JP2014532746A - Carboxamide and urea derivatives based on substituted pyrazolyls bearing phenyl moieties substituted with CO-containing groups as vanilloid receptor ligands - Google Patents

Abstract

The present invention relates to carboxamide and urea derivatives based on substituted pyrazolyls bearing phenyl moieties substituted with CO-containing groups as vanilloid receptor ligands, pharmaceutical compositions containing these compounds, as well as pain and further diseases And / or to these compounds for use in the treatment and / or prevention of disorders.

Description

  The present invention relates to carboxamides and urea derivatives based on substituted pyrazolyls bearing phenyl moieties substituted with CO-containing groups as vanilloid receptor ligands, pharmaceutical compositions containing these compounds, pain, Relates to these compounds for use in treating and / or preventing diseases and / or disorders.

  The treatment of pain, particularly neuropathic pain, is very important in medicine. Effective pain therapy is needed worldwide. There is an urgent need for activity for patient-focused, target-oriented treatment of chronic and non-chronic pain (which should be understood to mean successful and sufficient treatment of patient pain) This has been documented in numerous scientific studies that have recently emerged in the field of basic research on applied analgesics or nociception.

  Vanilloid receptor subtype 1 (VR1 / TRPV1), often referred to as capsaicin receptor, treats pain, particularly pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain Is a good starting point to do. This receptor is stimulated by vanilloids such as capsaicin, heat, and protons, among others, and plays a central role in pain generation. In addition, it is also important for a number of additional physiological and pathophysiological processes, such as migraine, depression, neurodegenerative diseases, cognitive impairment, anxiety, epilepsy, cough, diarrhea, pruritus, It is a suitable target for treating a number of additional disorders such as inflammation, cardiovascular disorders, eating disorders, medication addiction, medication misuse, and urinary incontinence.

  Compounds having affinity for vanilloid receptor subtype 1 (VR1 / TRPV1) are known from, for example, WO2010 / 127855 (A2) (Patent Document 1) and WO2010 / 127856 (A2) (Patent Document 2). .

WO2010 / 127855 (A2) WO2010 / 127856 (A2)

  There is a need for additional compounds that have comparable or better properties not only for their affinity for vanilloid receptor 1 (VR1 / TRPV1 receptor) but also for themselves (efficacy, efficacy).

  Thus, it may be advantageous to improve the metabolic stability, solubility in aqueous media, or permeability of the compound. These factors can have beneficial effects on oral bioavailability or can change the PK / PD (pharmacokinetic / pharmacodynamic) profile; this provides, for example, a more beneficial shelf life Can be done.

  A weak or non-existent interaction with transporter molecules involved in the uptake and excretion of the pharmaceutical composition can also be considered an improvement in the bioavailability of the pharmaceutical composition and a manifestation of at most slight interactions . Furthermore, the enzymes involved in the degradation and excretion of the pharmaceutical composition, as such test results also suggest that the pharmaceutical composition may be expected to have minimal or no interaction at all. The interaction with should be as little as possible.

  The object of the present invention was therefore to provide new compounds which preferably have advantages over prior art compounds. The compound has a pharmacological activity in a pharmaceutical composition, preferably for treating and / or preventing a disorder or disease mediated at least in part by vanilloid receptor 1 (VR1 / TRPV1 receptor). It should be particularly suitable as an ingredient.

  This object is achieved by the subject matter described herein.

  Substituted compounds of general formula (U) as shown below show outstanding affinity for vanilloid receptor subtype 1 (VR1 / TRPV1 receptor) and thus vanilloid receptor 1 (VR1 / It has surprisingly been found to be particularly suitable for preventing and / or treating disorders or diseases mediated at least in part by TRPV1).

  In addition to its activity with respect to the VR1-receptor, there is one or more additional advantageous properties, such as no adequate potency, appropriate efficacy, elevated body temperature and / or thermal pain threshold; Appropriate solubility in biologically relevant media, in particular in aqueous media of physiologically acceptable pH values, such as in buffer systems, for example in phosphate buffer systems; appropriate metabolic stability and diversity (E.g. sufficient stability with respect to the oxidizing ability of liver enzymes such as cytochrome P450 (CYP) enzyme, and sufficient diversity regarding metabolic excretion via these enzymes), etc. The substituted compound (U) is particularly suitable.

  The invention therefore relates to substituted compounds of the general formula (U), optionally in the form of a single stereoisomer or a mixture of stereoisomers, the free compound and / or the physiologically acceptable salts thereof.

[Where:
R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ are independently of each other 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 , OCHF ₂ , OCF ₂ H, OCF ₃ , OH, NH ₂ , C _1-4 alkyl, O—C _1-4 alkyl, NH—C _1-4 alkyl, and N ( C _1-4 alkyl) selected from the group consisting of ₂ , wherein C _1-4 alkyl is unsubstituted in each case;
R ² represents CF ₃ , unsubstituted C _1-4 alkyl, or unsubstituted C _3-6 cycloalkyl,
R ⁷ and R ⁹ are independently of each other from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, OH, OCF ₃ , C _1-4 alkyl, and O—C _1-4 alkyl. (Wherein the C _1-4 alkyl is unsubstituted in each case)
A represents N, CH, or C (CH ₃ );
R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or independently from each other from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents selected),
OR ¹⁰⁵ (where
R ¹⁰⁵ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Represents C _1-4 alkyl which is mono-, _di- or tri-substituted with 1, 2 or 3 substituents, or NR ¹⁰⁶ R ¹⁰⁷ (wherein
R ¹⁰⁶ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH _{3 Represents} C _1-4 alkyl which is mono-, _di- or tri-substituted with 1, 2 or 3 substituents
R ¹⁰⁷ is
H, C _1-4 alkyl (unsubstituted or independently from each other from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents selected),
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted or F, Cl, Br, 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 ), and N (CH ₃ ) _2, 1, 2, or 3 independently selected from each other Mono-, di-, or tri-substituted with at least one substituent, and at least one ring member of the heterocyclyl is selected from the group consisting of O, S, N, NH, and N (C _1-4 alkyl) And)
Phenyl (unsubstituted or _{F, Cl, Br, CN,} CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ,), With 1, 2, or 3 substituents, preferably R ²⁰¹ , R ²⁰² and / or R ²⁰² , independently selected from each other from the group consisting of N (CH ₃ ) ₂ , OH, OCF ₃ , and OCH ₃ ; Mono-, di- or tri-substituted) or heteroaryl (unsubstituted or F, Cl, Br, CN, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert .- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) 2, OH, OCF 3, and OCH ₃ 1, 2 are each independently selected from the group consisting of, or Monosubstituted with substituents,, disubstituted, or is selected from the group consisting of three is substituted) or R ¹⁰⁶ and R ^107, together with the nitrogen atom connecting them, unsubstituted or Or F, Cl, Br, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert. 1, 2, or 3 independently selected from the group consisting of butyl, cyclopropyl, OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ A 3- to 6-membered heterocyclyl that is mono-, di-, or tri-substituted with a substituent of

  The term “single stereoisomer” preferably means in the sense of the present invention individual enantiomers or diastereoisomers. The term “mixture of stereoisomers” in the sense of the present invention means racemic compounds and mixtures of enantiomers and / or diastereoisomers in any mixing ratio.

  The term “physiologically acceptable salt” preferably comprises, in the sense of the invention, a salt of at least one compound according to the invention with at least one physiologically acceptable acid or base.

  A physiologically acceptable salt of at least one compound according to the invention and at least one physiologically acceptable acid is preferably in the meaning of the invention at least one compound according to the invention, It refers to a salt with at least one inorganic or organic acid that is physiologically acceptable, particularly when used in humans and / or other 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, fumaric acid, Maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxoproline, 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, aspartic acid. Citric acid and hydrochloric acid are particularly preferred. Thus, hydrochloride and citrate are particularly preferred salts.

A physiologically acceptable salt of at least one compound according to the invention and at least one physiologically acceptable base is preferably in the meaning of the invention according to at least one invention as an anion. Refers to a salt of a compound and at least one preferably inorganic cation that is physiologically acceptable, particularly when used in humans and / or other mammals. Alkali metal and alkaline earth metal salts are particularly preferred, but ammonium salts [NH wherein x = 0, 1, 2, 3, or 4 and R represents a branched or unbranched C _1-4 alkyl residue [NH _x R _4−x ] ⁺ is also preferable, and (1) or (2) sodium, (1) or (2) potassium, magnesium, or calcium salt is particularly preferable.

The terms “alkyl” and “C _1-4 alkyl” are preferably individually branched or unbranched and may be unsubstituted or mono- or polysubstituted in the sense of the present invention. An acyclic saturated aliphatic hydrocarbon which may be, for example, mono-, di- or tri-substituted and may contain 1 to 4, ie 1, 2, 3 or 4 carbon atoms Including residues, ie, C _1-4 aliphatic residues, ie, C _1-4 alkanyl. Preferred C _1-4 alkanyl residues are methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -Butyl, and tert. -Selected from the group consisting of butyl.

In relation to the terms “alkyl” and “C _1-4 alkyl”, the term “monosubstituted” or “multisubstituted” such as disubstituted or trisubstituted, in the sense of the present invention, relates to the corresponding residue or group. , Refers to a single substitution or multiple substitutions of one or more hydrogen atoms, each independently of one another, with at least one substituent, eg di- or tri-substitution. With respect to polysubstituted residues and groups, such as disubstituted or trisubstituted residues and groups, the term “polysubstituted” such as disubstituted or trisubstituted refers to those residues and groups on different atoms or at the same atom. At various points, such as in the case of CF ₃ or CH ₂ CF ₃ , on the same carbon atom, or in the case of CH (OH) —CH ₂ CH ₂ —CHCl ₂ A tri-substitution with is included. Multiple substitutions can be performed using the same substituent or using different substituents.

The terms “cycloalkyl” and “C _3-6 cycloalkyl” are preferably cycloaliphatic (alicyclic) containing 3, 4, 5, or 6 carbon atoms for this purpose of the invention. Formula) hydrocarbons, i.e. the hydrocarbons may be saturated and unsubstituted or mono- or polysubstituted, e.g. mono-, di- or tri-substituted _C3-6 -Means an alicyclic residue. Cycloalkyls can be attached to the individual superstructures through any desirable ring member of the cycloalkyl residue. Preferably, cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, more preferably from the group consisting of cyclopropyl and cyclobutyl. A particularly preferred cycloalkyl is cyclopropyl.

The terms “heterocyclyl” and “3- to 6-membered heterocyclyl” are preferably in the meaning of the invention at least one, if appropriate even 2 or 3 carbon atoms are O, S, S ( ═O), S (═O) ₂ , N, NH, and N (C _1-8 alkyl) each replaced by a heteroatom or heteroatom group independently selected from each other and the ring members Can be unsubstituted or mono- or poly-substituted, for example mono-, di-, or tri-substituted 3-6 ring members, ie 3, 4, 5, or 6 ring members ( That is, it includes aliphatic saturated heterocycloalkyl having 3 to 6 membered heterocyclyl). Thus, heterocyclyl is a heteroalicyclic residue. Such heterocyclyl example, may be formed from the base R ^107. Preferred heterocyclyls according to the invention are azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxetanyl, pyrrolidinyl, piperazinyl, 4- Selected from the group consisting of methylpiperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiophenyl, thiazolidinyl, and thiomorpholinyl. The heterocyclyl according to the invention formed from the radicals R ¹⁰⁶ and R ¹⁰⁷ and the nitrogen atom connecting them contains at least one N as ring member and contains additional heteroatom (s) or heteroatom groups (Multiple) may be included. Azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dihydropyridinyl, imidazolidinyl, isoxazolidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, pyrazolidinyl, tetrahydropyrrolyl, tetrahydropyridinyl, thiazolidinyl And heterocyclyl residues from groups containing thiomorpholinyl are preferred heterocycles formed from R ¹⁰⁶ and R ¹⁰⁷ and the nitrogen atom linking them.

In relation to the terms “cycloalkyl”, “C _3-6 cycloalkyl”, “heterocyclyl”, and “3-6 membered heterocyclyl”, the term “monosubstituted” or “multisubstituted” such as disubstituted or trisubstituted In the sense of the present invention, in the context of the corresponding residue or group, a single substitution or a plurality of substitutions, independently of one another, of one or more hydrogen atoms by at least one substituent, for example di- or tri-substituted. Refers to substitution. With respect to polysubstituted residues and groups such as di- or tri-substituted residues and groups, the term “multi-substitution” such as di- or tri-substitution refers to these residues on different atoms or on the same atom and Polysubstitution of groups, for example disubstitution at various points, as in the case of 1,1-difluorocyclohexyl, on the same carbon atom, or in the case of 1-chloro-3-fluorocyclohexyl Is included. Multiple substitutions can be performed using the same substituent or using different substituents.

  Within the scope of the present invention, the symbols used in the formula:

Indicates the linkage of the corresponding residue to the individual super general structure.

In a preferred embodiment of the compounds according to the invention,
R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ are independently of one another, 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)} is selected from the group consisting of ₂ .

Preferably R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ are independently of each other H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , Selected from the 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 of each other H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OCH ₃ , OCF ₃ , CH ₃ , O—CH ₃ , O Selected from the group consisting of —CH ₂ CH ₃ and N (CH ₃ ) ₂ .

Even more preferably,
R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ are each independently composed of H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O—CH ₃ , and O—CH ₂ CH _3. Selected from the group.

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 .

In particular,
R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ are independently selected from the group consisting of H, F, Cl, CF ₃ , and O—CH ₃ .

Even more particularly preferably,
R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ are independently of each other selected from the group consisting of H, F, Cl, and O—CH ₃ .

In a preferred embodiment of the compounds according to the invention, at least one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ is not ≠ H.

In another preferred embodiment of the compounds according to the invention, one or two of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ , preferably R ¹⁰² and / or R ¹⁰³ represents H.

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

In another preferred embodiment of the compounds according to the invention,
R ¹⁰¹ and R ¹⁰² are independently of each other 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 Selected from the group consisting of 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 ¹⁰³ represents H.

Preferably,
R ¹⁰¹ and R ¹⁰² are independently of each other 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 Selected from the group consisting of —CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ , more preferably, independently of each other, 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 , even more preferred 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 CH ₃ , even more preferred Are independent of each other H, _F, Cl, selected from the group consisting of _{CF 3, OCF 3, CH 3} , and O-CH _3, in particular, independently of one another, consisting of H, F, Cl, CF _3, and O-CH ₃ Selected from the group, even more particularly preferably selected from the group consisting of H, F, Cl, and O—CH ₃ independently of each other;
R ¹⁰³ represents H.

In yet another preferred embodiment of the compounds according to the invention,
R ¹⁰¹ is 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 ,
R ¹⁰² and R ¹⁰³ both represent H.

Preferably,
R ¹⁰¹ is 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)} is selected from the group consisting of _2, more _{preferably, 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 , still more preferably F, Cl, CFH ₂ , CF ₂ H, _{CF 3, OCF 3, CH 3} , O-CH 3, and _O-CH 2 is selected from the group consisting of CH _3, even more _{preferably, F, Cl, CF 3,} OCF 3, CH 3, and O-CH It is selected from the group consisting of ₃ Particularly, F, Cl, selected from the group consisting of CF _3, and O-CH _3, even more particularly preferred, F, is selected from the group consisting of Cl, and O-CH _3,
R ¹⁰² and R ¹⁰³ both represent H.

In yet another preferred embodiment of the compounds according to the invention,
R ¹⁰² _{is, 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 ,
R ¹⁰¹ and R ¹⁰³ both represent H.

Preferably,
R ¹⁰² _{is, 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)} is selected from the group consisting of _2, more _{preferably, 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 , still more preferably F, Cl, CFH ₂ , CF ₂ H, Selected from the group consisting of CF ₃ , OCF ₃ , CH ₃ , O—CH ₃ , and O—CH ₂ CH ₃ , and more preferably F, Cl, CF ₃ , OCF ₃ , CH ₃ , and O—CH It is selected from the group consisting of ₃ Particularly, F, Cl, selected from the group consisting of CF _3, and O-CH _3, even more particularly preferred, F, is selected from the group consisting of Cl, and O-CH _3,
R ¹⁰¹ and R ¹⁰³ both represent H.

In a still further preferred embodiment of the compounds according to the invention,
R ¹⁰¹ is 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 ,
R ¹⁰² represents 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 ( Selected from the group consisting of CH ₃ ) ₂ , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ ;
R ¹⁰³ represents H.

Preferably,
R ¹⁰¹ is 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)} is selected from the group consisting of _2, more _{preferably, 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 , still more preferably F, Cl, CFH ₂ , CF ₂ H, _{CF 3, OCF 3, CH 3} , O-CH 3, and _O-CH 2 is selected from the group consisting of CH _3, even more _{preferably, F, Cl, CF 3,} OCF 3, CH 3, and O-CH It is selected from the group consisting of ₃ Particularly, F, Cl, selected from the group consisting of CF _3, and O-CH _3, even more particularly preferred, F, is selected from the group consisting of Cl, and O-CH _3,
R ¹⁰² _{is, 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- Selected from the group consisting of CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ , more preferably 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)} is selected from the group consisting of _2, even more preferably, H, F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O—CH ₃ , and O—CH ₂ CH ₃ , even more preferably H, F, Cl, CF ₃ , OCF _3. from CH _3, and O-CH ₃ Is selected from that group, in particular, H, F, Cl, selected from the group consisting of CF _3, and O-CH _3, even more particularly preferably, H, F, the group consisting of Cl, and O-CH ₃ Selected from
R ¹⁰³ represents H.

  In another particularly preferred embodiment according to the invention, the substructure (US2) is:

Selected from the group consisting of:

  Even more particularly preferably, the partial structure (US2) is:

Selected from the group consisting of:

  Most preferably, the partial structure (US2) is:

Selected from the group consisting of:

Preferably, it is selected from the group consisting of:

In another preferred embodiment of the compounds according to the invention,
R ² is CF ₃ , methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec. -Butyl, tert. -Represents butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Preferably,
R ² is CF ₃ , 2-propyl, n-butyl, iso-butyl, sec. -Butyl, tert. -Represents butyl, cyclopropyl or cyclobutyl.

More preferably,
R ² is CF ₃ , tert. -Represents butyl or cyclopropyl.

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

In another particularly preferred embodiment of the compound according to the invention, R ² is tert. -Represents butyl.

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

In a further preferred embodiment of the compound according to the invention,
R ⁷ and R ⁹ are independently of each other 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 Selected from the group consisting of —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 .

Even more preferably,
R ⁷ and R ⁹ are independently selected from the group consisting of H, F, Cl, and O—CH ₃ , and more preferably are independently selected from the group consisting of H, F, and Cl. .

In a still further preferred embodiment of the compounds according to the invention, at least one of R ⁷ and R ⁹ is ≠ H.

In a further preferred embodiment of the compound according to the invention, R ⁹ represents H.

In yet another preferred embodiment of the compounds according to the invention,
R ⁷ is a group consisting of 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. 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 , more preferably F, Cl , CF ₃ , O—CH ₃ , and O—CH ₂ CH ₃ , even more preferably selected from the group consisting of F, Cl, and O—CH ₃ , even more preferably F And Cl selected from the group consisting of
R ⁹ represents H.

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

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

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

In another preferred embodiment of the compounds according to the invention,
R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or independently from each other from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents selected),
OR ¹⁰⁵ (where
R ¹⁰⁵ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Represents C _1-4 alkyl that is mono-, _di- , or tri-substituted with 1, 2, or 3 substituents) or NR ¹⁰⁶ R ¹⁰⁷ (wherein
R ¹⁰⁶ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH _{3 Represents} C _1-4 alkyl which is mono-, _di- or tri-substituted with 1, 2 or 3 substituents
R ¹⁰⁷ is
H, C _1-4 alkyl (unsubstituted or independently from each other from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents selected),
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted or F, 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 ), and N (CH ₃ ) ₂ , 1, 2, independently selected from each other Or monosubstituted, disubstituted, or trisubstituted with three substituents),
Phenyl _{(F, Cl, Br, CN} , CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) 1, 2, or 3 substituents independently selected from each other from the group consisting of ₂ , OH, OCF ₃ and OCH ₃ , preferably R ²⁰¹ , R ²⁰² and / or R ²⁰³ , substituted, or tri are substituted), or heteroaryl (unsubstituted or _{F, Cl, Br, CF 3} , CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, cyclopropyl _{, NH 2, NH (CH 3} ), N (CH 3) 2, OH, OCF 3, and monosubstituted from the group consisting of OCH ₃ 1, 2 are selected independently of each other, or three substituents Disubstituted, or is selected from the group consisting of three is substituted),
Provided that when A represents CH or C (CH ₃ ), provided that R ¹⁰⁷ cannot represent H, or R ¹⁰⁶ and R ¹⁰⁷ together with the nitrogen atom connecting them, non substituted or _{F, Cl, Br, CF 3} , CH 3, CH 2 CH 3, CH (CH 3) 2, tert. 1, 2, or 3 independently selected from the group consisting of butyl, cyclopropyl, OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ A 3- to 6-membered heterocyclyl that is mono-, di-, or tri-substituted with the above substituents.

Preferably,
R ¹⁰⁴ is
1, 2 selected from the group consisting of H, C _1-4 alkyl (unsubstituted or NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Or mono-, di-, or tri-substituted with 3 substituents, or OR ¹⁰⁵ (where:
R ¹⁰⁵ is H, unsubstituted or mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of NH ₂ , OH, and OCH ₃ Represents C _1-4 alkyl, or NR ¹⁰⁶ R ¹⁰⁷ (wherein
R ¹⁰⁶ is 1, ₂ or ₂ , independently selected from the group consisting of H, unsubstituted or NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , ═O, OH, and OCH ₃ . Or C _1-4 alkyl which is mono-, _di- or tri-substituted with three substituents,
R ¹⁰⁷ is
1, 2 selected from the group consisting of H, C _1-4 alkyl (unsubstituted or NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH ₃ Or is mono-, di- or tri-substituted with three substituents),
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted or 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 ), and N (CH ₃ ) ₂ , one by one, two, or three substituents independently selected from each other Substituted, disubstituted or trisubstituted),
Phenyl _{(F, Cl, Br, CN} , CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) 1, 2, or 3 substituents independently selected from each other from the group consisting of ₂ , OH, OCF ₃ and OCH ₃ , preferably R ²⁰¹ , R ²⁰² and / or R ²⁰³ , substituted, or tri are substituted), or heteroaryl (unsubstituted or _{F, Cl, Br, CN,} CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) 2, OH, OCF 3, and OCH ₃ 1, 2 are each independently selected from the group consisting of, or three substituents Substituted, disubstituted, or is selected from the group consisting of three is substituted),
Provided that when A represents CH or C (CH ₃ ), provided that R ¹⁰⁷ cannot represent H, or R ¹⁰⁶ and R ¹⁰⁷ together with the nitrogen atom connecting them, non Or CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert. 1, 2, or 3 independently selected from the group consisting of butyl, cyclopropyl, OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ A 3- to 6-membered heterocyclyl that is mono-, di-, or tri-substituted with the above substituents.

More preferably,
R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ ), Or OR ¹⁰⁵ (where
R ¹⁰⁵ is H, unsubstituted, or mono-, di-, or tri-substituted C with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ Represents _1-4 alkyl) or NR ¹⁰⁶ R ¹⁰⁷ (where:
R ¹⁰⁶ is H, unsubstituted, or mono-, di-, or tri-substituted C with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH _{3 Represents 1-4} alkyl,
R ¹⁰⁷ is
H, C _1-4 alkyl (unsubstituted or mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl (in each case unsubstituted or each other from the group consisting of CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OH, and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 independently selected substituents),
Phenyl _{(F, Cl, Br, CN} , CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, NH 2, NH (CH 3), N (CH 3) 2, OH, OCF 3, and 1, 2 or 3 substituents independently selected from the group consisting of OCH ₃ , preferably R ²⁰¹ , R ²⁰² and / or R ²⁰³ , monosubstituted, disubstituted or trisubstituted Or heteroaryl (unsubstituted or F, Cl, Br, CN, CF ₃ , CH ₃ , CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , OH, OCF ₃ and OCH ₃ are selected from the group consisting of 1, 2 or 3 substituents which are independently selected from each other, mono-, di- or tri-substituted),
Provided that when A represents CH or C (CH ₃ ), provided that R ¹⁰⁷ cannot represent H, or R ¹⁰⁶ and R ¹⁰⁷ together with the nitrogen atom connecting them, non Substituted or from CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ A 3- to 6-membered heterocyclyl that is mono-, di-, or tri-substituted with 1, 2, or 3 substituents selected independently from each other.

Even more preferably,
R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
OR ¹⁰⁵ (where
R ¹⁰⁵ is H, unsubstituted, or mono-, di-, or tri-substituted C with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ Represents _1-4 alkyl), or NR ¹⁰⁶ R ¹⁰⁷ (where:
R ¹⁰⁶ is H, unsubstituted, or mono-, di-, or tri-substituted C with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH _{3 Represents 1-4} alkyl,
R ¹⁰⁷ is
C _1-4 alkyl (unsubstituted or mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl (in each case unsubstituted, 1, 2, or 3 independently selected from the group consisting of CH ₃ , OH, and OCH ₃ Mono-, di-, or tri-substituents)
Phenyl (F, Cl, CF ₃ , CH ₃ , OH, OCF ₃ , OCH _3, 1, 2, or 3 substituents independently selected from each other, preferably R ²⁰¹ , R ²⁰² , And / or R ²⁰³ is mono-, di-, or tri-substituted), or is selected from the group consisting of unsubstituted heteroaryl, or R ¹⁰⁶ and R ¹⁰⁷ are nitrogen atoms connecting them As well as mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of CH ₃ , OH, and OCH ₃ A 3-6 membered heterocyclyl is formed).

In a particularly preferred embodiment of the invention,
R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ are independently of each other H, F, Cl, Br, 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 ,
Preferably, wherein at least one of R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ is ≠ H,
R ² is CF ₃ , tert. -Represents butyl or cyclopropyl
R ⁷ and R ⁹ are independently of each other 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 Selected from the group consisting of —CH ₂ CH ₃ ;
Where at least one of R ⁷ and R ⁹ is ≠ H;
A represents N, CH or C (CH ₃ ), preferably N or C (CH ₃ ),
R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
OR ¹⁰⁵ (where
R ¹⁰⁵ is H, unsubstituted, or mono-, di-, or tri-substituted C with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ Represents _1-4 alkyl) or NR ¹⁰⁶ R ¹⁰⁷ (where:
R ¹⁰⁶ is H, unsubstituted, or mono-, di-, or tri-substituted C with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH _{3 Represents 1-4} alkyl,
R ¹⁰⁷ is
C _1-4 alkyl (unsubstituted or mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl (in each case unsubstituted, 1, 2, or 3 independently selected from the group consisting of CH ₃ , OH, and OCH ₃ Mono-, di-, or tri-substituents)
Phenyl (F, Cl, CF ₃ , CH ₃ , OH, OCF ₃ , OCH _3, 1, 2, or 3 substituents independently selected from each other, preferably R ²⁰¹ , R ²⁰² , And / or R ²⁰³ is mono-, di-, or tri-substituted), or is selected from the group consisting of unsubstituted heteroaryl, or R ¹⁰⁶ and R ¹⁰⁷ are nitrogen atoms connecting them As well as mono-, di-, or tri-substituted with 1, 2, or 3 substituents independently selected from the group consisting of CH ₃ , OH, and OCH ₃ A 3-6 membered heterocyclyl is formed).

  Preferred embodiments of the compounds according to the invention of general formula (U) have the general formula (U0-a) and / or (U0-b):

[Wherein the individual groups, variable symbols, and indications have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof].

  Further preferred embodiments of the compounds according to the invention of general formula (U) have the general formula (U1-a), (U1-a-1) and / or (U1-a-2):

[Wherein the individual groups, variable symbols, and indications have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof].

  Furthermore, preferred embodiments of the compounds of the general formula (U) according to the invention have the general formula (U1-b), (U1-b-1) and / or (U1-b-2):

[Wherein the individual groups, variable symbols, and indications have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof].

  In addition, preferred embodiments of the compounds of the general formula (U) according to the invention have the general formula (U1-c), (U1-c-1) and / or (U1-c-2):

[Wherein the individual groups, variable symbols, and indications have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof].

  Still further preferred embodiments of the compounds according to the invention of general formula (U) have the general formula (U1-d), (U1-d-1), and / or (U1-d-2):

[In the formula, preferably, at least one of R ²⁰¹ , R ²⁰² , and R ^{203 in} each of the partial structures (U1-d), (U1-d-1), and (U1-d-2) is ≠ H, and the individual groups, variable symbols, and readings have the meanings described herein in relation to the compounds according to the invention and preferred embodiments thereof].

In particularly preferred embodiments of the present invention, general formulas (U), (U0-a), (U0-b), (U1-a), (U1-a-1), (U1-a-2), ( U1-b), (U1-b-1), (U1-b-2), (U1-c), (U1-c-1), (U1-c-2), (U1-d), ( U1-d-1) and / or the group R ¹⁰¹ in the compound of (U1-d-2) is F, Cl, CF ₃ , or O—CH ₃ , preferably F or Cl, most preferably Cl. (Preferably when R ¹⁰³ is H and R ¹⁰² represents H, F, Cl, CF ₃ , or OCH ₃ , more preferably R ¹⁰³ is H and R ¹⁰² is H, F or to represent a Cl, even more ^preferably, both ^{R 102} and ^{R 103} are, when representing a H), the remaining, Another group, variables symbols, and readings have the meanings described herein in relation to compounds and preferred embodiments thereof according to the present invention.

In particularly preferred embodiments of the present invention, general formulas (U), (U0-a), (U0-b), (U1-a), (U1-a-1), (U1-a-2), ( U1-b), (U1-b-1), (U1-b-2), (U1-c), (U1-c-1), (U1-c-2), (U1-d), ( U1-d-1) and / or (U1-d-2)
The group R ¹⁰¹ represents F, Cl, CF ₃ , or O—CH ₃ , preferably F or Cl, most preferably Cl (preferably R ¹⁰³ is H and R ¹⁰² is H, F, Cl, When CF ₃ or OCH ₃ is represented, more preferably R ¹⁰³ is H, and even more preferably when R ¹⁰² represents H, F or Cl, both R ¹⁰² and R ¹⁰³ both represent H. In case),
At least one of the groups R ⁷ and R ⁹ is ≠ H;
R ⁷ and R ⁹ , as well as the remaining individual groups, variable symbols, and indications have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.

Particularly preferred are compounds according to the invention from the following group which are optionally in the form of a single stereoisomer or a mixture of stereoisomers, free compounds and / or physiologically acceptable salts thereof: is there:
E1 N-[[2- (3-Fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-propanoyl-phenyl) -propionamide ;
E2 2- (3-Fluoro-4-propanoyl-phenyl) -N-[[2- (3-methoxyphenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propionamide ;
E3 N-[[2- (3,4-Difluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-propanoyl-phenyl) -Propionamide;
E4 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-benzamide;
E5 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-benzamide;
E6 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-benzamide;
E7 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzamide;
E8 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N-methyl-benzamide;
E9 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N-methyl-benzamide;
E10 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-methyl-benzamide;
E11 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-methyl-benzamide ;
E12 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N, N-dimethyl-benzamide;
E13 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N, N-dimethyl-benzamide;
E14 1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (morpholine-4-carbonyl) -phenyl] -Urea;
E16 N-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (morpholine-4-carbonyl)- Phenyl] -propionamide;
E17 N-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (morpholin-4-carbonyl) -phenyl] -Propionamide;
E18 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N- (2-hydroxy-ethyl ) -Benzamide;
E19 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (oxetane- 3-yl) -benzamide;
E20 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (1- Methyl-piperidin-4-yl) -benzamide;
E21 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (1-methyl- Piperidin-4-yl) -benzamide;
E22 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N-tetrahydro-pyran-4- Ile-benzamide;
E23 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-tetrahydro-pyran -4-yl-benzamide;
E24 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-tetrahydro-pyran-4 -Yl-benzamide;
E25 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N-phenyl-benzamide;
E26 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N-phenyl-benzamide;
E27 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N-phenyl-benzamide;
E28 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N-phenyl-benzamide;
E29 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-phenyl-benzamide;
E30 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- (4-chlorophenyl) -benzamide;
E31 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (3-chlorophenyl) -benzamide;
E32 N- (3-chlorophenyl) -4- [1-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -benzamide ;
E33 N- (4-chlorophenyl) -4- [1-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -benzamide ;
E34 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-chlorophenyl) -benzamide;
E35 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-chlorophenyl) -2-fluoro -Benzamide;
E36 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- (4-fluorophenyl) -benzamide;
E37 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- (4-fluorophenyl) -benzamide;
E38 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -2-fluoro-N- (4-fluorophenyl ) -Benzamide;
E39 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -2-fluoro-N- (4-fluorophenyl)- Benzamide;
E40 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (3-fluorophenyl) -benzamide;
E41 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (3-fluorophenyl)- Benzamide;
E42 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-fluorophenyl) -benzamide;
E43 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-fluorophenyl)- Benzamide;
E44 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (4-fluorophenyl) ) -Benzamide;
E45 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (4- Fluorophenyl) -benzamide;
E46 N- (4-chlorophenyl) -4- [1-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2 -Fluoro-benzamide;
E47 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- [4- (trifluoromethyl)- Phenyl] -benzamide;
E48 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- [4- (Trifluoromethyl) -phenyl] -benzamide;
E49 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- [4- (tri Fluoromethyl) -phenyl] -benzamide;
E50 4-[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- [4- (trifluoromethyl) -phenyl] -Benzamide;
E51 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- [4- (trifluoromethyl)- Phenyl] -benzamide;
E52 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-thiazole-2 -Yl-benzamide;
E53 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-thiazol-2-yl -Benzamide;
E54 2-chloro-4-[[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -benzoic acid;
E55 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-chloro-benzoic acid;
E56 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzoic acid;
E57 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzoic acid methyl ester;
E58 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzoic acid methyl ester;
E59 2-chloro-4-[[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -benzoic acid methyl ester;
E60 4-[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-chloro-benzoic acid methyl ester; and E61 1- [ [2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -3- (3-fluoro-4-formyl-phenyl) -urea.

  Furthermore, in the FLIPR assay using CHO K1 cells transfected with the human VR1 gene, less than 2,000 nM, preferably less than 1,000 nM, particularly preferably less than 300 nM, most particularly preferably less than 100 nM, and even more preferably less than 75 nM. In addition, compounds according to the invention which cause a 50% replacement of capsaicin present at a concentration of 100 nM, preferably at a concentration of less than 50 nM, most preferably less than 10 nM may be preferred.

In the process, Ca ²⁺ influx was measured with a fluorescence imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA) in a FLIPR assay using a Ca ²⁺ sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, The Netherlands). Quantify as described later in the specification.

  The substituted compounds according to the invention and the corresponding stereoisomers and also the individual corresponding acids, bases, salts and solvates are toxicologically safe and are therefore suitable as pharmaceutically active ingredients in pharmaceutical compositions. Yes.

  Accordingly, the present invention is in each case, where appropriate, in its pure stereoisomers, in particular enantiomers or diastereoisomers, in one form of its racemates, or in any desired mixing ratio. At least one of the present invention in the form of stereoisomers, in particular enantiomers and / or mixtures of diastereoisomers, each in the form of a corresponding salt, or each in the form of a corresponding solvate And a pharmaceutical composition containing, if appropriate, one or more pharmaceutically compatible adjuvants.

  These pharmaceutical compositions according to the invention are in particular for modulating vanilloid receptor 1- (VR1 / TRPV1), preferably for inhibiting vanilloid receptor 1- (VR1 / TRPV1) and / or for vanilloid receptor. Suitable for stimulating the body 1- (VR1 / TRPV1), ie they exert agonistic or antagonistic effects.

  Similarly, the pharmaceutical composition according to the invention is preferably suitable for preventing and / or treating disorders or diseases mediated at least in part by vanilloid receptor 1.

  The pharmaceutical composition according to the invention is suitable for administration to adults and children including infants and infants.

  The pharmaceutical composition according to the invention can be used as a liquid, semi-solid or solid pharmaceutical form, for example, injectable solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters. May be present in the form of suppositories, suppositories, ointments, creams, lotions, gels, emulsions, aerosols, or in multiparticulate form, for example in the form of pellets or granules, if appropriate Or can be decanted into capsules or suspended in a liquid and administered in that amount.

  Where appropriate, the pure stereoisomers, in particular the enantiomers or diastereoisomers, one form of the racemate, or the stereoisomers in any desired mixing ratio, in particular the enantiomers or In addition to at least one substituted compound according to the invention, which is in the form of a mixture of diastereoisomers or, where appropriate, in the form of the corresponding salt or in the form of the corresponding solvate, according to the invention. Pharmaceutical compositions are conventionally made from, for example, excipients, extenders, solvents, diluents, surfactants, dyes, preservatives, blasting agents, slip agents, lubricants, perfumes, and binders. Contains further physiologically compatible pharmaceutical adjuvants that may be selected from the group consisting of:

  The choice of physiologically compatible adjuvants used, and the amount thereof, is such that the pharmaceutical composition is oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal. Depending on whether it is intended to be applied topically, rectally, or topically, for example to skin, mucous membrane, and eye infections. Formulations in the form of tablets, dragees, capsules, granules, pellets, drops, juices, and syrups are preferably suitable for oral application, solutions, suspensions, easily reconstituted Dry formulations as well as propellants are preferably suitable for parenteral, topical and inhalation applications. Substitute compounds according to the invention for use in pharmaceutical compositions according to the invention, either in dissolved form in a repository or in plasters, to which agents that promote skin penetration are added if appropriate It is a preparation for transdermal application. Oral or transdermally applicable dosage forms may release individual replacement compounds according to the invention in a delayed manner.

  For example, “Remington's Pharmaceutical Sciences”, A.M. R. Conventional means, devices, methods known in the art, such as described in Gennaro (editor), 17th edition, Mack Publishing Company, Easton, Pa, 1985, in particular Part 8, Chapters 76-93, And the process is used to prepare a pharmaceutical composition according to the present invention. The corresponding description is hereby incorporated by reference and forms part of the present disclosure. The amount administered to a patient of each of the above-mentioned substituted compounds of the general formula I as indicated above may vary, for example the patient's weight or age, as well as the type of application, indications and severity of the disorder Depends on. Usually 0.001-100 mg / kg, preferably 0.05-75 mg / kg, particularly preferably 0.05-50 mg of at least one such compound according to the invention is applied per kg body weight of the patient.

  The pharmaceutical composition according to the invention is preferably pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; burning pain Depression; neurological disease; axonal injury; preferably a neurodegenerative disease selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease; cognitive impairment, preferably cognition Insufficiency, particularly preferably memory impairment; epilepsy; preferably a respiratory disease selected from the group consisting of asthma, bronchitis, and lung inflammation; cough; urinary incontinence; overactive bladder (OAB); Duodenal ulcer; gastric ulcer; irritable bowel syndrome; stroke; eye irritation; skin irritation; neurological skin disease; allergic skin disease; psoriasis; vitiligo; herpes simplex; Disease, preferably inflammation of the small intestine, eyes, bladder, skin, or nasal mucosa; diarrhea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic disease; preferably bulimia, cachexia, decreased appetite, and Eating disorders selected from the group consisting of obesity; medication dependence; medication abuse; medication-dependent withdrawal symptoms; development of tolerance to medication, preferably natural or synthetic opioids; drug dependence; drug abuse; drug-dependent withdrawal symptoms; alcohol To treat and / or prevent a disorder and / or disease selected from the group consisting of alcohol abuse and alcohol withdrawal withdrawal; for diuresis; for anti-natriuretic; To affect; to increase arousal; to treat wounds and / or burns; to treat severed nerves; libido To increase; to modulate motor activity; to relieve anxiety; to local anesthesia and / or preferably capsaicin, resiniferatoxin, olbanil, albanyl, SDZ-249665, SDZ-249482 Selected from the group consisting of hyperthermia, hypertension, and bronchoconstriction elicited by administration of a vanilloid receptor 1 (VR1 / TRPV1 receptor) agonist selected from the group consisting of, navanyl, and capsavanyl Suitable for inhibiting unwanted side effects.

  Particularly preferably, the pharmaceutical composition according to the invention is pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; migraine; depression; preferably Is a neurodegenerative disease selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease; cognitive dysfunction, preferably cognitive dysfunction, particularly preferably memory impairment; inflammation, preferably small intestine, eye Inflammation of the bladder, skin, or nasal mucosa; urinary incontinence; overactive bladder (OAB); medication dependence; medication abuse; medication-dependent withdrawal symptoms; development of tolerance to medication, preferably development of tolerance to natural or synthetic opioids; Drug dependence; drug abuse; drug dependence withdrawal; alcohol dependence; alcohol abuse and alcohol dependence withdrawal It is suitable for the treatment and / or prevention one or more disorders and / or diseases are selected.

  Most particularly preferably, the pharmaceutical composition according to the invention is suitable for treating and / or preventing pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain. Yes.

  The present invention further preferably inhibits vanilloid receptor 1- (VR1 / TRPV1) and / or vanilloid receptor 1- (for use in modulating vanilloid receptor 1- (VR1 / TRPV1). It relates to substituted compounds according to the invention for use in stimulating VR1 / TRPV1) and, if appropriate, to substituted compounds according to the invention and one or more pharmaceutically acceptable auxiliaries.

  The invention therefore relates to substituted compounds according to the invention for use in preventing and / or treating disorders and / or diseases mediated at least in part by vanilloid receptor 1, and, if appropriate, according to the invention. It further relates to substituted compounds and one or more pharmaceutically acceptable adjuvants.

  Thus, in particular, the present invention relates to pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain, and joint pain; hyperalgesia; allodynia; burning pain; Depression; neurological disease; axonal injury; preferably a neurodegenerative disease selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease; cognitive dysfunction, preferably a cognitive deficit state; Particularly preferably memory impairment; epilepsy; preferably a respiratory disease selected from the group consisting of asthma, bronchitis and lung inflammation; cough; urinary incontinence; overactive bladder (OAB); gastrointestinal tract disorder and / or injury Duodenal ulcer; gastric ulcer; irritable bowel syndrome; stroke; eye irritation; skin irritation; neurological skin disease; allergic skin disease; psoriasis; vitiligo; herpes simplex; inflammation; Or inflammation of the small intestine, eyes, bladder, skin, or nasal mucosa; diarrhea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic disease; preferably from bulimia, cachexia, decreased appetite, and obesity Eating disorders selected from the group; medication dependent; medication abuse; medication dependent withdrawal symptoms; development of tolerance to medication, preferably natural or synthetic opioids; drug dependence; drug abuse; drug dependence withdrawal symptoms; alcohol dependence; For use in preventing and / or treating a disorder and / or disease selected from the group consisting of alcohol abuse and alcohol dependence withdrawal symptoms; for diuresis; for anti-natriuretic; to the cardiovascular system To influence; to increase arousal; to treat wounds and / or burns; to treat severed nerves; For modulating motor activity; for relieving anxiety; for local anesthesia and / or preferably capsaicin, resiniferatoxin, olbanil, albanyl, SDZ-249665, SDZ- Selected from the group consisting of hyperthermia, hypertension, and bronchoconstriction, preferably caused by administering a vanilloid receptor 1 (VR1 / TRPV1 receptor) agonist selected from the group consisting of 249482, nubanil, and capsavanyl. It further relates to substituted compounds according to the invention for inhibiting undesired side effects and, where appropriate, substituted compounds according to the invention and one or more pharmaceutically acceptable auxiliaries.

  Substitute compounds according to the invention for use in preventing and / or treating pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain, and visceral pain, and if appropriate, Most particularly preferred are substituted compounds according to the invention and one or more pharmaceutically acceptable auxiliaries.

  The present invention relates to modulating vanilloid receptor 1- (VR1 / TRPV1), preferably for inhibiting vanilloid receptor 1- (VR1 / TRPV1) and / or vanilloid receptor 1- (VR1 / TRPV1) Pain, preferably selected from the group consisting of pain, preferably acute pain, chronic pain, neuropathic pain, visceral pain, and joint pain; hyperalgesia Allodynia; burning pain; migraine; depression; neurological disease; axonal injury; preferably a neurodegenerative disease selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease; Cognitive dysfunction, preferably a cognitive deficit state, particularly preferably memory impairment; epilepsy; preferably from the group consisting of asthma, bronchitis, and lung inflammation Respiratory disease; cough; urinary incontinence; overactive bladder (OAB); gastrointestinal tract disorder and / or injury; duodenal ulcer; gastric ulcer; irritable bowel syndrome; stroke; eye irritation; skin irritation; Allergic skin disease; psoriasis; vitiligo; herpes simplex; inflammation, preferably inflammation of the small intestine, eyes, bladder, skin, or nasal mucosa; diarrhea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic disease; Eating disorders, preferably selected from the group consisting of bulimia, cachexia, loss of appetite, and obesity; medication dependence; medication abuse; medication-dependent withdrawal symptoms; development of tolerance to medication, preferably natural or synthetic opioids; Drug dependence; drug abuse; drug dependence withdrawal symptoms; alcohol dependence; disorders selected from the group consisting of alcohol abuse and alcohol dependence withdrawal symptoms and / or For preventing and / or treating disorders and / or diseases mediated at least in part by vanilloid receptor 1, such as patients; for diuresis; for anti-natriuretic; to affect the cardiovascular system To increase arousal; to treat wounds and / or burns; to treat severed nerves; to increase libido; to modulate motor activity; to relieve anxiety A vanilloid receptor 1 (VR1) for local anesthesia and / or preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, albanyl, SDZ-249665, SDZ-249482, nubanil, and capsavanyl. / TRPV1 receptor) induced by administering an agonist, preferably For inhibiting undesirable side effects selected from the group consisting of hyperthermia, hypertension, and bronchoconstriction; at least one substituted compound according to the present invention and, if appropriate, one or more pharmaceutically acceptable It further relates to the use of at least one substituted compound according to the invention as an auxiliary agent.

  Another aspect of the present invention is to modulate vanilloid receptor 1- (VR1 / TRPV1), preferably to inhibit vanilloid receptor 1- (VR1 / TRPV1) and / or vanilloid receptor 1- Methods for stimulating (VR1 / TRPV1), and also disorders and / or diseases mediated at least in part by vanilloid receptor 1 in mammals, preferably pain, preferably acute pain, chronic pain , Neuropathic pain, visceral pain, and pain selected from the group consisting of joint pain; hyperalgesia; allodynia; burning pain; migraine; depression; neurological disease; axonal injury; A neurodegenerative disease selected from the group consisting of sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease; cognitive impairment, preferably Intellectual dysfunction, particularly preferably memory impairment; epilepsy; preferably a respiratory disease selected from the group consisting of asthma, bronchitis, and lung inflammation; cough; urinary incontinence; overactive bladder (OAB); And / or injury; duodenal ulcer; gastric ulcer; irritable bowel syndrome; stroke; eye irritation; skin irritation; neurological skin disease; allergic skin disease; psoriasis; vitiligo; herpes simplex; inflammation, preferably small intestine, eye, bladder, Inflammation of the skin or nasal mucosa; diarrhea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; preferably eating selected from the group consisting of bulimia, cachexia, loss of appetite, and obesity Disorders; medication dependence; medication abuse; medication-dependent withdrawal symptoms; medication, preferably development of tolerance to natural or synthetic opioids; drug dependence; drug abuse; drug-dependent withdrawal symptoms; Treat and / or prevent disorders and / or diseases selected from the group consisting of alcohol abuse and alcohol dependence withdrawal symptoms; for diuresis; for anti-natriuretic; affect cardiovascular system For increasing arousal; for treating wounds and / or burns; for treating severed nerves; for increasing libido; for modulating motor activity; Vanilloid receptor 1 for local anesthesia and / or preferably selected from the group consisting of capsaicin, resiniferatoxin, olbanil, albanyl, SDZ-249665, SDZ-249482, nubanil, and capsavanyl. VR1 / TRPV1 receptor) induced by administering an agonist A method for inhibiting undesirable side effects, preferably selected from the group consisting of hyperthermia, hypertension, and bronchoconstriction, said method comprising administering an effective amount of at least one substitution compound according to the invention to a mammal Administration.

  For example, Bennett, or Chung model (Bennett, GJ and Xie, YK, A peripheral mononeuropathies in rat products disorders in the sensation of pain sensation in 198, Bennett, GJ and Xie, YK. ), 87-107; Kim, SH, and Chung, JM, An experimental model for peripheral neuropathic produced by segmental spinner ligation in 3), 35, 35, 35 Tail flick (E.g., D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941))) or formalin test (e.g., according to D. Dubuisson et al., Pain 1977, 4, 161-174). Can be indicated by

  The invention further relates to a process for preparing substituted compounds according to the invention.

  In particular, at least one compound of general formula (U-II) in the reaction medium, if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base.

[Wherein R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ² , and n have one of the aforementioned meanings], a compound of general formula (U-III), wherein D═OH or Hal

[Wherein Hal represents halogen, preferably Br or Cl, R ⁷ , R ⁹ and R ¹⁰⁴ each have one of the aforementioned meanings, and A represents CH or C (CH ₃ ). In the reaction medium, if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base, to form a compound of the general formula (U)

[Wherein A represents CH or C (CH ₃ ), R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , and R ² and R ⁷ , R ^9, and R ¹⁰⁴ have one of the aforementioned meanings] Or at least one compound of general formula (U-II) in the reaction medium in the presence of phenyl chloroformate, if appropriate in the presence of at least one base and / or at least one coupling reagent.

[Wherein R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , and R ² have one of the aforementioned meanings] to form a compound of general formula (U-IV)

[Wherein R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , and R ² have one of the aforementioned meanings], the compound is purified and / or isolated, if appropriate, in the reaction medium, if appropriate Reacting a compound of general formula (U-IV) with a compound of general formula (U-V) in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base.

[Wherein R ⁷ , R ⁹ and R ¹⁰⁴ have one of the above-mentioned meanings, A represents N] to form a compound of general formula (U)

[Wherein A represents N, and R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , and R ² and R ⁷ , R ^9, and R ¹⁰⁴ have any of the aforementioned meanings]
Depending on the process, the compounds according to the invention can be prepared.

  A compound of the general formula (U-II) shown above for forming a compound of the general formula (U) shown above, and in particular of the general formula (U-III) shown above where D = OH. The reaction with the carboxylic acid is preferably carried out in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1,2) -dichloroethane, dimethylformamide, dichloromethane and the corresponding mixtures. Preferably 1-benzotriazolyloxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N ′-(3-dimethylaminopropyl) -N-ethylcarbodiimide ( EDCI), diisopropylcarbodiimide, 1,1′- Rubonyldiimidazole (CDI), 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 (HBTU), O- (benzotriazol-1-yl) -N , N, N ′, N′-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxybenzotriazole (HOBt), and 1-hydroxy-7-azabenzotriazole (HOAt) If appropriate, in the presence of one coupling reagent, preferably triethylamine, pyridine. Emissions, dimethylaminopyridine, in the presence of at least one organic base selected from the group consisting of N- methylmorpholine and diisopropylethylamine, preferably at a temperature of -70 ° C. to 100 ° C..

  Alternatively, a compound of general formula (U-II) as shown above to form a compound of general formula (U) as shown above, and D = Hal (where Hal is a leaving group) Of the carboxylic acid halide of the general formula (U-III) shown above which is preferably a halogen, preferably a chlorine or bromine atom, preferably diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethyl In a reaction medium selected from the group consisting of formamide, dichloromethane, and the corresponding mixture, if appropriate, preferably in the presence of an organic or inorganic base selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine, and diisopropylamine. At a temperature of -70 ° C to 100 ° C.

  Each of the compounds of formula (U-II), (U-III), (U-IV), and (U-V) shown above are commercially available and / or known to those skilled in the art. Can be prepared using this process. In particular, processes for preparing these compounds are disclosed in, for example, WO2010 / 127855 (A2) (Patent Document 1) and WO2010 / 127856 (A2) (Patent Document 2). Corresponding portions of these references are considered part of this disclosure by this specification.

  All reactions that can be applied to synthesize the compounds according to the invention can each be carried out under conventional conditions familiar to the person skilled in the art, for example with regard to the order in which pressure or components are applied. If appropriate, one skilled in the art can determine the optimal procedure under individual conditions by performing simple prior tests. Each of the intermediates and final products obtained using the reactions described herein above, each using conventional methods known to those skilled in the art, if desired and / or necessary. Can be purified and / or isolated. Suitable purification processes are, for example, extraction processes and chromatographic processes such as column chromatography or preparative chromatography. The reaction sequences that can be applied to synthesize the compounds according to the invention, as well as the individual purification and / or isolation process steps of intermediates or final products, are all partially or completely inert gases. It can be carried out under an atmosphere, preferably under a nitrogen atmosphere.

  The substituted compounds according to the invention can be isolated both in their free base form and in the form of the corresponding salts, in particular physiologically acceptable salts, and also in the form of solvates such as hydrates. it can.

  For example, an inorganic acid or an organic acid, preferably 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, fumaric acid, maleic Acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2, 3, or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid By reacting with acids, α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid and / or aspartic acid, the free bases of the individual substituted compounds according to the invention can be converted into the corresponding salts, preferably physiologically acceptable. Can be converted to a different salt. The free bases of the individual substituted compounds according to the invention and the free bases of the corresponding stereoisomers likewise use the free acids to the corresponding physiologically acceptable salts or, for example, saccharin, cyclamate, or acesulfame. Can be converted into salts of sugar additives such as

Thus, a substituted compound according to the present invention, such as the free acid of the substituted compound according to the present invention, can be converted to the corresponding physiologically acceptable salt by reacting with a suitable base. 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 is a branched Or represents an unbranched C _1-4 alkyl residue).

  The substituted compounds according to the invention and the corresponding stereoisomers, if appropriate, can be prepared using conventional methods known to those skilled in the art, such as the corresponding acids, corresponding bases, or salts of these compounds. It can also be obtained in the form of a solvate, preferably in the form of its hydrate.

  After its preparation, the substitution according to the invention in the form of a mixture of its stereoisomers, preferably in the form of its racemates, or in the form of other mixtures of its various enantiomers and / or diastereoisomers Once the compounds are obtained, they can be separated and isolated if appropriate using conventional processes known to those skilled in the art. Examples include chromatographic separation processes, particularly liquid chromatography processes under standard pressure or high pressure, preferably MPLC and HPLC processes, and fractional crystallization processes. Individual mirror images formed by these processes, by chiral stationary phase HPLC, or by crystallization with chiral acids such as (+)-tartaric acid, (-)-tartaric acid, or (+)-10-camphorsulfonic acid. Isomers, for example diastereomeric salts, can be separated from one another.

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

  In step j01, acid halide J-0, where Hal preferably represents Cl or Br, can be esterified with methanol to form compound JI using methods familiar to those skilled in the art. .

In step j02, conversion of methyl pivalate JI to oxoalkylnitrile J-II by methods known to those skilled in the art, eg using acetonitrile CH ₃ -CN in the presence of a base if appropriate. Can do.

  In step j03, compound J-II can be converted to amino-substituted pyrazolyl derivative J-III by cyclization by methods known to those skilled in the art, for example using hydrazine hydrate.

  In step j04, the amino compound J-III can first be converted to a diazonium salt by methods known to those skilled in the art, for example using nitrite, and the cyanide is suitably present in the presence of a coupling reagent. Used below, the diazonium salt can be converted to the cyano substituted pyrazolyl derivative J-IV by removing nitrogen.

In step j05, for example, the halide of the partial structure (US2), ie Hal- (US2), is used in the presence of a base and / or a coupling reagent if appropriate (where Hal is preferably Cl, Br or I), or boronic acid B (OH) ₂ (US2) or the corresponding boronic ester, if appropriate in the presence of a coupling reagent and / or base, methods known to those skilled in the art Substituting compound J-IV at the N-position can thus give compound J-V.

  Alternatively, in step k01, ester K-0 is first reduced to form aldehyde KI by methods known to those skilled in the art using, for example, a suitable hydrogenation reagent such as a metal hydride. The second synthetic route is suitable for preparing compound J-V.

  Then, in step k02, aldehyde K-I is reacted with hydrazine K-V which can be obtained in step k05 starting from primary amine K-IV by methods known to those skilled in the art. Hydrazine K-II can be formed by removing water by methods known to those skilled in the art.

  In step k03, hydrazine K-II can be halogenated, preferably chlorinated, by methods known to those skilled in the art that do not impair the double bond, for example using a chlorinating reagent such as NCS, In this way, compound K-III can be obtained.

  In step k04, the hydrazonoyl halide K-III can be converted to the cyano-substituted compound JV by cyclization by methods known to those skilled in the art, for example using halogen-substituted nitriles.

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

  In step j07, compound (U-II) is converted to compound (U-IV) by methods known to those skilled in the art, for example using phenyl chloroformate if appropriate in the presence of a coupling reagent and / or base. Can be converted to In addition to the methods disclosed in this document for the preparation of asymmetric ureas using phenyl chloroformate, those skilled in the art are familiar, if appropriate, based on the use of activated carbonic acid derivatives or isocyanates. There are additional processes.

  In step j08, the amine (U-V) can be converted to the urea compound (U) (where A = N). This can be achieved by reacting with (U-IV), if appropriate in the presence of a base, by methods familiar to the person skilled in the art.

In step J09, can be converted amine (U-II) amide (U) (wherein, A = CH or C _(CH 3)) to. For example, by methods familiar to the person skilled in the art, by reaction with acid halides, preferably chlorides of the formula (U-III), where D = Hal, if appropriate in the presence of a base, or if appropriate This can be achieved by reacting with an acid of formula (U-III) where D = OH, if appropriate, with the addition of a base, in the presence of a suitable coupling reagent, for example HATU or CDI. . Furthermore, the amine (U-II) can be reacted with the amide (U) (wherein A =) by reacting compound (U-IIIa), if appropriate in the presence of a base, by methods familiar to those skilled in the art. CH or C (CH ₃ )).

  Compounds according to general formula (U) in which A = N can be further prepared by a reaction sequence according to general reaction scheme 2.

  In step v1, compound (U-V) is converted to compound (U-Va) by methods known to those skilled in the art, for example using phenyl chloroformate if appropriate in the presence of a coupling reagent and / or base. ). In addition to the methods disclosed in this document for the preparation of asymmetric ureas using phenyl chloroformate, those skilled in the art are familiar, if appropriate, based on the use of activated carbonic acid derivatives or isocyanates. There are additional processes.

  In step v2, amine (U-II) can be converted to urea compound (U) (where A = N). This can be achieved by reacting with (U-Va), if appropriate in the presence of a base, by methods familiar to the person skilled in the art.

  Methods familiar to those skilled in the art for carrying out reaction steps j01 to j09, k01 to k05, and v1 and v2 are described, for example, in J. Am. March, Advanced Organic Chemistry, Wiley & Sons, 6th edition, 2007; A. Carey, R.C. J. et al. Sundberg, Advanced Organic Chemistry, Part A and B, Springer, 5th Edition, 2007; authors, Comprehensive of Organic Methods, canonical chemistry from Standards of Organic Chemistry, Wiley & Sons, etc. In addition, additional methods and references may be issued by common databases such as, for example, Elsevier, Amsterdam, NL's Rayxys® database, or the American Chemical Society, Washington, US SciFinder® database.

  The following examples further illustrate the present invention, but they should not be construed as limiting the scope of the invention.

  The designation “equivalent” (“eq.” Or “eq” or “equiv.” Or “equiv”) means molar equivalents, “RT” or “rt” means room temperature (23 ± 7 ° C.), “ “M” is an indication of the concentration in mol / l, “aq.” Means aqueous, “sat.” Means saturation, “sol.” Means solution, “conc.” Means concentration.

Other abbreviations:
d Days AcOH Acetic acid BH ₃ · S (CH ₃ ) ₂ borane-methyl sulfide complex (BH ₃ -DMS)
BINAP 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl brine saturated aqueous sodium chloride CC column chromatography on silica gel DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DCM Dichloromethane DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N, N-dimethylformamide EDC N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide EDCI N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydro Chloride ether Diethyl ether EtOAc Ethyl acetate EtOH Ethanol h Time (s)
GC gas chromatography HBTU O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate HOBt N-hydroxybenzotriazole H ₂ O water m / z Mass to charge ratio MeOH Methanol min or min. Minute MS Mass Spectrometry Pd / C Palladium Charcoal Pd (PPh ₃ ) ₄ Tetrakis (triphenylphosphine) palladium (0)
PE Petroleum ether TBTU O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate TLC thin layer chromatography TFA trifluoroacetic acid THF tetrahydrofuran v / v volume pair Volume w / w Weight vs. weight

  The yield of the prepared compound was not optimized.

  All temperatures are not corrected.

  All starting materials not explicitly described were either commercially available (eg, Acros, Avocado, Aldrich, Apollo, Bachem, Fluka, FluoroChem, Lancaster, Manchester Organic, MatrixScientific, MatrixRig, Can be found, for example, in MDL, San Ramon, US Symyx (R) Available Chemicals Database or ACS, Washington DC, US, SciFinder (R) Database, respectively. Already accurately described in the specialist literature (Experimental guidelines can be found, for example, in Elsevier, Amsterdam, NL's Reaxys® Database or ACS, Washington DC, US, SciFinder® Database, respectively) or known to those skilled in the art Can be prepared using conventional methods.

  The stationary phase used in column chromatography is E. coli. It was silica gel 60 (0.04-0.063 mm) manufactured by Merck, Darmstadt.

  The mixing ratio of the solvent or eluent for chromatography is defined by v / v.

All intermediate products and exemplary compounds were characterized by analysis by ¹ H-NMR spectroscopy. In addition, mass spectrometric studies (MS, m / z at [M + H] ⁺ ) were performed on all of the exemplary compounds and selected intermediate products.

Synthesis of selected intermediate products:
1. Synthesis of (3-tert-butyl-1- (3-chlorophenyl) -1H-pyrazol-5-yl) methanamine (steps j01 to j06)
Step j01: Pivaloyl chloride (J-0) (1 eq, 60 g) was added dropwise to a solution of methanol (120 mL) within 30 min at 0 ° C. and the mixture was stirred at room temperature for 1 h. After adding water (120 mL), the separated organic phase was washed with water (120 mL), dried over sodium sulfate and co-distilled with dichloromethane (150 mL). The liquid product J-I could be obtained with a purity of 99% (57 g).

  Step j02: NaH (50% in paraffin oil) (1.2 eq, 4.6 g) was dissolved in 1,4-dioxane (120 mL) and the mixture was stirred for several minutes. Acetonitrile (1.2 eq, 4.2 g) was added dropwise within 15 minutes and the mixture was stirred for an additional 30 minutes. Methyl pivalate (J-I) (1 eq, 10 g) was added dropwise within 15 minutes and the reaction mixture was refluxed for 3 hours. After the reaction was complete, the reaction mixture was taken up in ice cold water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 × 250 mL). After the combined organic phases were dried over sodium sulfate, distilled and recrystallized from n-hexane (100 mL), 5 g (51% yield) of product (J-II) was obtained as a solid brown material I was able to get it.

  Step j03: At room temperature, 4,4-dimethyl-3-oxopentanenitrile (J-II) (1 equivalent, 5 g) was placed in ethanol (100 mL) and mixed with hydrazine hydrate (2 equivalents, 4.42 g). And refluxed for 3 hours. The residue obtained after removing ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulfate, the solvent was removed in vacuo and the product (J-III) (5 g, 89% yield) was recrystallized from n-hexane (200 mL). Obtained as a pale red solid.

Step j04: 3-Tert-Butyl-1H-pyrazol-5-amine (J-III) (1 eq, 40 g) was dissolved in dilute HCl (HCl 120 mL in 120 mL water) and NaNO ₂ (1.03 eq, in 100 mL). And 25 g) at 0 to 5 ° C. for 30 minutes. After stirring for 30 minutes, the reaction mixture was neutralized with Na ₂ CO ₃ . The diazonium salt obtained from the reaction of KCN (2.4 eq, 48 g), water (120 mL), and CuCN (1.12 eq, 31 g) was added dropwise to the reaction mixture within 30 min and the mixture was further added to 30 min. Stir for 75 minutes at 75 ° C. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (3 × 500 mL), the combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel: 100-200 mesh, eluent: 20% ethyl acetate / n-hexane) to yield a white solid (J-IV) (6.5 g, 15%).

Step j05 (Method 1):
3-tert. -Butyl-1H-pyrazole-5-carbonitrile (J-IV) (10 mmol) was added to a suspension of NaH (60%) (12.5 mmol) in dimethylformamide (20 mL) at room temperature with stirring. It was. 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 mixed with water (150 mL) and extracted with dichloromethane (3 × 75 mL). The combined organic extracts were washed with water (100 mL) and saturated NaCl solution (100 mL) and dried over magnesium sulfate. After removing the solvent under vacuum, the residue is purified by column chromatography (silica gel: 100-200 mesh, eluent: various mixtures of ethyl acetate and cyclohexane as mobile solvent) to give the product JV. It was.

Step j05 (Method 2):
3-tert-butyl-1H-pyrazole-5-carbonitrile (J-IV) (10 mmol), boronic acid B (OH) ₂ (3-chlorophenyl) or the corresponding boronic ester (20 mmol), and copper acetate (II ) (15 mmol) in dichloromethane (200 mL), mixed with pyridine (20 mmol) with stirring at room temperature, and the mixture is stirred for 16 hours. After removing the solvent under vacuum, the residue obtained is purified by column chromatography (silica gel: 100-200 mesh, eluent: various mixtures of ethyl acetate and cyclohexane as mobile solvent) and thus product J -V is obtained.

Step j06: (Method 1):
JV was dissolved in methanol (30 mL) with palladium on carbon (10%, 500 mg) and concentrated HCl (3 mL) and exposed to a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel: 100-200 mesh, eluent: ethyl acetate), thus giving the product (U-II).

Step j06: (Method 2):
JV was dissolved in tetrahydrofuran (10 mL) and BH ₃ .S (CH ₃ ) ₂ (2.0 M in tetrahydrofuran, 3 mL, 3 eq) was added thereto. The reaction mixture was heated to reflux for 8 hours, to which was added 2N aqueous HCl (2N) and the reaction mixture was refluxed for an additional 30 minutes. The reaction mixture was mixed with aqueous NaOH (2N) and washed with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl and dried over magnesium sulfate. The solvent is removed under vacuum and the residue is purified by column chromatography (silica gel: 100-200 mesh, eluent: various mixtures of dichloromethane and methanol as mobile solvent), thus the product (U-II) Get.

2.1 Synthesis of 1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl-methanamine (steps k01-k05 and j06)
Step k01: Under a protective gas atmosphere, LAlH (lithium aluminum hydride) (0.25 equivalent, 0.7 g) was dissolved in anhydrous diethyl ether (30 mL) and stirred at room temperature for 2 hours. The resulting suspension was taken up in diethyl ether (20 mL). Ethyl-2,2,2-trifluoroacetate (K-0) (1 eq, 10 g) was taken in anhydrous diethyl ether (20 mL) and added dropwise to the suspension at −78 ° C. over 1 h. The mixture was then stirred at −78 ° C. for a further 2 hours. Ethanol (95%) (2.5 mL) was then added dropwise and the reaction mixture was heated to room temperature and poured into ice cold water (30 mL) with concentrated H ₂ SO ₄ (7.5 mL). The organic phase was separated and concentrated under vacuum and the reaction product KI was immediately introduced into the next reaction step k02.

Step k05: 3-Chloroaniline (K-IV) (1 eq, 50 g) was dissolved in conc. HCl (300 mL) at −5 to 0 ° C. and stirred for 10 min. While maintaining the temperature, a mixture of NaNO ₂ (1.2 eq, 32.4 g), water (30 mL), SnCl ₂ .2H ₂ O (2.2 eq, 70.6 g), and concentrated HCl (100 mL) was added. Added dropwise over 3 hours. After stirring for an additional 2 hours at −5 to 0 ° C., the reaction mixture was adjusted to pH 9 using NaOH solution and extracted with ethyl acetate (250 mL). The combined organic phases were dried over magnesium sulfate and the solvent removed in vacuo. Purification by column chromatography (silica gel: 100-200 mesh, eluent: 8% ethyl acetate / n-hexane) yields 40 g (72%) of (3-chlorophenyl) hydrazine (K-IV) as a brown oil did.

  Step k02: Aldehyde (KI) obtained from k01 (2 eq, 300 mL) and (3-chlorophenyl) hydrazine (K-IV) (1 eq, 20 g) are placed in ethanol (200 mL) and refluxed for 5 h. It was. The solvent is removed under vacuum and the residue is purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) to give the product (25 g, 72%) K-II as a brown oil. It was.

  Step k03: Hydrazine K-II (1 equivalent, 25 g) was dissolved in dimethylformamide (125 mL). N-chlorosuccinimide (1.3 eq, 19.5 g) was added in portions within 15 minutes at room temperature and the mixture was stirred for 3 hours. Dimethylformamide was removed by distillation and the residue was taken up in ethyl acetate. Ethyl acetate was removed under vacuum and the resulting residue was purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) to give product K-III (26.5 g, 92%). Obtained as an oil colored pink.

  Step k04: At room temperature, hydrazonoyl chloride K-III (1 eq, 10 g) was placed in toluene (150 mL) and mixed with 2-chloroacrylonitrile (2 eq, 6.1 mL) and triethylamine (2 eq, 10.7 mL). . The reaction mixture was stirred at 80 ° C. for 20 hours. The mixture was then diluted with water (200 mL) and the phases separated. The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel: 100-200 mesh, eluent: 5% ethyl acetate / n-hexane) to give the product (5.5 g, 52%) as a white solid JV.

Step j06 (Method 3):
Carbonitrile J-V (1 eq, 1 g) was dissolved in ammonia in methanol (150 mL, 1: 1) and hydrogenated in the H-cube (10 bar, 80 ° C., 1 mL / min, 0.25 mol / L). ). After removal of the solvent under vacuum, (1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (II) was obtained as a white solid (0.92 g, 91%) Could get as.

  In a similar manner, the following additional intermediate product could be synthesized using the process described hereinabove in 2: :

  3. Preparation of methylphenyl (3-tert-butyl-1- (3-chlorophenyl) -1H-pyrazol-5-yl) methylcarbamate

  Step a: To a solution of (3-tert-butyl-1- (3-chlorophenyl) -1H-pyrazol-5-yl) methanamine (5 g, 18 mmol) in dimethylformamide (25 mL) was added potassium carbonate (9.16 g, 66 mmol, 3.5 eq) was added and the contents were cooled to 0 ° C. Then phenyl chloroformate (3.28 g (2.65 mL), 20 mmol, 1.1 eq) was added dropwise over 15 minutes and the entire reaction mixture was stirred at 0 ° C. for an additional 15 minutes. The progress of the reaction was monitored by TLC (20% ethyl acetate-n-hexane). When the reaction was complete, the reaction contents were filtered, the filtrate was diluted with cold water (100 mL) and the product was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica gel: 100-200 mesh, eluent: 10% ethyl acetate in n-hexane) to give the required product as a white solid (3.2 g, 45% ).

Synthesis of exemplary compounds:
1. Preparation of Amides (A = CH or C (CH ₃ )) As in Scheme 1 (Step j09), an amine of general formula (U-II) is converted to a carboxylic acid of general formula or carboxylic acid of general formula (U-III) General instructions for reacting with derivatives to form compounds of general formula (U) wherein A = CH or C (CH ₃ ) (amide)

1.1 Method A:
An acid of general formula (U-III) (1 eq), an amine of general formula (U-II) (1.2 eq), and EDCI (1.2 eq) in DMF (acid 10 mmol / 20 mL) at room temperature. Stir for 12 hours, then add water to it. The reaction mixture is extracted repeatedly with EtOAc and the aqueous phase is saturated with NaCl followed by re-extraction with EtOAc. The combined organic phases are washed with 1N HCl and brine, dried over magnesium sulfate and the solvent removed in vacuo. The residue is purified by flash chromatography (SiO _{2 in} various ratios, such as 1: 2, EtOAc / hexane), thus obtaining the product (U).

1.2 Method B:
An acid of general formula (U-III) (1 eq) and an amine of general formula (U-II) (1.1 eq) are dissolved in dichloromethane (1 mmol of acid in 6 mL) and EDCI (1.5 eq), HOBt (1.4 eq), and triethylamine (3 eq) at 0 ° C. The reaction mixture is stirred at room temperature for 20 hours and the crude product is purified by column chromatography (SiO _{2 in} various ratios such as 2: 1, n-hexane / EtOAc), thus obtaining (U).

1.3 Method C:
The acid of the general formula (U-III) (1 equivalent) is first mixed with a chlorinating agent, preferably with thionyl chloride, and the mixture thus obtained is boiled under reflux, so that the acid (U-III) To the corresponding acid chloride. The amine of general formula (U-II) (1.1 eq) is dissolved in dichloromethane (1 mmol of acid in 6 mL) and mixed with triethylamine (3 eq) at 0 ° C. The reaction mixture is stirred at room temperature for 20 hours and the crude product is purified by column chromatography (SiO _{2 in} various ratios such as 2: 1, n-hexane / EtOAc), thus obtaining (U).

1.4 Method D:
After dissolving the phenyl ester (U-IIIa) (1 eq) and the corresponding amine (U-II) (1.1 eq) in THF (10 mmol of reaction mixture in 120 mL) and adding DBU (1.5 eq). Stir at room temperature for 16 hours. After removing the solvent under vacuum, the residue obtained is purified by flash chromatography (SiO _{2 in} various ratios such as 1: 1, EtOAc / hexanes), thus obtaining (U).

  Exemplary compounds E1-E4, E10, E11, E16, E17, E19-E21, and E23-E53 were obtained using any of the methods described herein above.

2. Preparation of urea (A = N) An amine of general formula (U-II) or (U-V) is reacted with phenyl chloroformate to form a compound of formula (U-IV) or (U-Va) ( Scheme 1, step j07 and scheme 2, step v1), followed by a compound of formula (U-IV) with an amine of general formula (UV) (scheme 1, step j08), or formula (U-Va) General instructions for reacting a compound of general formula (U-II) with an amine of general formula (U-II) (Scheme 2, step v2) to form a compound of general formula (U) wherein A = N:

Step j07 / Step v1: An amine of the general formula (U-II) or (U-V) (1 equivalent) is placed in dichloromethane (10 mmol of amine in 70 mL), to which phenyl chloroformate (1.1 equivalent) is added at room temperature. And stir the mixture for 30 minutes. After removing the solvent under vacuum, the residue is purified by flash chromatography (SiO _{2 in} various ratios such as 1: ₂ , diethyl ether / hexane), thus (U-IV) or (U-Va) obtain.

Step j08 / Step v2: The obtained carbamic acid phenyl ester (U-IV) or (U-Va) (1 equivalent) and the corresponding amine (U-V) or (U-II) (1.1 equivalent) Dissolve in THF (10 mmol of reaction mixture in 120 mL) and add DBU (1.5 eq) followed by stirring at room temperature for 16 h. After removing the solvent under vacuum, the residue obtained is purified by flash chromatography (SiO _{2 in} various ratios such as 1: 1, EtOAc / hexanes), thus obtaining (U).

  Exemplary compounds E5-E9, E12-E14, E18, E22, and E54-E62 were obtained using any of the methods described herein above.

Detailed Synthesis of Selected Exemplary Compounds Example E4: 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl]- Of ethyl] -2-fluoro-benzamide

Step 1: To a solution of 2- (4-amino-3-fluorophenyl) propionic acid (1) (1 g, 5.459 mmol) in EtOH was added SOCl ₂ (0.6 ml, 8.189 mmol) at 0 ° C. It was. The mixture was stirred at room temperature for 2 hours and then SOCl ₂ was removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated NaHCO ₃ solution. The resulting mixture was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography to give pure compound 2 (1 g, 87%).

Step 2: To a solution of compound 2 (1 g, 4.734 mmol) in water and H ₂ SO ₄ (0.5 ml) was added NaNO ₂ (490 mg, 7.101 mmol), KI (2358 mg, 14.202 mmol) at 0 ° C. Added in. The reaction mixture was stirred at room temperature overnight then treated with saturated NaHSO ₃ solution and eluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography to give pure compound 3 (1.15 g, 75%).

Step 3: To a solution of starting material 3 (1.15 g, 3.570 mmol) in DMF was added Zn (CN) ₂ (629 mg, 5.355 mmol) and Pd (PPh ₃ ) ₄ (825 mg, 0.714 mmol). It was. The reaction mixture was refluxed for 8 hours and then cooled to room temperature. The mixture was filtered through a celite plug and concentrated. The residue was diluted with EtOAc and washed with 10% HCl solution. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography to give pure compound 4 (520 mg, 66%).

Step 4: To a solution of compound 4 (520 mg, 2.351 mmol) in THF and water was added LiOH monohydrate (148 mg, 3.526 mmol). The reaction mixture was stirred at 40 ° C. for 2 hours and then acidified with 10% HCl solution. The mixture was extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give the desired compound 5 (440 mg, 97%).

Step 5: To a solution of compound 5 (440 mg, 2.278 mmol) in acetonitrile was added HOBt (462 mg, 3.417 mmol), EDC (655 mg, 3.417 mmol), and (1- (3-chlorophenyl) -3- ( Trifluoromethyl) -1H-pyrazol-5-yl) methanamine (659 mg, 2.392 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was added to water and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound 6 (870 mg, 85%).

Step 6: To a solution of compound 6 (870 mg, 1.930 mmol) in EtOH was added 2N NaOH (9.7 ml, 19.300 mmol). The reaction mixture was stirred at 100 ° C. overnight and then cooled to room temperature. The mixture was acidified with 10% HCl solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound 7 (550 mg, 61%).

Step 7: To 7 (150 mg, 0.319 mmol) in DCM was added SOCl ₂ (0.12 ml, 1.597 mmol). The reaction mixture was refluxed for 2 hours and then SOCl ₂ was removed under reduced pressure. The residue was dissolved in 1,4-dioxane and a solution of NH ₃ (0.5M) in 1,4-dioxane (3.2 ml, 1.595 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then diluted with EtOAc and washed with water. The organic layer was dried over MgSO ₄ , filtered and concentrated. The crude was purified by column chromatography to give pure compound 8 (70 mg, 47%).

  Example E6: Synthesis of 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-benzamide

Step 1: 2-Fluoro-4-nitrobenzoic acid (1g, 5.402mmol) in _{MeOH, and} was added H ₂ SO 4 and (2.9 ml). The reaction mixture was refluxed overnight, then cooled to room temperature and concentrated. The residue was diluted with EtOAc and washed with saturated NaHCO ₃ solution. The organic layer was dried over MgSO ₄ and concentrated. The crude was purified by column chromatography to give the pure compound methyl 2-fluoro-4-nitrobenzoate (1.05 g, 98%).

Step 2: Methyl 2-fluoro-4-nitrobenzoate (1.05 g, 5.273 mmol) was dissolved in MeOH. Pd / C (105 mg) was added to the resulting mixture. The reaction mixture was stirred at room temperature under H ₂ for 2 hours. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude was purified by column chromatography to give the pure compound methyl 4-amino-2-fluorobenzoate (870 mg, 98%).

Step 3: To a solution of methyl 4-amino-2-fluorobenzoate (870 mg, 5.143 mmol) in acetonitrile was added DMAP (691 mg, 5.657 mmol) and phenyl (1- (3-chlorophenyl) -3- (tri Fluoromethyl) -1H-pyrazol-5-yl) methylcarbamate (2036 mg, 5.143 mmol) was added at room temperature. The reaction mixture was refluxed overnight and then cooled to room temperature. The mixture was added to water and extracted with EtOAC. The organic layer was dried over MgSO ₄ and concentrated. The crude product was purified by column chromatography to give pure methyl 4- (3-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) ureido)- 2-Fluorobenzoate (1.3 g, 54%) was obtained.

Step 4: Methyl 4- (3-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) ureido) -2-fluorobenzoate (1.3 g, LiOH monohydrate (174 mg, 4.142 mmol) was added to a solution of 2.761 mmol) in THF and water. The reaction mixture was stirred at 40 ° C. for 2 hours and then acidified with 10% HCl solution. The mixture was extracted with EtOAc. The organic layer is dried over MgSO ₄ and concentrated under reduced pressure to give the desired compound 4- (3-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl). ) Methyl) ureido) -2-fluorobenzoic acid (1.1 g, 87%) was obtained.

Step 5: Compound 4- (3-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) ureido) -2-fluorobenzoic acid (100 mg,. 219 mmol) in DMF, HBTU (125 mg, 0.329 mmol), DIPEA (0.11 ml, 0.657 mmol), and NH ₃ (0.5 M solution in 1,4-dioxane; 1.3 ml, 0 .657 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure example compound E6 (60 mg, 60%).
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.13 (br.s, NH), 7.76 (m, 1H, Ar), 7.61 (m, 4H, Ar), 7.47 ( m, 2H, Ar, NH), 7.39 (br. s, NH), 7.07 (dd, 1H, J = 8.61, 2.04 Hz, Ar), 6.91 (t, NH, J _{= 5.49Hz, Ar-CH 2 NH} ), 6.85 (s, 1H, pyrazole -H), 4.44 (d, 2H , J = 5.49Hz, Ar-CH 2).

  Example E9: 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N-methyl-benzamide Composition

  Steps 1-4: as described for Example Compound E6.

Step 5: Compound 4- (3-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) ureido) -2-fluorobenzoic acid (150 mg, .0. 328 mmol) in DMF was added HBTU (187 mg, 0.492 mmol), DIPEA (0.11 ml, 0.657 mmol), and methylamine (2 M solution in THF; 0.33 ml, 0.657 mmol). . The reaction mixture was stirred at room temperature for 2 hours. The mixture was added to water and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give Example Compound E9 (130 mg, 84%) which was a pure compound.
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.10 (br.s, NH), 7.93 (m, NH), 7.75 (m, 1H, Ar), 7.52 (m, 5H, Ar), 7.06 (m, 1H, Ar), 6.89 (m, NH), 6.83 (s, 1H, pyrazole-H), 4.42 (d, 2H, J = 5. _{67Hz, Ar-CH 2),} 2.73 (d, 3H, J = 4.56Hz, CONHCH 3).

  Example E13: 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N, N-dimethyl- Synthesis of benzamide

  Steps 1-4: as described for Example Compound E6.

Step 5: Compound 4- (3-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) ureido) -2-fluorobenzoic acid (150 mg, .0. 328 mmol) in DMF was added HBTU (187 mg, 0.492 mmol), DIPEA (0.11 ml, 0.657 mmol), and dimethylamine (2 M solution in THF; 0.33 ml, 0.657 mmol). . The reaction mixture was stirred at room temperature for 2 hours. The mixture was added to water and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude was purified by column chromatography to give pure example compound E13 (110 mg, 69%).
¹ H NMR (300 MHz, CD ₃ OD): δ 7.64 (m, 1H, Ar), 7.55 (m, 3H, Ar), 7.45 (m, 1H, Ar), 7.25 (m , 1H, Ar), 7.08 (m, 1H, Ar), 6.76 (s, 1H, pyrazole-H), 4.48 (m, 2H, Ar—CH ₂ ), 3.09 (s, 3H, CON (CH ₃ ) ₂ ), 2.96 (d, 3H, J = 1.50 Hz, CON (CH ₃ ) ₂ ).

  Example E18: 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N- (2-hydroxy Synthesis of -ethyl) -benzamide

  Steps 1-4: as described for Example Compound E6.

Step 5: 4- (3-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) ureido) -2-fluorobenzoic acid (150 mg, 0.328 mmol ) In DMF was added HBTU (187 mg, 0.492 mmol), DIPEA (0.11 ml, 0.657 mmol), and ethanolamine (0.021 ml, 0.344 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was added to water and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give Example Compound E18 (115 mg, 70%) which was a pure compound.
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 9.12 (br.s, NH), 7.86 (m, NH), 7.75 (m, 1H, Ar), 7.53 (m, 5H, Ar), 7.07 (m, 1H, Ar), 6.90 (m, NH), 6.84 (s, 1H, pyrazole-H), 4.73 (t, 1H, J = 5. 70 Hz, ethanol -OH), 4.42 (d, 2H , J = 5.70Hz, Ar-CH 2), 3.43 (m, 2H, ethanol _{-CH 2), 3.33 (m,} 2H, ethanol -CH _2).

  Example E45: 4- [1-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- ( Synthesis of 4-fluorophenyl) -benzamide

Step 1: To a solution of 2- (4-amino-3-fluorophenyl) propionic acid (1 g, 5.559 mmol) in EtOH was added SOCl ₂ (0.6 ml, 8.189 mmol) at 0 ° C. The mixture was stirred at room temperature for 2 hours and then SOCl ₂ was removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated NaHCO ₃ solution. The resulting mixture was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography to give ethyl 2- (4-amino-3-fluorophenyl) propanoate (1 g, 87%).

Step 2: Ethyl 2- (4-amino-3-fluorophenyl) propanoate (1g, 4.734mmol) to a solution of water and _H 2 _SO 4 in (0.5 ml) _of, NaNO 2 _{(490mg, 7.101mmol)} , KI (2358 mg, 14.202 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature overnight then treated with saturated NaHSO ₃ solution and eluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography to give ethyl 2- (3-fluoro-4-iodophenyl) propanoate (1.15 g, 75%).

Step 3: To a solution of ethyl 2- (3-fluoro-4-iodophenyl) propanoate (1.15 g, 3.570 mmol) in DMF was added Zn (CN) ₂ (629 mg, 5.355 mmol) and Pd (PPh ₃ ) ₄ (825 mg, 0.714 mmol) was added. The reaction mixture was refluxed for 8 hours and then cooled to room temperature. The mixture was filtered through a celite plug and concentrated. The residue was diluted with EtOAc and washed with 10% HCl solution. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography to give the pure compound ethyl 2- (4-cyano-3-fluorophenyl) propanoate (520 mg, 66%).

Step 4: To a solution of ethyl 2- (4-cyano-3-fluorophenyl) propanoate (520 mg, 2.351 mmol) in THF and water was added LiOH monohydrate (148 mg, 3.526 mmol). The reaction mixture was stirred at 40 ° C. for 2 hours and then acidified with 10% HCl solution. The mixture was extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give the desired compound 2- (4-cyano-3-fluorophenyl) propanoic acid (440 mg, 97%).

Step 5: To a solution of 2- (4-cyano-3-fluorophenyl) propanoic acid (440 mg, 2.278 mmol) in acetonitrile, HOBt (462 mg, 3.417 mmol), EDC (655 mg, 3.417 mmol), and (1- (3-Chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (659 mg, 2.392 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was added to water and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound N-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) -2- (4- Cyano-3-fluorophenyl) propanamide (870 mg, 85%) was obtained.

Step 6: Compound N-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) -2- (4-cyano-3-fluorophenyl) propanamide ( To a solution of 870 mg (1.930 mmol) in EtOH was added 2N NaOH (9.7 ml, 19.300 mmol). The reaction mixture was stirred at 100 ° C. overnight and then cooled to room temperature. The mixture was acidified with 10% HCl solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound 4- (1-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methylamino) -1 -Oxopropan-2-yl) -2-fluorobenzoic acid (550 mg, 61%) was obtained.

Step 7: 4- (1-((1- (3-Chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methylamino) -1-oxopropan-2-yl) in acetonitrile To 2-fluorobenzoic acid (150 mg, 0.319 mmol) was added SOCl ₂ (0.12 ml, 1.597 mmol). The reaction mixture was refluxed for 2 hours and then SOCl ₂ was removed under reduced pressure. The residue was dissolved in acetonitrile and added to a solution of 4-fluoroaniline (0.032 ml, 0.335 mmol) and TEA (0.067 ml, 0.479 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 2 hours, then diluted with acetonitrile and washed with water. The organic layer was dried over MgSO ₄ and then concentrated. The crude product was purified by column chromatography to give Example Compound E41 (80 mg, 45%).
¹ H NMR (300 MHz, acetone-d ₆ ): δ 9.41 (br.s, NH), 7.72 (m, 8H, Ar), 7.19 (m, 4H, Ar), 6.71 ( s, 1H, pyrazole-H), 4.57 (m, 2H, Ar—CH ₂ ), 3.78 (quadruplex, 1H, J = 6.93 Hz, amide-CH), 1.42 (d, 3H, J = 7.14Hz, amide _-CH 3).

  Example E59: Synthesis of 2-chloro-4-[[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -benzoic acid methyl ester

Step 1: To a stirred solution of 2-chloro-4-nitrobenzoic acid (500 mg, 2.48 mmol) in methanol, sulfuric acid was added in a catalytic amount. The mixture was heated at reflux overnight. TLC showed complete consumption of starting material. The reaction mixture was gradually cooled to room temperature and neutralized with sodium bicarbonate. The mixture was extracted with EtOAc and washed with water and brine. The extract was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give the pure compound methyl 2-chloro-4-nitrobenzoate (468 mg).

Step 2: Sn (II) chloride was added to a stirred solution of methyl 2-chloro-4-nitrobenzoate (468 mg, 2.17 mmol) in ethanol and heated to reflux for 1.5 hours. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo and extracted with EtOAc. The organic layer was washed with water and brine. The extract was dried over MgSO ₄ and concentrated under reduced pressure to give the desired product methyl 4-amino-2-chlorobenzoate (407 mg).

Step 3: Methyl 4-amino-2-chlorobenzoate (407 mg, 2.2 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.3 ml, 2.4 mmol) and phenyl chloroformate (0.21 ml, 2.6 mmol) and the mixture was stirred under N ₂ at room temperature for 1 hour. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give the pure compound methyl 2-chloro-4- (phenoxycarbonylamino) benzoate (713 mg).

Step 4: To a solution of methyl 2-chloro-4- (phenoxycarbonylamino) benzoate (80 mg, 0.26 mmol) in DMF was added DMAP (32 mg, 0.26 mmol) and (1- (3-chlorophenyl) -3. -(Trifluoromethyl) -1H-pyrazol-5-yl) methanamine (74 mg, 0.27 mmol) was added at room temperature. The reaction mixture was heated to 50 ° C. overnight. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound Example Compound E59 (77 mg).
¹ H NMR (300 MHz, CDCl 3): 7.84 (d, 1H, J = 8.61 Hz, Ar), 7.52 (s, 1H, Ar), 7.47-7.45 (m, 3H, Ar) ), 7.40-7.38 (m, 1H, Ar), 7.30 (d, 1H, J = 2.19 Hz, Ar), 6.68 (s, 1H, pyrazole), 6.57 (s) , 1H, NH), 5.06 (bs, s, 1H), 4.55 (d, 2H, J = 5.31 Hz, -CH2), 3.90 (s, 3H, methoxy).

  Example E61: Synthesis of 1-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) -3- (3-fluoro-4-formylphenyl) urea

Step 1: To a stirred solution of methyl 2-fluoro-4-nitrobenzoate (10.0 g, 49.7 mmol, 1 eq) in methanol (100 mL) was added sodium borohydride (9.40 g, 248.7 mmol, 5 Equivalent) was added at room temperature and stirred for 4 hours. Methanol was evaporated and the residue was diluted with ethyl acetate (50 mL × 2) and washed with water (50 mL) and brine (50 mL). The ethyl acetate layer was dried over Na ₂ SO ₄ and evaporated under vacuum to give (2-fluoro-4-nitrophenyl) methanol (8 g, 94%, off-white solid; TLC system: EtOAc / PE ( 3: 7) and R _f : 0.30).

Step 2: To a stirred solution of (2-fluoro-4-nitrophenyl) methanol (3.0 g, 1.0 eq) in EtOAc (30 mL) was added 10% Pd—C and the reaction mixture was H ₂ gas balloon. The mixture was stirred at room temperature for 6 hours. The reaction mixture was passed through a celite pad and the solvent was evaporated. The residue was purified by neutral alumina column using PE / EtOAc (3: 2) as eluent to give (4-amino-2-fluorophenyl) methanol (1.1 g, 48%) as a solid. TLC system: EtOAc / PE (1: 1), _Rf : 0.3).

Step 3: To a stirred solution of (4-amino-2-fluorophenyl) methanol (100 mg, 0.709 mmol, 1 eq) in acetone (1.0 mL) was added pyridine (0.17 mL, 2.12 mmol, 3 eq). Followed by phenyl chloroformate (0.092 mL, 0.709 mmol, 1 eq) at 0 ° C. and stirred at room temperature for 1 hour. The solvent was evaporated and the resulting residue was purified by CC using ethyl acetate / PE (7:13) as eluent to give phenyl 3-fluoro-4- (hydroxymethyl) phenylcarbamate (110 mg, 60 %, Off-white solid; TLC system: EtOAc / PE (1: 1), R _f : 0.4).

Step 4: (1- (3-Chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (100 mg, 0.316 mmol, 1.0 equiv) in DCM (2.0 mL). To the stirred solution was added TEA (0.07 mL, 0.632 mmol, 3.0 eq) followed by phenyl 3-fluoro-4- (hydroxymethyl) phenylcarbamate (82.4 mg, 0.316 mmol, 1.0 eq). ) At room temperature and stirred for 16 hours. After the reaction was complete, the solid precipitate was filtered, washed with DCM (2 mL) followed by n-pentane (5 mL), dried and 1-((1- (3-chlorophenyl) -3- ( Trifluoromethyl) -1H-pyrazol-5-yl) methyl) -3- (3-fluoro-4- (hydroxymethyl) phenyl) urea (Compound A59) (80 mg; 47%, white solid; TLC system: EtOAc / PE (3: 2); R _f : 0.2) was obtained.

Step 5: 1-((1- (3-Chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) -3- (3-fluoro-4- (hydroxy) cooled to 0 ° C. To a stirred solution of (methyl) phenyl) urea (240 mg, 0.54 mmol, 1.0 equiv) in DCM (10 mL) is gradually added Dess-Martin periodinane (345 mg, 0.813 mmol, 1.5 equiv) in small portions. At 0 ° C., stirred at 0 ° C. for 1 hour, and then stirred at room temperature for 30 minutes. DCM was evaporated and EtOAC (50 mL) was added. The mixture was washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and evaporated under vacuum. The crude was purified by CC using EtOAc / PE (2: 3) to give compound 1-((1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl). Methyl) -3- (3-fluoro-4-formylphenyl) urea (120 mg; 48%) was obtained as a yellow solid (TLC: EtOAc / PE (1: 1); R _f : 0.5).

  The mass spectroscopic data are listed herein below, with the following exemplary compounds listed as examples (Table 1):

Pharmacological Methods I. Functional tests performed with vanilloid receptor 1 (VRI / TRPV1 receptor) The agonistic or antagonistic effects of substances tested with vanilloid receptor 1 (VR1 / TRPV1) of rat species are determined using the following assay be able to. This assay uses a Ca ²⁺ sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, The Netherlands) via a receptor channel in a fluorescence imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA). The Ca ²⁺ influx is quantified.

Method:
Complete medium: 10% by volume FCS (fetal calf serum, Gibco Invitrogen GmbH, Karlsruhe, Germany, heat inactivated); 2 mM L-glutamine (Sigma, Munich, Germany); 1% by weight AA solution (antibiotic / antifungal HAMS F12 nutrient mixture 50 mL (Gibco Invitrogen GmbH, Karlsruhe), including solution, PAA, Pasching, Austria) and 25 ng / mL NGF medium (2.5S, Gibco Invitrogen GmbH, Karlsruhe, Germany).

  Cell culture plate: A black 96-well plate (96-well black / clear plate, BD Biosciences, Heidelberg, Germany) with clear bottom and poly-D-lysine-coated is added to laminin (Gibco Invitrogen GmbH, Coat with Karlsruhe (Germany), where laminin is diluted with PBS (PBS without Ca-Mg, Gibco Invitrogen GmbH, Karlsruhe, Germany) to a concentration of 100 μg / mL. An aliquot with a laminin concentration of 100 μg / mL is removed and stored at −20 ° C. Aliquots were diluted with PBS in a 1:10 ratio to 10 μg / mL laminin, and 50 μL of each solution was pipetted into the wells of the cell culture plate. The cell culture plate is incubated at 37 ° C. for at least 2 hours, excess solution is removed by aspiration and the wells are washed twice each with PBS. Store the coated cell culture plate with excess PBS and do not remove this PBS until just before feeding the cells.

Cell preparation:
From the decapitated rat, the spinal column was removed and immediately cold HBSS buffer (Hanks buffered saline) mixed with 1% by volume (volume percent) AA solution (antibiotic / antimycotic solution, PAA, Pasching, Austria) Aqueous solution, Gibco Invitrogen GmbH, Karlsruhe, Germany), ie in a buffer placed in an ice bath. The spinal column is cut longitudinally and removed from the spinal canal along with the fascia. Subsequently, dorsal root ganglia (DRG) are removed and stored again in cold HBSS buffer mixed with 1% by volume AA solution. DRG from which all blood debris and spinal nerves have been removed is transferred in each case to 500 μL of cold type 2 collagenase (PAA, Pasching, Austria) and incubated at 37 ° C. for 35 minutes. After addition of 2.5% by volume trypsin (PAA, Pasching, Austria), incubation is continued at 37 ° C. for 10 minutes. After the incubation is complete, the enzyme solution is carefully removed with a pipette and 500 μL of complete medium is added to each remaining DRG. Each of the DRGs was suspended several times and cannula no. 1, no. 12, and no. Aspirate through 16 using a syringe and transfer to a 50 mL Falcon tube, which is filled to 15 mL with complete medium. The contents of each Falcon tube are each filtered through a 70 μm Falcon filter element and centrifuged at 1200 rpm and room temperature for 10 minutes. Each resulting pellet is placed in 250 μL of complete medium and the cell number is determined.

The number of cells in the suspension is set to 3 × 10 ⁵ per mL, and 150 μL of this suspension is in each case placed into the wells in the cell culture plate that are coated as previously described herein. Introduce. The plate is left in the incubator for 2-3 days at 37 ° C., 5% by volume CO ₂ and 95% relative humidity. Subsequently, the cells were treated with 2 μM Fluo-4 and 0.01 vol% Pluronic F127 (Molecular Probes Europe BV, Leiden, The Netherlands) in HBSS buffer (Hanks buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany). Load for 30 minutes at 0 ° C, wash 3 times with HBSS buffer, and further incubate for 15 minutes at room temperature before use for Ca ²⁺ measurements in the FLIPR assay. In this case, Ca ²⁺ dependent fluorescence is measured before and after the substance is added (λex = 488 nm, λem = 540 nm). Quantification is performed by measuring the highest fluorescence intensity (FC, fluorescence count) over time.

FLIPR assay:
The FLIPR protocol consists of adding two substances. First, the compound to be tested (10 μM) is pipetted into the cells and the Ca ²⁺ influx is compared to a control (10 μM capsaicin). This gives results in% activation against the Ca ²⁺ signal after addition of 10 μM capsaicin (CP). After 5 minutes incubation, 100 nM capsaicin is applied and Ca ²⁺ influx is also determined.

Desensitizing agonists and antagonists result in suppression of Ca ²⁺ influx. The% inhibition is calculated relative to the maximum inhibition achievable with 10 μM capsazepine.

  Three analyzes (n = 3) are performed and repeated in at least three independent experiments (N = 4).

Starting from the percent substitution resulting from various concentrations of the compound to be tested of general formula I, the IC ₅₀ inhibitory concentration resulting in 50% displacement of capsaicin was calculated. The K _i value of the test substance was obtained by conversion using the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

II. Functional tests performed with vanilloid receptor 1 (VRI / TRPV1 receptor) The agonistic or antagonistic effects of substances tested with vanilloid receptor 1 (VR1) can also be determined using the following assay. This assay uses a Ca ²⁺ sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, The Netherlands) using a Ca channel via channel within a fluorescence imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA). Quantify ²⁺ influx.

Method:
Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC), UK) are stably transfected with the VR1 gene. For functional testing, these cells were placed on a black 96-well plate (BD Biosciences, Heidelberg, Germany) with a clear bottom and poly-D-lysine-coated at a density of 25,000 cells / well. Sow. Cells are incubated overnight at 37 ° C. and 5% CO ₂ in medium (Ham F12 nutrient mixture, 10 vol% FCS (fetal calf serum), 18 μg / ml L-proline). The next day, cells were incubated with Fluo-4 (Fluo-4 2 μM, HBSS (0.01 vol% Pluronic F127 (Molecular Probes) in Hanks buffered saline, Gibco Invitrogen GmbH, Karlsruhe, Germany)) for 30 minutes at 37 ° C. To do. The plates are then washed 3 times with HBSS buffer and used for Ca ²⁺ measurements in the FLIPR assay after further incubation for 15 minutes at room temperature. Ca ²⁺ -dependent fluorescence is measured before and after the addition of the substance to be tested (λex wavelength = 488 nm, λem = 540 nm). Quantification is performed by measuring the highest fluorescence intensity (FC, fluorescence count) over time.

FLIPR assay:
The FLIPR protocol consists of adding two substances. First, the compound to be tested (10 μM) is pipetted into the cells and Ca ²⁺ influx is compared to the control (10 μM capsaicin) (% activation relative to the Ca ²⁺ signal after addition of 10 μM capsaicin). After 5 minutes incubation, 100 nM capsaicin is applied and Ca ²⁺ influx is also determined.

Desensitizing agonists and antagonists resulted in suppression of Ca ²⁺ influx. The% inhibition is calculated relative to the maximum inhibition achievable with 10 μM capsazepine.

Starting from the percent substitution resulting from various concentrations of the compound to be tested of the general formula I, the IC ₅₀ inhibitory concentration resulting in a 50 percent displacement of capsaicin was calculated. The K _i value of the test substance was obtained by conversion using the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

Pharmacological data The affinity of the compounds according to the invention for vanilloid receptor 1 (VR1 / TRPV1 receptor) was determined as described herein before (pharmacological method I or II).

  The compounds according to the invention show an outstanding affinity for the VR1 / TRPV1 receptor (Table 2).

In Table 2, the following abbreviations have the following meanings:
Cap = Capsaicin AG = Agonist The value after the “@” symbol indicates the concentration at which the inhibition (as a percentage) was each determined.

Claims (15)

A substituted compound of the general formula (U), optionally in the form of a single stereoisomer or a mixture of stereoisomers and in the form of a free compound and / or a physiologically acceptable salt thereof.

[Where:
R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently of each other 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 , OCHF ₂ , OCF ₂ H, OCF ₃ , OH, NH ₂ , C _1-4 alkyl, O—C _1-4 alkyl, NH—C _1-4 alkyl and N (C _1-4 alkyl) selected from the group consisting of ₂ (wherein the C _1-4 alkyl is in each case unsubstituted);
R ² represents CF ₃ , unsubstituted C _1-4 alkyl or unsubstituted C _3-6 cycloalkyl,
R ⁷ and R ⁹ are independently of each other from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, OH, OCF ₃ , C _1-4 alkyl and O—C _1-4 alkyl. (Wherein the C _1-4 alkyl is in each case unsubstituted);
A represents N, CH or C (CH ₃ );
R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents
OR ¹⁰⁵ (where
R ¹⁰⁵ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH and OCH _3. Represents C _1-4 alkyl which is mono-, _di- or tri-substituted with 1, 2 or 3 substituents), or NR ¹⁰⁶ R ¹⁰⁷ (wherein
R ¹⁰⁶ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH and OCH _3. Represents C _1-4 alkyl which is mono-, _di- or tri-substituted with 1, 2 or 3 substituents;
R ¹⁰⁷ is
H, C _1-4 alkyl (unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents
C _3-6 cycloalkyl or 3-6 membered heterocyclyl (in each case unsubstituted or F, Cl, Br, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert.- 1, 2 or 3 substituents independently selected from the group consisting of butyl, cyclopropyl, OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ At least one ring member of the heterocyclyl is selected from the group consisting of O, S, N, NH and N (C _1-4 alkyl)),
Phenyl (unsubstituted or _{F, Cl, Br, CN,} CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ,), N (CH ₃ ) ₂ , OH, OCF ₃ and OCH ₃ are mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from each other), or heteroaryl (unsubstituted or _{F, Cl, Br, CN,} CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N _{(CH 3)} 2, OH, monosubstituted with 1, 2 or 3 substituents selected independently of one another from the group consisting of OCF _3, and OCH _3, from the group consisting of disubstituted or trisubstituted) Either-option,
Or, R ¹⁰⁶ and R ¹⁰⁷ together with the nitrogen atom connecting them are unsubstituted or F, Cl, Br, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert . 1, 2 or 3 substitutions independently selected from the group consisting of butyl, cyclopropyl, OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ A 3- to 6-membered heterocyclyl which is mono-, di- or tri-substituted with a group]. R ² is CF ₃ , tert. 2. A compound according to claim 1, characterized in that it represents -butyl or cyclopropyl. R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently of each other 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. A compound according to claim 1 or 2, characterized. The compound according to claim 1, wherein at least one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ is not ≠ H. R ⁷ and R ⁹ are independently of each other 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—. characterized in that it is selected from the group consisting of CH ₂ CH _3, a compound according to any one of claims 1 to 4. Characterized in that at least one of R ⁷ and R ⁹ are ≠ H, compounds according to any one of claims 1 to 5. The compound according to claim 1, wherein A represents N or C (CH ₃ ). R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents
OR ¹⁰⁵ (where
R ¹⁰⁵ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH and OCH _3. Represents C _1-4 alkyl which is mono-, _di- or tri-substituted with 1, 2 or 3 substituents) or NR ¹⁰⁶ R ¹⁰⁷ (where
R ¹⁰⁶ is H or unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH, and OCH _3. Represents C _1-4 alkyl which is mono-, _di- or tri-substituted with 1, 2 or 3 substituents,
R ¹⁰⁷ is
H, C _1-4 alkyl (unsubstituted or independently selected from the group consisting of F, Cl, Br, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ ═O, OH and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted or F, 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 ) and N (CH ₃ ) _2, 1, 2 or 3 independently selected from each other Mono-, di- or tri-substituted with
Phenyl _{(F, Cl, Br, CN} , CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) ₂ , mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from each other from the group consisting of OH, OCF ₃ and OCH ₃ , or heteroaryl (unsubstituted, or _{F, Cl, Br, CF 3} , CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) 2, OH Is selected from the group consisting of OCF ₃ and OCH ₃ independently, mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from each other,
Provided that when A represents CH or C (CH ₃ ), R ¹⁰⁷ cannot represent H;
Or, R ¹⁰⁶ and R ¹⁰⁷ together with the nitrogen atom linking them are unsubstituted or F, Cl, Br, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert . 1, 2 or 3 substitutions independently selected from the group consisting of butyl, cyclopropyl, OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ Forming a 3- to 6-membered heterocyclyl mono-, di- or tri-substituted with groups),
The compound according to any one of claims 1 to 7, characterized in that R ¹⁰⁴ is
₁ , ₂ , or H, C _1-4 alkyl (unsubstituted or independently selected from the group consisting of NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , ═O, OH and OCH ₃ Monosubstituted, disubstituted or trisubstituted with three substituents),
OR ¹⁰⁵ (where
R ¹⁰⁵ is H, or unsubstituted or mono-, di- or tri-substituted C with 1, 2 or 3 substituents independently selected from the group consisting of NH ₂ , OH and OCH ₃ . Represents _1-4 alkyl) or NR ¹⁰⁶ R ¹⁰⁷ (where:
R ¹⁰⁶ is H, unsubstituted or 1, 2 or 3 independently selected from the group consisting of NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , ═O, OH and OCH ₃ A C _1-4 alkyl which is mono-, _di- or tri-substituted with a substituent of
R ¹⁰⁷ is
₁ , ₂ , or H, C _1-4 alkyl (unsubstituted or independently selected from the group consisting of NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , ═O, OH and OCH ₃ Monosubstituted, disubstituted or trisubstituted with three substituents),
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted or CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert.-butyl, cyclopropyl Monosubstituted with 1, 2 or 3 substituents independently selected from the group consisting of OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ , Di- or tri-substituted),
Phenyl _{(F, Cl, Br, CN} , CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) ₂ , mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from each other from the group consisting of OH, OCF ₃ and OCH ₃ , or heteroaryl (unsubstituted, or _{F, Cl, Br, CN,} CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, tert.- butyl, _{cyclopropyl, NH 2, NH (CH 3} ), N (CH 3) 2 , OH, OCF ₃ and OCH ₃ are selected from the group consisting of mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from each other,
Provided that when A represents CH or C (CH ₃ ), R ¹⁰⁷ cannot represent H;
Alternatively, R ¹⁰⁶ and R ¹⁰⁷ can be unsubstituted or combined with a nitrogen atom connecting them, CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , tert. 1, 2 or 3 substitutions independently selected from the group consisting of butyl, cyclopropyl, OH, ═O, OCH ₃ , OCF ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ Forming a 3- to 6-membered heterocyclyl mono-, di- or tri-substituted with groups),
The compound according to any one of claims 1 to 8, characterized in that R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
OR ¹⁰⁵ (where
R ¹⁰⁵ is C _{1 -4} which is mono-, di- or tri-substituted with 1, 2 or 3 substituents which are H, unsubstituted or independently selected from the group consisting of OH and OCH ₃ Represents alkyl) or NR ¹⁰⁶ R ¹⁰⁷ (wherein
R ¹⁰⁶ is C _1-4 which is mono-, di- or tri-substituted with 1, 2 or 3 substituents which are H or unsubstituted or independently selected from the group consisting of OH and OCH ₃ Represents alkyl, and R ¹⁰⁷ is
H, C _1-4 alkyl (unsubstituted or mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted or independent from the group consisting of CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OH and OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents selected from
Phenyl _{(F, Cl, Br, CN} , CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, NH 2, NH (CH 3), N (CH 3) 2, OH, OCF 3 and OCH Mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of ₃ or heteroaryl (unsubstituted or F, Cl, Br, CN) , CF ₃ , CH ₃ , CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , OH, OCF ₃ and OCH _3, 1, 2 or 3 independently selected from each other Mono-, di- or tri-substituted with one substituent)
Selected from the group consisting of
Provided that when A represents CH or C (CH ₃ ), R ¹⁰⁷ cannot represent H;
Or, R ¹⁰⁶ and R ¹⁰⁷ , together with the nitrogen atom connecting them, are unsubstituted or CF ₃ , CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OH, ═O, OCH ₃ Mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of, OCF ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ Forming a 3-6 membered heterocyclyl),
The compound according to claim 1, characterized in that R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
OR ¹⁰⁵ (where
R ¹⁰⁵ is C _{1 -4} which is mono-, di- or tri-substituted with 1, 2 or 3 substituents which are H, unsubstituted or independently selected from the group consisting of OH and OCH ₃ Represents alkyl) or NR ¹⁰⁶ R ¹⁰⁷ (wherein
R ¹⁰⁶ is C _1-4 which is mono-, di- or tri-substituted with 1, 2 or 3 substituents which are H or unsubstituted or independently selected from the group consisting of OH and OCH ₃ Represents alkyl,
R ¹⁰⁷ is
C _1-4 alkyl (unsubstituted or mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted, 1, 2 or 3 substituted independently selected from the group consisting of CH ₃ , OH and OCH ₃ Monosubstituted, disubstituted or trisubstituted with groups),
Phenyl (mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, CF ₃ , CH ₃ , OH, OCF ₃ and OCH ₃ ), Or unsubstituted heteroaryl,
Selected from the group consisting of
Or, R ¹⁰⁶ and R ¹⁰⁷ , together with the nitrogen atom connecting them, are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of CH ₃ , OH and OCH ₃ Forming a 3- to 6-membered heterocyclyl mono-, di- or tri-substituted with groups),
The compound according to claim 1, characterized in that R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently of each other H, F, Cl, Br, 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 ,
R ² is CF ₃ , tert. -Represents butyl or cyclopropyl,
R ⁷ and R ⁹ are independently of each other 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. is selected from the group consisting of -CH ₂ CH _3, wherein at least one of ^{R 7} and ^{R 9} are ≠ H,
A represents N, CH or C (CH ₃ );
R ¹⁰⁴ is
H, C _1-4 alkyl (unsubstituted or mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
OR ¹⁰⁵ (where
R ¹⁰⁵ is C _{1 -4} which is mono-, di- or tri-substituted with 1, 2 or 3 substituents which are H, unsubstituted or independently selected from the group consisting of OH and OCH ₃ Represents alkyl) or NR ¹⁰⁶ R ¹⁰⁷ (wherein
R ¹⁰⁶ is C _1-4 which is mono-, di- or tri-substituted with 1, 2 or 3 substituents which are H or unsubstituted or independently selected from the group consisting of OH and OCH ₃ Represents alkyl,
R ¹⁰⁷ is
C _1-4 alkyl (unsubstituted or mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and OCH ₃ ),
C _3-6 cycloalkyl or _3-6 membered heterocyclyl (in each case unsubstituted, 1, 2 or 3 substituents independently selected from the group consisting of CH ₃ , OH and OCH ₃ Monosubstituted, disubstituted or trisubstituted)
Phenyl (mono-, di- or tri-substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, CF ₃ , CH ₃ , OH, OCF ₃ and OCH ₃ ), Or unsubstituted heteroaryl,
Selected from the group consisting of
Or R ¹⁰⁶ and R ¹⁰⁷ together with the nitrogen atom connecting them are 1, 2 or 3 substituents which are unsubstituted or independently selected from the group consisting of CH ₃ , OH and OCH ₃ Forming a 3- to 6-membered heterocyclyl mono-, di- or tri-substituted with a radical)
The compound according to any one of claims 1 to 6 and 8 to 11, characterized in that Optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of a free compound and / or a physiologically acceptable salt thereof,
E1 N-[[2- (3-Fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-propanoyl-phenyl) -propionamide ;
E2 2- (3-Fluoro-4-propanoyl-phenyl) -N-[[2- (3-methoxyphenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propionamide ;
E3 N-[[2- (3,4-Difluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-propanoyl-phenyl) -Propionamide;
E4 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-benzamide;
E5 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-benzamide;
E6 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-benzamide;
E7 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzamide;
E8 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N-methyl-benzamide;
E9 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N-methyl-benzamide;
E10 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-methyl-benzamide;
E11 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-methyl-benzamide ;
E12 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N, N-dimethyl-benzamide;
E13 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N, N-dimethyl-benzamide;
E14 1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (morpholine-4-carbonyl) -phenyl] -Urea;
E16 N-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (morpholine-4-carbonyl)- Phenyl] -propionamide;
E17 N-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (morpholin-4-carbonyl) -phenyl] -Propionamide;
E18 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N- (2-hydroxy-ethyl ) -Benzamide;
E19 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (oxetane- 3-yl) -benzamide;
E20 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (1- Methyl-piperidin-4-yl) -benzamide;
E21 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (1-methyl- Piperidin-4-yl) -benzamide;
E22 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-fluoro-N-tetrahydro-pyran-4- Ile-benzamide;
E23 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-tetrahydro-pyran -4-yl-benzamide;
E24 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-tetrahydro-pyran-4 -Yl-benzamide;
E25 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N-phenyl-benzamide;
E26 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N-phenyl-benzamide;
E27 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N-phenyl-benzamide;
E28 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N-phenyl-benzamide;
E29 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-phenyl-benzamide;
E30 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- (4-chlorophenyl) -benzamide;
E31 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (3-chlorophenyl) -benzamide;
E32 N- (3-chlorophenyl) -4- [1-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -benzamide ;
E33 N- (4-chlorophenyl) -4- [1-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -benzamide ;
E34 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-chlorophenyl) -benzamide;
E35 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-chlorophenyl) -2-fluoro -Benzamide;
E36 4-[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- (4-fluorophenyl) -benzamide;
E37 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- (4-fluorophenyl) -benzamide;
E38 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -2-fluoro-N- (4-fluorophenyl ) -Benzamide;
E39 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -2-fluoro-N- (4-fluorophenyl)- Benzamide;
E40 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (3-fluorophenyl) -benzamide;
E41 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (3-fluorophenyl)- Benzamide;
E42 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-fluorophenyl) -benzamide;
E43 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- (4-fluorophenyl)- Benzamide;
E44 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (4-fluorophenyl) ) -Benzamide;
E45 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- (4- Fluorophenyl) -benzamide;
E46 N- (4-chlorophenyl) -4- [1-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2 -Fluoro-benzamide;
E47 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -N- [4- (trifluoromethyl)- Phenyl] -benzamide;
E48 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- [4- (Trifluoromethyl) -phenyl] -benzamide;
E49 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N- [4- (tri Fluoromethyl) -phenyl] -benzamide;
E50 4-[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- [4- (trifluoromethyl) -phenyl] -Benzamide;
E51 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -methyl] -N- [4- (trifluoromethyl)- Phenyl] -benzamide;
E52 4- [1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-thiazole-2 -Yl-benzamide;
E53 4- [1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] -ethyl] -2-fluoro-N-thiazol-2-yl -Benzamide;
E54 2-chloro-4-[[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -benzoic acid;
E55 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-chloro-benzoic acid;
E56 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzoic acid;
E57 4-[[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzoic acid methyl ester;
E58 4-[[[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-methoxy-benzoic acid methyl ester;
E59 2-chloro-4-[[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -benzoic acid methyl ester;
E60 4-[[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl-carbamoyl] amino] -2-chloro-benzoic acid methyl ester; and E61 1- [ [2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -3- (3-fluoro-4-formyl-phenyl) -urea The compound according to any one of claims 1 to 12.   A pharmaceutical composition comprising at least one substituted compound according to any one of claims 1 to 13.   Pain, preferably acute pain, chronic pain, neuropathic pain, pain selected from the group consisting of visceral pain and joint pain; hyperalgesia; allodynia; burning pain; migraine; depression; Axonal injury; preferably a neurodegenerative disease selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunction, preferably cognitive impairment, particularly preferably memory impairment; epilepsy; Is a respiratory disease selected from the group consisting of asthma, bronchitis and pulmonary inflammation; cough; urinary incontinence; overactive bladder (OAB); gastrointestinal tract disorder and / or injury; duodenal ulcer; Stroke; eye irritation; skin irritation; neurological skin disease; allergic skin disease; psoriasis; vitiligo; herpes simplex; inflammation, preferably small intestine, eye, bladder, skin or Inflammation of the nasal mucosa; diarrhea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; preferably eating disorders selected from the group consisting of bulimia, cachexia, decreased appetite and obesity; Medication abuse; medication dependent withdrawal symptoms; medication, preferably development of tolerance to natural or synthetic opioids; drug dependence; drug abuse; drug dependence withdrawal symptoms; alcohol dependence; alcohol abuse and alcohol dependence withdrawal symptoms For use in the treatment and / or prevention of one or more selected diseases and / or disorders; for diuresis; for anti-natriuretic; for affecting the cardiovascular system; For treating wounds and / or burns; for treating severed nerves; for increasing libido; For modulating activity; for anxiolytic; for local anesthesia and / or preferably consisting of capsaicin, resiniferatoxin, olvanil, albanyl, SDZ-249665, SDZ-249482, nubanil and capsavanyl To inhibit undesirable side effects caused by administering a vanilloid receptor 1 (VR1 / TRPV1 receptor) agonist selected from the group, preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction The substituted compound according to any one of claims 1 to 13.