KR20140091041A - Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an so2-containing group as vanilloid receptor ligands - Google Patents

Abstract

The present invention relates to substituted pyrazolyl carboxamides and urea derivatives having a phenyl moiety substituted with an SO ₂ -containing group as a vanilloid acceptor ligand, pharmaceutical compositions containing such compounds, / RTI > and / or < RTI ID = 0.0 > and / or < / RTI >
T

Description

SUBSTITUTED PYRAZOLYL-BASED CARBOXAMIDE AND UREA DERIVATIVES BEARING A PHENYL MOIETY SUBSTITUTED WITH AN SO2-CONTAINING GROUP AS Phenylmorphides substituted with SO2-containing Groups as Vanilloid Receptor Ligands VANILLOID RECEPTOR LIGANDS}

The present invention relates to substituted pyrazolyl carboxamides and urea derivatives having a phenyl moiety substituted with an SO ₂ -containing group as a vanilloid acceptor ligand, pharmaceutical compositions containing such compounds, and pain And to the aforementioned compounds for use in the treatment and / or prophylaxis of further diseases and / or disorders.

The treatment of pain, especially neuropathic pain, is very important in the medical field. Effective pain therapies are required worldwide. The urgent need for treatment for patient-centered and target-oriented therapies of chronic and non-chronic pain states (which is understood to mean successful and satisfactory treatment of patient pain) It is also reported in a number of scientific studies.

The subtype 1 vanilloid receptor (VR1 / TRPV1), sometimes also referred to as the capsaicin receptor, is a suitable starting point for the treatment of pain, especially pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain. This receptor is stimulated, among other things, by vanilloids, such as capsaicin, heat and proton, and plays an important role in the development of pain. It is also important for a number of additional physiological and pathophysiological processes and is associated with numerous additional disorders such as migraine, depression, neurodegenerative disease, cognitive disorders, anxiety states, epilepsy, coughing, diarrhea, itching , Inflammation, cardiovascular disorders, eating disorders, drug dependence, drug abuse and urinary incontinence.

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

Additional compounds with comparable or better properties (potency, potency) are required as well as with respect to the affinity for the vanilloid receptor 1 (VR1 / TRPV1 receptor) itself.

Thus, it may be advantageous to improve the metabolic stability, solubility or permeability of the compounds in aqueous media. These factors may have beneficial effects on oral bioavailability or may alter the PK / PD (pharmacokinetic / pharmacodynamic) profile; This may lead, for example, to a more beneficial period of validity.

Mild or nonexistent interactions with transport molecules associated with digestion and excretion of pharmaceutical compositions are also regarded as indicators of improved bioavailability and minimally interactions of pharmaceutical compositions. In addition, the interaction with enzymes involved in degradation and excretion of pharmaceutical compositions should also be as low as possible, and such test results also suggest that the interaction of pharmaceutical compositions is expected to be as low as possible or not at all.

It is therefore an object of the present invention to provide novel compounds, preferably those which have advantages over the prior art compounds. The compounds are useful as pharmaceutical compositions for the treatment and / or prophylaxis of disorders or diseases which are mediated at least in part by the vanilloid receptor 1 (VR1 / TRPV1 receptor), preferably in a pharmaceutical composition, Lt; / RTI >

This object is achieved by the subject matter described herein.

Surprisingly, the substituted compounds of formula (T) as described below exhibit excellent affinity for the subtype 1 vanilloid receptor (VR1 / TRPV1 receptor) and are therefore at least partially mediated by vanilloid receptor 1 (VR1 / TRPV1) Disorders or diseases, in particular for the treatment and / or prophylaxis of diseases or disorders.

In addition to activity against the VR1-receptor, one or more additional beneficial properties, such as a suitable effect, an appropriate efficacy, no increase in body temperature and / or heat pain threshold; Adequate solubility in aqueous media such as buffer systems, such as phosphate buffer systems, and in biologically relevant media, such as aqueous media, especially at physiologically acceptable pH values; Sufficient stability against the oxidative capacity of liver enzymes such as cytochrome P450 (CYP) enzymes, and sufficient diversity with respect to metabolic elimination through these enzymes), and the like as described below Substituted compounds of the same general formula T are particularly suitable.

Accordingly, the present invention relates to the use of a compound of formula (T), optionally in the form of a single stereoisomer or mixture of stereoisomers, a free compound and / or a physiologically acceptable salt thereof and / or a physiologically acceptable solvate, .

T

In the above formula (T)

R ^101, R ¹⁰² and R ¹⁰³ is H, F, Cl, Br, CFH 2, CF 2 H, CF 3, CN, CH 2 -OH, CH 2 CH 2 -OH, CH 2 -OCH 3, CH 2 CH _{2 -OCH 3, OCFH 2, OCF} 2 H, OCF 3, OH, NH 2, C 1-4 alkyl, OC _1-4 alkyl, NH-C _1-4 alkyl, and N (C _1-4 alkyl) _2, are independently selected from each other from the group consisting of, wherein the C _{1 -4} alkyl is not substituted 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 one another from H, F, Cl, Br, CFH _2, CF ₂ H, CF _3, CN, OH, OCF _3, C _1-4 alkyl, and OC _1-4 alkyl group consisting of selected, and wherein the C _{1 -4} alkyl is not substituted in each case,

A is N, CH or C (CH _3),

t is 0, 1 or 2,

R ¹⁰⁸ is C _{1 -4} alkyl (which, is optionally substituted, F, is mono- substituted, disubstituted or trisubstituted by Cl, Br, OH, = O, and one, two or three substituents selected from the group consisting of OCH ₃₎ .

details

The term "mono-stereoisomer" preferably means, in the sense of the present invention, an individual enantiomer or diastereomer. The term "mixture of stereoisomers" means, in the sense of the present invention, mixtures of enantiomers and / or diastereomers of racemates and any mixing ratio.

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

Physiologically acceptable salts of at least one compound according to the invention and at least one physiologically acceptable acid are preferably used in the sense of the present invention (especially when used in humans and / or other mammals Quot; refers to a salt of at least one compound according to the invention having at least one physiologically acceptable inorganic or organic acid. Examples of the physiologically acceptable acid include 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, But are not limited to, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2,3 or 4-aminobenzoic acid, Glycine, hippuric acid, phosphoric acid, and aspartic acid. Particularly preferred are citric acid and hydrochloric acid. Hydrochloride salts and citric acid salts are therefore particularly preferred salts.

The physiologically acceptable salts of at least one compound according to the invention with at least one physiologically acceptable base are preferably used in the sense of the present invention (especially in the context of the use in humans and / or other mammals Refers to a salt of at least one compound according to the invention as an anion having at least one, preferably inorganic, cation that is physiologically acceptable. Alkali metal salts and alkaline earth metal salts, especially sodium salt or sodium salt, (potassium salt) or potassium salt, magnesium salt or calcium salt, and ammonium salt [NH _x R _{4 -x} ] ⁺ (where, x is 0, 1, 2, 3 or 4, R is unbranched or branched C _{1 -4} alkyl moiety represents a) is particularly preferred.

The term "alkyl" and "C _{1 -4} alkyl" preferably can not be respectively branched or branched, in the sense of the present invention, unsubstituted or mono- or polysubstituted, for example monosubstituted, disubstituted or trisubstituted And includes acyclic, saturated aliphatic hydrocarbon residues, i.e., C _1-4 aliphatic residues, i.e., C _1-4 alkanyl, containing from one to four, i.e., one, two, three, or four carbon atoms . Preferred C _1-4 alkanyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

In relation to the term "alkyl" and "C _1-4 alkyl", the term "monosubstituted" or "polysubstituted", for example, disubstituted or in Spanish mackerel ring means of the present invention, with respect to the corresponding residues or groups of Quot; means single or multiple substitution, e. G., Disubstituted or trisubstituted, of at least one hydrogen atom, each independently of the others by one or more substituents. The term "multisubstitution ", e.g., disubstituted or tricyclic, with respect to substituted moieties and groups, e. G., Disubstituted or trisubstituted moieties and groups, As well as at the same carbon atom as in the case of CF ₃ or CH ₂ CF ₃ or in various places such as in the case of CH (OH) -CH ₂ CH ₂ -CHCl ₂ , do. Multiple substitutions may be made using the same or different substituents.

The term "cycloalkyl" and "C _{3 -6} cycloalkyl" is preferably, for purposes of this invention, three, four, cyclic containing 5 or 6 carbon atoms, aliphatic (cycloaliphatic) hydrocarbons, that is, C _{3 -6} - means a cycloaliphatic moiety, wherein the hydrocarbon is saturated, which is not substituted. Cycloalkyl can be attached to each parent general structure via any desired possible ring member of the cycloaliphatic moiety. Preferably, the 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.

는 상응하는 잔기의 각각의 상위의 일반 구조에 대한 연결을 나타낸다.Within the scope of the present invention, the symbols used in the formulas

Represents the connection to the general structure of each of the corresponding residues.

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

Preferably, R ¹⁰¹ , R ¹⁰² and R ¹⁰³ are independently selected from H, F, Cl, Br, CFH ₂ , CF ₂ H, CF ₃ , CN, CH ₂ -OH, CH ₂ -OCH ₃ , OCF ₃ , _3, O-CH _3, O-CH ₂ CH _3, NH _second, NH (CH _3), and N (CH ₃₎ are independently selected from each other from the group consisting of _2.

More preferably, R ^101, R ¹⁰² and R ¹⁰³ is _{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 .

In still more preferably, R ^101, R ¹⁰² and R ¹⁰³ is _{H, F, Cl, CFH 2} , CF 2 H, CF 3, OCF 3, CH 3, O-CH 3, and O-CH ₂ CH ₃ Lt; / RTI > are independently selected from each other.

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 selected from the group consisting of H, F, Cl and O-CH ₃ .

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

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

In another preferred embodiment of the compounds according to the invention,

R ¹⁰¹ and 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, 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₎ are independently selected from each other from the group consisting of _2,

R ¹⁰³ represents H;

Preferably,

R ¹⁰¹ and 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-CH 2 CH 3, NH} 2, NH (CH 3), and N (CH ₃₎ independently selected from each other from the group consisting of _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 ) ₂ , H, F, Cl, CFH _2, CF ₂ H, CF _3, OCF _3, CH _3, O-CH _3, and O-CH ₂ CH ₃ are independently selected from each other from the group consisting of, even more preferably H , F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ and is selected independently from each other from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ and, even more particularly preferably are independently selected from each other from the group consisting of H, F, Cl, and O-CH ₃ ,

R ¹⁰³ represents H;

In 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) 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 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 from 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 and still more preferably F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH ₃ and even more preferably selected from the group consisting of F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ And especially selected from the group consisting of F, Cl, CF ₃ and O-CH ₃ , even more particularly preferably selected from the group consisting of F, Cl, and O-CH ₃ ,

R ¹⁰² and R ¹⁰³ both represent H.

In 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) 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 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 from 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 and still more preferably F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH ₃ and even more preferably selected from the group consisting of F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ And especially selected from the group consisting of F, Cl, CF ₃ and O-CH ₃ , even more particularly preferably selected from the group consisting of F, Cl, and O-CH ₃ ,

R ¹⁰¹ and R ¹⁰³ both represent H.

In a 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) 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 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 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 from 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 and still more preferably F, Cl, CFH ₂ , CF ₂ H, CF ₃ , OCF ₃ , CH ₃ , O-CH ₃ and O-CH ₂ CH ₃ and even more preferably selected from the group consisting of F, Cl, CF ₃ , OCF ₃ , CH ₃ and O-CH ₃ And especially selected from the group consisting of F, Cl, CF ₃ and O-CH ₃ , even more particularly preferably selected from the group consisting of F, 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-CH _{2 CH 3, NH 2, NH} (CH 3), and N (CH ₃₎ is selected from the group consisting of _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 a _second and, 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 is selected from the group consisting of, and, even more preferably H, F, Cl, CF _3, OCF _3, CH _3, and O-CH ₃ and is particularly preferably selected from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ and even more preferably H, F, Cl, and O-CH ₃ , < / RTI >

R ¹⁰³ represents H;

In 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₎ is selected from the group consisting of _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₎ is selected from the group consisting of a _second and, even more preferably F, CFH _2, CF ₂ H, CF _3, OCF _3, CH ₃ , O-CH _3, and O-CH is selected from the group consisting of ₂ CH _3, and even more preferably F, CF _3, OCF _3, is selected from the group consisting of CH ₃ and O-CH _3, in particular F, CF ₃ and O-CH ₃ , even more particularly preferably selected from the group consisting of F and O-CH ₃ ,

R ¹⁰² and R ¹⁰³ both represent H.

In 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₎ is selected from the group consisting of _2,

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, 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 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₎ is selected from the group consisting of _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₎ is selected from the group consisting of a _second and, even more preferably F, CFH _2, CF ₂ H, CF _3, OCF _3, CH ₃ , O-CH _3, and O-CH is selected from the group consisting of ₂ CH _3, and even more preferably F, CF _3, OCF _3, is selected from the group consisting of CH ₃ and O-CH _3, in particular F, CF ₃ and O-CH ₃ , even more particularly preferably 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-CH _{2 CH 3, NH 2, NH} (CH 3), and N (CH ₃₎ is selected from the group consisting of _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 a _second and, 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 is selected from the group consisting of, and, even more preferably H, F, Cl, CF _3, OCF _3, CH _3, and O-CH ₃ and is particularly preferably selected from the group consisting of H, F, Cl, CF ₃ and O-CH ₃ and even more preferably H, F, Cl, and O-CH ₃ < / RTI >

는 다음의 화합물들로 이루어진 그룹으로부터 선택된다:In another particularly preferred embodiment according to the invention, in particular when t is 0, 1 or 2, preferably 1 or 2 and A is N, the partial structure (TS2)

Is selected from the group consisting of the following compounds:

는 다음의 화합물들로 이루어진 그룹으로부터 선택된다:Even more particularly preferably, especially when t is 0, 1 or 2, preferably 1 or 2 and A is N, the partial structure (TS2)

Is selected from the group consisting of the following compounds:

는 다음의 화합물들로 이루어진 그룹으로부터 선택되고:Most preferably, especially when t is 0, 1 or 2, preferably 1 or 2 and A is N, the partial structure (TS2)

Is selected from the group consisting of:

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

는 다음의 화합물들로 이루어진 그룹으로부터 선택된다:If in another particularly preferred embodiment according to the present invention, especially where t is 0,1 or 2, preferably 1 or 2, A is a CH or C (CH _3), a partial structure (TS2)

Is selected from the group consisting of the following compounds:

는 다음의 화합물들로 이루어진 그룹으로부터 선택된다:For even more particularly preferably, especially t is 1 or 2, preferably 1 or 2, A is CH or C (CH _3), a partial structure (TS2)

Is selected from the group consisting of the following compounds:

는 다음의 화합물들로 이루어진 그룹으로부터 선택되고:The most preferably, especially where t is 1 or 2, preferably 1 or 2, A is a CH or C (CH _3), a partial structure (TS2)

Is selected from the group consisting of:

Preferably, particularly where t is 1 or 2, preferably 1 or 2 and when A is CH or C (CH _3), is selected from the group consisting of the following compounds:

In another preferred embodiment of the compounds according to the invention R ² is selected from the group consisting of CF ₃ , methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, , Cyclobutyl, cyclopentyl or cyclohexyl.

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

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

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

In another particularly preferred embodiment of the compounds according to the invention, R < ² > represents tert-butyl.

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

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

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

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

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

In a further preferred embodiment of the compounds according to the invention, at least one of R < ⁷ > and R < ⁹ >

In a further preferred embodiment of the compounds according to the invention, R < ⁹ > is H.

In another preferred embodiment of the compounds according to the invention,

R ⁷ is from _{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 group consisting of CH ₃ is selected and, preferably F, Cl, CF _3, CN, OH, OCF _3, CH _3, O-CH _3, and O-CH is selected from the group consisting of 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 < / RTI >

R ⁹ represents H.

In another preferred embodiment of the compounds according to the invention, A is N or C (CH _3).

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

In another particularly preferred embodiment of the compounds according to the invention, A is C (CH _3).

In another preferred embodiment of the compounds according to the invention, t is 1 or 2.

In a particularly preferred embodiment of the compounds according to the invention, t is 1.

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

In a further preferred embodiment of the compounds according to the invention,

t is 1 or 2, preferably 1,

A is 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; 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} ; < / RTI > More preferably, is selected from _{H, F, Cl, CFH 2} , CF 2 H, CF 3, OCF 3, CH 3, O-CH 3, and O-CH ₂ CH ₃ group consisting of; Even more preferably is selected from the group consisting of _{H, F, Cl, CF 3} , OCF 3, CH 3 and O-CH _3; Even more preferably is selected from the group consisting of H, F, Cl, CF _3, and O-CH _3; In particular it is selected from the group consisting of H, F, Cl, and O-CH _3; Most preferably F or Cl;

R ¹⁰² and R ¹⁰³ 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₎ independently selected from each other from the group consisting of _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} , < / RTI > 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 are independently selected from each other from the group consisting of; Still more preferably _{H, F, Cl, CF 3} , OCF 3, CH 3 O-CH _3, and are independently selected from each other from the group consisting of; Even more preferably they are independently selected from each other from the group consisting of H, F, Cl, CF _3, and O-CH _3; In particular H, F, Cl, and O-CH ₃ are independently selected from each other from the group consisting of; Most preferably independently of one another are F or Cl;

t is 0, 1 or 2, preferably 1 or 2, more preferably 1,

A is 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} is selected from the group consisting of; Preferably a _{H, F, CFH 2, CF} 2 H, CF 3, CN, CH 2 -OCH 3, OCF 3, CH 3, O-CH 3, O-CH 2 CH 3 and N (CH _{3) 2} ≪ / RTI > And more preferably is selected from the group consisting of _{H, F, CFH 2, CF} 2 H, CF 3, OCF 3, CH 3, O-CH 3, and O-CH ₂ CH _3; Even more preferably is selected from the group consisting of _{H, F, CF 3, OCF} 3, CH 3 and O-CH _3; Even more preferably is selected from the group consisting of H, F, CF _3, and O-CH _3; In particular it is selected from the group consisting of H, F and O-CH _3; Most preferably F;

R ¹⁰² and R ¹⁰³ 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₎ independently selected from each other from the group consisting of _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} , < / RTI > 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 are independently selected from each other from the group consisting of; Still more preferably _{H, F, Cl, CF 3} , OCF 3, CH 3 O-CH _3, and are independently selected from each other from the group consisting of; Even more preferably they are independently selected from each other from the group consisting of H, F, Cl, CF _3, and O-CH _3; In particular H, F, Cl, and O-CH ₃ are independently selected from each other from the group consisting of; Most preferably independently of one another are F or Cl.

는 부분 구조 (PT1)

, (PT2)

또는 (PT3)

을 나타내고, 여기서, R¹⁰⁸는 치환되지 않은 C_{1 -4} 알킬, 바람직하게는 CH₃ 또는 CH₂CH₃, 더욱 바람직하게는 CH₃을 나타낸다.In a further preferred embodiment of the compounds according to the invention, the partial structure (TS1)

(PT1)

, (PT2)

Or (PT3)

A represents wherein, R ¹⁰⁸ is is the unsubstituted C _{1 -4} alkyl, preferably represents a CH ₃ or CH ₂ CH _3, more preferably CH _3.

는 부분 구조 (PT2)

또는 (PT3)

을 나타내고, 여기서, R¹⁰⁸는 CH₃ 또는 CH₂CH₃, 바람직하게는 CH₃를 나타낸다. Preferably, the partial structure (TS1)

(PT2)

Or (PT3)

, Wherein R ¹⁰⁸ represents CH ₃ or CH ₂ CH ₃ , preferably CH ₃ .

In a particularly preferred embodiment of the compounds according to the invention,

A is N,

R ¹⁰¹ is H, F, Cl, Br, ₂ CFH, CF ₂ H, ₃ CF, CN, CH ₂ -OH, -OCH ₂ CH _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 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₎ are independently selected from each other from the group consisting of _2,

Preferably, at least one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ is not H;

A is 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) 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 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₎ are independently selected from each other from the group consisting of _2,

Preferably, at least one of R ¹⁰¹ , R ¹⁰² and R ¹⁰³ is not H,

R ² represents CF ₃ , tert-butyl or cyclopropyl,

R ⁷ and R ⁹ is H, F, Cl, Br, CF 3, CN, OH, OCF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, O-CH 3, and O-CH ₂ CH _{3 &lt}; / RTI > independently from each other,

Preferably, at least one of R < ⁷ > and R < ⁹ >

는 부분 구조 (PT2)

또는 (PT3)

을 나타내고, 여기서, R¹⁰⁸은 CH₃ 또는 CH₂CH₃, 바람직하게는 CH₃이다.Substructure (TS1)

(PT2)

Or (PT3)

, Wherein R ¹⁰⁸ is CH ₃ or CH ₂ CH ₃ , preferably CH ₃ .

Preferred embodiments of the compounds according to the invention of the formula (T) have the formulas T0-a and / or T0-b.

The formula T0-a

The formula T0-b

Here, the specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

Further preferred embodiments of the compounds according to the invention of the formula (T) have the formulas T1-a, T1-a-1 and / or T1-a-2.

Formula T1-a

Formula T1-a-1

Formula T1-a-2

Here, the specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

In addition, preferred embodiments of the compounds according to the invention of formula (T) have the formulas T1-b, T1-b-1 and / or T1-b-2.

Formula T1-b

Formula T1-b-1

Formula T1-b-2

Here, the specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

A further preferred embodiment of the compounds according to the invention of the formula (T) has the formulas T2-a, T2-a-1 and / or T2-a-2.

The formula T2-a

The compound of formula (T2-a-1)

The formula T2-a-2

Here, the specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

In addition, preferred embodiments of the compounds according to the invention of formula (T) have the formulas T2-b, T2-b-1 and / or T2-b-2.

The formula T2-b

The formula T2-b-1

The formula T2-b-2

Here, the specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

A further preferred embodiment of a compound according to the invention of formula (T) has the formula T3-a, T3-a-1 and / or T3-a-2.

The formula T3-a

The compound of formula T3-a-1

The compound of formula T3-a-2

Here, the specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

In addition, preferred embodiments of the compounds according to the invention of formula (T) have the general formula T3-b, T3-b-1 and / or T3-b-2.

The formula T3-b

Formula T3-b-1

Formula T3-b-2

Here, the specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

Particularly preferred embodiments of the compounds of the present invention are those compounds of formula T2-a, T2-a-1, T2-a-2, T2-b, T2-b- 1, T3-a-2, T3-b, T3-b-1 and / or T3-b-2.

In a particularly preferred embodiment of the present invention, the compounds of formula (T), T0-a, T0-b, T1-a, T1-a-1, T2-a-1, T2-a-2, T2-b, T2-b-1, T2-b-2, T3-a, T3- In the compounds of -b, T3-b-1 and / or T3-b-2, preferably when R ¹⁰³ is H and R ¹⁰² represents H, F, Cl, CF ₃ or OCH ₃ , When R ¹⁰³ is H and R ¹⁰² is H, F or Cl, still more preferably when both R ¹⁰² and R ¹⁰³ are H, the radical R ¹⁰¹ is F, Cl, CF ₃ or O-CH ₃ , Preferably F or Cl, most preferably Cl and the remaining specific radicals, variables and indices have the meanings given herein in connection with the compounds according to the invention and their preferred embodiments.

In a further particularly preferred embodiment of the present invention there is provided a compound of formula I wherein T1-a-1, T1-b, T1-b-1, T2-a, Wherein R ¹⁰³ is H and R ¹⁰² is H, F, Cl, CF _3, or OCH ₃ , in compounds of Formula I-1, T3-a, T3-a-1, T3- , More preferably when R ¹⁰³ is H and R ¹⁰² represents H, F or Cl, still more preferably when both R ¹⁰² and R ¹⁰³ are H, the radical R ¹⁰¹ is F, Cl, CF ₃ or O-CH ₃ , preferably F or Cl, most preferably Cl, and the remaining specific radicals, variables and indices are referred to herein in connection with the compounds according to the invention and their preferred embodiments Have the stated meaning.

In a further particularly preferred embodiment of the present invention there is provided a compound of formula I wherein T1-a-2, T1-b, T1-b-2, T2-a, T2- Wherein R ¹⁰³ is H and R ¹⁰² is H, F, Cl, CF _3, or OCH ₃ , in compounds of Formula _(I) , More preferably when R ¹⁰³ is H and R ¹⁰² is H, F or Cl, still more preferably when both R ¹⁰² and R ¹⁰³ are H, the radical R ¹⁰¹ is F, CF ₃ or O-CH _3, and preferably represents an F, the remaining particular radicals, variables and indices have the meaning set forth in the compounds according to the invention and the disclosure of this in connection with the preferred embodiments thereof.

Particularly preferred are compounds according to the invention selected from the following group, optionally in the form of a single stereoisomer or mixture of stereoisomers, a free compound and / or a physiologically acceptable salt form thereof:

Yl ) -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -2H-pyrazol- - propionamide;

Yl ) -methyl] -2- (3-fluoro-4-methylsulfonyl-pyrimidin-2- Phenyl) -propionamide < / RTI >

D3 2- (3-Fluoro-4-methylsulfonyl-phenyl) -N - [[2- (3- fluorophenyl) -5- (trifluoromethyl) -Methyl] -propionamide; < / RTI >

Pyrazol -3-yl] -methyl] -2- (3-fluoro-phenyl) -5- (trifluoromethyl) 4-methylsulfonyl-phenyl) -propionamide;

D5 2- (3-Chloro-4-methylsulfonyl-phenyl) -N- [[2- (3- chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol- ] -Propionamide;

Yl ] -methyl] -2- [3-fluoro-4- (methylsulfonyl) -2H-pyrazol- -Methyl) -phenyl] - < / RTI >propionamide;

D7 N - [[5- tert -butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] ) -Phenyl] - < / RTI >propionamide;

Yl ] -methyl] -2- [3-fluoro-4- (4-fluoro-phenyl) (Methylsulfonyl-methyl) -phenyl] -propionamide;

D9 N - [[5- tert -butyl-2- (3-fluorophenyl) -2H-pyrazol-3-yl] Methyl) -phenyl] - < / RTI >propionamide;

D10 2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (3- fluorophenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;

Yl ] -methyl] -2- [3-fluoro-4- (methylsulfonyl-pyridin-2- Methyl) -phenyl] - < / RTI >propionamide;

D12 2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (4- fluorophenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;

D13 N - [[5- tert -butyl-2- (3,4-difluoro-phenyl) -2H-pyrazol-3- yl] Methylsulfonyl-methyl) -phenyl] - < / RTI >propionamide;

Pyrazol -3-yl] -methyl] -2- [3-fluoro-4- (trifluoromethyl) - (methylsulfonyl-methyl) -phenyl] -propionamide;

Pyrazol -3-yl] -methyl] -2- [3-fluoro-4- (trifluoromethyl) - (methylsulfonyl-methyl) -phenyl] -propionamide;

Yl ] -methyl] -2- [3-fluoro-4- ((3-fluoro-phenyl) Methylsulfonyl-methyl) -phenyl] - < / RTI >propionamide;

D17 N - [[5- tert -Butyl-2- (3-dimethylamino-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro- -Methyl) -phenyl] - < / RTI >propionamide;

Yl ] -methyl] -2- [3-fluoro-4- (4-fluoro-phenyl) (Methylsulfonyl-methyl) -phenyl] -propionamide;

D19 N - [[5- tert -butyl-2- (3-cyano-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro- -Methyl) -phenyl] - < / RTI >propionamide;

Yl ] -methyl] -2- [3-fluoro-4- (trifluoromethyl) phenyl] -2H-pyrazol- - (methylsulfonyl-methyl) -phenyl] -propionamide;

D21 N - [[5-3-tert-butyl-2- (3-methoxy-phenyl) -2H- pyrazol-3-yl] -methyl] -2- [4- (methylsulfonyl 3-fluoro sulfonyl - Methyl) -phenyl] - < / RTI >propionamide;

D22 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (3- methoxyphenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;

Yl ] -methyl] -2- [3-fluoro-4- ((3-fluoro-phenyl) -2H-pyrazol- Methylsulfonyl-methyl) -phenyl] - < / RTI >propionamide;

D24 N - [[5-3-tert-butyl-2- (m- tolyl) -2H- pyrazol-3-yl] methyl] -2- [3-fluoro-4- (methylsulfonyl-methyl) -Phenyl] - < / RTI >propionamide;

D25 2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (4- methoxyphenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;

Ylmethyl ] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) ) -Phenyl] -urea < / RTI >

D27 1 - [[2- (3- chlorophenyl) -5- (trifluoromethyl) -2H- pyrazol-3-yl] methyl] -3- [4- (2-methyl-3-fluoro Ethyl) -phenyl] -urea < / RTI >;

Pyrazol -3-yl] -methyl] -3- [3-fluoro-phenyl] -5- (trifluoromethyl) 4- (2-methylsulfonyl-ethyl) -phenyl] -urea;

D29 1 - [[5-3-tert-butyl-2- (3-chloro-phenyl) -2H- pyrazol-3-yl] methyl] -3- [4- (2-methylsulfonyl-fluorobenzyl -Ethyl) -phenyl] -urea < / RTI >;

D30 1 - [[5-3-tert-butyl-2- (3-Fluoro-phenyl) -2H- pyrazol-3-yl] methyl] -3- [4- (2-methylsulfonyl-fluorobenzyl Fluoro-ethyl) -phenyl] -urea; < / RTI >

D31 1 - [[5-3-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- 3-yl] -methyl] -urea; < / RTI > And

D33 1- [3-Fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -3 - [[2- (3- isopropyl- phenyl) -5- (trifluoromethyl) Pyrazol-3-yl] -methyl] -urea.

Also, in a FLIPR assay using CHO K1 cells transfected with the human VR1 gene, the expression level of less than 2,000 nM, preferably less than 1,000 nM, particularly preferably less than 300 nM, most particularly preferably less than 100 nM, Compounds according to the present invention that result in 50% displacement of capsaicin present at a concentration of 100 nM at a concentration of less than 50 nM, more preferably less than 50 nM, most preferably less than 10 nM, may be preferred.

In the process, Ca ^{2 +} influx, as will be described later, in the fluorescence imaging plate reader (FLIPR (fluorescent imaging plate reader), United States Sunny Molecular devices sheath (Molecular Devices), based on a bale Ca ^{2 +} - sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, The Netherlands).

The substituted compounds and corresponding stereoisomers according to the present invention and also the respective corresponding acids, bases, salts and solvates are toxicologically stable and therefore suitable as pharmaceutical active ingredients in pharmaceutical compositions.

The present invention therefore furthermore relates to the use of the compounds according to the invention in addition, in each case in the form of pure stereoisomers, in particular enantiomers or diastereoisomers, racemates thereof or stereoisomers of any desired mixing ratio, At least one compound according to the invention and, where appropriate, one or more pharmaceutically suitable adjuvants, in the form of a mixture of the two stereoisomers and / or mixtures of the diastereomers, or respectively in the form of the corresponding salts, or respectively in the form of the corresponding solvates, ≪ / RTI >

These pharmaceutical compositions according to the invention are useful for the modulation of vanilloid receptor 1- (VR1 / TRPV1) regulation, preferably vanilloid receptor 1- (VR1 / TRPV1) inhibition and / or vanilloid receptor 1- (VR1 / TRPV1) Particularly suitable, that is, they exert an action or antagonistic effect.

Likewise, the pharmaceutical compositions according to the invention are preferably suitable for the prophylaxis and / or treatment of disorders or diseases mediated at least in part by the vanilloid receptor 1.

The pharmaceutical compositions according to the invention are suitable for administration to adults and to children, including infants and infants.

The pharmaceutical composition according to the present invention may be in a liquid, semi-solid or solid pharmaceutical form such as injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, For example, in the form of a cream, a lotion, a gel, an emulsion, an aerosol or a multiparticulate form, for example in the form of pellets or granules, if appropriate, compressed to a tablet, decanted to a capsule, And may also be administered by itself.

Where appropriate, the stereoisomers of pure stereoisomers, in particular of the form of one of the enantiomers or diastereomers, of its racemates or of any desired mixing ratio, in particular of mixtures of enantiomers and / or diastereomers In addition to the at least one substituted compound according to the invention, which is in the form of, or where appropriate in the form of the corresponding salt or respectively in the form of the corresponding solvate, the pharmaceutical composition according to the invention is usually formulated with, for example, excipients, A further physiologically compatible pharmaceutical adjuvant which may be selected from the group consisting of diluents, surface active substances, dyes, preservatives, blasting agents, slip additives, lubricants, fragrances and binders.

The choice of physiologically compatible adjuvant and amount thereof to be used is such that the pharmaceutical composition can be administered to the affected area of the skin, mucosa and eye, for example, orally, subcutaneously, parenterally, intravenously, intraperitoneally, , Intranasal, buccal, rectal or topical administration. Formulations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral administration; Solutions, suspensions, easily reconstitutable dry preparations and spray preparations are preferably suitable for parenteral, topical and inhalational administration. Substituted compounds according to the present invention for use in the pharmaceutical compositions according to the invention in a dissolved form of the reservoir or in a plaster in which a skin penetration enhancer, if appropriate, is added are suitable transdermal formulations. Oral or transdermal dosage forms can also release each of the substituted compounds according to the invention in a delayed manner.

A pharmaceutical composition according to the invention, for example, in:. "Remington's Pharmaceutical Sciences" , AR Gennaro (Editor), 17 th Edition, Mack Publishing Company, Easton, Pa, 1985, in particular in Part 8, Chapters 76 to 93, under the auspices of conventional means, apparatus, methods and processes known in the art. The contents of which are incorporated herein by reference to form a part of the present invention. The amount of each of the substituted compounds according to the invention of formula I as described above administered to a patient can be variable and depends, for example, on the body weight or age of the patient and on the severity of the indication, manner of indication and disorder. Typically, at least one compound according to the present invention is administered in an amount of 0.001 to 100 mg, preferably 0.05 to 75 mg, particularly preferably 0.05 to 50 mg, per 1 kg of the patient's body weight.

The pharmaceutical compositions according to the invention are preferably pain selected from the group consisting of pain, preferably acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; Hyperalgesia; Allodynia; Burner; migraine; depression; Neuropathy; Axonal injury; Neurodegenerative diseases, preferably 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 a memory disorder; epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; cough; Incontinence; Overactive bladder (OAB); Disorders and / or damage of the gastrointestinal tract; Duodenal ulcer; Gastric ulcer; Irritable bowel syndrome; stroke; Eye irritation; Skin irritation; Neurogenic skin disease; Allergic skin disease; psoriasis; Vitiligo; Herpes simplex; Inflammation, preferably inflammation of the intestine, eye, bladder, skin or nasal mucosa; diarrhea; Itching; osteoporosis; arthritis; Osteoarthritis; Rheumatic diseases; An eating disorder selected from the group consisting of hyperphagia, cachexia, anorexia and obesity; Drug dependence; Drug misuse; Withdrawal symptoms due to drug dependence; The occurrence of resistance to drugs, preferably to natural or synthetic opioids; Drug dependence; Misuse of drugs; Withdrawal symptoms due to drug dependence; Alcohol dependence; For the treatment and / or prevention of one or more disorders and / or diseases selected from the group consisting of abuse of alcohol and abstinence due to alcohol dependence; In diuretic; To suppress sodium excretion; On cardiovascular stimulation; On an increase in awakening; For the treatment of wounds and / or burns; For the treatment of injured neurons; On increasing sexual desire; On the regulation of motor activity; To relieve anxiety; (VR1 / TRPV1 receptor) agonist (preferably capsaicin, resciniferatoxin, olanil, arvanil, SDZ-249665, SDZ-249482, novanyl and capsanabanil) for topical anesthesia and / (Which is preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction) that is triggered by the administration of < RTI ID = 0.0 >

Particularly preferably, the pharmaceutical composition according to the invention is pain selected from the group consisting of pain, preferably acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; migraine; depression; Neurodegenerative diseases, preferably 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 a memory disorder; Inflammation, preferably inflammation of the intestine, eye, bladder, skin or nasal mucosa; Incontinence; Overactive bladder (OAB); Drug dependence; Drug misuse; Withdrawal symptoms due to drug dependence; Occurrence of tolerance to drugs, preferably resistance to natural or synthetic opioids; Drug dependence; Misuse of drugs; Withdrawal symptoms due to drug dependence; Alcohol dependence; Or one or more disorders and / or diseases selected from the group consisting of abuse of alcohol and abstinence due to alcohol dependence.

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

(VR1 / TRPV1) inhibition and / or vanilloid receptor 1- (VR1 / TRPV1) stimulation for use in the modulation of the vanilloid receptor 1- (VR1 / TRPV1) The present invention relates to substituted compounds according to the invention and, where appropriate, substituted compounds according to the invention and one or more pharmaceutically acceptable adjuvants.

Thus, the present invention also relates to the use of substituted compounds according to the invention, and, if appropriate, compounds according to the invention for use in the prevention and / or treatment of disorders and / or disorders mediated at least in part by the vanilloid receptor 1 Substituted compounds and one or more pharmaceutically acceptable adjuvants.

Thus, in particular, the present invention further relates to pain selected from the group consisting of pain, preferably acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; Hyperalgesia; Allodynia; Burner; migraine; depression; Neuropathy; Axonal injury; Neurodegenerative diseases, preferably 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 a memory disorder; epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; cough; Incontinence; Overactive bladder (OAB); Disorders and / or damage of the gastrointestinal tract; Duodenal ulcer; Gastric ulcer; Irritable bowel syndrome; stroke; Eye irritation; Skin irritation; Neurogenic skin disease; Allergic skin disease; psoriasis; Vitiligo; Herpes simplex; Inflammation, preferably inflammation of the intestine, eye, bladder, skin or nasal mucosa; diarrhea; Itching; osteoporosis; arthritis; Osteoarthritis; Rheumatic diseases; An eating disorder selected from the group consisting of hyperphagia, cachexia, anorexia and obesity; Drug dependence; Drug misuse; Withdrawal symptoms due to drug dependence; The occurrence of resistance to drugs, preferably to natural or synthetic opioids; Drug dependence; Misuse of drugs; Withdrawal symptoms due to drug dependence; Alcohol dependence; For the treatment and / or prevention of one or more disorders and / or diseases selected from the group consisting of abuse of alcohol and abstinence due to alcohol dependence; In diuretic; To suppress sodium excretion; On cardiovascular stimulation; On an increase in awakening; For the treatment of wounds and / or burns; For the treatment of injured neurons; On increasing sexual desire; On the regulation of motor activity; To relieve anxiety; (VR1 / TRPV1 receptor) agonist (preferably capsaicin, resciniferatoxin, olanil, arvanil, SDZ-249665, SDZ-249482, novanyl and capsanabanil) for topical anesthesia and / (Preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction) induced by the administration of a therapeutically effective amount of a compound of the formula < RTI ID = 0.0 > Where appropriate, the present invention relates to substituted compounds and one or more pharmaceutically acceptable adjuvants according to the present invention.

For use in the prevention and / or treatment of pain selected from the group consisting of pain, preferably 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 adjuvants.

The present invention further provides pharmaceutical compositions for the modulation of vanilloid receptor 1- (VR1 / TRPV1) modulation, preferably vanilloid receptor 1- (VR1 / TRPV1) inhibition and / or vanilloid receptor 1- (VR1 / TRPV1) The use of at least one substituted compound according to the invention for the preparation of a composition and, where appropriate, the use of at least one substituted compound according to the invention and one or more pharmaceutically acceptable adjuvants, Selected from the group consisting of disorders and / or diseases that are at least in part mediated by vanilloid receptor 1, such as pain, preferably acute pain, chronic pain, neuropathic pain, visceral pain and joint pain Pain; Hyperalgesia; Allodynia; Burner; migraine; depression; Neuropathy; Axonal injury; Neurodegenerative diseases, preferably 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 a memory disorder; epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; cough; Incontinence; Overactive bladder (OAB); Disorders and / or damage of the gastrointestinal tract; Duodenal ulcer; Gastric ulcer; Irritable bowel syndrome; stroke; Eye irritation; Skin irritation; Neurogenic skin disease; Allergic skin disease; psoriasis; Vitiligo; Herpes simplex; Inflammation, preferably inflammation of the intestine, eye, bladder, skin or nasal mucosa; diarrhea; Itching; osteoporosis; arthritis; Osteoarthritis; Rheumatic diseases; An eating disorder selected from the group consisting of hyperphagia, cachexia, anorexia and obesity; Drug dependence; Drug misuse; Withdrawal symptoms due to drug dependence; The occurrence of resistance to drugs, preferably to natural or synthetic opioids; Drug dependence; Misuse of drugs; Withdrawal symptoms due to drug dependence; Alcohol dependence; For the prophylaxis and / or treatment of disorders and / or disorders selected from the group consisting of abuse of alcohol and abstinence due to alcohol dependence; For diuretic; For sodium urinary excretion inhibition; For cardiovascular stimulation; For increased awakening; For the treatment of wounds and / or burns; For the treatment of damaged nerves; For increased libido; For the regulation of locomotor activity; For anxiety relief; (Preferably VR1 / TRPV1 receptor) agonists for topical anesthesia and / or vanilloid receptor 1 (VR1 / TRPV1 receptor), preferably capsaicin, reniniferatoxin, olanil, arvanil, SDZ-249665, SDZ-249482, (Preferably selected from the group consisting of high fever, hypertension and bronchoconstriction) triggered by the administration of at least one substituted compound according to the present invention And, where appropriate, the use of at least one substituted compound according to the invention and one or more pharmaceutically acceptable adjuvants.

Another aspect of the invention is the use of a compound of formula (I) for the modulation of vanilloid receptor 1- (VR1 / TRPV1), preferably vanilloid receptor 1- (VR1 / TRPV1) inhibition and / or vanilloid receptor 1- A method of treatment and / or a method for the treatment and / or prophylaxis of a disorder and / or disease, preferably pain, preferably acute pain, chronic pain, neuropathic pain, visceral pain and / Pain selected from the group consisting of joint pain; Hyperalgesia; Allodynia; Burner; migraine; depression; Neuropathy; Axonal injury; Neurodegenerative diseases, preferably 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 a memory disorder; epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; cough; Incontinence; Overactive bladder (OAB); Disorders and / or damage of the gastrointestinal tract; Duodenal ulcer; Gastric ulcer; Irritable bowel syndrome; stroke; Eye irritation; Skin irritation; Neurogenic skin disease; Allergic skin disease; psoriasis; Vitiligo; Herpes simplex; Inflammation, preferably inflammation of the intestine, eye, bladder, skin or nasal mucosa; diarrhea; Itching; osteoporosis; arthritis; Osteoarthritis; Rheumatic diseases; An eating disorder selected from the group consisting of hyperphagia, cachexia, anorexia and obesity; Drug dependence; Drug misuse; Withdrawal symptoms due to drug dependence; The occurrence of resistance to drugs, preferably to natural or synthetic opioids; Drug dependence; Misuse of drugs; Withdrawal symptoms due to drug dependence; Alcohol dependence; For the treatment and / or prevention of disorders and / or disorders selected from the group consisting of abuse of alcohol and abstinence due to alcohol dependence; For diuretic; For sodium urinary excretion inhibition; For cardiovascular stimulation; For increased awakening; For the treatment of wounds and / or burns; For the treatment of damaged nerves; For increased libido; For the regulation of locomotor activity; For anxiety relief; (Preferably VR1 / TRPV1 receptor) agonists for topical anesthesia and / or vanilloid receptor 1 (VR1 / TRPV1 receptor), preferably capsaicin, reniniferatoxin, olanil, arvanil, SDZ-249665, SDZ-249482, (Preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction) induced by the administration of a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > Comprising administering an effective amount of at least one substituted compound according to the invention.

Effectiveness of the pain, e.g., Bennet or Chung model (Bennett or Chung model) [References: Bennett, GJ and Xie, YK, A peripheral mononeuropathy in rat, which produces pain sensation like that seen in Man, Pain 1988, 33 (1), 87-107; In an experimental model for peripheral neuropathy produced by segmental spinal nerve ligation, Pain 1992, 50 (3), 355-363, tail-cutting experiments (see, for example, (See, for example, D. Dubuisson et al., Pain 1977, 4 (1994)), , 161-174).

The present invention also relates to a process for the preparation of substituted compounds according to the invention.

In particular, the compounds according to the invention are prepared by reacting at least one compound of the formula T-II 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, Hal 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 formula (T)

Formula T-II

Formula T-III

T

[In the above formulas T-II, T-III and T,

R ² , R ⁷ , R ⁹ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁸ and t have one of the above meanings,

Hal represents halogen, preferably Br or Cl,

A means CH or C (CH _3)]

At least one compound of formula T-II is reacted in the presence of phenyl chloroformate, if appropriate in the presence of at least one base and / or at least one coupling reagent, in the presence of phenyl chloroformate to form a compound of formula T-IV Said compound is purified and / or isolated where appropriate and the compound of formula T-IV is reacted 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, With a compound of formula < RTI ID = 0.0 > T. ≪ / RTI >

The compounds of the formulas T-II,

Formula T-IV

The compound of formula T-V

T

[In the above formulas T-II, T-IV, T-V and T,

R ² , R ⁷ , R ⁹ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁸ and t have one of the above meanings,

A means N]

The reaction of the above compound of formula T-II with a carboxylic acid of formula T-III, especially where D is OH, to form the compound of formula T is preferably carried out in the presence of a base such as diethyl ether, tetrahydrofuran, acetonitrile, In a reaction medium selected from the group consisting of methanol, ethanol, (1,2) -dichloroethane, dimethylformamide, dichloromethane and the corresponding mixtures, preferably 1-benzotriazolyloxy-tris- ) -Phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N'- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDCI), diisopropylcarbodiimide, 1, 1'-carbonyldiimidazole (CDI), N - [(dimethylamino) -1H-1,2,3-triazolo [4,5- b] pyridino- (HATU), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethylammonium hexafluorophosphate N-oxide (HBTU), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) In the presence of at least one coupling reagent selected from the group consisting of benzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt), preferably in the presence of triethylamine, pyridine, dimethylamino In the presence of at least one organic base selected from the group consisting of pyridine, N-methylmorpholine and diisopropylethylamine, preferably at a temperature of from -70 ° C to 100 ° C.

Or by reacting a compound of formula T-II with a carboxylic acid halide of formula T-III wherein D is Hal wherein Hal represents a halogen, preferably a chlorine or bromine atom as the leaving group, The formation of the compound is preferably carried out in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and the corresponding mixtures, Is carried out 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.

Compounds of the above formulas T-II, T-III, T-IV and T-V are each commercially available and / or can be prepared using conventional processes known to those skilled in the art. In particular, processes for preparing these compounds are described, for example, in WO 2010/127855-A2 and WO 2010/127856-A2. Corresponding portions of these references are considered to be part of this disclosure.

All reactions that can be applied for the synthesis of compounds according to the invention can be carried out under conventional conditions familiar to the person skilled in the art, for example with regard to the pressure or composition addition sequence. Where appropriate, one skilled in the art can determine the optimal procedure under each condition by performing a brief preliminary test. The intermediates and end products obtained using the reactions described above can be purified and / or isolated, respectively, if desired and / or if desired, using conventional methods known to those skilled in the art. Suitable purification processes are, for example, extraction processes and chromatographic processes, for example, column chromatography or preparative chromatography. The purification and / or isolation of each of the intermediates or end products as well as all process steps of the reaction sequence which can be applied for the synthesis of the compounds according to the invention can be carried out, in part or in whole, in an inert gas atmosphere, Atmosphere. ≪ / RTI >

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

The free base of each substituted compound according to the present invention can be obtained, for example, by reaction with an inorganic or organic acid, preferably hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p- toluenesulfonic acid, carbonic acid, formic acid, acetic acid, But are not limited to, 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- Preferably a physiologically acceptable salt, by reaction with aminobenzoic acid, 2,4,6-trimethylbenzoic acid, alpha -lipoic acid, acetylglycine, hippuric acid, phosphoric acid and / or aspartic acid. have. Each of the substituted compounds of the present invention and the free stereochemistry of the corresponding stereoisomers according to the present invention can also be converted into the corresponding physiologically acceptable salts using the salts of free acids or sugar additives, for example, saccharin, cyclamate or acesulfame ≪ / RTI >

Thus, the free acid of the substituted compound according to the invention, for example the substituted compound according to the invention, can be converted into the corresponding physiologically acceptable salt by reaction with a suitable base. Examples thereof include alkali metal salts, alkaline earth metal salts or ammonium salts ^{_{[NH x R 4 -x] +}} ( wherein, x is 0, 1, 2, 3 or 4, R is a branched or unbranched C _{1 -4} alkyl Residue).

The substituted compounds and corresponding stereoisomers according to the present invention, if appropriate, as well as the corresponding acids, corresponding bases or salts of these compounds, can also be prepared in the form of their solvates using conventional methods known to those skilled in the art, Preferably in the form of their hydrates.

When the substituted compound according to the present invention is obtained in the form of a mixture of its stereoisomers after preparation thereof, preferably in the form of their racemates or other mixtures of various enantiomers and / or diastereomers, The compounds can be separated and isolated if appropriate using conventional procedures known to those skilled in the art. Examples thereof include chromatographic separation processes, in particular liquid chromatography processes under normal pressure or elevated pressure, preferably MPLC and HPLC processes, and fractional crystallization processes. These processes may be carried out either by chiral stationary phase HPLC or by reaction of the individual enantiomers formed, such as diastereomeric salts, with a chiral acid such as (+) - tartaric acid, (-) - tartaric acid or (+) - Are separated from each other by crystallization by sulfonic acid.

The chemicals and reaction components used in the reactions and reaction schemes described below may be commercially available, or in each case may be prepared by conventional methods known to those skilled in the art.

General Reaction 1 (Reaction 1)

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

By in step j02, methyl pivalate JI methods known to those skilled in the art, e.g., in the presence of a base, if appropriate, using acetonitrile CH ₃ -CN can be converted to an alkyl nitrile oxo J- II.

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

In step j04 , the amino compound J- III may first be converted to a diazonium salt by methods known to those skilled in the art, for example, using nitrites, and the diazonium salt is reacted with a coupling reagent In the presence of cyanide, the nitrogen can be removed to convert the cyano-substituted pyrazolyl derivative J- IV .

In step j05 , compound J- IV is reacted with halides of partial structure (TS2), i.e. Hal- (TS2), by methods known to the person skilled in the art, for example in the presence of a base and / (OH) ₂ (TS2) or the corresponding boronic acid ester in the presence of a coupling reagent and / or a base, if appropriate in the presence of a coupling reagent and / or a base, where Hal is preferably Cl, Br or I, , And can be substituted at the N position, and compound JV can be obtained in this manner.

Alternatively, a second synthetic route which by in step k01, esters K-0 a first technique known in the art, for example, forming an aldehyde KI by reduction using a suitable hydride reagent, such as a metal hydride is a compound JV ≪ / RTI >

In step k02 , the aldehyde KI is reacted with hydrazine KV , which can be obtained starting from the primary amine K- IV and obtained by methods known to a person skilled in the art at step k05 , by methods known to those skilled in the art, K- II can be formed.

In step k03, by a hydrazine K- II to methods known to those skilled in the art, for example, while complete a double bond using a chlorination reagent such as NCS halogenated, preferably chlorinated, and can, in this way the compound K - III . ≪ / RTI >

In step k04 , the hydrazanoyl halide K- III can be cyclized using methods known to those skilled in the art, for example, using a halogen-substituted nitrile to convert it to a cyano-substituted compound JV .

In step j06, by the compound JV to the methods known to those skilled in the art, for example, palladium / activated using a suitable catalyst, such as carbon, or may be hydrogenated using a suitable hydride reagent, in this way the compounds T - II Can be obtained.

In step j07 , the compound T- II can be converted into the 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 / have. In addition to the methods described in this document for preparing asymmetric ureas using phenyl chloroformate, there are additional processes familiar to those skilled in the art based on the use of activated carbon based acid derivatives or isocyanates where appropriate.

In step j08 , the amine TV can be converted to the urea compound T (where A is N). This can be accomplished by methods familiar to those skilled in the art, by reaction with T- IV , if appropriate in the presence of a base.

In step j09 , A T- amine II can then be converted to amide T (where, A is CH or C (CH _3)). This may be accomplished, for example, by methods familiar to those skilled in the art, by reaction with an acid halide, preferably a chloride of formula T- III , preferably wherein D is Hal, in the presence of a base, if appropriate, Can be accomplished, for example, by reaction with an acid of formula T- III wherein D is OH, in the presence of HATU or CDI, with the addition of a base where appropriate. Further, by the method familiar to those skilled in the art amine T- II, if appropriate in the presence of a base, an amide compound IIIa by T- and T reaction can be converted to (wherein, A is CH or C (CH ₃₎₎ .

Compounds according to formula (T), wherein A is N, can also be prepared by the reaction sequence according to general Reaction Scheme 2.

General Reaction 2 (Reaction 2)

In step v1 , compound TV can be converted to the compound T- Va by methods known to those skilled in the art, for example, using phenyl chloroformate, if appropriate in the presence of coupling reagents and / or bases. In addition to the methods described in this document for preparing asymmetric ureas using phenyl chloroformate, there are additional processes familiar to those skilled in the art based on the use of activated carbon based acid derivatives or isocyanates where appropriate.

In step v2 , Amine T- II can be converted to urea compound T (wherein A is N). This can be accomplished by methods familiar to those skilled in the art, if appropriate in the presence of a base, by reacting with T- Va .

Reaction step j01 To j09 And k01 Methods well known to those skilled in the art for carrying out v1 and v2 as well as v1 and v2 are described in standard studies in the field of organic chemistry [see, for example, J. March, Advanced Organic Chemistry, Wiley & Sons, 6th edition, 2007; FA Carey, RJ Sundberg, Advanced Organic Chemistry, Parts A and B, Springer, 5th edition, 2007; team of authors, Compendium of Organic Synthetic Methods, Wiley & Sons]. Further methods and references may be published in a conventional database, for example, Reaxys® Database of Elsevier, Amsterdam, NL or SciFinder® Database of the American Chemical Society, Washington, US.

Example

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

Refers to molar equivalents, "RT" or "rt" means room temperature (23 +/- 7 DEG C), and " M "is the concentration expressed in mol / l," aq. "Means aqueous," sat. "Means saturated," sol. "Means solution, and" conc. .

Other abbreviations:

d day

AcOH acetic acid

BH ₃ S (CH ₃ ) ₂ borane-methylsulfide complex (BH ₃ -DMS)

Brine Sodium chloride saturated aqueous solution

n-BuLi n-butyllithium

CC silica gel column chromatography

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

DCM dichloromethane

DIPEA Diisopropylethylamine

DMAP 4-Dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethylsulfoxide

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 charcoal supported palladium

TBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

TLC thin layer chromatography

TFA Trifluoroacetic acid

THF tetrahydrofuran

v / v volumetric capacity

w / w weight to weight

The yield of the prepared compounds was not optimized.

All temperatures are not calibrated.

All starting materials that are not explicitly described are either commercially available (such as those supplied by suppliers such as Acros, Avocado, Aldrich, Apollo, Bachem, Fluka, , FluoroChem, Lancaster, Manchester Organics, Matrix Scientific, Maybridge, Merck, Rovathin, Sigma, TCI, Oakwood, and the like can be found, for example, in the Symyx® Available Chemicals database of MDL in Ramon, USA or in the SciFinder® database of ACS in Washington, DC, (For example, the Reaxys® database from Elsevier, Amsterdam, The Netherlands, or the ACS SciFinder® database from Washington, DC, USA) Site can be found at the base) can be prepared using the conventional methods known to those skilled in the art.

The stationary phase used in the column chromatography was obtained from Darmstadt, Germany. Silica gel 60 (0.04 to 0.063 mm) from E. Merck.

The mixing ratio of solvent or eluent for chromatography is specified as v / v.

All intermediates and exemplary compounds were analytically characterized using < ¹ > H-NMR spectroscopy. Also, mass spectroscopy (MS, m / z for [M + H] ⁺ ) was performed on all example compounds and selected intermediate products.

Synthesis of the selected intermediate product:

One. (3-tert-butyl-1- (3- Chlorophenyl ) -1H- Pyrazole -5 days) Methanamine  Synthesis j01  To j06 )

Step j01 : Pivaloyl chloride ( J-0 ) (1 eq, 60 g) was added dropwise to a methanol solution (120 ml) at 0 ° C within 30 min and the mixture was stirred at room temperature for 1 h. After addition of water (120 mL), the separated organic phase was washed with water (120 mL), dried over sodium sulfate, and aqueous-washed with dichloromethane (150 mL). The liquid product JI was obtained with 99% purity (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 min and the mixture was stirred for an additional 30 min. Methyl pivalate ( JI ) (1 eq, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After the reaction was complete, the reaction mixture was taken up in ice water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried with sodium sulfate, distilled and recrystallized from n-hexane (100 mL) to give the product ( J- II ) (51% yield) as a brown solid material.

Step J03 : 4,4-Dimethyl-3-oxopentanenitrile ( J-II ) (1 eq., 5 g) was taken up in ethanol (100 ml) at room temperature, mixed with hydrazine hydrate (2 eq., 4.42 g) And refluxed for 3 hours. After removing ethanol by distillation, the obtained residue was taken up in water (100 ml) and extracted with ethyl acetate (300 ml). The combined organic phases were dried with sodium sulfate, the solvent was removed in vacuo and the product ( J- III ) (5 g, 89% yield) was obtained as a light red solid after recrystallization from n-hexane (200 mL).

Step J04 : 3-3-Butyl-1H-pyrazol-5-amine ( J-III ) (1 eq, 40 g) was diluted with dilute HCl Is dissolved in HCl 120㎖) of 120㎖, and mixed with NaNO ₂ (1.03 eq., Of 100㎖ 25g) added dropwise over a 30 minutes at 0 to 5 ℃. After stirring for 30 min, then it neutralized the reaction mixture with Na ₂ CO _3. The diazonium salt obtained by reacting 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 stirred at 75 [ Lt; / RTI > After the reaction was complete, the reaction mixture was extracted with ethyl acetate (3 x 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 to 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 Respectively. 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 < 0 > C for 30 min, the reaction mixture was mixed with water (150 ml) and extracted with dichloromethane (3 x 75 ml). The combined organic extracts were washed with water (100 mL) and saturated NaCl solution (100 mL) and dried over magnesium sulfate. After removal of the solvent in vacuo, the residue was purified by column chromatography (silica gel: 100-200 mesh, eluant: various mixtures of ethyl acetate and cyclohexane as mobile solvent) to give the product JV .

Step j05 (Method 2):

3-tert-butyl -1H- pyrazol-5-carbonitrile (J- IV) (10mmol), boronic acid B (OH) ₂ (3- chlorophenyl) or a corresponding boronic ester (20mmol), and the copper ( II) acetate (15 mmol) was added to dichloromethane (200 ml) and stirred with pyridine (20 mmol) at room temperature while stirring, and the mixture was stirred for 16 hours. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (silica gel: 100 to 200 mesh, eluent: various mixtures of ethyl acetate and cyclohexane as mobile solvent), and product JV was obtained in this way .

Step j06 : (Method 1):

JV was dissolved in methanol (30 mL) with carbon-supported palladium (10%, 500 mg) and conc. 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 to 200 mesh, eluant: ethyl acetate) and the product ( U- II ) was obtained in this way.

Step j06 : (Method 2):

JV was dissolved in tetrahydrofuran (10 ml), to which BH ₃ S (CH ₃ ) ₂ (2.0 M in tetrahydrofuran, 3 ml, 3 eq.) Was added. The reaction mixture was heated at reflux for 8 hours, to which was added aqueous 2N HCl (2N) and the reaction mixture was refluxed for a further 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 solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel: 100-200 mesh, eluant: various mixtures of dichloromethane and methanol as mobile solvent) to give the product ( U- II ) Respectively.

The following additional intermediate products were synthesized / in a similar manner using the process described in 1. above:

2. 1- (3- Chlorophenyl ) -3- ( Trifluoromethyl ) -1H- Pyrazole -5-yl-methanamine (step k01  To k05  And j06 )

Step k01 : LAlH (lithium aluminum hydride) (0.25 eq, 0.7 g) was dissolved in dry diethyl ether (30 mL) under a protective gas atmosphere 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-O ) (1 eq., 10 g) was taken up in dry diethyl ether (20 ml) and added dropwise to the suspension over 1 h at -78 <0> C. The mixture was then stirred at -78 [deg.] 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 water (30 ml) with concentrated H ₂ SO ₄ (7.5 ml). The organic phase was separated, concentrated under reduced pressure and the reaction product KI was immediately introduced into the subsequent reaction step k02 .

Step k05 : 3-Chloroaniline ( K-IV ) (1 eq., 50 g) was dissolved in concentrated HCl (300 mL) at -5 to 0 <0> C and stirred for 10 min. 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 dropwise over 3 hours maintaining the temperature . 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 was removed in vacuo. Purification by column chromatography (silica gel: 100 to 200 mesh, eluent: 8% ethyl acetate / n-hexane) afforded 40 g (72%) of (3- chlorophenyl) hydrazine ( K- IV ) as a brown oil .

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

Step k03 : Hydrazine K- II (1 eq., 25 g) was dissolved in dimethylformamide (125 mL). N-Chlorosuccinimide (1.3 eq, 19.5 g) was added in portions at room temperature within 15 min and the mixture was stirred for 3 h. Dimethylformamide was removed by distillation, and the residue was taken up in ethyl acetate. The ethyl acetate was removed in vacuo and the obtained residue was purified by column chromatography (silica gel: 100 to 200 mesh, eluent: n-hexane) to give the product K- III (26.5 g, 92%) as a pink oil .

Step k04 : Hydrazanoyl chloride K- III (1 equiv., 10 g) was taken up in toluene (150 ml) at room temperature and 2-chloroacrylonitrile (2 eq, 6.1 ml) and triethylamine Ml). The reaction mixture was stirred at 80 &lt; 0 &gt; C for 20 hours. The mixture was then diluted with water (200 mL) and the phases were separated. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel: 100 to 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 JV (1 eq., 1 g) was dissolved in a methanolic ammonia solution (150 mL, 1: 1) and hydrogenated in H-cube (10 bar, 80 C, 1 mL / min, 0.25 mol / l). After removal of the solvent under reduced pressure, the (1- (3-chlorophenyl) -3- (methyl) -1H- pyrazol-5-yl trifluoromethyl) methanamine (II) as a white solid (0.92g, 91%) .

The following additional intermediate products can be synthesized / in a similar manner using the process described in 2. above:

3. methyl  Phenyl (3-tert-butyl-1- (3- Chlorophenyl ) -1H- Pyrazole -5 days) Methyl carbamate Manufacturing

Step a : To a solution of (3- tert -butyl-l- (3-chlorophenyl) -lH-pyrazol-5-yl) methanamine (5g, 18mmol) in dimethylformamide (25ml) was added potassium carbonate (9.16g, 66 mmol, 3.5 eq.) Was added and the contents were cooled to 0 &lt; 0 &gt; C. Subsequently, 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 further stirred at 0 &lt; 0 &gt; C for 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 x 25 ml). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (silica gel: 100 to 200 mesh, eluent: 10% ethyl acetate in n-hexane) to obtain the required product as a white solid (3.2 g, 45%).

4. (1- (3- Chlorophenyl ) -3- Cyclopropyl -1H- Pyrazole -5 days) Methanamine Hydro Preparation of chloride

Step a : Diethyl oxalate (0.92 mL, 6.85 mmol, 1 eq.) Was added at room temperature to a sodium ethoxide solution (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1.2 eq.) In ethanol Cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 eq.) Was added dropwise at 0 &lt; 0 &gt; C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. Ice cold water (10 ml) was added and the ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2N aqueous HCl (15 mL) and extracted with diethyl ether (2 x 25 mL). The organic layer was washed with brine solution, dried over sodium sulfate, filtered and concentrated to give a pale brown liquid (400 mg, 31%).

Step b : To a solution of the product of step a (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) And the reaction mixture was stirred for 1 hour. The ethanol was evaporated under reduced pressure and the residual 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 : A mixture of the product of step b (1.1 g, 5.164 mmol, 1 eq) and 3-chlorophenylhydrazine hydrochloride (1.84 g, 10.27 mmol, 2 eq.) Was dissolved in acetic acid (20 mL) and 2- methoxyethanol 10 ml), and the reaction mixture was heated at 105 [deg.] 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 to 200 mesh; eluent: ethyl acetate-petroleum ether (4:96)) yielded a pale brown solid (1.15 g, 77%).

Step d : To a solution of the product of step c (2.5 g, 8.62 mmol, 1 eq) in tetrahydrofuran (15 mL) -methanol (9 mL) -water (3 mL) at 0 C was added lithium hydroxide (1.08 g, 25.71 mmol, 3 eq.) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the pH was adjusted to about 3 using 2N aqueous HCl (1.2 mL) of the residue. The acidic aqueous layer was extracted with ethyl acetate (2 x 60 ml); The combined organic layers were washed with water (10 ml), brine solution (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give an off-white solid (1.4 g, 62%).

Step e : To a solution of the product of step d (1.4 g, 5.34 mmol, 1 eq.) In 1,4-dioxane (30 mL) at 0 C was added pyridine (0.25 mL, 3.2 mmol, 0.6 eq.) And di- -Butyl dicarbonate (1.4 mL, 6.37 mmol, 1.2 eq.) Was added 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 overnight at room temperature. The reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with ethyl acetate (2 x 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 to 200 mesh; eluent: ethyl acetate-petroleum ether (16:84)) afforded a white solid (1 g, 72%).

Step f: Step e The product (2g, 7.66mmol, 1 eq) in tetrahydrofuran (25㎖) to the solution at 0 ℃ was added _{BH 3 .DMS (1.44㎖, 15.32mmol,} 2 eq) and the reaction of The mixture was heated at 70 &lt; 0 &gt; C for 3 hours. The reaction mixture was cooled to 0 C, methanol (15 mL) was added and the reaction mixture was heated at reflux for 1 hour. The reaction mixture was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ether (15 mL), cooled to 0 &lt; 0 &gt; C and HCI solution in 1,4-dioxane (3 mL) was added (the 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 salt compound as a white solid (600 mg, 28%).

Synthesis of Exemplary Compounds:

One. Amide (A = CH  Or C ( CH ₃ ))

Scheme 1, as shown in (Step j09), the formula T - II of the amine is reacted with carboxylic acid or carboxylic acid derivative of formula III the compounds of formula T- T (a, where, A is CH or C (CH ₃₎₎ (amide) General direction for forming:

1.1 Method A:

The acid (1 eq.) Of the formula T - III , the amine (1.2 eq) and the EDCI (1.2 eq.) Of the formula T- II were stirred in DMF (10 mmol / 20 ml) for 12 hours at room temperature, . The reaction mixture is extracted repeatedly with EtOAc, the aqueous phase is saturated with NaCl and then extracted again with EtOAc. The combined organic phases are washed with 1N HCl and brine, dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue was purified by flash chromatography (SiO _2, different ratio, for example, 1: EtOAc / hexane 2) to give the to give the product (T) in this manner.

1.2 Method B:

The acid (1 equiv.) Of the formula T - III and the amine (1.1 equiv.) Of the formula T- II were dissolved in dichloromethane (1 mmol of acid in 6 ml) and EDCI (1.5 eq.), HOBt And mixed with triethylamine (3 eq.). To the reaction mixture was stirred at room temperature for 20 hours, and the crude product was purified by column chromatography (SiO _2, different ratio, for example, 2: n- hexane / EtOAc in 1) to give, in this manner and the product (T) &Lt; / RTI &gt;

1.3 Method C :

The acid (1 equivalent) of formula T- III is first mixed with a chlorinating agent, preferably thionyl chloride, the mixture obtained in this way is boiled under reflux and in this way the acid T- III is converted to the corresponding acid chloride . The amine of formula T- II (1.1 eq.) Is dissolved in dichloromethane (1 mmol of acid in 6 ml) and mixed with triethylamine (3 eq.) At 0 ° C. To the reaction mixture was stirred at room temperature for 20 hours, and the crude product was purified by column chromatography (SiO _2, different ratio, for example, 2: n- hexane / EtOAc in 1) to give, in this manner and the product (T) &Lt; / RTI &gt;

1.4 Method D :

Phenyl ester (T- IIIa) (1 eq) and corresponding amines (T-II) (1.1 equiv.) Was dissolved in THF (reaction mixture of 10mmol 120㎖), 16 at room temperature after the addition of DBU (1.5 eq) of Lt; / RTI &gt; The solvent was removed in vacuo, and the obtained residue was purified by flash chromatography (SiO _2, different ratio, for example, 1: EtOAc / hexanes 1) to give the to give the product (T) in this manner.

Exemplary Compounds D1 to D10 were obtained using one of the methods described herein. Exemplary Compounds D11 to D25 can be obtained using one of the methods described herein.

2. Preparation of urea (A = N)

Reaction of an amine of formula T- II or TV with phenyl chloroformate to form a compound of formula T-IV or T- Va ( Reaction 1, step j07 and Reaction 2, step v1 ) followed by reaction with a compound of formula T- IV to the reaction of the amine with the general formula TV or (reactions 1, step j08), by reacting the formula II and the amine of a compound of formula T- T- Va (reactions 2, step v2) compounds of the formula T (wherein, a is N Lt; RTI ID = 0.0 &gt; direction:

Step j07 / step v1 : The amine (1 eq.) of the formula T- II or TV is added to dichloromethane (10 mmol of amine in 70 ml), to which phenyl chloroformate (1.1 eq.) is added at room temperature and the mixture is stirred for 30 minutes . The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO _2, different ratio, for example, 1: 2 diethyl ether / hexane) and purification, the product in this way, a T- T- IV or Va .

Step J08 / Step v2 : The resulting carbamic acid phenyl ester ( T- IV ) or ( T- Va ) (1 eq.) And the corresponding amine ( TV ) or ( T- II ) (1.1 eq.) Were dissolved in THF 10 mmol of the reaction mixture in 120 ml), DBU (1.5 eq.) Was added, followed by stirring at room temperature for 16 hours. The solvent was removed in vacuo, and the obtained residue was purified by flash chromatography (SiO _2, different ratio, for example, 1: EtOAc / hexanes 1) to give the to give the product (T) in this manner.

Exemplary compounds D26 to D29, D31 and D33 were obtained using one of the methods described herein. Exemplary Compounds D30 and D32 can be prepared using one of the methods described herein.

selected Example  Detailed synthesis of compounds

Synthesis of Exemplified Compound D1: N - [[5- tert -butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] Sulfonyl-phenyl) -propionamide &lt; / RTI &gt;

Step 1: Sodium hydroxide (1.8 g) was added at room temperature to 2-fluorobenzenethiol (4.8 g, 3.6 mmol) (0.03 mol). Dimethyl sulfide (4.7 g, 1 eq) was neutralized with potassium carbonate and added to the contents at room temperature. The entire reaction mixture was stirred for 3 hours at room temperature. The progress of the reaction was monitored by TLC (5% ethyl acetate / hexane, _Rf -0.8). After the reaction was complete, cold water was added to the contents and the compound was extracted with ethyl acetate (2 x 50 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to (2-fluorophenyl) (methyl) sulfan as a light blue liquid (5 g, crude material). The crude material obtained was used directly in the next step.

Step 2: Ethyl (chlorocarbonyl) formate (7.3 g, 0.05 mol, 1.6 eq) was added dropwise to a solution of AlCl ₃ (9.2 g, 0.06 mol, 2 eq) in chloroform The reaction mixture was stirred at the same temperature for 30 to 45 minutes. (2-fluorophenyl) (methyl) sulfan (5 g, crude material) 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, _Rf -0.5). After the reaction was completed, ice-breaking was added, and the mixture was stirred for a certain period of time. The organic layer was separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined extracts were washed with NaHCO ₃ solution, dried over sodium sulfate and concentrated under reduced pressure to give ethyl 2- (3-fluoro-4- (methylthio) phenyl) -2-oxoacetate as a yellow liquid .

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 times) was added 3M sodium hydroxide solution ) Was added at 50 &lt; 0 &gt; 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 / hexanes, _Rf -0.1). After the reaction was complete, the contents were cooled to 0 C, the mixture was acidified with diluted HCl, and the precipitated solid was filtered. The obtained crude 2- (3-fluoro-4- (methylthio) phenyl) -2-oxoacetic acid was used directly in the next step as a yellow solid (4.5 g, crude material).

Step 4: 2- (3-Fluoro-4- (methylthio) phenyl) -2-oxoacetic acid (4.5 g, crude material) was added to hydrazine hydrate (5.1 ml, 5 eq) at -50 ° C. The contents were heated to 80 DEG C, KOH (2.7 g, 2.3 eq) was added and the entire reaction mixture was stirred at 100 DEG C for 12 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, Rf to 0.8). After the reaction was complete, water and ethyl acetate were added to the contents and the layers were separated. The aqueous layer was acidified with diluted HCl at 0-5 ° C and the precipitate was filtered off and dried to give 2- (3-fluoro-4- (methylthio) phenyl) acetic acid as a white 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 <0> C. Lithium bis (trimethylsilyl) amide (45 mL, 3 eq) was added at -78 [deg.] C and the mixture was stirred at the same temperature for 1 h. Methyl iodide (0.93 ml, 1 eq) was added at -78 [deg.] C and the mixture was allowed to come to room temperature and stirred at the same temperature for 3 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexanes, _Rf ~ 0.5). Although the reaction was not complete, the mixture was post-treated. The reaction contents were quenched at 0 &lt; 0 &gt; C with saturated ammonium chloride solution. The contents were acidified with diluted HCl, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure and the obtained crude material was purified by column chromatography (10% ethyl acetate / hexane) to give 2- (3-fluoro-4- (methylthio) Acid as a yellow solid (1 g, 31%).

Step 6: Potassium carbonate (0.63 g) was added to a solution of 2- (3-fluoro-4- (methylthio) phenyl) propanoic acid (1 g, 0.009 mol) in acetone (10 ml) at room temperature. DMS (0.58 g, 1 eq) was neutralized with potassium carbonate and filtered. The filtered DMS was added to the above contents and the whole reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexanes, _Rf -0.9). After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was taken up in water and the compound was extracted with ethyl acetate (2 x 25 mL). The combined extracts were dried over sodium sulfate, concentrated under reduced pressure and the crude product obtained as a brown liquid (1 g) was used directly in 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 <0> C. Hydrogen peroxide (1.4 ml, 3 eq) was added dropwise at 0 &lt; 0 &gt; C and the reaction mixture was stirred overnight at room temperature. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexane, Rf ~ 0.4). After the reaction was complete, the contents were cooled to 0 C, water was added, and the mixture was extracted with ethyl acetate (2 x 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 ). The crude product obtained was used immediately in 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- A solution of sodium (0.32 g, 1 eq) was added at 0 &lt; 0 &gt; C. The contents were allowed to reach room temperature and the mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, _Rf -0.1). After the reaction was completed, the methanol was completely distilled off and the residue obtained was taken up in water. The contents were acidified to pH 4 with diluted HCl and the precipitate was filtered and dried to give 2- (3-fluoro-4- (methylsulfonyl) phenyl) propanoic acid as a white solid (1.7 g, 85% .

Step 9: To a solution of (3- tert -butyl-l- (3-chloro-4-fluorophenyl) -lH-pyrazol- 5- yl) methanamine (49 mg, 0.189 mmol) in DCM 1-Chloro-N, N, 2-trimethyl-l-propylamine (48 L, 0.369 mmol) was added under nitrogen atmosphere at room temperature. After 1 hour of stirring, 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 overnight at room temperature, washed with NaHCO ₃ solution (2 x ₁₀ mL), dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (eluent: ethyl acetate / cyclohexane (2: 1)) to give pure N - [[5- tert- butyl- 2- (3- chlorophenyl) -2H- pyrazole 3- yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide (Ex. D1) (66 mg, 71%).

Synthesis of Exemplified Compound D2: Synthesis of N [[2- (3-chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -Methylsulfonyl-phenyl) -propionamide &lt; / RTI &gt;

Steps 1 to 8: As described in the example of Example Compound 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) N, N, N ', N'-tetramethyluronium tetrafluoroborate (78 mg, 0.244 mmol), N-ethyldiisopropylamine (0.083 ml, (Trifluoromethyl) -lH-pyrazol-5-yl) methanamine (67 mg, 0.244 mmol) was added. 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) Yl] -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -propionamide (Ex. D2) (93 mg, 76%).

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

Synthesis of Exemplified Compound D5: 2- (3-Chloro-4-methylsulfonyl-phenyl) -N - [[2- (3- chlorophenyl) -5- (trifluoromethyl) -Yl] -methyl] -propionamide &lt; / RTI &gt;

Step 1: To a well stirred solution of AlCl ₃ (16.58 g, 2 eq) in chloroform (100 ml) was added ethyl (chlorocarbonyl) formate (10.02 g (8.35 ml), 1.6 eq) Was stirred for 30 minutes. Then, (2-chlorophenyl) (methyl) sulfan (10 g (8.33 ml), 0.06 mol) was added at 0 ° C and the entire reaction was stirred at room temperature for 3 to 4 hours. The progress of the reaction was monitored by TLC (5% ethyl acetate / hexane, _Rf -0.3). After the reaction was completed, ice-breaking was added and the contents were stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with DCM (2 x 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 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 times) 3M NaOH solution (2.23 g, 1.2 eq) was added dropwise at 50 &lt; 0 &gt; C and the contents were refluxed at 60 &lt; 0 &gt; C for 3 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexane, _Rf -0.1). After the reaction was completed, the toluene was distilled off and the obtained residue was added to ice water. The contents were then acidified with diluted HCl at O &lt; 0 &gt; 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 solid (10 g, 93%).

Step 3: 2- (3-Chloro-4- (methylthio) phenyl) -2-oxoacetic acid (10 g, 0.04 mol) was added to hydrazine hydrate (10 g, 5 eq) cooled to -50 ° C. The contents were first warmed to room temperature and slowly 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, _Rf -0.4). After 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 x 100 mL). The aqueous layer was then acidified with dilute HCl and stirred at room temperature for a period of time. The precipitate was filtered and dried to give 2- (3-chloro-4- (methylthio) phenyl) acetic acid as a white solid (8g, 85%).

Step 4: 2- (3-Chloro-4- (methylthio) phenyl) acetic acid (2 g, 0.009 mol) was added to THF (20 mL, 10 times) and cooled to -78 ° C. Lithium bis (trimethylsilyl) amide (27.77 ml, 3 eq) was added dropwise at -78 [deg.] C and stirred at the same temperature for 2 hours. Methyl iodide (1.31 g, 1 eq) was then added dropwise at -78 [deg.] C and the total reaction was stirred for 3 h at the same temperature. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexanes, _Rf -0.2). Because the reaction was not complete, the reaction was warmed to room temperature and stirred for 10 hours. Again monitored by TLC, and the reaction was still not complete. The reaction contents were then quenched with saturated sodium chloride solution and acidified with diluted HCl. The THF layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure and the obtained crude material was purified by column chromatography (10% ethyl acetate / n-hexane) to give 2- (3-chloro-4- (methylthio) Propanoic acid as a light yellow 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 eq) Respectively. DMS (1.91 g, 1 eq) was neutralized with potassium carbonate and filtered. Filtered DMS was added to the contents and the entire reaction mixture was stirred for 2 hours at room temperature. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexanes, _Rf -0.9). After the reaction was completed, the contents were filtered and the filtrate was concentrated under reduced pressure. The residue obtained was taken up in water, and the compound was extracted with ethyl acetate (2 x 100 ml). The combined extracts were dried over sodium sulfate, concentrated under reduced pressure and the crude product obtained as a brown liquid (3.5 g) was used directly in 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 material) and cooled to 0 <0> C. Hydrogen peroxide (4.48 mL, 3 eq) was added dropwise at 0 &lt; 0 &gt; C and the reaction was stirred overnight at room temperature. The progress of the reaction was monitored by TLC (30% ethyl acetate / hexanes, _Rf -0.3). After the reaction was complete, the contents were cooled to 0 C, water was added, and the mixture was extracted with ethyl acetate (2 x 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 ). The crude product obtained was used immediately in 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- 0.46 g, 1 eq) at 0 &lt; 0 &gt; 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, _Rf -0.1). After the reaction was completed, the methanol was completely distilled off and the residue obtained was poured into water. The contents were acidified with diluted HCl to pH 4 at 0 C and the precipitate was filtered and dried to give 2- (3-chloro-4- (methylsulfonyl) phenyl) propanoic acid as a white 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) N, N, N ', N'-tetramethyluronium tetrafluoroborate (74 mg, 0.229 mmol) and N- ethyldiisopropylamine (0.078 ml, 0.458 mmol) and (1- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methanamine (63 mg, 0.229 mmol). 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- (Example Compound D5) (100 mg, 84%) was obtained as a colorless oil.

Synthesis of Exemplified Compound D6: N - [[2- (3-Chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] - (methylsulfonyl-methyl) -phenyl] -propionamide &lt; / RTI &gt;

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 Ml), manganese (822 mg, 14.974 mmol) and (2,2'-bipyridine) nickel (II) -dibromide (196 mg, 0.524 mmol). Trifluoroacetic acid (4 drops) was added. The reaction mixture was stirred at 60 &lt; 0 &gt; C overnight. After cooling to room temperature, the mixture was hydrated with 1N HCl (30 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed in vacuo. The crude material 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: To a stirred solution of ethyl 2- (3-fluoro-4- (methylsulfonylmethyl) phenyl) propanoate (950 mg, 3.295 mmol) in tetrahydrofuran and water co-solvent (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 x 50 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent of the filtrate was removed in vacuo to give 2- (3-fluoro-4- (methylsulfonylmethyl) -phenyl) propanoic acid (846 mg, 99%).

Step 3: To a solution of 2- (3-fluoro-4- (methylsulfonylmethyl) phenyl) propanoic acid (68 mg, 0.231 mmol) and (1- (3- chlorophenyl) -3- (1H-benzotriazol-1-yl) -N, N, N ', N', N'-tetramethyluronium hexafluorophosphate in a stirred solution of 4- -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 was stirred at room temperature for 48 h, concentrated in vacuo and the residue was purified by CC (eluent: ethyl acetate / cyclohexane (3: 2)) to give N - [[2- (3- chlorophenyl) (3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -propionamide (83 mg, 69 &lt; RTI ID = %).

Exemplary Compound D10 was prepared in accordance with D6 in the same manner.

Synthesis of Exemplified Compound D7: Synthesis of N - [[5- tert -butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] Methylsulfonyl-methyl) -phenyl] -propionamide &lt; / RTI &gt;

Step 1 to Step 2: As described in Example of Exemplary Compound D6.

Step 3: To a solution of 2- (3-fluoro-4- (methylsulfonylmethyl) phenyl) propanoic acid (60 mg, 0.231 mmol) and (3- tert- butyl- (1 H-benzotriazol-1-yl) -N, N, N ', N ' -tetra Methylboronium 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 was stirred at room temperature for 48 h, concentrated in vacuo and the residue was purified by CC (eluent: ethyl acetate / cyclohexane (3: 2)) to give N - [[5- tert- Phenyl) -propionamide (94 mg, 80%) was obtained as colorless crystals from 2- (3-fluoro-4- (methylsulfonyl- &Lt; / RTI &gt;

Exemplary Compounds D8, D9, D11, D13, D16 to D21, D23 and 24 can be prepared or prepared in a similar manner according to the embodiment of Exemplary Compound D7.

Synthesis of Exemplified Compound D12: 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (4- fluorophenyl) -5- (trifluoromethyl) 2H-pyrazol-3-yl] -methyl] -propionamide

Step 1: DMAP (4.25 g, 34 mmol) was added to DCM (3 L) and the contents were cooled to -10 [deg.] C. Trifluoroacetic anhydride (765 g, 3.2 mol) was added followed by ethyl vinyl ether (250 g, 3.04 mol) dropwise at -10 ° C for 45 min. The entire reaction mixture was then stirred for 8 hours at 0 &lt; 0 &gt; C and then overnight at room temperature. The progress of the reaction was monitored by TLC (10% ethyl acetate / hexanes, _Rf -0.7). After the reaction was completed, 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 x 500 mL). The combined organic layers were washed with water (2 x 1 L), dried over sodium sulfate and concentrated under reduced pressure to give (E) -4-ethoxy-1,1,1-trifluorobut- Obtained as a brown liquid (450 g, crude material).

Step 2: Hydrazine dihydrochloride (225 g, 2.14 mol) in ethanol (1400 mL) was well stirred. TEA (185.4 mL, 1.34 mol) was added dropwise at ambient temperature for 45 min. Then, (E) -4-ethoxy-1,1,1-trifluorobut-3-en-2-one (225 g, crude material) was 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). After the reaction was completed, the ethanol was completely distilled, the residue was taken up in ice water (500 ml), and the product was extracted with ethyl acetate (2 x 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 a yellowish white solid (175 g, crude material).

Step 3: 33.08 g (19.85 mol, 60%) of NaH was washed with n-hexane and then anhydrous DMF (500 mL) was added dropwise under N ₂ atmosphere and the mixture was stirred well. 3- (trifluoromethyl) -1H- pyrazole (75g, 0.55mol) was added dropwise under a N ₂ atmosphere. Subsequently, the 4-methoxyl benzyl chloride (86.3g, 0.55mol) in DMF (125㎖) solution The reaction mixture was stirred for 12 hours at room temperature and the progress of the reaction was monitored by TLC (10% ethyl acetate / hexane, _Rf -0.4) The ethyl acetate layer was washed with 2N HCl (2 x 200ml), then the contents were dried over sodium sulfate and concentrated under reduced pressure . The crude material obtained was purified by CC with 10% ethyl acetate / n-hexane to give 1- (4-methoxybenzyl) -3- (tri By Luo methyl) to give the -1H- pyrazole as a brown liquid (98g, 70%).

Step 4: Diisopropylamine (28.4 mol, 39.4 mL) was added to THF (500 mL), stirred well and cooled to 0 &lt; 0 &gt; C. n-BuLi (234.4 ml) was added dropwise at 0 占 폚, and the mixture was stirred at 0 占 폚 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) Min, and the contents were stirred at -78 &lt; 0 &gt; C for an additional hour. Anhydrous CO ₂ gas was then bubbled through the reaction mixture for 1.5 hours. The progress of the reaction was monitored by TLC (10% ethyl acetate / hexane, _Rf -0.1). After the reaction was complete, the reaction contents were poured into ice water (300 mL) and the aqueous layer was extracted with ethyl acetate (2 x 200 mL) under basic conditions. The aqueous layer was acidified with 20% HCl solution and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 1- (4-methoxybenzyl) -3- (trifluoromethyl) -lH-pyrazole-5-carboxylic acid as a light yellow solid (40g, 55% &Lt; / RTI &gt;

Step 5: To a solution of 1- (4-methoxybenzyl) -3- (trifluoromethyl) -lH-pyrazole-5-carboxylic acid (50 g, 0.16 mol) in DCM (750 ml) The mixture was cooled to 0 &lt; 0 &gt; C. Thionyl chloride (61 mL, 0.83 mol) was added dropwise at 0 &lt; 0 &gt; C for 30 min. The entire reaction mixture was heated to reflux and held for 2 hours. The progress of the reaction was monitored by TLC (10% ethyl acetate / hexanes, _Rf -0.4). After the starting material disappeared, the DCM was completely distilled. The acid chloride prepared above was dissolved in DCM (500 mL) and added dropwise at 0 &lt; 0 &gt; C to aqueous ammonia solution (700 mL). The entire reaction mixture was stirred for 1 hour and the progress of the reaction was monitored by TLC (10% ethyl acetate / hexanes, _Rf -0.7). After the reaction was complete, ice water (200 mL) was added and the product was extracted with ethyl acetate (2 x 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 a light yellow solid Material). The crude material obtained was used immediately in the next step.

Step 6: LAH (4.7 g, 0.12 mol) was placed in a flask. THF (250 mL) was added at 0 &lt; 0 &gt; C. A solution of l- (4-methoxybenzyl) -3- (trifluoromethyl) -lH-pyrazole-5-carboxamide (37 g, 0.12 mol) in THF (120 ml) , And the reaction mixture was heated to reflux for 5 hours. The progress of the reaction was monitored by TLC (50% ethyl acetate / hexanes, _Rf -0.2). Because the reaction was not complete, LAH (2.3 g) was added again and the mixture was refluxed for an additional 4 h. After the reaction was complete, the reaction contents were slowly added to a saturated sodium sulfate (1 L) solution, dried over celite, and the product was extracted with ethyl acetate (2 x 500 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give crude (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5- yl) methanamine as a light yellow solid g, crude material). The crude material obtained was used directly in the next step.

Step 7: To a solution of (1- (4-methoxybenzyl) -3- (trifluoromethyl) -lH-pyrazol-5-yl) methanamine (80 g, 0.28 mol ) Was added TEA (30.2 mL, 0.026 mol) dropwise over 10 minutes. Boc anhydride (62.5 ml, 0.28 mol) was then obtained at 0 &lt; 0 &gt; C for 20-30 min. The entire reaction mixture was stirred at 0 &lt; 0 &gt; C for 30 min and at room temperature for 1 h. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexanes, _Rf ~ 0.6). After the reaction was complete, the DCM was completely distilled, the residue was taken up in ice water (500 mL) and the product was extracted with ethyl acetate (2 x 300 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was recrystallized from n-hexane (200 ml) to obtain tert-butyl (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H- Carbamate as a light yellow solid (80 g, 74%).

Step 8: To a solution of tert-butyl (1- (4-methoxybenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) methylcarbamate (20 g, 0.052 mol) was added aluminum chloride (17.34 g, 0.129 mol) in portions over 30 minutes. The reaction mixture was slowly heated to 50-60 &lt; 0 &gt; C and stirred at the same temperature for 2 hours. The progress of the reaction was monitored by TLC (20% ethyl acetate / hexane, _Rf -0.1). After the reaction was complete, the reaction contents were treated with diluted HCl, ice water (300 mL) was added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The aqueous layer was basified with sodium hydroxide solution, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to give (3- (trifluoromethyl) -lH-pyrazol-5-yl) (4.6 g, crude material). The crude material obtained was used directly in 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 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 &lt; 0 &gt; C. (Boc) ₂ O (9.24 g, 42.4 mmol) was added dropwise to the reaction mixture over 30 minutes and maintained at 0-5 &lt; 0 &gt; C for 3 hours. The progress of the reaction was monitored by TLC (30% ethyl acetate / n-hexane). After the reaction was completed, the reaction mixture was allowed to come to room temperature for 2 hours, the DCM was distilled off, the residue obtained 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 in vacuo. The obtained crude substance was purified by CC to obtain tert-butyl (3- (trifluoromethyl) -1H-pyrazol-5-yl) methylcarbamate as a white solid (5 g, 44%).

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

Step 11: To a solution of (3- (trifluoromethyl) -lH-pyrazol-5-yl) methanamine hydrochloride (194 mg, 0.96 mmol) and 2- (3- N, N ', N ' -tetramethyluronium tetrafluoro (N, N &apos; Borate (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 overnight at room temperature, concentrated in vacuo and purified by CC (eluent: ethyl acetate / cyclohexane 9: 1) to give 2- (3-fluoro-4- (methylsulfonylmethyl) phenyl Yl) methyl) propanamide (335 mg, 86%) was obtained as a white amorphous solid.

Step 12: 4-Fluorophenylboronic acid (41 mg, 0.295 mmol), 2- (3-fluoro-4- (methylsulfonylmethyl) 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- ] - N - [[2- (4-fluorophenyl) -5- (trifluoromethyl) -2H-pyrazol-3-yl] -methyl] -propionamide (55 mg, 75%).

Exemplary Compounds D14, D15, D22 and D25 can be prepared or prepared in a similar manner, according to the embodiment of Exemplary Compound D12.

Synthesis of Exemplified Compound D26: 1 - [[2- (3-Chlorophenyl) -5-cyclopropyl-2H-pyrazol-3- Methylsulfonyl-ethyl) -phenyl] -urea &lt; / RTI &gt;

Step 1: tetrahydrofuran (10㎖) of 2- (2-fluoro-4-nitrophenyl) acetic acid _{(1g, 5.02mmol) BH 3 ·} S (CH 3) 2 (7.5㎖, 7.53 To a stirred solution of mmol) at 0 &lt; 0 &gt; C. The reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was then cooled to 0 C and the excess borane was quenched with methanol (10 mL). The reaction mixture was concentrated under reduced pressure to give a crude compound that was purified by CC (eluent: ethyl acetate / n-hexane (1: 1)) to give 2- (2-fluoro-4- nitrophenyl) g, 95%).

Step 2: 2- (2-Fluoro-4-nitrophenyl) ethanol (0.89 g, 4.8 mmol) was added to a stirred solution of 48% aqueous hydrobromic acid (0.77 g, 9.62 mmol) and concentrated sulfuric acid &Lt; / RTI &gt; The reaction mixture was heated to 100 &lt; 0 &gt; C for 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give the crude compound. The crude material 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 l- (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 &lt; 0 &gt; 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 and the residue was washed with water (2 x 5 mL) to give pure 2-fluoro-1- (2- Phenyl) ethyl) -4-nitrobenzene (700 mg, 70%).

Step 4: Dissolve 2-fluoro-1- (2- (methylsulfonyl) ethyl) -4-nitrobenzene (700 mg, 2.83 mmol) in ethyl acetate (7 mL) C (70 mg) was added under an argon atmosphere, hydrogenated in a Parr apparatus, and the reaction continued stirring for 2 h. The reaction mixture was filtered through celite, washed thoroughly with ethyl acetate and concentrated under reduced pressure to give 3-fluoro-4- (2- (methylsulfonyl) ethyl) aniline (590 mg, 96%).

Step 5: To a stirred solution of 3-fluoro-4- (2- (methylsulfonyl) ethyl) aniline (200 mg, 0.92 mmol) in acetone / DMF (3 ml + 1.27 ml) was added 0.222 ml ) Was added dropwise phenyl chloroformate (0.152 mL, 1.197 mmol) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The acetone was evaporated and the residue was diluted with DCM (30 mL). The mixture was washed with a saturated NaHCO ₃ solution (15㎖), and extracted the organic layer with DCM (2 × 20㎖). 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: To a solution of phenyl 3-fluoro-4- (2- (methylsulfonyl) ethyl) phenylcarbamate (90 mg, 0.267 mmol) and (1- (3- chlorophenyl) Ethyldiisopropylamine (0.087 ml, 0.507 mmol) was added to a stirred solution of 2-methyl-propyl-1H-pyrazol-5-yl) methanamine (70 mg, 0.286 mmol) , 7 bar). The reaction mixture was concentrated in vacuo and purified by CC (eluent: ethyl acetate / cyclohexane (2: 1)) to give l- [[2- (3- chlorophenyl) -5- cyclopropyl-2H- Yl] -methyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -urea (30 mg, 23%).

Exemplary compounds D27 to D33 can be prepared or prepared in an analogous manner to the example of example compound D26.

Mass spectrometry data are presented below by way of example for the following exemplary compounds (Table 1): &lt; RTI ID = 0.0 &gt;

Pharmacological method

I. Vaniloid  Receptor 1 ( VRI / TRPV1  &Lt; / RTI &gt; receptor)

The functional or antagonistic effect of test substances on rat-longitudinal vanilloid receptor 1 (VR1 / TRPV1) can be determined using the following assay. In this assay, the uptake of Ca ^{2 +} through the receptor channel was measured using a Ca ^{2 +} -dense dye (Type Fluo-4, Molecular Biotechnology, Leiden, Netherlands) in a fluorescence imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, Lt; RTI ID = 0.0 &gt; BV). &Lt; / RTI &gt;

Way:

Complete medium: 10% by volume FCS (fetal bovine serum, Gibco Invitrogen GmbH, Karlsruhe, Germany), heat-inactivated); 2 mM L-glutamine (Sigma, Munich, Germany); A 50 mL HAMS F12 nutrient mixture (diluted in water) with 1 wt% AA solution (antibiotic / antifungal solution, PAA in Austria Parsing) and 25 ng / mL NGF medium (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany) Gibco INVITROGEN GmbH in Suruere).

Cell culture plates: Poly-D-lysine coated black 96 well plates (96 well black / clear plates, BD Biosciences, Heidelberg, Germany) with a transparent substrate were coated with laminin (Karlsruhe, Germany) (Laminin was diluted to 100 μg / ml concentration by PBS (Ca-Mg-free PBS, Gibco In Vitro GmbH, Karlsruhe, Germany)). Remove aliquots with a laminin concentration of 100 μg / ml and store at -20 ° C. The aliquots are diluted with PBS to a ratio of 1: 10 to 10 μg / ml of laminin, and 50 μl each of the solution is pipetted into the concave portion of the cell culture plate. The cell culture plate is incubated at 37 ° C for at least 2 hours, the excess solution is aspirated off, and the wells are washed twice each with PBS. The coated cell culture plate is stored with an excess of PBS (which is not removed until just before cell supply).

Preparation of cells:

Spinal rats were removed from the ruptured rats and placed in cold HBSS buffer (Hank buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) mixed with 1 vol% of AA solution (antibiotic / antifungal solution, PAA in Austria Parsing) ), I. E., In a buffer placed in an ice bath. The spine is longitudinally cut and removed along with the fascia from the spinal canal. The gangrene ganglion (DRG) is then removed and stored again in cold HBSS buffer mixed with 1 vol% AA solution. The DRG, from which all blood residues and spinal cord nerves have been removed, is transferred to 500 [mu] l of cold type 2 collagenase (PAA in Austria Parsing) in each case and incubated at 37 [deg.] C for 35 minutes. 2.5% by volume of trypsin (PAA in Parsing, Austria) is added and incubation is continued for 10 minutes at 37 ° C. After the incubation is complete, carefully pipette the enzyme solution and add 500 μl of complete medium to each of the remaining DRGs. The DRGs are each suspended several times, drawn through cannulae 1, 12 and 16 using a syringe and transferred to a 50 ml Falcon tube filled to 15 ml with complete medium. The contents of each Falcon tube are each filtered through a 70 [micro] m Falcon filter element and centrifuged at 1.200 rpm and room temperature for 10 minutes. The pellets obtained are each taken in 250 쨉 l of complete medium, and the number of cells is measured.

The number of cells in the suspension is set at 3 x 10 &lt; ⁵ &gt; per 1 ml, and 150 [mu] l of the suspension is introduced in each case into the recesses of the coated cell culture plate as described above. In the incubator, the plates are left for 2 to 3 days at 37 占 폚, 5% by volume CO ₂ and 95% relative humidity. The cells were then incubated for 30 min at 37 ° C with 2 μM Fluo-4 and 0.01 vol% Pluronic F127 (Molecular Probes, Leiden, Netherlands) in HBSS buffer (Hank buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) load a page BV) outside the bath, washed 3 times with HBSS buffer, and uses the measurement of Ca ^{2 +} in the incubation after 15 min at room temperature, FLIPR assay. In this case, Ca ^{2 +} -dependent fluorescence is measured before and after the addition of the substance (λex = 488 nm, λem = 540 nm). Quantification is performed by measuring the highest fluorescence intensity (FC, fluorescence number) with time.

FLIPR black:

The FLIPR protocol consists of two material additions. First, the test compound (10 μM) is pipetted onto the cells and the Ca ^{2 +} influx is compared to the control (capsaicin 10 μM). This provides an activation (%) result based on the Ca ^& lt ^{; 2 + & gt ;} signal after addition of 10 [mu] M capsaicin (CP). After 5 minutes incubation, applying capsaicin 100nM, and again measures the Ca ^{2 +} influx.

Desensitizing agonists and antagonists leads to inhibition of Ca ^{+ 2} influx. The inhibition rate (%) is calculated as compared to the maximum achievable inhibition by the 10 μM cap made pin.

Triplicate analysis (n = 3) is performed, which is repeated in at least three independent experiments (N = 4).

Starting from the substitution rates caused by different concentrations of the test compounds of formula I, IC ₅₀ inhibitory concentrations resulting in 50% displacement of capsaicin were calculated. The K _i values for the test substance are determined using the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

II . Vaniloid  Receptor 1 ( VRI / TRPV1  &Lt; / RTI &gt; receptor)

The functional or antagonistic effect of the test substances on vanilloid receptor 1 (VR1) can also be measured using the following assay. Influx of Ca ^{2 +} through the channel in the art assay is a fluorescent imaging plate reader (FLIPR, USA Sunny Molecular devices sheath, based in bales) in Ca ^{2 +} - sensitive dye (type Fluo-4, Molecular Pro in the Netherlands Leiden RTI ID = 0.0 &gt; BV). &Lt; / RTI &gt;

Way:

Chinese hamster ovary cells (CHO K1 cells, UK's European Collection of Cell Cultures (ECACC)) are stably transfected with the VR1 gene. For functional testing, these cells are plated at a density of 25,000 cells / well on a poly-D-lysine-coated black 96-well plate (BD Biosciences, Heidelberg, Germany) with a transparent substrate. The cells are incubated at 37 ° C and 5% CO ₂ overnight in a culture medium (Ham's F12 nutrient mixture, 10% by volume FCS (fetal bovine serum), 18 μg / ml L-proline). On the next day, the cells were incubated with Fluo-4 (Fluo-4, 2 [mu] M, 0.01% by volume Pluronic F127, Molecular Probes in HBSS (Hank buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, RTI ID = 0.0 &gt; 30 C &lt; / RTI &gt; Then, the plates washed three times with HBSS buffer, and uses the measurement of Ca ^{2 +} in the after incubation for a further 15 minutes at room temperature, FLIPR assay. The Ca ^{2 +} -dependent fluorescence is measured before and after addition of the test substance (? Ex = 488 nm,? Em = 540 nm). Quantification is performed by measuring the highest fluorescence intensity (FC, fluorescence number) over time.

FLIPR black:

The FLIPR protocol consists of two material additions. First, a pipetting the test compound (10μM) on the cells, and comparing the Ca ^{2 +} inflow to the control (capsaicin 10μM) (activation (%) based on the Ca ^{2 +} signal after capsaicin addition of 10μM). After 5 minutes incubation, applying capsaicin 100nM, and again measures the Ca ^{2 +} influx.

Desensitizing agonists and antagonists leads to inhibition of Ca ^{+ 2} influx. The inhibition rate (%) is calculated as compared to the maximum achievable inhibition by the 10 μM cap made pin.

Starting from the substitution rates caused by different concentrations of the test compounds of formula I, IC ₅₀ inhibitory concentrations resulting in 50% displacement of capsaicin were calculated. The K _i value for the test substance is calculated using the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

Pharmacological data

The affinities of the compounds according to the invention for vanilloid receptor 1 (VR1 / TRPV1 receptor) were determined as described above (pharmacological method I or II).

Compounds according to the invention exhibit excellent 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 respective inhibition rate (%) is measured.

Claims (15)

Optionally a single stereoisomeric form or a mixture of stereoisomers, a free compound and / or a physiologically acceptable salt form thereof.
T

In the above formula (T)
R ^101, R ¹⁰² and R ¹⁰³ is H, F, Cl, Br, CFH 2, CF 2 H, CF 3, CN, CH 2 -OH, CH 2 CH 2 -OH, CH 2 -OCH 3, CH 2 CH _{2 -OCH 3, OCFH 2, OCF} 2 H, OCF 3, OH, NH 2, C 1-4 alkyl, OC _1-4 alkyl, NH-C _1-4 alkyl, and N (C _1-4 alkyl) _2, are independently selected from each other from the group consisting of, wherein the C _{1 -4} alkyl is not substituted in each case,
R ² is CF _3, C _{1 -4} are not substituted alkyl or unsubstituted C _{3 -6} represents cycloalkyl,
R ⁷ and R ⁹ are independently of one another from H, F, Cl, Br, CFH _2, CF ₂ H, CF _3, CN, OH, OCF _3, C _1-4 alkyl, and OC _1-4 alkyl group consisting of selected, and wherein the C _{1 -4} alkyl is not substituted in each case,
A is N, CH or C (CH _3),
t is 0, 1 or 2,
R ¹⁰⁸ is C _{1 -4} alkyl (which, is optionally substituted, F, Cl, Br, OH, = O, and is optionally substituted mono-, di- or tri from the group consisting of OCH ₃ to the selected one, two or three substituents) . The method of claim 1 wherein, R ² is CF _3, 3-tert-butyl or cyclopropyl, characterized in that the compound. According to claim 1 or 2, R ^101, R ¹⁰² and R ¹⁰³ is H, F, Cl, Br, CFH 2, CF 2 H, CF 3, CN, CH 2 -OH, CH 2 -OCH 3, consisting of _{OCF 3, OH, CH 3,} CH 2 CH 3, CH (CH 3) 2, O-CH 3, O-CH 2 CH 3, NH 2, NH (CH 3), and N (CH _{3) 2} Lt; / RTI &gt; are independently selected from each other from the group. 4. The method according to any one of claims 1 to 3,
t is 1 or 2,
A is 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 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₎ or independently selected from each other from the group consisting of _2;
t is 0, 1 or 2,
A is 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) 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 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 ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ . 5. The method according to any one of claims 1 to 4,
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) 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 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 ₃ ) ₂ , O-CH ₃ , O-CH ₂ CH ₃ , NH ₂ , NH (CH ₃ ) and N (CH ₃ ) ₂ . Claim 1 to claim according to any one of 5, wherein, R ^101, R ¹⁰² and R ¹⁰³ in, characterized in that at least one is not in an H compound. The method according to any one of to claim 6 wherein, R ⁷ and R ⁹ is H, F, Cl, Br, CF 3, CN, OH, OCF 3, CH 3, CH 2 CH 3, CH (CH 3 ) _2, O-CH _3, and O-CH ₂ CH _3, characterized in that independently from each other selected from the group consisting of the compound. 8. Compounds according to any one of claims 1 to ⁷ , characterized in that at least one of R &lt; ⁷ &gt; and R &lt; ⁹ &gt; 9. A method according to any one of claims 1 to 8, wherein the partial structure (TS1)

In this partial structure PT1,

, (PT2)

Or (PT3)

Characterized in that represents a (wherein, R ¹⁰⁸ is C _{1 -4} alkyl represents a non-substituted) compound. 10. The method according to any one of claims 1 to 9,

In this partial structure PT2,

Or (PT3)

(Wherein R ¹⁰⁸ represents unsubstituted C _1-4 alkyl). Claim 1 to claim 10 according to any one of wherein, A is characterized in that the N or C (CH _3), compounds. 11. The method according to any one of claims 1 to 4, 6 to 8 and 10,
A is 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 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₎ or independently selected from each other from the group consisting of _2;
A is 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) 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 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₎ are independently selected from each other from the group consisting of _2,
R ² represents CF ₃ , tert-butyl or cyclopropyl,
R ⁷ and R ⁹ is H, F, Cl, Br, CF 3, CN, OH, OCF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, O-CH 3, and O-CH ₂ CH _{3 &lt}; / RTI &gt; independently from each other,
Substructure (TS1)

In this partial structure PT2,

Or (PT3)

(Wherein R ¹⁰⁸ represents CH ₃ or CH ₂ CH ₃ ). 13. The method according to any one of claims 1 to 12,
Yl) -methyl] -2- (3-fluoro-4-methylsulfonyl-phenyl) -2H-pyrazol- - propionamide;
Yl) -methyl] -2- (3-fluoro-4-methylsulfonyl-pyrimidin-2- Phenyl) -propionamide &lt; / RTI &gt;
D3 2- (3-Fluoro-4-methylsulfonyl-phenyl) -N - [[2- (3- fluorophenyl) -5- (trifluoromethyl) -Methyl] -propionamide; &lt; / RTI &gt;
Pyrazol-3-yl] -methyl] -2- (3-fluoro-phenyl) -5- (trifluoromethyl) 4-methylsulfonyl-phenyl) -propionamide;
D5 2- (3-Chloro-4-methylsulfonyl-phenyl) -N- [[2- (3- chlorophenyl) -5- (trifluoromethyl) -2H-pyrazol- ] -Propionamide;
Yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl) -2H-pyrazol- -Methyl) -phenyl] - &lt; / RTI &gt;propionamide;
D7 N - [[5- tert -butyl-2- (3-chlorophenyl) -2H-pyrazol-3-yl] ) -Phenyl] - &lt; / RTI &gt;propionamide;
Yl] -methyl] -2- [3-fluoro-4- (4-fluoro-phenyl) (Methylsulfonyl-methyl) -phenyl] -propionamide;
D9 N - [[5- tert -butyl-2- (3-fluorophenyl) -2H-pyrazol-3-yl] Methyl) -phenyl] - &lt; / RTI &gt;propionamide;
D10 2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (3- fluorophenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;
Yl] -methyl] -2- [3-fluoro-4- (methylsulfonyl-pyridin-2- Methyl) -phenyl] - &lt; / RTI &gt;propionamide;
D12 2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (4- fluorophenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;
D13 N - [[5- tert -butyl-2- (3,4-difluoro-phenyl) -2H-pyrazol-3- yl] Methylsulfonyl-methyl) -phenyl] - &lt; / RTI &gt;propionamide;
Pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (trifluoromethyl) - (methylsulfonyl-methyl) -phenyl] -propionamide;
Pyrazol-3-yl] -methyl] -2- [3-fluoro-4- (trifluoromethyl) - (methylsulfonyl-methyl) -phenyl] -propionamide;
Yl] -methyl] -2- [3-fluoro-4- ((3-fluoro-phenyl) Methylsulfonyl-methyl) -phenyl] - &lt; / RTI &gt;propionamide;
D17 N - [[5- tert -Butyl-2- (3-dimethylamino-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro- -Methyl) -phenyl] - &lt; / RTI &gt;propionamide;
Yl] -methyl] -2- [3-fluoro-4- (4-fluoro-phenyl) (Methylsulfonyl-methyl) -phenyl] -propionamide;
D19 N - [[5- tert -butyl-2- (3-cyano-phenyl) -2H-pyrazol-3-yl] -methyl] -2- [3-fluoro- -Methyl) -phenyl] - &lt; / RTI &gt;propionamide;
Yl] -methyl] -2- [3-fluoro-4- (trifluoromethyl) phenyl] -2H-pyrazol- - (methylsulfonyl-methyl) -phenyl] -propionamide;
Methyl-2- [3-fluoro-4- (methylsulfonyl-pyridin-2-yl) Methyl) -phenyl] - &lt; / RTI &gt;propionamide;
D22 2- [3-Fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (3- methoxyphenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;
Yl] -methyl] -2- [3-fluoro-4- ((3-fluoro-phenyl) -2H-pyrazol- Methylsulfonyl-methyl) -phenyl] - &lt; / RTI &gt;propionamide;
Methyl-2- [3-fluoro-4- (methylsulfonyl-methyl) -2,3-dihydro-2H-pyrazol- -Phenyl] - &lt; / RTI &gt;propionamide;
D25 2- [3-fluoro-4- (methylsulfonyl-methyl) -phenyl] -N - [[2- (4- methoxyphenyl) -5- (trifluoromethyl) 3-yl] -methyl] -propionamide;
Ylmethyl] -3- [3-fluoro-4- (2-methylsulfonyl-ethyl) ) -Phenyl] -urea &lt; / RTI &gt;
3- [3-fluoro-4- (2-methyl-pyridin-2-ylmethyl) Ethyl) -phenyl] -urea &lt; / RTI &gt;;
Pyrazol-3-yl] -methyl] -3- [3-fluoro-phenyl] -5- (trifluoromethyl) 4- (2-methylsulfonyl-ethyl) -phenyl] -urea;
3- [3-fluoro-4- (2-methylsulfonyl) -2H-pyrazol-3-yl] -Ethyl) -phenyl] -urea &lt; / RTI &gt;;
3- [3-fluoro-4- (2-methylsulfanyl) -2H-pyrazol-3-yl] Fluoro-ethyl) -phenyl] -urea; &lt; / RTI &gt;
3- [3-fluoro-4- ((3-fluoro-phenyl) -2H- 2-methylsulfonyl-ethyl) -phenyl] -urea;
D32 1- [3-Fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -3 - [[2- (m- tolyl) -5- (trifluoromethyl) -2H- 3-yl] -methyl] -urea; &lt; / RTI &gt; And
D33 1- [3-Fluoro-4- (2-methylsulfonyl-ethyl) -phenyl] -3 - [[2- (3- isopropyl- phenyl) -5- (trifluoromethyl) Pyrazol-3-yl] -methyl] -urea
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers, a free compound and / or a physiologically acceptable salt thereof. 14. A pharmaceutical composition comprising at least one substituted compound according to any one of claims 1 to 13. 14. The method of any one of claims 1 to 13, wherein the pain is selected from the group consisting of pain, preferably acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; Hyperalgesia; Allodynia; Burner; migraine; depression; Neuropathy; Axonal injury; Neurodegenerative diseases, preferably 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 a memory disorder; epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; cough; Incontinence; Overactive bladder (OAB); Disorders and / or damage of the gastrointestinal tract; Duodenal ulcer; Gastric ulcer; Irritable bowel syndrome; stroke; Eye irritation; Skin irritation; Neurogenic skin disease; Allergic skin disease; psoriasis; Vitiligo; Herpes simplex; Inflammation, preferably inflammation of the intestine, eye, bladder, skin or nasal mucosa; diarrhea; Itching; osteoporosis; arthritis; Osteoarthritis; Rheumatic diseases; An eating disorder selected from the group consisting of hyperphagia, cachexia, anorexia and obesity; Drug dependence; Drug misuse; Withdrawal symptoms due to drug dependence; The occurrence of resistance to drugs, preferably to natural or synthetic opioids; Drug dependence; Misuse of drugs; Withdrawal symptoms due to drug dependence; Alcohol dependence; For the treatment and / or prevention of one or more diseases and / or disorders selected from the group consisting of abuse of alcohol and abstinence due to alcohol dependence; For diuretic; For sodium urinary excretion inhibition; For cardiovascular stimulation; For increased awakening; For the treatment of wounds and / or burns; For the treatment of damaged nerves; For increased libido; For the regulation of locomotor activity; For anxiety relief; (Preferably VR1 / TRPV1 receptor) agonists for topical anesthesia and / or vanilloid receptor 1 (VR1 / TRPV1 receptor), preferably capsaicin, reniniferatoxin, olanil, arvanil, SDZ-249665, SDZ-249482, (Which is preferably selected from the group consisting of hyperthermia, hypertension and bronchoconstriction) which is triggered by the administration of a therapeutically effective amount of a compound of formula (I).