, an injection, a drop, a juice, a syrup, a spray, a suspension, a lozenge, a patch, a capsule, a plaster, a stopper In the form of a medicament, ointment, emulsion, emulsion, gel, aqueous emulsion, aerosol or complex, for example, in the form of pellets or granules, if appropriate, can be compressed into tablets, injected into capsules or suspended in a liquid, And in this form.

In addition to at least one substituted compound according to the invention, the pharmaceutical dosage form according to the invention conventionally contains other physiologically acceptable pharmacological adjuvants, for example, which may be selected from the group consisting of excipients, fillers, vehicles, diluents a group of surface active substances, dyes, preservatives, blasting agents, slip additives, lubricants, perfumes, and binders, if appropriate, as one of its pure stereoisomers a form, in particular in the form of an enantiomer or diastereomer, a racemate or a mixture of stereoisomers, especially an enantiomer or diastereomer, in any desired form Mixing ratio, or if appropriate, in the form of the corresponding salt or the corresponding solvate.

The choice of physiologically compatible adjuvant and the dosage thereof to be used depend on whether the pharmaceutical dosage form is orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, bucally, orally. Rectal or topical administration, for example, in the treatment of skin, mucous membranes and eye infections. Preparation of tablets, sugar-coated pills, capsules, granules, pills, drops, juices and syrups, etc., suitable for oral application; solutions, suspensions, easy-to-rehydrate dry preparations and sprays for non-oral, topical Sexual and inhalation applications are preferred. Stored in a dissolved form or a plaster form for use in a pharmaceutical dosage form according to the invention The compound to be substituted according to the present invention is a suitable preparation for transdermal application, and if appropriate, an agent for enhancing skin penetration can be added. Orally or transdermally prepared forms may release the corresponding substituted compound according to the invention, which may also be released in a manner that delays release.

The pharmaceutical dosage form according to the present invention is prepared with the aid of conventional methods, apparatus, methods and processes known to those skilled in the art, such as "Remington's Pharmaceutical Sciences", ARGennaro (ed.), The 17th edition, described by Mack Publishing Company, Easton, Pa, 1985, in particular Chapters 86 through 93 of Section 8. The relevant description is described below by reference and disclosure. The dosage of the above-described substituted compound of the above formula I according to the present invention administered to a patient may vary depending on, for example, the weight or age of the patient, the mode of application, the symptoms, and the severity of the disorder. The dose is usually from 0.001 to 100 mg/kg, preferably from 0.05 to 75 mg/kg, and particularly preferably from 0.05 to 50 mg of the compound according to the invention relative to the body weight of the patient (per kilogram).

The pharmaceutical dosage form according to the invention is suitable for the treatment and/or prevention of one or more disorders and/or diseases selected from the following types of pain: acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia , allodynia, burning pain, migraine, depression, nervousness, axonal injury, neurodegenerative disease, selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease Better group, cognitive dysfunction, better cognitive deficits, especially memory disorders, epilepsy, respiratory diseases, selected from the group consisting of asthma, bronchitis and lung inflammation, cough, urinary incontinence, bladder Hyperactivity disorder (OAB), gastrointestinal disorders and/or injuries, duodenal ulcer, gastric ulcer, irritating enteropathy, stroke, eye irritation, skin irritation, neuropathic skin disease, allergic skin disease, dryness, leukoplakia , herpes simplex, inflammation, inflammation of the intestines, eyes, bladder, skin or nasal mucosa, diarrhea, itching, osteoporosis, arthritis, bone Arthritis, rheumatic disease, eating disorders, selected from the group consisting of bulimia to, cachexia, anorexia The combination of disease and obesity is better, drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence Withdrawal symptoms, alcohol dependence, alcohol abuse, alcohol-dependent withdrawal symptoms, use in diuresis, use in inhibiting urinary sodium excretion, influencing the cardiovascular system, for alertness, for treating wounds and/or burns, For the treatment of neurological blockade, for lifting libido, for regulating motor activity, for anxiolytic, for local anesthesia and/or for inhibiting adverse side effects, selected from the use of vanilloid receptor 1 (VR1/TRPV1 receptor) The group of agonist-induced fever, hypertension, and bronchoconstriction is preferably selected from the group consisting of capsaicin, cactus toxin, olvanil, arvanil, SDZ-249665, SDZ-249482, A group consisting of nuvanil and capsavanil is preferred.

The pharmaceutical dosage form of the present invention is particularly useful for treating and/or preventing one or more disorders and/or diseases constituting pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain, Visceral pain and joint pain, migraine, depression, neurodegenerative diseases, selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive dysfunction Better cognitive impairment, especially memory impairment, inflammation, inflammation in the intestine, eyes, bladder, skin or nasal mucosa, urinary incontinence, overactive bladder, drug dependence, drug abuse, drug dependence withdrawal symptoms, Drug tolerance is better with natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse, and alcohol dependence withdrawal symptoms.

The pharmaceutical dosage form according to the invention is suitable for the treatment and/or prevention of disorders and/or diseases consisting of one or more pains, the most suitable type of pain being selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain. .

The invention further relates to a substituted compound according to the invention for use in the regulation of vanilloid receptor 1 (VR1/TRPV1) and, if appropriate, a compound according to formula (I) The substituted compound and one or more pharmacologically acceptable adjuvants are preferred for inhibiting the vanilloid receptor 1-(VR1/TRPV1) and/or the eliciting vanilloid receptor 1-(VR1/TRPV1).

Accordingly, the invention further relates to a substituted compound according to the invention for use in the prevention and/or treatment of a disorder and/or a disease mediated at least in part by a vanilloid receptor 1 and, if appropriate, a substituted according to the invention a compound and one or more pharmacologically acceptable adjuvants.

In particular, the invention therefore relates to a substituted compound according to the invention for use in the prevention and/or treatment of disorders and/or diseases constituting pain, and, if appropriate, a compound and one or more substituted compounds according to the invention Pharmacologically acceptable adjuvants, the more suitable types of pain are selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, Depression, tension, axonal injury, neurodegenerative diseases, selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive dysfunction, cognition Defects are better, especially memory disorders, epilepsy, respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and inflammation of the lungs, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and/or injuries , duodenal ulcer, gastric ulcer, irritating enteropathy, stroke, eye irritation, skin irritation, nervous skin disease, allergic skin disease, Hemorrhoids, leukoplakia, herpes simplex, inflammation, inflammation of the mucous membranes of the intestines, eyes, bladder, skin or nasal cavity, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, Preferably, it is selected from the group consisting of bulimia nervosa, cachexia, anorexia and obesity, drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, and natural or synthetic opioids. Drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse, alcohol withdrawal symptoms, use in diuresis, use in inhibiting urinary sodium excretion, influencing the cardiovascular system, for alertness, use For the treatment of wounds and / or burns, for the treatment of nerve resistance Broken, used to boost libido, used to regulate motor activity, used for anxiolytic, for local anesthesia, and/or to suppress adverse side effects, selected from agonists induced by the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) The group consisting of fever, hypertension, and bronchoconstriction is preferred, and is selected from the group consisting of capsaicin, cactus toxin, ovanov, arva, SDZ-249665, SDZ-249482, Newvni and Casavalni. The group is preferred.

Preferred is a compound substituted according to the invention for preventing and/or treating pain, and, if appropriate, a compound substituted according to the invention and one or more pharmaceutically acceptable adjuvants, which are more suitable for the following pains Groups of types: groups of acute pain, chronic pain, neuropathic pain, and visceral pain.

The invention further relates to the use of at least one compound according to the invention and, if appropriate, at least one compound according to the invention and one or more pharmaceutically acceptable adjuvants for the preparation of a medicament for modulating vanilloid receptor 1 (VR1/TRPV1) Formulations for inhibiting vanilloid receptor 1 (VR1/TRPV1) and/or eliciting vanilloid receptor 1 (VR1/TRPV1), and further for preventing and/or treating at least in part by vanilloid Body 1 mediated disorders and/or diseases, for example, selected from disorders and/or diseases consisting of pain. The more appropriate type of pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, internal organs. Pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, tension, axonal injury, neurodegenerative diseases, selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease and The group consisting of Huntington's disease is better, cognitive dysfunction, better cognitive deficits, especially memory disorders, epilepsy, respiratory diseases, selected from asthma, bronchitis and inflammation of the lungs. Better group, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and / or injury, duodenal ulcer, gastric ulcer, irritating intestinal syndrome, stroke, eye irritation, skin irritation, nervous skin disease, allergies Skin diseases, dryness, leukoplakia, herpes simplex, inflammation, inflammation of the intestines, eyes, bladder, skin or nasal mucosa, diarrhea, itching, osteoporosis, off Hyperbaria, osteoarthritis, rheumatic diseases, abnormal diet, selected from the group consisting of bulimia, cachexia, anorexia and obesity, drug dependence, drug abuse, drug dependence withdrawal symptoms, drugs Tolerance, preferably natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse and alcohol dependence withdrawal symptoms, for diuresis, for inhibition of urinary sodium excretion, For influencing the cardiovascular system, for alertness, for treating wounds and/or burns, for treating nerve blockage, for lifting libido, for regulating motor activity, for anti-anxiety, for local anesthesia and / or inhibiting adverse side effects, preferably selected from the group consisting of fever, hypertension, and bronchoconstriction induced by the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist, selected from capsaicin, cactus toxin, A group consisting of ovanov, arva, SDZ-249665, SDZ-249482, novva and casafani is preferred.

Another aspect of the invention is a method of modulating vanilloid receptor 1 (VR1/TRPV1) for use in inhibiting vanilloid receptor 1 (VR1/TRPV1) and/or eliciting vanilloid receptor 1 (VR1/TRPV1) Preferably, and a method of treating and/or preventing at least a portion of a disorder and/or disease mediated by a vanilloid receptor 1 in a mammal, preferably selected from the group consisting of disorders and/or diseases consisting of pain, The more appropriate type of pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, tension, axonal Injury, neurodegenerative diseases, selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive dysfunction, better cognitive deficits, especially Memory disorders, epilepsy, respiratory diseases, preferably selected from the group consisting of asthma, bronchitis, and inflammation of the lungs, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and/or injuries, duodenal ulcers, gastric ulcers, Irritating bowel After the group, stroke, eye irritation, skin irritation, nervousness skin diseases, allergic skin diseases, psoriasis, vitiligo, herpes simplex, inflammation, Inflammation of the intestine, eyes, bladder, skin or nasal mucosa is better, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, selected from bulimia, cachexia, anorexia The combination of disease and obesity is better, drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, natural or synthetic opioids, drug dependence, drug abuse, drug dependence withdrawal symptoms , alcohol dependence, alcohol abuse and alcohol dependence withdrawal symptoms, for diuresis, for inhibiting urinary sodium excretion, for influencing the cardiovascular system, for alertness, for treating wounds and/or burns, for treating nerves Blocking, for lifting libido, for regulating motor activity, for anxiolytic, for local anesthesia and/or for inhibiting adverse side effects, selected from the group consisting of the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist The group consisting of fever, hypertension and bronchoconstriction is preferred, selected from the group consisting of capsaicin, cactus toxin, ovanov, arva, SDZ-249665, SDZ-249482, Newvni and Kasavage Preferably, the group consisting of nimes comprises at least one compound according to formula (I) administered to a mammal in an effective amount.

Bennett as the efficacy against pain or the Chung model (Bennett or Chung model) (Bennett , GJ and Xie, YK, pain disorders such as human peripheral mononeuropathy in rat initiator of the findings (A peripheral mononeuropathy in rat that produces disorders of pain sensation Like those seen in man), Pain 1988, 33(1), 87-107; Kim, SH and Chung, JM, an experimental model for peripheral neuropathy By segmental spinal nerve ligation in the rat, Pain 1992, 50 (3), 355-363) (eg, according to D'Amour and Smith (Journal of Pharmacology and Experimental Therapeutics (J. Pharm. Exp. Ther.) 72, 74 79 (1941)), or the formalin test (for example, according to D. Dubuisson et al., Pain 1977, 4, 161-174).

The invention further relates to a process for the preparation of a substituted compound according to the invention.

In particular, the compounds according to the invention can be prepared by the preparation of at least one compound according to formula (R-II). R ¹⁰¹ , R ¹⁰² , R ¹⁰³ and R ² have one of the foregoing meanings, which are in a reaction medium, if appropriate, in the presence of at least one suitable couple and reagent, if appropriate, at least one base In the presence of a reaction with a compound of the formula (R-III) wherein D = OH or Hal, Hal thereof represents a halogen to represent Br or Cl, and R ⁷ , R ⁹ , R ¹¹² , R ¹¹³ and q have one of the aforementioned meanings, and A represents CH or C(CH ₃ ) in a reaction medium. Where appropriate, if appropriate, in the presence of at least one suitable coupling reagent, if appropriate, in the presence of at least one base, a compound of formula (R) is formed, A represents CH or C(CH ₃ ), and R ¹⁰¹ , R ¹⁰² , R ¹⁰³ and R ² and R ⁷ , R ⁹ , R ¹¹² , R ¹¹³ and q have one of the foregoing meanings; or at least one formula (R -II) of the compounds, R ¹⁰¹ , R ¹⁰² , R ¹⁰³ and R ² have one of the foregoing meanings, and are reacted to form a compound of the formula (R-IV), R ¹⁰¹ , R ¹⁰² , R ¹⁰³ and R ² have one of the foregoing meanings, in a reaction medium, in the presence of phenyl chloroformate, if appropriate, at least one base and/or at least one coupling reagent And, if appropriate, purifying and/or isolating the alleged compound, and reacting a compound of the formula (R-IV) with a compound of the formula (RV), And R ⁷ , R ⁹ , R ¹¹² , R ¹¹³ and q have one of the foregoing meanings, and A represents N, if appropriate, in the presence of at least one suitable couple and reagent, if appropriate, at least one base a compound of the formula (R) formed in a reaction medium, Its A represents N, and R ¹⁰¹ , R ¹⁰² , R ¹⁰³ and R ² and R ⁷ , R ⁹ , R ¹¹² , R ¹¹³ and q have one of the aforementioned meanings.

The compound of the above formula (R-II) and the carboxylic acid of the above formula (R-III), especially D=OH, are reacted in a reaction medium to produce a compound of the above formula (R), which The reaction medium is preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1,2)-dichloroethane, dimethylformamide, dichloromethane and corresponding mixtures, if appropriate And in the presence of at least one coupling reagent selected from the group consisting of 1-benzotriazolyloxy-tris-(dimethylamino) 1-benzotriazolyl- s-tris-(dimethylamino) -phosphonium hexafluorophosphate) (BOP), dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI), diisopropyl Carboimine, 1,1'-carbonyldiimidazole (CDI), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1 -yl-methene]-N-dimethylammonium hexafluorophosphate N-oxide (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-yl-methylene ]-N-methylmethanaminium hexafluorophosphate N-oxide)(HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (O-(benzotriazol) -1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)(HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea Tetrafluoroboric acid (O-(benzotriaz) Ol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate) (TBTU), N-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazine Preferably, the group consisting of 1-hydroxy-7-azabenzotriazole (HOAt), if appropriate, in the presence of at least one organic base, is selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine, and N. The group consisting of -methylmorpholinyl and diisopropylethylamine is preferred, and is preferably carried out at a temperature between -70 ° C and 100 ° C.

Alternatively, the compound of the above formula (R-II) is reacted with a carboxylic acid halide of D = Hal in the above formula (R-III), and Hal represents a halogen which is a leaving group, preferably a chlorine or bromine atom. And the compound of the above formula (R) is formed in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and the corresponding a group of mixtures is preferred, if appropriate, It is carried out in the presence of an organic or a base-free base, preferably selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine and diisopropylamine, to be between -70 ° C and 100 ° C. The temperature between them is preferred.

The above compounds of the formulae (R-II), (R-III), (R-IV) and (R-V) are each commercially available, and/or can be prepared using conventional methods well known to those skilled in the art. In particular, methods for preparing such compounds have been disclosed, for example, in WO 2010/127855-A2 and WO 2010/127856-A2. The relevant part of the reference is hereby considered as part of the disclosure.

All reactions which can be applied to the synthesis of the compounds according to the invention can be carried out separately by conventional methods well known to those skilled in the art, such as pressure or the order in which the ingredients are added. If appropriate, those skilled in the art can determine the optimal procedure for each condition by conducting a preliminary preliminary test. The intermediate and final products obtained by the reactions described herein are separately purified and/or isolated, if desired and/or necessary, by conventional methods known to those skilled in the art. Suitable purification procedures, such as extraction procedures and chromatography procedures, are column chromatography or preparative chromatography. All treatment steps which can be applied to the synthesis of the reaction sequence of the compounds according to the invention, and the corresponding intermediate or final product purification and/or separation, can be carried out partially or completely in an inert gas atmosphere for comparison in a nitrogen atmosphere. good.

The substituted compound according to the present invention may be isolated in the form of its free base and free radicals, or may be separated from its corresponding salt form, especially a physiologically compatible salt, or may be in the form of a solvate. Separation, such as hydrates.

The free base corresponding to the substituted compound according to the present invention may be converted into the corresponding salt, preferably a physiologically compatible salt, for example, by reacting it with an inorganic or organic acid, with hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, crotonic acid, maleic acid, lactic acid, citric acid, glutamic acid, Glycolic acid, monomethyl sebacic acid, 5-oxoquinone Acid, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, Hippuric acid, phosphoric acid and/or aspartic acid are preferred. Similarly, a salt of a free acid or saccharide additive, for example, saccharin, cyclamate or acesulphame, may be used, the free bases and corresponding stereoisomers of the corresponding inventive substituted compounds. The substance is converted to the corresponding physiologically acceptable salt.

Thus, a substituted compound according to the invention, such as a free acid of a substituted compound according to the invention, can be converted to the corresponding physiologically compatible salt by reaction with a suitable detector. Examples include alkali metal salts, alkaline earth metal salts or ammonium salts [NH _x R _4-x ] ⁺ , where x = 0, 1, 2, 3 or 4, and R represents a chain or an unbranched C _1-4 Alkyl residue.

If appropriate, the substituted compounds according to the invention and the corresponding stereoisomers can be obtained in the form of their solvates by conventional methods known to those skilled in the art, such as the corresponding acids, corresponding bases or salts. The form of the hydrate is preferred.

After preparation, if the compound to be substituted according to the invention is obtained in the form of a mixture of stereoisomers thereof, in the form of its racemate or its various enantiomers and/or mixtures of diastereomers Preferably, they can be separated and, if appropriate, separated by conventional methods known to those skilled in the art. Examples include chromatographic separation methods, especially liquid chromatography based on normal pressure or higher pressure, preferably by medium pressure chromatography (MPLC) and high performance liquid chromatography (HPLC). Separation crystallization is employed. The method can separate individual enantiomers, for example, high performance liquid chromatography for palmate stationary phase, or diastereomeric salts formed by crystallization of palmitic acid, such as +) - tartaric acid, (-)-tartaric acid or (+)-10-camphorsulfonic acid.

The chemicals and reaction components used in the reactions and methods described below are either commercially available or can be prepared by conventional methods known to those skilled in the art.

General Reaction Scheme 1 (Scheme 1):

In step j01 , the acid halide J-0 can be obtained by a method well known to those skilled in the art, and Hal is preferably represented by Cl or Br, and esterified with methanol to form compound JI .

In step j02 , methyl trimethylacetate JI can be converted to oxoalkylnitrile J-II by methods known to those skilled in the art, for example using acetonitrile (CH ₃ -CN), if appropriate, It is carried out under the condition that one base is present.

In step j03 , compound J-II can be converted to the pyrazolyl derivative J-III substituted with an amine group by a method known to those skilled in the art, for example, using a cyclized hydrazine hydrate.

In step j04 , the amine compound J-III can be first converted to a diazonium salt by a method known to those skilled in the art, for example, using nitrous acid, and nitrogen can be eliminated by using a cyanide to convert the diazonium salt. A pyrazolyl derivative J-IV substituted with a cyano group, if appropriate, is carried out in the presence of a coupling reagent.

In step j05 , compound J-IV can be substituted at the N position by methods known to those skilled in the art, for example, using a partial structure (RS2) halide, ie, Hal-(RS2), if appropriate, in one base. And/or in the presence of a coupling reagent, wherein Hal is preferably Cl, Br or I, or boric acid B(OH) ₂ (RS2) or the corresponding borate, if appropriate, in one base and / or a coupling reagent is present in the presence of the compound JV in this way.

Alternatively, a second synthetic route is also suitable for the preparation of compounds JV, in which in step k01 to methods well known to those known in the art of this technique the K-0 reduction of the ester group, to form aldehyde groups KI, the hydrogenation using a suitable reagent e.g. , such as metal hydrides.

Subsequent to step k02 , the aldehyde KI can be reacted with the hydrazine KV obtained in step k05 starting from the primary amine K-IV using methods well known to those skilled in the art, and the water can be removed using methods well known to those skilled in the art. To form hydrazine K-II .

In step k03 , hydrazine K-II can be halogenated to maintain chlorination of the hydrazine K-II while maintaining the double bond integrity, for example, using a chlorinating agent such as NCS, using methods known to those skilled in the art. Compound K-III was obtained .

In step k04 , the fluorenylene halide K-III can be converted to a cyano substituted compound JV using methods known to those skilled in the art, for example, using a cyclized nitrite substituted with a halide.

In step j06 , compound JV can be hydrogenated using methods well known to those skilled in the art, for example, using a suitable catalyst such as palladium/activated carbon, or using a suitable hydrogenating reagent, to obtain compound ( R-II ).

In step j07 , the compound ( R-II ) can be converted to the compound ( R-IV ) using methods well known to those skilled in the art, for example using phenyl chloroformate, if appropriate, in a coupling reagent and/or one base. Performed under the conditions of existence. In addition to the methods of preparing asymmetric urea using phenyl chloroformate as disclosed herein, other methods well known to those skilled in the art, based on the use of reactive carbonic acid derivatives or isocyanates, may be used as appropriate.

In step j08 , the amine ( RV ) can be converted to the urea compound ( R ) (where A = N). This conversion reaction can be carried out by reacting with ( R-IV ) by a method well known to those skilled in the art, and if appropriate, in the presence of a base.

In step j09, the amine (R-II) may be converted to Amides (R & lt) (where, A = CH or C (CH _3)). For example, the conversion can be achieved by reacting it with an acid halide, preferably with a chemical formula ( R-III ), and D = Hal, using methods well known to those skilled in the art; It is carried out in the presence of one base or by reacting it with an acid of the formula ( R-III ) of D = OH; if appropriate, in the presence of a suitable coupling reagent, for example, N-[(Dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyrido-1-yl-mene]-N-dimethylammonium hexafluorophosphate N-oxidation Or 1,1 '-carbonyldiimidazole; if appropriate, one base may be added. Furthermore, a method familiar to those skilled in the art can be known to convert an amine ( R-II ) to a guanamine ( R ) by reaction with a compound ( R-IIIa ) (wherein A = CH or C (CH _{3 )} )); if appropriate, in the presence of one base.

The compound according to the formula ( R ) can be further prepared in the reaction sequence according to Reaction Scheme 2, wherein A = N.

General Reaction Scheme 2 (Scheme 2):

In step v1 , the compound ( RV ) can be converted to the compound ( R-Va ) by methods well known to those skilled in the art, for example using phenyl chloroformate, if appropriate, in a coupling reagent and/or one base. Under the conditions. In addition to the methods of preparing asymmetric ureas using phenyl chloroformate disclosed herein, other methods well known to those skilled in the art, based on the use of activated carbonic acid derivatives or isocyanates, may be used as appropriate.

In step v2 , the amine ( R-II ) can be converted to the urea compound ( R ) (where A = N). This conversion can be achieved by reacting it with ( R-Va ) using methods well known to those skilled in the art, and if appropriate, in the presence of one base.

Standard procedures in organic chemistry, such as J. March, Advanced Organic Chemistry, Wiley & Sons, Sixth Edition, 2007; FA Carey, RJ Sundberg, Advanced Organic Chemistry, Part A and Part B, Springer , Fifth Edition, 2007, and of the team, an overview of organic synthesis method (Compendium of organic synthetic methods), Wiley & Sons, inferred well known in the art are familiar with this technique of reacting step j01 to j09, k01 to k05 and v1 and The method of v2 . In addition, other methods and citations are published in common databases such as Elsevier's Reaxys® database, Amsterdam, the Netherlands, or the American Chemical Society's SciFinder® database, Washington, USA.

Instance

The following examples further illustrate the invention but are not to be construed as limiting its scope.

"Equivalents (eq. or eq or equiv. or equiv)" means Mohr equivalents, "RT or rt" means room temperature (23 ± 7 ° C), and "M" means mol / l The concentration of the unit, "aq. (aqueous)" means an aqueous solution, "sat. (saturated)" means saturated, "sol. (solution)" means a solution, and "conc. (concentrated)" means concentrated.

Other acronyms:

The productivity of the prepared compounds was not optimized.

All temperatures have not been corrected.

All starting materials not specifically described are commercially available (suppliers such as Acros, Avocado, Aldrich, Apollo, Bachem, Fluka, FluoroChem, Lancaster, Manchester Organics, Matrix Scientific, Maybridge, Merck, Rovathin, Sigma, TCI, Oakwood) Details can be obtained from the MDL's Symyx® Available Chemicals Database of MDL, San Ramon, USA, or the ACS SciFinder® database, Washington DC, USA. Accurately described in the professional literature (for example, experimental guidelines can be found in Elsevier's Reaxys® database, Amsterdam, the Netherlands, or ACS's SciFinder® database, Washington DC, USA), or It is prepared by conventional methods known to those skilled in the art.

The stationary phase for column chromatography was E. Merck, Darmstadt's silicone 60 (0.04 to 0.063 mm).

The mixing ratio of the solvent or the eluent used for the column chromatography method is expressed by volume/volume ratio.

All intermediates and exemplary compounds were characterized by hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR spectroscopy). In addition, mass spectrometry (mass spectrometry, [M+H] ⁺ mass-to-charge ratio) was also performed on all exemplary compounds and selected intermediates.

Synthesis of selected intermediates:

1. Method for synthesizing (3-tertiary butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (steps j01 to j06 )

Step j01 : Trimethylethyl hydrazine chloride ( J-0 ) (1 equivalent, 60 g) was added dropwise to a methanol solution (120 mL) at 0 ° C over a period of 30 minutes, and the mixture was Stir at room temperature for 1 hour. After addition of water (120 mL), EtOAcq. The obtained liquid product JI has a purity of 99% (57 g).

Step j02 : Sodium hydride (50% in paraffin oil) (1.2 equivalent, 4.6 g) was dissolved in 1,4-dioxane (120 mL), and the mixture was stirred for several minutes. Acetonitrile (1.2 equivalent, 4.2 g) was added dropwise over 15 minutes, and the mixture was stirred again for 30 minutes. Methyl trimethylacetate ( JI ) (1 equivalent, 10 g) was added dropwise over 15 minutes, and the reaction mixture was refluxed for 3 hours. After completion of the reaction, the reaction mixture was taken in ice water (200 g), which was acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulfate and evaporated. After recrystallization from n-hexane (100 mL), 5 g of product ( J-II ) (yield of 51%) was obtained as brown solid. Shaped matter.

Step j03 : adsorption of 4,4-dimethyl-3-oxopentanenitrile ( J-II ) in ethanol (100 mL) at room temperature (1 equivalent, 5 g), it was mixed with hydrazine hydrate (2 equivalent, 4.42 g) and allowed to reflux for 3 hours. After the ethanol was removed by distillation, the obtained residue was applied to water (100 mL), and ethyl acetate (300 mL). The combined organic phases were dried over sodium sulfate, and the solvent removed in vacuum, after recrystallized from n-hexane (200 mL), i.e., to obtain the product as a light red solid (J-III) (5 g , 89% of yield).

Step j04 : Dissolving 3-tertiary butyl-1H-pyrazole-5-amine ( J-III ) (1 equivalent, 40 g) with dilute hydrogen chloride (120 mL of hydrogen chloride in 120 mL of water); It was mixed dropwise with sodium nitrite (1.03 equivalent, 25 g in 100 mL) at 0 to 5 °C before 30 minutes. After stirring for 30 minutes, the reaction mixture was neutralized with sodium carbonate. The diazonium salt obtained by reacting potassium cyanide (2.4 equivalent, 48 g), water (120 mL) and cuprous cyanide (1.12 equivalent, 31 g) was added dropwise to the reaction mixture over 30 minutes. The mixture was stirred at 75 ° C for 30 minutes. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (3×500 mL), and the combined organic phases were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by column chromatography (EtOAc: 100 to 200 mesh, eluting solvent: 20% ethyl acetate / n-hexane) to yield a white solid ( J-IV ) (6.5 g, 15%) ).

Step j05 ( method 1 ):

Add 3-tris-butyl-1H-pyrazole-5-carbonitrile under stirring at room temperature with a suspension of sodium hydride (60%) in dimethylformamide (20 mL). J-IV ) (10 mmol). After stirring for 15 minutes, 1-iodo-3-chlorobenzene (37.5 mmol) was added dropwise to the reaction mixture at room temperature. After stirring at 100 ° C for 30 minutes, the reaction mixture was combined with water (150 mL) and evaporated. The combined organic extracts were washed with water and a saturated sodium chloride solution (100 mL). After the solvent is removed in a vacuum state, the residue is purified by column chromatography (silicone: 100 to 200 mesh, eluent: a mixture of various ethyl acetate and cyclohexane) to obtain a product. JV .

Step j05 ( Method 2):

1-3-tert-butyl-1H-pyrazole-5-carbonitrile ( J-IV ) (10 mmol), boric acid B (hydroxyl) ₂ (3-chlorophenyl) or a corresponding borate A mixture of (20 mmol) and copper acetate (15 mmol) was taken in dichloromethane (200 mL), and the mixture was stirred at room temperature with pyridine (20 mmol) and the mixture was stirred for 16 hr. After removing the solvent in a vacuum state, the residue obtained by column chromatography (powder: 100 to 200 mesh, eluent: a mixture of various ethyl acetate and cyclohexane) is used to purify the residue. This method obtains the product JV .

Step j06 : ( Method 1):

JV was dissolved in palladium on carbon (10%, 500 mg) and concentrated hydrogen chloride (3 mL) in methanol (30 mL); The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo. The product ( U-II ) was obtained by rapid chromatography (purine: 100 to 200 mesh, eluent: ethyl acetate).

Step j06 : ( Method 2):

JV was dissolved in tetrahydrofuran (10 mL), and borane-methyl sulfide complex (2.0 M in tetrahydrofuran, 3 mL, 3 equivalents) was added to the solution. The reaction mixture was heated to reflux for 8 hrs, then 2N aqueous hydrogen chloride (2N) was added and the mixture was refluxed for 30 min. The reaction mixture was mixed with aqueous sodium hydroxide (2N) and washed with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is removed in a vacuum state, and the residue is purified by column chromatography (silicone: 100 to 200 mesh, eluent: a mixture of various dichloromethane and methanol as a mobile solvent). ( U-II ).

The following other intermediates are synthesized or may be synthesized in a manner similar to that described in 1 .

2. 1- (3-chlorophenyl) -3- (trifluoromethyl) lH-pyrazol-5-yl - methylamine The synthetic method (step k01 to k05 and J06)

Step k01 : Lithium aluminum hydride (LAlH) (0.25 equivalent, 0.7 g) was dissolved in anhydrous diethyl ether (30 mL) under a protective atmosphere and stirred at room temperature for 2 hr. The resulting suspension was adsorbed with diethyl ether (20 mL). 2,2,2-trifluoroacetic acid ethyl ester (K-0 ) (1 equivalent, 10 g) was adsorbed in anhydrous diethyl ether (20 mL), and the suspension was added dropwise at -78 ° C over 1 hour. In the liquid. The mixture was then stirred at -78 °C for 2 hours. Ethanol (95%) (2.5 mL) was then added dropwise, the reaction mixture was warmed to room temperature and placed with iced water (30 mL) with concentrated sulfuric acid (7.5 mL). The organic phase is separated and concentrated under vacuum, and the reaction product KI is immediately introduced to the next reaction step k02 .

Step k05 : 3-Chloroaniline ( K-IV ) (1 equivalent, 50 g) was dissolved in concentrated hydrogen chloride (300 mL) at -5 to 0 ° C and stirred for 10 min. Sodium nitrite (1.2 equivalent, 32.4 g), water (30 mL), stannous chloride. Dihydrate (2.2 equivalent, 70.6 g) and concentrated hydrogen chloride (100) were added dropwise over a period of 3 hours. A mixture of mL) while maintaining the temperature. After stirring at -5 to 0 ° C for 2 hours, the pH of the reaction mixture was adjusted to 9 with sodium hydroxide and extracted with ethyl acetate (250 mL). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. It was purified by column chromatography (tank: 100 to 200 mesh; eluent: 8% ethyl acetate/n-hexane) to yield 40 g (72%) of brown oil (3) -Chlorophenyl) hydrazine ( K-IV ).

Step k02: k01 will be obtained from the aldehyde (KI) (2 equivalent amount, 300 mL) and (3-chlorophenyl) hydrazine (K-IV) (1 equivalent amount, 20 g) is placed in ethanol (200 mL ) and let it reflux for 5 hours. State solvent removed in vacuo to column Chromatography (silica gel: 100-200 mesh, elution solution: n-hexane) to give the residue, to obtain a brown oily product of K-II (25 g, 72 %) .

Step k03 : The hydrazine K-II (1 equivalent, 25 g) was dissolved in dimethylformamide (125 mL). N-chlorobutanediimine (1.3 equivalent, 19.5 g) was added portionwise at room temperature over 15 minutes, and the mixture was stirred for 3 hours. The dimethylformamide was removed by distillation and the residue was adsorbed with ethyl acetate. The ethyl acetate was removed in a vacuum state, and the residue obtained was purified by column chromatography (yield: 100 to 200 mesh, eluting solution: n-hexane) to obtain the product K-III (26.5 g, 92%). It is a pink oily substance.

Step k04 : Adsorption of hydrazonoyl chloride K-III (1 equivalent, 10 g) in toluene (150 mL) at room temperature, and 2-chloroacrylonitrile (2 equivalent, 6.1 mL) and Triethylamine (2 equivalents, 10.7 mL) was mixed. The reaction mixture was stirred at 80 ° C for 20 hours. The mixture was then diluted with water (200 mL) to separate the phases. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. Analysis by column chromatography (silica gel: 100-200 mesh, elution solution: 5% ethyl acetate / hexane) to give the residue to obtain white solid product of JV (5.5 g, 52%) .

Step j06 ( method 3 ):

The carbonized nitrile JV (1 equivalent, 1 g) was dissolved in methanolic ammonia solution (150 mL, 1:1) and hydrogenated in a hydrogen cube (H-cube) (10 bar, 80 ° C, 1 mL/min, 0.25) Mol/L). After removal of the solvent in vacuo, (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine ( II ) (0.92) g, 91%).

The following other intermediates are synthesized or may be similar to the methods described in 2. above.

3. Method for preparing tolyl (methyl 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)aminecarboxylate

Step a: (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (5 g) dissolved in dimethylformamide (25 mL) Potassium carbonate (9.16 g, 66 mmol, 3.5 equivalent) was added to a solution of 18 mmol) and the mixture was cooled to 0 °C. Phenyl chloroformate (3.28 g (2.65 mL), 20 mmol, 1.1 eq.) was then added dropwise over 15 min and then the mixture was stirred at 0<0>C for 15 min. The progress of the reaction was monitored by thin layer chromatography (20% ethyl acetate present). After the reaction was completed, the reaction mixture was filtered, and the filtrate was diluted with ice water (100 mL), and the product was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with aq. EtOAc EtOAc The crude product was purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 45%).

4. Method for preparing (1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methylamine hydrochloride

Step a: Add diethyl oxalate (0.92 mL, 6.85 mmol, 1) at room temperature in a solution of sodium ethoxide (sodium (1 g, 8.2 mmol, 1.2 equivalent) in ethanol (30 mL)) Equally), then cyclopropylmethyl ketone (0.74 mL, 7.5 mmol, 1.1 equivalent) was added dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. Ice water (10 mL) was added and the ethanol was evaporated at a lower pressure. The residual aqueous layer was diluted with aq. EtOAc (EtOAc) (EtOAc) The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate, filtered and concentrated to give a light brown liquid (400 mg, 31%).

Step b: at room temperature, in a step was dissolved in ethanol (8 mL) of - a product (200 mg, 0.543 mmol, 1 equivalent) was added methoxyamine hydrochloride (dissolved in 30% solution in water , 0.4 mL, 0.651 mmol, 1.2 eq.), and the reaction mixture was stirred for 1 hour. Ethanol was evaporated at a lower pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with EtOAc (EtOAc) (EtOAc) ).

Step c: Adsorption of one step - b product (1.1 g, 5.164 mmol, 1 equivalent) with 3-chlorophenylhydrazine hydrochloride (3-chlorophenyl) in acetic acid (20 mL) and 2-methoxyethanol (10 mL) A mixture of hydrazine hydrochloride (1.84 g, 10.27 mmol, 2 equivalents) and the reaction mixture was heated at 105 °C for 3 hours. The solvent was evaporated and the residue was purified ethyl acetate (EtOAc) The organic layer was washed with water (10 mL) EtOAc. Purification by column chromatography (tank: 100 to 200 mesh, eluent: ethyl acetate- petroleum ether (4:96)) to yield pale brown semi solid (1.15 g, 77%).

Step d: at 0 ° C, in a solution of the solution - c product (2.5 g, 8.62 mmol, 1 equivalent) in tetrahydrofuran (15 mL)-methanol (9 mL)-water (3 mL) Lithium (1.08 g, 25.71 mmol, 3 equivalents), the reaction mixture was stirred at room temperature for 2 hr. The solvent was evaporated, and the pH of the residue was adjusted to about 3 with 2N aqueous hydrogen chloride (1.2 mL). The acidic aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic layer was washed with water (10 mL) and saturated aqueous sodium chloride (10 mL). Concentrate at low pressure to produce an off-white solid (1.4 g, 62%).

Step e: Add pyridine (0.25 mL, 3.2 mmol) to a solution of the step- d product (1.4 g, 5.34 mmol, 1 equivalent) in 1,4-dioxane (30 mL) at 0 ° C. , 0.6 equal amount) and di-tert-butyl dicarbonate (1.4 mL, 6.37 mmol, 1.2 equivalent), and the resulting mixture was stirred at the same temperature for 30 minutes. Ammonium hydrogencarbonate (0.84 g, 10.63 mmol, 2 eq.) was added at 0 ° C and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL). The organic layer was washed with 2N aqueous hydrogen chloride (20 mL), water (10 mL) and saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, filtered and concentrated at lower pressure to yield residue . Purification by column chromatography (tank: 100 to 200 mesh; eluent: ethyl acetate- petroleum ether (16:84)) afforded white solid (1 g, 72%).

Step f: Add borane-methyl sulfide complex (1.44 mL, 15.32 mmol) in a solution of the e- product (2 g, 7.66 mmol, 1 equivalent) in THF (25 mL). 2 equivalents), the reaction mixture was heated at 70 ° C for 3 hours. The reaction mixture was cooled to 0.degree. C., MeOH (15 mL). The reaction mixture was allowed to warm to room temperature and the solvent was evaporated at lower pressure. The residue was dissolved in diethyl ether (15 mL), cooled to 0 <0>C, and a solution of <RTI ID=0.0>> The solid precipitate was filtered and washed with diethyl ether (5 mL, EtOAc)

Synthesis of exemplary compounds:

1. Preparation method of decylamine (A=CH or C(CH ₃ ))

The amine of the formula ( R-II ) is reacted with a carboxylic acid of the formula or a carboxylic acid derivative of the formula ( R-III ) to form a general direction of the compound of the formula ( R ) wherein A=CH or C (CH ₃ ) ( decylamine ), as in Scheme 1 (step j09 ).

1.1 Method A :

The acid of the formula ( R-III ) (1 equivalent), the amine of the formula ( R-II ) (1.2 equivalent), and N-ethyl-N'-(3-dimethylamine) at room temperature The propyl)carbodiimide hydrochloride (1.2 equivalent) was mixed in dimethylformamide (10 mmol of acid / 20 mL) for 12 hours, then water was added to the mixture. The reaction mixture was repeatedly extracted with ethyl acetate to saturate the aqueous sodium chloride, followed by ethyl acetate. The combined organic phases were washed with 1N hydrogen chloride and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated. The product ( R ) is obtained by flash chromatography (purine, different ratios of ethyl acetate/hexane, such as 1:2).

1.2 Method B :

The acid of the formula ( R-III ) (1 equivalent) and the amine of the formula ( R-II ) (1.1 equivalent) are dissolved in dichloromethane (1 mmol of acid in 6 mL) and with N- Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 equivalents), N-hydroxybenzotriazole (1.4 equivalents) and triethylamine (3 equivalents) ) mixed at 0 °C. The reaction mixture was stirred at room temperature for 20 hours, and the crude product was purified by column chromatography (yield, hexanes, hexanes, ethyl acetate, e.g., 2:1) to obtain ( R ).

1.3 Method C :

First, the acid of the formula ( R-III ) (1 equivalent) is mixed with a monochlorinating agent, preferably sulfinium chloride; the mixture obtained by this method is boiled under reflux to the acid ( R-III ) Converted to the corresponding acid chlorine. The amine of formula ( R-II ) (1.1 equivalent) was dissolved in dichloromethane (1 mmol of acid in 6 mL) and mixed with triethylamine (3 equivalent) at 0 °C. The reaction mixture was stirred at room temperature for 20 hours, and the crude product was purified by column chromatography (cerium dioxide, different ratios of n-hexane / ethyl acetate, such as 2:1) to obtain ( R ). .

1.4 Method D :

Phenyl ester ( R-IIIa ) (1 equivalent) and the corresponding amine ( R-II ) (1.1 equivalent) were dissolved in tetrahydrofuran (10 mmol of the reaction mixture in 120 mL) and added 1,8- After diazabicyclo[5.4.0]undec-7-ene (1.5 equivalent), it was stirred at room temperature for 16 hours. After the solvent is removed in a vacuum state, the residue obtained is purified by a rapid chromatography method (cerium oxide, different ratios of ethyl acetate/hexane, for example, 1:1) to obtain ( R ).

Exemplary Compounds B1 to B10, B13, B15 to B23, B26, B29 to B30, B37, B42 to B43, B47, B63 to B68, B76, B82, B88, B93 to B98, and B102 to B104 and B106 to B107 One of the above methods is prepared.

2. Preparation method of urea (A = N)

The amine of the formula ( R-II ) or ( RV ) is reacted with phenyl chloroformate to form the general direction of the formula ( R-IV ) or ( R-Va ) (step j07 of Scheme 1 and step v1 of Scheme 2) And the subsequent reaction of a compound of the formula ( R-IV ) with an amine of the formula ( RV ) (step j08 of Scheme 1), or a compound of the formula ( R-Va ) with an amine of the formula ( R-II ) Reaction (step v2 of Scheme 2) to form the general direction of the compound of formula ( R ) wherein A = N:

Step j07 / Step v1 : At room temperature, an amine of the formula ( R-II ) or ( RV ) (1 equivalent) is placed in dichloromethane (10 mmol of amine in 70 mL), and chlorine is added thereto. Phenyl formate (1.1 equivalent) and the mixture was stirred for 30 minutes. After removing the solvent in a vacuum state, the residue is purified by flash chromatography (cerium oxide, diethyl ether/hexane in different ratios, for example, 1:2) to obtain ( R-IV ) or ( R-Va). ).

Step j08 / step v2 : dissolving the obtained phenyl carbamate ( R-IV ) or ( R-Va ) (1 equivalent) and the corresponding amine ( RV ) or ( R-II ) (1.1 equivalent) in tetrahydrofuran (10 mmol of this reaction mixture in 120 mL); after adding 1,8-diazabicyclo [5.4.0]undec-7-ene (1.5 equivalent), it was stirred at room temperature 16 hour. After the solvent is removed in a vacuum state, the residue obtained is purified by a rapid chromatography method (cerium oxide, different ratios of ethyl acetate/hexane, for example, 1:1) to obtain ( R ).

Exemplary Compounds B11 to B12, B15, B24 to B25, B27 to B28, B31 to B36, B38 to B41, B44 to B46, B48 to B62, B69 to B75, B77 to B81, B83 to B87, B89 to B92 and B99 -B101, and B105 It is prepared by one of the methods described above.

Synthesis details of selected exemplary compounds

Synthesis of Example B5: N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(A Sulfonyl-methyl)-phenyl]-propanamide

Step 1 : To a solution of (4-bromophenyl)methylamine (500 mg, 2.687 mmol), EtOAc (0.4 mL, 5. The reaction mixture was stirred for 1 hour and then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give N-(4-bromophenyl)methanesulfonamide (675 mg) (95% yield).

Step 2 : Add 2-chloropropanoic acid to a solution of N-(4-bromophenyl)methanesulfonamide (675 mg, 2.555 mmol) dissolved in N,N-dimethylformamide Ester (0.42 mL), manganese (280 mg) and (2,2'-bipyridyl) nickel(II)-dibromide (NiBr ₂ bipy) (67 mg, 0.17885 mmol). Trifluoroacetic acid (1 to 2 drops) was added. The reaction mixture was stirred at 60 ° C for 36 hours. After it was cooled to room temperature, the mixture was hydrolyzed with 1N hydrogen chloride and extracted with diethyl ether. The organic layer was dried (MgSO4) and concentrated. The solvent is removed under vacuum. The crude product was purified by column chromatography to give ethyl 2-(4-methylsulfonamidemethyl)phenyl)propanoate (325 mg).

Step 3 : A solution of ethyl 2-(4-methanesulfonylamino)phenyl)propionate (325 mg, 1.139 mmol) in tetrahydrofuran and water (1:1) as a solvent. Sodium hydroxide (114 mg, 2.8475 mmol) was added. The reaction mixture was refluxed for 16 hours, then cooled to room temperature and acidified with acetic acid to a pH of from 3 to 4. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 2-(4-(methylsulfonamidemethyl)phenyl)propanoic acid (74 mg);

Step 4 : 2-(4-(methylsulfonamidemethyl)phenyl)propanoic acid (37 mg, 0.144 mmol) and (1-(3-chlorophenyl)-3-) dissolved in acetonitrile Addition of N-(3-dimethylaminopropyl)-N'-ethylcarbazide to a solution of (trifluoromethyl)-1H-pyrazol-5-yl)methylamine (44 mg, 0.158 mmol) Imine (41 mg, 0.216 mmol), N-hydroxybenzotriazole (29 mg, 0.216 mmol) and triethylamine (0.05 mL, 0.36 mmol). The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed in a vacuum state. The crude product was purified by column chromatography to afford the title compound B5 (62 mg).

Hydrogen nuclear magnetic resonance (300 MHz, deuterated chloroform): δ 7.35 (m, 8H); 6.35 (s, 1H); 5.56 (t, 1H); 4.5 (m, 3H); 4.32 (d, 2H); 3.53 ( q, 1H); 2.94 (s, 3H); 1.50 (d, 3H).

Synthesis of Example B17: N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-[[ (ethanesulfonyl)amino]-methyl]-3-fluoro-phenyl]-propanamide

Step 1 : 4-Bromo-2-fluorobenzylamine (924 mg, 4.53 mmol) was dissolved in pyridine. EtOAc EtOAc EtOAc (EtOAc) The mixture was stirred at 0 ° C for 1 hour. Subsequently, the mixture was quenched with 1 N of hydrogen chloride and extracted with ethyl acetate. It was dried (magnesium sulfate), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (solvent: ethyl acetate / n-hexane) to obtain N-(4-bromo Benzyl-2-fluorobenzyl)ethanesulfonamide (1.06 g, 79%).

Step 2 : Adding manganese to a solution of N-(4-bromo-2-fluorobenzyl)ethanesulfonamide (305 mg, 1.03 mmol) dissolved in N,N-dimethylformamide 113 mg, 2.06 mmol), (2,2'-bipyridyl) nickel(II)-dibromo compound (27 mg, 0.07 mmol), ethyl 2-chloropropionate (0.17 ml, 1.34 mmol), followed by three Fluoroacetic acid (0.002 ml, 0.028 mmol). The mixture was stirred at 65 ° C for 1 day. The reaction mixture was quenched with concentrated hydrogen chloride (7 drops), then extracted with diethyl ether, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography (ethyl acetate / n-hexane) to afford ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate (65) Mg, 20%).

Step 3 : a solution of ethyl 2-(4-(ethylsulfonylamino)-3-fluorophenyl)propanoate (305 mg, 1.03 mmol) dissolved in N,N-dimethylformamide Add manganese (113 mg, 2.06 mmol), (2,2'-bipyridyl) nickel(II)-dibromo compound (27 mg, 0.07 mmol), ethyl 2-chloropropionate (0.17 mL, 1.34 mmol) ), followed by the addition of trifluoroacetic acid (0.002 mL, 0.028 mmol). The mixture was stirred at 65 ° C for 1 day. The reaction mixture was quenched with concentrated hydrogen chloride (7 drops), then extracted with diethyl ether, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography (ethyl acetate / n-hexane) to afford 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (65 mg, 20%).

Step 4 : 2-(4-(ethylsulfonamidemethyl)-3-fluorophenyl)propionic acid (60 mg, 0.207 mmol) and (1-(3-chlorophenyl)-3-(trifluoro) Methyl)-1H-pyrazol-5-yl)methylamine (63 mg, 0.228 mmol) was dissolved and mixed with 1,4-dioxane, followed by the addition of N-hydroxybenzotriazole (42 mg, 0.310 mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (60 mg, 0.313 mmol) and triethylamine (0.07 mL, 0.518 mmol). The reaction mixture was stirred overnight, then quenched with water and extracted with ethyl acetate. This was dried (MgSO.sub.4), EtOAc (EtOAc)EtOAc.

Hydrogen nuclear magnetic resonance (deuterated methanol): δ 7.50 (m, 5H, Ar); 7.05 (m, 2H, Ar); 6.57 (s, 1H, Ar); 4.43 (m, 2H, Ar-CH ₂ ); 4.27 (s, 2H, Ar-CH ₂ ); 3.58 (q, 1H, J = 7.14 Hz, decylamine 1H); 2.97 (q, 2H, J = 7.32 Hz, ethanesulfonamide 2H); 1.36 (d, 3H, J = 7.14 Hz, decylamine 3 H); 1.27 (t, 3H, J = 7.32 Hz, ethanesulfonamide 3H).

Synthesis of Example B22: 2-[3-Chloro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2-(3-chlorophenyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-propanamide

Step 1 : Sulfuric acid (0.3 mL) was added to a solution of 1 (3 g, 16.078 mmol) in methanol (35 mL). The reaction mixture was refluxed for 15 hours and then cooled to room temperature. The solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The residue was purified by column chromatography to give 2 (3.557 g);

Step 2 : Trifluoromethanesulfonic anhydride (3 mL) was added dropwise at 0 ° C with stirring in 2 (3.557 g, 17.73 mmol) and triethylamine (2.5 mL, 17.73 mmol) , 17.73 mmol). The reaction mixture was stirred for 2 hours. The residue was extracted with dichloromethane and washed with water and saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The residue was purified by column chromatography to afford 3 (5.15 g);

Step 3 : Add zinc cyanide (1.6 g, 13.681 mmol) and tetrakis(triphenylphosphine)palladium in a solution of 3 (4.419 g, 13.283 mmol) dissolved in N,N-dimethylformamide. 1.5 g, 1.3283 mmol). The reaction mixture was stirred at 80 ° C for 34 hours, then cooled to room temperature and diluted with ethyl acetate. The mixture was filtered using a diatomaceous earth filter. The filtrate was diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 4 (1.044 g);

Step 4 : Sodium hydride (60% by weight in mineral oil, 178 mg, added to a solution of N,N-dimethylformamide 4 (931 mg, 4.441 mmol) at 0 ° C 4.441 mmol) and methyl iodide (0.3 ml, 4.441 mmol). The reaction mixture was stirred at 0 ° C for 1 hour and then diluted with water. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 5 (642 mg);

Step 5 : Sodium hydroxide (287 mg, 7.175 mmol) was added to a solution of 5 (642 mg, 2.870 mmol) in tetrahydrofuran and water (1:1) as a solvent. The reaction mixture was stirred at room temperature for 15 hours and then acidified to a pH of 3 to 4 with acetic acid. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 6 (665 mg);

Step 6 : Add N-(3-dimethylaminopropyl)-N'-ethyl group in a solution of 6 (224 mg, 1.069 mmol) and 7 (324 mg, 1.175 mmol) in acetonitrile with stirring. Carboimine (307 mg, 1.064 mmol), N-hydroxybenzotriazole (217 mg, 1.064 mmol) and triethylamine (0.4 mL, 2.673 mmol). The reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with ethyl acetate and washed with water and a saturated sodium chloride solution. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 8 (366 mg).

Step 7 : Cool a solution of 8 (366 mg, 1.460 mmol) dissolved in methanol to 0 ° C, and add di-tert-butyl dicarbonate (Boc ₂ O) (342 mg, 1.566 mmol) and nickel chloride Hydrate (19 mg, 0.0783 mmol). Sodium borohydride (207 mg, 5.481 mmol) was then added in small portions. This reaction is an exothermic and foaming reaction. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Diethylenetriamine (DETA) (0.09 mL, 0.783 mmol) was added to the mixture. The mixture was stirred for 1 hour. The solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 9 (227 mg);

Step 8 : A solution of 9 (227 mg, 0.397 mmol) dissolved in dichloromethane (4 mL) was cooled to 0 <0>C, and trifluoroacetic acid (2 mL). The resulting reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 1 hour, then was acidified to pH 8 to 9 with aqueous sodium hydrogen carbonate. The mixture was filtered through a diatomaceous earth filter. The filtrate was dissolved in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 10 (116 mg);

Step 9 : After stirring, the solution of 10 (116 mg, 0.246 mmol) dissolved in pyridine was cooled to 0 ° C, and methanesulfonium chloride (116 mg) was added. The resulting reaction mixture was stirred at room temperature for 15 hours. The mixture was dissolved in dichloromethane and washed with 1N hydrogen chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 11 (108 mg);

Hydrogen nuclear magnetic resonance (300 MHz, deuterated chloroform): δ 7.43 (m, 4H); 7.29 (m, 3H); 7.15 (dd, 1H, J = 7.86 Hz); 6.43 (s, 1H); 5.63 (t, 1H); 4.76(t,1H); 4.48(d,2H); 4.40(d,2H); 3.48(q,1H,J=7.14 Hz); 2.90(s,3H);1.47(d,3H,J =7.14 Hz).

Synthesis method of Example B28: 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonate) Amine-methyl)-phenyl]-urea

Step 1 : Triethylamine (0.3 ml, 2.147 mmol) was added to a solution of 1 (299 mg, 1.952 mmol). Methanesulfonium chloride (0.18 ml, 2.343 mmol) was then added dropwise at 0 °C. The reaction mixture was heated to 80 ° C and stirred for 4 hours, then cooled to room temperature and diluted with dichloromethane. The mixture was washed with water. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 2 (333 mg);

Step 2 : Potassium iodide (293 mg, 1.584 mmol) was added to a solution of N,N-dimethylformamide 2 (333 mg, 1.440 mmol). The reaction mixture was stirred for 16 hours. The mixture was dissolved in ethyl acetate and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent was evaporated under vacuum. The crude product was purified by column chromatography. The obtained product 3 (535 mg) was in a crude state.

Step 3 : Add hydrazine monohydrate (246 mg, 3.089 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.0772 mmol) in a solution of 3 (218 mg, 0.772 mmol) in tetrahydrofuran with stirring. . The reaction mixture was stirred at 80 ° C for 4 hours, then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 4 (46 mg);

Step 4 : After stirring, the solution in 4 (46 mg, 0.302 mmol) of pyridine was cooled to 0 ° C, and methanesulfonium chloride (46 mg) was added. The resulting reaction mixture was stirred at room temperature for 1 hour. The mixture was dissolved in dichloromethane and washed with 1N hydrogen chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 5 (43 mg);

Step 5 : 10% palladium on carbon (5 mg) was added to a solution of 5 (43 mg, 0.188 mmol) in ethyl acetate. The mixture was aerated in a hydrogen gas cylinder. The resulting mixture was stirred for 3 hours and then filtered over Celite. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 6 (41 mg);

Step 6 : Add phenyl chloroformate (34 mg, 0.2142 mmol) and pyridine (0.02 mL, 0.2448 mmol) in a solution of 6 (41 mg, 0.204 mmol) with tetrahydrofuran and acetonitrile as a solvent. . The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and washed with a saturated sodium chloride solution. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 7 (54 mg);

Step 7 : 4-Methylaminopyridine (11 mg, 0.087 mmol) was added in a solution of 7 (28 mg, 0.087 mmol) and 8 (23 mg, 0.087 mmol). The reaction mixture was stirred at 50 ° C for 15 hours. The mixture was diluted with ethyl acetate and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 9 (yield of compound B28) (32 mg);

Hydrogen nuclear magnetic resonance (400 MHz, deuterated chloroform): δ 7.43 (s, 1H); 7.30 (m, 2H); 7.12 (q, 4H); 6.89 (s, 1H); 6.24 (s, 1H); 5.28 ( d, 1H); 4.92 (t, 1H); 4.39 (d, 2H); 4.15 (d, 2H); 4.09 (q, 1H); 2.85 (s, 3H); 1.28 (s, 9H).

Synthesis of Example B29: N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro- 4-[(methyl-methylsulfonyl-amino)-methyl]-phenyl]-propanamide

Step 1 : The commercially available (4-bromo-2-fluorophenyl)methanamine was stirred in a pyridine, and methanesulfonium chloride (1.9 equivalent) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with 1N hydrogen chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was evaporated. The crude product was purified by column chromatography to obtain 1 .

Step 2 : Compound 1 was dissolved in anhydrous N,N-dimethylformamide and aerated with nitrogen. Commercially available ethyl 2-chloropropionate (1.3 equivalent) was added dropwise, and manganese (2 equivalents), (2,2'-bipyridyl) nickel(II)-dibromo compound (0.1) were added sequentially. Equal amount) and trifluoroacetic acid (0.026 equivalent). The reaction mixture was refluxed overnight. The reaction mixture was allowed to warm to ambient temperature. The reaction was quenched with 1N hydrogen chloride and the organic layer was extracted with diethyl ether. The extracted organic layer over magnesium sulfate, and concentrated to compound 2, which was used without further purification in the next step.

Step 3 : The crude compound was stirred in acetone at 0 ° C and potassium carbonate (1.5 eq.) was added. Methyl iodide (3 equivalents) was added dropwise and the reaction mixture was refluxed. After 15 hours, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The crude product was purified column chromatography analysis, to obtain the desired product 3.

Step 4 : Sodium hydroxide (2.5 equivalent) was added to a solution of Compound 3 dissolved in tetrahydrofuran and water (1:1), and the resulting mixture was stirred at room temperature. After 15 hours, the reaction mixture was acidified to a pH of 2 to 3 with acetic acid. The mixture was extracted with dichloromethane and water. The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography to give the desired product 4 .

Step 5 : Add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (1.5) to a solution of carboxylic acid ( 4 ) dissolved in 1,4-dioxane. Equal amounts), N-hydroxybenzotriazole (1.5 equivalents) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (1 Equal amount), and triethylamine (2.5 equivalent) was added dropwise. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate. The solvent was evaporated, followed by purification by column chromatography (ethyl acetate / n-hexane) to afford the title compound B29.

Hydrogen nuclear magnetic resonance (300 MHz, deuterated chloroform): δ 7.41-7.32 (m, 5H, Ar-H); 6.99-6.95 (m, 3H, Ar-H); 6.06 (s, 1H, Ar-H); 5.643 (bs, 1H, Ar-NH); 4.46 (d, 2H, J = 6.00 Hz, pyrazole-α-H); 3.88 (s, 2H, Ar-α-H); 3.49 (q, 1H, J) = 7.50 Hz, Ar-α-H); 2.48 (s, 3H, methanesulfonyl-CH ₃ ); 1.47 (d, 3H, J = 6.00 Hz, Ar-α-CH ₃ ).

Synthesis method of Example B31: 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4- (Methanesulfonamide-methyl)-phenyl]-urea

Step 1 : After stirring and dissolving in a solution of carbon tetrachloride 1 (1.993 g, 12.847 mmol), add benzamidine peroxide (497 mg, 1.2847 mmol) and N-bromosinium imine (2.972 g). , 16.701 mmol). The reaction mixture was refluxed for 18 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate and then washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 2 (780 mg);

Step 2 : Potassium iodide (1.235 g, 6.666 mmol) was added to a solution of N,N-dimethylformamide in 2 (780 mg, 3.33 mmol). The reaction mixture was stirred for 18 hours. The mixture was dissolved in ethyl acetate and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 3 (1.034 g) as crude.

Step 3 : Add a solution of hydrazine monohydrate (1.104 g, 13.776 mmol) and p-toluenesulfonic acid monohydrate (66 mg, 0.3444 mmol) in a solution of 3 (1.034 g, 3.444 mmol) in tetrahydrofuran. . The reaction mixture was refluxed for 6 h then cooled to rt and diluted with ethyl acetate. The mixture was washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 4 (329 mg);

Step 4 : After stirring, the solution of 4 (131 mg, 0.770 mmol) in pyridine was cooled to 0 ° and methanesulfonium chloride (131 mg) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane and washed with 1N hydrogen chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 5 (173 mg);

Step 5 : 10% palladium on carbon (20 mg) was added to a solution of 5 (187 mg, 0.753 mmol) in tetrahydrofuran and ethanol as a solvent. The mixture was aerated in a hydrogen gas cylinder. The resulting mixture was stirred for 15 hours and then filtered over celite. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 6 (135 mg);

Step 6 : Add phenyl chloroformate (0.08 mL, 0.6489 mmol) and pyridine (0.06 mL, 0.7416 mmol) in a solution of 6 (135 mg, 0.618 mmol) with tetrahydrofuran and acetonitrile as a solvent. . The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 7 (140 mg);

Step 7 : 4-Methylaminopyridine (17 mg, 0.136 mmol) was added in a solution of 7 (46 mg, 0.136 mmol) and 8 (36 mg, 0.136 mmol) of acetonitrile. The reaction mixture was stirred at 50 ° C for 15 hours. The mixture was diluted with ethyl acetate and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 9 (72 mg).

Hydrogen nuclear magnetic resonance (300 MHz, dimethyl hydrazine-d ₆ ): δ 8.84 (s, 1H); 7.60 (s, 1H); 7.45 (m, 4H); 7.26 (t, 1H); 7.01 (dd, 1H) 6.76 (t, 1H); 6.32 (s, 1H); 4.40 (d, 2H); 4.09 (d, 2H); 2.85 (s, 3H); 1.27 (s, 9H).

Synthesis of Example B35: 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[( Amidoxime)-methyl]-phenyl]-urea

Step 1 : In a solution of 4-nitrotoluene 1 (1.2 g, 7.735 mmol) dissolved in carbon tetrachloride, N-bromo-succinimide (1.51 g, 8.509 mmol) was added. 70% of benzamidine peroxide (120 mg) was added to the mixture at room temperature. The mixture was refluxed. After 24 hours, the mixture was extracted with ethyl acetate. This was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 2 in pure form;

Step 2 : To a solution of compound 2 (1.1 g, 4.69 mmol) in N,N-dimethylformamide was added potassium succinimide (1.9 g, 10.314 mmol). The mixture was stirred overnight, then extracted with ethyl acetate and washed with saturated aqueous sodium chloride. This was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 3 in pure form;

Step 3 : To a solution of compound 3 (1.6 g, 5.33 mmol) dissolved in tetrahydrofuran, hydrazine monohydrate (4 equivalents) was added. The mixture was refluxed for 6 hours and then cooled to room temperature. The mixture was treated with potassium hydrogencarbonate to give a pH of 12 to 13. The mixture was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. It was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 4 in pure form; Mg).

Step 4 : Mix chlorosulfonium isocyanate (0.063 mL) with tert-butanol (0.07 mL) in dichloromethane. After 10 minutes, a solution of Compound 4 (100 mg, 0.657 mmol) dissolved in dichloromethane was added at 50 °C. After stirring for 30 minutes, the mixture was cooled to room temperature, then triethylamine (0.11 mL) was added, and the mixture was stirred for 3 hr, then extracted with ethyl acetate and washed with saturated aqueous sodium chloride. This was dried (magnesium sulfate), and ethyl acetate was evaporated, then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 5 in pure form; Mg).

Step 5 : 10% palladium on carbon (7 mg) was added to a solution of compound 5 (65 mg) dissolved in ethanol and tetrahydrofuran, and the mixture was inflated with hydrogen. After the reaction mixture was stirred for 6 hours, the mixture was filtered over celite, and solvent was evaporated in vacuo to afford compound 6 in pure form; yield 58% (98 mg).

Step 6 : Compound 6 (86 mg, 0.285 mmol) was dissolved in tetrahydrofuran / acetonitrile. Pyridine (0.03 mL, 0.342 mmol) was added followed by phenyl chloroformate (0.04 mL, 0.300 mmol). The mixture was stirred at 0 ° C for 30 minutes, allowed to warm to room temperature and stirred again for 30 minutes. Thereafter, it was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. This was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 7 in pure form; Mg).

Step 7 : Compound 7 (58 mg, 0.138 mmol) was dissolved in acetonitrile. Compound 8 (38 mg, 0.138 mmol) and 4-dimethylaminopyridine (16 mg) were added to the solution. The reaction mixture was stirred at 50 ° C overnight. The mixture was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. It was dried (magnesium sulfate), and ethyl acetate was evaporated, then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 9 in pure form; 60 mg).

Step 8 : To a solution of compound 9 (80 mg, 0.133 mmol The mixture was stirred for 30 minutes and then at room temperature for 2 hours. The mixture was neutralized with sodium bicarbonate to a pH of 7 to 8, then extracted with ethyl acetate and washed with saturated aqueous sodium chloride. It was dried (magnesium sulfate), and the ethyl acetate was evaporated, and then the residue was purified by column chromatography, ethyl acetate / n-hexane to afford compound 10 in pure form; yield 75% (50 mg) ).

Hydrogen nuclear magnetic resonance (deuterated methanol): 7.64 (m, 1H, Ar); 7.55 (m, 3H, Ar); 7.28 (m, 4H, Ar); 6.75 (s, 1H, Ar); 4.47 (s, 2H) , CH ₂ NH); 4.09 (s, 2H, CH ₂ NH).

Synthesis of Example B40: 1-[4-(Aminomethyl)-3-fluoro-phenyl]-3-[[5-tert-butyl 1-2-(3-chlorophenyl)-2H-pyridyl Zyrid-3-yl]-methyl]-urea

Steps 1 to 3 were prepared by the synthesis method as described in Example B31 .

Step 4 : Compound 4 (100 mg, 0.588 mmol) was dissolved in dichloromethane. Di-tert-butyl dicarbonate (154 mg, 0.705 mmol) was added to the solution at 0 °C. After stirring for 30 minutes, the mixture was warmed to room temperature then triethylamine (0.13 ml) was added and the mixture was stirred overnight. It was then extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. It was dried (magnesium sulfate), and ethyl acetate was evaporated, then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 5 in pure form; 136 mg).

Step 5 : To a solution of Compound 5 (136 mg) in ethanol and tetrahydrofuran, 10% palladium on carbon (20 mg) was added, and the mixture was inflated with hydrogen. After the reaction mixture was stirred for 6 hours, the mixture was filtered over Celite, and solvent was evaporated in vacuo to afford 85% Compound 6 (103 mg).

Step 6 : Compound 6 (103 mg, 0.429 mmol) was dissolved in tetrahydrofuran / acetonitrile. Pyridine (0.04 mL, 0.515 mmol) and phenyl chloroformate (0.06 mL, 0.450 mmol) were added sequentially at 0 °C. The mixture was stirred at 0 ° C for 30 minutes, heated to room temperature and then stirred for another 30 minutes. Thereafter, it was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. This was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 7 in pure form; Mg).

Step 7 : Compound 7 (70 mg, 0.194 mmol) was dissolved in acetonitrile. Compound 8 (52 mg, 0.137 mmol) and 4-dimethylaminopyridine (24 mg) were added to the solution. The reaction mixture was stirred at 50 ° C overnight. The mixture was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. This was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 9 in pure form; 100 mg).

Step 8 : To a solution of compound 9 (100 mg, 0.189 mmol) in dichloromethane (6 mL), EtOAc (2 mL) Stir for 2 hours. The mixture was neutralized with sodium bicarbonate to a pH of 7 to 8, then extracted with ethyl acetate and washed with saturated aqueous sodium chloride. It was dried (magnesium sulfate), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 10 in pure form; Mg).

Hydrogen nuclear magnetic resonance (300 MHz, dimethyl hydrazine-d6): δ 9.00 (s, 1H, urea); 7.60 (s, 1H, Ar); 7.47 (m, 4H, Ar, urea); 7.33 (m, 1H) , Ar); 7.07 (m, 1H, Ar); 6.94 (m, 1H, Ar); 6.31 (s, 1H, Ar); 4.39 (m, 2H, Ar-CH ₂ ); 3.88 (s, 2H, Ar -CH ₂ ); 1.26 (s, 9H, tert-butyl 9H).

Synthesis of Example B46: 1-[[5-Tris-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4- [(Aminosulfonylamino)-methyl]-phenyl]-urea

Steps 1 to 3 were prepared by the synthesis method as described in Example B31 .

Step 4 : Mix chlorosulfonium isocyanate (0.1 mL) and tert-butanol (0.12 mL) in dichloromethane. After 10 minutes, a solution of Compound 4 (200 mg, 1.176 mmol) in dichloromethane was added at 50 °C. After stirring for 30 minutes, the mixture was cooled to room temperature, then triethylamine (0.11 mL) was added and the mixture was stirred for 3 hr, then extracted with ethyl acetate and washed with saturated aqueous sodium chloride. This was dried (magnesium sulfate), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 5 in pure form; Mg).

Step 5 : To a solution of Compound 5 (135 mg) in ethanol and tetrahydrofuran, 10% palladium on carbon (42 mg) was added, and the mixture was inflated with hydrogen. After the reaction mixture was stirred for 6 hours, the mixture was filtered over celite, and solvent was evaporated in vacuo to afford compound 6 in pure form; yield 99% (127 mg).

Step 6 : Compound 6 (127 mg, 0.398 mmol) was dissolved in tetrahydrofuran / acetonitrile. Pyridine (0.04 ml, 0.478 mmol) and phenyl chloroformate (0.05 mL, 0.418 mmol) were added sequentially at 0 °C. The mixture was stirred at 0 ° C for 30 minutes, allowed to warm to room temperature and then stirred for 30 minutes. After that, it was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The dried (magnesium sulfate), the ethyl acetate was evaporated, the residue was purified in a column of chromatography (ethyl acetate / n-hexane) to obtain pure form of the compound 7; yield of 91% (160 mg ).

Step 7 : Compound 7 (50 mg, 0.114 mmol) was dissolved in EtOAc. Compound 8 (30 mg, 0.114 mmol) and 4-dimethylaminopyridine (14 mg) were added to the solution. The reaction mixture was stirred at 50 ° C overnight. The mixture was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. It was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 9 in pure form; Mg).

Step 8 : To a solution of compound 9 (45 mg, EtOAc. The mixture was stirred for 30 minutes and then at room temperature for 2 hours. The mixture was neutralized to a pH of 7 to 8 with sodium hydrogencarbonate, then extracted with ethyl acetate and washed with saturated aqueous sodium chloride. It was dried (MgSO.sub.4), and ethyl acetate was evaporated, and then the residue was purified by column chromatography (ethyl acetate / n-hexane) to afford compound 10 in pure form; Mg).

Hydrogen nuclear magnetic resonance (300 MHz, deuterated methanol): δ 7.48 (m, 4H, Ar); 7.33 (m, 2H, Ar); 6.96 (m, 1H, Ar); 6.36 (s, 1H, Ar); 4.41 (s, 2H); 4.17 (s, 2H); 1.32 (s, 9H, tert-butyl 9H).

Synthesis of Example B63: N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (methylamino-methyl)-phenyl]-propanamide

Step 1 : Sulfuric acid (0.3 mL) was added to a solution of 2-(3-fluoro-4-nitro-phenyl)-propionic acid in methanol. The reaction mixture was allowed to reflux for 15 hours and then cooled to room temperature. The solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium hydrogen sulfate. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to obtain 1 .

Step 2 : 10% palladium on carbon was added to a solution of ethyl acetate ( 1 ) dissolved in ethanol and tetrahydrofuran, and the mixture was aerated with hydrogen. After the reaction mixture was stirred for 6 hours, the mixture was filtered with celite and purified by column chromatography to afford 2 .

Step 3 : Add a solution of 2 (1 equivalent) of cyanide in a solution of p-toluenesulfonic acid monohydrate (3 equivalents) dissolved in cyanide. The resulting suspension was cooled to 10 to 15 ° C, and sodium nitrite (2 equivalents) and potassium iodide (2.5 equivalents) dissolved in water were slowly added to the suspension. The reaction mixture was stirred for 10 minutes, then allowed to warm to 20 ° C and stirred until starting material was consumed. After 4 hours, water and sodium bicarbonate (until pH = 9 to 10) were added and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography to obtain 3 .

Step 4 : placing compound 3 , tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphinoferrocene, zinc powder and zinc cyanide in a round bottom flask, The mixture was aerated with nitrogen, and then dimethylacetamide (0.02 equivalent) was added dropwise using a syringe. The reaction mixture was stirred at 120 ° C for 15 hours, and after cooling to room temperature, extracted with ethyl acetate to 2N The organic layer was washed with water, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography to give the desired product 4 .

Step 5 : To a solution of Compound 4 dissolved in tetrahydrofuran and water (1:1), sodium hydroxide (2.5 equivalent) was added and the mixture was stirred at room temperature. After 15 hours, the reaction mixture was acidified to pH = 2 to 3 with acetic acid. The mixture was extracted with dichloromethane and water. The organic layer was washed with water, dried (MgSO4) and evaporated. The product was purified by column chromatography (solvent: 10:1 dichloromethane:methanol) to afford the desired product 5 .

Step 6 : N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (1.5 equivalent), N-hydroxybenzotriazole (1.5 equivalent) and (3-three Butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylamine (1 equivalent) was added to the ( 5 ) solution, followed by dropwise addition of triethylamine (2.5 mL). The reaction mixture was stirred at room temperature overnight. The reactant was quenched with water and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (eluent: ethyl acetate / n-hexane) to afford 6 .

Step 7 : Nickel chloride hexahydrate (1 equivalent) and Compound 6 were stirred in absolute ethanol over 15 minutes to activate them. Sodium borohydride (7 equivalents) was added and the mixture was stirred for 2 hours. The diatomaceous earth was added to the reaction, and the reaction was filtered through a filter containing diatomaceous earth and washed with ethanol. The residue was concentrated and then purified to give 7 .

Step 8 : To a solution of Compound 7 dissolved in methanol, sodium methoxide (1M in methanol) was added followed by triacetal (5 equivalents). The reaction mixture was refluxed for 1.5 hours and then cooled to 0 ° C in an ice bath. Sodium borohydride (6 equivalents) was carefully added. The mixture was again refluxed for 1 hour and then cooled. The mixture was extracted with dichloromethane and washed with water. After evaporating the solvent, the mixture was purified by column chromatography (dichloromethane:methanol = 4:1) to afford the title compound B63.

Hydrogen nuclear magnetic resonance (300 MHz, deuterated chloroform): δ 7.41-7.32 (m, 5H, Ar-H); 6.99-6.95 (m, 3H, Ar-H); 6.06 (s, 1H, Ar-H); 5.643 (bs, 1H, Ar-NH); 4.46 (d, 2H, J = 6.00 Hz, pyrazole-α-H); 3.88 (s, 2H, Ar-α-H); 3.49 (q, 1H, J) = 7.50 Hz, Ar-α-H); 2.48 (s, 3H, methanesulfonyl-CH ₃ ); 1.47 (d, 3H, J = 6.00 Hz, Ar-α-CH ₃ ); 1.33 (s, 9H) , tertiary butyl).

Synthesis of Example B64: N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(dimethylamine) Methyl)-3-fluoro-phenyl]-propanamide

Steps 1 through 7 were carried out in the same manner as the synthesis described in Example B63 .

Step 8 : Add sodium cyanoborohydride to a solution of the compound 7 and the paraformaldehyde dissolved in acetic acid. The reaction mixture was stirred at room temperature for 15 hours and then poured onto ice. The pH was adjusted to 9 with sodium bicarbonate. The mixture was extracted with ethyl acetate and dried over sodium sulfate. After evaporation of the solvent, the mixture was purified by column chromatography to afford the desired compound.

Hydrogen nuclear magnetic resonance (400 MHz, deuterated chloroform): δ 7.38 (s, 1H, Ar-H); 7.35-7.27 (m, 3H, Ar-H); 7.21 (d, 1H, Ar-H); 6.95 ( m, 2H, Ar-H); 6.01 (s, 1H, Ar-H); 5.48 (bs, 1H, Ar-NH); 4.46 (d, 2H, J = 6.00 Hz, pyrazole-α-H); 3.68 (s, 2H, Ar-α-H); 3.49 (q, 1H, J = 7.50 Hz, Ar-α-H); 2.30 (s, 6H, methanesulfonyl-CH ₃ and N-CH ₃ ) ; 1.47 (d, 3H, J = 6.00 Hz, Ar-α-CH ₃ ); 1.33 (s, 9H, tert-butyl).

Synthesis of Example B86: 1-[4-(Methanesulfonylamino-methyl)-3-methoxy-phenyl]-3-[[2-(m-tolyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-urea

Step 1 : To a solution of 1 (300 mg, 1.683 mmol) of THF (m.). The reaction mixture was stirred at 66 ° C for 16 hours and then cooled to room temperature. The residue was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to give 2 (270 mg);

Step 2 : Toluene chloride was added at 0 ° C with stirring in a solution of pyridine 2 (190 mg, 1.04 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with 1 N of hydrogen chloride. The residue was diluted with dichloromethane and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 3 (205 mg);

Step 3 : 10% palladium on carbon (21 mg) was added to a solution of 3 (205 mg, 0.79 mmol) in tetrahydrofuran and ethanol as a solvent. The mixture was aerated in a hydrogen gas cylinder. The resulting mixture was stirred for 16 hours and then filtered over celite. The filtrate was removed under vacuum. The crude product was purified by column chromatography to afford 4 (190 mg);

Step 4 : Add phenyl chloroformate (0.11 mL, 0.866 mmol) to a solution of 4 (190 mg, 0.83 mmol) in tetrahydrofuran (6 mL) and cyanomethane (8 mL). And pyridine (0.08 mL, 0.99 mmol). The reaction mixture was stirred at room temperature for 3 hours. The residue was dissolved in ethyl acetate and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 5 (238 mg);

Step 5: To a stirred, dissolved in acetonitrile and 6 (57 mg, 0.225 mmol) of 5 (79 mg, 0.225 mmol) was added 4-dimethylamino pyridine (28 mg, 0.225 mmol). The reaction mixture was stirred at 50 ° C for 16 hours. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and filtered. The solvent is removed under vacuum. The crude product was purified by column chromatography to afford 7 (104 mg);

Hydrogen nuclear magnetic resonance (300 MHz, dimethyl hydrazine): δ 7.42 (m, 4H, Ar); 7.17 (m, 2H, Ar); 6.83 (d, J = 9.87 Hz, 1H, Ar); 6.77 (s) , 1H, Ar); 4.38 (d, 2H, J = 5.67 Hz, CH ₂ ); 4.03 (d, 2H, J = 6.06 Hz, CH ₂ ); 3.74 (s, 3H, methoxy); 2.81 (s , 3H, methanesulfonyl); 2.40 (s, 3H, Ar-CH ₃ ).

Synthesis of Example B95: N-[[2-(3-Chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[ (amine sulfonamide)-methyl]-phenyl]-propanamide

Steps 1 to 5 were carried out by the synthesis method as described in Example B63 .

Step 6 : Add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (1.5 equivalent), N-hydroxybenzotriazole (1.5 equivalent) to ( 5 ) solution And (1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methylamine (1 eq.), then triethylamine (2.5 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (eluent: ethyl acetate / n-hexane) to afford 6 .

Step 7 : Nickel chloride hexahydrate (1 equivalent) and Compound 6 were stirred in absolute ethanol over 15 minutes to activate them. Sodium borohydride (7 equivalents) was added to the mixture and stirred for 2 hours. To the reaction was added diatomaceous earth, which was filtered with a filter containing diatomaceous earth and washed with ethanol. The residue was concentrated and then purified to give 7 .

Step 8 : Compound 7 and Compound 8 were dissolved in dichloromethane, and triethylamine (0.1 equivalent) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours and then quenched with water. The organic layer was extracted with dichloromethane and concentrated. Purification was carried out by column chromatography to obtain compound 9 .

Step 9 : To a solution of Compound 9 in methylene chloride solution was added trifluoroacetic acid (12 mL). Water was added to the mixture, and the separated mixture was extracted with dichloromethane. The residue was purified by column chromatography to give Compound 10 (Example B95).

Hydrogen nuclear magnetic resonance (400 MHz, deuterated chloroform): δ 7.41-7.33 (m, 5H, Ar-H); 6.94 (m, 2H, Ar-H); 5.39 (s, 1H, Ar-H); 5.39 ( Bs, 1H, α-NH); 4.43 (bs, 1H, Ar-α-NH); 4.46 (2, 2H, Ar-α-CH ₂ ); 4.41 (m, 2H, J = 6.00 Hz, α-CH ₂ ); 4.32 (d, 2H, α-CH ₂ ); 3.47 (m, 1H); 2.38 (s, 3H, Ar-CH ₃ ); 1.44 (d, 3H, J = 6.00 Hz, α-CH ₃ ) ; 0.93 (m, 2H, cyclopropyl-CH ₂ ); 0.68 (m, 2H, cyclopropyl-CH ₂ ).

Step 10 : Add 1 equal amount of chlorosulfonium isocyanate (CSI) dropwise to a solution of ice-cold tertiary butanol (1 equivalent) dissolved in anhydrous dichloromethane; then add 4-dimethylaminopyridine (2 equal amount). The mixture was stirred at room temperature for 3 hours. The organic layer was extracted with dichloromethane and washed with water. After purification by column chromatography, a colorless powdery product (Compound 8 ) was obtained.

Synthesis of Example B97: N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro- 4-[(Aminosulfonylamino)-methyl]-phenyl]-propanamide

Steps 1 through 5 were carried out as described in Example B95 .

Step 6 : Add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (1.5 equivalent), N-hydroxybenzotriazole (1.5 equivalent) to ( 5 ) solution And (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamine (1 equivalent), followed by dropwise addition of triethylamine (2.5 mL) . The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography (eluent: ethyl acetate / n-hexane) to afford 6 .

Steps 7 to 10 were carried out in the same manner as the synthesis method described in Example B95 .

NMR characteristics of Example B97 (Compound 10 ):

Hydrogen nuclear magnetic resonance (400 MHz, deuterated chloroform): δ 7.41-7.33 (m, 5H, Ar-H); 6.94 (m, 2H, Ar-H); 6.40 (s, 1H, Ar-H); 5.59 ( Bs, 1H, α-NH); 4.64 (bs, 1H, Ar-α-NH); 4.46 (s, 2H, Ar-α-CH ₂ ); 4.32 (d, 2H, J = 8.00 Hz, α-CH ₂ ); 4.09 (q, 1H, α-CH); 1.44 (d, 3H, J = 6.00 Hz, α-CH ₃ ).

The mass spectrometry data for the following exemplary compounds are cited below by way of example (Table 1):

Pharmacological method

I. Functional testing at vanilloid receptor 1 (VRI/TRPV1 receptor)

The following tests can be used to determine the vanilloid receptor of a substance against rat species. 1 (VR1/TRPV1) stimulating or antagonistic effects. In this assay, the influx of calcium ions through the receptor channel is complemented by a calcium ion sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, The Netherlands) with a fluorescence imaging plate reader ( FLIPR, Molecular Instruments, Sunnyvale, USA) Quantification.

method:

Complete medium: 50 mL of HAMS F12 nutrient mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany) containing 10% by volume of fetal bovine serum (FCS) (foetal calf serum, Gibco Invitrogen GmbH, Karlsruche, Germany, heat-killed Live), 2 mM L-glutamate (Sigma, Munich, Germany), 1% by weight antibiotic/antimytic solution (PAA, Pasching, Austria), and 25 ng/ mL of nerve growth factor (NGF) medium (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany).

Cell culture plate: A black 96-well plate (96-well black/transparent plate, BD) coated with polylysine and having a transparent base was coated with laminin (Gibco Invitrogen GmbH, Karlsruhe, Germany). Biosciences, Heidelberg, Germany); the concentration of this layer of mucin was diluted to 100 μg/mL with a phosphate solution (free of calcium and magnesium phosphate, Gibco Invitrogen GmbH, Karlsruhe, Germany). An aliquot of laminin at a concentration of 100 μg/mL was dispensed and transferred and stored at -20 °C. The aliquot was diluted to a 10 μg/mL layer of mucin with a phosphate solution at a ratio of 1:10, and 50 μL of the solution was separately pipetted into the recess of the cell culture plate. The cell culture plates were incubated at 37 ° C for at least 2 hours, the excess solution was aspirated, and the recesses were washed twice with a phosphate solution. The coated cell culture plates are stored in a large amount of phosphate solution until they are removed before culturing the cells.

Preparation of cells:

The spine of the rat that was sacrificed by the decapitation was removed and immediately placed in the ice-cold Hank's buffered saline solution (Gibco Invitrogen GmbH, Karlsruhe, Germany), the balanced salt placed in the ice bath. The solution was mixed with 1% by volume (by volume) antibiotic/antimycotic solution (PAA, Pasching, Austria). The spine is cut longitudinally and removed from the spinal canal along with the fascia. Subsequently, the dorsal root ganglia (DRG) was removed and stored in ice-cold, Hank's balanced salt solution mixed with 1% by volume antibiotic/antimycotic solution. All remaining blood and spinal nerves were removed from the dorsal root ganglia, and the dorsal root ganglia were transferred to 500 μL of ice-cold type 2 collagenase (PAA, Pasching, Austria) at 37 ° C in each case. Incubate for 35 minutes. After adding 2.5% by volume of trypsin (PAA, Pasching, Austria), incubation was continued for 10 minutes at 37 °C. After the incubation was completed, the enzyme-containing solution was carefully removed by pipette, and 500 μL of complete medium was added to each of the remaining dorsal root ganglia. Each dorsal root ganglion was suspended several times, passed through a No. 1, No. 12, and No. 16 cannulae with a syringe and transferred to a 50 mL tipped centrifuge tube containing 15 mL of complete medium. (Falcon tube). The contents of each of the sharp-bottomed centrifuge tubes were separately filtered through a 70 μm Falcon filter and centrifuged at 1,200 rpm for 10 minutes at room temperature. The obtained cell pellets were separately suspended in 250 μL of complete medium, and the number of cells was determined.

The cell number of the suspension was adjusted to 3 x 10 ⁵ cells per ml, and 150 μL of each of the suspensions was placed in a recess of the coated cell culture plate. The plate was placed in an incubator for 2 to 3 days at 37 ° C, 5% by volume of carbon dioxide and 95% relative humidity. Subsequently, the cells were placed in a Hank's balanced salt solution (Gibco Invitrogen GmbH, Karlsruhe, Germany) containing 2 μM of Fluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV, Leiden, The Netherlands). The cells were incubated at 37 ° C for 30 minutes and then washed 3 times with Hank's balanced salt solution; they were then incubated at room temperature for 15 minutes for measurement of calcium ions by fluorescent imaging plates. In this case, the calcium-dependent light was measured before and after the addition of the substance (λex = 488 nm, λem = 540 nm). It is quantified by the strongest fluorescence intensity (fluorescence counts, FC) as a function of time.

Fluorescence imaging reading board inspection:

The Fluorescence Imaging Plate Reader protocol includes the addition of two substances. First, the compound to be tested (10 μM) was pipetted onto the cells, and the amount of calcium ion influx was compared with the control group (10 μM capsaicin). This comparison provides a percentage of activation based on calcium ion signal after addition of 10 μM capsaicin (CP). After 5 minutes of incubation, 100 nM of capsaicin was added and the influx of calcium ions was interpreted.

Desensitization of agonists and antagonists results in inhibition of calcium ion influx. The percent inhibition was calculated by comparing it to the maximum inhibitory effect that can be achieved with 10 μM anti-capsaicin.

A triple analysis (n=3) was performed and independent experiments were repeated at least 3 times (N=4).

From the result of the formula to be tested at different concentrations of the displacement caused by the compound (I) from the percentage calculated capsaicin causes displacement of 50% of inhibitory concentration IC _50. The K _i value of the test substance was converted in the manner of the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

II. Functional testing at vanilloid receptor 1 (VRI/TRPV1 receptor)

The following test can also be used to determine the effect of a substance on the priming or antagonism of vanilloid receptor 1 (VR1). In this assay, the influx of calcium ions through the receptor channel is complemented by a calcium ion sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, The Netherlands) with a fluorescence imaging plate reader ( FLIPR, Molecular Instruments, Sunnyvale, USA) was quantified.

method:

Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC), UK) were stably transfected with the VR1 gene. For functional testing, these cells were seeded at a density of 25,000 cells per well in a black 96-well plate coated with polylysine, with a transparent base (96-well black/transparent plate, BD Biosciences, Heidelberg, Germany). The cells were incubated overnight in medium (HAM'S F12 nutrient mixture, 10% by volume fetal bovine serum, 18 μg/mL L-proline) at 37 ° C and 5% carbon dioxide. On the next day, cells were incubated with Fluo-4 (2 μM Fluo-4, 0.01% by volume Pluronic F127 (Molecular Probes) in Hank's balanced salt solution (Gibco Invitrogen GmbH, Karlsruhe, Germany) at 37 °C. After 30 minutes, the cells were washed three times with Hank's balanced salt solution, and the cells were again incubated at room temperature for 15 minutes for fluorescence imaging to measure calcium ions. The calcium dependence of the material was measured before and after the addition of the material. Sexual fluorescence (λex = 488 nm, λem = 540 nm) was quantified by the strongest fluorescence intensity (fluorescence count) as a function of time.

Fluorescence imaging reading board inspection:

The Fluorescence Imaging Plate Reader protocol includes the addition of two substances. First, the compound to be tested (10 μM) was pipetted onto the cells, and the calcium ion influx of the compound (10 μM capsaicin) was compared (10 μM capsaicin) (based on addition) Percentage of activity of calcium ion signal after 10 μM capsaicin). After 5 minutes of incubation, 100 nM capsaicin was added and the influx of calcium ions was interpreted.

Desensitization of agonists and antagonists results in inhibition of calcium ion influx. The percent inhibition was calculated by comparing it to the maximum inhibitory effect achieved by 10 μM anti-capsaicin.

From the result of the formula to be tested at different concentrations of the displacement caused by the compound (I) from the percentage calculated capsaicin causes displacement of 50% of inhibitory concentration IC _50. The K _i value of the test substance was converted in the manner of the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

Pharmacological data

The affinity of the compound according to the present invention for the vanilloid receptor 1 (VR1/TRPV1 receptor) is determined by the above method (Pharmacological Method I or II).

The compounds according to the invention have a strong affinity for the VR1/TRPV1 receptor (Table 2).

The abbreviations in Table 2 have the following meanings:

Cap=Capsaicin

AG = agonist

The value after the "@" symbol is the concentration at which the inhibition (in percent) is determined.

Claims (15)

a substituted compound of the formula (R), Wherein R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ CH ₂ —OH, CH ₂ -OCH ₃ , CH ₂ CH ₂ -OCH ₃ , OCFH ₂ , OCF ₂ H, OCF ₃ , OH, NH ₂ , a C _1-4 alkyl group, an OC _1-4 alkyl group, a NH-C _1-4 a group consisting of an alkyl group and a N(C _1-4 alkyl) ₂ group, wherein the C _1-4 alkyl group is unsubstituted in each case, and R ² represents CF ₃ and an unsubstituted C _{1- a 4-} alkyl or an unsubstituted C _3-6 cycloalkyl group, the R ⁷ and R ⁹ groups being independently selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, OH, a group consisting of OCF ₃ , a C _1-4 alkyl group, and an OC _1-4 alkyl group, wherein the C _1-4 alkyl group is unsubstituted in each case, and A represents N, CH or C (CH) ₃ ), q represents 0, 1 or 2, R ¹¹² represents H or a C _1-4 alkyl group, which is unsubstituted or is selected from 1, 2 or 3 selected from F, Cl, Br, OH, = a group consisting of a group consisting of a substituent such as OCH ₃ monosubstituted, disubstituted or trisubstituted, R ¹¹³ represents H, S(=O) ₂ -NH ₂ , a C _1-4 alkyl group or a S(=O) ₂ -C _1-4 alkyl, wherein the C _1-4 alkyl group is unsubstituted in each case, or Is mono-, di- or tri-substituted with 1, 2 or 3 groups independently selected from the group consisting of substituents such as F, Cl, Br, OH, =0 and OCH ₃ , or - premise q ≠ 0- R ¹¹² and R ¹¹³ together with the nitrogen atom to which they are bonded form a 3- to 6-membered heterocyclic group which is unsubstituted or is independently selected from 1, 2 or 3 independently from F, Cl, Br, CN. , CF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , tertiary butyl, cyclopropyl, OH, =O, OCH ₃ , OCF ₃ , NH ₂ , NH(CH ₃ ) and N ( a group monosubstituted, disubstituted or trisubstituted, consisting of a substituent such as CH ₃ ) ₂ , optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and/or physiologically Accept the form of salt. A compound according to claim 1, wherein R ² represents CF ₃ , a tertiary butyl group or a cyclopropyl group. The compound according to claim 1 or 2, wherein R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF _{3 .} , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH A group consisting of (CH ₃ ) and N(CH ₃ ) ₂ . A compound according to any one of the preceding claims, characterized in that A represents N, R ¹¹² represents H or a C _1-4 alkyl group, which is unsubstituted or is selected in 1, 2 or 3 a group of mono-, di- or tri-substituted groups of substituents such as free F, Cl, Br, OH, =O and OCH ₃ , and R ¹¹³ represents H, S(=O) ₂ -NH ₂ , a C _1-4 An alkyl group or an S(=O) ₂ -C _1-4 alkyl group, wherein the C _1-4 alkyl group is unsubstituted in each case, or is selected from 1, 2 or 3 selected from F, Cl, a group consisting of a substituent consisting of a substituent such as Br, OH, =O, and OCH ₃ , a mono-, di- or tri-substituted, or - assuming that q ≠ 0-R ¹¹² and R ¹¹³ together with the nitrogen atom to which they are bonded form a 3 to a 6-membered heterocyclic group which is unsubstituted or which is selected from 1, 2 or 3 independently of each other from F, Cl, Br, CN, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , a group of mono-butyl, cyclopropyl, OH, =O, OCH ₃ , OCF ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) _2, such as a mono-, di- or Trisubstituted, or A represents CH or C(CH ₃ ), R ¹¹² represents H or a C _1-4 alkyl group, which is unsubstituted or is selected from 1, 2 or 3 a group of mono-, di- or tri-substituted substituents composed of substituents such as F, Cl, Br, OH, =O and OCH ₃ , and R ¹¹³ represents H, S(=O) ₂ -NH ₂ , a C _1-4 alkane a group which is unsubstituted or monosubstituted, disubstituted or trisubstituted with 1, 2 or 3 groups selected from substituents such as F, Cl, Br, OH, =0 and OCH ₃ or Provided that q≠0-R ¹¹² and R ¹¹³ together with the nitrogen atom to which they are bonded form a 3- to 6-membered heterocyclic group which is unsubstituted or is independently selected from F, 1, 2 or 3 , Cl, Br, CN, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , tert-butyl, cyclopropyl, OH, =O, OCH ₃ , OCF ₃ , NH ₂ , NH ( CH ₃ ) is a group monosubstituted, disubstituted or trisubstituted with a substituent such as N(CH ₃ ) ₂ . A compound according to any one of the preceding claims, characterized in that q represents 0, 1 or 2, A represents N, and R ¹⁰¹ is selected from the group consisting of H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , a group consisting of NH(CH ₃ ) and N(CH ₃ ) ₂ , and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) a group consisting of N(CH ₃ ) ₂ , or q represents 1 or 2, A represents CH or C(CH ₃ ), and R ¹⁰¹ is selected from H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH ( a group consisting of CH ₃ ) and N(CH ₃ ) ₂ , and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ - OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-C A group consisting of H ₂ CH ₃ , NH ₂ , NH(CH ₃ ), and N(CH ₃ ) ₂ . A compound according to any one of the preceding claims, characterized in that at least one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ is ≠H. A compound according to any one of the preceding claims, wherein R ⁷ and R ⁹ are independently selected from the group consisting of H, F, Cl, Br, CF ₃ , CN, OH, OCF ₃ , CH ₃ , CH A group consisting of ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ and O-CH ₂ CH ₃ . A compound according to any one of the preceding claims, characterized in that at least one of R ⁷ and R ⁹ is ≠H. The compound according to items 1 to 3 and 5 to 8 of the aforementioned patent application, which is characterized by a partial structure (RS1) Representative part structure (PR1) Wherein R ¹¹⁴ represents NH ₂ or an unsubstituted C _1-4 alkyl group. The compound according to items 1 to 3 and 5 to 9 of the aforementioned patent application, which is characterized by a partial structure (RS1) Representative part structure (PR1) Wherein R ¹¹⁴ represents NH ₂ , CH ₃ or CH ₂ CH ₃ . A compound according to any one of the preceding claims, characterized in that A represents N or C(CH ₃ ). The compound according to the first to fifth, seventh, ninth and tenth aspects of the preceding claims, wherein A represents N and R ¹⁰¹ is selected from H, F, Cl, Br , CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O a group consisting of -CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ , and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ a group of NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ , or A represents CH or C(CH ₃ ), and R ¹⁰¹ is selected from H, F, Br, CFH ₂ , CF ₂ H , CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , a group consisting of NH(CH ₃ ) and N(CH ₃ ) ₂ , and R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN , CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ a group of O-CH ₂ CH ₃ , NH ₂ , NH(CH ₃ ) and N(CH ₃ ) ₂ ; R ² represents CF ₃ , a tertiary butyl or a cyclopropyl group, and R ⁷ and R ⁹ are mutually Independently selected from the group consisting of H, F, Cl, Br, CF ₃ , CN, OH, OCF ₃ , CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , O-CH ₃ and O-CH ₂ CH ₃ Group, part of its structure (RS1) Representative part structure (PR1) Wherein R ¹¹⁴ represents NH ₂ , CH ₃ or CH ₂ CH ₃ . A compound according to any one of the preceding claims, which is selected from the group consisting of the following groups B1 N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H- Pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B2 N-[[2-(3- Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl) (B)-phenyl]-propanin; B3 N-[[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl ]-2-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B4 N-[[2-(3-chlorophenyl)-5-cyclopropyl -2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamide; B5 N-[[2- (3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-phenyl] -propanamide; B6 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonate) Amino-methyl)-phenyl]-propionamide; B7 2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2-(3-fluoro Phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B8 2-[3-fluoro-4-(methylsulfonylamino-methyl )-phenyl]-N -[[5-(Trifluoromethyl)-2-[3-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-methyl]-propanamide; B9 N-[[ 5-tert-butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl) -phenyl]-propanamide; B10 N-[[5-tert-butyl-2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2 -[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B11 1-[[5-trit-butyl-2-(3-chlorophenyl)-2H -pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-3-methoxy-phenyl]-urea; B12 1-[[2-(3 -Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-3-methoxy -phenyl]-urea; B13 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-chloro- 4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B14 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazole- 3-yl]-methyl]-3-[4-(methylamino-methyl)-phenyl]-urea; B15 2-[3-fluoro-4-(methylsulfonylamino-methyl)- Phenyl]-N-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B16 N- [[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-A 2-[4-[[(ethylsulfonyl)amino]-methyl]-3-fluoro-phenyl]-propanamine; B17 N-[[2-(3-chlorophenyl)- 5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-[[(ethylsulfonyl)amino]-methyl]-3-fluoro-phenyl] -propanolamine; B18 N-[[2-(4-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro- 4-(Methanesulfonylamino-methyl)-phenyl]-propanamine; B19 N-[[2-(3,4-difluoro-phenyl)-5-(trifluoromethyl)-2H -pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B20 N-[[5-third Butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl] -propanolamine; B21 N-[[5-tert-butyl-2-(4-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (Methanesulfonylamino-methyl)-phenyl]-propanamine; B22 2-[3-chloro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2- (3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B23 N-[[2-(3-chlorophenyl)- 5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-acetamide ; B24 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3 -[4-(ethylamine-methyl)-3-fluoro-phenyl]-urea; B25 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazole-3 -yl]-methyl]-3-[4-(ethylamine-methyl)-3-fluoro-phenyl]-urea; B26 N-[[5-tert-butyl-2-(3-chlorobenzene) -2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-acetamide; B27 1-[[ 2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3,5-difluoro-4-(methylsulfonamide Base-methyl)-phenyl]-urea; B28 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3- [4-(Methanesulfonylamino-methyl)-phenyl]-urea; B29 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3 -yl]-methyl]-2-[3-fluoro-4-[(methyl-methylsulfonyl-amino)-methyl]-phenyl]-propanamine; B30 N-[[5-three Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[(methyl-methylsulfonyl-amino)- Methyl]-phenyl]-propanin; B31 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3- [3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-urea; B32 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazole -3-yl]-methyl]-3-[3,5-difluoro-4-(methylsulfonylamino-methyl)- Yl] - urea; B33 N - [[4 - [[[2- (3- chlorophenyl) -5- (trifluoromethyl) -2H- pyrazol-3-yl] - methyl - urethane Mercapto]amino]-2-fluoro-phenyl]-methyl]-acetamide; B34 N-[[4-[[[5-tris-butyl-2-(3-chlorophenyl)-) 2H-pyrazol-3-yl]-methyl-aminomethylindenyl]amino]-2-fluoro-phenyl]-methyl]-acetamide; B35 1-[[2-(3-chloro Phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl]-urea ; B36 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(amine sulfonamide) -methyl]-phenyl] -urea ; B37 2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2-(3-fluorophenyl)- 5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-acetamide; B38 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-3-[4-(dimethylaminomethyl)-3-fluoro-phenyl] -urea ; B39 1-[4-(aminomethyl) 3-fluoro-phenyl]-3-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; B40 1 -[4-(Aminomethyl)-3-fluoro-phenyl]-3-[[5-trit-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-A Base]-urea; B41 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyridyl Zyrid-3-yl]-methyl]-3-[3-fluoro-4-[(amine sulfonylamino)-methyl]-phenyl]-urea; B42 2-[4-(aminomethyl) 3-fluoro-phenyl]-N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamide; B43 N-[[5-Tris-butyl-2-[3-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (Methanesulfonylamino-methyl)-phenyl]-propanamine; B44 1-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazole-3- ]]-methyl]-3-[4-(methylsulfonylamino-methyl)-phenyl]-urea; B45 1-[[5-tri-tert-butyl-2-(3-fluorophenyl) -2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-phenyl] -urea ; B46 1-[[5-tertiary butyl-2 -(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(aminosulfonylamino)-methyl]-phenyl]-urea ; B47 2-[4-(Aminomethyl)-3-fluoro-phenyl]-N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl ]-Methyl]-propanamide; B48 1-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-3-[[2-(3-fluorophenyl)-5 -(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B49 1-[[2-(3,4-difluoro-phenyl)-5-(trifluoromethyl) )-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino-methyl)- Yl] - urea; B50 1 - [[5- three-Butyl-2- (3-fluorophenyl) -2H- pyrazol-3-yl] - methyl] -3- [3-fluoro-4- (Methanesulfonamide-methyl)-phenyl]-urea; B51 1-[[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazole-3 -yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl] -urea ; B52 1-[[2-(3-chlorophenyl)-5 -(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl] -urea ; B53 1 -[[5-tert-butyl-2-(4-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino)- Methyl)-phenyl] -urea ; B54 1-[[5-tert-butyl-2-[3-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-methyl] -3-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-urea; B55 1-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl ]-3-[[5-(Trifluoromethyl)-2-[3-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-methyl]-urea; B56 1-[ [5-tert-butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]- Phenyl]-urea; B57 1-[[2-(3,4-difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3- [4-[(Aminosulfonylamino)-methyl]-phenyl] -urea ; B58 1- [3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-3-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyridyl Zyridin-3-yl]-methyl] -urea ; B59 1-[[5-tert-butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3 -[3-fluoro-4-[(aminesulfonylamino)-methyl]-phenyl]-urea; B60 1-[[2-(3-fluorophenyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(aminesulfonylamino)-methyl]-phenyl] -urea ; B61 1-[[2- (3-Chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(aminesulfonylamino)-methyl]- Phenyl] -urea ; B62 1-[[2-(3,4-difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3- [3-Fluoro-4-[(amine sulfonylamino)-methyl]-phenyl] -urea ; B63 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H- Pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylamine-methyl)-phenyl]-propanamine; B64 N-[[5-tert-butyl-2 -(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(dimethylaminomethyl)-3-fluoro-phenyl]-propanamine; B65 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(dimethylaminomethyl) -3-fluoro-phenyl]-propanamine; B66 2-[4-(ethylamido-methyl)-3-fluoro-phenyl] -N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propanamine; B67 2-[4-(B Amidino-methyl)-3-fluoro-phenyl]-N-[[5-tri-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl] -propanamide; B68 2-[3-Fluoro-4-(methylsulfonylamino-methyl)-phenyl]-N-[[2-(m-tolyl)-5-(trifluoromethyl) -2H-pyrazol-3-yl]-methyl]-propanamide; B69 1-[[5-tert-butyl-2-(3,4-difluoro-phenyl)-2H-pyrazole- 3-yl]-methyl]-3-[3-fluoro-4-[(amine sulfonylamino)-methyl]-phenyl]-urea; B70 1-[[2-(3-chloro-4) -fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[(aminesulfonylamino)-methyl ]-Phenyl]-urea; B71 1-[3-Fluoro-4-[(Aminosulfonylamino)-methyl]-phenyl]-3-[[2-(3-methoxyphenyl) -5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B72 1-[[5-tert-butyl-2-(3,4-difluoro-phenyl) -2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-urea; B73 1-[3-fluoro- 4-(Methanesulfonylamino-methyl)-phenyl]-3-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazole-3- Base]-methyl]-urea; B74 1-[[5-tert-butyl-2-(3,4-difluoro-phenyl)-2H- Pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl]-urea; B75 1-[[2-(3-chlorophenyl) -5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl] -urea ; B76 N-[[ 2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-3 -methoxy-phenyl]-propanamine; B77 1-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -3-[4-[(Aminosulfonylamino)-methyl]-phenyl] -urea ; B78 1-[[2-(3-chloro-4-fluoro-phenyl)-5-(trifluoro) Methyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl]-phenyl] -urea ; B79 1-[[2-( 3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[(aminosulfonylamino)-methyl] -phenyl]-urea; B80 1-[3-fluoro-4-[(aminosulfonylamino)-methyl]-phenyl]-3-[[2-(3-isopropyl-phenyl) -5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B81 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)- 2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-phenyl] -urea ; B82 2-[3-fluoro-4-(methylsulfonate) Amino-methyl)-phenyl]-N-[[2-(3-isopropyl-phenyl)-5-(three Ylmethyl) -2H- pyrazol-3-yl] - methyl] - propan Amides; B83 1 - [[2- ( 3- isopropyl-phenyl) - 5- (trifluoromethyl) -2H -pyrazol-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-phenyl]-urea; B84 1-[[2-(3-chlorophenyl)- 5-(Trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[[(ethylsulfonyl)amino]-methyl]-phenyl] -urea ; B85 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[[(ethanesulfonyl)amino] -methyl]-phenyl] -urea ; B86 1-[4-(methylsulfonylamino-methyl)-3-methoxy-phenyl]-3-[[2-(m-tolyl)- 5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl] -urea ; B87 1-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]- 3-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea; B88 N-[[5-tert-butyl-2 -(m-tolyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonylamino-methyl)-phenyl]-propanamine; B89 1-[4-(Methanesulfonylamino-methyl)-phenyl]-3-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl] -methyl]-urea; B90 1-[[5-tert-butyl-2-(m-tolyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(methylsulfonate) Amino-methyl)-phenyl]-urea; B91 1-[4-[[(ethylsulfonyl)amino]-methyl]-phenyl]-3-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazole -3-yl]-methyl]-urea; B92 1-[[5-trit-butyl-2-(m-tolyl)-2H-pyrazol-3-yl]-methyl]-3-[4 -[[(ethanesulfonyl)amino]-methyl]-phenyl] -urea ; B93 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazole-3 -yl]-methyl]-2-[3-fluoro-4-[(amine sulfonylamino)-methyl]-phenyl]-propanamine; B94 2-[3-fluoro-4-[( Amidoxime)-methyl]-phenyl]-N-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl] -methyl]-propanamine; B95 N-[[2-(3-chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro -4-[(Aminosulfonylamino)-methyl]-phenyl]-propanamine; B96 N-[[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl) -2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[(amine sulfonylamino)-methyl]-phenyl]-propanamide; B97 N-[[ 2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-[(aminesulfonylamino) -methyl]-phenyl] -propanamine ; B98 N-[[5- trit -butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2 -[4-(Methanesulfonylamino-methyl)-3-methoxy-phenyl]-propanamide; B99 1-[ [2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(rhodin-1-yl-methyl) -phenyl]-urea; B100 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3- Fluoro-4-(piperidin-1-yl-methyl)-phenyl]-urea; B101 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazole-3 -yl]-methyl]-3-[3-fluoro-4-(rhodindin-1-yl-methyl)-phenyl]-urea; B102 N-[[2-(3-chlorophenyl)- 5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-[(aminosulfonylamino)-methyl]-phenyl]-propanamide; B103 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-[(aminosulfonylamino)-- ]]-phenyl] -propanin ; B104 N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2 -[4-(Methanesulfonylamino-methyl)-phenyl]-propanamine; B105 1-[[2-(3-Fluorophenyl)-5-(trifluoromethyl)-2H-pyridyl Zyrid-3-yl]-methyl]-3-[4-(methylsulfonylamino-methyl)-3-methoxy-phenyl] -urea ; B106 N-[[2-(3-chloro) Phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-3-methyl-phenyl ]-propanamide; and B107 N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazole- 3-yl]-methyl]-2-[4-(methylsulfonylamino-methyl)-3-methyl-phenyl]-propanamide; optionally in the form of a single stereoisomer or stereo The form of the mixture of structures, in the form of a free compound and/or in the form of a physiologically acceptable salt. A pharmaceutical dosage form comprising at least one substituted compound according to any one of claims 1 to 13. A substituted compound according to any one of claims 1 to 13 for use in the treatment and/or prevention of one or more diseases and/or disorders constituting pain, selected from the following types of pain The composition group is better: acute pain, chronic pain, neuropathic pain, visceral pain and joint pain, hyperalgesia, allodynia, burning pain, migraine, depression, nervousness, axonal injury, neurodegenerative disease, Choose from multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease group, cognitive dysfunction, better cognitive deficits, especially memory impairment, epilepsy, respiratory diseases Preferably, it is selected from the group consisting of asthma, bronchitis and inflammation of the lungs, cough, urinary incontinence, overactive bladder, gastrointestinal disorders and/or injuries, duodenal ulcer, gastric ulcer, irritating enteropathy, and stroke. Eye irritation, skin irritation, neuropathic skin disease, allergic skin disease, dryness, leukoplakia, herpes simplex, inflammation, intestines, eyes, bladder, skin or Cavity mucosa is better in inflammation, diarrhea, itching, osteoporosis, arthritis, osteoarthritis, rheumatic diseases, abnormal diet, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity. , drug dependence, drug abuse, drug dependence withdrawal symptoms, drug tolerance, Natural or synthetic opioids are better, drug dependence, drug abuse, drug dependence withdrawal symptoms, alcohol dependence, alcohol abuse, alcohol dependence withdrawal symptoms, use in diuresis, inhibition of urinary sodium excretion, and effects on the cardiovascular system For alertness, for treating wounds and/or burns, for treating nerve blockage, for lifting libido, for regulating motor activity, for anti-anxiety, for local anesthesia and/or for inhibiting adverse side effects, Preferably, it is selected from the group consisting of fever, hypertension, and bronchoconstriction induced by the use of a vanilloid receptor 1 (VR1/TRPV1 receptor) agonist, selected from the group consisting of capsaicin, cactus toxin, ovanov, a The group consisting of Fani, SDZ-249665, SDZ-249482, Newvni and Casavalni is preferred.