WO2011054773A1

WO2011054773A1 - Novel lactam compounds

Info

Publication number: WO2011054773A1
Application number: PCT/EP2010/066545
Authority: WO
Inventors: Steven Mark Bromidge; Maria Pia Catalani; Jag Paul Heer; Christian Alan Paul Smethurst; Simona Tommasi
Original assignee: Glaxosmithkline Llc
Priority date: 2009-11-03
Filing date: 2010-10-29
Publication date: 2011-05-12

Abstract

There are provided according to the invention novel compounds of formula (I) or a pharmaceutically acceptable salt thereof: wherein R is halogen, C_1-4 alkyl or trifluoromethyl; R₁, R₂, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are independently hydrogen, halogen, C(O)NH₂, C(O)NHC _1-6 alkyl, C(O)N(C _1-6 alkyl)₂, C _3-8 cycloalkyl, haloC_1-6 alkyl or C _1-6 alkyl optionally substituted by one or more hydroxyl groups, C _3-8 cycloalkyl or C _1-6 alkoxy; R₃ is hydrogen, C _1-6 alkyl or haloC _1-6 alkyl; R₄ and R₅ are independently hydrogen or C _1-4 alkyl; R₆ is trifluoromethyl, halogen, trifluoromethoxy, C _1-6 alkoxy or C _1-4 alkyl; m is an integer from 0 to 2; q is 1 or 2; n is 1 and p is 0 or n is 0 and p is 1.

Description

NOVEL LACTAM COMPOUNDS

The present invention relates to novel lactam compounds having pharmacological activity, to processes for their preparation, to compositions containing them and to their medical uses.

WO 2005/002577 (F. Hoffmann-La Roche AG), WO 2006/013050 (F. Hoffmann-La Roche AG) and WO 2007/028654 (SmithKline Beecham Corporation) describe series of pyridine derivatives which are claimed to be dual NK1/NK3 antagonists for treating schizophrenia. WO 2002/16324 (F. Hoffmann-La Roche AG) describes 4-phenyl pyridine derivatives as NK1 receptor antagonists.

The present invention provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof,

R is halogen, C 1.4 alkyl or trifluoromethyl;

R-| , R2, R7, Re, R9. Rl 0' Rl 1 ^ar,d R12 ^are independently hydrogen, halogen, C(0)NH2, C(0)NHC i_6 alkyl , C(0)N(C i_g alkyl)₂ , C 3.8 cycloalkyl, haloC-|_g alkyl or C i_g alkyl optionally substituted by one or more hydroxyl groups , C 3.3 cycloalkyl or C -|.g alkoxy; R3 is hydrogen, C -|.g alkyl or haloC -|.g alkyl;

R4 and R5 are independently hydrogen or C 1.4 alkyl;

Rg is trifluoromethyl, halogen, trifluoromethoxy, C -|.g alkoxy or C 1.4 alkyl;

m is an integer from 0 to 2;

q is 1 or 2;

n is 1 and p is 0 or n is 0 and p is 1.

Compounds of formula (I) may form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric, p- toluenesulfonic, benzoic and methanesulphonic.

Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Salts, solvates and hydrates of compounds of formula (I) therefore form an aspect of the invention.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids. Salts having a non-pharmaceutically acceptable anion are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).

Compounds of formula (I) may be obtained as crystalline forms.

It is to be understood that these crystalline forms or a mixture thereof are encompassed within the scope of the invention.

Furthermore, some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included in the present invention.

Hereinafter, compounds of formula (I), their pharmaceutically acceptable salts, solvates, hydrates and crystalline forms thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "the compounds of the invention".

The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention or pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as ^H, 3H, H e, 13C, 14_C, 15N, 17₀, 18₀, 31 _P, 32_Pj 35_Sj 18_f, 36_C|, 123, _and 125,.

Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ^H, 1^C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3Η, and carbon-14, i.e., 1^C, isotopes are particularly preferred for their ease of preparation and detectability. H e and 1^F isotopes are particularly useful in PET (positron emission tomography), and 125| isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ^H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

The term 'halogen' as used herein refers to a fluorine, chlorine, bromine or iodine atom.

The term -|.g alkyl' as used herein as a group or a part of the group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.

The term "C -|.g alkoxy' as used herein refers to an -0-C1-6 alkyl group wherein C1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.

The term 3.3 cycloalkyl' as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.

The term 'halo C -|.g alkyl' as used herein refers to a C-|.g alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.

It will be appreciated by those skilled in the art that compounds of formula (I) contain at least one asymmetric carbon atom at 3 position at lactam ring as shown in the formulae (la) and (lb).

(la) (lb)

The wedge shaped bond indicates that the bond is above the plane of the paper and it is referred to as β configuration. The broken bond indicates that the bond is below the plane of the paper and is in the a configuration.

Further asymmetric carbon atoms exist, for example, when R-| is different from R2 and/ or R-I 0 is different from R-| -| It will be understood that the invention encompasses all the above diastereoisomers or enantiomers of the compound of formula(l) and the mixture thereof including racemates and the reference to a compound of formula (I) includes all said stereoisomeric forms unless otherwise stated.

In one embodiment of the invention p is 0 and n is 1.

In a further embodiment p is 1 and n is 0.

In a further embodiment R4 and R5 are methyl. In a further embodiment R3 is methyl.

In a further embodiment Rg is trifluoromethyl or halogen and q is 2.

In a further embodiment R is halogen or C 1.4 alkyl and m is 2.

In a further embodiment Rg is hydrogen.

In a further embodiment R-12 is hydrogen or methyl. In a further embodiment of the invention p is 0 and n is 1 , R-| is hydrogen or methyl optionally substituted by a hydroxyl group , R2 is hydrogen, C -|.g alkyl optionally substituted by hydroxyl, Rg is hydrogen, R-| Q is hydrogen or methyl optionally substituted by a hydroxyl group, R-| i is hydrogen, C -| .g alkyl optionally substituted by a hydroxyl group , R-12 is hydrogen or methyl, R3,R4 and R5 are methyl, Rg is trifluoromethyl or halogen and q is 2, R is halogen or methyl and m is 2. In a further embodiment of the invention p is 1 and n is 0, R-| and R2 are hydrogen, R7 is hydrogen, RQ is C -|.g alkyl optionally substituted by a hydroxyl group , Rg is hydrogen. R-| Q is hydrogen or methyl optionally substituted by a hydroxyl group , -12 '^s hydrogen or methyl, R3,R4 and R5 are methyl, Rg is trifluoromethyl or halogen and q is 2, R is halogen or methyl and m is 2.

In a further embodiment the compounds of the invention are selected from

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-[4-(4-fluoro-2-methylphenyl)-6-(5-oxo-3-pyrrolidinyl)-3- pyridinyl]-/V,2-dimethylpropanamide;

yAni/^'-2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[4-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (racemate);

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 1);

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 2);

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-1- methyl-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (enantiomer 2);

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(3-(hydroxymethyl)-5- oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (syn: enantiomer 1 );

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(3-(hydroxymethyl)-5- oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (anti: enantiomer 1 );

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(3-(hydroxymethyl)-5- oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (syn; enantiomer 2);

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(3-(hydroxymethyl)-5- oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (anti: enantiomer 2;)

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(2-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (syn: enantiomer 1 );

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(2-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (syn: enantiomer 2);

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(2-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (anti: enantiomer 1 );

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(2-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (anti: enantiomer 2);

/V-[6-[2,2-Bis(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-2- [3,5-bis(trifluoromethyl)phenyl]-/V,2-dimethylpropanamide;

/V-[6-[2,2-Bis(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-2- [3,5-bis(trifluoromethyl)phenyl]-/V,2-dimethylpropanamide (enantiomer 1 );

2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[2-(hydroxymethyl)-1 - methyl-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide;

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[2-(hydroxymethyl)-5-oxo- 1 -(2,2,2-trifluoroethyl)-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide; 2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-(2,2-dimethyl-5-oxo-3-pyrTolidinyl)-4-(4-fluoro-2- methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide;

2-[3,5-Bis(trifluoromethyl)phenyl]-^

methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (enantiomer 1 );

2-[3,5-Bis(trifluoromethyl)phenyl]-^

methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (enantiomer 2);

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[4-(hydroxymethyl)-2,2- dimethyl-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide;

N-[6-[4,4-Bis(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-2- [3,5-bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamide;

2-[3,5-bis(trifluoromethyl)phenyl]-/V-[4-(4-fluoro-2-methylphenyl)-6-(2-methyl-5-oxo-3- pyrrolidinyl)-3-pyridinyl]-/V,2-dimethylpropanamide;

2- [3,5-bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[4-(hydroxymethyl)-2- methyl-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide;

2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[2-(1 -hydroxyethyl)-5-oxo-

3- pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide;

2-[3,5-bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[4-(1 -hydroxy-1 - methylethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide;

2-[3,5-bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[4-(hydroxymethyl)-4- methyl-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide;

or a pharmaceutically salt thereof.

In a further embodiment the compound is

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 2) or a pharmaceutically salt thereof.

In a further embodiment the compound is

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 2).

In a further embodiment the compound is

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide hydrochloride (enantiomer 2).

CH₂OH may be obtained in accordance with the following Scheme 1 .

Scheme 1

Step (i) typically comprises reacting a chlorine of formula (I), with 2-ethenyl-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane, Pd(PPh₃)₄, in the presence of a suitable solvent such as dioxane/ water and a suitable base such as Na₂C0₃ at reflux temperature.

Step (ii) typically comprises oxidation with osmium tetroxide in the presence of sodium periodate in a suitable solvent such as tetrahydrofuran and water. Alternatively, the oxidation reaction may be carried out by ozonolysis in the presence of a suitable solvent such an alcohol i.e. methanol.

Step (iii) typically comprises reacting an aldehyde (III) with a phosphorus ylide ethyl

(triphenyl- ⁵-phosphanylidene)acetate, in the presence of a suitable solvent such as toluene, to obtain compound of formula (IV), wherein R2_a is hydrogen. Compounds of formula (IV), wherein R2_a is C(0)OEt, may be prepared by reacting (III) with diethylmalonate in the presence of T1CI4 and pyridine in a suitable solvent such as a mixture of tetrahydrofuran and tetrachloromethane at room temperature.

Alternatively, compounds of formula (IV), wherein R2_a is hydrogen, may be obtained by Suzuki reaction (step(vii)) reacting a compound of formula (I) with ethyl-3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-propenoate in the presence of bis(triphenylphosphine)palladium(ll) chloride and sodium carbonate, in a suitable solvent such as mixture of dimethoxyethane, water and ethanol at temperature of 140-150°C with microwave irradiation for 20 min.

Step (v) typically comprises cyclisation of (V), wherein R2_a is hydrogen, in the presence of Raney-Ni, in a suitable solvent such as ethanol under H2 atmosphere to obtain compounds of formula (I), wherein p is 0 and n is 1 , R-12 is hydrogen, R-| -| and R-| Q are independently hydrogen or C -|_g alkyl, Rg is hydrogen, R-| is hydrogen and R2 is hydrogen.

Step (vi) typically comprises cyclisation of (V), wherein R2_a is C(0)OEt, in the presence of Raney-Ni, in a suitable solvent such as ethanol under H2 atmosphere, followed by reduction reaction with Sodium borohydride in the presence of calcium chloride in a suitable solvent such as methanol, to obtain compounds of formula(l), wherein p is 0 and n is 1 , R-12 is hydrogen, R-| -| and R-| Q are independently hydrogen or C -|.g alkyl, Rg is hydrogen, R-| is hydrogen and R2 is CH2OH.

Alternatively, compounds of formula (I), wherein p is 0 and n is 1 , R-12 _> R9. Rl and R-| -| are hydrogen, and R-| Q is hydrogen or C -|.g alkyl, R2 is CH2OH may be obtained in accordance with the following Scheme 2.

Scheme 2

R3 Step (i) typically comprises reacting an aldehyde (III) with nitroCH2R"i o_> wherein R-| g is hydrogen or C-|.g alkyl, in the presence of triethylamine.

Step (ii) typically comprises reacting compounds (VI) with diethylmalonate in the presence of T1CI4 and pyridine in a suitable solvent such as a mixture of tetrahydrofuran and tetrachloromethane at room temperature to obtain compounds (Va) wherein R2a is C(0)OEt. Compounds(Va) may be converted into compounds (I), wherein p is 0 and n is 1 , R-| 2_> R9. R-| and R-| -| are hydrogen, and R-| Q is hydrogen or C -|.g alkyl, R2 is CH2OH, using the synthetic procedure described in the Scheme 1 to convert compounds (V) into compounds(l) as described in Step (vi).

Scheme 3

Step (i) typically comprises protecting a compound of formula (I) with a suitable nitrogen protecting group P, such as tertbutyloxycarbonyl (Boc) by reaction of (I) with di-tert- butyldicarbonate in the presence of triethylamine and 4-dimethylaminopyridine in a suitable solvent such as dichloromethane, followed by reaction with Lithium bis(trimethylsilyl)amide then methyl chloroformate in a suitable solvent such as tetrahydrofuran at -78°C to obtain compounds (VII) wherein R-| 3 is ethyl. Step (ii) typically comprises reduction of compounds (VII) with sodium borohydride in the presence of calcium chloride in a suitable solvent such as methanol followed by deprotection of the amine to obtain compounds (I), wherein R-| is hydrogen and R2 is CH2OH .

Step (iii) typically comprises the reaction of a compound of formula (I) with methylchloroformate in the presence of a suitable organic base such as n-butyl lithium in a suitable solvent such as tetrahydrofuran.

Step (iv) typically comprises deprotection of the amine group of (VIII) and the reduction to alcohol as described in Scheme 1 step (vi) to obtain compounds of formula (I), wherein R-| and R2 are CH2OH.

Step (v) typically comprises a reaction of a compound of formula (I) with acetone in the presence of a base such lithium bis(trimethylsilyl)amide in a suitable solvent such as tetrahydrofuran at temperature of -78°C to obtain compounds of formula (I) wherein R-| is

C(CH3)₂OH.

Step (vi) typically comprises a reaction of a compound of formula (VII) with C(1 -6)alkylL wherein L is a leaving group such as halogen (i.e iodine, chlorine) in the presence of a base such as sodium hydride in a suitable solvent such tetrahydrofuran to obtain compounds of formula(VI la) wherein R-| is C-|.g alkyl.

Step (vii) typically comprises a reduction of the ethyl ester group in (Vila) to CH2O H as described in step (ii) above to obtain compounds of formula (I) wherein R-| is C-|.g alkyl and R₂ is CH₂OH.

Compounds of formula (I), wherein p is 0 and n is 1 , R-12 is hydrogen, R-| -| and R-| Q are CH2OH or R-i o is hydrogen and R-| i is CH2O H, CH(OH)CH3 or CH2CON H2, Rg, Ri and R2 are hydrogen, may be obtained in accordance with the following Scheme 4.

Scheme 4

Step (i) typically comprises reacting compound (IV) with diethyl(acetylamino)propanedioate in the presence of a base such as NaOEt in a suitable solvents such as ethanol, dimethylsulfoxide or a mixture thereof to obtain compounds (IX), wherein R-| -| _a and R-| rja ^are

C(0)OEt and R2_a is hydrogen or C(0)OEt.

Step (ii) typically comprises reduction of compounds (IX) with sodium borohydride in a suitable solvent such as methanol to obtain compounds of formula (I) wherein R"i i ,R"io are CH2OH and R2 is hydrogen or CH2OH.

Step (iii) typically comprises reaction of compounds (IX), with a base such as sodium hydroxide in a solvent such as a mixture of water and methanol, followed by addition of methanol and hydrochloride to obtain compounds (X), wherein R₁₀ is hydrogen and R-| -| a is

C(0)OEt.

Step (iv) typically comprises reduction as described above in step (ii) to obtain compounds of formula (I) wherein R2 is CH2OH or hydrogen, R-| -| is CH2OH and R-| Q is hydrogen.

Step (v) typically comprises reducing a compound of formula (X), wherein R₂ is hydrogen with lithium hydroxide in a solvents such as methanol, water or tetrahydrofuran or a mixture thereof, to the compounds of formula (X) wherein R"i i _aa is carboxylic acid and R-| Q is hydrogen.

Step (vi) typically comprises a reaction of compound of formula (X), wherein R-| -| _A is carboxylic acid, with 0-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro phosphate and N-hydroxybenzotriazole and bistrimethylsilylamine in the presence of diisopropylethyl amine in a suitable solvent such dimethylformamide to obtain compounds of formula (I) wherein R-| -| is CH2CONH2 and R-| Q is hydrogen.

Step (vii) typically comprises a reaction of compounds of formula (X), wherein R-| -| _A is carboxylic acid with methylmagnesiumbromide in the presence of N,0- dimethylhydroxylamine hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-methylmorpholine in a suitable solvent such as tetrahydrofuran, followed by treatment with sodiumborohydride in methanol to obtain compounds of formula (I) wherein R-| -| is CH(OH)CH3 and R-| Q is hydrogen. Compounds of formula (I), wherein p is 1 and n is 0, R-| , R2 R7 R-| 2 ^and R9 ^are hydrogen and Re is CH2OH may be obtained in accordance with the following Scheme 5.

Sche

Step (i) typically comprises oxidation of compounds (II) with osmium tetroxide in the presence of sodium periodate in a suitable solvent such as tetrahydrofuran and water, following by esterification reaction with methanol in the presence of hydrochloric acid. Step (ii) typically comprises reaction of compounds (XI) in ethyl acetate in the presence of a suitable base such as for example potassium tert-butoxide at temperature of 75°C.

Step (iii) typically comprises reaction of compounds (XII) with ethyl choloroacetate in the presence of a base such as potassium carbonate and sodium iodide in a suitable solvent such as acetone, dimethoxyethane or mixture thereof.

Step (iv) typically comprises reductive amination of compounds (XIII) with sodium cyanoborohydride in methanol and in the presence of ammonium acetate, followed by in situ cyclisation.

Step (v) typically comprises reduction of compounds (XIV) with lithium borohydride in the presence of calcium chloride in a suitable solvent such as tetrahydrofuran.

Compounds of formula (I), wherein R-|2 is C-|.g alkyl may be prepared by reaction of a compound of formula (I) wherein R-|2 is hydrogen with C-|.g alkylL, wherein L is a suitable leaving group such as halogen i.e chlorine and iodine.

Compounds of formula (I) and its pharmaceutically acceptable salts have affinity for and are specific antagonists of tachykinins, including substance P and other neurokinins.

Tachykinins are a family of peptides that share a common carboxyl-terminal sequence (Phe- X-Gly-Leu-Met-NH2). They are actively involved in the physiology of both lower and advanced life forms. In mammalian life forms, the main tachykinins are substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmitters and neuromodulators. Mammalian tachykinins may contribute to the pathophysiology of a number of human diseases.

Three types of tachykinin receptors have been identified, namely NK1 (SP-preferring), NK2 (NKA-preferring) and NK3 (NKB-preferring) which are widely distributed throughout the central nervous (CNS) and peripheral nervous system. Particularly, compounds of formula (I) and their pharmaceutically acceptable salts have affinity for and are antagonists of the NK1 and NK3 receptor and thus may be of use in the treatment of psychotic disorders.

Within the context of the present invention, the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

Within the context of the present invention, the term "psychotic disorder" includes: Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).

Compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may also be of use in the treatment of the following disorders: Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301 .13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):

Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood- Injection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00):

Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance- Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance- Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291 .9); Amphetamine (or Amphetamine- Like)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis- Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine- Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant- Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine- Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid- Induced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic- Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic- Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide.

Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome:

Eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50):

Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism). Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321 .81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23):

Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301 .20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301 .50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):

Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease. Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).

Skin disorders including psoriasis, pruriginous diseases, urticaria, herpes, photodermatosis, atopic dermatitis, contact dermatitis, lichen, prurigo, pruritus, erythema, in particular solar erythema, insect bites, in fibrosis and other collagen maturation disorders such as for example scleroderma, in hair disorders such as alopecia areata, alopecia totalis and alopecia universalis.

All of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention. Thus, the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment of skin disorders.. The invention furthermore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment of hair disorders.

The invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above psychotic disorders, in particular schizophrenia and Alcohol-Related Disorders such as Alcohol Dependence, Alcohol Abuse, Alcohol Intoxication.

The invention further provides a method of treating schizophrenia and Alcohol-Related Disorders such as Alcohol Dependence, Alcohol Abuse, Alcohol Intoxication which comprises administering to a host in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention further provides a method of treating skin disorders. The invention further provides a method of treating hair disorders.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of schizophrenia and Alcohol-Related Disorders such as Alcohol Dependence, Alcohol Abuse, Alcohol Intoxication.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of skin disorders.

The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders. When used in therapy, the compounds of formula (I) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures. Thus, the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine). The compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.

The compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants. The compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion. The compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.

The compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.

The compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.

The compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.

The compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline. The compounds of the invention may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.

Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions suitable for transdermal administration include ointments, gels and patches.

The composition may contain from 0.1 % to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1 .0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

Experimental

The following Intermediates and Examples illustrate the preparation of compounds of the invention.

In the procedures that follow, after each starting material, reference to a description is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada). For reactions involving microwave irradiation, a Personal Chemistry EmrysTM Optimizer was used.

Proton Magnetic Resonance (NMR) spectra were recorded either on Varian instruments at 400, 500 or 600 MHz, or on a Bruker instrument at 400 MHz. Chemical shifts are reported in ppm (δ) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The NMR spectra were recorded at a temperature ranging from 25 to 100 °C. When more than one conformer was detected the chemical shifts for the most abundant one is usually reported. HPLC analyses indicated by HPLC (walk-up): rt = x min, were performed on a Agilent 1 100 series instrument using a Luna 3u C18(2) 100A column (50 x 2.0 mm, 3 μηη particle size) [Mobile phase and Gradient: 100% (water + 0.05% TFA) to 95% (acetonitrile + 0.05% TFA) in 8 min. Column T = 40 °C. Flow rate = 1 mL/min. UV detection wavelength = 220 nm]. The usage of this methodology is indicated by "HPLC" in the analytical characterization of the described compounds.

Optical rotation data were recorded with Polarimeter Jasco DIP360.

Agilent LC/MSD 1 100 Mass Spectrometer coupled with HPLC instrument Agilent 1 100 Series, operating in positive or negative electrospray ionization mode and in both acidic and basic gradient conditions [Acidic gradient LC/MS - ES (+ or -): analyses performed on a Sunfire C18 column (30 x 4.6 mm, 3.5 μιτι). Mobile phase: A - water + 0.1 % HC0₂H / B - CH₃CN + 0.1 % HC0₂H. Gradient: t=0 min 0% (B), from 0% (B) to 100% (B) in 3 min lasting for 1 min, from 100% (B) to 0% (B) in 0.1 min, stop time 4.10 min. Column T = rt. Flow rate = 2 mL/min. Basic gradient LC/MS - ES (+ or -): analyses performed on a XTerra MS C18 column (30 x 4.6 mm, 2.5 μηη). Mobile phase: A - 5 mM aq. NH₄HC0₃ + ammonia (pH 10) / B - CH₃CN. Gradient: t = 0 min 0% (B), from 0% (B) to 50% (B) in 0.4 min, from 50% (B) to 95% (B) in 3.6 min lasting for 1 min, from 95% (B) to 0% (B) in 0.1 min, stop time 5.8 min. Column T = rt. Flow rate = 1.5 mL/min]. Mass range ES (+ or -): 100-1000 amu. UV detection range: 220-350 nm (the usage of this methodology is indicated by "HPLC/MS" in the analytical characterization of the described compounds)

Total ion current (TIC) and DAD UV chromatographic traces together with MS and UV spectra associated with the peaks were taken on a UPLC/MS AcquityTM system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQTM mass spectrometer operating in positive or negative electrospray ionisation mode [LC/MS - ES (+ or -): analyses performed using an AcquityTM UPLC BEH C18 column (50 x 2.1 mm, 1.7 μηη particle size). Acidic conditions: Mobile phase: A - water + 0.1 % HC0₂H / B - CH₃CN + 0.06% HC0₂H. Gradient: t = 0 min 3% B, t = 0.05 min 6% B, t = 0.57 min 70% B, t = 1.06 min 99% B lasting for 0.389 min, t = 1.45 min 3% B, stop time 1.5 min. Column T = 40 °C. Flow rate = 1.0 mL/min. Mass range: ES (+): 100-1000 amu. ES (-): 100-800 amu. UV detection range: 210- 350 nm.

Basic conditions: Mobile phase: A - NH₄HC0₃ 10 mM, pH 10 / B - CH₃CN . Gradient: t = 0 min 3% B, t = 1.06 min 99% B, t = 1.45 min 99% B, t = 1.46 min 3% B, stop time 1 .5 min. Column T = 40 °C. Flow rate = 1 .0 mL/min. Mass range: ES (+): 100-1000 amu. ES (-): 100- 800 amu. UV detection range: 210-350 nm.

The usage of this methodology is indicated by "LC/MS" or "UPLC" in the analytical characterization of the described compounds.

In a number of preparations, purification was performed using Biotage manual flash chromatography (Flash+), Biotage automatic flash chromatography (Horizon, SP1 and SP4), Companion CombiFlash (ISCO) automatic flash chromatography, Flash Master Personal or Vac Master systems.

Flash chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), Varian Mega Be-Si pre-packed cartridges, pre-packed Biotage silica cartridges (e.g. Biotage SNAP cartridge), KP-NH pre-packed flash cartridges or ISCO RediSep Silica cartridges.

SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian. The eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol. SPE-Si cartridges are silica solid phase extraction columns supplied by Varian.

^* indicates a stereocentre of fixed but unknown relative and absolute stereochemistry i.e. either R or S stereochemistry.

Enantiomer 1 or 2 means a compound of the invention or an intermediate thereof as a single enantiomer whose absolute configuration was not determined either R or S stereochemistry. "Anti isomer" indicates that the two substituents on two distinct carbon atoms of the lactam ring are on the opposite side respect to the plane.

"Syn isomer" indicates that the two substituents on two distinct carbon atoms of the lactam ring are on the same side respect to the plane.

Thus for example the anti isomers of compounds of formula(l), wherein p is 0, R-| , Rg, R-| Q and R-| -| are hydrogen, as in formulae (la), (lb) and the syn isomers can be represented as (lc),(ld).

The following table lists the abbreviations used:

Aq Aqueous

BOC₂0 Di-tert-butyldicarbonate

CV Column Volume

DBU Diazabicyclo[5.4.0]undec-7-ene

DCM Dichloromethane

DIPEA Diisopropyl ethylamine

DME 1 ,2-Dimethoxyethane

DMF N,N dimethylformamide

DMSO Dimethyl sulfoxide

DMAP 4-Dimethylaminopyridine

EtOAc Ethyl acetate

Et₂0 Diethylether

HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate

HOBT N-Hydroxybenzotriazole LiBH₄ Lithium borohydride

□ HMDS Lithium bis(trimethylsilyl)amide

MDAP Mass directed autoprep

MeOH Methanol

NaBH₄ Sodium borohydride

NaHC0₃ Sodium bicarbonate

Na₂S0₄ Sodium sulfate

Nal Sodium hydride

NH₄CI Ammonium Chloride

Ni-Raney Nickel-Raney

Mel Methyl Iodide

HCI Hydrochloric acid

TEA Triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

h Hour

min Minute

Rt Retention time

r.t. room temperature

Sat. Sol. Saturated Solution

Intermediatel

2-r3,5-Bisitrifluoromethyl)phenyl1-A/-r6-ethenyl-4-i4-fluoro-2-methylphenyl)-3- pyridinyll-A/,2-dimethylpropanamide

To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3- pyridinyl]-/V,2-dimethylpropanamide (WO2005/002577 4.4 g, 8.26 mmol) in 1 ,4-dioxane (65 ml) and water (20 ml) 2-ethenyl-4,4_!5_!5-tetramethyl-1 _!3,2-dioxaborolane (1 .908 g, 12.39 mmol), tetrakis(triphenylphosphine)palladium(0) (0.954 g, 0.826 mmol) and sodium carbonate (4.38 g, 41.3 mmol) were added and the reaction mixture was refluxed for 8 h. After cooling the mixture was diluted with water (100 ml) and extracted with EtOAc (2x100 ml). The combined organic layers were dried (Na₂S0₄), filtered and evaporated and the residue was purified by chromatography on silica gel eluting with EtOAc in cyclohexane (0- 20%) to afford the title compound (Intermediate 1 ; 3.62 g, 6.90 mmol).

1H NMR (400 MHz, DMSO-d6): δ ppm 1.40 (s, 6 H) 2.12 (br s, 3 H) 2.50 (br s, 3 H) 5.51 (d, J=12.38 Hz, 1 H) 6.29 (d, 1 H) 6.74 - 6.93 (m, 1 H) 6.97 - 7.24 (m, 3 H) 7.46 (s, 1 H) 7.78 (br s, 2 H) 8.04 (s, 1 H) 8.36 (br s, 1 H).

HPLC Rt: 6.73 min.

Intermediate 2

2-f3,5-Bis(trifluoromethyl)phenyl1-A/-f4-(4-fluoro-2-methylphenyl)-6-formyl-3-pyridinyl1- A/,2-dimethylpropanamide

Method A

To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-ethenyl-4-(4-fluoro-2-methylphenyl)-3- pyridinyl]-N,2-dimethylpropanamide (Intermediate 1 , 3.6 g, 6.86 mmol) in THF/water (60 ml/20 ml) osmium tetroxide (5.39 ml of a 4% solution in water 0.686 mmol) was added and the reaction mixture was stirred at r.t. for 30 min.

Sodium periodate (2.202 g, 10.30 mmol) was then added and the mixture was stirred for 4 h at r.t. The reaction was diluted with water (50 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried (Na₂S0₄) and evaporated. The residue was purified using chromatography on silica gel eluting with EtOAc in cyclohexane (0-40%) to afford the title compound (Intermediate 2; 3.08 g, 5.85 mmol).

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.40 (br s, 6 H) 2.10 (s, 3 H) 2.50 (br s, 3 H) 6.94 - 7.28 (m, 3 H) 7.64 - 7.90 (m, 3 H) 8.04 (s, 1 H) 8.71 (s, 1 H) 10.04 (s, 1 H).

HPLC Rt: 6.89 min.

Method B

2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-ethenyl-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2- dimethylpropanamide (Intermediate 1 , 7.7 g, 14.68 mmol) was dissolved in MeOH (230 ml) and the yellow solution cooled to -65°C (internal T) under nitrogen. Ozone was then bubbled into the solution at -65°C for 15 min when the yellow colour was observed to fade.

The reaction mixture was purged with nitrogen at -65°C for 30 min and dimethyl sulfide (7.55 ml, 103 mmol) was then added at -65°C. The temperature was allowed to rise gradually to 20°C over 3 h.

The solvent was evaporated (bath temp 30°C) and the residue taken-up with AcOEt (150 ml) and washed with NH₄CI sat (2x50 ml). The organic layer was dried (Na₂S0₄) and evaporated to give 7.9 g of crude yellow foam that was purified by chromatography (silica 230-400Mesh) eluting with cyclohexane/AcOEt 8/2, 7/3 to give the title compound (5.7 g, 10.83 mmol, 74% yield) as a white foam.

UPLC (acidic conditions): Rt 1.08 min , m/z 527.2 [M+H⁺].

Intermediate 3

Ethyl -3-r5-r{2-r3,5-bis(trifluoromethyl)phenyl1-2-methylpropanoylMmethyl)ami fluoro-2-methylphenyl)-2-pyridinvn-2-propenoate

Method A

To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-formyl-3- pyridinyl]-N,2-dimethylpropanamide (Intermediate 2, 0.503 g, 0.955 mmol) in dry toluene (5 ml), ethyl (triphenyl- ⁵-phosphanylidene)acetate (0.499 g, 1.433 mmol) was added and the reaction mixture was refluxed for 2 h. After cooling the solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc in cyclohexane (0- 10%) to afford the title compound (Intermediate 3; 0.564 g, 0.879 mmol).

1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .36 (t, 3 H) 1.48 (br s, 6 H) 2.18 (br s, 3 H) 2.52 (br s, 3 H) 4.30 (q, 2 H) 6.88 - 7.08 (m, 4 H) 7.32 (s, 1 H) 7.70 (d, 1 H) 7.70 (br s, 2 H) 7.81 (br s, 1 H) 8.46 (br s, 1 H).

LC/MS (acidic conditions): Rt 1.03 min, m/z 597.15 [M+H]⁺. Method B

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2- dimethylpropanamide (WO2005/002577, 1 g, 1.877 mmol), ethyl-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-propenoate (0.636 g, 2.81 mmol), Na₂C0₃ (0.597 g, 5.63 mmol) and a 7:3:2 mixture of DME:water: EtOH (8 ml) were added to a 20 ml microwave vial followed by bis(triphenylphosphine)palladium(ll) chloride (0.066 g, 0.094 mmol). This mixture was heated at 140°C with microwave irradiation for 20 min. The reaction mixture was evaporated and the crude partitioned between DCM (100 ml) and water (100 ml). The DCM layer was collected by filtration through hydrophobic frit and evaporated to give the crude product which was purified by filtration through a small pad of silica (chromatography-eluting with DCM). The resulting ethyl (2£)-3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}-(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-propenoate

(Intermediate 3, 1 g, 1.341 mmol, 72% yield) was used without further purification. Intermediate 4

Ethyl 3-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4-(4- fluoro-2-methylphenyl)-2-pyridinvn-4-nitrobutanoate

DBU (0.143 ml, 0.945 mmol) was added to a solution of ethyl -3-[5-[{2-[3,5- bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2- pyridinyl]-2-propenoate (Intermediate 3, 0.564 g, 0.945 mmol) in nitromethane (3 ml, 55.6 mmol) at 0°C and the reaction was stirred overnight at r.t. The resulting yellow solution was diluted with Et₂0 and washed with aqueous HCI 1 N. The two layers were separated and the organic phase was dried (Na₂S0₄) and removed in vacuo to give the title compound (Intermediate 4; 0.612 g, 0.931 mmol).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .25 (t, 3 H) 1.46 (br s, 6 H) 2.13 (br s, 3 H) 2.47 (br s, 3 H) 2.79 (dd, 1 H) 2.95 (dd, 1 H) 4.02 - 4.25 (m, 3 H) 4.81 (dd, 1 H) 4.94 - 5.09 (m, 1 H) 6.86 - 7.17 (m, 3 H) 7.23 (br s, 1 H) 7.69 (br s, 2 H) 7.82 (br s, 1 H) 8.38 (br s, 1 H). LC/MS (acidic conditions): Rt 0.99 min, m/z 658.25 [M+H]⁺.

Intermediate 5

1 ,1 -Dimethylethyl 4-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoyl)- (methyl)amino1-4-(4-fluoro-2-methylphenyl)-2-pyridinvn-2-oxo-1 -pyrrolidinecarboxylate

To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-(5-oxo-3- pyrrolidinyl)-3-pyridinyl]-N,2-dimethylpropanamide (Example 1 , 0.412 g, 0.708 mmol) in dry DCM (7 ml), BOC₂0 (0.41 1 ml, 1.771 mmol) , TEA (0.099 ml, 0.708 mmol) and then DMAP (26.0 mg, 0.213 mmol) were added and the reaction mixture was stirred for 24 h at r.t. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with EtOAc in cyclohexane (20-50%) to give the title compound (Intermediate 5, 0.410 g, 0.601 mmol).

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.40 (br s, 6 H) 1.46 (s, 9 H) 2.12 (br s, 3 H) 2.33 (br s, 3 H) 2.74 - 2.92 (m, 2 H) 3.69 - 3.85 (m, 2 H) 4.03 - 4.18 (m, 1 H) 6.94 - 7.25 (m, 3 H) 7.37 (br s, 1 H) 7.75 (br s, 2 H) 8.04 (br s, 1 H) 8.39 (br s, 1 H).

LC/MS (acidic conditions): Rt 0.99 min, m/z 682.42 [M+H]⁺.

Intermediate 6

1 -( 1 ,1 -Dimethylethyl) 3-methyl 4-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methyl- propanoylMmethyl)amino1-4-(4-fluoro-2-methylphenyl)-2-pyridinvn-2-oxo-1 ,3- pyrrol i d i ned i carboxyl ate

To a solution of 1 ,1-dimethylethyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methyl- propanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-oxo-1 -pyrrolidine- carboxylate (Intermediate 5, 0.315 g, 0.462 mmol) in THF (6 ml), at -78°C, LiHMDS (0.924 ml, 0.924 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 1 h at the same temperature and then for 5 min at r.t. The mixture was then cooled to -78°C and methyl chloroformate (0.054 ml, 0.693 mmol) was added. The reaction mixture was stirred for 15 min at the same temperature and then quenched with aqueous NH₄CI (sat. sol.). The mixture was diluted with water and extracted with EtOAc and then the combined organic phases were dried (Na₂S0₄) and evaporated. The residue was purified by silica gel chromatography eluting with EtOAc in cyclohexane (0-30%) affording the title compound (Intermediate 6, 0.270 g, 0.365 mmol, 79% yield).

¹H NMR (500 MHz, CHLOROFORM-d): δ ppm 1.42 (br s, 6 H) 1.56 (br s, 9 H) 2.16 (br s, 3 H) 2.55 (br s, 3 H) 3.79 (s, 3 H) 3.88 - 4.03 (m, 1 H) 4.05 - 4.27 (m, 3 H) 6.95 (br s, 1 H) 6.97 - 7.05 (m, 1 H) 7.14 (s, 1 H) 7.21 (br s, 1 H) 7.68 (br s, 2 H) 7.80 (s, 1 H) 8.40 (br s, 1 H). LC/MS (acidic conditions): Rt 1.01 min, m/z 740.27 [M+H]⁺. Intermediate 7

Methyl 4-r5-r{2-r3,5-bis(trifluoromethyl)phenyl1^

i4-fluoro-2-methylphenyl)-2-pyridinyl1-2-oxo-3-pyrrolidinecarboxylate

Method A

To 1-(1 ,1 -dimethylethyl) 3-methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methyl- propanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-oxo-1 ,3-pyrrolidine- dicarboxylate (Intermediate 6, 0.270 g, 0.365 mmol) in DCM (6 ml) TFA (1.5 ml) was added dropwise and the reaction was stirred at r.t. for 2 h. The solvent was removed in vacuo and the residue dissolved in DCM then washed with aqueous NaHC0₃ (sat. sol.). The organic phase was dried (Na₂S0₄) and evaporated in vacuo to afford the title compound (Intermediate 7, 0.228 g, 0.314 mmol).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.44 (br s, 6 H) 2.13 (br s, 3 H) 2.48 (br s, 3 H) 3.70 - 3.80 (m, 2 H) 3.81 (s, 3 H) 3.96 (dd, 1 H) 4.27 - 4.39 (m, 1 H) 5.76 (br s, 1 H) 6.89 - 7.07 (m, 3 H) 7.14 (s, 1 H) 7.68 (br s, 2 H) 7.80 (br s, 1 H) 8.42 (br s, 1 H).

LC/MS (acidic conditions): Rt 0.84 min, m/z 640.18 [M+H]⁺.

Method B

Dimethyl {1 -[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-nitroethyl}propanedioate (Intermediate 33, 0.200 g, 0.285 mmol) was dissolved in MeOH (10 ml) and Raney-Ni (0.5 g, of a suspension in water, Fluka) was added. The mixture was hydrogenated (1 atm) at 25°C for 2.5 h. Further Raney- Ni (0.2 g) was added and the mixture hydrogenated (1 atm) at 25°C for 1 h. The mixture was filtered through a Gooch filter to remove the catalyst. To the filtrate 4 drops of Et₃N were added and the solution was refluxed for 30 min. The solvent was evaporated to give crude title compound (0.147 g, 0.228 mmol, 80% yield) as a grey foam.

UPLC (acidic conditions): Rt 1.04 min , m/z 640.3 [M+H⁺].

Intermediate 8 5-r{2-r3,5-Bis(trifluoromethyl)phenyl1-2-mefo^

methylphenyl)-2-pyridinecarboxylic acid

A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-ethenyl-4-(4-fluoro-2-methylphenyl)-3- pyridinyl]-N,2-dimethylpropanamide (Intermediate 1 , 500 mg, 0.953 mmol) in THF (9 ml) and water (3 ml) was treated with osmium tetroxide (0.748 ml of a 4% aqueous solution, 0.095 mmol, Aldrich) and the reaction mixture was stirred at r.t. for 30 min. Sodium periodate (306 mg, 1.430 mmol, Aldrich) was added and the resulting mixture was stirred at r.t. overnight. The reaction mixture was treated with water and then extracted with EtOAc. The combined organic extracts were dried (Na₂S0₄) and concentrated in vacuo to afford a residue which was purified by silica gel chromatography eluting with 10% MeOH in DCM to give the title compound (Intermediate 8, 200 mg, 0.369 mmol, 38.7 % yield).

1H NMR (400 MHz, DMSO-d6): δ ppm 1.21 - 1.66 (br m, 6 1-1) 2.12 (br m, 3 H) 2.35 - 2.66 (m, 3 H) 7.05 - 7.29 (m, 3 H) 7.59 - 7.95 (m, 3 H) 8.00 - 8.13 (m, 2 H) 8.58 (br m, 1 H).

UPLC (acidic conditions): Rt 0.85 min, m/z 543.06 [M+H⁺].

Intermediate 9

Methyl 5-rf2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoyl)-imethyl)amino1-4-i4- fluoro-2-methylphenyl)-2-pyridinecarboxylate

A solution of 5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinecarboxylic acid (Intermediate 8, 0.250 g, 0.461 mmol) in MeOH (9 ml) was treated with HCI (5 ml, 1 .25 M solution in MeOH, 6.25 mmol, Aldrich) and the reaction was heated at reflux overnight. After the removal of the volatiles, the crude was taken-up in EtOAc (15 ml) and quenched with a saturated aqueous solution of NaHC0₃. The separated organic phase was washed with aqueous NaHC0₃ (saturated solution) and brine and then dried (Na₂S0₄), filtered and evaporated affording the title compound (Intermediate 9, 0.230 g, 0.413 mmol, 90% yield). ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.44 (br m, 6 H) 2.15 (br m, 3 H) 2.50 (br m, 3 H) 4.00 (s, 3 H) 6.87 - 7.14 (m, 3 H) 7.69 (br m, 2 H) 7.82 (br m, 1 H) 7.98 (s, 1 H) 8.50 (br m, 1 H).

UPLC (acidic conditions): Rt 0.93 min, m/z 557.08 [M+H⁺]. Intermediate 10

Ethyl 3-r5-r{2-r3,5-bis(trifluoromethyl)phenyl1-2-^

fluoro-2-methylphenyl)-2-pyridinvn-3-oxopropanoate

To a solution of methyl 5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}-(methyl)- amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinecarboxylate (Intermediate 9, 0.255 g, 0.458 mmol) in EtOAc (20 ml), potassium tert-butoxide (77 mg, 0.687 mmol, Aldrich) was added and the reaction mixture was stirred at 75°C for 2 h. After cooling, another portion of potassium tert-butoxide (80 mg, 0.714 mmol, Aldrich) was added and the reaction was stirred at 75°C for an additional 2 h. The mixture was cooled, diluted with EtOAc and water was added. The organic phase was separated and washed with brine (x 2), dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc in cyclohexane (0-30%) to give the title compound (Intermediate 10, 94 mg, 0.153 mmol, 33.5 % yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.24 - 1 .37 (m, 9H) 2.15 (br m, 3 H) 2.49 (br m, 3H) 4.17 - 4.30 (m, 4 H) 6.87 - 7.09 (m, 3 H) 7.66 - 7.73 (m, 2 H) 7.78 - 7.84 (m, 1 H) 7.96 - 8.02 (m, 1 H) 8.49 (s, 1 H).

UPLC (acidic conditions): Rt 1.01 min, m/z 613.07 [M+H⁺].

Intermediate 11

Diethyl 2-{r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoyl)-(methyl)amino1-4- (4-fluoro-2-methylphenyl)-2-pyridinyllcarbonyl)butanedioate

A stirred mixture of ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}- (methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-3-oxopropanoate (Intermediate 10, 148 mg, 0.242 mmol) in acetone (6 ml) and DME (4 ml) was treated with K₂C0₃ (37 mg, 0.266 mmol, Aldrich), sodium iodide (18 mg, 0.121 mmol, Aldrich) and ethyl chloroacetate (0.028 ml_, 0.266 mmol, Aldrich) and the reaction mixture was stirred and heated at reflux overnight. The mixture was filtered and evaporated in vacuo to give the crude product which was purified by silica gel chromatography eluting with EtOAc in cyclohexane (10-30%) to afford the title compound (Intermediate 11 , 85 mg, 0.12 mmol, 50% yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.24 (m, 6 H) 1.44 (m, 6 H) 2.15 (br s, 3 H) 2.50 (br s, 3 H) 2.94 - 3.06 (m, 1 H) 3.1 1 - 3.22 (m, 1 H) 4.18 (m, 4 H) 5.27 - 5.38 (m, 1 H) 6.84 - 7.19 (m, 3 H) 7.69 (br s, 2 H) 7.82 (s, 1 H) 7.98 (s, 1 H) 8.50 (s, 1 H).

UPLC (acidic conditions): Rt 1.05 min, m/z 699.13 [M+H⁺].

Intermediate 12

Ethyl 2-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoylMmethyl)-amino1-4-i4- fluoro-2-methylphenyl)-2-pyridinvn-5-oxo-3-pyrrolidinecarboxylate (mixture of diastereoisomers)

To a stirred mixture of diethyl 2-{[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]carbonyl}- butanedioate (Intermediate 11 , 46 mg, 0.066 mmol) in MeOH (3 ml), ammonium acetate (50.8 mg, 0.658 mmol, Aldrich) and NaBH₃CN (2.90 mg, 0.046 mmol, Aldrich) were added and the reaction mixture was stirred at r.t. for 6 h and then refluxed overnight. After evaporation of the volatiles in vacuo, the residue was dissolved in EtOAc, washed with brine and sat. aq. NaHC0₃, then dried (Na₂S0₄) and evaporated. The crude product was purified by silica gel chromatography eluting with MeOH in DCM (0-10%) affording the title compound (Intermediate 12, 22 mg, 0.034 mmol, 51 % yield).

UPLC (acidic conditions): Rt 0.84 min and 0.87 min, m/z 654.14 [M+H⁺].

Intermediate 13

Diethyl 3-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoyl) (methyl)amino1-4-

Diethyl (acetylamino)propanedioate (0.546 g, 2.51 mmol) was added to a mixture of ethanol (3 ml) and DMSO (3 ml) followed by sodium ethoxide (0.171 g, 2.51 mmol). The resulting mixture was stirred at r.t. for 30 min. Then ethyl -3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-propenoate

(Intermediate 3, 1 .5 g, 2.51 mmol) was added and the resulting mixture was heated at 1 10°C for 18 h. The cooled solution was acidified with glacial acetic acid, and volatiles removed by evaporation. The crude residue was dissolved in EtOAc (100 ml) and washed with water (3 x 100 ml) and sat. brine (3 x 100 ml). The combined organics were dried (hydrophobic frit) and evaporated. The resulting crude material was purified by column chromatography (eluting with DCM then 10% EtOAc in DCM) to yield diethyl 3-[5-[{2-[3,5- bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2- pyridinyl]-5-oxo-2,2-pyrrolidinedicarboxylate (Intermediate 13, 0.87 g, 1.079 mmol, 43% yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.03 (br s, 2 H) 1.21 - 1.30 (m, 3 H) 1 .41 (br s, 4 H) 1 .63 (s, 2 H) 1.93 - 2.71 (m, 5 H) 2.71 - 2.95 (m, 1 H) 3.01 - 3.33 (m, 1 H) 3.77 - 3.90 (m, 1 H) 4.04 (br s, 1 H) 4.16 - 4.35 (m, 2 H) 4.16 - 4.35 (m, 2 H) 4.52 (br s, 1 H) 6.26 (br s, 1 H) 6.83 - 7.05 (m, 2 H) 7.07 - 7.25 (m, 1 H) 7.28 - 7.44 (m, 1 H) 7.65 (br s, 2 H) 7.79 (s, 1 H) 8.34 (s, 1 H).

UPLC (acidic conditions): Rt 1.49 min, m/z 813.98 [M+H]⁺.

Intermediate 14

Ethyl 3-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoyl) (methyl)amino1-4-(4- fluoro-2-methylphenyl)-2-pyridinvn-5-oxoprolinate

Diethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-

2- methylphenyl)-2-pyridinyl]-5-oxo-2,2-pyrrolidinedicarboxylate (Intermediate 13, 0.70 g, 0.965 mmol) was dissolved in MeOH (20 ml) and treated with sodium hydroxide (38.6 mg, 0.965 mmol) in water (2 ml). The reaction mixture was stirred at r.t. for 18 h before MeOH was removed by evaporation and the reaction mixture was acidified with aq. HCI (2N). The intermediate ester-acid was extracted into EtOAc, dried (hydrophobic frit) and evaporated before dissolving in toluene (20 ml) and DMSO (1 ml) and heating at 100°C for 3 h. The volatiles were removed from the cooled reaction mixture by evaporation under reduced pressure and the resulting residue was diluted with EtOAc (100 ml) and washed three times with water. The combined organics were dried (hydrophobic frit) and evaporated to a residue which was filtered through an NH2 column (ISOLUTE Flash) eluting with EtOAc to give the crude product which was purified by column chromatography eluting with EtOAc to afford the title compound (Intermediate 14, 0.45 g, 0.689 mmol, 71 % yield).

1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.18 - 1 .62 (m, 8 H) 1.70 (s, 2 H) 1.97 - 2.71 (m, 5 H) 2.72 - 2.98 (m, 2 H) 3.83 - 3.96 (m, 1 H) 4.12 - 4.29 (m, 2 H) 4.66 (br s, 1 H) 6.17 (s, 1 H) 6.88 - 7.06 (m, 2 H) 7.15 (s, 1 H) 7.17 - 7.26 (m, 1 H) 7.67 (s, 2 H) 7.80 (s, 1 H) 8.43 (s, 1 H);

UPLC (acidic conditions): Rt 1.35min, m/z 653.87 [M+H]⁺.

Intermediate 15

3- r5-r{2-r3,5-Bis(trifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4-(4-fluoro- 2-methylphenyl)-2-pyridinyl1-5-oxoproline

Ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro- 2-methylphenyl)-2-pyridinyl]-5-oxoprolinate (Intermediate 14, 94 mg, 0.144 mmol) was dissolved in a MeOH:THF:water mixture (2 ml). Then LiOH (5.17 mg, 0.216 mmol) was added and the mixture heated at 140°C for 10 min. in a microwave. The cooled reaction was evaporated to dryness and purified by MDAP to give the title compound (Intermediate 15, 80 mg, 0.128 mmol, 89% yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .01 - 1.74 (m, 6 H) 1.94 - 3.12 (m, 8 H) 3.47 (s, 1 H) 3.80 - 4.05 (m, 1 H) 4.07 - 4.25 (m, 1 H) 4.43 - 4.76 (m, 1 H) 6.76 - 7.05 (m, 2 H) 7.07 - 7.25 (m, 1 H) 7.29 - 7.46 (m, 1 H) 7.66 (s, 2 H) 7.71 - 7.85 (m, 1 H) 8.40 (br s, 1 H) LC/MS : Rt 0.97 min, m/z 625.85 [M+H]⁺.

Intermediate 16

Ethyl 3-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4-(4- fluoro-2-methylphenyl)-2-pyridinvn-1 -methyl -5-oxoprolinate

Ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro- 2-methylphenyl)-2-pyridinyl]-5-oxoprolinate (Intermediate 14, 205 mg, 0.314 mmol) in DMF (2 ml) was added to a slurry of sodium hydride (60% w/w in mineral oil) (15 mg, 0.376 mmol) in DMF (2 ml) at -30°C. The mixture was stirred for 10 min. and then methyl iodide (0.025 ml, 0.408 mmol) in DMF (1 ml) was added. The reaction mixture was stirred for 1 h. at -30°C and then allowed to warm to r.t. over 4 h. It was then stirred at r.t. for 48 h. The reaction was quenched with a sat. aq. solution of ammonium chloride (1 ml). The solvent was then removed in vacuo and the residue was purified by mass directed autoprep. The product containing fractions were combined and the solvent removed. This afforded the title compound (Intermediate 16, 81 mg, 0.121 mmol, 39% yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .28 (t, 3 H) 1.36 - 1.60 (br m, 6 H) 2.05 - 2.20 (br s, 3 H) 2.35 - 2.70 (br m, 3 H) 2.74 - 2.85 (br m, 1 H) 2.93 (s, 3 H) 2.88-2.96 (br m, 1 H) 3.72 (m, 1 H) 4.26 (q, 2 H) 4.49 (br m, 1 H) 6.92 - 6.98 (br m, 1 H) 7.01 (d, 1 H) 7.07 (s, 1 H) 7.13 - 7.25 (br m, 1 H) 7.67 (s, 2 H) 7.79 (s, 1 H) 8.40 (s, 1 H).

UPLC (acidic conditions): Rt 1.33 min, m/z 668.1 1 [M+H⁺]. Intermediate 17

Ethyl 3-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4-i4- fluoro-2-methylphenyl)-2-pyridinvn-5-oxo-1 -i2,2,2-trifluoroethyl)prolinate

Ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro- 2-methylphenyl)-2-pyridinyl]-5-oxoprolinate (Intermediate 14, 147 mg, 0.225 mmol) was dissolved in DMF (5 ml) under argon. The mixture was cooled to -30°C and treated with sodium hydride (60% w/w in mineral oil) (10 mg, 0.250 mmol). The mixture was stirred for 15 min at -35°C and then 2,2,2-trifluoroethyl trichloromethanesulfonate (127 mg, 0.450 mmol) was added in DMF (1 ml). The reaction mixture was allowed to warm to r.t. over 2 h. and then stirred at r.t. overnight. The reaction mixture was quenched by the addition of a sat. sol. of ammonium chloride (1 ml) and then extracted into EtOAc (2 x 50 ml) from water (10 ml). The organic phase was dried (Na₂S0₄) and then concentrated in vacuo. The residue was purified by mass directed autoprep to afford the title compound (Intermediate 17, 80 mg, 0.109 mmol, 48% yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .27 (t, 3 H) 1.37 - 1.64 (br m, 6 H) 2.03 - 2.22 (br s, 3 H) 2.34 - 2.70 (br m, 3 H) 2.84 - 2.98 (br m, 2 H) 3.67 (m, 1 H) 3.76 (m, 1 H) 4.26 (q, 2 H) 4.50 (m, 1 H) 4.69 (m, 1 H) 6.91 - 6.98 (br m, 1 H) 7.01 (d, 1 H) 7.07 (s, 1 H) 7.12 - 7.23 (br m, 1 H) 7.66 (s, 2 H) 7.79 (s, 1 H) 8.41 (s, 1 H);

UPLC (acidic conditions): Rt 1.43 min, m/z 736.10 [M+H⁺].

Intermediate 18

Ethyl 3-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4-i4- fluoro-2-methylphenyl)-2-pyridinvn-4-methyl-4-nitropentanoate

To ethyl-3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-propenoate (Intermediate 3, 177 mg, 0.297 mmol) in 2- nitropropane (1.6 ml, 17.80 mmol) at 0°C was added DBU (44.7 μΙ, 0.297 mmol) and the reaction was left stirring at r.t. overnight. The mixture was then diluted with Et₂0 (-30 ml) and washed with 1 N HCI (-30 ml), the separated organic layer was dried (Na₂S0₄) and evaporated to yield the title compound as a yellow crystalline solid (170 mg, -70% purity) which was used directly in the next step without further purification.

UPLC (acidic conditions): Rt 1.51 min, m/z 686.1 1 [M+H]⁺. Intermediate 19

1 ,1 -Dimethylethyl 3-r5-rf2-r3,5-bis(trifluoromethyl)phenyl1-2- methylpropanoylMmethyl)amino1-4-(4-fluoro-2-methylphenyl)-2 -pyridinyl1-2,2-dimethyl- 5-OXO-1 -pyrrolidinecarboxylate

To a solution of the 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-(2,2-dimethyl-5-oxo-3-pyrrolidinyl)- 4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (Compound 20, 514 mg, 0.843 mmol) in DCM (8.5 ml) was added BOC₂0 (0.489 ml, 2.108 mmol), TEA (0.1 18 ml, 0.843 mmol) and DMAP (30.9 mg, 0.253 mmol). The resulting reaction mixture was then stirred at r.t. overnight. The reaction was then concentrated to dryness and purified by column chromatography eluting with EtOAc: iso-hexane (1 :1 ) to yield the title compound as a white crystalline solid (Intermediate 19, 438 mg, 0.717 mmol, 85% yield).

UPLC (acidic conditions): Rt 1.32 min, m/z 610.1 1 [M+H - Boc]⁺.

Intermediate 20

1 - M .1 -Dimethylethyl) 3-methyl 4-r5-rf2-r3.5-bis(trifluoromethyl)phenvn-2- methylpropanoylMmethyl)amino1-4-(4-fluoro-2-methylphenyl)-2-pyridinvn-5,5-dimethyl-

2- oxo-1 ,3-pyrrolidinedicarboxylate

To a solution of 1 ,1-dimethylethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2,2-dimethyl-5-oxo- 1 -pyrrolidinecarboxylate (Intermediate 19, 438 mg, 0.617 mmol) in THF (30 ml) at -78°C was added LiHMDS (1.234 ml, 1 M in THF, 1.234 mmol). The resulting reaction mixture was stirred at -78°C for 30 min. before methyl chloroformate (0.072 ml, 0.926 mmol) was added. The reaction was then stirred at -78 °C for a further 1 h. before being partitioned between water (50 ml) and EtOAc (50 ml). The organic layer was separated, dried (Na₂S0₄) and concentrated to to afford a residue which was purified by MDAP to yield the title compound as a colourless gum (Intermediate 20, 474 mg, 0.617mmol, 100% yield).

UPLC (acidic conditions): Rt 1.53 min, m/z 768.08 [M+H]⁺.

Intermediate 21

Methyl 4-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4- (4-fluoro-2-methylphenyl)-2-pyridinvn-5,5-dimethyl-2-oxo-3-pyrrolidinecarboxylate

TFA (3 ml) was added to a stirred solution of 1 -(1 ,1-dimethylethyl) 3-methyl 4-[5-[{2-[3,5- bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2- pyridinyl]-5,5-dimethyl-2-oxo-1 ,3-pyrrolidinedicarboxylate (Intermediate 20, 474 mg, 0.617 mmol) in DCM (30 ml) at r.t.. After 2 h the mixture was concentrated in vacuo and the residue was dissolved in saturated NaHC0₃ solution (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried (Na₂S0₄) and concentrated in vacuo to yield the crude product (-50% purity) as a yellow crystalline solid (386 mg) which was used in the next step without purification.

UPLC (acidic conditions): Rt 1.38 min, m/z 667.94 [M+H]⁺. Intermediate 22

1 -(1.1 -Dimethylethyl) 3.3-dimethyl 4-r5-rf2-r3.5-bis(trifluoromethyl)phenvn-2- methylpropanoylMmethyl)amino1-4-(4-fluoro-2-methylphenyl)-2-pyridinvn-2-oxo-1 ,3,3- pyrrolidinetricarboxylate

To a solution of 1 ,1-dimethylethyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methyl- propanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-oxo-1 -pyrrolidine- carboxylate (Intermediate 5, 500 mg, 0.734 mmol) in THF (17.8 ml) at -15°C was added "BuLi (1 .146 ml, 1.834 mmol). The resulting reaction mixture was stirred for 30 min. before methyl chloroformate (0.142 ml, 1 .834 mmol) was added and the reaction was then stirred at -15°C for a further 1 h. before partitioning between water (100 ml) and EtOAc (100 ml). The organic layer was separated, dried (Na₂S0₄) and concentrated to dryness to yield the crude product which was purified by column chromatography eluting with 1 :1 EtOAc :iso-hexane to yield the title compound as a yellow oil (Intermediate 22, 250 mg, 0.313 mmol, 42% yield). UPLC (acidic conditions): Rt 1.46 min, m/z 798.15 [M+H]⁺.

Intermediate 23

1 ,1 -Dimethylethyl 4-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoyl)- imethyl)amino1-4-i4-fluoro-2-methylphenyl)-2-pyridinvn-3,3-bisihvdroxymethyl)-2-oxo-

1 -pyrrolidinecarboxylate

To a solution of 1 -(1 ,1-dimethylethyl) 3,3-dimethyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-oxo-1 ,3,3- pyrrolidinetricarboxylate (Intermediate 22, 250 mg, 0.313 mmol) in EtOH (13.9 ml) and water (2.3 ml) at 0°C was added calcium chloride (174 mg, 1.567 mmol). The resulting mixture was stirred for 30 min. before NaBH₄ (1 19 mg, 3.13 mmol) was added. The reaction was then stirred at 0°C for a further 2 h then acidified with 5N HCI before being concentrated to dryness and partitioned between water (100 ml) and DCM (100 ml). The organic layer was separated, dried (Na₂S0₄) and concentrated to dryness to yield the title compound as a yellow crystalline solid (Intermediate 23, 100 mg, 0.135mmol, 43% yield).

UPLC (acidic conditions): Rt 1.19 min, m/z 642.18 [M+H - Boc]⁺. Intermediate 24

Ethyl 3-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4-(4- fluoro-2-methylphenyl)-2-pyridinvn-4-nitropentanoate

Ethyl (2E)-3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-2-propenoate (Intermediate 3, 589 mg, 0.987 mmol) was dissolved in nitroethane (4.24 ml, 59.2 mmol). To the solution at 0°C was added DBU (0.149 ml, 0.987 mmol) and the reaction was left stirring at room temperature overnight. The solution was then diluted with diethyl ether (-100 ml) and washed with 1 N HCI (-100 ml), the two layers were separated and the ether layer was dried (Na₂S0₄) and concentrated to dryness. The crude material was then carried straight through to the next reaction without further purification (Intermediate 24, 61 1 mg, 0.91 mmol, 92% yield).

UPLC (acidic conditions): Rt 1.52 min , m/z 671 .98 [M+H⁺].

Intermediate 25

1 ,1 -Dimethylethyl 4-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoyl)- imethyl)amino1-4-i4-fluoro-2-methylphenyl)-2-pyridinvn-3-i1 -hvdroxy-1 -methylethyl)-2- oxo-1 -pyrrolidinecarboxylate

To a solution of the 1 ,1 -dimethylethyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-oxo-1 - pyrrolidinecarboxylate (Intermediate 5, 200 mg, 0.293 mmol) in THF (10 ml) at -78 °C was added LiHMDS (0.587 ml, 0.587 mmol). The resulting reaction mixture was left stirring under an atmosphere of argon for 1 h at -78 °C then 5 min. at r.t. the mixture was then cooled to - 78°C and acetone (0.032 ml, 0.440 mmol) was added. The reaction was then stirred at -78°C for a further 15 min. before being quenched with a saturated aqueous solution of NH₄CI. The quenched reaction mixture was then partitioned between water (100 ml) and EtOAc (100 ml), the organic layer was separated, dried (Na₂S0₄) and concentrated to dryness to yield the title compound as a yellow crystalline solid (Intermediate 25, 219 mg, 0.293 mmol, 100% yield).

UPLC (acidic conditions): Rt 1.43 min , m/z 740.07 [M+H⁺].

Intermediate 26

1 ,1 -Dimethylethyl 3-r5-r{2-r3,5-bis(trifluoromethyl)phenvn-2-methylpropanoyl)- imethyl)amino1-4-i4-fluoro-2-methylphenyl)-2-pyridinvn-2-methyl-5-oxo-1 - pyrrol i d i necarboxyl ate :

To a solution of the 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-(2- methyl-5-oxo-3-pyrrolidinyl)-3-pyridinyl]-N,2-dimethylpropanamide (Compound 25, 1.05 g, 1.763 mmol) in DCM (18 ml) was added BOC₂0 (0.962 g, 4.41 mmol), triethylamine (0.246 ml, 1 .763 mmol) and DMAP (0.065 g, 0.529 mmol). The resulting reaction mixture was then stirred at r.t. The reaction was concentrated to dryness and purified by column chromatography on a silica gel column using EtOAc in iso-hexane, 0%-20% (3CV), 20%- 50% (10CV) to yield the title compound as a white crystalline solid (Intermediate 26, 928 mg, 1.334 mmol, 76% yield).

UPLC (acidic conditions): Rt 1.45 min , m/z 595.87 [M+H⁺]. Intermediate 27

1 -(1 ,1 -Dimethylethyl) 3-methyl 4-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2- methylpropanoylMmethyl)amino1-4-(4-fluoro-2-methylphenyl)-2-pyridinvn-5-methyl-2- oxo-1 ,3-pyrrolidinedicarboxylate

To a solution of the 1 ,1 -dimethylethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-5-oxo-1 - pyrrolidinecarboxylate (Intermediate 26, 1 .0068 g, 1 .447 mmol) in THF (40 ml) at -78°C was added LiHMDS (2.89 ml, 2.89 mmol). The resulting reaction mixture was left stirring at -78°C under an atmosphere of argon for 30 min., then allowed to reach 0°C, returning to -78°C, before methyl chloroformate (0.168 ml, 2.171 mmol) was added. The reaction was then stirred at -78°C for a further 1 h before being partitioned between water (50 ml) and EtOAc (50 ml). The organic layer was then separated, dried (Na₂S0₄) and concentrated to dryness. This material (containing 77% desired product by LCMS) was carried onto the next step without purification (Intermediate 27, 1.028 g, 1.364 mmol).

UPLC (acidic conditions): Rt 1.47 min , m/z 753.99 [M+H⁺]. Intermediate 28

Methyl 4-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4- i4-fluoro-2-methylphenyl)-2-pyridinvn-5-methyl-2-oxo-3 -pyrrolidinecarboxylate

To a stirred solution of 1-(1 ,1 -dimethylethyl) 3-methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]- 2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-5-methyl-2-oxo- 1 ,3-pyrrolidinedicarboxylate (Intermediate 27, 1.028 g, 1.364 mmol) in DCM (30 ml) was added TFA (3 ml) and the mixture was stirred for 2 h then concentrated in vacuo. The residue was dissolved in saturated aqueous NaHC0₃ (50 ml) and extracted with EtOAc (1 x 50 ml). The organic phase was dried (Na₂S0₄) and concentrated in vacuo to afford the crude product which was carried through to the next step without purification (Intermediate 28, 0.892 g, 1.365 mmol, 100% yield).

UPLC (acidic conditions): Rt 1.28 min , m/z 653.91 [M+H⁺]. Intermediate 29

1 -(1 ,1 -Dimethylethyl) 3-methyl 4-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2- methylpropanoylMmethyl)amino1-4-i4-fluoro-2-methylphenyl)-2-pyridinvn-3-methyl-2- oxo-1 ,3-pyrrolidinedicarboxylate

To a solution of the 1-(1 ,1-dimethylethyl) 3-methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-oxo-1 ,3- pyrrolidinedicarboxylate (Intermediate 6, 300 mg, 0.406 mmol) in THF (10 ml) at 0 °C was added sodium hydride (24.3 mg, 0.608 mmol). The resulting reaction mixture was left stirring under an atmosphere of argon for 25 min. Methyl iodide (0.038 ml, 0.608 mmol) was added and the reaction mixture was stirred at 0°C for a further 1 h then partitioned between water (50 ml) and EtOAc (50 ml). The organic layer was separated, dried (Na₂S0₄) and concentrated to dryness. The crude product was purified on a silica gel column in 0% EtOAc: iso-hexane (2CV) 0-40% EtOAc: iso-hexane (15CV) to yield the title compound as a white crystalline solid (Intermediate 29, 296 mg, 0.39 mmol, 96% yield).

UPLC (acidic conditions): Rt 1.46 min , m/z 754.00 [M+H⁺].

Intermediate 30

Methyl 4-r5- 2-r3,5-bisitrifluoromethyl)phenvn-2-methylpropanoylMmethyl)amino1-4- i4-fluoro-2-methylphenyl)-2-pyridinvn-3-methyl-2-oxo-3-pyrrolidinecarboxylate

To a stirred solution of 1-(1 ,1 -dimethylethyl) 3-methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]- 2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-3-methyl-2-oxo- 1 ,3-pyrrolidinedicarboxylate (Intermediate 29, 195 mg , 0.259 mmol) in DCM (4 ml) was added TFA (0.2 ml). After 2 h. the mixture was concentrated in vacuo and saturated aqueous NaHC0₃ solution (50 ml) was added. The resulting aqueous mixture was extracted with EtOAc (1 x 50 ml). The organic phase was dried (Na₂S0₄) and concentrated in vacuo to yield the title compound as a colourless gum (Intermediate 30, 169mg, 0.259mmol, 100% yield).

UPLC (acidic conditions): Rt 1.27 min , m/z 653.94 [M+H⁺]. Intermediate 31

N-r6-(2-Acetyl-5-oxo-3-pyrrolidinyl)-4-(4-fluoro-2-methylphenyl)-3-pyridinvn-2-r3.5- bis(trifluoromethyl)phenyll-N,2-dimethylpropanamide

Intermediate 15 (92.5 mg, 0.148 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.156 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (15 mg, 0.154 mmol) were dissolved in anhydrous DCM (3 ml). N-Methylmorpholine (0.050 ml, 0.455 mmol) was added and the reaction was stirred at r.t. overnight. The mixture was extracted into EtOAc (2 x 50 ml) from 10% aqueous citric acid (50 ml). The organic phases were combined and extracted with brine (50 ml) then dried (Na₂S0₄) and concentrated in vacuo. The crude reaction product (84 mg, 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-N-methyl-N- (methyloxy)-5-oxoprolinamide was dissolved in THF (5 ml) and cooled to 0°C. Methylmagnesium bromide (3M in Et₂0) (0.2 ml, 0.600 mmol) was added and the mixture was stirred at 0°C for 2 h. The reaction was allowed to warm to r.t. and stirred overnight. Additional methylmagnesium bromide (3M in Et₂0) (0.2 ml, 0.600 mmol) was added and the reaction stirred at r.t. for a further 4 h before the reaction was quenched by addition of saturated aqueous NH₄CI (1 ml). Water (20 ml) was added and the mixture was extracted into EtOAc (2 x 50 ml). The combined organic phases were dried (Na₂S0₄) and the solvent was removed in vacuo to afford a residue which was purified by mass directed autoprep. The product containing fraction was concentrated in vacuo to afford the title compound as a mixture of stereoisomers (Intermediate 31 , 13 mg, 0.021 mmol, 14% yield).

1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.38 - 1.60 (m, 6 H) 2.06 - 2.19 (m, 6 H) 2.35 - 2.65 (m, 3H) 2.77 - 2.84 (m, 2H) 3.68 - 3.78 (m, 1 H) 4.67 - 4.90 (m, 1 H) 6.39 - 6.52 (m, 1 H) 6.92 - 7.04 (m, 2 H) 7.13 (s, 1 H) 7.15 - 7.25 (m, 1 H) 7.68 (s, 2 H) 7.80 (s, 1 H) 8.45 (s, 1 H).

UPLC (acidic conditions): Rt 1.23 min, m/z 624.05 [M+H⁺].

Intermediate 32

2-r3,5-Bisitrifluoromethyl)phenvn-A/-f4-i4-fluoro-2-methylphenyl)-6-r2-nitroethenvn-3- pyridinyl)-A/,2-dimethylpropanamide

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-formyl-3-pyridinyl]-N,2- dimethylpropanamide (Intermediate 2, 1 .0 g, 1.900 mmol) was suspended in MeOH (10 ml) and nitromethane (0.512 ml, 9.50 mmol) was added. Triethylamine (1.324 ml, 9.517 mmol) was added dropwise at 25°C and dissolution occured to give a clear pale yellow solution. The mixture was stirred at 25°C for 1 h then water (20 ml) was addded and the aqueous phase was extracted with DCM (3x20 ml). The combined organic layers were dried (Na₂S0₄) then evaporated to give 1.2 g of nitro-alchohol as white powder. This powder was dissolved in dry THF (10 ml) and triethylamine (0.528 ml, 3.79 mmol) was added at 25°C. Methanesulfonyl chloride (0.296 ml, 3.80 mmol) was added dropwise at 25°C (immediate formation of yellow suspension that turned to orange) and the mixture stirred at 25°C for 15 min. Saturated aqueous NaHC0₃ (20 ml) was added and the aqueous phase was extracted with EtOAc (2x20 ml). The combined organic phases were dried (Na₂S0₄) and evaporated to give a residue which was chromatographed (silica 230-400Mesh) eluting with cyclohexane/EtOAc 9/1 , 8/2 to give title compound (0.952 g, 1.67 mmol, 88% yield) as a yellow foam.

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.37-1.53 (m, 6 H) 2.08 - 2.26 (m, 3 H) 2.31 - 2.70 (m, 3 H) 6.89 - 7.25 (m, 3 H) 7.36 (s, 1 H) 7.68 (s, 2 H) 7.81 (s, 1 H) 7.94 (d, 1 H) 8.03 (d, 1 H) 8.42- 8.53 (m, 1 H).

UPLC (acidic conditions): Rt 1.13 min , m/z 570.3 [M+H⁺].

Intermediate 33

Dimethyl {1 -r5-r{2-r3,5-bis(trifluoromethyl)phenyl1-2-methylpropanoylMmethyl)amino1- 4-(4-fluoro-2-methylphenyl)-2-pyridinvn-2-nitroethyl)propanedioate

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[2-nitroethenyl]-3- pyridinyl}-N,2-dimethylpropanamide (Intermediate 32, 0.935 g, 1.642 mmol) and dimethylmalonate (0.375 ml, 3.28 mmol) were dissolved in dry THF (10 ml). The mixture was cooled to 0°C before DBU (0.495 ml, 3.28 mmol) was added dropwise at 0°C and the mixture was stirred at 25°C for 30 min. Saturated aqueous NaHC0₃ (30 ml) and EtOAc (30 ml) were added and the phases separated. The aqueous phase was back-extracted with EtOAc (30 ml). The combined organic phases were dried (Na₂S0₄) and then evaporated to a residue which was chromatographed over silica (230-400Mesh) eluting with cyclohexane/EtOAc 9/1 , 8/2 to give title compound (0.887 g, 1.26 mmol, 77% yield) as a white foam.

1H NMR (400 MHz, DMSO-d6): δ ppm 1.50 (br s, 6 H) 1.98 (br s, 3 H) 2.50 (br s, 3 H) 3.52 (br s, 3 H) 3.67 (br s, 3 H) 4.18 (d, 1 H) 4.32 (m, 1 H) 5.1 1 (m, 2 H) 6.91 - 7.28 (m, 3 H) 7.41 (m, 1 H) 7.59-7.91 (m, 2H) 8.02 (br s, 1 H) 8.36 (m, 1 H).

UPLC (acidic conditions): Rt 1.12 min , m/z 702.3 [M+H⁺].

Example 1

2-r3,5-Bisitrifluoromethyl)phenvn-A/-r4-i4-fluoro-2-methylphenyl)-6-i5-oxo-3- pyrrolidinyl)-3-pyridinvn-A/,2-dimethylpropanamide

To ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-4-nitrobutanoate (Intermediate 4, 0.612 g, 0.931 mmol) in EtOH (6 ml) Raney-Ni (1 g of a suspension in water, Fluka) was added and the reaction was stirred under H₂ atmosphere for 4 h. The reaction mixture was filtered through a celite pad and the solvent was removed in vacuo affording the title compound (0.441 g, 0.758 mmol, 81 % yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.44 (br s, 6 H) 2.16 (br s, 3 H) 2.41 (br s, 3 H) 2.64 - 2.88 (m, 2 H) 3.66 - 3.85 (m, 2 H) 3.85 - 3.99 (m, 1 H) 5.56 (br s, 1 H) 6.87 - 7.07 (m, 3 H) 7.1 1 (s, 1 H) 7.64 - 7.74 (m, 2 H) 7.81 (br s, 1 H) 8.42 (br s, 1 H).

LC/MS (acidic conditions): Rt 0.82 min, m/z 582.17 [M+H]⁺.

Example 2

>¾nf/-2-r3,5-Bisitrifluoromethyl)phenvn-A/-f4-i4-fluoro-2-methylphenyl)-6-r4- ihvdroxymethyl)-5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide

(racemate)

Preparation 1

To a suspension of methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}- (methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-oxo-3-pyrrolidinecarboxylate

(Intermediate 7, Method A 0.228 g, 0.356 mmol) and calcium chloride (39.6 mg, 0.356 mmol) in MeOH (5 ml) at 0°C was added NaBH₄ (40.5 mg, 1.069 mmol) and the reaction mixture was stirred at r.t. for 2 h. Citric Acid (sat. aq. sol.) was added until pH = 3-4, and then the mixture was extracted with DCM. The combined organic phases were dried (Na₂S0₄) and evaporated in vacuo to give the crude product which was purified by silica gel chromatography eluting with MeOH in DCM (2-5%) to afford the title compound (0.173 g, 0.283 mmol) as a mixture of enantiomers. ¹H NMR (500 MHz, DMSO-d6): δ ppm 1.41 (br s, 6 H) 2.1 1 (br s, 3 H) 2.50 (br s, 3 H) 3.36 - 3.46 (m, 1 H) 3.46 - 3.65 (m, 2 H) 3.67 - 3.77 (m, 1 H) 3.77 - 3.88 (m, 1 H) 4.67 - 4.82 (m, 1 H) 7.03 (br s, 1 H) 7.12 (br s, 1 H) 7.15 - 7.22 (m, 1 H) 7.30 (s, 1 H) 7.75 (br s, 2 H) 7.71 - 7.74 (m, 1 H) 8.03 (s, 1 H) 8.38 (s, 1 H).

LC/MS (basic conditions): Rt 0.93 min, m/z 612.25 [M+H]⁺.

Preparation 2

(Intermediate 7 Method B, 0.136 g, 0.213 mmol) and calcium chloride (0.024 g, 0.213 mmol) in MeOH (3 ml) at 0°C was added sodium borohydride (0.024 g, 0.638 mmol) and the reaction mixture was stirred at r.t. for 1 h. Further NaBH₄ (0.012 g, 0.319 mmol) was added and the mixture stirred at 25°C for 15 min. A saturated aqueous solution of citric acid (5 ml) and DCM (5 ml) were added. Phases were separated and aqueous phase was back- extracted with DCM (5 ml). The combined organic phases were dried (Na₂S0₄) and evaporated and the residue chromatographed (silica 230-400Mesh) eluting with DCM/MeOH 98/2, 95/5 to give title compound (0.086 g, 0.141 mmol, 66% yield) as a mixture of enantiomers.

¹H NMR (500 MHz, DMSO-d6): δ ppm 1.41 (br s, 6 H) 2.1 1 (br s, 3 H) 2.50 (br s, 3 H) 3.36 - 3.46 (m, 1 H) 3.46 - 3.65 (m, 2 H) 3.67 - 3.77 (m, 1 H) 3.77 - 3.88 (m, 1 H) 4.67 - 4.82 (m, 1

Example 3

2-r3,5-Bis(trifluoromethyl)phenvn-N-{4-(4-fluoro-2-methylphenyl)-6-r(4- ihvdroxymethyl)-5-oxo-3-pyrrolidinvn-3-pyridinyl)-N,2-dimethylpropanamide

hydrochloride (enantiomer 1) and

Example 4

2-r3,5-Bisitrifluoromethyl)phenvn-N-f4-i4-fluoro-2-methylphenyl)-6-r(4- (hvdroxymethyl)-5-oxo-3-pyrrolidinvn-3-pyridinyl)-N,2-dimethylpropanamide

hydrochloride (enantiomer 2)

Preparation 1

The mixture of enantiomers (Example 2, Preparation 1 0.173 g, 0.283 mmol ) was separated by chiral chromatography.

Preparative chromatographic conditions Column: Chiralpak AD-H (25 x 0.46 cm), Mobile phase: n-hexane/EtOH 65/35 % v/v

Flow rate: 0.8 ml/min

DAD: 210-340 nm to give according to the order of elution:

(Rt 4.79 min): 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(4- (hydroxymethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide hydrochloride {enantiomer 1){68.5 mg, 0.1 12 mmol, 31 % yield).

¹H NMR (500 MHz, DMSO-d6): δ ppm 1.41 (br s, 6 H) 2.1 1 (br s, 3 H) 2.50 (br s, 3 H) 3.36 - 3.46 (m, 1 H) 3.46 - 3.65 (m, 2 H) 3.67 - 3.77 (m, 1 H) 3.77 - 3.88 (m, 1 H) 4.67 - 4.82 (m, 1 H) 7.03 (br s, 1 H) 7.12 (br s, 1 H) 7.15 - 7.22 (m, 1 H) 7.30 (s, 1 H) 7.75 (br s, 2 H) 7.71 -

7.74 (m, 1 H) 8.03 (s, 1 H) 8.38 (s, 1 H).

LC/MS (basic conditions): Rt 0.93 min, m/z 612.24 [M+H]⁺.

A portion of this material (20 mg, 0.033 mmol) in Et₂0 (0.5 ml) and DCM (0.5 ml) at 0°C was treated with HCI (0.065 ml of 1 M solution in Et₂0, 0.065 mmol) and the mixture was stirred for 10 min then the solvent was removed in vacuo. The resulting solid was washed several times with Et₂0 and dried to give Example 3 (21 mg, 0.031 mmol).

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.41 (br s, 6 H) 2.09 (br s, 3 H) 2.31 (br s, 3 H) 2.56 - 2.74 (m, 1 H) 3.49 - 3.64 (m, 2 H) 3.68 - 3.77 (m, 1 H) 3.79 - 3.90 (m, 1 H) 4.04 - 4.20 (m, 1 H) 6.97 - 7.26 (m, 3 H) 7.35 (br s, 1 H) 7.76 (br s, 3 H) 8.05 (br s, 1 H) 8.41 (br s, 1 H).

LC/MS (basic conditions): Rt 0.93 min, m/z 612.21 [M+H]⁺.

(Rt 17.82 min): 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[4-

(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 2)

(70.1 mg, 0.1 15 mmol, 32 % yield).

1H NMR (500 MHz, DMSO-d6): δ ppm 1.41 (br s, 6 H) 2.1 1 (br s, 3 H) 2.50 (br s, 3 H) 3.36 -

3.46 (m, 1 H) 3.46 - 3.65 (m, 2 H) 3.67 - 3.77 (m, 1 H) 3.77 - 3.88 (m, 1 H) 4.67 - 4.82 (m, 1

H) 7.03 (br s, 1 H) 7.12 (br s, 1 H) 7.15 - 7.22 (m, 1 H) 7.30 (s, 1 H) 7.75 (br s, 2 H) 7.71 -

7.74 (m, 1 H) 8.03 (s, 1 H) 8.38 (s, 1 H).

LC/MS (basic conditions): Rt 0.93 min, m/z 612.26 [M+H]⁺.

A portion of this material (20 mg, 0.033 mmol) in Et₂0 (0.5 ml) and DCM (0.5 ml) at 0°C was treated with HCI (0.065 ml of a 1 M solution in Et₂0, 0.065 mmol) and the mixture was stirred for 10 min, then the solvent was removed in vacuo. The resulting solid was washed several times with Et₂0 and dried to give Example 4 (21 mg, 0.031 mmol).

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.42 (br s, 6 H) 2.1 1 (br s, 3 H) 2.31 (br s, 3 H) 2.62 - 2.74 (m, 1 H) 3.34 - 3.47 (m, 1 H) 3.48 - 3.67 (m, 3 H) 3.76 - 3.91 (m, 1 H) 7.01 - 7.24 (m, 3 H) 7.31 - 7.37 (m, 1 H) 7.77 (br s, 3 H) 8.05 (br s, 1 H) 8.40 (br s, 1 H).

LC/MS (basic conditions):Rt 0.93 min, m/z 612.20 [M+H]⁺.

Preparation 2

The mixture of enantiomers (Example 2, preparation 2 8.7 g, 14.22 mmol) was separated by Chiral chromatography.

Flow rate: 0.8 ml/min

DAD: 210-340 nm to give according to the order of elution:

(Rt 4.59 min): 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[4- (hydroxymethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 1) eluted but not collected.

(Rt 15.21 min): 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[4- (hydroxymethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 2) (3.5 g, 5.72 mmol, 40% yield). ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.33-1.77 (m, 6 H) 1 .97-2.29 (m, 3 H) 2.54 (br s, 3 H) 2.94-4.1 1 (m, 6 H) 5.75 (br s, 1 H) 6.84-7.37 (m, 4 H) 7.68 (s, 2 H) 7.81 (s, 1 H) 8.42 (s, 1 H).

This material (enantiomer 2) plus a previous preparation (5 g, 8.18 mmol) was added to Et₂0 (100 ml). Resulting mixture was cooled down to 0°C then HCI 1 M in ether (16.35 ml, 16.35 mmol) was added and the suspension was allowed to reach r.t. and stirred for 1 h. Solvent was removed and the residue dried overnight at 50°C under reduced pressure to give Example 4 (5.25 g, 8.10 mmol).

¹H NMR (600 MHz, DMSO-d6): δ ppm 1.40 (br s, 6 H) 2.13 (br s, 3 H) 2.48 (br s, 3 H) 2.71 (dt, 1 H) 3.43 (t, 1 H) 3.58 (dd, 1 H) 3.60 (m, 1 H) 3.72 (dd, 1 H) 3.88 (q, 1 H) 7.08 (m, 1 H) 7.14 (m, 1 H) 7.18 (dd, 1 H) 7.42 (s, 1 H) 7.65 (br s, 1 H) 7.75 (br s, 2 H) 8.00 (s, 1 H) 8.45 (br s, 1 H).

UPLC (acidic conditions): Rt 4.61 min , m/z 612.1 1 [M+H⁺].

Specific optical rotation at 20°C : +26.97°degree (c=1.06, MeOH, Sodium D-line wavelenght 589 nm, Cell volume 1 ml, Cell pathlenght 1 dm ).

Example 5

2-r3,5-Bis(trifluoromethyl)phenvn-A/-{4-(4-fluoro-2-methylphenyl)-6-r(4- (hvdroxymethyl)-1 -methyl-5-oxo-3-pyrrolidm

hydrochloridei enantiomer 2)

To 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[4-(hydroxy-methyl)-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (enantiomer 2) (Example 4, 40 mg, 0.065 mmol) in DMF (0.5 ml) at 0°C was added NaH (2.88 mg, 0.072 mmol) followed after 20 min by Mel (4.50 μΙ_, 0.072 mmol) and the resulting mixture was stirred at r.t. for 4 h. To the resulting yellow solution, NH₄CI (sat. aq. sol.) and DCM were added. The organic phase was washed with water, dried (Na₂S0₄) and evaporated. The crude product was purified by silica gel chromatography eluting with MeOH in DCM (0-10%) to give 2-[3,5- Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-1 -methyl-5- oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (16 mg, 0.026 mmol, 40% yield). ¹H NMR (500 MHz, DMSO-d6): δ ppm 1.36 (br s, 6 H) 2.08 (br s, 3 H) 2.49 (br s, 3 H) 2.69 (br s, 1 H) 2.78 (s, 3 H) 3.44 - 3.59 (m, 2 H) 3.61 - 3.70 (m, 1 H) 3.69 - 3.83 (m, 2 H) 4.80 (br s, 1 H) 7.02 (br s, 1 H) 7.12 (br s, 1 H) 7.16 - 7.22 (m, 1 H) 7.33 (s, 1 H) 7.77 (br s, 2 H) 8.04 (s, 1 H) 8.37 (s, 1 H).

LC/MS (basic conditions): Rt 0.96 min, m/z 626.26 [M+H]⁺.

A portion of this material (14 mg, 0.022 mmol) in Et₂0 (0.5 ml) was treated with HCI (0.045 ml of a 1 M solution in Et₂0, 0.045 mmol) and the mixture was stirred at r.t. for 10 min. before the solvent was removed in vacuo. The residue was washed with Et₂0 and dried to afford the title compound (13.5 mg, 0.020 mmol).

¹ H N MR (500 MHz, DMSO-d6): δ ppm 1 .38 (br s, 6 H) 2.10 (br s, 3 H) 2.31 (br s, 3 H) 2.62 - 2.74 (m, 2 H) 2.78 (s, 3 H) 3.56 - 3.61 (m, 2 H) 3.62 - 3.69 (m, 1 H) 3.70 - 3.84 (m, 2 H) 7.02 (br s, 1 H) 7.08 - 7.16 (m, 1 H) 7.16 - 7.22 (m, 1 H) 7.33 (s, 1 H) 7.76 (br s, 2 H) 8.03 (s, 1 H) 8.38 (s, 1 H).

LC/MS (basic conditions): Rt 0.96 min, m/z 626.21 [M+H]⁺.

Examples 6-9

Example 6

2-r3,5-Bisitrifluoromethyl)phenvn-N-f4-i4-fluoro-2-methylphenyl)-6-r3-ihvdroxymethyl)- 5-oxo-2-pyrrolidinvn-3-pyridinyl)-N,2-dimethylpropanamide (syn: enantiomer 1 ) Example 7

2-r3.5-Bis(trifluoromethyl)phenvn-N-f4-(4-fluoro-2-methylphenyl)-6-r(3- ihvdroxymethyl)-5-oxo-2-pyrrolidinvn-3-pyridinyl)-N,2-dimethylpropanamide (anti: enantiomer 1 )

Example 8

2-r3,5-Bisitrifluoromethyl)phenvn-N-f4-i4-fluoro-2-methylphenyl)-6-r3-ihvdroxymethyl)- 5-oxo-2-pyrrolidinvn-3-pyridinyl)-N,2-dimethylpropanamide (syn; enantiomer 2;

Example 9

2-r3.5-Bis(trifluoromethyl)phenvn-N-f4-(4-fluoro-2-methylphenyl)-6-r(3- (hvdroxymethyl)-5-oxo-2-pyrrolidinvn-3-pyridinyl)-N,2-dimethylpropanamide(anf/^': enantiomer 2;)

To a stirred solution of ethyl 2-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methyl- propanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-5-oxo-3- pyrrolidinecarboxylate as a mixture of diastereoisomers (Intermediate 12, 22 mg, 0.034 mmol) in THF (3 ml) LiBH₄ (0.034 ml of a 2M solution in THF, 0.067 mmol, Aldrich) was added and the reaction mixture was stirred at r.t. overnight. After evaporation of the volatiles, the crude was dissolved in EtOAc and washed with HCI (2N aq sol). The aqueous phase was extracted with EtOAc and the combined organics were dried (Na₂S0₄) and evaporated. The residue was purified by silica gel chromatography eluting with MeOH in DCM (0-10%) to afford 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[3-(hydroxymethyl)- 5-oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (10 mg, 0.016 mmol, 49% yield) as a mixture of diastereoisomers.

HPLC-MS (acidic conditions): Rt 2.64 min, m/z 612.2 [M+H⁺].

The four stereoisomers of 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6- [3-(hydroxymethyl)-5-oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (61 mg, 0.094 mmol) were separated by Chiral SFC.

Analytical chromatographic conditions: [Column: ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm]

Preparative chromatographic conditions: [Column: ChiralPak AD-H (25 x 2.1 cm); Modifier: 12% (EtOH+0.1 % isopropylamine) 12%, 15% after third peak; Flow rate (ml/min) 50.0; UV detection 220 nm; Loop 500 μΙ_]

Injection of 10 mg in the modifier to give in order of elution:

Example 6: 9.6 mg (0.016 mmol): Chiral analysis Rt 2.71 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].

1H NMR (500 MHz, DMSO-d6): δ ppm 1.49 (br s, 6 H) 2.15 (br s, 4 H) 2.32 - 2.39 (m, 1 H) 2.57 (br s, 3 H) 2.87 - 2.94 (m, 1 H) 2.94 - 3.02 (m, 1 H) 3.02 - 3.12 (m, 1 H) 4.52 - 4.60 (m, 1 H) 4.82 - 4.96 (m, 1 H) 7.19 (br s, 2 H) 7.22 - 7.29 (m, 2 H) 7.82 (br s, 2 H) 8.1 1 (br s, 2 H) 8.45 (s, 1 H). Example 7 1 1 .2 mg (0.018 mmol): Chiral analysis Rt 3.16 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].

¹H NMR (500 MHz, DMSO-d6): δ ppm 1.54 (br. s., 6 H) 2.19 (br. s., 3 H) 2.57 (br. s., 3 H) 2.39 - 2.47 (m, 2 H) 2.48 - 2.54 (m, 1 H) 3.52 - 3.65 (m, 2 H) 4.59 (d, 1 H) 4.95 (t, 1 H) 7.22 (br. s., 1 H) 7.15 - 7.23 (m, 1 H) 7.23 - 7.29 (m, 1 H) 7.29 - 7.35 (m, 1 H) 7.82 (br. s., 2 H) 8.10 (s, 1 H) 8.16 (br. s., 1 H) 8.46 (s, 1 H).

Example 8: 9.5 mg (0.016 mmol): Chiral analysis Rt 5.69 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].

¹ H N MR (500 MHz, DMSO-d6): δ ppm 1 .49 (br s, 6 H) 2.15 (br s, 4 H) 2.32 - 2.39 (m, 1 H) 2.57 (br s, 3 H) 2.87 - 2.94 (m, 1 H) 2.94 - 3.02 (m, 1 H) 3.02 - 3.12 (m, 1 H) 4.52 - 4.60 (m, 1 H) 4.82 - 4.96 (m, 1 H) 7.19 (br s, 2 H) 7.22 - 7.29 (m, 2 H) 7.82 (br s, 2 H) 8.1 1 (br s, 2 H) 8.45 (s, 1 H).

Example 9: 1 1 .2 mg (0.018 mmol): Chiral analysis Rt 10.72 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].

¹ H N MR (400 MHz, METHANOL-^): δ ppm 1 .47 (br. s., 6 H) 2.18 (br. s., 3 H) 2.26 - 2.86 (m, 3 H) 2.52 (br. s., 3 H) 3.66 - 3.77 (m, 2 H) 4.74 (d, J=4.29 Hz, 3 H) 7.02 (br. s., 1 H) 7.08 - 7.15 (m, 1 H) 7.21 (br. s., 1 H) 7.35 (s, 1 H) 7.80 (br. s., 2 H) 7.94 (s, 1 H) 8.40 (s, 1 H).

Example 10-13

Example 10

2-r3,5-Bisitrifluoromethyl)phenyl1-A/-f4-i4-fluoro-2-methylphenyl)-6-r(2ihvdroxymethyl)- 5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide (syn: enantiomer 1 );

Example 1 1

2-r3,5-Bisitrifluoromethyl)phenyl1-A/-f4-i4-fluoro-2-methylphenyl)-6-r(2ihvdroxymethyl)- 5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide (syn: enantiomer 2);

Example 12

2-r3,5-Bisitrifluoromethyl)phenvn-A/-f4-i4-fluoro-2-methylphenyl)-6-r(2ihvdroxymethyl)- 5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide (anti: enantiomer 1 );

Example 13

2-r3,5-Bisitrifluoromethyl)phenvn-A/-f4-i4-fluoro-2-methylphenyl)-6-r(2ihvdroxymethyl)- 5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide (anti: enantiomer 2);

Calcium chloride (76 mg, 0.689 mmol) was dissolved in water (0.3 ml) then ethyl 3-[5-[{2- [3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-5-oxoprolinate (Intermediate 14, 450 mg, 0.689 mmol) was added as an EtOH solution (3 ml). The mixture was cooled to 0°C and NaBH₄ (78 mg, 2.066 mmol) was added. The reaction mixture was allowed to reach r.t. and stirred for 18 h. Then aq. HCI (5M) was added to acidify the reaction mixture before evaporation under reduced pressure. The residue was partitioned between DCM and sat. NaHC0₃. The DCM layer was collected and evaporated and the resulting material was filtered through a small pad of silica, eluting with 5% MeOH in EtOAc to give the crude product (380 mg, 0.620 mmol, 90% yield) as a mixture of 4 diastereoisomers by analytical chiral hplc (3: 1 anti to syn).

Analytical conditions: [Column : Chiralpak IA (4.6 mm x 250 mm, 5 μηη); Heptane: Absolute Ethanol 90: 10 v/v pump-mixed; Flow rate = 1 .0 ml/min; U.V. Absorbance @ 215 nm; Autosampler injection (10 μΙ or 50 μΙ of 1 .0mg/ml sample in absolute ethanol on column); Isocratic Run time = 55.0 min.]. Under these chiral hplc conditions the 4 diastereoisomers had the following Rts:

Example 10 (syn: enantiomer 1 ) Rt = 18.18 min.

Example 1 1 (syn: enantiomer 2) Rt = 25.92 min.

Example 12 (anti: enantiomer 1 ) Rt = 29.76 min.

Example 13 (anti: enantiomer 2) Rt = 36.1 1 min.

Examples 10 and 13 were isolated (in order of elution) from the mixture of 4 diastereoisomers using the following preparative chiral hplc conditions:

Preparative conditions: (Examples 10 and 13): [Column: Chiralpak IA (20 mm x 250 mm, 5 μηη); Heptane : Absolute Ethanol 90: 10 v/v pump-mixed; Flow rate = 17.0 ml/min; U.V. Absorbance @ 215 nm; Autosampler injection (900 μΙ of 95.0 mg/ml sample in DCM:MeOH 8:2 on column); Isocratic Run time = 50.0 min.; Solubility = 95.0 mg/ml in DCM:MeOH 8:2] Example 10 44 mg (0.071 mmol) isolated.

¹ H NMR (400 MHz, CH LOROFORM-d): δ ppm 1 .14 - 1 .80 (m, 9 H) 2.14 (br s, 5 H) 2.97 -

3.17 (m, 1 H) 3.49 (br s, 1 H) 3.83-4.13 (m, 2 H) 4.44 - 4.70 (m, 1 H) 6.86 - 7.08 (m, 2 H)

7.19 (s, 1 H) 7.27 (s, 2 H) 7.66 (s, 2 H) 7.80 (s, 1 H) 8.41 (s, 1 H).

LC/MS : m/z 612 [M+H]⁺

Rt (chiral analytical hplc; conditions described above) = 18.18 min.

Example 13 132 mg (0.216 mmol) isolated.

¹ H N MR (400 MHz, CHLOROFORM-d): δ ppm 1 .13 - 1 .75 (m, 6 H) 1 .95 - 2.95 (m, 8 H) 3.61 (br s, 2 H) 3.72 - 3.90 (m, 1 H) 4.05 (d, J=3.29 Hz, 1 H) 4.13 - 4.54 (m, 1 H) 6.78 - 7.30 (m, 5 H) 7.66 (s, 2 H) 7.79 (s, 1 H) 8.39 (s, 1 H)

LC/MS : m/z 612 [M+H]⁺

Rt (chiral analytical hplc; conditions described above) = 36.1 1 min.

The resultant mixture of Examples 1 1 and 12 were subsequently separated (in order of elution) using the following preparative chiral hplc conditions: Preparative conditions: (Examples 1 1 and 12): [Column: Chiralpak IC (20 mm x 250 mm, 5 μηη); Heptane : I.P.A. 70:30 v/v pump-mixed; Flow rate = 17.0 ml/min; U.V. Absorbance @ 215 nm; Autosampler injection (900 μΙ of 95.0 mg/ml sample in DCM:MeOH 8:2 on column); Isocratic Run time = 60.0 min.; Solubility = 95.0 mg/ml in DCM:MeOH 8:2]

Example 11 25 mg (0.040 mmol) isolated.

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .14 - 1.86 (m, 9 H) 1.98 - 2.75 (m, 5 H) 2.97

- 3.16 (m, 1 H) 3.48 (br s, 1 H) 3.84 - 4.09 (m, 1 H) 4.46 - 4.66 (m, 1 H) 6.13 (br s, 1 H) 6.87 - 7.08 (m, 2 H) 7.10 - 7.31 (m, 3 H) 7.66 (s, 2 H) 7.80 (s, 1 H) 8.40 (s, 1 H).

LC/MS : m/z 612 [M+H]⁺

Rt (chiral analytical hplc; conditions described above) = 25.92 min.

Example 12 62 mg (0.102 mmol) isolated. ¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .16 - 1.87 (m, 9 H) 1.98 - 2.74 (m, 4 H) 2.75

- 2.94 (m, 2 H) 3.48 - 3.90 (m, 3 H) 4.06 (br s, 1 H) 6.46 - 6.66 (m, 1 H) 6.83 - 7.06 (m, 2 H) 7.07 - 7.33 (m, 2 H) 7.66 (s, 2 H) 7.79 (s, 1 H) 8.39 (s, 1 H).

¹H NMR (500 MHz, DMSO-d6): δ ppm 1.38 (br s, 6H) 2.10 (br s 3H) 2.58 (br s, 2H) 2.64 (br s, 3H) 3.42 (dd, J=10.9, 5.0 Hz, 1 H) 3.49 (m, 1 H) 3.56 (m, 1 H) 3.65 (br s, 1 H) 4.90 (m, 1 H) 7.06 (br s, 1 H) 7.13 (br s, 1 H) 7.20 (d, J=9.9 Hz, 1 H) 7.28 (br s, 1 H) 7.73 (br s, 1 H) 7.77 (br s; 2H) 8.04 (s, 1 H) 8.38 (s, 1 H).

¹³C NMR (500 MHz, DMSO-d6): δ ppm 19.52, 25.34, 28.98, 36.48, 42.74, 47.10, 61.78, 63.36, 1 16.76, 120.75, 123.12, 123.12, 124.4, 125.63, 125.63, 130.12, 131.01 , 131.01 , 137.93, 145.78, 148.42, 149.24, 160.21 , 161.94, 175.17.

LC/MS : m/z 612 [M+H]⁺

Rt (chiral analytical hplc; conditions described above) = 29.76 min.

Example 14:

A/-f6-f2,2-Bis(hvdroxymethyl)-5-oxo-3-pyrrolidinvn-4-(4-fluoro-2-methylphenyl)-3- pyridinvn-2-r3,5-bisitrifluoromethyl)phenvn-A/,2-dimethylpropanamide hydrochloride

Calcium chloride (38.2 mg, 0.345 mmol) was dissolved in water (0.3 ml) then diethyl 3-[5-[{2- [3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-5-oxo-2,2-pyrrolidinedicarboxylate (Intermediate 13, 100 mg, 0.138 mmol) was added as an ethanol (2 ml) solution. The reaction mixture was cooled to 0°C and NaBH₄ (26.1 mg, 0.689 mmol) was added. The resulting mixture was allowed to reach r.t. and stirred for 18 h. Aqueous HCI (5N) was added to acidify the reaction mixture before evaporation under reduced pressure. The resulting residue was partitioned between DCM and sat. NaHC0₃ and the DCM layer was collected and evaporated. The resulting crude material was filtered through a small pad of silica, eluting with 5% MeOH in EtOAc to give the free base of the title compound which was treated with 1 N HCI in ether and evaporated to give the title compound (Example 14, 75 mg, 0.100 mmol, 72 % yield).

1H NMR (500 MHz, DMSO-d₆): (Temperature = 363K) δ ppm 1.4 (s, 6 H) 2.10 (s, 3H) 2.48 (m, 4H) 2.91 (dd, J=16.4, 8.9 Hz, 1 H) 3.10 (d, J=1 1.2 Hz, 1 H) 3.15 (d, J=1 1.2 Hz, 1 H) 3.54 (s, 2H) 3.80 (t, J=9.1 Hz, 1 H) 7.02 (m, 2 H) 7.13 (m, 2 H) 7.24 (s, 1 H) 7.73 (s, 2 H) 7.93 (s, 1 H) 8.32 (s, 1 H).

LC/MS : m/z 642 [M+H]⁺. Example 14a

A/-f6-f2,2-Bis(hvdroxymethyl)-5-oxo-3-pyrrolidinvn-4-(4-fluoro-2-methylphenyl)-3-

Calcium chloride (185 mg, 1 .667 mmol) was dissolved in water (1 ml) then diethyl 3-[5-[{2- [3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2- methylphenyl)-2-pyridinyl]-5-oxoprolinate (Intermediate 14, 484 mg, 0.667 mmol) was added as an EtOH solution (7 ml). The mixture was cooled to 0°C and NaBH₄ (126 mg, 3.33 mmol) was added. The reaction mixture was allowed to reach r.t. and stirred for 3 days. HCI (aq) (5M) was added to acidify the reaction mixture before evaporation under reduced pressure. The resulting crude material was partitioned between DCM and saturated aqueous NaHC0₃. After separation of the layers the aqueous phase was re-extracted with DCM (x2). The combined organic layers were passed through a hydrophobic frit and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20 g silica column) eluting with 0-6% MeOH in DCM to give the title compound as a colourless solid (420 mg, 98% yield) which was characterised as a mixture of enantiomers by analytical chiral HPLC.

Analytical conditions: [Column: Chiralpak IA (4.6 mm x 250 mm, 5 μηη); Heptane : Absolute Ethanol 90:10 v/v pump-mixed; Flow rate = 1.0 mls/min; U.V. Absorbance @ 215 nm; Autosampler injection (10 μΙ of 1 .0 mgs/ml sample in EtOH on column); Isocratic run time = 30.0 min.] Example 14a (420 mg) was separated using the following preparative HPLC conditions to give Examples 15 and 16:

Preparative conditions: [Column: Chiralpak IC (20 mm x 250 mm, 5 μηη); Heptane : I.P.A. 70:30 v/v pump-mixed; Flow rate = 17.0 mls/min; U.V. Absorbance @ 215 nm; Autosampler injection (500 μΙ of 140.0 mgs/ml sample in DCM: MeOH 8:2 on column); Isocratic Run time = 50.0 min.; Solubility = 140.0 mgs/ml in DCM: MeOH 8:2]

Example 15

A/-r6-r2,2-Bis(hvdroxymethyl)-5-oxo-3-pyrro

PVridinyll-2-r3,5-bis(trifluoromethyl)phenyll- V,2-dimethylpropanamide(enantiomer 1 )

189 mg was isolated from preparative HPLC and was subsequently passed through a plug of silica gel eluting with 6% MeOH in DCM to give a colourless solid (173 mg).

Rt (chiral analytical HPLC; conditions described above) = 19.55 min.

1H NMR (400 MHz, DMSO-d₆) (Temperature = 372K) δ: 1.41 (s, 6 H) 2.10 (s, 3H) 2.48 (m, 1 H) 2.51 (s, 3 H), 2.89 (m, 1 H) 3.14 (m, 2 H) 3.55 (s, 2 H) 3.80 (m, 1 H) 6.82 (br s, 1 H) 7.00 (m, 1 H), 7.1 1 (m, 2 H) 7.21 (s, 1 H) 7.73 (s, 2 H) 7.89 (s, 1 H) 8.30 (s, 1 H).

LC/MS : m/z 642 [M+H]⁺.

Example 16

A/-r6-r2,2-Bisihvdroxymethyl)-5-oxo-3-pyrrolidinvn-4-i4-fluoro-2-methylphenyl)-3-

PVridinyll-2-r3,5-bis(trifluoromethyl)phenyll-A/,2-dimethylpropanamide (enantiomer 2)

198 mg was isolated from preparative HPLC and was subsequently passed through a plug of silica gel eluting with 6% MeOH in DCM to give a colourless solid (187 mg).

Rt (chiral analytical HPLC; conditions described above) = 24.45 min.

¹H NMR (400 MHz, DMSO-d₆) (Temperature = 372K) δ: 1.41 (s, 6 H) 2.10 (s, 3H) 2.48 (m, 1 H) 2.51 (s, 3 H), 2.89 (m, 1 H) 3.14 (m, 2 H) 3.56 (s, 2 H) 3.80 (m, 1 H) 4.13 (m, 1 H), 4.51 (m, 1 H), 6.83 (br s, 1 H) 7.00 (m, 1 H), 7.1 1 (m, 2 H) 7.21 (s, 1 H) 7.73 (s, 2 H) 7.89 (s, 1 H)

8.30 (s, 1 H).

LC/MS : m/z 642 [M+H]⁺. Example 17

3-r5-r{2-r3,5-Bis(trifluoromethyl)phenyl1-2-m

2-methylphenyl)-2-pyridinyll-5-oxoprolinamide hydrochloride

3-[5-[{2-[3,5-Bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)am

methylphenyl)-2-pyridinyl]-5-oxoproline (Intermediate 15, 30 mg, 0.048 mmol) was dissolved in DMF (2 ml) and treated with bis-trimethylsilylamine (31 .0 mg, 0.192 mmol), HBTU (18.24 mg, 0.048 mmol) and HOBT (7.34 mg, 0.048 mmol). Finally DIPEA (0.017 ml, 0.096 mmol) was added and the reaction stirred at r.t. for 24 h. The resulting mixture was evaporated to dryness under reduced pressure and partitioned between DCM (20 ml) and water (20 ml). The DCM layer was collected, dried (hydrophobic frit) and evaporated. The formate salt of the title compound was obtained by MDAP purification. MDAP fractions were combined and evaporated with ethereal HCI to yield the title compound (Compound 17, 15 mg, 0.023 mmol, 47 % yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.98 - 1.84 (m, 9 H) 2.04 - 2.26 (m, 3 H) 2.27 - 3.01 (m, 4 H) 4.53 - 4.80 (m, 1 H) 5.68 - 6.02 (m, 1 H) 6.58 - 6.81 (m, 1 H) 6.86 - 7.08 (m, 2 H) 7.17 (s, 2 H) 7.68 (s, 2 H) 7.78 - 7.83 (m, 1 H) 7.84 - 7.97 (m, 1 H) 8.31 - 8.50 (m, 1 H). LC/MS : Rt 1.17 min, m/z 624.98 [M+H]⁺.

Example 18

2-r3,5-Bisitrifluoromethyl)phenvn-N-f4-i4-fluoro-2-methylphenyl)-6-r2-ihvdroxymethyl)- 1 -methyl -5-oxo-3-pyrrolidinvn -3 -pyridinyl)-N,2-dimethylpropanamide

To ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropano

fluoro-2-methylphenyl)-2-pyridinyl]-1-methyl-5-oxoprolinate (Intermediate 16, 81 mg, 0.121 mmol) in EtOH (2 ml) at 0°C was added a solution of calcium chloride (14 mg, 0.126 mmol) in water (0.4 ml) and the mixture was stirred for 10 min. NaBH₄ (14 mg, 0.370 mmol) was added and the mixture was allowed to warm to r.t. over 2 h. and then stirred at r.t. for 18 h. The solvent was removed in vacuo and the residue was purified by mass directed autoprep. to afford the title compound (49.2 mg, 0.079 mmol, 65% yield).

1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.34 - 1 .60 (br m, 6 H) 2.05 - 2.23 (br s, 3 H) 2.32 - 2.68 (br m, 3 H) 2.78 (dd, 1 H) 2.90 (s, 3 H) 2.86 - 2.95 (m, 1 H) 3.30 - 3.80 (br m, 1 H) 3.68 - 3.81 (m, 2 H) 3.86 (m, 1 H) 3.92 (dd, 1 H) 6.90 - 6.98 (br m, 1 H) 7.01 (d, 1 H) 7.12 (s, 1 H) 7.14 - 7.23 (br m, 1 H) 7.67 (s, 2H) 7.79 (s, 1 H) 8.38 (s, 1 H).

UPLC (acidic conditions): Rt 1.19 min, m/z 626.05 [M+H⁺].

Example 19

2-r3,5-Bisitrifluoromethyl)phenyl1-N-f4-i4-fluoro-2-methylphenyl)-6-r2-ihvdroxymethyl)- 5-oxo-1 -(2,2,2-trifluoroethyl)-3-pyrrolidinyl1-3-pyridinyl)-N,2-dimethylpropanamide

Ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro- 2-methylphenyl)-2-pyridinyl]-5-oxo-1 -(2,2,2-trifluoroethyl)prolinate (Intermediate 17, 80 mg, 0.109 mmol) in EtOH (2 ml) was added to a solution of calcium chloride (12 mg, 0.108 mmol) in water (0.3 ml). The mixture was cooled to 0°C and NaBH₄ (12 mg, 0.317 mmol) was added. The resulting reaction mixture was allowed to reach r.t. over 2 h. and then stirred for 18 h. The volatiles were removed in vacuo and the white solid residue was purified by mass directed autoprep. to afford the title compound (48 mg, 0.069 mmol, 64% yield).

1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.39 - 1 .58 (br m, 6 H) 2.08 - 2.14 (br s, 3 H) 2.32 - 2.68 (br m, 3 H) 2.89 (m, 2 H) 3.60 - 4.20 (br m, 1 H) 3.70 (m, 2 H) 3.85 (m, 1 H) 3.97 (dd, 1 H) 4.1 1 (m, 1 H) 4.40 (m, 1 H) 6.92 - 6.98 (br m, 1 H) 7.01 (d, 1 H) 7.10 (s, 1 H) 7.14 - 7.23 (br m, 1 H) 7.67 (s, 2H) 7.79 (s, 1 H) 8.39 (s, 1 H). UPLC (acidic conditions): Rt 1.30 min, m/z 694.1 1 [M+H⁺].

Example 20

2-r3,5-Bisitrifluoromethyl)phenyl1-N-r6-i2,2-dimethyl-5-oxo-3-pyrrolidinyl)-4-i4-fluoro-2^ methylphenyl)-3-pyridinvn-N,2-dimethylpropanamide

Ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro- 2-methylphenyl)-2-pyridinyl]-4-methyl-4-nitropentanoate (Intermediate 18, 187.4 mg, 0.273 mmol) was dissolved in EtOH (10 ml) and water (4 ml) and treated with iron powder (153 mg, 2.73 mmol) and acetic acid (0.360 ml, 6.29 mmol). The resulting reaction mixture was then heated at 75°C for 3.5 h. Further iron powder (153 mg, 2.73 mmol) and acetic acid (0.360 ml, 6.29 mmol) were added and the reaction was heated overnight at 60°C. The iron was removed using a magnetic rod and sodium carbonate was added to make the solution basic, concentrating in vacuo before dissolving in water (50 ml) and extracting with DCM (3 x 50 ml). The combined organics were dried and evaporated to afford the crude product which was purified by MDAP (high pH system) to yield the title compound as a white crystalline solid (mixture of enantiomers) (49 mg, 0.08 mmol, 29% yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.87-0.91 (m, 1 H) 0.95 (br s, 1 H) 1.26 (br s, 2H) 1.41 (br s, 3H) 1.48 (br s, 3H) 1 .55 (br s, 1 H) 1.67 (br s, 2H) 2.1 1 (br s, 3H) 2.39 (br s, 1 H) 2.61 -2.71 (m, 2H) 3.22 (br s, 1 H) 3.56-3.64 (m, 1 H) 5.82 (br s, 1 H) 6.90-7.04 (br m, 3H) 7.07 (s, 1 H) 7.67 (br s, 2H) 7.79 (s, 1 H) 8.42 (s, 1 H).

UPLC (acidic conditions): Rt 1.31 min, m/z 609.99 [M+H]⁺. The mixture of enantiomers (Example 20, 49 mg) was separated by chiral chromatography to afford Compounds 21 and 22 in order of elution.

Preparative chromatographic conditions: [Column: Chiralpak IA (20 mm x 250 mm, 5 μηη); Mobile phase: heptane/absolute EtOH 80/20 % v/v; Flow rate: 17 ml/min; DAD: 215 nm] Example 21

2-r3,5-Bis(trifluoromethyl)phenyl1-N-r6-^

methylphenyl)-3-pyridinyll-N,2-dimethylpropanamide (enantiomer 1 ):

1^st eluted, Rt 4.50 min.: 21.9 mg isolated

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.88-0.91 (m, 1 H) 0.96 (br s, 1 H) 1.26 (br s, 2 H) 1 .41 (br s, 3 H) 1.47 (br s, 3 H) 1.55 (br s, 1 H) 1.67 (br s, 2 H) 2.1 1 (br s, 3 H) 2.38 (br s, 1 H) 2.61 -2.71 (m, 2 H) 3.22 (br s, 1 H) 3.58 - 3.65 (m, 1 H) 5.82 (br s, 1 H) 6.92 - 7.02 (br m, 3 H) 7.07 (s, 1 H) 7.67 (br s, 2 H) 7.78 (s, 1 H) 8.42 (s, 1 H).

UPLC (acidic conditions): Rt 1.34 min, m/z 609.87 [M+H]⁺.

Example 22:

2-r3,5-Bis(trifluoromethyl)phenvn-N-r6-r2,2-dimethyl-5-oxo-3-pyrrolidinyl1-4-(4-fluoro methylphenyl)-3-pyridinyll-N,2-dimethylpropanamide (enantiomer 2)

2nd eluted, Rt 5.88 min.: 22.5 mg isolated

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.88 (m, 1 H) 0.95 (br s, 3 H) 1 .22 - 1 .32 (m, 3 H) 1 .42 (br s, 2 H) 1.47 (br s, 3 H) 1.63 (s, 2 H) 2.10 (br s, 3 H) 2.39 (br s, 1 H) 2.66 (m, 1 H) 3.24 (br s, 1 H) 3.56 - 3.64 (m, 1 H) 5.71 (br s, 1 H) 6.91 - 7.04 (br m, 3 H) 7.07 (s, 1 H) 7.67 (br s, 2 H) 7.80 (s, 1 H) 8.41 (s, 1 H).

UPLC (acidic conditions): Rt 1.34 min, m/z 609.87 [M+H]⁺.

Example 23

2-r3,5-Bisitrifluoromethyl)phenyl1-A/-|^'4-i4-fluoro-2-methylphenyl)-6-r4-ihvdroxymethyl)- 2,2-dimethyl-5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide

To a solution of the methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-5,5-dimethyl-2-oxo- 3-pyrrolidinecarboxylate (Intermediate 21 , 193 mg, 0.289 mmol) in MeOH (20 ml) at 0°C was added calcium chloride (32.1 mg, 0.289 mmol). The resulting reaction mixture was stirred for 5 min. before NaBH₄ (32.8 mg, 0.867 mmol) was added, then after a further 20 min. stirring at 0°C the reaction was allowed to warm up to r.t. and stirred overnight. After cooling to 0°C further calcium chloride (32.1 mg) and NaBH₄ (32.8 mg) were added and the reaction mixture was allowed to warm to r.t. and stirred for a further 2 h. 5 M HCI (5 ml) was added and the mixture was concentrated in vacuo. The residue was partitioned between water (50 ml) and DCM (50 ml). The organic phase was dried (Na₂S0₄) and then concentrated in vacuo. The product was purified by MDAP to yield the title compound as a white crystalline solid (40 mg, 0.06 mmol, 21 % yield).

1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.74 (br, s, 2H) 0.96 (br s, 3 H) 1.43 (br s, 5H) 1.46 (br s, 2 H) 2.12 (br s, 3 H) 2.51 (br s, 3 H) 3.46 - 3.50 (m, 1 H) 3.65 - 3.70 (m, 2 H) 3.90 - 3.95 (m, 1 H) 5.49 (s, 1 H) 6.90 - 7.02 (m, 4 H) 7.08 (s, 1 H) 7.66 (br s, 2 H) 7.78 (s, 1 H) 8.39 (s, 1 H).

UPLC (acidic conditions): Rt 1.29 min, m/z 639.92 [M+H]⁺.

Example 24

N-f6-f4,4-Bis(hvdroxymethyl)-5-oxo-3-pyrrolidinyl1-4-(4-fluoro-2-methylphenyl)-3- Pyridinyll-2-r3,5-bis(trifluoromethyl)phenyll-N,2-dimethylpropanamide

To a solution of 1 ,1-dimethylethyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-3,3- bis(hydroxymethyl)-2-oxo-1 -pyrrolidinecarboxylate (Intermediate 23, 99 mg, 0.134 mmol) in DCM (10 ml) was added TFA (10.29 μΙ_, 0.134 mmol). The resulting reaction mixture was stirred for 1 h. at r.t. and then concentrated to dryness. Purification by MDAP afforded the desired material as a white crystalline solid (35.8 mg, 0.06 mmol, 41 % yield).

1H NMR (400 MHz, DMSO-d6): δ ppm 0.80 - 0.88 (m, 3 H) 1.12 - 1.41 (br m, 8 H) 1.52 (br s, 1 H) 1 .82 (m, 1 H) 2.15 (br s, 2 H) 2.27 - 2.35 (m, 1 H) 3.10 - 3.30 (br m, 2 H) 3.35 - 3.55 (m, 1 H) 7.13 (br s, 2 H) 7.22 (d, 2 H) 7.39 (br s, 1 H) 7.77 (br s, 2 H) 8.03 (br s, 3 H) 8.50 (br s, 1 H).

UPLC (acidic conditions): Rt 1.19min, m/z 642.13 [M+H]⁺. Example 25

2-r3,5-Bisitrifluoromethyl)phenyl1-A/-r4-i4-fluoro-2-methylphenyl)-6-i2-methyl-5-ox

PVrrolidinyl)-3-pyridinyll-A/,2-dimethylpropanamide

The ethyl 3-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4- fluoro-2-methylphenyl)-2-pyridinyl]-4-nitropentanoate (Intermediate 24, 61 1 mg, 0.910 mmol) was dissolved in EtOH (32.5 ml) and treated with iron (508 mg, 9.10 mmol), acetic acid (1.3 ml, 22.74 mmol) and water (13 ml). The resulting reaction mixture was then heated at 60°C for 16 h. After this time the reaction mixture was concentrated to dryness and partitioned between DCM (100 ml) and water (100 ml). The organic layer was then dried (Na₂S0₄) and concentrated to dryness to yield the desired product as a white crystalline solid (350 mg). A portion of this material (100 mg) was purified by MDAP to yield the title compound as a white crystalline solid (33.7 mg, 0.06 mmol, 6% yield).

1H NMR (400 MHz, DMSO-d6): δ ppm 1.21 (d, 2 H) 1.41 (br m, 6 H) 2.09 (br m, 3 H) 3.75 - 4.10 (br m, 8 H) 6.95 - 7.21 (m, 5 H) 7.72 (br m, 2 H) 7.89 (s, 1 H) 8.31 (s, 1 H)

UPLC (acidic conditions): Rt 1.32 min , m/z 595.87 [M+H⁺].

Example 26

2-r3,5-Bisitrifluoromethyl)phenyl1-A/-f4-i4-fluoro-2-methylphenyl)-6-r4-ihvdroxymethyl)- 2-methyl-5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide:

To a solution of the methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-5-methyl-2-oxo-3- pyrrolidinecarboxylate (Intermediate 28, 0.892 g, 1.365 mmol) in MeOH (20 ml) at 0°C was added calcium chloride (0.151 g, 1.365 mmol). The resulting reaction mixture was stirred for 30 min. before sodium borohydride (0.155 g, 4.09 mmol) was added and the resulting mixture was then strired in an ice bath for 3 h. The reaction mixture was quenched with 5M HCI and concentrated in vacuo, before being partitioned between water (100 ml) and EtOAc. The organic phase was dried (Na₂S0₄) and concentrated in vacuo to give a crude product which was purified by flash chromotography on a silica gel column, using 20% EtOAc in iso- hexane (3CV) 20-50% EtOAc in iso-hexane (12CV) 50-100% EtOAc in isohexane (3CV) 100% EtOAc (9CV). The product did not elute, so 10% MeOH in DCM (6CV) 10-20% methanol in DCM (6CV) and 20-30% MeOH in DCM (9CV) was used. The product though impure finally eluted. The material was purified by MDAP to yield the title compound as a white crystalline solid (32.8 mg, 0.05 mmol., 4% yield)

1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.88 - 0.91 (m, 2 H) 1.27 - 1 .30 (m, 2 H) 1.43 (br m, 4 H) 2.12 (br m, 3 H) 2.50 (br m, 3 H) 2.58 (s, 1 H) 2.77 - 2.93 (m, 1 H) 3.14 - 3.18 (m, 1 H) 3.77 - 4.10 (m, 3 H) 5.53 - 5.70 (m, 1 H) 6.90 - 6.96 (m, 1 H) 6.97 - 7.02 (m, 1 H) 7.06 - 7.14 (m, 2 H) 7.66 (br s, 2 H) 7.78 (s, 1 H) 8.37 - 8.41 (s, 1 H).

UPLC (acidic conditions): Rt 1.19 min , m/z 625.63 [M+H⁺].

Example 27

2-r3,5-Bis(trifluoromethyl)phenvn-N-{4-(4-fluoro-2-methylphenyl)-6-r2-(1 -hvdroxyethyl)- 5-oxo-3-pyrrolidinvn-3-pyridinyl)-N,2-dimethylpropanamide

N-[6-(2-Acetyl-5-oxo-3-pyrrolidinyl)-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-2-[3,5- bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamide (Intermediate 31 , 13 mg, 0.021 mmol) was dissolved in EtOH (1 ml) and sodium borohydride (2 mg, 0.053 mmol) was added. The reaction was stirred at r.t. for 1 h. The solvent was removed in vacuo and the residue was extracted into EtOAc (2 x 25 ml) from a saturated aqueous solution of ammonium chloride (5 ml). The organic phases were combined and dried (Na₂S0₄). The solvent was removed in vacuo and the residue was purified by column chromatography on a 2 g silica gel column using a gradient running from 100% DCM to 10% MeOH/DCM. The product containing fractions were combined and concentrated in vacuo to afford the title compound (7.7 mg, 0.012 mmol. 59% yield).

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.18 -1.45 (m, 6H) 1.50 -1.72 (m, 3H) 2.04 - 2.22 (br s, 3H) 2.32 - 2.70 (m, 3H) 2.69 - 2.90 (m, 2H) 3.58 - 3.68 (m, 1 H) 3.73 - 3.83 (m, 1 H) 3.88 - 3.97 (m, 2H) 6.27 - 6.53 (m, 1 H) 6.92 - 7.04 (m, 2 H) 7.09 - 7.12 (m, 1 H) 7.15 - 7.25 (m, 1 H) 7.67 (s, 2 H) 7.79 (s, 1 H) 8.38 - 8.42 (m, 1 H)

UPLC (acidic conditions): Rt 1.18 min, m/z 626.05 [M+H⁺].

Example 28

2-r3,5-bis(trifluoromethyl)phenyl1-A/-W

methylethyl)-5-oxo-3-pyrrolidinyl1-3-pyridinyl)-A/,2-dimethylpropanamide

To a solution of the 1 ,1 -dimethylethyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2- methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-3-(1-hydroxy-1- methylethyl)-2-oxo-1-pyrrolidinecarboxylate (Intermediate 25, 219 mg, 0.296 mmol) in DCM (20 ml) was added TFA (4 ml) and the resulting reaction mixture was stirred at r.t. for 2 h. After this time the reaction mixture was concentrated to dryness, re-dissolved in DCM (75 ml) and washed with aqueous saturated NaHC0₃ solution (75 ml). The organic layer was then dried (Na₂S0₄) and concentrated to dryness to yield the desired material as a yellow crystalline solid which was purified by MDAP to yield the title compound as a white crystalline solid (156 mg, 0.239 mmol, 81 % yield).

¹H NMR (400 MHz, DMSO-d6): δ ppm 1.05 (s, 2 H) 1.23 (s, 2 H) 1 .36 (br m, 2 H) 2.10 (br m, 2 H) 2.30 (br m, 1 H) 2.75 (br m, 1 H) 3.30 (br m, 1 H) 3.50 - 3.60 (m, 1 H) 3.80 - 3.90 (m, 1 H) 4.35 - 4.60 (br m, 9 H) 7.12 (br m, 2 H) 7.20 (d, 1 H) 7.45 (s, 1 H) 7.76 (br m, 2 H) 7.94 (s, 1 H) 8.05 (s, 1 H) 8.45 (br, s, 1 H).

UPLC (acidic conditions): Rt 1.24 min , m/z 639.94 [M+H⁺]. Example 29

2-f3,5-Bis(trifluoromethyl)phenvn-A/-{4-(4-fluoro-2-methylphenyl)-6-f4-(hvdroxymethyl)^ 4-methyl-5-oxo-3-pyrrolidinvn-3-pyridinyl)-A/,2-dimethylpropanamide:

To a solution of methyl 4-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}- (methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-3-methyl-2-oxo-3- pyrrolidinecarboxylate (169 mg, 0.259 mmol) in MeOH (1.6 ml) at 0 °C was added calcium chloride (71.7 mg, 0.646 mmol). The resulting mixture was stirred for 30 min. before sodium borohydride (48.9 mg, 1.293 mmol) was added. The reaction mixture was left to stir in an ice bath for 3 h. After this time 5M HCI was added, the reaction mixture was concentrated in vacuo, before being partitioned between water (100 ml) and EtOAc. The organic phase was dried (Na₂S0₄) and concentrated in vacuo. The product was purified by flash chromotography on a silica gel column, using 20% EtOAc in iso-hexane (3CV) 20-50% EtOAc in iso-hexane (12CV) 50-100% EtOAc in isohexane (3CV) 100% EtOAc (9CV). The product did not elute, so 10% MeOH in DCM (6CV) 10-20% MeOH in DCM (6CV) and 20- 30% MeOH in DCM (9CV) was used to elute the product, though the compound was still impure. The crude compound was then purified by MDAP to yield the title compound as a white crystalline solid (43.3 mg, 0.069 mmol, 27% yield)

¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 1 .09 (s, 3 H) 1 .43 (br m, 3 H) 1.59 (br m, 6 H) 2.16 (br m, 2 H) 2.44 (br m, 1 H) 3.23 (br, s, 1 H) 3.55 - 3.66 (m, 3 H) 3.96 (br m, 1 H) 5.26 (br m, 1 H) 5.96 (br m, 1 H) 6.94 - 7.04 (br m, 3 H) 7.18 (s, 1 H) 7.66 (s, 2 H) 7.81 (s, 1 H) 8.42 (s, 1 H).

UPLC (acidic conditions): Rt 1.26 min , m/z 626.36 [M+H⁺].

Biological Data

Compounds of the invention may be tested for in vitro biological activity in accordance with the following assays:

Measurement of NK functional potency:

Compounds of the invention were further characterised in a functional assay using FLIPR (Molecular Devices Co.) technology for the determination of their effect to inhibit the intracellular calcium release induced by interaction of NK receptors with their respective ligands. Human U20S cells transiently transduced with recombinant BacMam virus expressing human NK1 , NK2 and NK3 receptors were used in the studies (see J. P. Condreay et al, Proc. Natl. Acad. Sci. USA 1999, 96(1 ): 127-132). Briefly, U20S cells were harvested from tissue culture flasks, re-suspended to a cell density of 200-300K/ml and mixed with recombinant BacMam virus carrying NKR gene in a virus/cell ratio of 1 % (v/v). 10K-15K cells/well were then seeded in 384-well Greiner bio-one plate in culture medium (DMEM with 10% FBS), incubated overnight in 5% C0₂ at 37°C. After aspirating the medium, cells were loaded 18-24 hr later with cytoplasmic calcium indicator Fluo-4 Calcium (Invitrogen)

in 30uL/well buffer (Hank's balanced salts with 20 mM Hepes) and incubated in C0₂ at 37°C for 60 min. 10uL/well assay buffer (Hank's balanced salts with 20 mM Hepes) containing different concentrations of compounds were then added to the cells for 30 min. incubation at 37°C. Finally, 10 uL/well of NKR ligands in assay buffer containing 0.1 % BSA was added to the cells and fluorescence signal read on a FLIPR system. Substance P, NKA and NKB peptides were used as the ligands for NK1 , NK2 and NK3 receptor, respectively. IC₅₀ values of each compound were determined by an 1 1 -point 3X-dilution inhibition curve. The potency each antagonist (fpK,) was calculated from plC₅₀ by the Cheng-Prusoff equation using EC₅₀ of ligand determined in a separate experiment.

Claims

CLAI MS

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein

R is halogen, C 1.4 alkyl or trifluoromethyl;

R4 and R5 are independently hydrogen or C 1.4 alkyl;

Rg is trifluoromethyl, halogen, trifluoromethoxy, C -| .g alkoxy or C 1.4 alkyl;

m is an integer from 0 to 2;

q is 1 or 2;

n is 1 and p is 0 or n is 0 and p is 1 .

2. A compound according to claim 1 selected from 2-[3,5-Bis(trifluoromethyl)phenyl]-/V-[4-(4-fluoro-2-methylphenyl)-6-(5-oxo-3-pyrrolidinyl)-3- pyridinyl]-/V,2-dimethylpropanamide;

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(4-(hydroxymethyl)-1 - methyl-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (enantiomer 2);

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(3-(hydroxymethyl)-5- oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (anti: enantiomer 1 ); 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(3-(hydroxymethyl)-5- oxo-2-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide (syn; enantiomer 2);

2-[3,5-Bis(trifluoromethyl)phenyl]-/V-{4-(4-fluoro-2-methylphenyl)-6-[(2-(hydroxyme oxo-3-pyrrolidinyl]-3-pyridinyl}-/V,2-dimethylpropanamide (syn: enantiomer 1 );

/V-[6-[2,2-Bis(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-2-

[3,5-bis(trifluoromethyl)phenyl]-/V,2-dimethylpropanamide;

[3,5-bis(trifluoromethyl)phenyl]-/V,2-dimethylpropanamide (enantiomer 1 );

2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[2-(hydroxymethyl)-5-oxo- 1 -(2,2,2-trifluoroethyl)-3-pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide;

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-(2,2-dimethyl-5-oxo-3-pyrrolidinyl)-4-(4-fluoro-2- methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide;

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-[2,2-dimethyl-5-oxo-3-pyrrolidinyl]-4-(4-fluoro-2- methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (enantiomer 1 );

2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-[2,2-dimethyl-5-oxo-3-pyrrolidinyl]-4-(4-fluoro-2- methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (enantiomer 2);

3- pyrrolidinyl]-3-pyridinyl}-N,2-dimethylpropanamide;

or a pharmaceutically salt thereof.

3. A compound which is 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2- methylphenyl)-6-[(4-(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2- dimethylpropanamide (enantiomer 2) or a pharmaceutically salt thereof.

4. A compound which is 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2- methylphenyl)-6-[(4-(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2- dimethylpropanamide (enantiomer 2). 5. A compound which is 2-[3,

5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2- methylphenyl)-6-[(4-(hydroxymethyl)-5-oxo-3-pyrrolidinyl]-3-pyridinyl}-N,2- dimethylpropanamide hydrochloride (enantiomer 2).

6. A pharmaceutical composition which comprises compounds of formula (I) as defined in any of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a

pharmaceutically acceptable carrier or excipient.

7. A compound as defined in any of claims 1 to 5 for use in therapy.

8, A compound as defined in any of claims 1 to 5 for use in the treatment of

skin disorders.

9, Use of a compound as fefined in any of claims 1 to 5 in the manufacture of a medicamente for the treatment of skin disorders,

10. A method of treatment of skin disorders which comprises administering to a host in need thereof an effective amount of a compound of formula (I) as defined in any of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

1 1. A compound as defined in any of claims 1 to 5 for use in the treatment of hair disorders.

12. Use of a compound as defined in any of claims 1 to 5 in the manufacture of a medicament for the treatment of hair disorders.

13. A method of treatment of hair disorders which comprises administering to a host in need thereof an effective amount of a compound of formula (I) as defined in any of claims 1 to 5 or a pharmaceutically acceptable salt thereof.