PYRAZOLE DERIVATIVES AS CBI MODULATORS

Field of invention

The present invention relates to certain compounds of formula I ₅ to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them. Background of the invention

It is known that certain CB] modulators (known as antagonists or inverse agonists) are useful in the treatment of obesity, psychiatric and neurological disorders (WO01/70700 EP 658,546 and EP 656,354).

Pyrazoles having anti-inflammatory activity are disclosed in WO 95/15316, WO96/38418, WO97/11704, WO99/64415, EP 418 845 and WO2004050632. WO2004050632 discloses 1 , 1 -dimethylethyl [2- [4- [3 - [(ethylmethylamino)carbonyl] - 1 -(4-methoxyphenyl)- 1 H- pyrazol-5-yl]phenoxy]ethyl]carbamate, 5-[4-(2-aminoethoxy)phenyl]-iV-ethyl-l-(4- methoxyphenyl)-N-methyl-lH-pyrazole-3-carboxamide, l-[[5-[4-(2-aminoethoxy)phenyl]- l-(4-methoxyphenyl)-lH-pyrazol-3-yl]carbonyl]piperidine and 1,1 -dimethylethyl [2-[4- [l-(4-methoxyphenyl)-3-(l-piperidinylcarbonyl)-lH-pyrazol-5- yl]phenoxy]ethyl]- carbamate. All compounds exemplified in WO2004050632 and salts thereof are excluded from the scope of the compound claims of the present invention. l,5-Diarylpyrazole-3-carboxamide derivatives are disclosed as having CBi modulatory activity in US 5,624,941, WOO 1/29007, WO2004/052864, WO03/020217, US 2004/0119972, Journal of Medicinal Chemistry, 46(4), 642-645 2003, Bioorganic & Medicinal Chemistry Letters, 14(10), 2393-2396 2004, Biochemical Pharmacology, 60(9), 1315-1323 2000, Journal of Medicinal Chemistry, 42(4), 769-776 1999 and U.S. Pat. Appl. Publ. US 2003199536. AU compounds disclosed in these documents are disclaimed from the present application.

Co-pending application number PCT/GB2005/000534 discloses CBl antagonists of formula (A)

A and pharmaceutically acceptable salts thereof, in which R ¹ represents a) a Ci _-3 alkoxy group substituted by one or more of the following i) fluoro ii) a group NR ^c R ^d in which R ^c and R ^d independently represent H, a Ci^alkyl group or C ₁ . βallcoxycarbonyl group provided that one of R° and R ^d is other than H or iii) a 1,3- dioxolan-2-yl group b) R ¹ represents a C _4-6 alkoxy group optionally substituted by one or more of the following i) fluoro ii) a group NR ^c R ^d in which R ^c and R ^d independently represent H, a Ci- ₆ alkyl group or d-βalkoxycarbonyl group provided that one of R ^c and R ^d is other than H or iii) a l,3-dioxolan-2-yl group c) a group of formula phenyl(CH ₂ ) _p O- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted by 1, 2 or 3 groups represented by Z, d) a group R ⁵ S(O) ₂ O or R ⁵ S(O) ₂ NH in which R ⁵ represents a Ci^alkyl group optionally substituted by one or more fluoro, or R ⁵ represents phenyl or a heteroaryl group each of which is optionally substituted by 1, 2 or 3 groups represented by Z e) a group of formula (R ⁶ ) ₃ Si in which R ⁶ represents a C^alkyl group which may be the same or different or f) a group of formula R ^b O(CO)O in which R ^b represents a Cμealkyl group optionally substituted by one or more fluoro; R ^a represents halo, a group or a Ci _-3 alkoxy group; m is 0, 1, 2 or 3;

R ² represents a Ci _-3 alkyl group, a Ci-3alkoxy group, hydroxy, nitro, cyano or halo n is O, 1, 2 or 3;

R ³ represents a) a group X-Y-NR ⁷ R ⁸ in which X is CO or SO ₂ ,

Y is absent or represents NH optionally substituted by a C _1-3 alkyl group;

and R ⁷ and R ⁸ independently represent : a Ci-βalkyl group optionally substituted by 1, 2, or 3 groups represented by W; a C3.i5cycloalkyl group optionally substituted by 1, 2, or 3 groups represented by W; a (C _3- 15cycloalkyl)Ci _-3 alkylene group optionally substituted by 1, 2, or 3 groups represented by W; a group -(CH ₂ ) _r (phenyl ) _s in which r is 0,1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one, two or three groups represented by Z; a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following : oxygen, sulphur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more Ci _-3 alkyl groups, hydroxy or benzyl ; a group - (CH ₂ ) _t Het in which t is 0,1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more Ci_ ₃ alkyl groups and Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a Ci.salkyl group, a Ci.salkoxy group or halo wherein the alkyl and alkoxy group are optionally independently substituted by one of more fluoro; or R ⁷ represents H and R ⁸ is as defined above; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following : oxygen, sulphur or an additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more C^alkyl groups, hydroxy, fluoro or benzyl; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl, each optionally substituted by 1, 2 or 3 groups Z;

R ⁴ represents H, halo, hydroxy, cyano, a group, a Cμ ₆ alkoxy group or a C]- βalkoxyCi-ealkylene group which contains a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more fluoro or cyano;

Z represents a Ci _-3 alkyl group, a Ci _-3 alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono or di Ci _-3 alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di Ci.3alkyl carbamoyl and acetyl; and

W represents hydroxy, fluoro, a C _1-3 alkyl group, a Ci^alkoxy group, amino, mono or di C ₁ .

₃ alkylamino, a Ci-ealkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic amine is optionally substituted by a Ci _-3 alkyl group or hydroxyl; but excluding 1,1-dimethylethyl [2-[4-[3-[(ethylmethylamino)carbonyl]-l-(4- methoxyρhenyl)-lH-pyrazol-5-yl]phenoxy]ethyl]carbamate and 1,1-dimethylethyl [2-[4-

[l-(4-methoxyphenyl)-3-(l-piperidinylcarbonyl)-lH-pyrazol -5- yl]phenoxy]ethyl]carbamate. Compounds exemplified in this application are disclaimed from the present application. However, there is still a need for CBi modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties. A select group of compounds has been found that addresses this need.

Description of the invention

The invention relates to a compound of formula (I)

'

R ¹ represents a group R ⁵ O- in which R ⁵ represents a C ₃ , ₇ alkyl group substituted by one or more fluoro or R ⁵ represents a C _3-7 alkylsulphonyl group which is optionally substituted by one or more fluoro; R ² represents a group, hydroxy, fluoro, chloro or cyano wherein each R ² is independently selected when n is >1 ;

R ³ represents a) cyclohexyl optionally substituted by one or more of the following: hydroxy, fluoro, amino, mono or diCi _-3 alkylammo, carboxy or a Ci _-4 alkoxycarbonyl group b) piperidino substituted by one or more hydroxy c) unsubstituted piperidino but only when one of the following applies: R ⁴ represents cyano or R ¹ represents 3- fluoropropylsulphonyloxy or R ¹ represents 3,3,3-trifluoropropoxy or R ¹ represents 3- fluoropropoxy or R ² is methyl d) phenyl substituted by one or more of the following:

hydroxy, halo or a Ci. ₄ alkyl group e) pyridyl substituted by a Ci _-4 alkyl group or f) a C _4-

₉ alkyl group;

R ⁴ represents cyano or methyl; and n is 1, 2 or 3 and pharmaceutically acceptable salts thereof.

It will be understood that when n is 2 or 3 then the groups R ² are independently selected so that they may be the same or different.

In a first group of compounds of formula I, R ¹ represents n-butylsulfonyloxy, n- propylsulfonyloxy, 3-methylbutylsulfonyloxy, 4,4,4-trifluorobutyl-l-sulfonyloxy, 4- fluorobutyl- 1 -sulfonyloxy, 3 ,3 ,3 -trifluoropropyl- 1 -sulfonyloxy, 3 -fluoropropyl- 1 - sulfonyloxy, 4,4,4 -trifluorobutoxy, 4 -fluorobutoxy, 3,3,3-trifluoropropoxy or 3- fluoropropoxy.

In a second group of compounds of formula I, R ² represents chloro, fluoro, cyano, hydroxy or methyl and n is 1, 2 or 3. In a third group of compounds of formula I, R ³ represents cyclohexyl substituted by one or more of the following: hydroxy, fluoro, amino, mono or di Ci-aalkylamino, carboxy or a

Ci _-4 alkoxycarbonyl group; for example 2-hydroxycyclohexyl, 3 -hydroxy cyclohexyl, 4- hydroxycyclohexyl, 2-aminocyclohexyl, 3-aminocyclohexyl, 2-dimethylaminocyclohexyl,

3-dimethylaminocyclohexyl or 4,4-difluorocyclohexyl. In one group of compounds the substituent is in the 2 or 3 position. In another group of compounds the substituent on the cyclohexyl ring is in the cis conformation with respect to the nitrogen of the amide. In another group of compounds the substituent on the cyclohexyl ring is in the trans conformation with respect to the nitrogen of the amide.

In a fourth group of compounds of formula I ₃ R ³ represents piperidino substituted by one or more hydroxy for example 3-hydroxypipridino or 4 hydroxypiperidino.

In a fifth group of compounds of formula I, R ³ represents unsubstituted piperidino but only when one of the following applies: R ⁴ represents cyano or R ¹ represents 3- fluoropropylsulphonyloxy or R ¹ represents 3,3,3-trifluoropropoxy or R ¹ represents 3- fluoropropoxy or R ² is methyl. In a sixth group of compounds of formula I, R ³ represents phenyl substituted by one or more of the following: hydroxy, halo or a Ci _-4 alkyl group, for example 3,4-difluoro-2- hydroxyphenyl.

In a seventh group of compounds of formula I, R ³ represents pyridyl substituted by a Ci. ₄ alkyl group or fluoro, for example methylpyridyl e.g. 5-methyl-2-pyridyl or for example fluoro pyridyl e.g. 5-fluoro-2-pyridyl. In an eighth group of compounds of formula I, R ³ represents a G^alkyl group for example 2-ethyl-l -butyl.

In a ninth group of compounds of formula I, R ⁴ represents cyano.

In a tenth group of compounds of formula I, R ⁴ represents methyl.

Particularly the fluoro substitution in R ⁵ is in the teπninal carbon atom of the R ⁵ chain.

"Pharmaceutically acceptable salt", where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt,or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates. Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC. The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention. AU tautomers, where possible, are included within the scope of the invention. The present invention also encompasses compounds containing one or more isotopes for example ¹⁴ C, ¹¹ C or

¹⁹ F and their use as isotopically labelled compounds for pharmacological and metabolic studies.

The present invention also encompasses prodrugs of a compound of formula I that is compounds which are converted into a compound of formula I in vivo. The following definitions shall apply throughout the specification and the appended claims.

Unless otherwise stated or indicated, the term "alkyl" denotes either a straight or branched alkyl group. Examples of said alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl . Preferred alkyl groups are methyl, ethyl, propyl, isopropyl and tertiary butyl.

Unless otherwise stated or indicated, the term "alkoxy" denotes a group O-alkyl, wherein alkyl is as defined above.

Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine. Specific compounds of the invention are one or more of the following:

4- {4-cyano- 1 -(2,4-dichlorophenyl)-3 -[(piperidin- 1 -ylamino)carbonyl] - lH-pyrazol-5- yl} phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate;

4-{4-cyano-l-(2,4-dichlorophenyl)-3-[(ρiperidin-l-ylamin o)carbonyl]-lH-pyrazol-5- yl}phenyl 3-methylbutane-l-sulfonate; 4-[l-(2,4-dichlorophenyl)-3-({[(lR,2S)-2-hydroxycyclohexyl]a mino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3 ,3 ,3-trifluoropropane- 1 -sulfonate;

4-[l-(2,4-dichlorophenyl)-3-({[(lS,2R)-2-hydroxycyclohexy l]amino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate;

4-(l-(2,4-dichlorophenyl)-3-{[(5-fluoropyridin-2-yl)amino ]carbonyl}-4-methyl-lH- pyrazol-5-yl)phenyl 3, 3, 3 -trifluoropropane- 1 -sulfonate;

4-( 1 -(2,4-dichlorophenyl)-3 - { [(3 ,4-difluoro-2-hydroxyphenyl)amino] carbonyl} -4-methyl- lH-pyrazol-5-yl)phenyl 3,3,3-trifluoropropane-l -sulfonate;

4-{l-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-l-ylamin o)carbonyl]-lH-pyrazol-5- yljphenyl 3-fluoroproρane-l -sulfonate; 3,3,3-trifluoropropane-l -sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-(4-hydroxy-piperidin-l- ylcarbamoyl)-4-methyl-2η-pyrazol-3 -yljphenyl ester;

3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-(3-hydroxy-piperidin-l- ylcarbamoyl)-4-methyl-2H-pyrazol-3 -yl]phenyl ester;

3 -methylbutane-1 -sulfonic acid 4-[2~(2,4-dichlorophenyl)-4-methyl-5-(5-methyl-pyridin-2- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester; 3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(5-methyl- pyridin-2-ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester;

(-)-4-[l-(2,4-dichlorophenyl)-3-({[cis-2-hydroxycyclohexy l]amino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate;

(+)-4-[l-(2,4-dichlorophenyl)-3-({[cis-2-hydroxycyclohexy l]amino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate;

4-[l-(2,4-dichloroρhenyl)-3-({[3-(dimethylamino)cyclohex yl]amino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate;

4- [ 1 -(2,4-dichlorophenyl)-3 -( { [trans-3 -(dimethylamino)cyclohexyl] amino } carbonyl)-4- methyl-lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate; 4-[l-(2,4-dichlorophenyl)-3-({[cis-3-(dimethylamino)cyclohex yl]amino}carbonyl)-4- methyl-lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate;

4-[3-({[cis-3-aminocyclohexyl]amino}carbonyl)-l-(2,4-dich lorophenyl)-4-methyl-lH- pyrazol-5-yl]phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate;

4-[3-[({trans-3-[(ter^-butoxycarbonyl)amino]cyclohexyl}am ino)carbonyl]-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazol-5-yl]phenyl 3,3,3-trifiuoropropane-l-sulfonate;

1 -(2,4-dichlorophenyl)-4-methyl-N-piperidin- 1 -yl-5-[4~(3,3,3-trifluoropropoxy)phenyl]- lH-pyrazole-3-carboxamide;

N-cyclohexyl-l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3- trifluoropropoxy)phenyl]-lH- pyrazole-3 -carboxamide; l-(2,4-dichlorophenyl)-N-[(cis)-2-hydroxycyclohexyl]-4-methy l-5-[4-(3,3,3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamide; l-(2,4-dichlorophenyl)-N-(4,4-difluorocyclohexyl)-4-methyl-5 -[4-(3,3,3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamide; l-(2,4-dichlorophenyl)-4-methyl-N-(5-methylpyridin-2-yl)-5-[ 4-(3,3,3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamide;

4-[ 1 -(2-chlorophenyl)-3- { [( 1 £,2i?)-2-hydroxycyclohexyl]carbamoyl} -4-methyl- IH- pyrazol-5-yl]phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate;

4-[l-(2-chlorophenyl)-3-{[(li?,2iS)-2-hydroxycyclohexyl]c arbamoyl}-4-methyl-lH- pyrazol-5-yl]plienyl 3,3,3-trifluoropropane-l-sulfonate:

4-[l-(2-chlorophenyl)-3-(cyclohexylcarbamoyl)-4-niethyl-l H-pyrazol-5-yl]phenyl 3,3,3- trifluoropropane- 1 -sulfonate; 4-{l-(4-chloro-2-methylphenyl)-4-methyl-3-[(piperidin-l-ylam ino)carbonyl]-lH-pyrazol-

5-yl} phenyl 3,3,3-trifluoropropane-l -sulfonate;

4-[l-(4-chloro-2-methylphenyl)-3-({[(liS ^r ,2i?)-2-hydroxycyclohexyl]amino}carbonyl)-4- methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate;

4-[l-(4-chloro-2-methylphenyl)-3-({[(lR,26)-2-hydroxycycl ohexyl]amino}carbonyl)-4- methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifiuoropropane-l-sulfonate;

4-[l-(2,4-dichlorophenyl)-3-({[(lιS',3i?)-3-hydroxycyclo hexyl]amino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate;

4-[l-(2,4-dichlorophenyl)-3-({[(li?,35)-3-hydroxycyclohex yl]amino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate; 4- [ 1 -(2,4-dichlorophenyl)-3-( { [( lS,3S)-3 -hydroxycyclohexyl]amino} carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane- 1 -sulfonate;

4-[l-(2,4-dichlorophenyl)-3-({[(li?,3i?)-3-hydroxycyclohe xyl]amino}carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate; l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methy l-N-piperidin-l-yl-lH- pyrazole-3-carboxamide; l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-N-[(cis )-2-hydroxycyclohexyl]-4- methyl- lH-pyrazole-3 -carboxamide; l-(2,4-dichlorophenyl)-N-(4,4-difluorocyclohexyl)-5-[4-(3-fl uoropropoxy)phenyl]-4- methyl-lH-pyrazole-3-carboxamide; l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methy l-N-(5-methylpyridin-2-yl)- lH-pyrazole-3-carboxamide; l-(2,4-Dichlorophenyl)-4-methyl-5-[4-(3,3,3-trifluoropropoxy )-phenyl]-lη-pyrazole-3- carboxylic acid (2-hydroxyeyclohexyl)amide l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3-trifluoropropoxy )phenyl]-lH-pyrazole-3- carboxylic acid (3-hydroxycyclohexyl)amide;

3 -fluoropropane-1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-((l S,2R)-2- hydroxycyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester;

4,4,4-trifluorobutane- 1 -sulfonic acid 4-[2-(3 -cyano-5-fluorophenyl)-5-( 1 - ethylbutylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester;

3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(3-cyano-5-fluorophenyl)-5-(4,4-difluoro- cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester; 3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(3-cyanophenyl)-5-(4,4~difiuoro- cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3 -yljphenyl ester;

3,3,3-trifluoropropane-l-sulfonic acid 4-[5-(2-aminocyclohexylcarbamoyl)-2-(3-cyano-5- fluorophenyl)-4-methyl-2H-pyrazol-3 -yl] -phenyl ester;

3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(3-cyano-5-fluorophenyl) -5-(3-dimethylaminocyclohexylcarbamoyl)-4-methyl-2H-pyrazol- 3-yl]phenyl ester;

3,3,3-trifluoropropane-l-sulfonic acid 4~[2-(3-cyano~5-fluorophenyl)-5-((lS,2R)-2- hydroxycyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester;

3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(3-cyanophenyl)-5-(2-hydroxy- cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester; 3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(3-cyano-5~fluorophenyl)-5-(3-hydroxy- cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3 -yljphenyl ester;

N-cyclohexyl-l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy )phenyl]-4-methyl-lH- pyrazole-3 -carboxamide ;

3 ,3 ,3-trifluoropropane- 1 -sulfonic acid 4-[2-(2-chlorophenyl)-5-(2-hydroxy- cyclohexylcarbamoyl)-4-methyl-2η-pyrazol-3-yl]phenyl ester; and

3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2-chlorophenyl)-5-(4,4- difluorocyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester; as well as pharmaceutically acceptable salts thereof.

Methods of preparation

The compounds of the invention may be prepared as outlined below according to any of the following methods. However, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds in the prior art. Compounds of formula I in which R ¹ represents a) a Cs-galkoxy group substituted by one or more fluoro or b) a group of formula phenyl(CH ₂ ) _p O- in which p is 1, 2 or 3 and the

phenyl ring is optionally substituted by 1, 2 or 3 groups represented by Z, or c) a group R ⁵ S(O) ₂ O may be prepared by reacting a compound of formula II

in which R ² , R ³ , R ⁴ , and n are as previously defined with a group R ^1A -X in which R ^1A represents a group such that R ^1A 0 represents R ¹ and X represents a leaving group for example halo, at a temperature in the range of -25 to 150 ⁰ C, in the presence of an inert solvent, for example dichloromethane, and optionally in the presence of a base for example triethylamine or pyridine. Compounds of formula I in which R ¹ , R ² , R ³ , R ⁴ , and n are as previously defined may be prepared by reacting a compound of formula III

III in which R ¹ , R ² , R ⁴ and n are as previously defined and R ¹⁰ represents OH or a Cμealkoxy group or chloro with a compound of formula IV or a salt thereof

R ³ NH ₂ IV in which R ³ is as previously defined, for example in an inert solvent, for example toluene, in the presence of a Lewis Acid, for example trimethylaluminium, at a temperature in the range of -25°C to 150 ⁰ C when R ¹⁰ is a Ci_ ₆ alkoxy group; or alternatively when R ¹⁰ is OH by reacting a compound of formula III with a chlorinating agent for example oxalyl

chloride, and then reacting the acid chloride produced with an amine of formula IV in an inert solvent, for example dichloromethane, in the presence of a base, for example triethylamine or pyridine, at a temperature in the range of -25°C to 15O ⁰ C. Certain intermediate compounds of Formula II are believed to be novel and form part of the present invention. Compounds of formula II may be prepared as described in the Examples.

It will be appreciated by those skilled in the art that during the reaction sequence certain functional groups will require protection followed by deprotection at an appropriate stage see "Protective Groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts. For example compounds of formula I in which R ³ represents a cyclohexyl group substituted by an amino may be prepared by deprotecting a compound of formula II in which R ² , R ⁴ , and n are as previously defined and R ³ represents cyclohexyl substituted by a protected amino group, for example fert-butoxycarbonylamino. Deprotection may be carried out by methods known to those skilled in the art for example by acid hydrolysis for example using hydrochloric acid. Similarly compounds of formula I in which R ² is hydroxy may be prepared by deprotecting a compound of formula II in which R ² represents a protected hydroxy group , for example allyloxy. Deprotection may be carried out by methods known to those skilled in the art for example using tetrakis(triphenylphosphine)palladium optionally in the presence of a base for example morpholine in the presence of a solvent for example dichloromethane. Pharmaceutical preparations

The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight. Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in

the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.

According to a further aspect of the invention there is also provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers. Pharmacological properties

The compounds of formula (I) are useful for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or nonessential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.g., Guillain- Barre syndrome). The compounds are also potentially useful for the prevention or treatment of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.

The compounds are also potentially useful for the prevention or treatment of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.

The compounds are also potentially useful for the treatment of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyper lipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g. treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastroesophageal reflux, ulcers).

The compounds are also potentially useful as agents in treatment of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (e.g. arthritis deformans, inflammation, inflammatory sequelae of

viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds are also potentially useful as agents in treatment of (esophageal) achalasia. In another aspect the present invention provides a compound of formula I as previously defined for use as a medicament. In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.g., Guillain- Barre syndrome).

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g. treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnoπnalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-esophageal reflux, ulcers). In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix,

gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disoerders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication- induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.g., Guillain-Barre syndrome).

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma. In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g. treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-esophageal reflux, ulcers). In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of dermatological disorders, cancers (e.g. colon,

rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders.

The compounds of the present invention are particulary suitable for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention or reversal of weight gain (e.g., rebound, medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items). The compounds of formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders(e.g. Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease. The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea). The compounds are also potentially useful as agents in treatment of extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms. The compounds may also eliminate the increase in weight that normally accompanies the cessation of smoking.

In another aspect the present invention provides a compound of formula I as previously defined for use as a medicament.

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio- depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and

related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.

In a still further aspect the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof. The compounds of the present invention are particulary suitable for the treatment of obesity, e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound.

The compounds of the present invention may also be used to prevent or reverse medication-induced weight gain, e.g. weight gain caused by antipsychotic (neuroleptic) treatment(s). The compounds of the present invention may also be used to prevent or reverse weight gain associated with smoking cessation.

The compounds of the present invention are suitable for use in treating the above indications in juvenile or adolescent patient populations. The compounds of the present invention may also be suitable for use in the regulation of bone mass and bone loss and therefore useful in the treatment of osteoporosis and other bone diseases.

Combination Therapy

The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of obesity such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.

The compounds of the invention may further be combined with another therapeutic agent that is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, sleep apnea, asthma, heart disorders, atherosclerosis, macro and micro vascular diseases, liver steatosis, cancer, joint disorders, and gallbladder disorders. For example, a compound of the present invention may be used in combination with a another therapeutic agent that lowers blood pressure or that decreases the ratio of LDLrHDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to microangiopathies.

The compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors). In another aspect of the invention, the compound of formula I, or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art. In addition the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin.

In the present application, the term "cholesterol-lowering agent" also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin.

The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.

According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha/beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, an AT-I blocker, a saluretic, a diuretic or a vasodilator; a melanin concentrating hormone (MCH) modulator; an NPY receptor modulator;

an orexin receptor modulator; a phosphoinositide-dependent protein kinase (PDK) modulator; or modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRα, β, PP ARa, β, γ and RORalpha; a monoamine transmission-modulating agent, for example a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent (TCA), a noradrenergic and specific serotonergic antidepressant (NaSSA); an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptin/leptin receptor modulator; a ghrelin/ghrelin receptor modulator; a DPP-IV inhibitor; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warmblooded animal, such as man in need of such therapeutic treatment. According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low-calorie diets (LCD). Therefore in an additional feature of the invention, there is provided a method for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier. According to a further aspect of the present invention there is provided a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other

compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of obesity and its associated complications in a warm-blooded animal, such as man. According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man. According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment. Furthermore, a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.

It will be understood that there are medically accepted definitions of obesity and being overweight. A patient may be identified by, for example, measuring body mass index (BMI), which is calculated by dividing weight in kilograms by height in metres squared, and comparing the result with the definitions. Pharmacological Activity

Compounds of the present invention are active against the receptor product of the CBl gene. The affinity of the compounds of the invention for central cannabinoid receptors is demonstrable in methods described in Devane et al , Molecular Pharmacology, 1988, 34,605 or those described in WOO 1/70700 or EP 656354. Alternatively the assay may be performed as follows.

10μg of membranes prepared from cells stably transfected with the CBl gene were suspended in 200μl of 10OmM NaCl, 5mM MgCl ₂ , ImM EDTA, 5OmM HEPES (pH 7.4), ImM DTT ₃ 0.1% BSA and lOOμM GDP. To this was added an EC80 concentration of agonist (CP55940), the required concentration of test compound and 0.1 μCi [ ³⁵ S]-GTPyS. The reaction was allowed to proceed at 30°C for 45 min. Samples were then transferred on to GF/B filters using a cell harvester and washed with wash buffer (5OmM Tris (pH 7.4), 5mM MgCl ₂ , 5OmM NaCl). Filters were then covered with scintilant and counted for the amount of [ ^3S S]-GTPγS retained by the filter. Activity is measured in the absence of all ligands (minimum activity) or in the presence of an EC80 concentration of CP55940 (maximum activity). These activities are set as 0% and 100% activity respectively. At various concentrations of novel ligand, activity is calculated as a percentage of the maximum activity and plotted. The data are fitted using the equation y=A+((B-A)/l+((C/x) UD)) and the IC50 value determined as the concentration required to give half maximal inhibition of GTPγS binding under the conditions used.

The compounds of the present invention are active at the CBl receptor (IC50 <1 micromolar). Most preferred compounds have IC50 <200 nanomolar. For example the IC50 of Example 10 is 1.95nM. The compounds of the invention are believed to be selective CBl antagonists or inverse agonists. The potency, selectivity profile and side effect propensity may limit the clinical usefulness of hitherto known compounds with alleged CBl antagonistic/inverse agonistic properties. In this regard, preclinical evaluation of compounds of the present invention in models of gastrointestinal and/or cardiovascular function indicates that they offer significant advantages compared to representative reference CBl antagonist/inverse agonist agents.

The compounds of the present invention may provide additional benefits in terms of potency, selectivity profile, bioavailability, half-life in plasma, blood brain permeability, plasma protein binding (for example higher free fraction of drug) or solubility compared to representative reference CBl antagonists/inverse agonist agents. The utility of the compounds of the present invention in the treatment of obesity and related conditions is demonstrated by a decrease in body weight in cafeteria diet-induced obese mice. Female C57B1/6J mice were given ad libitum access to calorie-dense

'cafeteria' diet (soft chocolate/cocoa-type pastry, chocolate, fatty cheese and nougat) and standard lab chow for 8-10weeks. Compounds to be tested were then administered systemically (iv, ip, sc or po) once daily for a minimum of 5 days, and the body weights of the mice monitored on a daily basis. Simultaneous assessment of adiposity was carried by means of DEXA imaging at baseline and termination of the study. Blood sampling was also carried out to assay changes in obesity-related plasma markers.

Examples

Abbreviations abs. absolute AcOH acetic acid aq aqueous

DCM dichloromethane

DMF dimethylformamide

DEA diethylamine DEAD diethyl azodicarboxylate

DIEA N,N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

EtOAc ethyl acetate

Et ₃ N triethylamine Ex or EX Example

LiHMDS lithium hexamethyldisilazide

NH ₄ Ac ammonium acetate

Me methyl

MeOH methanol MeCN acetonitrile rt or RT room temperature

TEA triethylamine

THF tetrahydrofuran t triplet s singlet d doublet q quartet

qvint quintet m multiplet br broad bs broad singlet dm doublet of multiplet bt broad triplet dd doublet of doublet

General Experimental Procedures

Mass spectra were recorded on either a Micromass ZQ single quadrupole or a Micromass LCZ single quadrupole mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS). ¹ H NMR measurements were performed on either a

Varian Mercury 300 or a Varian Inova 500, operating at ¹ H frequencies of 300 and 500

MHz respectively. Chemical shifts are given in ppm with CDCl ₃ as internal standard.

CDCl ₃ is used as the solvent for NMR unless otherwise stated. Purification was performed on a semipreparative HPLC ( High Performance Liquid Chromatography ) with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with 19 x 100 mm C8 column. The mobile phase used was, if nothing else is stated, acetonitrile and buffer (0.1 M ammonium acetateracetonitrile 95:5).

For isolation of isomers, a Kromasil CN E9344 (250 x 20 mm i.d.) column was used. Heptane:ethyl acetate:DEA 95:5:0.1 was used as mobile phase (1 ml/min). Fraction collection was guided using a UV-detector (330 nm).

Typical HPLC -parameters for purity analysis:

HPLC-system: Agilent 1100

Column: Zorbax Eclipse XDB-C8 150x4.6 mm Time of analysis: 15 min

Flow: 1.5 ml/min

Mobilphase: A: water, 5% MeOH B: MeOH

Temperature: 40 ⁰ C Detector: Uv 240nm

Examples of the Invention Example 1

4- (4-cyano- 1 -(2,4-dichlorophenyl)-3-[(piperidin- 1 -ylamino)carbonyl ^" |- lH-pyrazol-5- yl } phenyl 3 , 3 ,3 -trifluoropropane- 1 -sulfonate Step A: Ethyl chlorolY∑λ-dichlorophenyDhydrazonoiacetate

Sodium nitrite (877 mg, 12.71 mmol) in water (5 ml) was added to a suspension of 2,4- dichloroaniline (2.0 g, 12.34 mmol) in 24% HCl (5 ml, aq) at O ⁰ C. The reaction was continued at room temperature for 1 hour. A suspension of ethyl 2-chloro-3-oxobutanoate (2.03 g, 12.32 mmol) in 30% acetic acid (12 ml, aq) was added at O ⁰ C and the reaction continued at room temperature for 16 hours. The mixture was filtered and the filtrate washed with water, dissolved in DCM, washed with 5% NaHCOβ (50 ml, aq) and water and dried over MgSO ₄ . The product was further purified by flash chromatography (SiO ₂ , toluene) to give a yellow powder (1.87 g, 51%). ¹ H NMR (399.964 MHz) δ 8.65 (s, IH), 7.48 (d, IH), 7.27 (s, IH), 7.18 (d, IH), 4,36 (q, 2H), 1.37 (t, 3H).

Step B : 3 - [4-(benzyloxy)phenyl] -3 -oxopropanenitrile

Acetonitrile (9.65 ml, 185.74 mmol) was added to a solution of iV-butyllithium (2.5 M in hexane, 75 ml) in dry THF (30 ml) at -78 ⁰ C. The reaction was continued at -78 ⁰ C for 20 minutes. A suspension of 4-benzyloxybenzoic acid methyl ester (15.00 g, 61.91 mmol) in dry THF/diethylether (4:1, 100 ml) was added over 20 minutes at -78 ⁰ C. The reaction was continued at -78°C for 30 minutes and then quenched with HCl (4M, 120 ml). The product was collected by filtration, washed with water and further purified by recrystallisation from ethanol (8.55 g, 55%). ¹ H NMR (399.964 MHz) δ 7.86 (d, 2H), 7.44-7.34 (m, 5H), 7.03 (d, 2H), 5.13 (s, 2H), 3.98 (S, 2H).

Step C: Ethyl 5-[4-fbenzyloxy)phenyl]-4-cyano-l-(2,4-dichlorophenyl)-lH-py razole-3- carboxylate

Ethyl chloro[(2,4-dichlorophenyl)hydrazono]acetate (1.84 g, 6.24 mmol) and 3-[4- (benzyloxy)phenyl]-3-oxoproρanenitrile (1.57 g, 6.24 mmol) were dissolved in ethanol (150 ml). Sodium ethoxide was added (3.5 ml, 21 wt% in ethanol) and the mixture boiled under reflux for 28 hours. The mixture was cooled to room temperature and the solvent evaporated. The mixture was redissolved in ethyl acetate, washed with water and dried

over MgSO ₄ . The product was further purified by flash chromatography (SiO ₂ , toluene/ethyl acetate, product came at 3% ethyl acetate) and preparatory HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 100% acetonitrile) to give an almost white powder (403 mg, 13%). ¹ H NMR (399.964 MHz) δ 7.45-7.20 (m, 10H), 6.93 (d, 2H), 5.03 (s, 2H), 4.49 (q, 2H), 1.43 (t, 3H). MS m/z 492, 494, 496 (M+H) ⁺ .

Step D: 5-[4-(benzyloxo)phenyl1-4-cyano-l-(2,4-dichlorophenyl)-lH-py razole-3- carboxylic acid Ethyl 5-[4-(benzyloxy)phenyl]-4-cyano-l-(2,4-dichlorophenyl)-lH-py razole-3-carboxylate (243 mg, 0.49 mmol) and sodium hydroxide (1.02 g, 25.41 mmol) were boiled under reflux in water/ethanol (1:5, 30 ml) for 2 hours. The solvent was evaporated and the mixture suspended in water and neutralised with HCl (cone). The product was collected by filtration, washed with water and dried at reduced pressure (181 mg, crude). ¹ H NMR (399.964 MHz) δ 8.20-6.80 (m, 12H), 5.00 (s, 2H). MS m/z 464, 466, 468 (M+H) ⁺ .

Step E: 5-[4-(benzyloxy ^' )phenyl1-4-cvano-l-(2,4-dichlorophenyl ^' )-JV-piperidm-l-yl-lH- pyrazole-3-carboxamide

A solution of oxalyl chloride (ImI) in DCM (2 ml) was added to 5-[4-(benzyloxo)phenyl]-

4-cyano-l-(2,4-dichlorophenyl)-lH-pyrazole-3-carboxylic acid (181 mg crude) in DCM (3 ml). One drop of DMF was added and the reaction continued at room temperature for 1 hour. The solvent and excess oxalyl chloride was evaporated off and the mixture suspended in 3 ml DCM and added to piperidin-1 -amine hydrochloride (64 mg, 0.47 mmol) in DCM/K ₂ CO ₃ (10%, aq) (2:3, 5ml). The reaction was continued at room temperature for 3 hours. The phases were separated and the organic phase washed with water and dried over MgSO ₄ (226 mg, crude).

¹ H NMR (399.964 MHz) δ 7.60-7.10 (m, HH), 6.92 (d, 2H), 5.03 (s, 2H), 2.96-2.80 (br,

4H), 1.84-1.68 (br, 4H), 1.58-1.30 (br, 2H). MS m/z 546, 548, 560 (M+H) ⁺ .

Step F: 4-cyano-l -(2,4-dichlorophenyl)-5-f4-hvdroxyphenyl)-iV-piperidin-l-yl- IH- pyrazole-3-carboxamide Dimethyl sulfide (440 μl, 6.0 mmol) and boron trifmoride diethyl etherate (740 μl, 6.0 mmol) were added to 5-[4-(benzyloxy)phenyl]-4-cyano-l-(2,4-dichlorophenyl)-N- piperidin-l-yl-lH-pyrazole-3-carboxamide (226 mg, crude) in DCM (5 ml). The reaction

was continued at room temperature for 47 hours. Water was added and the phases separated. The organic phase was washed with water and then evaporated. The mixture was stirred in methanol at room temperature for 3 hours. Water was added, the methanol evaporated and the water extracted with diethyl ether. The organic phase washed with water and dried over MgSO ₄ (146 mg, crude).

¹ H NMR (399.964 MHz) δ 7.45-6.30 (m, 4H), 7.09 (d, 2H), 6.82 (d, 2H), 2.93-2.83 (br, 4H), 1.73-1.59 (br, 4H), 1.43-1.32 (br, 2H). MS m/z 456, 458, 460 (M+H) ⁺ . Step G: 4-{4-cvano-l-(2,4-dichlorophenyl)-3-[(piperidin-l-ylamino)ca rbonyll-lH- pyrazol-5-yl) phenyl 333-trifluoropropane-l -sulfonate 3,3,3-trifluoropropane-l-sulfonyl chloride (90 mg, 0.46 mmol) was added to a mixture of 4-cyano- 1 -(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-N-piperidin- 1 -yl-lH-pyrazole-3- carboxamide (146 mg, crude) and TEA (125 μl, 0.90 mmol) in DCM (5 ml) at -78 ⁰ C, under N ₂ (g). The reaction was continued at -78 ⁰ C for 1 hour. Water was added, the phases were separated and the organic phase was washed with water. The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 97% acetonitrile) to give an almost white powder (93 mg, 30% yield for 4 steps). ¹ H NMR (399.964 MHz) δ 7.60-7.20 (m, 8H), 3.54-3.44 (m, 2H), 2.90-2.80 (br, 4H), 2.80-2.65 (m, 2H), 1.76-1.66 (br, 4H), 1.46-1.36 (br, 2H). HRMS Calcd for [C ₂₅ H ₂₂ Cl ₂ F ₃ N ₅ O ₄ SH-H] ⁺ : 616.080. Found: 616.084. Example 2

4-{4-cyano-l-(2 ₁ 4-dichlorophenyl)-3-[(piperidm-l-ylamino)carbonyl ^' |-lH-pyrazol-5- yl } phenyl 3 -methylbutane- 1 -sulfonate

3-methylbutane-l-sulfonyl chloride (80 mg, 0.47 mmol) was added to a mixture of A- cyano- 1 ~(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-N-piperidin- 1 -yl- lH-pyrazole-3- carboxamide, prepared as in Ex. 1, Step F (113 mg, crude) and TEA (70 μl, 0.50 mmol) in DCM (5 ml) at -78 ⁰ C under ν ₂ (g). The reaction was continued at -78 ⁰ C for 1.5 hour. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, product came at 100% acetonitrile) to give an almost white powder (100 mg, 52% yield for 4 steps).

¹ H NMR (399.964 MHz) δ 7.60-7.20 (m, 8H), 3.25-3.15 (m, 2H), 2.90-2.80 (br, 4H), 1.84- 1.75 (m, 2H), 1.75-1.64 (m, 5H), 1.44-1.34 (br, 2H), 0.90 (d, 6H).

HRMS Calcd for [C ₂₇ H ₂₉ Cl ₂ N ₅ O ₄ S+H] ⁺ : 590.140. Found: 590.137.

Example 3

4-F 1 -(2,4-dichlorophenvD-3-( { \( 1 R,2S)-2-hydroxycvclohexyll amino } carbonylV4-methyl- lH-pyrazol-5-vnphenyl 3,3,3-trifluoroρropane-l-sulfonate and 4-[l-(2,4-dichloroρhenyl)- 3-((F(IS ,2RV2-hydroxycyclohexyl1 amino I carbonyl)-4-methyl- lH-pyrazol-5 -yllphenyl 3 ,3 ,3-trifluoropropane- 1 -sulfonate Step A 1 -(4-B enzyloxy-phenvD-propane- 1 -one

4-ηydroxypropiophenone (15.0 g, 0.10 mol) was dissolved in acetone (200 ml) together with potassium carbonate (13.8 g, 0.10 mol). Benzyl bromide (17.1 g, 0.10 mol) was added and the reaction mixture boiled under reflux overnight. After cooling to room temperature the mixture was filtered and concentrated on the rotary evaporator to afford 24.0 g (100%) of the title compound as a white solid Step B 1 -(4-Benzyloxyphenyl)-2-bromo-propane- 1 -one l-(4-Benzyloxyphenyl)propane-l-one (4.80 g, 20.0 mmol) was suspended in acetic acid (25 ml) and cooled to 0 ⁰ C. Bromine (3.20 g, 20.0 mmol) was added dropwise and the reaction mixture was stirred for two hours at room temperature at which point the reaction mixture was a clear, yellow solution. After cooling, water (100 ml) was added and the product extracted with ether (2 x 100 ml). The combined organic extracts were washed with water, sodium hydrogen carbonate (caution! Gas evolves) and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated leaving the title compound as a pale yellow solid (6.17 g, 97%).

Step C 2-[2-(4-Benzyloxyphenyl)-2-oxoethyl]-3-oxo-butyric acid ethyl ester A solution of sodium ethoxide was generated from sodium metal (0.53 g, 23.0 mmol) in 30 ml abs. ethanol. To this solution was added ethyl acetoacetate (3.00 g, 23.0 mmol) at 0 ⁰ C. After 30 min. this solution was added to a solution of l-(4-Benzyloxy-phenyl)-2-bromo- propane-1-one (6.17 g, 19.0 mmol) in ethanol : toluene (30 : 15 ml) and the reaction mixture stirred overnight. Acidic work-up with 1 M HCl, extraction with ethyl acetate (3 x), washing with brine, drying (Na ₂ SO ₄ ), filtering and evaporation left a crude product purified by flash chromatography (hexane : EtOAc 95 : 5 - 70 : 30) affording 5.18 g of the title compound as a pale yellow oil.

Step D 5-(4-Benzyloxyphenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyr azole-3- carboxylic acid

A solution of sodium ethoxide was generated from sodium metal (0.19 g, 8.26 mmol) in 20 ml abs. ethanol. To this solution was added 2-[2-(4-benzyloxy-phenyl)-2-oxoethyl]-3-oxo- butyric acid ethyl ester (2.13 g, 6.00 mmol) and the reaction mixture stirred at room temperature for 30 min. A previously prepared solution of 2,4-dichlorodiazonium chloride (prepared from 2,4-dichloroaniline (1.19 g, 7.30 mmol) in 3 ml 24% HCl and sodium nitrite (0.52 g, 7.50 mmol) in 3 ml water at 0 ⁰ C) was added in 5 portions keeping the temperature below 5 ⁰ C. After stirring at room temperature for 2.5 hours water was added, the product extracted with EtOAc (3 x). The combined organic extracts was dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was dissolved in ethanol (40 ml) and sodium hydroxide (0.80 g, 20.0 mmol) in 10 ml of water was added. After 2 hours boiling under reflux the reaction mixture was cooled, acidified with HCl and the product extracted with EtOAc (3 x). After washing, drying (Na ₂ SO ₄ ), filtration and concentration, the residue was purified by flash chromtography (hexane : EtOAc 70:30 - 50:50) affording 1.84 g (68%) of the title compound as a pale yellow solid. Step E: 5-r4-fbenzyloxv)phenyl]-l -(2.4-dichlorophenvn-N-[(lR, 2S1-2- hydroxycyclohexyll-4-methyl- lH-pyrazole-3-carboxamide and 5-| ^" 4-(benzyloxy)phenyl]- l-f2.4-dichlorophenyl)-N-f f 1 S. 2R)-2-hydroxycyclohexyl1-4-methyl-lH-pyrazole-3- carboxamide

Oxalyl chloride (ImI) was added to 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-carboxylic acid (500 mg, 1.10 mmol) in DCM (5 ml). One drop of DMF was added and the reaction continued at room temperature for 1 hour. The solvent and excess oxalyl chloride was evaporated and the mixture suspended in 3 ml DCM and added to cis-2-aminocyclohexanol hydrochloride (204 mg, 1.35 mmol) in DCM/K ₂ CO ₃ (10%, aq) (2:4, 6 ml). The reaction was continued at room temperature for 2 hours. The phases were separated and the organic phase washed with water and dried over MgSO ₄ (610 mg, crude).

¹ H νMR (499.961 MHz) δ 7.50-7.25 (m, 9H). 7.08 (d, 2H), 6.94 (d, 2H), 5.05 (s, 2H), 4.20-4.10 (br, IH), 4.05-4.00 (br, IH), 3.10-2.85 (br, IH), 2.39 (s, 3H), 1.84-1.56 (m, 6H), 1.50-1.36 (br, 2H). MS m/z 550, 552, 554 (M+H) ⁺ . Step F: l-(2 ₁ 4-dichlorophenyl)-A/-[(lR, 2S)-2-hydroxycyclohexyl1-5-(4-hydroxyphenyl)-4- methyl-lH-pyrazole-3-carboxamide and l-(2 ₁ 4-dichlorophenyl)-N-[(lS, 2R)-2- hvdroxvcvclohexvl]-5-(4-hydroxyphenyl)-4-methvl-lH-pvrazole- 3-carboxamide

Dimethyl sulfide (813 μl, 11.08 mmol) and boron trifluoride diethyl etherate (1.40 ml, 11.05 mmol) were added to a mixture of 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)- N-[(1R, 2S)-2-hydroxycyclohexyl]-4-methyl-lH-pyrazole-3-carboxamide and 5-[4- (ben2yloxy)phenyl]-l-(2,4-dichloroρhenyl)-N-[(lS, 2R)-2-hydroxycyclohexyl]-4-methyl~ lH-pyrazole-3-carboxamide (610 mg, crude) in DCM (5 ml). The reaction was continued at room temperature for 40 hours. Water was added and the phases separated. The organic phase was washed with water and dried over MgSO ₄ (531 mg, crude). ¹ H NMR (399.964 MHz) δ 9.00-8.00 (br, IH), 7.42-7.32 (m, 2H), 7.30-7.18 (m, 2H), 6.90 (d, 2H), 6.78 (d, 2H), 4.17-4.07 (br, IH), 4.03-3.96 (br, IH), 4.00-3.00 (br, IH), 2.31 (s, 3H), 1.80-1.50 (m, 6H), 1.45-1.30 (br, 2H). MS m/z 460, 462, 464 (M+H) ⁺ .

Step G: 4-[l-(2,4-dichlorophenyl)-3-({[(lR,2S)-2-hydroxycyclohexyl1a mino|carbonylV4- methyl-lH-pyrazol-5-yliphenyl 3,3,3-trifluoropropane-l-sulfonate and 4-[l-f2,4- dichlorophenyl)-3 -( ^" {[(IS ,2R)-2-hydroxycyclohexyllaminol carbonyl)-4-methyl- IH- pyrazol-5-yllphenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate 3,3,3-trifluoropropane-l-sulfonyl chloride (59 mg, 0.30 mmol) was added to a mixture of TEA (50 μl, 0.35 mmol), racemic mixture of l-(2,4-dichlorophenyl)-N-[(lR, 2S)-2- hydroxycyclohexyl]-5-(4-hydroxyphenyl)-4-methyl-lH-pyrazole- 3-carboxamide and 1- (2,4-dichlorophenyl)-N-[(lS, 2R)-2-hydroxycyclohexyl]-5-(4-hydroxyphenyl)-4-methyl- lH-pyrazole-3-carboxamide (139 mg, crude) in DCM (5 ml) at -78 ⁰ C, under ν ₂ (g). The reaction was continued at -78 ⁰ C for 1 hour. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 98% acetonitrile) to give an almost white powder (103 mg, 57% yield for 3 steps). ¹ H NMR (399.964 MHz) δ 7.39 (s, IH), 7.30-7.15 (m, 7H), 4.17-4.07 (m, IH), 4.05-3.99 (m, IH), 3.50-3.43 (m, 2H), 2.84-2.70 (m, 2H), 2.35 (s, 3H), 2.05-1.90 (br, IH), 1.80-1.50 (m, 6H), 1.50-1.35 (m, 2H).

HRMS Calcd for [C ₂₆ H ₂₆ Cl ₂ F ₃ N ₃ O ₅ S+^: 620.100. Found: 620.101. Example 4 4-fl-(2,4-dichlorophenyl)-3-{[(5-fluoropyridin-2-yl)amino]ca rbonyl|-4-methyl-lH- pyrazol-5-yl)phenyl 3,3,3-trifluoropropane-l-sulfonate

Step A: 5-[4-(benzyloxy)phenyl ^" |- 1 -(2,4-dichlorophenyl)-iV-(5-fluoropyridin-2-yl)-4- methyl-lH-ρyrazole-3-carboxamide

Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (252 nag, 0.48 mmol) in DCM (ImI) was added to a suspension of 5-[4-benzyloxy)phenyl]-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (200 mg, 0.44 mmol), 5- fluoropyridin-2-amine (57 mg, 0.51 mmol) and TEA (61 μl, 0.44 mmol) in DCM (4 ml) at O ⁰ C. The reaction was continued at O ⁰ C for 15 minutes and then at room temperature for 72 hours. Water was added and the phases separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by flash chromatography (SiO ₂ , toluene/ethyl acetate, product came at 2% ethyl acetate) (165 mg, 68%).

¹ H NMR (399.964 MHz) δ 9.48 (s, IH), 8.44-8.34 (m, IH), 8.15-8.10 (m, IH), 7.50-7.10

(m, 9H), 7.06 (d, 2H), 6.91 (d, 2H), 5.01 (s, 2H), 2.41 (s, 3H).

MS m/z 547, 549, 551 (M+H) ⁺ .

Step B: l-(2,4-dichlorophenyl)-N-(5-fluoropyridin-2-yl)-5-(4-hydroxy phenyl)-4-methyl- 1 H-pyrazole-3 -carboxamide

Dimethyl sulfide (221 μl, 3.01 mmol) and boron trifluoride diethyl etherate (382 μl, 3.01 mmol) were added to 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-N-(5-fluoroρ yridin- 2-yl)-4-methyl-lH-pyrazole-3-carboxamide (165 mg, 0.301 mmol) in DCM (5 ml). The reaction was continued at room temperature for 67 hours. Water was added and the phases separated. The organic phase was washed with water and then evaporated. The mixture was stirred in methanol at room temperature for 24 hours. Water was added, the methanol evaporated and the water extracted with diethyl ether. The organic phase washed with water and dried over MgSO ₄ (142 mg, crude). ¹ H νMR (399.964 MHz) δ 9.50 (s, IH), 8.50-6.20 (m, 10H), 2.43 (s, 3H). MS m/z 457, 459, 462 (M+H) ⁺ . Step C: 4-(l-(2,4-dichlorophenyl)-3--[J(5-fluoropyridin-2-yl)ammolca rbonyU-4-methyl- lH-pyrazol-5-yl)phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate

3,3,3-trifluoropropane-l-sulfonyl chloride (82.5 mg, 0.42 mmol) was added to a mixture of l-(2,4-dichlorophenyl)-N-(5-fluoropyridin-2-yl)-5-(4-hydroxy phenyl)-4-methyl-lH- pyrazole-3 -carboxamide (142 mg, crude) and TEA (50 μl, 0.35 mmol) in DCM (2 ml) at -78 ⁰ C, under ν2(g). The reaction was continued at -78 ⁰ C for 2 hours. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparatory ηPLC (kromasil C8 column,

ammonium acetate (aq, 0.1 M):acetonitrile, product came at 100% acetonitrile) to give an almost white powder (111 mg, 60% yield for 2 steps). ¹ H NMR (399.964 MHz) δ 9.43 (s, IH), 8.40-8.33 (m, IH), 8.15-8.10 (m, IH), 7.48-7.40 (m, 2H), 7.33-7.26 (m, 2H), 7.26- 7.17 (m, 4H), 3.51-3.43 (m, 2H), 2.85-2.70 (m, 2H), 2.41 (s, 3H). HRMS Calcd for [C ₂₅ H ₁₈ Cl ₂ F ₄ N ₄ O ₄ SH-H] ⁺ : 617.044. Found: 617.047. Example 5

4-(l-(2,4-dichlorophenyl)-3-{[(3,4-difluoro-2-hvdroxyphenyl) amino]carbonyl}-4-methyl- lH-pyrazol-5-yi)phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate Step A: 5-r4-fbenyloxy ^' )phenyll-l-r2.4-dichlorophenylVN-f3.4-difluoro-2- hydiOxyphenyl)-4-methyl-lH-pyrazole-3-carboxamide

Oxalyl chloride (1 ml) was added to 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-carboxylic acid (300 mg, 0.66 mmol) in DCM (5 ml). One drop of DMF was added and the reaction continued at room temperature for 4 hours. The solvent and excess oxalyl chloride was evaporated and the mixture suspended in 3 ml DCM and added to 6-amino-2,3-difluorophenol (162 mg, 1.12 mmol) in DCM/K ₂ CO ₃ (10%, aq) (2:3, 5 ml). The reaction was continued at room temperature for 19 hours. DMAP (50 mg, 0.41 mmol) was added and the reaction continued at room temperature for 5 hours. The phases were separated and the organic phase washed with water and dried over MgSO ₄ (435 mg, crude). ¹ H νMR (399.964 MHz) δ 10.00-9.60 (br, IH), 9.04 (s, IH), 7.45-6.58 (m, 14H), 5.02 (s, 2H), 2.37 (s, 3H). MS m/z 580, 582, 584 (M+H) ⁺ .

Step B: l-(2,4-dichlorophenyl)-N-(3,4-difluoro-2-hydroxyphenyl)-5-(4 -hydroxyphenyl)-4- methyl-lH-pyrazole-3-carboxamide

Dimethyl sulfide (275 μl, 3.75 mmol) and boron trifluoride diethyl etherate (475 μl, 3.75 mmol) were added to 5-[4-(benyloxy)phenyl]-l-(2,4-dichlorophenyl)-N-(3,4-difluor o-2- hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxamide (435 mg, crude) in DCM (5 ml). The reaction was continued at room temperature for 86 hours. Water was added and the phases separated. The organic phase was washed with water and dried over MgSO ₄ (325 mg, crude). ¹ H νMR (399.964 MHz) δ 9.85-9.65 (br, IH), 9.03 (s, IH), 7.45-6.55 (m, 10H), 2.34 (s, 3H). MS m/z 490, 492, 494 (M+H) ⁺ . Step C: N-[2-fallyloxy)-3,4-difluorophenyl]-l-(2,4-dichlorophenyl)-5 -(4-hydroxyphenyl)- 4-methyl-lH-r>yrazole-3-carboxamide

Allyl bromide (44 μl, 0.52 mmol) was added to l-(2,4-dichlorophenyl)-N-(3,4-difluoro-2- hydroxyphenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyrazole-3-ca rboxamide (256 mg, crude) and cesium carbonate (170 mg, 0.52 mmol) in acetonitrile (6 ml). The reaction was continued at room temperature for 23 hours. Water and DCM were added, the phases separated and the organic phase washed with water and dried over MgSO ₄ (196 mg, crude). ¹ H νMR (399.964 MHz) δ 9.39 (s, IH), 8.26-8.16 (m, IH), 7.50-6.60 (m, 8H), 6.08-5.94 (m, IH), 5.35 (d, IH), 5.12 (d, IH), 4.64 (d, 2H), 2.38 (s, 3H). MS m/z 530, 532, 534 (M+H) ⁺ . Step D: 4-r3-fir2-(allyloxy)-3,4-difluorophenyl]amino|carbonyl)-l-(2 ,4-dichlorophenyl)- 4-methyl-lH-pyrazol-5-yl]phenyl 3,3.3-trifluoropropane-l-sulfonate

3,3,3-trifluoropropane-l-sulfonyl chloride (75 mg, 0.38 mmol) was added to a mixture of N-[2-(allyloxy)-3,4-difluorophenyl]-l-(2,4-dichlorophenyl)-5 -(4-hydroxyphenyl)-4- methyl-lH-pyrazole-3-carboxamide (196 mg, crude) and TEA (50 μl, 0.35 mmol) in DCM (2 ml) at -78 ⁰ C, under ν ₂ (g). The reaction was continued at -78 ⁰ C for 3 hours. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ (249 mg, crude).

¹ H NMR (399.964 MHz) δ 9.37 (s, IH), 8.28-8.18 (m, IH), 7.50-6.80 (m, 8H), 6.08-5.92 (m, IH), 5.35 (d, IH), 5.11 (d, IH), 4.64 (d, 2H), 3.51-3.43 (m, 2H), 2.90-2.70 (m, 2H), 2.38 (s, 3H). MS m/z 690, 692, 694 (M+H) ⁺ . Step E: 4-(l-(2,4-dichlorophenyl)-3-{[(3,4-difluoro-2-hydroxyphenyl) amino]carbonyl|-4- methyl- 1 H-pyrazol-5-vDphenyl 3 ,3 ,3-trifluoropropane- 1 -sulfonate Morpholine (350 μl) was added to 4-[3-({[2-(allyloxy)-3,4- difluorophenyl] amino } carbonyl)- 1 -(2 ,4-dichlorophenyl)-4-methyl- lH-ρyrazol-5 -yl]phenyl 3,3,3-trifluoropropane-l-sulfonate (249 mg, crude) and tetrakis(triphenylphosphine)palladium (90 mg, 0.08 mmol) in DCM (3 ml) under N2(g). The reaction was continued at room temperature under N ₂ (g) for 3 hours. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, product came at 100% acetonitrile) to give an almost white powder (77 mg, 23% yield for five steps). ¹ H NMR (399.964 MHz) δ 9.55 (s, IH), 8.96 (s, IH), 7.46-7.42 (m, IH), 7.35-7.18 (m, 6H), 6.90-6.83 (m, IH), 6.70-6.60 (m,

IH), 3.53-3.45 (m, 2H), 2.85-2.71 (m, 2H), 2.38 (s, 3H). HRMS Calcd for [C ₂₆ Hi ₈ Cl ₂ F ₅ N ₃ O ₅ S-I-H] ⁺ : 650.034. Found: 650.038. Example 6 4-U-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-l-ylamino)ca rbonyll-lH-pyrazol-5- yljphenyl 3-fluoroproρane-l -sulfonate

A solution of 3-fluoropropane-l-sulfonyl chloride (160 mg, 1.00 mmol) in DCM (1.5 ml) was added to l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-ρiper idin-l-yl-lH- pyrazole-3-carboxamide (200 mg, 0.45 mmol) and TEA (100 μl, 0.72 mmol) in DCM (1.5 ml) at -78 ⁰ C under ν ₂ (g). The reaction was continued at -78 ⁰ C under N ₂ (g) for 3 hours. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 97% acetonitrile) to give an almost white powder (191 mg, 74% yield). ¹ H NMR (399.964 MHz) δ 7.70-7.55 (br, IH), 7.38 (s, IH), 7.28-7.10 (m, 6H), 4.57 (dt, 2H), 3.42-3.34 (m, 2H), 2.87-2.77 (m, 4H), 2.32 (s, 3H), 2.40-2.22 (m, 2H), 1.76-1.66 (m, 4H), 1.45-1.33 (m, 2H). HRMS Calcd for [C ₂₅ H ₂₇ Cl ₂ FN4θ ₄ S+H] ⁺ : 569.119. Found: 569.119. Example 7

3,3,3-Trtfluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-(4-hydroxypiperidin-l- ylcarbamoyl)-4-methyl-2H-pyrazol-3-yl ^" |phenyl ester Step A: 5-(4-Benzyloxyphenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyr azole-3- carboxylic acid (4-hydroxypiperidin-l-yl ^' )amide

5-(4-B enzyloxyphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- 1 H-pyrazole-3 -carboxylic acid (750 mg, 1.65 mmol, 1 equiv.) and thionyl chloride (20 equiv) were mixed and the resulting mixture was boiled under reflux for 3.5h. Excess SOCl ₂ was removed under reduced pressure and the residue was azeotroped with toluene to give the acid chloride. 4- Hydroxy-1-aminopiperidine (2 equiv.) was mixed with dichloromethane (10 ml) and THF (7 ml) and triethylamine (5 equiv). The mixture was cooled to -30 ⁰ C under a nitrogen atmosphere. A THF (5 ml) mixture of the acid chloride from above was added dropwise during 20 minutes. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. Aqueous NaOH (IM, 3 ml) was added and the mixture was left for 15 minutes. The reaction mixture was then diluted to 50 ml with dichloromethane and washed with water (2x20 ml) and brine (20 ml). The organic layer was dried (Na ₂ SO ₄ ),

filtered and concentrated under reduced pressure. The residue was purified by Horizon flash chromatography, 8% methanol in dichloromethane. The product fraction was concentrated under reduced pressure to give the title compound (506 mg 55% yield) as a solid). ¹ H-NMR (CDCl ₃ ): 1.72-1.83 (m, 2H), 1.93-2.02 (m, 2H), 2.32 (s, 3H), 2.75-2.84 (m, 2H), 3.04-3.13 (m, 2H), 3.74-3.82 (m,lH), 5.00 (s,2H), 6.87 (d, 2H), 7.00 (d, 2H), 7.20-7.41 (m, 8H), 7.66 (s, IH). MS: 551 (M+l).

Step B:l-(2,4-Dichlorophenyl)-5-r4-hydroxyphenyl)-4-methyl-lH-pyr azole-3-carboxylic acid (4-hydroxypiperidin- 1 -ypamide 5-(4-Ben2yloxyphenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyr azole-3-carboxylic acid (4-hydroxy-piperidin-l-yl)-amide (475 mg, 0.86 mmol, 1 equiv.) and Me ₂ S (5 equiv) were mixed in dichloromethane under a nitrogen atmosphere. BF ₃ XOEt ₂ (5 equiv.) was added dropwise and the resulting mixture was stirred for 6 days at ambient temperature while continuously adding small volumes of dichloromethane and 1,4-dioxane. Methanol and water were then added and the mixture was stirred for 30 mins and was then concentrated under reduced pressure. The residue was extracted with ethyl acetate (3x50 ml). The organic layer was washed with brine (20 ml) and was then dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude material was purified by Horizon flash chromatography (8% methanol in dichloromethane) to give the title compound (304 mg, 76%) as a white solid. MS: 461 (M+l). 0 Step C: 333-Trifluoropropane-l -sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-(4-hydroxy- piperidin-l-ylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]-phenyl ester l-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyraz ole-3-carboxylic acid (4- hydroxy-piperidin-l-yl)-amide (99 mg, 0.21 mmol, 1 equiv.) was dissolved in dichloromethane (15 ml), THF (15 ml) and NEt ₃ (3 equiv.) under nitrogen atmosphere. The 5 solution was cooled to -78 and a solution of 3,3,3-trifluoro-propane-l-sulfonyl chloride in dichloromethane (1 ml) was added slowly while monitoring the progress with LC-MS. The reaction mixture was quenched by addition of methanol and water. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Kromasil C8, 5-100% acetonitrile in water with 0.1M ammonium acetate). The product o fraction was freeze-dried to give the title compound (36 mg, 27%) as a white powder.

¹ H-NMR (CDCl ₃ ): 1.74-1.85 (m, 2H), 1.95-2.04 (m, 2H), 2.35 (s, 3H), 2.70-2.86 (m, 4H), 3.06-3.14 (m, 2H), 3.43-3.50 (m, 2H), 3.76-3.85 (m, IH), 7.12-7.40 (m, 7H), 7.66 (s, IH).

HRMS: Calculated for [C ₂₅ H ₂₅ Cl ₂ F ₃ N ₄ O ₅ SH-H ⁺ ] 621.0953, found 621.0939

HPLC-UV: 98%

Example 8

3,3,3-Trifluoro-propane-l-sulfonic acid 4-[2-(2 ₁ 4-dichlorophenyr)-5-(3-lrydroxy-piperidin- 1 -ylcarbamoyl)-4-methyl-2H-pyrazol-3-vHphenyl ester

Step A: 5-(4-B6nzyloxyphenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyr azole-3- carboxylic acid (3-hydroxy-piperidin-l-yl)amide

This compound was prepared as described in Ex. 7, Step A using 3-hydroxy-l- aminopiperidine instead of 4-hydroxy-l-aminopiperidine. The title compound was obtained as a semisolid, 518mg (48%).

MS: 551 (M+l).

Step B:l-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyr azole-3-carboxylic acid (3-hydroxy-piperidin-l -vDamide

This compound was prepared from the product of Step A above by the method described in Ex. 7, Step B and was obtained as a yellow oil, 385mg (89%). MS: 461 (M+l).

Step C: 3,3,3-Trifluoropropane-l-sulfonic acid 4-[ ^" 2-(2,4-dichlorophenyl)-5-(3-hydroxy- piperidin- 1 -ylcarbamoylV 4-methyl-2H-pyrazol-3 -yl]phenyl ester

This compound was prepared, in a similar manner to that described in Ex. 7, Step C, as a white solid, 37mg (24%). after freeze-drying. ¹ H-NMR (MeOH-d ₄ ): 1.30-1.43 (m, IH), 1.60-1.93 (3H), 2.29-2.37 (3H), 2.59-2.96 (m, 5H), 3.08-3.16 (m, IH), 3.66-3.76 (m, 2H),

3.81-3.91 (m, IH), 7.30-7.38 (m, 4H), 7.42-7.49 (IH), 7.52-7.59 (m, 2H).HRMS:

Calculated for [C ₂₅ H ₂₅ Cl ₂ F ₃ N ₄ O ₅ S+^] 621.0953, found 621.0947. HPLC-UV:99%

Example 9

3 -Methyl-butane- 1 -sulfonic acid 4-[2-(2.4-dichlorophenyl)-4-methyl-5-(5-methyl-pyridin- 2-ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester or 4-fl-(2,4-dichloroρhenyP)-4-methyl-3-

{f(5-methylpyridm-2-yl)amino1carbonyl}-lH-pyrazol-5-yl)ph enyl 3 -methylbutane- 1 - sulfonate

Step A: 4-benzyloxy propiophenone

To a solution of 4-hydroxy propiophenone (50 g, 0.3329 mol) in dry acetone (500 ml) was added benzyl bromide (56.94 g, 0.333 mol) followed by anh. K ₂ CO ₃ (91.8 g, 0.665 mol).

Reaction mixture was refluxed for 18h, cooled to RT, filtered and filtrate was concentrated to yield 4-benzyloxy propiophenone (75 g, 93%) as a white solid.

Step B Lithium 1 -f 4-Benzyloxy-phenyl)-3-ethoxycarbonyl-2-methyl-3-oxopropen-l -ol To a solution of 4-benzyloxypropioρhenone (50 g, 0.2083 mol) in dry THF (500 ml) at O ⁰ C was added LiHMDS (IM solution in THF, 208.3 ml) drop wise over a period of Ih under N ₂ atm. The reaction mixture was stirred at O ⁰ C for lhr. Added diethyl oxalate (33.49 g, 0.2296 mol) drop wise. Reaction mixture was allowed to warm to RT and stirred at RT for 16 hrs under N ₂ atm. Reaction mixture was concentrated in the rotary evaporator at RT. To the residue was added dry diethyl ether (1 L) and the solid was filtered, washed with dry ether, and dried under vacuum to yield lithium salt of the diketoester (50 g) as yellow solid. Step C: 4-(4-Benzyloxyphenyl)-4-[(2,4-dichloro-phenyl)hydrazono]-3-m ethyl-2-oxo- butyric acid ethyl ester

A mixture of lithium salt from step 2 (50 g, 0.1461 mol) and 2,4-dichlorophenylhydrazine hydrochloride (34.33 g, 0.1608 mol) in ethanol (500 ml) was stirred at RT under N ₂ atm for 18 hrs. The precipitate was filtered, washed with dry ether and dried under vacuum to yield hydrazone intermediate (35 g). Step D: ethyl 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4-methyl-lH-p yrazole-3- carboxylate

Hydrazone intermediate (35 g) was dissolved in acetic acid (250 ml) and heated under reflux for 18 hrs. Reaction mixture was poured into cold water (2 L) and extracted with ethyl acetate (2 x 500 ml). Combined organic layer was washed with water, sat. NaHCO ₃ and brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography over silica gel using 20% ethyl acetate in pet ether as eluent to yield the title compound (22 g) as yellow solid.

Step E 5-[ ^" 4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4-methyl-N-(5-me thylpyridin-2- yl)- 1 H-pyrazole-3 -carboxamide 5-Methylpyridin-2-amine (1.08 g, 10.0 mmol) was suspended in anhydrous toluene (10 mL) under an atmosphere of argon. Upon cooling to 0 ⁰ C trimethylaluminium (5.0 mL, 2.0 M in toluene, 10 mmol) was added dropwise at such a rate as to keep the evolution of methane under control. The obtained mixture was stirred at 0 ⁰ C for 30 min and then at ambient temperature for additional two hours before use. It was assumed that the formation of the desired aluminium amide was quantitative and the concentration thereof was thus calculated to be ca 0.67 M [c= 10/(10+5.0)]. At that point ethyl 5-[4-(benzyloxy)phenyl]-l- (2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylate (1.00 g, 2.08 mmol) was added

in one portion to the prepared aluminium amide and the resulting mixture was heated at 50 ⁰ C overnight. Next morning, as judged by LC/MS, unreacted starting material still remained. Therefore the reaction mixture was heated at 80 °C for three additional hours in order to drive the reaction to completion. Upon cooling to 0 ⁰ C the reaction was quenched by the dropwise addition of HCl (aq., 2 M) until further addition no longer resulted in gas evolution. At that point the ice bath was removed and the mixture was allowed to stir at ambient temerature for an additional hour. The obtained mixture was transferred to a separation funnel with the aid of CH ₂ CI2 (100 mL). H ₂ O (100 mL) was added and the pH of the aqueous phase was adjusted to 9-10. The organic phase was separated and the aqueous phase was extracted further with CH ₂ Cl ₂ (5 x 30 mL). The collected organic phases (emulsion-like, brine was of no use) were dried over large amounts OfMgSO ₄ . Upon evaporation of the solvents the obtained residue was purified by column chromatography (silica gel, EtOAc-CH ₂ Cl ₂ , 0-4 %) to yield the desired 5-[4- (benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4-methyl-N-(5-meth ylpyridin-2-yl)-lH- pyrazole-3-carboxamide (1.020 g, 1.88 mmol, 90 %) as a pinkish solid.

¹ H νMR (500 MHz, CDCl ₃ ) δ 9.40 (s, IH), 8.28 (d, IH, J=8.4 Hz), 8.14 (s, IH), 7.56 (d, IH, J=8.5 Hz), 7.48-7.26 (m, 8H), 7.09 (d, 2H, J=8.9 Hz), 6.94 (d, 2H, J=8.8 Hz) ₃ 5.06 (s, 2H), 2.44 (s, 3H), 2.32 (s, 3H). Step F l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl- N-(5-methylpyridin-2-yl)- lH-pyrazole-3 -carboxamide

The 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4-methyl-N-(5 -methylpyridin-2-yl)- lH-pyrazole-3-carboxamide (0.100 g, 0.184 mmol) was put in a round flask and a solution of HBr in acetic acid (ca. 4.1 M, 1.8 mL) was added. After stirring at ambient temperature for four hours the reaction mixture was poured onto ice (20 g). Upon melting the pH was adjusted to ca. 7 by the addition of solid Na ₂ CO ₃ . The mixture was transferred to a separation funnel with the aid OfCH ₂ Cl ₂ (30 mL). The organic phase was separated and the aqueous phase was extracted further with CH ₂ Cl ₂ (5 x 10 mL). The collected organic phases were dried over MgSO ₄ . Evaporation of the solvents yielded the crude l-(2,4- dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl- N-(5-methylpyridin-2-yl)- lH-pyrazole-3 - carboxamide (83 mg, 0.18 mmol, 99 %) as a white solid of sufficient purity for the next step. ¹ H NMR (500 MHz, MeOD-THF-^ (1:1)) δ 8.17 (d, IH, J=8.4 Hz), 8.05 (s, IH),

7.58 (d, IH, J=9.0 Hz), 7.54 (s, IH), 7.45 (d, IH, J=8.4 Hz), 7.39 (d, IH, J=8.5 Hz), 6.97 (d, 2H, J=8.7 Hz), 6.67 (d, 2H, J=8.7 Hz), 2.30 (s, 3H), 2.24 (s, 3H). Step G 4-( 1 -(2,4-dichlorophenyl)-4-methyl-3- { [Y 5-methylpyridin-2-yl)amino ^' |carbonyl} - 1 H-pyrazol-5 -ypphenyl 3 -methylbutane- 1 -sulfonate The crude l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-(5-met hylpyridin-2- yl)-lH-pyrazole-3-carboxamide (0.076 g, 0.17 mmol) was suspended in anhydrous CH ₂ Cl ₂ (1.7 mL) under an atmosphere of Ar and triethylamine (35 μL, 25 mg, 0.25 mmol) was added in one portion. Upon cooling to 0 ⁰ C 3-methylbutane-l-sulfonyl chloride (34 mg, 0.20 mmol) was added dropwise during one min. When the addition had been completed the ice bath was removed and the reaction mixture was allowed to reach ambient temperature. After stirring overnight the mixture was transferred to a separation funnel with the aid OfCH ₂ Cl ₂ (30 mL). H ₂ O (30 mL) was added. The organic phase was separated and the aqueous phase was extracted further with CH ₂ Cl ₂ (3 x 10 mL). The collected organic phases were dried over MgSO ₄ . Upon evaporation of the solvents the obtained residue was purified by column chromatography (silica gel, EtOAc-CH ₂ Cl ₂ , 0-10 %) to yield the desired 4-(l-(2,4-dichlorophenyl)-4-methyl-3-{[(5-methylpyridin-2- yl)amino]carbonyl}-lH-pyrazol-5-yl)phenyl 3 -methylbutane-1 -sulfonate (69 mg, 0.12 mmol, 70 %) as a colourless, viscous oil. ¹ H νMR (500 MHz, CDCl ₃ ) δ 9.38 (s, IH), 8.27 (d, IH, J=8.4 Hz), 8.14 (s, IH), 7.56 (d, IH, J=8.4 Hz), 7.45 (s, IH), 7.34 (d, IH, J=8.4 Hz), 7.31 (d, IH, J=8.3 Hz), 7.27 (d, 2H, J=8.5 Hz), 7.21 (d, 2H, J=8.8 Hz), 3.27 (m, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 1.88 (m, 2H), 1.77 (m, IH), 0.98 (d, 6H, J=6.6 Hz). HRMS Calcd for [C ₂₈ H ₂₈ C1 ₂ ν ₄ O ₄ S+H] ⁺ : 587.1287. Found: 587.1332. Example 10 3,3,3-Trifluoro-propane-l-sulfonic acid 4-[2-f2,4-dichlorophenyl)-4-methyl-5-(5-methyl- pyridin-2-ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester

The crude l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl- N-(5-methylpyridin-2- yl)-lH-pyrazole-3-carboxamide, Ex. 9, Step F (0.100 g, 0.221 mmol) was suspended in anhydrous CH ₂ Cl ₂ (2.2 mL) under an atmosphere of Ar and triethylamine (65 μL, 47 mg, 0.47 mmol) was added in one portion. Upon cooling to 0 °C 3,3,3-trifluoropropane-l- sulfonyl chloride (65 mg, 0.33 mmol) was added dropwise during ca. 5 min. When the addition had been completed the ice bath was removed and the reaction mixture was allowed to reach ambient temperature. After stirring overnight the mixture was transferred

to a separation funnel with the aid OfCH ₂ Cl ₂ (30 mL). H ₂ O (30 mL) was added. The organic phase was separated and the aqueous phase was extracted further with CH ₂ Cl ₂ (2 x 10 mL). The collected organic phases were dried over MgSO ₄ . Upon evaporation of the solvents the obtained residue was purified by column chromatography (silica gel, EtOAc- s CH ₂ Cl ₂ , 0-5 %) to yield the 4-(l-(2,4-dichlorophenyl)-4-methyl-3- {[(5-methylpyridin-2- yl)amino]carbonyl}-lH-pyrazol-5-yl)phenyl 3,3,3-trifluoropropane-l-sulfonate (88 mg, 0.14 mmol, 65 %) as a colourless, viscous oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.41 (s, IH), 8.28 (d, IH, J=8.2 Hz), 8.14 (s, IH), 7.58 (d, IH, J=8.5 Hz), 7.46 (s, IH), 7.38-7.30 (m, 2H), 7.30-7.20 (m, 4H), 3.58-3.44 (m, 2H), 2.90-2.74 (m, 2H), 2.46 (s, 3H), 2.33 (s, 3H). o HRMS Calcd for [C ₂₆ H ₂₁ Cl ₂ F ₃ N ₄ O ₄ SS-H] ⁺ : 613.0691. Found: 613.0724. Example 11

(-)-4-[l-(2,4-dichlorophenyl)-3-f{[cis-2-hydroxycyclohexy l1amino}carbonyl)-4-methyl- lH-pyrazol-5-yllphenyl 3,3 ,3-trifluoropropane- 1 -sulfonate The enantiomer was purified by preparatory ηPLC (Chiralpak AD column, heptane:IPA 5 80:20) from Ex.3 step G to give an almost white powder (661 mg, ee=98.6%)

[«£° = ~ ⁷ - ⁵ ( ^{c L07} _> acetonitrile). ¹ H NMR (399.964 MHz) δ 7.39 (s, IH), 7.30-7.15 (m, 7H), 4.17-4.07 (m, IH), 4.05-3.99 (m, IH), 3.50-3.43 (m, 2H), 2.84-2.70 (m, 2H), 2.35 (s, 3H), 2.05-1.90 (br, IH), 1.80-1.50 (m, 6H), 1.50-1.35 (m, 2H). HRMS Calcd for [C ₂₆ H ₂₆ Cl ₂ F ₃ N ₃ O ₅ SH-H] ⁺ : 620.100. Found: 620.097. 0 Example 12

(+)-4-[l-(2,4-dichlorophenyl)-3-({[cis-2-hydroxycyclohexy l]amino)carbonyl)-4-methyl- lH-pyrazol-5-yliphenyl 3 ,3 ,3-trifluoropropane- 1 -sulfonate

The enantiomer was purified by preparatory ηPLC (Chiralpak AD column, heptane:IPA 80:20) from Ex.3 step G to give an almost white powder (634 mg, ee=99.8%). 5 [af° = +7.3 (c 1.32, acetonitrile). ¹ H NMR (399.964 MHz) δ 7.39 (s, IH), 7.30-7.15 (m, 7H), 4.17-4.07 (m, IH), 4.05-3.99 (m, IH), 3.50-3.43 (m, 2H), 2.84-2.70 (m, 2H), 2.35 (s, 3H), 2.05-1.90 (br, IH), 1.80-1.50 (m, 6H), 1.50-1.35 (m, 2H). HRMS Calcd for [C ₂₆ H ₂ 6C1 ₂ F ₃ N ₃ O ₅ S+H] ⁺ : 620.100. Found: 620.099. Example 13 0 4-[l-(2,4-dichlorophenyl)-3-({r3-(dimethylamino)cyclohexyl]a mino}carbonyl)-4-methyl- lH-pyrazol-5-yllphenyl 3,3,3-trifluoropropane-l-sulfonate

Step A: N-(3-aminocyclohexyl)-5-r4-( ^' b6nzyloxy)phenyl1-l-f2,4-diclilorophenyl)-4- methyl-lH-pyrazole-3-carboxamide

Oxalyl chloride (2 ml) was added to 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-carboxylic acid, prepare as in Ex. 3, Step D (400 mg, 0.88 mmol) in DCM (10 ml). One drop of DMF was added and the reaction continued at room temperature for 50 minutes. The solvent and excess oxalyl chloride was evaporated and the mixture dissolved in DCM (100 ml) and added dropwise to 1,3-cyclohexanediamine (2.01 g, 17.65 mmol) in DCM/K ₂ CO ₃ (10%, aq) (1 : 1, 40 ml). The phases were separated and the organic phase washed with water and dried over MgSO ₄ (538 mg, crude). MS m/z 549, 551, 553 (M+η) ⁺ .

Step B: S44-0)enzyloxy>phenyl1-l-f2.4-dichlorophenylV.V-r3- (dimethylamino)cyclohexyl]-4-methyl-lH-pyrazole-3-carboxamid e iV-(3-aminocyclohexyl)-5-[4-(benzyloxy)phenyl]-l-(2,4-dichlo rophenyl)-4-methyl-lH- pyrazole-3-carboxamide (231 mg, crude) was dissolved/suspended in 5 ml acetonitrile. Formaldehyde (160 μl, 36%, aq) and NaBH ₃ CN (43 mg, 2.03 mmol) were added and the reaction continued at room temperature for Ih. 3M NaOH (aq) was added untill pH=10 and the mixture stirred for Ih. DCM and water were added. The phases separated and the organic phase washed with water and dried over MgSO ₄ . (240 mg, crude). MS m/z 577, 579, 581 (M+H) ⁺ . Step C: l-(2,4-dichlorophenyl)-N-[3-(dimethylamino)cyclohexyll-5-(4- hydroxyphenyl)-4- methyl-lH-pyrazole-3-carboxamide

Dimethyl sulfide (305 μl, 4.16 mmol) and boron trifluoride diethyl etherate (527 μl, 4.16 mmol) were added to 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-N-[3- (dimethylamino)cyclohexyl]-4-methyl-lH-pyrazole-3-carboxamid e (240 mg, crude) in DCM (5 ml). The reaction was continued at room temperature for 91 hours. Water was added and the phases separated. The water phase was extracted with ethylacetate. The organic phase was washed with water and dried over MgSO ₄ (227 mg, crude). MS m/z 487, 489, 491 (M+η) ⁺ . Step D: 4- [ ^" 1 -(2 ,4-dichlorophenyl ^' )-3 -( { [3 -f dimethylaminolcyclohexyl] amino I carbonyl)-4- methyl- 1 H-pyrazol-5-yl]phenyl 3,3,3 -trifluoropropane- 1 -sulfonate

A solution of 3, 3, 3 -trifluoropropane- 1-sulfonyl chloride (166 mg, 0.85 mmol) in DCM (2 ml) was added to a mixture of l-(2,4-dichlorophenyl)-N-[3-(dimethylamino)cyclohexyl]-5-

(4~hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxamide (227 mg, crude) and TEA (97 μl, 0.70 mmol) in DCM (6 ml) at -78 ⁰ C, under N ₂ (g). The reaction was continued at -78 ⁰ C for 1 hour. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . (241 mg, crude). MS m/z 641, 649, 651 (M+η) ⁺ . Example 14

4-[l-(2,4-dichlorophenyl)-3-({rtrans-3-fdimethylamino)cvcloh exyllamino}carbonyl)-4- methyl- lH-pyrazol-5-yl]phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate The trans racemic mixture was separated from Ex. 13 Step D by prep LC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 95% acetonitrile) to give a white powder after freeze drying. (26 mg, 10% yield for 4 steps). ¹ H NMR (399.964 MHz) δ 7.45-7.12 (m, 7H), 6.96 (d, IH), 4.48-4.38 (br, IH), 3.52-3.40 (m, 2H), 2.84-2.68 (m, 2H), 2.50-2.40 (br, IH), 2.35 (s, 3H), 2.30 (s, 6H), 2.00-1.35 (m, 8H). HRMS Calcd for [C ₂₈ H _3I Cl ₂ F ₃ N ₄ O ₄ S+H] ⁺ : 647.147. Found: 647.148. Example 15 4-ri-(2,4-dichlorophenyl)-3-({| ^" cis-3-(dimethylamino)cvclohexyl]ammolcarbonyl)-4- methyl-lH-pyrazol-5-yl]phenyl 3, 3,3-trifluoropropane-l -sulfonate The cis racemic mixture was separated from Ex 13 Step D by prep LC (lcromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, product came at 100% acetonitrile) to give a white powder after freeze drying. (13 mg, 5.3% yield for 4 steps). ¹ H NMR (399.964 MHz) δ 7.43-7.15 (m, 7H), 7.02-6.90 (br, IH), 4.05-3.91 (m, IH), 3.50-3.41 (m, 2H), 2.85-2.70 (m, 2H), 2.36 (s, 3H), 2.35-2.28 (m, IH), 2.26 (s, 6H), 2.25-1.80 (m, 4H), 1.45-1.05 (m, 4H). HRMS Calcd for [C _2g H ₃ iCl ₂ F ₃ N ₄ O ₄ S+H] ⁺ : 647.147. Found: 647.148. Example 16 4- [3 -( { [cis-3 -aminocyclohexyliamino) carbonyl)-! -(2,4-dichlorophenyl)-4-methyl- IH- pyrazol-5-yl]phenyl 3,3 ,3 -trifluoropropane- 1 -sulfonate hydrochloride

Step A: N-( ^" 3-aminocyclohexyl)-5-[4-(benzyloxy)phenyll-l-f2,4-dichloroph enyl)-4- methyl- 1 H-pyrazole-3 -carboxamide

Oxalyl chloride (1 ml) was added to 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-carboxylic acid, prepared as in Ex. 3, Step D (200 mg, 0.44 mmol) in DCM (5 ml). One drop of DMF was added and the reaction continued at room temperature for 1 hour. The solvent and excess oxalyl chloride was evaporated and the mixture dissolved in DCM (50 ml) and added dropwise to 1,3-cyclohexanediamine (1.01 g,

8.82 mmol) in DCM/K ₂ CO ₃ (10%, aq) (1:1, 20 ml). The phases were separated and the organic phase washed with water and dried over MgSO ₄ (259 mg, crude).

MS m/z 549, 551, 553 (M+H) ⁺ .

Step B: N-(3-aminocyclohexyl)-l-( ^' 2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl- lH-pyrazole-3-carboxamide

Dimethyl sulfide (346 μl, 4.71 mmol) and boron trifluoride diethyl etherate (597 μl, 4.71 mmol) were added to N-(3-aminocyclohexyl)-5~[4-(benzyloxy)phenyl]-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxamide (259 mg, crude) in DCM (5 ml). The reaction was continued at room temperature for 70 hours. Water was added and the phases separated. The water phase was extracted with ethylacetate. The organic phase was washed with water and dried over MgSO ₄ (207 mg, crude). MS m/z 459, 461, 463 (M+η) ⁺ .

Step C: N-(3-aminocyclohexyl)-5-(4-{| ^" te?t-butyl(dimethyl)silyl1oxy|phenyl)-l-(2,4- dichlorophenyl)-4-methyl- lH-pyrazole-3 -carboxamide A solution of fe/Y-butyl(chloro)dimethylsilane (538 mg, 3.57 mmol) in DCM (2 ml) was added to a suspension of N-(3-aminocyclohexyl)-l-(2,4-dichlorophenyl)-5-(4- hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxamide (207 mg, crude) in DCM (5 ml) and TEA (754 μl, 5.41 mmol). The reaction was continued at room temperature for 24 hours. Water was added, the phases separated and the organic phase washed with water and dried over MgSO ₄ (454 mg, crude). MS m/z 573, 575, 577 (M+η) ⁺ .

Step D: te7^-butvU3-f{[ ^" 5-(4-{Cfe^-butyl(dimethyl)silylloxy)phenyl)-l-f2.4- dichlorophenyl ^' )-4-methyl-lH-pyrazol-3-yl]carbonvUamino)cvclohexyllcarbamat e

A solution of di-tørt-butyl dicarbonate (163 mg, 0.75 mmol) in TηF (ImI) was added to N-

(3-aminocyclohexyl)-5-(4-{[te7t-butyl(dimethyl)silyl]oxy}phe nyl)-l-(2,4-dichlorophenyl)- 4-methyl-lH-pyrazole-3 -carboxamide (454 mg, crude) in TηF (2 ml). The reaction was continued at room temperature for 2.5 hours. The solvent was evaporated at reduced pressure. Water and DCM were added. The phases were separated and the organic phase washed with νaOη (0.2 M, aq) and water and dried over MgSO ₄ . The product was further purified by flash chromatography (SiO ₂ , heptane/ethyl acetate, product came at 100% ethyl acetate (149 mg, 50% yield for 4 steps). MS m/z 673, 675, 677 (M+η) ⁺ .

Step E: fert-butyl [3-(IfI -( ^' 2,4-dichlorophenyl ^s )-S-(4-hvdroxyphenvl)-4-methvl-lH- pyrazol-3-yl1carbonyllamino)cvclohexyllcarbamate

TBAF (IM in THF, 3.2 ml) and acetic acid (142 μl, 2.48 mmol) were added to tert-hutyl [3-( { [5-(4- { |>rt-butyl(dimethyl)silyl]oxy} phenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- IH- pyrazol-3-yl]carbonyl}amino)cyclohexyl]carbamate (143 mg, 0.21 mmol) in TηF (5 ml) under N2(g). The reaction was continued at room temperature under N2(g) for 1 hour. Silica gel was added. The mixture filtered through a small silica plug. The plug was washed with ethyl acetate. The solution was washed with water and dried over MgSO ₄ (123 mg, crude). MS m/z 559, 561, 563 (M+η) ⁺ .

Step F: 4-| ^' 3-( ^' ( ^' {3-[(ter^-butoxycarbonyl)amino1cyclohexyl}amino)carbonyl1-l- ( ^' 2,4- dichlorophenyl)-4-methyl-lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate A solution of 3,3,3 -trifluoropropane-1-sulfonyl chloride (100 mg, 0.51 mmol) in DCM (2 ml) was added to a mixture of tør^-butyl [3-({[l-(2,4-dichlorophenyl)-5-(4- hydroxyphenyl)-4-methyl-lH-pyrazol-3-yl]carbonyl}amino)cyclo hexyl]carbamate (123 mg, crude) and TEA (50 μl, 0.36 mmol) in DCM (3 ml) at -78 ⁰ C, under N ₂ (g). The reaction was continued at -78 ⁰ C for 50 minutes. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . (177 mg, crude). MS m/z 719, 721, 723 (M+η) ⁺ .

Step G 4-[3-| ^" ({cis-3-[(fe?^-butoxycarbonyl)amino]cyclohexyl}amino)carbony l]-l-(2,4- dichlorophenyl)-4-rnethyl- lH-pyrazol-5-yl1phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate The product was separated from its isomer by prep LC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 100% acetonitrile) to give a white powder after freeze drying. (60 mg, 39% yield for 2 steps). ¹ H NMR (399.964 MHz) δ 7.42-7.14 (m, 7H) ₅ 6.77 (d, IH), 4.40 (d, IH), 4.04-3.91 (m, IH), 3.60-3.42 (br, IH), 3.50-3.42 (m, 2H), 2.84-2.68 (m, 2H), 2.34 (s, 3H), 2.35-1.65 (m, 4H), 1.40 (s, 9H), 1.45-0.90 (m, 4H). MS m/z 719, 721, 723 (M+H) ⁺ . Step H 4-[3-r{[cis-3-aminocyclohexyl1amino}carbonyl)-l-(2,4-dichlor ophenyl)-4-methyl- lH-pyrazol-5-yi ^~ |phenyl 3,3,3-trifluoropropane-l-sulfonate hydrochloride HCl (4M in dioxane, 5 ml) was added to 4-[3-[({cis-3-[(tert-butoxycarbonyl)- amino]cyclohexyl}amino)carbonyl]-l-(2,4-dichlorophenyl)-4-me thyl-lH-pyrazol-5- yl]phenyl 3,3,3-trifluoropropane-l-sulfonate (60 mg, 0.08 mmol) and reacted at room temperature for 45 minutes. The solvent was evaporated and the compound freeze-dried (54 mg, 99%). ¹ H NMR 499.962 MHz) δ 7.61-7.32 (m, 7H), 4.04-3.94 (m, IH), 3.75-3.70 (m, 2H), 3.28-3.20 (m, IH), 2.94-2.82 (m, 2H), 2.34 (s, 3H), 2.38-2.30 (br, IH), 2.10-1-94

(m, 3H), 1.60-1.30 (m, 4H). HRMS Calcd for [C ₂₆ H ₂₇ Cl ₂ F ₃ N ₄ O ₄ S+H] ⁺ : 619.116. Found:

619.117.

Example 17

4- [3 -( { [trans-3 -aminocyclohexyl] amino } carbonyl)- 1 -(2 ,4-dichlorophenyl)-4-methyl- 1 H- pyrazol-S-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate hydrochloride

Step A: 4-[3-[ ^' ({trans-3-f(/er^-butoxycarbonyl)amino1cvclohexyl|amino ^' )carbonyl1-l-f2,4- dichlorophenyl)-4-methyl-lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate The trans racemic mixture was separated from 4-[3-[({3-[(ter/-butoxycarbonyl)amino]- cyclohexyl}amino)carbonyl]-l-(2,4-dichlorophenyl)-4-methyl-l H-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate, Ex. 16, Step F by prep LC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 100% acetonitrile) to give a white powder after freeze drying. (31 mg, 20% yield for 2 steps).

¹ HNMR (399.964 MHz) δ 7.42-7.14 (m, 7H), 6.94 (d, IH), 4.70-4.62 (br, IH), 4.30-3.20 (m, IH), 3.90-3.80 (br, IH), 3.50-3.42 (m, 2H), 2.84-2.68 (m, 2H), 2.35 (s, 3H), 1.85-1.40 (m, 8H), 1.40 (s, 9H). MS m/z 719, 721 , 723 (M+H) ⁺ .

Step B 4-[3-({[trans-3-ammocvclohexyl]amino}carbonyl)-l-(2,4-dichlo rophenyl)-4- methyl- lH-pyrazol-5-yl]phenγl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate hydrochloride HCl (4M in dioxane, 3 ml) was added to 4-[3-[({trans-3-[(^er?-butoxycarbonyl)- amino]cyclohexyl}amino)carbonyl]-l-(2,4-dichlorophenyl)-4-me thyl-lH-pyrazol-5- yljphenyl 3,3,3-trifluoropropane-l-sulfonate (31 mg, 0.04 mmol) and reacted at room temperature for 1 hour. The solvent was evaporated and the compound freezedried (28 mg, 99%). ¹ H NMR (499.962 MHz) δ 7.62-7.33 (m, 7H), 4.38-4.33 (m, IH), 3.75-3.70 (m, 2H), 3.56-3.48 (m, IH), 2.94-2.82 (m, 2H), 2.34 (s, 3H), 2.22-1.55 (m, 8H). HRMS Calcd for [C ₂₆ H ₂₇ Cl ₂ F ₃ N ₄ O ₄ S+H] ⁺ : 619.116. Found: 619.117. Example 18 l-(2,4-dichlorophenyl)-4-methyl-N-piperidin-l-yl-5-[4-(3,3,3 - trifluoropropoxy)phenyl1-lH-pyrazole-3-carboxamide

Step A Ethyl 1 -(2,4-dichlorophenyl)-5-(4-hvdroxyphenyl)-4-methyl- lH-pyrazole-3 - carboxylate Ethyl 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4-methyl-lH-p yrazole-3- carboxylate, Ex 9, Step D (4.82 g, 10 mmol) was dissolved in 80 ml HBr (33 % in acetic acid) and stirred overnight at room temperature with exclusion of light. The solvents were evaporated and the residue coevaporated twice with ethanol. The residue was dissolved in

EtOAc and washed with water basified with triethylamine and then brine. The organic layer was dried over Na ₂ SO ₄ and evaporated to give ethyl l-(2,4-dichlorophenyl)-5-(4- hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxylate (4.54 g) as a brown, viscous oil of sufficient purity for the next step. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.45-7.23 (m, 3H) ₅ 6.98 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 4.43 (q, J=7.1 Hz, 2H), 2.33 (s, 3H), 1.40 (t, J=7.1 Hz, 3H)

Step B Ethyl l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3-trifluoropropoxy )phenyl]-lH- pyrazole-3-carboxylate Ethyl l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyraz ole-3-carboxylate (1.51 g, 3.87 mmol), 3,3,3-trifluoro-l-propanol (2.21 g, 19.4 mmol) and triphenylphosphine (5.08 g, 19.4 mmol) were dissolved in anhydrous TηF (20 ml). Then DEAD (3.2 ml of a ca. 40% solution in toluene, d=0.95, 7.76 mmol) was added. The resulting mixture warms and was stirred at room temperature for 2Oh, then an additional portion of DEAD (3.2 ml of a ca. 40% solution in toluene, d=0.95, 7.76 mmol) was added and stirring continued for 7h, then again DEAD (1.6 ml of a ca. 40% solution in toluene, d=0.95, 3.88 mmol) was added and stirring continued for 16 h. The solvents were evaporated, the residue dissolved in 20 ml EtOAc and 80 ml of hexanes were added. Precipitation occurs. The resulting mixture was sonicated for ca. 5 min, the solid was filtered off and washed with hexanes/EtOAc 4:1. The combined filtrates were evaporated and the residue purified by column chromatography (silica gel, hexanes/EtOAc, 10-20 %) to yield ethyl l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3-trifluoropropoxy )phenyl]-lH- pyrazole-3-carboxylate (1.81 g, 3.34 mmol, 86%) as a yellowish foam which contains ca. 10% of diethyl hydrazine- 1,2-dicarboxylate, which does not interfere with the next transformation. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.22 (m, 3H), 7.00 (d, J=8.7 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 4.43 (q, J=7.1 Hz, 2H), 4.18-4.13 (m, 2H), 2.65-2.55 (m, 2H), 2.30 (s, 3H), 1.40 (t, 1=7 λ Ez, 3H)

Step C l-(2,4-dichlorophenyl)-4-methyl-5-r4-f3,3.3-trifluoropropoxy )phenyll-lH- pyrazole-3-carboxylic acid Ethyl l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3-trifluoropropoxy )phenyl]-lH-pyrazole- 3-carboxylate (700 mg, 1.29 mmol, ca. 90% pure) was dissolved in a mixture of 15 ml TηF and 15 ml EtOH, then KOη (870 mg, 15.5 mmol) dissolved in 10 ml water was added and the resulting mixture stirred at 50 ⁰ C. After Ih the reaction mixture was cooled

to room temperature and the solvents were evaporated. The residue was partitioned between EtOAc and IN HCl and after phase separation the organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated to give l-(2,4-dichlorophenyl)-4-methyl-5-[4- (3,3,3-trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxylic acid (640 mg, 1.28 mmol, 99%) as a yellowish foam which was sufficiently pure for the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.23 (m, 3H), 7.05 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 4.18-4.13 (m, 2H), 2.65-2.55 (m, 2H), 2.30 (s, 3H)

Step D 1 -(2,4-dichloroρhenyl ^' )-4-methyl-5-[ ^" 4-(3 ,3 ,3-trifluoropropoxy)phenyll- IH- pyrazole-3-carbonyl chloride l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3-trifluoropropoxy )phenyl]-lH-pyrazole-3- carboxylic acid (640 mg, 1.28 mmol) was dissolved in 10 ml DCM, then oxalyl chloride (200 μl, 2.36 mmol) was added, followed by 10 μl DMF. The resulting mixture was stirred for 90 min at room temperature, then the solvents were evaporated and the residue dried in oil pump vacuum to give l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carbonyl chloride (664 mg, 1.39 mmol, 99%) as a yellowish foam which was used without further purification in the next step. Step E General procedure for the synthesis of l-(2,4-dichlorophenyl)-4-methyl-5-[4- 0.3,3-trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamides To a mixture of amine or amine hydrochloride (0.3 mmol) and 100 μl pyridine in 1 ml DCM was added crude l-(2,4-dichlorophenyl)-4-methyl-5-[4-(3,3,3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carbonyl chloride (96 mg, 0.2 mmol) in 1 ml DCM and the resulting mixture stirred at room temperature for 2h30min. The reaction mixture was washed with 2 ml of sat. NaHCO ₃ and after phase separation filtered through a phase separator. The solvents were evaporated and the residue purified by preparative HPLC eluting on a reverse-phase column with 5 to 100% acetonitrile in 0.1 M NH ₄ Ac. l-f2,4-dichlorophenyl)-4-methyl-N-piperidin-l-yl-5-[ ^' 4-(3,3,3-trifluoropropoxy)phenyll- lH-ρyrazole-3-carboxamide

Using piperidin-1 -amine hydrochloride as amine component gave l-(2,4-dichlorophenyl)~ 4-methyl-N-piperidin-l-yl-5-[4-(3,3,3-trifluoropropoxy)pheny l]-lH-pyrazole-3- carboxamide (36 mg, 65 μmol, 33%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 7.65 (s, IH), 7.44-7.27 (m, 3H), 7.06 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 4.21-4.17

(m, 2H), 2.90-2.86 (m, 4H), 2.67-2.59 (m, 2H), 2.38 (s, 3H), 1.80-1.75 (m, 4H), 1.47-1.43 (m, 2H). HRMS Calcd for [C ₂₅ H ₂₅ Cl ₂ F ₃ N ₄ O^H] ⁺ : 541.1385. Found: 541.1365. Example 19 N-cvclohexyl-l-f2,4-dichlorophenyl ^N )-4-methyl-5-[4-f3,3 ₁ 3-trifluoropiOpoxy)phenyl1-lH- pyrazole-3-carboxamide

Using cyclohexylamine as amine component gave N-cyclohexyl-l-(2,4-dichlorophenyl)-4- methyl-5-[4-(3,3,3-trifluoropropoxy)phenyl]-lH-pyrazole-3-ca rboxamide (43 mg, 80 μmol, 40%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 7.44-7.28 (m, 3H), 7.07 (d, J=8.7 Hz, 2H), 6.86-6.83 (m, 3H), 4.21-4.17 (m, 2H), 4.01-3.93 (m, IH), 2.68-2.59 (m, 2H), 2.38 (s, 3H), 2.06-2.02 (m, 2H), 1.79-1.75 (m, 2H), 1.67-1.64 (m, IH), 1.47-1.37 (m, 2H), 1.34-1.16 (m, 3H) HRMS Calcd for [C ₂₆ H ₂₆ Cl ₂ F ₃ N ₃ OrHH] ⁺ : 540.1432. Found: 540.1439. Example 20 l-(2,4-dichlorophenyl)-N-rfcisV2-hvdroxycvclohexyl1-4-methyl -5-i:4-(3,3 ₁ 3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamide

Using cis-2-aminocyclohexanol hydrochloride as amine component gave l-(2,4- dichlorophenyl)-N-[(cis)-2-hydroxycyclohexyl]-4-methyl-5-[4- (3,3,3~ trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamide (32 mg, 58 μmol, 29%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 7.43-7.28 (m, 3H) ₅ 7.23 (d, J=8.2 Hz, IH), 7.07 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 4.19-4.16 (m, 3H), 4.07-4.05 (m, IH), 2.67- 2.59 (m, 4H), 2.37 (s, 3H), 2.32 (s, IH), 1.81-1.45 (m, 6H). HRMS Calcd for [C ₂₆ H ₂₆ Cl ₂ F ₃ N ₃ O^H] ⁺ : 556.1382. Found: 556.1398. Example 21 l-(2,4-dichlorophenyl)-N-(4,4-difluorocyclohexyl)-4-methyl-5 -[4-(3,3,3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamide

Using 4,4-difluorocyclohexylamine as amine component gave l-(2,4-dichlorophenyl)-iV- (4,4-difluorocyclohexyl)-4-methyl-5-[4-(3,3,3-trifluoropropo xy)phenyl]-lH-pyrazole-3- carboxamide (54 mg, 94 μmol, 47%) as a colorless solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.49-7.28 (m, 3H), 7.07 (d, J=8.7 Hz, 2H), 6.88-6.84 (m, 3H), 4.20-4.17 (m, 2H), 4.12-4.10 (m, IH), 2.68-2.59 (m, 2H), 2.38 (s, 3H), 2.13-2.10 (m, 4H), 1.98-1.86 (m, 2H), 1.71-1.64 (m, 2H). HRMS Calcd for [C ₂₆ H ₂₄ Cl ₂ F ₅ N ₃ O ₂ H-H] ⁺ : 576.1244. Found: 576.1262.

Example 22 l-(2.4-dichlorophenylV4-methyl-iV-r5-methylpyridin-2-yl)-5-r 4-r33,3- trifluoropropoxy)phenyl]-lH-pyrazole-3-carboxamide

Using 2-amino-5-picoline as amine component gave l-(2,4-dichlorophenyl)-4-methyl-N- (5-methylpyridin-2-yl)-5-[4-(3,3,3-trifluoropropoxy)phenyl]- lH-pyrazole-3-carboxamide (52 mg, 95 μmol, 47%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 9.39 (s, IH), 8.28 (d, J=8.3 Hz, IH), 8.14 (s, IH), 7.57-7.55 (m, IH), 7.45-7.28 (m, 3H), 7.10 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 4.22-4.18 (m, 2H), 2.68-2.61 (m, 2H), 2.44 (s, 3H), 2.32 (s, 3H)HRMS Calcd for [C ₂₆ H _2I C1 ₂ F ₃ ν ₄ O ₂ +H] ⁺ : 549.1072. Found: 549.1074. Example 23

4-[ 1 -(2-chlorophenvl)-3 - { [Y 1 ,S,2i;y2-hvdroxycvclohexyl ^" ]carbamovU -4-methyl- IH- pyrazol-5-yllphenyl 3,3,3-trifluoropropane-l-sulfonate and 4-[l-(2-chlorophenyl ^" )-3- { [( 1 J?,2i$ ^r )-2-hvdroxycvclohexyl]carbamoyU -4-methyl- lH-pyrazol-5-yl ^" |phenyl 3,3,3- trifluoropropane- 1 -sulfonate Step A: Lithium- 1 -[4-(benzyloxy)phenyl] -4-ethoxy-2-methyl-3 ,4-dioxobut- 1 -en- 1 -olate Pύ7"α-benzyloxypropiophenone (3.84 g, 15.98 mmol) in dry TηF (30 ml) was added to a solution of lithium bis(trimethylsilyl)amide (17.6 ml, IM in hexanes) in diethyl ether (100 ml) at -78 ⁰ C, under N2 (g). The reaction was continued at -78°C, under N2 (g) for 1 hour. Ethyl oxalate (2.44 ml, 18.04 mmol) was added. The reaction was continued at room temperature for 19 hours. The mixture was filtered and the filtrate washed with

TηF/diethyl ether 1:5 and diethyl ether and evaporated under reduced pressure (3.66 g crude).

Step B: Ethyl 5-[4-(benzyloxy)phenyl]-l-(2-chlorophenyl)-4-methyl-lH-pyraz ole-3- carboxylate Ethyl 3-[4-(benzyloxy)phenyl]-2-methyl-3-oxopropanoate lithium salt or lithium-l-[4- (benzyloxy)phenyl]-4-ethoxy-2-methyl-3,4-dioxobut-l-en-l-ola te (3.66 g, crude) and (2- chlorophenyl)hydrazine hydrochloride (1.30 g, 7.26 mmol) were mixed in ethanol (50 ml) and reacted at room temperature for 16 hours. The solvent was evaporated and the mixture was suspended in acetic acid (40 ml). The temperature was increased to 100 ⁰ C and the reaction continued for 4 hours. The solvent was evaporated. Water and DCM were added. The phases separated and the organic phase washed with water and dried over MgSO ₄ . The

product was purified further by flash chromatography (SiO ₂ , heptane/ethyl acetate, product came at 30% ethyl acetate) (771 mg, 10% for two steps).

¹ H NMR (399.964 MHz) δ 7.50-7-25 (m, 9H), 7.10 (d, 2H), 6.90 (d, 2H), 5.01 (s, 2H),

4.46 (q, 2H), 2.36 (s, 3H), 1.43 (t, 3H). MS m/z 447, 449 (M+H) ⁺ . Step C: 5-f4-(benzyloxy)phenyl]-l-(2-chlorophenyl)-4-methyl-lH-pyraz ole-3-carboxylic acid

Ethyl 5-[4-(benzyloxy)phenyl]-l-(2-chlorophenyl)-4-methyl-lH-pyraz ole-3-carboxylate

(771 mg, 1.73 mmol) and sodium hydroxide (2.93 g, 73.13 mmol) were reacted in water/ethanol (1:5, 60 ml) for 1 hour. The solvent was evaporated and the mixture suspended in water and neutralised with HCl (cone). The product was collected by filtration, washed with water and dried at reduced pressure (647 mg, crude).

¹ H NMR (399.964 MHz) δ 7.40-7.20 (m, 9H), 7.07 (d, 2H). 6.88 (d, 2H), 5.00 (s, 2H), 2.34

(s, 3H). MS m/z 419, 421 (M+H) ⁺ .

Step D: 2.2,2-trichloroethyl 5-r4-(benzyloxy)phenyll-l-(2-chlorophenyl)-4-methyl-lH- pyrazole-3 -carboxylate

Oxalyl chloride (1.5 ml) and 1 drop of DMF were added to a mixture of 5-[4-

(benzyloxy)phenyl]-l-(2-chlorophenyl)-4-methyl-lH-pyrazol e-3-carboxylic acid (632 mg, crude) in DCM (15 ml). The reaction was continued at room temperature for 1 hour. The solvent and excess oxalyl chloride were evaporated. The acid chloride was dissolved in DCM (10 ml) and added to a mixture of 2,2,2-trichloroethanol (325 mg, 12.18 mmol) and

DIPEA (350 μl, 2.01 mmol) in DCM (5 ml). DMAP (6 mg, 0.05 mmol) was added and the reaction continued at room temperature for 3 hours. Water was added. The phases were separated and the organic phase washed with water, NaOH (3M, aq), HCl (2M, aq) and water, and dried over MgSO ₄ (807 mg, crude). ¹ H NMR (399.964 MHz) δ 7.40-7.22 (m, 9H), 7.07 (d, 2H), 6.88 (d, 2H), 5.04 (s, 2H), 4.99

(s, 2H), 2.37 (s, 3H). MS m/z 549, 551, 553, 555 (M+H) ⁺ .

Step E: 2,2,2-trichloroethyl l-(2-chlorophenyl)-5-( ^' 4-hvdroxyphenyl)-4-methyl-lH- pyrazole-3 -carboxylate

2,2,2-Trichloroethyl 5-[4-(benzyloxy)phenyl]- 1 -(2-chlorophenyl)-4-methyl- lH-pyrazole- 3-carboxylate (807 mg, crude) was dissolved in HBr in acetic acid (33%, 10 ml) and reacted at room temperature for 1 hour. Ethanol was added and the mixture stirred for 1 hour. The solvent was evaporated. Methanol was added, the mixture neutralised with

NaHCO ₃ (5%, aq) and the solvent evaporated. Water and DCM were added. The phases were separated and the organic phase washed with water and dried over MgSO ₄ (627 mg, crude). ¹ H NMR (399.964 MHz) δ 7.36-7.20 (m, 4H), 6.96 (d, 2H), 6.69 (d, 2H), 6.10-5.60 (br, IH), 5.01 (s, 2H), 2.34 (s, 3H). MS m/z 459, 461, 463, 465 (M+H) ⁺ . Step F: 2.2,2-trichloroethyl l-(2-chlorophenyl)-4-methyl-5-(4- {[(3,3,3- trifluoropropyl)sulfonyl1oxylphenyl)-lH-pyrazole-3-carboxyla te 3,3,3-Trifluoropropane-l-sulfonyl chloride (350 mg, 1.78 mmol) in DCM (2 ml) was added to a mixture of 2,2,2-trichloroethyl l-(2-chlorophenyl)-5-(4-hydroxyphenyl)-4- methyl-lH-pyrazole-3-carboxylate (595 mg, crude) and TEA (250 μl, 1.79 mmol) in DCM (10 ml) at -78 ⁰ C, under N2(g). The reaction was continued at -78 ⁰ C for 1 hour. Water was added, the phases were separated and the organic phase was washed with water and dried (865 mg, crude). ¹ H NMR (399.964 MHz) δ 7.45-7.15 (m, 8H), 5.02 (s, 2H), 3.48-3.42 (m, 2H), 2.82-2.68 (m, 2H), 2.36 (s, 3H). MS m/z 619, 621, 623, 625 (MH-H) ⁺ . Step G: 1 -(2-chlorophenyl)-4-methyl-5-(4- { [ ^" (3 ,3 ,3-trifluoropropyl)sulfonylloxy} phenyl)- lH-pyrazole-3-carboxylic acid

Zinc dust (840 mg, 12.85 mmol) was added to a mixture of 2,2,2-trichloroethyl l-(2- chlorophenyl)-4-methyl-5-(4- { [(3 ,3 ,3 -trifluoropropyl)sulfonyl]oxy} phenyl)- lH-pyrazole- 3-carboxylate (865 mg, crude) in acetic acid (10 ml). The reaction was continued at room temperature for 1 hour. DCM was added and the mixture was filtered through Celite 521. The solvent was evaporated and the mixture dissolved in DCM and washed with HCl (IM, aq) and water, and dried over MgSO ₄ . The mixture was dried further by co-evaporation with toluene (599 mg, crude). ¹ H NMR (399.964 MHz) δ 7.13-6.80 (m, 8H), 3.20-3.10 (m, 2H), 2.54-2.38 (m, 2H), 2.06 (s, 3H). MS m/z 489, 491 (M+H) ⁺ . Step H: 4-[3-( chlorocarbonyD- 1 -(2-chlorophenyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3- trifluoropropane- 1 -sulfonate

Oxalyl chloride (1.5 ml) was added to l-(2-chlorophenyl)-4-methyl-5-(4-{[(3,3,3- trifluoropropyl)sulfonyl]oxy}phenyl)-lH-pyrazole-3-carboxyli c acid (599 mg, crude) in DCM (10 ml). One drop of DMF was added and the reaction continued at room temperature for 1.5 hours. The solvent and excess oxalyl chloride were evaporated at reduced pressure.

Step I: 4-π -f 2-chlorophenylV 3 - { |Y 1 ^.2i?)-2-hvdroxycvclohexyl1carbamoyll -4-methyl- 1 H- pyrazol-5-yliphenyl 3,3,3-trifluoropropane-l-sulfonate and 4-[ ^~ l-(2-chlorophenyl)-3-

{ r(li?,2^)-2-hvdroxycyclohexyl]carbamovU -4-methyl- lH-pyrazol-5-yliphenyl 3,3,3- trifluoropropane- 1 -sulfonate

4- [3 -Chlorocarbonyl)- 1 -(2-chlorophenyl)-4-methy 1- 1 H-pyrazol-5-yl]phenyl 3,3,3- trifluoroproρane-1 -sulfonate (207 mg, crude) suspended in DCM (3 ml) was added to cis- 2-aminocyclohexanol hydrochloride (81 mg, 0.53 mmol) in DCM/K ₂ CO3 (10%, aq) (1 :1, 6 ml). The reaction was continued at room temperature for 1 hour. The phases were separated and the organic phase was washed with water and dried. The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 96% acetonitrile) to give an almost white powder (135 mg, 43% yield for 7 steps). ¹ !! NMR (399.964 MHz) δ 7.32-7.07 (m, 9H), 4.08-3.97 (m, IH), 3.97-3.89 (m, IH), 3.40-3.32 (m, 2H), 2.74-2.58 (m, 2H), 2.28 (s, 3H), 1.70-1.25 (m, 9H). HRMS Calcd for [C ₂₆ H ₂₇ ClF ₃ N ₃ O ₅ S+^*: 586.139. Found: 586.142. Example 24 4-ri-(2-chlorophenyl)-3-(cyclohexylcarbamoyl)-4-methyl-lH-py razol-5-yllphenyl 3,3,3- trifluoropropane- 1 -sulfonate

4-[3-(chlorocarbonyl)-l-(2-chlorophenyl)-4-methyl-lH-pyrazol -5-yl]phenyl 3,3,3- trifluoropropane-1 -sulfonate, from Ex. 23, Step η (207 mg, crude) suspended in DCM (3 ml) was added to cyclohexylamine (167 mg, 1.68 mmol) in DCM/K2CO3 (10%, aq) (1:1, 6 ml). The reaction was continued at room temperature for 1 hour. The phases were separated and the organic phase was washed with water and dried. The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 100% acetonitrile) to give an almost white powder (155 mg, 51% yield for 7 steps). ¹ HNMR (399.964 MHz) δ 7.42-7.15 (m, 8H), 6.83 (d, IH), 4.00-3.86 (m, IH), 3.48-3.40 (m, 2H), 2.82-2.68 (m, 2H), 2.38 (s, 3H), 2.05-1.10 (m, 10H). HRMS Calcd for [C ₂₆ H ₂₇ C1F ₃ N ₃ O ₄ S+H] ⁺ : 570.144. Found: 570.146. Example 25

4-{l-(4-chloro-2-methylphenyl)-4-methyl-3-[(piperidin-l-y lamino)carbonyl]-lH-pyrazol- 5-yl}phenyl 3,3,3-trifluoropropane-l-surfonate Step A: Ethyl 3-[4-(benzyloxy)phenyll-2-methyl-3-oxopropanoate lithium salt (lithium- 1- [4-(benzyloxy)phenyl]-4-ethoxy-2-methyl-3,4-dioxobut-l-en-l- olate)

Pαrø-benzyloxypropiophenone (1.92 g, 7.99 mmol) in dry TηF (15 ml) was added to a solution of lithium bis(trimethylsilyl)amide (8.8 ml, IM in hexanes) in diethyl ether (50

ml) at -78 ⁰ C, under N ₂ (g). The reaction was continued at -78 ⁰ C, under N2 (g) for 1 hour. Ethyl oxalate (1.22 ml, 9.02 mmol) was added. The reaction was continued at room temperature for 21 hours. The mixture was filtered and the filtrate washed with THF/diethyl ether 1:5 and diethyl ether and dried at reduced pressure (1.09 g crude). Step B: Ethyl 5-f4-(benzyloxy)phenyll-l-(4-chloro-2-methylphenyl)-4-methyl -lH- pyrazole-3-carboxylate

Ethyl 3-[4-(benzyloxy)phenyl]-2-methyl-3-oxopropanoate lithium salt (lithium- 1 -[4- (benzyloxy)phenyl]-4-ethoxy-2-methyl-3,4-dioxobut-l-en-l-ola te) (1.09 g, crude) and (4- chloro-2-methylphenyl)hydrazine hydrochloride (0.846 g, 4.38 mmol) were mixed in acetic acid (20 ml) and reacted at room temperature for 17 hours. The temperature was increased to 100 ⁰ C and the reaction continued for 5 hours. The product was purified by flash chromatography (SiO ₂ , heptane/ethyl acetate, product came at 20% ethyl acetate) (577 mg, 15% for two steps). ¹ !! NMR (399.964 MHz) δ 7.40-7-20 (m, 5H), 7.12 (s, 3H), 6.99 (d, 2H), 6.87 (d, 2H), 4.99 (s, 2H), 4.42 (q, 2H), 2.32 (s, 3H), 1.89 (s, 3H), 1.39 (t, 3H). MS m/z 461, 463 (M+H) ⁺ .

Step C: 5-[4-(benzyloxy)phenyll-l-(4-chloro-2-methylphenyl)-4-methyl -lH-pyrazole-3- carboxylic acid

Ethyl 5-[4-(benzyloxy)ρhenyl]-l-(4-chloro-2-methylphenyl)-4-methy l-lH-pyrazole-3- carboxylate (577 mg, 1.25 mmol) and sodium hydroxide (2.15 g, 53.85 mmol) were reacted in water/ethanol (1:5, 60 ml) for 1 hour. The solvent was evaporated and the mixture suspended in water and neutralised with HCl (cone). The product was collected by filtration, washed with water and dried at reduced pressure (576 mg, crude). ¹ H NMR (399.964 MHz) δ 7.36-7.22 (m, 5H), 6.96-6.84 (m, 3H), 6.80-6.68 (4H), 4.89 (s, 2H), 1.99 (s, 3H), 1.56 (s, 3H). MS m/z 433, 435 (M+H) ⁺ . Step D: 2,2,2-trichloroethyl 5-[4-fbenzyloxy)phenyl]-l-f4-chloro-2-methylphenyl)-4- methyl- lH-pyrazole-3 -carboxylate

Oxalyl chloride (1.5 ml) and 1 drop of DMF were added to a mixture of 5-[4- (benzyloxy)phenyl]-l-(4-chloro-2-methylphenyl)-4-methyl-lH-p yrazole-3-carboxylic acid (576 mg, crude) in DCM (6 ml). The reaction was continued at room temperature for 1 hour. The solvent and excess oxalyl chloride were evaporated. The acid chloride was dissolved in DCM (3 ml) and added to a mixture of 2,2,2-trichloroethanol (140 μl, 1.46 mmol) and DIPEA (280 μl, 1.60 mmol) in DCM (3 ml). The reaction was continued at

room temperature for 2 hours. Water was added. The phases were separated and the organic phase washed with water, NaOH (aq), HCl (aq) and water, and dried over MgSO ₄ (662 mg, crude). ¹ H NMR (399.964 MHz) δ 7.44-7.28 (m, 5H), 7.17-7.10 (m, 3H) ₅ 7.00 (d, 2H), 6.89 (d, 2H), 5.04 (s, 2H), 5.01 (s, 2H), 2.37 (s, 3H), 1.93 (s, 3H). MS m/z 563, 565, 567, 569 (M+H) ⁺ .

Step E: 2,2,2-trichloroethyl l-(4-chloro-2-methylphenyl)-5-(4-hydroxyρhenyl)-4-methyl- lH-pyrazole-3 -carboxylate

2,2,2-trichloroethyl 5-[4-(benzyloxy)phenyl]- 1 -(4-chloro-2-methylphenyl)-4-methyl- IH- pyrazole-3-carboxylate (662 mg, crude) was dissolved in HBr in acetic acid (33%, 15 ml) and reacted at room temperature for 1 hour. Ethanol was added and the mixture stirred for 1.5 hours. The solvent was evaporated. Methanol was added, the mixture neutralised with NaHCθ ₃ (5%, aq) and the solvent evaporated. Water and DCM were added. The phases separated and the organic phase washed with water and dried over MgSO ₄ (543 mg, crude). ¹ H NMR (399.964 MHz) δ 7.10-7.04 (m, 3H), 6.84 (d, 2H), 6.66 (d, 2H), 4.99 (s, 2H), 2.33 (s, 3H), 1.85 (s, 3H). MS m/z 413, Al 5, All, 479 (M+H) ⁺ .

Step F: 2,2,2-trichloroethyl l-(4-chloro-2-methylphenylV4-methyl-5-f4-{rf3,3,3- trifluoropropyDsulfonyl]oxy}phenyl)-lH-pyrazole-3-carboxylat e 3,3,3-Trifluoropropane-l-sulfonyl chloride (320 mg, 1.63 mmol) in DCM (2 ml) was added to a mixture of 2,2,2-trichloroethyl l-(4-chloro-2-methylphenyl)-5-(4- hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxylate (543 mg, crude) and TEA (240 μl, 1.72 mmol) in DCM (15 ml) at -78 ⁰ C, under N ₂ (g). The reaction was continued at -78 ⁰ C for 1 hour. Water was added, the phases were separated and the organic phase was washed with water and dried over MgSO ₄ (707 mg, crude). ¹ H NMR (399.964 MHz) δ 7.25-7.05 (m, 7H), 5.01 (s, 2H), 3.50-3.42 (m, 2H), 2.82-2.68 (m, 2H), 2.35 (s, 3H), 1.92 (s, 3H). MS m/z 633, 635, 637, 639 (M+H) ⁺ . Step G: 1 -f 4-chloro-2-methylphenylM-methyl-5-(4- {[(3,3,3- trifluoropropyl)smfonylloxy|phenyl)-lH-pyrazole-3-carboxylic acid Zinc dust (729 mg, 11.15 mmol) was added to a mixture of 2,2,2-trichloroethyl l-(4- chloro-2-methylphenyl)-4-methyl-5-(4-{[(3,3,3-trifluoropropy l)sulfonyl]oxy}phenyl)-lH- pyrazole-3-carboxylate (707 mg, crude) in acetic acid (10 ml). The reaction was continued at room temperature for 1.5 hours. DCM was added and the mixture was filtered through Celite 521. The solvent was evaporated and the mixture dissolved in DCM and washed

with HCl (IM, aq) and water, and dried over MgSO ₄ . The mixture was dried further by coevaporation with toluene (498 mg, crude). ¹ H NMR (399.964 MHz) δ 7.25-7.05 (m, 7H), 3.52-3.42 (m, 2H), 2.84-2.70 (m, 2H), 2.36 (s, 3H), 1.93 (s, 3H). MS m/z 503, 505 (M+H) ⁺ . Step H: 4-| ^" 3-(chlorocarbonyl)-l-f4-chloro-2-methylphenyl ^' )-4-methyl-lH-pyrazol-5- yllphenyl 3 ,3 ,3-trifluoropropane- 1 -sulfonate

Oxalyl chloride (1 ml) was added to l-(4-chloro-2-memylρhenyl)-4-methyl-5-(4-{[(3,3,3- trifluoropropyl)sulfonyl]oxy}phenyl)-lH-pyrazole-3-carboxyli c acid (378 mg, crude) in DCM (20 ml). One drop of DMF was added and the reaction continued at room temperature for 50 minutes. The solvent and excess oxalyl chloride was evaporated at reduced pressure.

Step I: 4-{l-(4-chloro-2-methylphenyl)-4-methyl-3-[fpiperidin-l-ylam ino)carbonyl1-lH- pyrazol-5-yl) phenyl 3,3,3-trifluoropropane-l -sulfonate

4-[3-(Chlorocarbonyl)-l-(4-chloro-2-methylphenyl)-4-methyl-l H-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate (196 mg, crude) suspended in DCM (5 ml) was added to piperidin-1 -amine hydrochloride (78 mg, 0.57 mmol) in DCM/K ₂ CO ₃ (10%, aq) (1:1, 6 ml). The reaction was continued at room temperature for 1.5 hours. The phases were separated and the organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparatory ηPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 99% acetonitrile) to give an almost white powder (144 mg, 51% yield for 7 steps). ¹ H NMR (399.964 MHz) δ 7.70-7.55 (br, IH), 7.26-7.04 (m, 7H), 3.50-3.44 (m, 2H), 2.89-2.70 (m, 6H), 2.37 (s, 3H), 1.92 (s, 3H), 1.77- 1.69 (m, 4H), 1.45-1.36 (m, 2H). HRMS Calcd for [C ₂₆ H ₂₈ ClF ₃ N ₄ O^H] ⁺ : 585.155. Found: 585.155. Example 26 4-[l-(4-chloro-2-methylphenyl)-3-({( ^" (1^2i?V2-hvdroxycyclohexyl1aminolcarbonyl)-4- methyl-lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate and 4-[l-(4-chloro-2- methylphenyl)-3 -( { IT 1 R,2ιSV2-hydroxy cyclohexy H amino 1 carbonyl)-4-methyl- lH-pyrazol- 5-yl ^" |phenyl 3 ,3 ,3 -trifluoropropane- 1 -sulfonate 4-[3-(chlorocarbonyl)-l-(4-chloro-2-methylphenyl)-4-methyl-l H-pyrazol-5-yl]phenyl 3, 3, 3-trifluoropropane-l -sulfonate, from Ex. 25, Step η (196 mg, crude) suspended in DCM (5 ml) was added to cis-2-aminocyclohexanol hydrochloride (76.8 mg, 0.51 mmol) in DCM/K2CO3 (10%, aq) (1:1, 6 ml). The reaction was continued at room temperature for

2 hours. The phases were separated and the organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparatory HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 98% acetonitrile) to give an almost white powder (151 mg, 53% yield for 7 steps). ¹ H NMR (399.964 MHz) δ 7.26-7.04 (m, 8H), 4.16-4.08 (m, IH), 4.04-3.98 (m, IH), 3.50- 3.42 (m, 2H), 2.84-2.70 (m, 2H), 2.37 (s, 3H), 1.92 (s, 3H), 1.80-1.35 (m, 8H). HRMS Calcd for [C ₂₇ H ₂₉ C1F ₃ N ₃ O ₅ S+H] ⁺ : 600.155. Found: 600.154. Example 27 :4-| ^' l-(2,4-dichlorophenyl)-3-f{[(16',3i?)-3-hydroxycyclohexyllam ino)carbonyl)-4-methyl- lH-pyrazol-5-yliphenyl 3,3,3-trifluoropropane-l-sulfonate and 4-| ^" l-(2,4-dichlorophenyl)- 3-( { \( li?,3S^-3-hydroxycyclohexyl]amino} carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3 -trifluoroprop ane- 1 -sulfonate

Step A: 2,2,2-trichloroethyl 5-[4-(benzyloxy)phenyll-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3 -carboxylate Oxalyl chloride (20 ml) and 1 drop of DMF were added to a mixture of 5-[4-

(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazo le-3-carboxylic acid, prepared as in Ex. 3, Step D (10 g, 22.06 mmol) in DCM (150 ml). The reaction was continued at room temperature for 3 hours. The solvent and excess oxalyl chloride were evaporated. The acid chloride was dissolved in DCM (100 ml) and added to a mixture of 2,2,2-trichloroethanol (4.7 g, 31.46 mmol) and DIPEA (5.0 ml, 28.70 mmol) in DCM (50 ml). DMAP (100 mg, 0.82 mmol) was added and the reaction was continued at room temperature for 2 hours. Water was added. The phases were separated and the organic phase washed with NaOH (aq), HCl (aq) and water, and dried over MgSO ₄ (12.43 g, crude). ¹ H NMR (399.964 MHz) δ 7.42-7.22 (m, 8H), 7.05 (d, 2H), 6.90 (d, 2H), 5.04 (s, 2H), 5.02 (s, 2H), 2.35 (s, 3H). MS m/z 583, 585, 587, 589 (M+H) ⁺ .

Step B: 2,2,2-trichloroethyl l-(2.4-dichlorophenyl)-5-(4-hvdroxyphenyl ^' )-4-methyl-lH- pyrazole-3-carboxylate

2,2,2-Trichloroethyl 5-[4-(benzyloxy)phenyl]-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3 -carboxylate (12.43 g, crude) was dissolved in HBr in acetic acid (33%, 110 ml) and reacted at room temperature for 2.5 hours. The mixture was cooled to O ⁰ C, ethanol was added and the material stirred for 20 minutes. The solvent was evaporated. Methanol was added, the mixture neutralised with NaHCO ₃ (5%, aq) and the solvent evaporated. Water

and DCM were added. The phases separated and the organic phase washed with water and dried over MgSO ₄ (9.49 g, crude). ¹ H NMR (399.964 MHz) δ 7.34-7.18 (m, 3H), 6.93 (d, 2H), 6.71 (d, 2H), 6.25-6.10 (br, IH), 5.01 (s, 2H), 2.33 (s, 3H). MS m/z 493, 495, 497, 499 (M+H) ⁺ . Step C: 2.2,2-trichloroethyl l-(2.4-dichlorophenylV4-methyl-5-(4-{[Y333- tritluoropropyl)sulfonyl]oxy}phenyl)-lH-pyrazole-3-carboxyla te 3,3,3-Trifluoropropane-l-sulfonyl chloride (2.44 g, 12.42 mmol) in DCM (10 ml) was added to a mixture of 2,2,2-trichloroethyl l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4- methyl-lH-pyrazole-3-carboxylate (4.49 g, crude) and TEA (1.65 ml, 11.84 mmol) in DCM (100 ml) at -78 ⁰ C ₅ under N ₂ (g). The reaction was continued at -78 ⁰ C for 1 hour. Water was added, the phases were separated and the organic phase was washed with water and dried over MgSO ₄ (6.06 g, crude). ¹ H NMR (399.964 MHz) δ 7.38-7.16 (m, 7H), 5.02 (s, 2H), 3.50-3.43 (m, 2H), 2.82-2.68 (m, 2H), 2.34 (s, 3H). MS m/z 653, 655, 657, 659 (M+H) ⁺ . Step D: 1 -f 2,4-dichlorophenyl)-4-methyl-5-(4- {[(3,3,3- trifluoropropyl)sulfonylloxy}phenviyiH-pyrazole-3-carboxylic acid

Zinc dust (6.3 g, 96.35 mmol) was added to a mixture of 2,2,2-trichloroethyl l-(2,4- dichlorophenyl)-4-methyl-5-(4-{[(3,3,3-trifluoropropyl)sulfo nyl]oxy}phenyl)-lH- pyrazole-3-carboxylate (6.06 g, crude) in acetic acid (100 ml). The reaction was continued at room temperature for 2.5 hours. DCM was added and the mixture was filtered through Celite 521. The solvent was evaporated and the mixture dissolved in DCM and washed with HCl (IM, aq) and water, and dried over MgSO4. The mixture was dried further by coevaporation with toluene (3.75 g, crude). ¹ H NMR (399.964 MHz) δ 7.76-7.64 (m, 2H), 7.58-7.50 (m, IH), 7.40-7.28 (m, 4H), 3.90-3.82 (m, 2H), 2.95-2.80 (m, 2H), 2.21 (s, 3H). MS m/z 523, 525, 527 (M+H) ⁺ .

Step E: 4-(l-(2,4-dichlorophenyl)-3-{[(3-hydroxycyclohexyl)amino]car bonyl}-4-methyl- lH-pyrazol-5-yl)phenyl 3 ,3 ,3-trifluoropropane- 1 -sulfonate

Oxalyl chloride (ImI) was added to l-(2,4-dichlorophenyl)-4-methyl-5-(4-{[(3,3,3- trifluoropropyl)sulfonyl]oxy}phenyl)-lH-pyrazole-3-carboxyli c acid (314 mg, crude) in DCM (10 ml). One drop of DMF was added and the reaction continued at room temperature for 35 minutes. The solvent and excess oxalyl chloride was evaporated at reduced pressure. The acid chloride was suspended in DCM (5 ml) and added to 3-

aminocyclohexanol (80 mg, 0.69 mmol) in DCM/K ₂ CO ₃ (10%, aq) (1:1, 10 ml). The reaction was continued at room temperature for 24 hours. The phases were separated and the organic phase was washed with water and dried over MgSO ₄ (389 mg, crude). Step F :4-[l-(2,4-dichlorophenyl)-3-({[(l _l $',3i?)-3-hvdroxycvclohexyl]amino)carbonyl)-4- methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate and 4-[l-(2,4- dichlorophenyl)-3-({f(li?,3^-3-hydroxycyclohexyllamino}carbo nyl)-4-methyl-lH- pyrazol-5-yllphenyl 3 ,3 ,3-trifluoropropane-l -sulfonate

The product was separated from its isomer from Step E by prep LC (kromasil C 8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at 94% acetonitrile) to give a white powder after freeze drying (141 mg, 26% yield for 6 steps).

¹ H NMR (399.964 MHz) δ 7.42-7.38 (m, IH), 7.30-7.15 (m, 6H), 7.04 (d, IH), 4.10-3.97 (m, IH), 3.80-3.71 (m, IH), 3.50-3.42 (m, 2H), 2.84-2.70 (m, 2H), 2.35 (s, 3H), 2.29-2.21 (m, IH), 2.00-1.14 (m, 8H). HRMS Calcd for [C ₂₆ H ₂₆ Cl ₂ F ₃ N ₃ O ₅ S+H] ⁺ : 620.100. Found: 620.104. Example 28

4-ri-(2,4-dichlorophenyl)-3-({[d _l S',3 _t S)-3-hvdroxycyclohexyl]amino|carbonyl)-4-methyl- lH-pyrazol-5-yl]phenyl 3,3,3-trifluoropropane-l-sulfonate and 4-[l-(2,4-dichlorophenyl)- 3-({[(li?,3i?)-3-hvdroxycyclohexyl]amino)carbonyl)-4-methyl- lH-pyrazol-5-yl1phenyl 3,3,3 -trifluoropropane- 1 -sulfonate The product was separated from its isomer, Ex. 27; Step E by prep LC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, product came at 95% acetonitrile) to give a white powder after freeze drying (127 mg, 23% yield for 6 steps). ¹ HNMR (399.964 MHz) δ 7.42-7.38 (m, IH), 7.30-7.15 (m, 6H), 6.83 (d, IH), 4.44-4.32 (m, IH), 4.14-4.06 (m, IH), 3.50-3.42 (m, 2H), 2.84-2.70 (m, 2H), 2.35 (s, 3H), 2.05-1.35 (m, 9H). HRMS Calcd for [C ₂₆ H ₂₆ Cl ₂ F ₃ N ₃ O ₅ S^-H] ⁺ : 620.100. Found: 620.101. Example 29 l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methy l-N-piperidin-l-yl-lH- pyrazole-3 -carboxamide Step A Ethyl l-f2.4-dichlorophenyl)-5-r4-f3-fluoropropoxy)phenyll-4-methy l-lH- pyrazole-3 -carboxylate

Ethyl l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyraz ole-3-carboxylate, (prepared by debenzylation of Ex 9, Step D using a method as described in Ex.7 Step B )

(1.137 g, 2.5 mmol), 3-fluoropropan-l-ol (293 mg, 3.75 mmol) and triphenylphosphine (984 mg, 3.75 mmol) were dissolved in anhydrous THF (16 ml), then di-tert-butyl azodicarboxylate (863 mg, 3.75 mmol) was added. The resulting mixture warms and was stirred at room temperature for 3 days. Then 3-fluoropropan-l-ol (97 mg, 1.25 mmol), triphenylphosphine (327 mg, 1.25 mmol) were added, followed by di-tert-butyl azodicarboxylate (288 mg, 1.25 mmol). The resulting mixture was stirred at room temperature overnight. Trifluoroacetic acid (2 ml) was added and the resulting mixture stirred at room temperature for 2h. EtOAc was added the organics washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 10-20 %). The product containing fractions were dissolved in ethanol and 3 ml of HCl (4M in dioxane) was added and the resulting mixture stirred at room temperature for 2 h. The solvents were evaporated, the residue partitioned between EtOAc and water.The organic layer was washed with water, then dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 10-15 %) to yield ethyl l-(2,4- dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methyl-lH-py razole-3-carboxylate (1.12g, 2.23 mmol, 89 %) as a yellow oil of ca. 90% purity which was used in the next transformation without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.22 (m, 3H), 7.02 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 4.68-4.53 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 4.07-4.03 (m, 2H), 2.30 (s, 3H), 2.18-2.08 (m, 2H), 1.40 (t, J=7.1 Hz, 3H)

Step B l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyll-4-methy l-lH-pyrazole-3- carboxylic acid

Ethyl l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methy l-lH-pyrazole-3- carboxylate (1.12 g, 2.23 mmol, ca. 90% pure) was dissolved in a mixture of 15 ml TηF and 15 ml EtOH, then KOη (1.25 g, 22.33 mmol) dissolved in 10 ml water was added and the resulting mixture stirred at 5O ⁰ C. After 3h30min the reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was partitioned between DCM and IN HCl. After phase separation the aqueous layer was extracted two times with DCM. The combined organic layers were dried over MgSO ₄ and evaporated to give l-(2,4- dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methyl-lH-py razole-3-carboxylic acid (1.05 g, 2.23 mmol, 99%) as a yellowish foam which was sufficiently pure for the next

step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.23 (m, 3H), 7.03 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 4.68-4.54 (m, 2H), 4.07-4.04 (m, 2H) ₃ 2.32 (s, 3H), 2.18-2.09 (m, 2H) Step C l-(2,4-dichlorophenyl ^' )-5-r4-(3-fluoropropQxy)phenyl]-4-methyl-lH-pyrazole-3- carbonyl chloride l-(2,4-dichloroρhenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-meth yl-lH-ρyrazole-3-carboxylic acid (593 mg, 1.4 mmol) was dissolved in 10 ml DCM, then oxalyl chloride (200 μl, 2.36 mmol) was added, followed by 10 μl DMF. The resulting mixture was stirred for 90 min at room temperature, then the solvents were evaporated and the residue dried in oil pump vacuum to give l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methy l~lH- pyrazole-3-carbonyl chloride (620 mg, 1.40 mmol, 99%) as a yellowish foam which was used without further purification in the next step.

Step D General procedure for the synthesis of l-(2,4-dichlorophenyl)-5-[4-(3- fluoropropoxy)phenyl]-4-methyl-lH-pyrazole-3-carboxamides To a mixture of amine or amine hydrochloride (0.3 mmol) and 100 μl pyridine in 1 ml DCM was added crude l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methy l- lH-pyrazole-3-carbonyl chloride (88 mg, 0.2 mmol) in 1 ml DCM and the resulting mixture stirred at room temperature for 2h30min. The reaction mixture was washed with 2 ml of sat. NaHCO ₃ and after phase separation filtered through a phase separator. The solvents were evaporated and the residue purified by preparative HPLC eluting on a reverse-phase column with 5 to 100% acetonitrile in 0.1 M NH ₄ Ac.

1 -( 2 ,,4-dichlorophenviy 5 -[ 4-(3 -fluoropropoxy)phenyl] -4-methyl-N-piperidin- 1 -yl- 1 H- pyrazole-3 -carboxamide

Using piperidin-1 -amine hydrochloride as amine component gave l-(2,4-dichlorophenyl)- 5-[4-(3-fluoropropoxy)phenyl]-4-methyl-N-piperidin-l-yl-lH-p yrazole-3-carboxamide (36 mg, 71 μmol, 36%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 7.65 (s, IH), 7.44- 7.26 (m, 3H), 7.05 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 4.71-4.59 (m, 2H), 4.11-4.08 (m, 2H), 2.89-2.86 (m, 4H), 2.38 (s, 3H), 2.21-2.11 (m, 2H), 1.80-1.75 (m, 4H), I Al A A3 (m, 2H). HRMS Calcd for [C ₂₅ H ₂₇ C1 ₂ Fν ₄ O ₂ +H] ⁺ : 505.1573. Found: 505.1554. Example 30 1 -(2,4-dichlorophenyl)-5 - [4-(3 -fluoropropoxy)phenyll -N- [(cis)-2-hydroxy cyclohexyl] -A- methyl-lH-pyrazole-3-carboxamide

Using cis-2-aminocyclohexanol hydrochloride as amine component gave l-(2,4- dichlorophenyl)-5 - [4-(3 -fluoropropoxy)phenyl] -N- [(cis)-2-hy droxy cyclohexyl] -4-methyl- lH-pyrazole-3-carboxamide (27 mg, 52 μmol, 26%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 7.49-7.28 (m, 3H), 7.23 (d, J=8.2 Hz, IH), 7.05 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 4.71-4.59 (m, 2H), 4.18-4.16 (m, IH), 4.11-4.08 (m, 3H), 2.64-2.62 (m, 2H) ₃ 2.38 (s, 3H), 2.34 (s, IH), 2.23-2.12 (m, 2H), 1.81-1.45 (m, 6H) HRMS Calcd for [C ₂₆ H ₂₈ Cl ₂ FN ₃ O^H] ⁺ : 520.1570. Found: 520.1558. Example 31 l-f2,4-dichlorophenyl)-N-f4,4-difluorocvclohexyl)-5-r4-(3-fl uoropropoxy)phenyl ^' l-4- methyl-lH-pyrazole-3-carboxamide

Using 4,4-difiuorocyclohexylamine as amine component gave l-(2,4-dichlorophenyl)-N- (4,4-difluorocyclohexyl)-5-[4-(3-fluoropropoxy)phenyl]-4-met hyl-lH-pyrazole-3- carboxamide (48 mg, 89 μmol, 44%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 7.45-7.28 (m, 3H), 7.05 (d, J=8.7 Hz, 2H), 6.88-6.84 (m, 3H), 4.71-4.59 (m, 2H), 4.11-4.08 (m, 3H), 2.38 (s, 3H), 2.25-2.10 (m, 6H), 1.98-1.86 (m, 2H), 1.71-1.64 (m, 2H). HRMS Calcd for [C ₂₆ H ₂₆ Cl ₂ F ₃ N ₃ C^H] ⁺ : 540.1432. Found: 540.1447. Example 32

1 -(2 ,4-dichlorophenyl)- 5 - [4-(3 -fluoropropoxy)phenyl] -4-methyl-N-(5 -methylpyridin-2-vD- lH-pyrazole-3-carboxamide Using 2-amino-5-picoline as amine component gave l-(2,4-dichlorophenyl)-5-[4-(3- fluoropropoxy)phenyl]-4-methyl-N-(5-methylpyridin-2-yl)-lH-p yrazole-3-carboxamide (48 mg, 93 μmol, 47%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 9.40 (s, IH), 8.28 (d, J=8.3 Hz, IH), 8.14 (d, J=2.2 Hz, IH), 7.57-7.55 (m, IH), 7.45-7.28 (m, 3H), 7.08 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 4.71-4.60 (m, 2H), 4.12-4.09 (m, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 2.23-2.13 (m, 2H). HRMS Calcd for [C ₂₆ H ₂₃ Cl ₂ FN ₄ C^H] ⁺ : 513.1260. Found: 513.1245.

The following compounds are prepared in a similar manner to those described above: Example 33: l-(2,4-Dichlorophenyl)-4-methyl-5-[4-(3,3,3-trifluoropropoxy )-phenyl]-lH- pyrazole-3-carboxylic acid (2-hydroxycyclohexyl)amide Example 34: l-(2,4-Dichlorophenyl)~4-methyl-5-[4-(3,3,3-trifluoro-propox y)-phenyl]-lH- pyrazole-3-carboxylic acid (3-hydroxy-cyclohexyl)amide

Example 35: 3 -Fluoropropane-1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-((lS,2R)-2- hydroxycyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester Example 36: 4,4,4-Trifluorobutane-l -sulfonic acid 4-[2-(3-cyano-5-fluorophenyl)-5-(l- ethylbutylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester Example 37: 3,3 ,3 -Trifluoropropane-1 -sulfonic acid 4-[2-(3-cyano-5-fluorophenyl)-5- (4,4-difluorocyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]p henyl ester Example 38: 3, 3, 3 -Trifluoropropane-1 -sulfonic acid 4-[2-(3-cyanophenyl)-5-(4,4-difluoro- cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3 -yljphenyl ester Example 39: 3,3,3-Trifluoropropane-l-sulfonic acid 4-[5-(2-aminocyclohexylcarbamoyl)- 2-(3-cyano-5-fluorophenyl)-4-methyl-2H-pyrazol-3-yl]-phenyl ester

Example 40: 3,3,3-Trifluoroρropane-l-sulfonic acid 4-[2-(3-cyano-5-fluorophenyl) -5-(3-dimethylamino-cyclohexylcarbamoyl)-4-methyl-2H-pyrazol -3-yl]-phenyl ester Example 41: 3, 3, 3 -Trifluoropropane-1 -sulfonic acid 4-[2-(3-cyano-5-fluorophenyl)-5- ((lS,2R)-2-hydroxy-cyclohexylcarbamoyl)-4-methyl-2H-pyrazol- 3-yl]phenyl ester Example 42: 3,3,3-Trifluoropropane-l -sulfonic acid 4-[2-(3-cyanophenyl)-5-(2-hydroxy- cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]-phenyl ester

Example 43: 3, 3, 3 -Trifluoropropane-1 -sulfonic acid 4-[2-(3-cyano-5-fluoro-phenyl)-5-(3- hydroxy-cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]-pheny l ester Example 44: N-cyclohexyl-l-(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)ph enyl]-4-methyl-lH- pyrazole-3-carboxamide

Using cyclohexylamine as amine component and reacting with the product of Ex. 29 Step C gave N-cyclohexyl- 1 -(2,4-dichlorophenyl)-5-[4-(3-fluoropropoxy)phenyl]-4-methyl - IH- pyrazole-3-carboxamide (39 mg, 77 μmol, 39%) as a colorless solid. ¹ H νMR (500 MHz, CDCl ₃ ) δ 7.44-7.28 (m, 3H), 7.05 (d, J=8.7 Hz, 2H), 6.86-6.83 (m, 3H), 4.71-4.59 (m, 2H), 4.11-4.08 (m, 2H), 4.01-3.93 (m, IH), 2.38 (s, 3H), 2.22-2.12 (m, 2H), 2.06-2.02 (m, 2H), 1.79-1.75 (m, 2H), 1.67-1.64 (m, IH), 1.47-1.38 (m, 2H), 1.31-1.16 (m, 3H). HRMS Calcd for [C ₂₆ H ₂ SCl ₂ FN ₃ O ₂ H-H] ⁺ : 504.1621. Found: 504.1630. Example 45: 3,3,3-Trifiuoropropane-l-sulfonic acid 4-[2-(2-chlorophenyl)-5-(2-hydroxy- cyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3 -yljphenyl ester

Example 46: 3,3,3-Trifluoropropane-l -sulfonic acid 4-[2-(2-chlorophenyl)-5-(4,4- difluorocyclohexylcarbamoyl)-4-methyl-2H-pyrazol-3-yl]phenyl ester.