JP2014532744A - Carboxamide and urea derivatives based on substituted pyrazolyls bearing phenyl moieties substituted with SO2-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 SO2-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 carboxamide and urea derivatives based on substituted pyrazolyl carrying a phenyl moiety substituted with a SO ₂ containing group as vanilloid receptor ligands, pharmaceutical compositions containing these compounds, pain, It further 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 (T) as shown below exhibit 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. Substituted compounds of (T) are particularly suitable.

  Accordingly, the present invention may optionally be in the form of a single stereoisomer or a mixture of stereoisomers, free compounds and / or physiologically acceptable salts thereof and / or physiologically acceptable solvates thereof. Relates to substituted compounds of the general formula (T) in the form

[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 );
t represents 0, 1 or 2,
R ¹⁰⁸ is unsubstituted or unsubstituted or mono-substituted, di-substituted, 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, OH, ═O and OCH ₃ , or Represents tri-substituted C _1-4 alkyl].

  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 residue which may be, for example, mono-, di- or tri-substituted and contains 1 to 4, ie 1, 2, 3 or 4 carbon atoms 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) means a hydrocarbon, i.e. a _C3-6 -alicyclic residue saturated with an unsubstituted hydrocarbon. 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.

  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 yet another further preferred embodiment of the compounds according to the invention,
R ¹⁰¹ _{is, F, Br, CFH 2,} CF 2 H, CF 3, CN, CH 2 -OH, CH 2 -OCH 3, OCF 3, OH, CH 3, O-CH 3, O-CH 2 CH 3 , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ , more preferably F, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OCH ₃ , OCF ₃ , CH ₃ , O—CH ₃ , O—CH ₂ CH ₃ , and N (CH ₃ ) ₂ , still more preferably F, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , Selected from the group consisting of CH ₃ , O—CH ₃ , and O—CH ₂ CH ₃ , even more preferably selected from the group consisting of F, CF ₃ , OCF ₃ , CH ₃ , and O—CH ₃ ; in particular, F, CF ₃ And O-CH ₃ is selected from the group consisting of, even more particularly preferred are selected from the group consisting of F and O-CH _3,
R ¹⁰² and R ¹⁰³ both represent H.

In yet another further preferred embodiment of the compounds according to the invention,
R ¹⁰¹ is F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) _2. , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ ,
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, 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 ) ₂ , more preferably F, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OCH ₃ , OCF ₃ , CH ₃ , O—CH ₃ , O—CH ₂ CH ₃ , and N (CH ₃ ) ₂ , still more preferably F, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , Selected from the group consisting of CH ₃ , O—CH ₃ , and O—CH ₂ CH ₃ , even more preferably selected from the group consisting of F, CF ₃ , OCF ₃ , CH ₃ , and O—CH ₃ ; in particular, F, CF ₃ And O-CH ₃ is selected from the group consisting of, even more particularly preferred are selected from the group consisting of F 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, from the group consisting of Cl and O-CH ₃ Selected.

  In another particularly preferred embodiment according to the invention, the substructure (TS2) is:

In particular, when t represents 0, 1, or 2, preferably 1 or 2, and A represents N, it is selected from the group consisting of the following.

  Even more preferably, the partial structure (TS2) is:

In particular, when t represents 0, 1, or 2, preferably 1 or 2, and A represents N, it is selected from the group consisting of the following.

  Most preferably, the partial structure (TS2) is:

In particular, when t represents 0, 1, or 2, preferably 1 or 2, and A represents N, it is selected from the group consisting of:

Preferably, when t represents 0, 1, or 2, preferably 1 or 2, and A represents N, it is selected from the group consisting of:

  In another particularly preferred embodiment according to the invention, the substructure (TS2) is:

In particular, when t represents 0, 1, or 2, preferably 1 or 2, and A represents CH or C (CH ₃ ), it is selected from the group consisting of:

  Even more preferably, the partial structure (TS2) is:

In particular, when t represents 1 or 2, preferably 1 or 2, and A represents CH or C (CH ₃ ), it is selected from the group consisting of:

  Most preferably, the partial structure (TS2) is:

In particular, when t represents 1 or 2, preferably 1 or 2, and A represents CH or C (CH ₃ ), it is selected from the group consisting of:

Preferably, in particular when t represents 1 or 2, preferably 1 or 2, and A represents CH or C (CH ₃ ), 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,
t represents 1 or 2.

In a particularly preferred embodiment of the compound according to the invention,
t represents 1.

In another particularly preferred embodiment of the compounds according to the invention,
t represents 2.

In a further preferred embodiment of the compound according to the invention,
t represents 1 or 2, preferably 1,
A represents N,
R ¹⁰¹ 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 , 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 ; 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 ) ₂ ; _{preferably, H, F, Cl,} selected from _{CFH 2, CF 2 H, CF} 3, OCF 3, CH 3, O-CH 3, and the group consisting of _O-CH 2 _{CH 3;} even more preferably, H _{, F, Cl, CF 3,} OCF 3, CH , And it is selected from the group consisting of O-CH _3; Even more preferably, H, F, Cl, selected from the group consisting of CF _3, and O-CH _3; especially, H, F, Cl, and O Selected from the group consisting of —CH ₃ ; most preferably F or Cl;
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)} is selected from the group consisting of _2; preferably together _{independently, 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 ) Selected from the group consisting of ₂ ; more preferably, independently of each other, 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 consisting of: Preferably independently of one _{another, H, F, Cl, CF} 3, OCF 3, CH 3, and O-CH ₃ is selected from the group consisting of; The even more preferably independently of one _{another, H, F, Cl, CF} 3, and O-CH ₃ is selected from the group consisting of; especially, independently of one another, H, F, Cl, and O-CH ₃ is selected from the group consisting of; shown most preferably, independently of one another, F or Cl Or t represents 0, 1, or 2, preferably 1 or 2, more preferably 1,
A represents CH or C (CH ₃ ), preferably C (CH ₃ ),
R ¹⁰¹ is H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ ; preferably H, F, CFH ₂ , CF ₂ Selected from the group consisting of 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 ; more preferably H _{, F, CFH 2, CF 2} H, CF 3, OCF 3, CH 3, O-CH 3, and _O-CH 2 _{CH 3} is selected from the group consisting of; even more preferably, H, F, _CF 3, or OCF _3, CH _3, and O-CH ₃ Is selected from the group consisting of tetrahydrofuran, more preferably more, H, F, is selected from the group consisting of CF _3, and O-CH _3; especially, is selected from the group consisting of H, F, and O-CH _3; most Preferably, F is shown;
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)} is selected from the group consisting of _2; preferably together _{independently, 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 ) Selected from the group consisting of ₂ ; more preferably, independently of each other, 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 consisting of: Preferably independently of one _{another, H, F, Cl, CF} 3, OCF 3, CH 3, and O-CH ₃ is selected from the group consisting of; The even more preferably independently of one _{another, H, F, Cl, CF} 3, and O-CH ₃ is selected from the group consisting of; especially, independently of one another, H, F, Cl, and O-CH ₃ is selected from the group consisting of; shown most preferably, independently of one another, F or Cl .

  In a further preferred embodiment of the compound according to the invention, the partial structure (TS1) is

Partial structure (PT1), (PT2), or (PT3)

[Wherein R ¹⁰⁸ represents unsubstituted C _1-4 alkyl, preferably CH ₃ or CH ₂ CH ₃ , more preferably CH ₃ ]
Represents.

  Preferably, the partial structure (TS1) is

Partial structure (PT2) or (PT3)

[Wherein R ¹⁰⁸ represents CH ₃ or CH ₂ CH ₃ , preferably CH ₃ ]
Represents.

In a particularly preferred embodiment of the compound according to the invention,
A represents N,
R ¹⁰¹ 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 , 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 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 , Selected from the group consisting of 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, here, at least one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ is not H, or A represents CH or C (CH ₃ ), preferably C (CH ₃ ),
R ¹⁰¹ is H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ), and N (CH ₃ ) ₂ ,
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 , Selected from the group consisting of 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 Selected from the group consisting of O—CH ₂ CH ₃ ;
Preferably, wherein at least one of R ⁷ and R ⁹ is ≠ H,
The partial structure (TS1) is

Partial structure (PT2) or (PT3)

[Wherein R ¹⁰⁸ represents CH ₃ or CH ₂ CH ₃ , preferably CH ₃ ]
Represents.

  Preferred embodiments of the compounds of the general formula (T) according to the invention have the general formula (T0-a) and / or (T0-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 of the general formula (T) according to the invention have the general formula (T1-a), (T1-a-1) and / or (T1-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 (T) according to the invention have the general formula (T1-b), (T1-b-1) and / or (T1-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].

  Further preferred embodiments of the compounds of the general formula (T) according to the invention have the general formula (T2-a), (T2-a-1) and / or (T2-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 according to the invention of general formula (T) have the general formula (T2-b), (T2-b-1) and / or (T2-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].

  Further preferred embodiments of the compounds according to the invention of general formula (T) have the general formula (T3-a), (T3-a-1) and / or (T3-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 (T) according to the invention have the general formula (T3-b), (T3-b-1) and / or (T3-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].

  Particularly preferred embodiments of the compounds of the present invention are general formulas (T2-a), (T2-a-1), (T2-a-2), (T2-b), (T2-b-1), ( T2-b-2), (T3-a), (T3-a-1), (T3-a-2) (T3-b), (T3-b-1), and / or (T3-b- 2).

In a particularly preferred embodiment of the present invention, the general formulas (T), (T0-a), (T0-b), (T1-a), (T1-a-1), (T1-a-2), ( T1-b), (T1-b-1), (T1-b-2), (T2-a), (T2-a-1), (T2-a-2), (T2-b), ( T2-b-1), (T2-b-2), (T3-a), (T3-a-1), (T3-a-2) (T3-b), (T3-b-1), And / or the group R ¹⁰¹ in the compound of (T3-b-2) represents F, Cl, CF ₃ , or O—CH ₃ , preferably F or Cl, most preferably Cl (preferably R ¹⁰³ There are H, and ^{when R 102} represents H, F, Cl, a CF ₃ or OCH _3,, more ^{preferably, R 103} is H, and ^{R 102} is H, F or, to represent the l, even more preferably, both R ¹⁰² and R ¹⁰³ are, when representing a H), the remaining individual groups, variables symbols, and readings, the compounds according to the invention and preferred embodiments thereof Have the meanings described in this specification.

In a further particularly preferred embodiment of the invention, the general formulas (T), (T1-a), (T1-a-1), (T1-b), (T1-b-1), (T2-a), (T2-a-1), (T2-b), (T2-b-1), (T3-a), (T3-a-1), (T3-b), and / or (T3-b- The group R ¹⁰¹ in the compound of 1) represents F, Cl, CF ₃ , or O—CH ₃ , preferably F or Cl, most preferably Cl (preferably R ¹⁰³ is H, R ¹⁰² More preferably when R represents H, F, Cl, CF ₃ , or OCH ₃ , even more preferably when R ¹⁰³ represents H and R ¹⁰² represents H, F, or Cl. when ^{the 102} and ^{R 103} represents a H both), the remaining individual groups, variables symbols, and readings are present Have the meanings described herein in relation to compounds and preferred embodiments thereof by light.

In a further particularly preferred embodiment of the invention, the general formulas (T), (T1-a), (T1-a-2), (T1-b), (T1-b-2), (T2-a), (T2-a-2), (T2-b), (T2-b-2), (T3-a), (T3-a-2), (T3-b), and / or (T3-b- The group R ¹⁰¹ in the compound of 2) represents F, CF ₃ , or O—CH ₃ , preferably F (preferably R ¹⁰³ is H and R ¹⁰² is H, F, Cl, CF ₃ , or OCH ₃ , more preferably, when R ¹⁰³ is H and R ¹⁰² represents H, F, or Cl, even more preferably, both R ¹⁰² and R ¹⁰³ are both H. When indicated, the remaining individual groups, variable symbols, and readings represent the compounds according to the invention and preferred Have the meanings described herein in relation to the form.

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:
D1 N-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide;
D2 N-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide ;
D3 2- (3-Fluoro-4-methylsulfonyl-phenyl) -N-[[2- (3-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propion An amide;
D4 N-[[2- (3-Chloro-4-fluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl -Phenyl) -propionamide;
D5 2- (3-Chloro-4-methylsulfonyl-phenyl) -N-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propionamide ;
D6 N-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl ] -Propionamide;
D7 N-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl]- Propionamide;
D8 N-[[5-tert-Butyl-2- (3-chloro-4-fluoro-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D9 N-[[5-tert-Butyl-2- (3-fluorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -Propionamide;
D10 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (3-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D11 N-[[5-tert-Butyl-2- (4-fluorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -Propionamide;
D12 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (4-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D13 N-[[5-tert-Butyl-2- (3,4-difluoro-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -Phenyl] -propionamide;
D14 N-[[2- (3,4-Difluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D15 N-[[2- (3,5-Difluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D16 N-[[5-tert-Butyl-2- [3- (methoxymethyl) -phenyl] -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) ) -Phenyl] -propionamide;
D17 N-[[5-tert-Butyl-2- (3-dimethylamino-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl)- Phenyl] -propionamide;
D18 N-[[5-tert-Butyl-2- (3-fluoro-5-methyl-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D19 N-[[5-tert-Butyl-2- (3-cyano-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl ] -Propionamide;
D20 N-[[5-tert-Butyl-2- [3- (difluoro-methyl) -phenyl] -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D21 N-[[5-tert-Butyl-2- (3-methoxyphenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -Propionamide;
D22 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (3-methoxyphenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D23 N-[[5-tert-Butyl-2- [3- (trifluoromethyl) phenyl] -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) ) -Phenyl] -propionamide;
D24 N-[[5-tert-Butyl-2- (m-tolyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl]- Propionamide;
D25 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (4-methoxyphenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D26 1-[[2- (3-Chlorophenyl) -5-cyclopropyl-2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -Urea;
D27 1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -Phenyl] -urea;
D28 1-[[2- (3-Chloro-4-fluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2 -Methylsulfonyl-ethyl) -phenyl] -urea;
D29 1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl ] -Urea;
D30 1-[[5-tert-Butyl-2- (3-fluorophenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl)- Phenyl] -urea;
D31 1-[[5-tert-Butyl-2- (3,5-difluoro-phenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-) Ethyl) -phenyl] -urea;
D32 1- [3-Fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -3-[[2- (m-tolyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -Methyl] -urea; and D33 1- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -3-[[2- (3-isopropyl-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -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 (T-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 above-mentioned meanings], a compound of general formula (T-III) in which D═OH or Hal;

[Wherein Hal represents halogen, preferably Br or Cl, R ⁷ , R ⁹ , R ¹⁰⁸ , and t each have one of the aforementioned meanings, and A is CH or C (CH ₃ In a 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 (T) Or

[Wherein A represents CH or C (CH ₃ ), R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , and R ² and R ⁷ , R ⁹ , R ^108, and t have one of the aforementioned meanings. Or 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, of at least one general formula (T-II) Compound

[Wherein R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , and R ² have one of the aforementioned meanings] to form a compound of the general formula (T-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 (T-IV) with a compound of general formula (T-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 , R ¹⁰⁸ and t have one of the aforementioned meanings, A represents N] to form a compound of general formula (T)

[Wherein A represents N, and R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , and R ² and R ⁷ , R ⁹ , R ^108, and t 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 (T-II) shown above for forming a compound of the general formula (T) shown above, and in particular of the general formula (T-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..

  In another method, the compound of the general formula (T-II) shown above to form the compound of the general formula (T) shown above, and D = Hal (where Hal is a leaving group) Of the carboxylic acid halide of the general formula (T-III) shown above, preferably halogen, preferably chlorine or bromine, is 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 (T-II), (T-III), (T-IV), and (T-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 (TS2), ie Hal- (TS2), 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 (TS2) or the corresponding boronic acid 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 (T-II) can be obtained.

  In step j07, compound (T-II) is converted to compound (T-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 (T-V) can be converted to the urea compound (T) (where A = N). This can be accomplished by reacting with (T-IV), if appropriate in the presence of a base, by methods familiar to the person skilled in the art.

In step j09, amine (T-II) can be converted to amide (T), where A = CH or C (CH ₃ ). For example, by methods familiar to the person skilled in the art, by reaction with acid halides, preferably chlorides of the formula (T-III) in which D = Hal, if appropriate in the presence of a base, or if appropriate This can be achieved by reacting with an acid of formula (T-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 (T-II) can be reacted with the amide (T) (wherein A =) by reacting the compound (T-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 (T) in which A = N can be further prepared by a reaction sequence according to general reaction scheme 2.

  In step v1, compound (TV) is converted to compound (T-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, the amine (T-II) can be converted to the urea compound (T) (where A = N). This can be accomplished by reacting with (T-Va), if appropriate in the presence of a base, by methods familiar to those 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)
Brine Saturated aqueous sodium chloride solution n-BuLi n-butyllithium 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 EDCI N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride 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 TEA Triethylamine Pd / C Palladium Charcoal TBTU O- (Benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate TLC Thin layer chromatography TFA Trifluoroacetic acid THF tetrahydrofuran v / v volume to volume w / w weight to 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 (120 mL HCl 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.

  In a similar manner, the following additional intermediate product could be synthesized using the process described hereinabove in 1:

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 was (possibly) synthesized using the process described hereinbefore 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% ).

  4). Preparation of (1- (3-chlorophenyl) -3-cyclopropyl-1H-pyrazol-5-yl) methanamine hydrochloride

  Step a: To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 eq) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by the dropwise addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 equivalents) at 0 ° C. The reaction mixture was gradually warmed to room temperature and stirred for 3 hours. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The remaining aqueous layer was diluted with 2N aqueous HCl (15 mL) and extracted with diethyl ether (2 × 25 mL). The organic layer was washed with brine solution, dried over sodium sulfate, filtered and concentrated to give a light brown liquid (400 mg, 31%).

  Step b: Step-a To a solution of the product (200 mg, 0.543 mmol, 1 eq) in ethanol (8 mL) was added methoxylamine hydrochloride (30% solution in water, 0.4 mL, 0.651 mmol, 1.2 eq). ) Was added at room temperature and the reaction mixture was stirred for 1 hour. Ethanol was evaporated under reduced pressure and the remaining aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78%).

  Step c: Step-b A mixture of product (1.1 g, 5.164 mmol, 1 eq) and 3-chlorophenylhydrazine hydrochloride (1.84 g, 10.27 mmol, 2 eq) was taken up in acetic acid (20 mL), 2-Methoxyethanol (10 mL) and the reaction mixture were heated at 105 ° C. for 3 hours. The solvent was evaporated and the residue was extracted with ethyl acetate (60 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography (silica gel: 100-200 mesh; eluent: ethyl acetate-petroleum ether (4:96)) gave a light brown semi-solid (1.15 g, 77%).

  Step d: Step-c To a solution of the product (2.5 g, 8.62 mmol, 1 eq) in tetrahydrofuran (15 mL) -methanol (9 mL) -water (3 mL) was added lithium hydroxide (1.08 g, 25. 71 mmol, 3 eq) was added at 0 ° C. and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the pH of the residue was adjusted to about 3 using 2N aqueous HCl (1.2 mL). The acidic aqueous layer is extracted with ethyl acetate (2 × 60 mL) and the combined organic layers are washed with water (10 mL), brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Off-white solid (1.4 g, 62%).

  Step e: Step-d To a solution of the product (1.4 g, 5.34 mmol, 1 eq) in 1,4-dioxane (30 mL), add pyridine (0.25 mL, 3.2 mmol, 0.6 eq) and Di-tert-butyl dicarbonate (1.4 mL, 6.37 mmol, 1.2 eq) was added at 0 ° C. and the resulting mixture was stirred at the same temperature for 30 minutes. Ammonium bicarbonate (0.84 g, 10.63 mmol, 2 eq) was added at 0 ° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with 2N HCl (20 mL), water (10 mL), brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography (silica gel: 100-200 mesh; eluent: ethyl acetate-petroleum ether (16:84)) gave a white solid (1 g, 72%).

Step f: Step-e To a solution of the product (2 g, 7.66 mmol, 1 eq) in tetrahydrofuran (25 mL) was added BH ₃ . DMS (1.44 mL, 15.32 mmol, 2 eq) was added at 0 ° C. and the reaction mixture was heated at 70 ° C. for 3 h. The reaction mixture was cooled to 0 ° C., methanol (15 mL) was added and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was brought to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ether (15 mL), cooled to 0 ° C., and a solution of HCl in 1,4-dioxane (3 mL) was added (pH of the reaction mixture was about 4). The precipitated solid was filtered and washed with diethyl ether (5 mL, 3 times) to give the hydrochloride compound as a white solid (600 mg, 28%).

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 (T-II) can be converted to a carboxylic acid of general formula or carboxylic acid of general formula (T-III) General instructions for reacting with derivatives to form compounds of general formula (T) [wherein A = CH or C (CH ₃ ) (amide)]

1.1 Method A:
An acid of general formula (T-III) (1 eq), an amine of general formula (T-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 giving the product (T).

1.2 Method B:
An acid of general formula (T-III) (1 eq) and an amine of general formula (T-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 (T).

1.3 Method C:
The acid of the general formula (T-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 (T-III) To the corresponding acid chloride. The amine of general formula (T-II) (1.1 equiv) is dissolved in dichloromethane (1 mmol acid in 6 mL) and mixed with triethylamine (3 equiv) 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 (T).

1.4 Method D:
After dissolving the phenyl ester (T-IIIa) (1 eq) and the corresponding amine (T-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 removal of the solvent under vacuum, the residue obtained is purified by flash chromatography (SiO _{2 in} various ratios such as 1: 1, EtOAc / hexane), thus obtaining (T).

  Exemplary compounds D1-D10 were obtained using any of the methods described herein above. Exemplary compounds D11-D25 can be obtained using any of the methods described herein above.

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

Step j07 / Step v1: An amine of general formula (T-II) or (TV) (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 (T-IV) or (T-Va) obtain.

Step j08 / Step v2: The obtained carbamic acid phenyl ester (T-IV) or (T-Va) (1 equivalent) and the corresponding amine (T-V) or (T-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 removal of the solvent under vacuum, the residue obtained is purified by flash chromatography (SiO _{2 in} various ratios such as 1: 1, EtOAc / hexane), thus obtaining (T).

  Exemplary compounds D26-D29, D31 and D33 were obtained using any of the methods described herein above. Exemplary compounds D30 and D32 can be prepared using any of the methods described herein above.

Detailed Synthesis of Selected Exemplary Compounds Example D1: N-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro- Synthesis of 4-methylsulfonyl-phenyl) -propionamide

Step 1: To 2-fluorobenzenethiol (4.8 g (3.6 mL), 0.03 mol) was added sodium hydroxide (1.8 g) at room temperature. Dimethyl sulfide (4.7 g, 1 equivalent) was neutralized with potassium carbonate and added to the above contents at room temperature. The entire reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC (5% ethyl acetate / hexane, R _f ˜0.8). When the reaction was complete, cold water was added to the contents and the compound was extracted with ethyl acetate (2 × 50 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to (2-fluorophenyl) (methyl) sulfane (5 g, crude) as a light blue colored liquid. The resulting crude was used as such for the next step.

Step 2: To a solution of AlCl ₃ (9.2 g, 0.06 mol, 2 eq) in chloroform (50 mL) cooled to 0 ° C., ethyl (chlorocarbonyl) formate (7.3 g, 0.05 mol, 1.6 Eq.) Was added dropwise and the reaction mixture was stirred at the same temperature for 30-45 min. (2-Fluorophenyl) (methyl) sulfane (5 g, crude) was added at 0 ° C. and the reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC (5% ethyl acetate in n-hexane, R _f ˜0.5). When the reaction was complete, crushed ice was added and the mixture was stirred for a while. The organic layer was separated and the aqueous layer was extracted with DCM (2 × 50 mL). The combined extracts were washed with NaHCO ₃ solution, dried over sodium sulfate and concentrated under reduced pressure to color ethyl 2- (3-fluoro-4- (methylthio) phenyl) -2-oxoacetate yellow. Obtained as a liquid (5.5 g).

Step 3: To a solution of ethyl 2- (3-fluoro-4- (methylthio) phenyl) -2-oxoacetate (5.5 g, 0.02 mol) in toluene (55 mL, 10 ×), 3M sodium hydroxide solution (9.09 mL) was added at 50 ° C. and the reaction mixture was stirred at the same temperature for 3 hours. The progress of the reaction was monitored by TLC (30% ethyl acetate / hexane, R _f ˜0.1). When the reaction was complete, the contents were cooled to 0 ° C., the mixture was acidified with dilute HCl, and the precipitated solid was filtered. Crude 2- (3-fluoro-4- (methylthio) phenyl) -2-oxoacetic acid (4.5 g, crude) obtained as a yellow colored solid was used as such for the next step.

Step 4: 2- (3-Fluoro-4- (methylthio) phenyl) -2-oxoacetic acid (4.5 g, crude) was added to hydrazine hydrate (5.1 mL, 5 eq) at −50 ° C. The contents were heated to 80 ° C., KOH (2.7 g, 2.3 eq) was added and the entire reaction mixture was stirred at 100 ° C. for 12 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.8). When the reaction was complete, water and ethyl acetate were added to the contents and the layers were separated. The aqueous layer was acidified with dilute HCl at 0-5 ° C., the precipitate was filtered and dried to give 2- (3-fluoro-4- (methylthio) phenyl) acetic acid as a white colored solid (3 g, 71 %).

Step 5: 2- (3-Fluoro-4- (methylthio) phenyl) acetic acid (3 g, 0.01 mol) was dissolved in anhydrous THF (60 mL) and the mixture was cooled to -78 ° C. Lithium bis (trimethylsilyl) amide (45 mL, 3 eq) was added at −78 ° C. and the mixture was stirred at the same temperature for 1 hour. Methyl iodide (0.93 mL, 1 eq) was added at −78 ° C. and the mixture was allowed to reach room temperature and stirred at the same temperature for 3 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.5). The reaction was not complete, but the mixture was worked up. The reaction contents were quenched at 0 ° C. with saturated ammonium chloride solution. The contents were acidified with dilute HCl, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure, and the resulting crude was purified by column chromatography (10% ethyl acetate / hexanes) to give 2- (3-fluoro-4- ( Methylthio) phenyl) propanoic acid was obtained as a yellow solid (1 g, 31%).

Step 6: To a solution of 2- (3-fluoro-4- (methylthio) phenyl) propanoic acid (1 g, 0.009 mol) in acetone (10 mL) was added potassium carbonate (0.63 g) at room temperature. DMS (0.58 g, 1 eq) was neutralized with potassium carbonate and filtered. Filtered DMS was added to the above contents and the entire reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexane, R _f ˜0.9). When the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was taken up in water and the compound was extracted with ethyl acetate (2 × 25 mL). The combined extracts were dried over sodium sulfate, concentrated under reduced pressure and the crude product (1 g) obtained as a brown colored liquid was used as such for the next step.

Step 7: Formic acid (6.5 mL, 1 eq) was added to methyl 2- (3-fluoro-4- (methylthio) phenyl) propanoate (1 g, crude) and the mixture was cooled to 0 ° C. Hydrogen peroxide (1.4 mL, 3 eq) was added dropwise at 0 ° C. and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexane, R _f ˜0.4). When the reaction was complete, the contents were cooled to 0 ° C., water was added and the mixture was extracted with ethyl acetate (2 × 25 mL). The combined extracts were washed with NaHCO ₃ solution, dried over sodium sulfate and concentrated under reduced pressure to give methyl 2- (3-fluoro-4- (methylsulfonyl) phenyl) propanoate as a colorless thick liquid ( 1 g, crude). The resulting crude product was used as such for the next step.

Step 8: To a solution of methyl 2- (3-fluoro-4- (methylsulfonyl) phenyl) propanoate (2.1 g, 0.008 mol) in methanol (21 mL, 10 ×) was added sodium hydroxide (0.32 g, A solution of 1 equivalent) in water (3 mL) was added at 0 ° C. The contents were brought to room temperature and the mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.1). When the reaction was complete, the methanol was completely distilled off and the resulting residue was taken up in water. Acidify the contents to pH 4 with dilute HCl, filter the precipitate and dry to give 2- (3-fluoro-4- (methylsulfonyl) phenyl) propanoic acid as a white colored solid (1.7 g, 85%).

Step 9: To a solution of (3-tert-butyl-1- (3-chloro-4-fluorophenyl) -1H-pyrazol-5-yl) methanamine (49 mg, 0.189 mmol) in DCM (1.3 mL). 1-Chloro-N, N, 2-trimethyl-1-propenylamine (48 μL, 0.369 mmol) was added at room temperature under a nitrogen atmosphere. After stirring for 1 hour, 2- (3-fluoro-4- (methylsulfonyl) phenyl) propanoic acid (93 mg, 0.378 mmol) and N-ethyldiisopropylamine (0.11 mL, 0.662 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with NaHCO ₃ solution (2 × 10 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained is purified by column chromatography (eluent: ethyl acetate / cyclohexane (2: 1)) to give pure N-[[5-tert-butyl-2- (3-chlorophenyl)- 2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide (Example Compound D1) (66 mg, 71%) was obtained.

  Example D2: N-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl)- Synthesis of propionamide

  Steps 1-8: as described for Example D1.

  Step 9: To a solution of 2- (3-fluoro-4- (methylsulfonyl) phenyl) propanoic acid (60 mg, 0.244 mmol) in THF (1.9 mL) was added 1-hydroxybenzotriazole (32 mg, 0.244 mmol). ), O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate (78 mg, 0.244 mmol), N-ethyldiisopropylamine (0.083 mL) , 0.488 mmol), and (1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (67 mg, 0.244 mmol). The solution was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate / cyclohexane (2: 1)) to give pure N-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H- Pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide (Example Compound D2) (93 mg, 76%) was obtained.

  Exemplary compounds D3 and D4 were prepared in a similar manner.

  Example D5: 2- (3-Chloro-4-methylsulfonyl-phenyl) -N-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl]- Synthesis of propionamide

Step 1: To a well-stirred solution of AlCl ₃ (16.58 g, 2 eq) in chloroform (100 mL), ethyl (chlorocarbonyl) formate (10.02 g (8.35 mL), 1.6 eq) Was added at 0 ° C. and the contents were stirred for 30 minutes. (2-Chlorophenyl) (methyl) sulfane (10 g (8.33 mL), 0.06 mol) was then added at 0 ° C. and the entire reaction was stirred at room temperature for 3-4 hours. The progress of the reaction was monitored by TLC (5% ethyl acetate / hexane, R _f ˜0.3). When the reaction was complete, crushed ice was added and the contents were stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with DCM (2 × 100 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give ethyl 2- (3-chloro-4- (methylthio) phenyl) -2-oxoacetate as a pale yellow colored liquid (12 g, 73% ).

Step 2: A solution of ethyl 2- (3-chloro-4- (methylthio) phenyl) -2-oxoacetate (12 g, 0.49 mol) in toluene (120 mL, 10 ×) was heated to 50 ° C. 3M NaOH solution (2.23 g, 1.2 eq) was added dropwise at 50 ° C. and the contents were refluxed at 60 ° C. for 3 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.1). When the reaction was complete, toluene was distilled off and the resulting residue was placed in ice cold water. The contents were then acidified with dilute HCl at 0 ° C. and stirred at room temperature for 1 hour. The precipitate was filtered and dried to give 2- (3-chloro-4- (methylthio) phenyl) -2-oxoacetic acid as a yellow colored solid (10 g, 93%).

Step 3: To hydrazine hydrate (10 g, 5 eq) cooled to −50 ° C. was added 2- (3-chloro-4- (methylthio) phenyl) -2-oxoacetic acid (10 g, 0.04 mol). . The contents were initially warmed to room temperature and gradually heated to 80 ° C. KOH (5.59 g, 2.3 eq) was then added in portions at 80 ° C. and the entire reaction was refluxed at the same temperature for 12-16 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.4). When the reaction was complete, the reaction contents were diluted with a mixture of water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The aqueous layer was then acidified with dilute HCl and stirred at room temperature for 1 hour. The precipitate was filtered and dried to give 2- (3-chloro-4- (methylthio) phenyl) acetic acid as a white colored solid (8 g, 85%).

Step 4: 2- (3-Chloro-4- (methylthio) phenyl) acetic acid (2 g, 0.009 mol) was placed in THF (20 mL, 10 ×) and cooled to −78 ° C. Lithium bis (trimethylsilyl) amide (27.77 mL, 3 eq) was added dropwise at −78 ° C. and stirred at the same temperature for 2 hours. Methyl iodide (1.31 g, 1 eq) was then added dropwise at −78 ° C. and the entire reaction was stirred at the same temperature for 3 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.2). Since the reaction was not complete, the reaction was warmed to room temperature and stirred for 10 hours. When TLC was monitored again, the reaction was not yet completed. The reaction contents were then quenched with saturated ammonium chloride solution and acidified with dilute HCl. The THF layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure, and the resulting crude was purified by column chromatography (10% ethyl acetate / n-hexane) to give 2- (3-chloro-4 -(Methylthio) phenyl) propanoic acid was obtained as a pale yellow colored solid (1.2 g, 53%).

Step 5: To a solution of 2- (3-chloro-4- (methylthio) phenyl) propanoic acid (3.5 g, 0.015 mol) in acetone (35 mL) was added potassium carbonate (2.06 g, 0.01 mol, 1 Equivalent) was added at room temperature. DMS (1.91 g, 1 eq) was neutralized with potassium carbonate and filtered. Filtered DMS was added to the above contents and the entire reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.9). When the reaction was complete, the contents were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was taken up in water and the compound was extracted with ethyl acetate (2 × 100 mL). The combined extracts were dried over sodium sulfate, concentrated under reduced pressure, and the crude product (3.5 g) obtained as a brown colored liquid was used as such for the next step.

Step 6: Formic acid (20.8 mL, 1 eq) was added to methyl 2- (3-chloro-4- (methylthio) phenyl) propanoate (3.2 g, crude) and cooled to 0 ° C. Hydrogen peroxide (4.48 mL, 3 eq) was added dropwise at 0 ° C. and the reaction was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (30% ethyl acetate / hexane, R _f -0.3). When the reaction was complete, the contents were cooled to 0 ° C., water was added and the mixture was extracted with ethyl acetate (2 × 100 mL). The combined extracts were washed with NaHCO ₃ solution, dried over sodium sulfate and concentrated under reduced pressure to give methyl 2- (3-chloro-4- (methylsulfonyl) phenyl) propanoate as a colorless thick liquid ( 3.2 g, crude). The resulting crude product was used as such for the next step.

Step 7: To a solution of methyl 2- (3-chloro-4- (methylsulfonyl) phenyl) propanoate (3.2 g, crude) in methanol (32 mL, 10 ×) was added sodium hydroxide (0.46 g, 1 equivalent). ) In water (5 mL) was added at 0 ° C. The contents were warmed to room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.1). When the reaction was complete, the methanol was completely distilled off and the resulting residue was taken up in water. The contents were acidified to pH 4, diluted with HCl at 0 ° C., the precipitate was filtered and dried to give 2- (3-chloro-4- (methylsulfonyl) phenyl) propanoic acid as a white colored solid ( 2.7 g, 88%).

  Step 8: To a solution of 2- (3-chloro-4- (methylsulfonyl) phenyl) propanoic acid (60 mg, 0.229 mmol) in THF (1.9 mL) was added 1-hydroxybenzotriazole (30 mg, 0.229 mmol). ), O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate (74 mg, 0.229 mmol), N-ethyldiisopropylamine (0.078 mL) , 0.458 mmol), and (1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (63 mg, 0.229 mmol) were added. The solution was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: ethyl acetate / cyclohexane (1: 2)) to give 2- (3-chloro-4-methylsulfonyl-phenyl) -N-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propionamide (Example Compound D5) (100 mg, 84%) was obtained.

  Example D6: N-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -Phenyl] -propionamide synthesis

  Step 1: To a stirred solution of 4-bromo-2-fluoro-1- (methylsulfonylmethyl) benzene (2 g, 7.487 mmol) in dimethylformamide (11 mL) was added ethyl 2-chloropropionate (1.24 mL, 9 .733 mmol), manganese (822 mg, 14.974 mmol), and (2,2′-bipyridine) nickel (II) -dibromide (196 mg, 0.524 mmol) were added. Trifluoroacetic acid (4 drops) was added. The reaction mixture was stirred at 60 ° C. overnight. After cooling to room temperature, the mixture was hydrolyzed with 1N HCl (30 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed in vacuo. The crude was purified by CC (eluent: ethyl acetate / cyclohexane (1: 1)) to give ethyl 2- (3-fluoro-4- (methylsulfonylmethyl) phenyl) propanoate (966 mg, 45%). .

  Step 2: Ethyl 2- (3-fluoro-4- (methylsulfonylmethyl) phenyl) propanoate (950 mg, 3.295 mmol) was hydroxylated into a stirred solution in a co-solvent containing tetrahydrofuran and water (1: 1). Lithium (236 mg, 9.885 mmol) was added. The reaction mixture was refluxed overnight, then cooled to room temperature and diluted with water (25 mL) and diethyl ether (25 mL). After phase separation, the aqueous layer was acidified with HCl to pH = 3 and extracted with DCM (3 × 50 mL). The organic layer was dried over magnesium sulfate and filtered. The filtrate's solvent was removed in vacuo to give 2- (3-fluoro-4- (methylsulfonylmethyl) -phenyl) propanoic acid (846 mg, 99%).

  Step 3: 2- (3-Fluoro-4- (methylsulfonylmethyl) phenyl) propanoic acid (68 mg, 0.231 mmol) and (1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole- To a stirred solution of 5-yl) methanamine (60 mg, 0.231 mmol) in THF (1.8 mL) was added O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyl. Uronium tetrafluoroborate (73 mg, 0.231 mmol), 1-hydroxybenzotriazole (30 mg, 0.231 mmol), and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol) were added. The reaction mixture is stirred at room temperature for 48 hours, concentrated in vacuo and the residue is purified by CC (eluent: ethyl acetate / cyclohexane (3: 2)) to give N-[[2- (3-chlorophenyl) -5- (Trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -propionamide (83 mg, 69%) was obtained.

  Exemplary compound D10 was similarly prepared according to D6.

  Example D7: N-[[5-tert-butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl ] -Synthesis of propionamide

  Steps 1-2: As described for Example Compound D6.

  Step 3: 2- (3-Fluoro-4- (methylsulfonylmethyl) phenyl) propanoic acid (60 mg, 0.231 mmol) and (3-tert-butyl-1- (3-chlorophenyl) -1H-pyrazole-5 Yl) methanamine (60 mg, 0.231 mmol) in THF (1.8 mL) to a stirred solution of O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium. Tetrafluoroborate (73 mg, 0.231 mmol), 1-hydroxybenzotriazole (30 mg, 0.231 mmol), and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol) were added. The reaction mixture is stirred at room temperature for 48 hours, concentrated in vacuo and the residue is purified by CC (eluent: ethyl acetate / cyclohexane (3: 2)) to give N-[[5-tert-butyl-2- (3 -Chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -propionamide (94 mg, 80%) was obtained.

  Exemplary compounds D8, D9, D11, D13, D16-D21, D23, and 24 were prepared in a similar manner or can be similarly prepared according to D7.

  Example D12: 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (4-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl ] -Methyl] -propionamide synthesis

Step 1: DMAP (4.25 g, 34 mmol) was added to DCM (3 L) and the contents were cooled to −10 ° C. Trifluoroacetic anhydride (765 g, 3.2 mol) was added, followed by the dropwise addition of ethyl vinyl ether (250 g, 3.04 mol) at −10 ° C. for 45 minutes. The entire reaction mixture was then stirred at 0 ° C. for 8 hours and later at room temperature overnight. The progress of the reaction was monitored by TLC (ethyl acetate 10% / hexane, R _f ˜0.7). When the reaction was complete, the reaction contents were treated with saturated NaHCO ₃ solution (600 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (2 × 500 mL). The combined organic layers were washed with water (2 × 1 L), dried over sodium sulfate and concentrated under reduced pressure to give (E) -4-ethoxy-1,1,1-trifluorobut-3-ene. 2-one was obtained as a brown colored liquid (450 g, crude).

  Step 2: Hydrazine dihydrochloride (225 g, 2.14 mol) in ethanol (1400 mL) was stirred well. TEA (185.4 mL, 1.34 mol) was added dropwise over 45 minutes at ambient temperature. (E) -4-Ethoxy-1,1,1-trifluorobut-3-en-2-one (225 g, crude) was then added dropwise at room temperature and the entire reaction mixture was refluxed overnight. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexane, Rf ˜0.4). When the reaction was complete, the ethanol was distilled off completely, the residue was taken up in ice water (500 mL) and the product was extracted with ethyl acetate (2 × 400 mL). The combined extracts were washed with ice water (300 mL), dried over sodium sulfate and concentrated under reduced pressure to give 3- (trifluoromethyl) -1H-pyrazole as an off-white solid (175 g, crude). Obtained.

Step 3: NaH (33.08 g (19.85 mol, 60%) was washed with n-hexane, then anhydrous DMF (500 mL) was added dropwise under N ₂ atmosphere and the mixture was stirred well. A solution of trifluoromethyl) -1H-pyrazole (75 g, 0.55 mol) in DMF (125 mL) was added dropwise under an N ₂ atmosphere, followed by 4-methoxylbenzyl chloride (86.3 g, 0.55 mol, A solution of 1 eq) in DMF (125 mL) was added dropwise and the entire reaction mixture was stirred for 12 h at room temperature The progress of the reaction was monitored by TLC (10% ethyl acetate / hexanes, R _f ˜0.4). When the reaction was complete, the reaction contents were poured into ice water (500 mL) and the product was extracted with ethyl acetate (2 × 400 mL). The contents were then dried over sodium sulfate and concentrated under reduced pressure, and the resulting crude was purified by CC using 10% ethyl acetate / n-hexane. -(4-Methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazole was obtained as a brown colored liquid (98 g, yield 70%).

Step 4: Diisopropylamine (28.4 mol, 39.4 mL) was placed in THF (500 mL), stirred well and cooled to 0 ° C. n-BuLi (234.4 mL) was added dropwise at 0 ° C. and the mixture was stirred at 0 ° C. for 1 hour. The contents were then cooled to −78 ° C. and a solution of 1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazole (62 g, 0.24 mol) in THF (200 mL) was added for 30 minutes. The contents were added dropwise, the contents were added dropwise for 30 minutes, and the contents were stirred at −78 ° C. for an additional hour. Anhydrous CO ₂ gas was then bubbled into the reaction mixture for 1.5 hours. The progress of the reaction was monitored by TLC (10% ethyl acetate / hexane, R _f ˜0.1). When the reaction was complete, the reaction contents were poured into ice water (300 mL) and the aqueous layer was extracted with ethyl acetate (2 × 200 mL) under basic conditions. The aqueous layer was acidified with 20% HCl solution and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid as an off-white solid. (40 g, 55%).

Step 5: To a solution of 1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid (50 g, 0.16 mol) in DCM (750 mL) was added a catalytic amount of DMF. In addition, the mixture was cooled to 0 ° C. Thionyl chloride (61 mL, 0.83 mol) was added dropwise at 0 ° C. for 30 minutes. The entire reaction mixture was heated to reflux and maintained for 2 hours. The progress of the reaction was monitored by TLC (10% ethyl acetate / hexane, R _f ˜0.4). When the starting material disappeared, DCM was distilled off completely. The acid chloride prepared above was dissolved in DCM (500 mL) and added dropwise to aqueous ammonia (700 mL) at 0 ° C. The entire reaction mixture was stirred for 1 h and the progress of the reaction was monitored by TLC (10% ethyl acetate / hexane, R _f ˜0.7). When the reaction was complete, ice cold water (200 mL) was added and the product was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxamide as an off-white solid ( 37 g, crude). The resulting crude was used as such for the next step.

Step 6: LAH (4.7 g, 0.12 mol) was charged to the flask. THF (250 mL) was added at 0 ° C. A solution of 1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxamide (37 g, 0.12 mol) in THF (120 mL) was then added dropwise at 0 ° C. over 30 minutes. The reaction mixture was heated to reflux for 5 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, R _f ˜0.2). Since the reaction was not complete, LAH (2.3 g) was added again and the mixture was refluxed for an additional 4 hours. After completion of the reaction, the reaction contents were slowly added to saturated sodium sulfate (1 L) solution, filtered through celite and the product was extracted with ethyl acetate (2 × 500 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to turn off crude (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine. Obtained as a white solid (32.5 g, crude). The resulting crude was used as such for the next step.

Step 7: (1- (4-Methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (80 g, 0.28 mol) cooled to 0 ° C. in DCM (600 mL) To the solution was added TEA (30.2 mL, 0.026 mol) dropwise over 10 minutes. Boc anhydride (62.5 mL, 0.28 mol) was then added dropwise at 0 ° C. for 20-30 minutes. The entire reaction mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexane, R _f ˜0.6). When the reaction was complete, DCM was completely distilled off, the residue was taken up in ice water (500 mL) and the product was extracted with ethyl acetate (2 × 300 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was recrystallized from n-hexane (200 mL) to give tert-butyl (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methylcarba The mart was obtained as an off-white solid (80 g, 74% yield).

Step 8: of tert-butyl (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methylcarbamate (20 g, 0.052 mol) cooled to 0 ° C. To a stirred solution in toluene (300 mL), aluminum chloride (17.34 g, 0.129 mol) was added in small portions for 30 minutes. The reaction mixture was gradually heated to 50-60 ° C. and stirred at the same temperature for 2 hours. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexane, R _f ˜0.1). When the reaction was complete, the reaction contents were treated with dilute HCl, ice cold water (300 mL) was added, and the mixture was extracted with ethyl acetate (2 × 100 mL). The aqueous layer is basified with sodium hydroxide solution, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to give (3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine. Was obtained as a brown colored solid (4.6 g, crude). The resulting crude was used as such for the next step.

Step 9: (3- (Trifluoromethyl) -1H-pyrazol-5-yl) methanamine (7 g, 42.4 mmol) was dissolved in DCM (7 mL) at room temperature, then this was added to TEA (5.86 mL, 72 .4 mmol) was added at room temperature and the mixture was stirred for 10 minutes and cooled to 0-5 ° C. (Boc) ₂ O (9.24 g, 42.4 mmol) was added dropwise to the reaction mixture for 30 minutes and maintained at 0-5 ° C. for 3 hours. The progress of the reaction was monitored by TLC (30% ethyl acetate / n-hexane). When the reaction was complete, the reaction mixture was allowed to reach room temperature for 2 hours, the DCM was distilled off, the resulting residue was treated with water (50 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate and the solvent was evaporated under vacuum. The resulting crude was purified by CC to give tert-butyl (3- (trifluoromethyl) -1H-pyrazol-5-yl) methylcarbamate as a white colored solid (5 g, 44%). .

  Step 10: To a stirred solution of tert-butyl (3- (trifluoromethyl) -1H-pyrazol-5-yl) methylcarbamate (5 g, 18.8 mmol) in MeOH (36 mL) was added HCl in 2-propanol. (5.8 mL, 29.2 mmol) was added and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo, diethyl ether (20 mL) was added, and the resulting precipitate was filtered off and washed with diethyl ether (5 mL). After drying, (3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine hydrochloride was obtained (3.67 g, 97%).

  Step 11: (3- (Trifluoromethyl) -1H-pyrazol-5-yl) methanamine hydrochloride (194 mg, 0.96 mmol) and 2- (3-Fluoro-4- (methylsulfonylmethyl) phenyl) propanoic acid To a stirred solution of (250 mg, 0.96 mmol) in THF (7.4 mL) was added O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate. Late (308 mg, 0.96 mmol), 1-hydroxybenzotriazole (135 mg, 0.96 mmol), and N-ethyldiisopropylamine (0.491 mL, 2.881 mmol) were added. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and purified by CC (eluent: ethyl acetate / cyclohexane (9: 1)) to give 2- (3-fluoro-4- (methylsulfonylmethyl) phenyl). -N-((3- (trifluoromethyl) -1H-pyrazol-5-yl) methyl) propanamide (335 mg, 86%) was obtained.

  Step 12: 4-Fluorophenylboronic acid (41 mg, 0.295 mmol), 2- (3-Fluoro-4- (methylsulfonylmethyl) phenyl) -N-((3- (trifluoromethyl) -1H-pyrazole- 5-yl) methyl) propanamide (60 mg, 0.147 mmol) and copper (II) acetate (0.021 mL, 0.221 mmol) were added to DCM (2.2 mL). Pyridine (0.238 mL, 2.946 mmol) was added at room temperature and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the resulting solid was purified by CC (eluent: cyclohexane / ethyl acetate (1: 2)) to give 2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl]. -N-[[2- (4-Fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propionamide (55 mg, 75%) was obtained.

  Exemplary compounds D14, D15, D22, and D25 were prepared in a similar manner or can be similarly prepared according to D12.

  Example D26: 1-[[2- (3-chlorophenyl) -5-cyclopropyl-2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl)- Synthesis of phenyl] -urea

Step 1: To a stirred solution of 2- (2-fluoro-4-nitrophenyl) acetic acid (1 g, 5.02 mmol) in tetrahydrofuran (10 mL) was added BH ₃ .S (CH ₃ ) ₂ (7.5 mL, 7. 53 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was then cooled to 0 ° C. and excess borane was quenched with methanol (10 mL). The reaction mixture was concentrated under reduced pressure to give the crude compound, which was purified by CC (eluent: ethyl acetate / n-hexane (1: 1)) to give 2- (2-fluoro-4-nitro Phenyl) ethanol (0.89 g, 95%) was obtained.

  Step 2: 2- (2-Fluoro-4-nitrophenyl) ethanol (0.89 g, 4.8 mmol) was added 48% aqueous hydrobromic acid (0.77 g, 9.62 mmol) and concentrated sulfuric acid (0.25 mL). ) Was added under cooling to the stirred solution. The reaction mixture was heated to 100 ° C. for 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude compound. The crude was purified by CC (eluent: 5% ethyl acetate in n-hexane) to give 1- (2-bromoethyl) -2-fluoro-4-nitrobenzene (1 g, 85%).

  Step 3: To a stirred solution of 1- (2-bromoethyl) -2-fluoro-4-nitrobenzene (1 g, 4.03 mmol) in isopropanol (15 mL) was added sodium methanesulfinate (2.05 g, 20.16 mmol). Was added at room temperature. The reaction mixture was heated to 70 ° C. for 10 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude compound, which was filtered off and the residue was washed with water (2 × 5 mL) to give pure 2-fluoro-1- (2 -(Methylsulfonyl) ethyl) -4-nitrobenzene (700 mg, 70%) was obtained.

  Step 4: 2-Fluoro-1- (2- (methylsulfonyl) ethyl) -4-nitrobenzene (700 mg, 2.83 mmol) is dissolved in ethyl acetate (7 mL) and the solution is (10%) Pd / C (70 mg). Was added under an argon atmosphere, which was subjected to hydrogenation in a Parr apparatus and the reaction continued to stir for 2 hours. The reaction mixture was filtered through celite, washed well with ethyl acetate and concentrated under reduced pressure to give 3-fluoro-4- (2- (methylsulfonyl) ethyl) aniline (590 mg, 96%).

Step 5: Stirred solution of 3-fluoro-4- (2- (methylsulfonyl) ethyl) aniline (200 mg, 0.92 mmol) in acetone / DMF (3 mL + 1.27 mL), pyridine (0.222 mL, 2.76 mmol). To this, phenyl chloroformate (0.152 mL, 1.197 mmol) was added dropwise at 0 ° C. and the mixture was stirred at room temperature for 1 hour. Acetone was evaporated and the residue was diluted with DCM (30 mL). The mixture was washed with saturated NaHCO ₃ solution (15 mL) and the organic layer was extracted with DCM (2 × 20 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give pure phenyl 3-fluoro-4- (2- (methylsulfonyl) ethyl) phenylcarbamate (260 mg, 84%).

  Step 6: Phenyl 3-fluoro-4- (2- (methylsulfonyl) ethyl) phenylcarbamate (90 mg, 0.267 mmol) and (1- (3-chlorophenyl) -3-cyclopropyl-1H-pyrazole-5 Yl) To a stirred solution of methanamine (70 mg, 0.286 mmol) in THF (4 mL) was added N-ethyldiisopropylamine (0.087 mL, 0.507 mmol) and 1 in microwave (150 ° C., 7 bar). Stir for hours. The reaction mixture was concentrated in vacuo and purified by CC (eluent: ethyl acetate / cyclohexane (2: 1)) to give 1-[[2- (3-chlorophenyl) -5-cyclopropyl-2H-pyrazole-3- Yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -urea (30 mg, 23%) was obtained.

  Exemplary compounds D27-D33 were prepared in a similar manner or can be similarly prepared according to D26.

  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 (T), 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 (where 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 composed of 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. Selected from the group (wherein C _1-4 alkyl is unsubstituted in each case);
A represents N, CH or C (CH ₃ );
t represents 0, 1 or 2,
R ¹⁰⁸ is C which is unsubstituted or mono-, di- or tri-substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, OH, ═O and OCH ₃ Represents _1-4 alkyl]. 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. t represents 1 or 2,
A represents N,
R ¹⁰¹ 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 , CH ₂ CH ₃ , CH ( CH ₃₎ is selected from _{2, O-CH 3, O} -CH 2 CH 3, NH 2, NH (CH 3) and N _{(CH 3)} group consisting of _2,
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 , Selected from the group consisting of 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 ,
Or
t represents 0, 1 or 2;
A represents CH or C (CH ₃ );
R ¹⁰¹ is H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ ,
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 , and wherein the _{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 The compound according to any one of claims 1 to 3. R ¹⁰¹ is H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ , and 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, 5. One of claims 1 to 4, characterized in that it is selected from the group consisting of O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) _2. Compound described in 1. R ^101, wherein at least one of ^{R 102} and ^{R 103} is ≠ H, compounds according to any one of claims 1 to 5. 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 6. Characterized in that at least one of R ⁷ and R ⁹ are ≠ H, compounds according to any one of claims 1 to 7. Partial structure (TS1)

Is a partial structure (PT1), (PT2) or (PT3)

[Wherein R ¹⁰⁸ represents unsubstituted C _1-4 alkyl]
The compound according to any one of claims 1 to 8, characterized in that Partial structure (TS1)

Is a partial structure (PT2) or (PT3)

[Wherein R ¹⁰⁸ represents CH ₃ or CH ₂ CH ₃ ]
The compound according to claim 1, characterized in that The compound according to claim 1, wherein A represents N or C (CH ₃ ). A represents N,
R ¹⁰¹ 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 , CH ₂ CH ₃ , CH ( CH ₃ ) ₂ , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ and R ¹⁰² and R ¹⁰³ are independently 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 , or A is CH or C (CH ₃ ) Show
R ¹⁰¹ is H, F, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ —OH, CH ₂ —OCH ₃ , OCF ₃ , OH, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , O—CH ₃ , O—CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ , and 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, Selected from the group consisting of 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. Selected from the group consisting of —CH ₂ CH ₃ ;
Partial structure (TS1)

Is a partial structure (PT2) or (PT3)

[Wherein R ¹⁰⁸ represents CH ₃ or CH ₂ CH ₃ ]
11. A compound according to any one of claims 1-4, 6-8 and 10, 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,
D1 N-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide;
D2 N-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide ;
D3 2- (3-Fluoro-4-methylsulfonyl-phenyl) -N-[[2- (3-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propion An amide;
D4 N-[[2- (3-Chloro-4-fluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- (3-fluoro-4-methylsulfonyl -Phenyl) -propionamide;
D5 2- (3-Chloro-4-methylsulfonyl-phenyl) -N-[[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propionamide ;
D6 N-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl ] -Propionamide;
D7 N-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl]- Propionamide;
D8 N-[[5-tert-Butyl-2- (3-chloro-4-fluoro-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D9 N-[[5-tert-Butyl-2- (3-fluorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -Propionamide;
D10 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (3-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D11 N-[[5-tert-Butyl-2- (4-fluorophenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -Propionamide;
D12 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (4-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D13 N-[[5-tert-Butyl-2- (3,4-difluoro-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -Phenyl] -propionamide;
D14 N-[[2- (3,4-Difluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D15 N-[[2- (3,5-Difluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D16 N-[[5-tert-Butyl-2- [3- (methoxymethyl) -phenyl] -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) ) -Phenyl] -propionamide;
D17 N-[[5-tert-Butyl-2- (3-dimethylamino-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl)- Phenyl] -propionamide;
D18 N-[[5-tert-Butyl-2- (3-fluoro-5-methyl-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D19 N-[[5-tert-Butyl-2- (3-cyano-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl ] -Propionamide;
D20 N-[[5-tert-Butyl-2- [3- (difluoro-methyl) -phenyl] -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl- Methyl) -phenyl] -propionamide;
D21 N-[[5-tert-Butyl-2- (3-methoxyphenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -Propionamide;
D22 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (3-methoxyphenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D23 N-[[5-tert-Butyl-2- [3- (trifluoromethyl) phenyl] -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) ) -Phenyl] -propionamide;
D24 N-[[5-tert-Butyl-2- (m-tolyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl]- Propionamide;
D25 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N-[[2- (4-methoxyphenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl]- Methyl] -propionamide;
D26 1-[[2- (3-Chlorophenyl) -5-cyclopropyl-2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -Urea;
D27 1-[[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -Phenyl] -urea;
D28 1-[[2- (3-Chloro-4-fluoro-phenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2 -Methylsulfonyl-ethyl) -phenyl] -urea;
D29 1-[[5-tert-Butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl ] -Urea;
D30 1-[[5-tert-Butyl-2- (3-fluorophenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl)- Phenyl] -urea;
D31 1-[[5-tert-Butyl-2- (3,5-difluoro-phenyl) -2H-pyrazol-3-yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-) Ethyl) -phenyl] -urea;
D32 1- [3-Fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -3-[[2- (m-tolyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -Methyl] -urea; and D33 1- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -3-[[2- (3-isopropyl-phenyl) -5- (trifluoromethyl) 13. A compound according to any one of claims 1 to 12 selected from the group consisting of -2H-pyrazol-3-yl] -methyl] -urea.   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.