New heterocyclic compounds for treatment of respiratory, airway or inflammatory disorders

THE FIELD OF THE INVENTION

The present invention relates to new compounds, to pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof.

BACKGROUND OF THE INVENTION

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma, chronic obstructive pulmonary disease (COPD), allergic diseases, rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.

Chemokines are attractants and activators of monocytes, lymphocytes and neutrophils. The C-C chemokines include potent chemoattractants such as human monocyte chemotactic proteins 1-3 (MCP-I, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins lα and lβ (MIP- lα and MIP- lβ). The C-X-C chemokines include several potent chemoattractants such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO, CXCRl, CXCR2, CXCR3 and CXCR4.

Chemokine Receptor 1 (CCRl) is highly expressed in tissues affected in different autoimmune, inflammatory, proliferative, hyper proliferative and immunologically

mediated diseases, e.g. asthma, chronic obstructive pulmonary disease, multiple sclerosis and rheumatoid arthritis. Therefore, inhibiting CCRl -mediated events is expected to be effective in the treatment of such conditions.

International publication numbers WO04/005295 describes spiropiperidines which modulate MIP- lα chemokine receptor activity.

A desirable property for a drug acting at the CCRl receptor is that it has high potency e.g. as determined by its ability to inhibit the activity of the CCRl receptor. It is also desirable for such drugs to possess good selectivity and pharmacokinetic properties in order to further enhance drug efficacy. As an example, it can be advantageous for such drugs to possess good metabolic stability and bioavailability.

It is also desirable for compounds to exhibit low activity against the human ether-a-go-go- related-gene (hERG)-encoded potassium channel. In this regard, low activity against hERG binding in vitro is indicative of low activity in vivo. The present inventors have identified new compounds which modulate CCRl receptor activity and which are contemplated to have a particularly beneficial potency, selectivity and/or pharmacokinetic properties.

In accordance with the present invention, there is provided a compound of formula I

wherein: m is 0, 1 or 2;

R ¹ is halogen, cyano, Ci-Cβalkyl or Ci-C ₃ haloalkyl;

Q is oxygen, CH ₂ or C(O);

X is a bond or CH ₂ ;

Y is oxygen or C(O); p is 1 or 2;

R ² is hydrogen or Ci-Cβalkyl;

R ³ is hydrogen, hydroxy 1 or amino;

A is a bond or oxygen;

R ⁴ is hydrogen, halogen, cyano, amino, hydroxyl, oxo, -NHC(O)R ⁷ , -NHS(O) ₂ R ⁷ , -C(O)NR ⁸ R ⁹ , Ci-C ₆ alkoxyC(O)NR ⁸ R ⁹ , -C(O)OR ¹⁰ or SO ₃ R ¹⁰ , Ci-C ₆ alkoxy, OrCi-C ₆ alkyl, optionally substituted with t substituents independently selected from halogen, cyano, NR ⁸ R ⁹ , hydroxyl and oxo; t is O, 1, 2 or 3;

R ⁵ is hydrogen, halogen, hydroxyl, Ci-C ₆ hydroxyalkyl, Ci-C ₆ alkoxy or -C ₁ - C ₃ alkoxyphenyl, optionally substituted with one or more substituent independently selected from halogen, cyano, amino, amido, hydroxyl, oxo, thiol, - Ci-C ₃ alkoxy, - C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -C(O)NR ¹⁰ R ¹¹ , -SR ¹⁰ and -SO ₂ R ¹⁰ ; n is O, 1 or 2;

R ⁶ is halogen, cyano, C(O)R ¹⁰ , C _r C ₃ alkoxy, C _r C ₃ alkyl or C _r C ₃ haloalkyl;

R ⁷ is hydrogen, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, Ci-C ₆ alkoxy or -NR ⁸ R ⁹ ; R ⁸ and R ⁹ independently are hydrogen, Ci-C ₆ alkyl, Ci-C ₆ alkylsulphonyl or

C ₃ -C ₆ cycloalkyl, or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and which ring may be optionally substituted with one or more substituent independently selected from halogen, cyano, amino, amido, hydroxyl, oxo or - OCi-C ₃ alkyl;

R ¹⁰ and R ¹¹ independently are hydrogen, amino, Ci-C ₃ alkyl or Ci-C ₃ cycloalkyl; or a pharmaceutically acceptable salt thereof.

One embodiment relates to compouds of formula I wherein: m is O or 1; R ¹ is halogen; Q is oxygen; X is a bond or CH ₂ ; Y is oxygen or C(O); p is 1 or 2; R ² is hydrogen; R ³ is hydrogen or hydroxyl; A is a bond; R ⁴ is hydrogen, -NHC(O)R ⁷ , -C(O)NR ⁸ R ⁹ , Ci-C ₆ alkoxyC(O)NR ⁸ R ⁹ , optionally substituted with t substituents independently selected from halogen, cyano, NR ⁸ R ⁹ , hydroxyl and oxo; t is O or 1; R ⁵ is hydrogen, halogen, hydroxyl, Ci-C ₄ alkoxy or -Ci-C ₃ alkoxyphenyl, optionally substituted with one or more substituent independently selected from halogen, cyano, amino, amido, hydroxyl, oxo, thiol, - C _r C ₃ alkoxy, -C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -

C(O)NR ¹⁰ R ¹¹ , -SR ¹⁰ and -SO ₂ R ¹⁰ ; n is 0 or 1; R ⁶ is halogen; R ⁷ is hydrogen, Ci-C ₆ alkyl, Ci-C ₆ alkoxy or -NR ⁸ R ⁹ ; R ⁸ and R ⁹ independently are hydrogen, Ci-C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and which ring may be optionally substituted with one or more substituent independently selected from halogen or hydroxyl; R ¹⁰ and R ¹¹ independently are hydrogen, amino or Ci-C ₃ alkyl; or a pharmaceutically acceptable salt thereof.

Another embodiment relates to compouds of formula I wherein: m is 1; R ¹ is halogen; Q is oxygen; X is a bond or CH ₂ ; Y is oxygen or C(O); p is 1 or 2;

R ² is hydrogen; R ³ is hydroxyl;

A is a bond; R ⁴ is hydrogen, -NHC(O)R ⁷ , -C(O)NR ⁸ R ⁹ , Ci-C ₆ alkoxyC(O)NR ⁸ R ⁹ ;

R ⁵ is hydrogen, halogen, hydroxyl, Ci-C ₄ alkoxy or -Ci-C ₃ alkoxyphenyl, optionally substituted with one or more substituent independently selected from halogen, cyano, amino, hydroxyl, -Ci-C ₃ alkoxy, -C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -C(O)NR ¹⁰ R ¹¹ , -SR ¹⁰ and -

SO ₂ R ¹⁰ ; n is O or 1 ; R ⁶ is halogen;

R ⁷ is hydrogen, Ci-C ₆ alkyl, Ci-C ₆ alkoxy or -NR ⁸ R ⁹ ; R ⁸ and R ⁹ independently are hydrogen, Ci-C _δ alkyl or C ₃ -C ₆ cycloalkyl, or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and which ring may be optionally substituted with hydroxyl;

R ¹⁰ and R ¹¹ independently are hydrogen or Ci-C ₃ alkyl; or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention m is 1 and R is a halogen atom, particularly chlorine. In another embodiment R ¹ is para-substituted on position 4.

In yet another embodiment Q is oxygen.

In one embodiment the integer p is 1. In another embodiment p is 2.

In a further embodiment p is 1 , X is CH ₂ and Y is an oxygen. In another embodiment of the present invention p is 2, X is a bond and Y is C(O).

In one embodiment of the present invention R ² is hydrogen, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl or tert-butyl. In a particular embodiment R ² is hydrogen.

In one embodiment R ³ is hydrogen or hydroxyl. In a particular embodiment of the present invention R ³ is hydroxyl.

In another embodiment of the present invention A is a bond.

In a further embodiment of the present invention, A is a bond and R ⁴ is hydrogen, -NHC(O)R ⁷ , -NC(O), -C(O)NR ⁸ R ⁹ , Ci-C ₆ alkoxyC(O)NR ⁸ R ⁹ . In one embodiment of the present invention R ⁴ is hydrogen. In another embodiment R ⁴ is Ci-C ₃ alkoxyC(O)NR ⁸ R ⁹ , particularly 2-methoxy-N,N-dimethyl-acetamide.

In another embodiment R ⁴ is -C(O)NR ⁸ R ⁹ wherein R ⁸ and R ⁹ independently are hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and which ring may be optionally substituted with hydroxyl. In a particular embodiment R ⁸ is hydrogen and R ⁹ hydrogen, methyl or cyclopropyl. In yet another embodiment of the present invention, R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 2-hydroxypyrrolidine ring. In yet another embodiment R ⁴ is -NC(O).

In one embodiment of the present invention R ⁴ is -NHC(O)R ⁷ wherein R ⁷ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy or -NR ⁸ R ⁹ and R ⁸ and R ⁹ independently are hydrogen, methyl and cyclopropyl. In another embodiment R ⁷ is -NH ₂ or cyclopropylamine. In a particular embodiment R ⁷ is hydrogen. In one embodiment R ⁷ is methyl. In another embodiment R ⁷ is ethoxy.

In one embodiment R ⁵ is hydrogen, halogen, hydroxyl, methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, i-butoxy, tert-butoxy, -methoxyphenyl, -ethoxyphenyl or - propoxyphenyl, optionally substituted with one or more substituent independently selected from halogen, cyano, amino, hydroxyl, methoxy, ethoxy, n-propoxy, i-propoxy, -

C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -C(O)NR ¹⁰ R ¹¹ , -SR ¹⁰ and -SO ₂ R ¹⁰ wherein R ¹⁰ and R ¹¹ independently are hydrogen, methyl, ethyl, n-propyl or i-propyl.

In another embodiment R ⁵ is hydrogen. In yet another embodiment R ⁵ is hydroxyl. In a further embodiment R ⁵ is chlorine or fluorine. In another embodiment R ⁵ is -methoxyphenyl substituted with methoxy.

In one embodiment R ⁵ is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy or tert-butoxy, which may be substituted with cyano, amino, hydroxyl, -Ci-Cβalkoxy, -

C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -C(O)NR ¹⁰ R ¹¹ , -SR ¹⁰ and -SO ₂ R ¹⁰ .

In another embodiment R ⁵ is methoxy. In yet another embodiment R ⁵ is methoxy substituted with cyano, -C(O)O-methyl or -S-methyl.

In one embodiment R ⁵ is ethoxy. In a further embodiment R ⁵ is ethoxy substituted with N- dimethyl, methoxy, -OC(O)-methyl, hydroxyl, -S-methyl or - Sθ ₂ -methyl.

In another embodiment R ⁵ is i-propoxy. In yet another embodiment R ⁵ is i-propoxy substituted with -C(O)OH, C(O)O-ethyl, -C(O)NH ₂ or -C(O)NH methyl. In a further embodiment R ⁵ is i-butoxy. In yet a further embodiment R ⁵ is i-butoxy substituted with hydroxyl.

In one embodiment of the present invention the integer n is O, 1 or 2. In a particular embodiment n is O. In yet another embodiment n is 1.

In one embodiment n is 1 and R ⁶ is a halogen. In a particular embodiment n is 1 and R ⁶ is chlorine. In another embodiment of the present invention R ⁶ is C(O)R ¹⁰ , in particular C(O)H, C(O)CH ₃ or C(O)NH ₂ .

For the avoidance of doubt the present invention relates to any one compound falling within the scope of formula I as defined above.

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.

For the avoidance of doubt it is to be understood that in this specification 'Ci-C ₆ ' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.

In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl. The term Ci-C ₄ alkyl having 1 to 4 carbon atoms and may b,e but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl or tert-butyl.

The term "alkoxy" and "hydroxyalkyl", unless stated otherwise, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. The term "alkoxy" may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy. The term 'hydroxyalkyl' may also include alkyl groups as defined above substituted by one or more hydroxyl groups.

In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system. The term "Ci-C ₆ cycloalkyl" may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In this specification, unless stated otherwise, the term "4- to 7-membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom", refers to a ringsystem having, in addition to carbon atoms, zero to three heteroatoms, including the oxidized form of nitrogen and sulfur and any quaternized form of a basic nitrogen, including, but not limited to cyclopropane, oxirane, cyclobutane,

azetidine, cyclopentane, cyclohexane, benzyl, furane, thiophene, pyrrolidine, morpholine, piperidine, piperazine, pyrazine, azepane.

In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluorine, iodine, chlorine or bromine.

In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, which is substituted with halogen as defined above. The term "C ₁ - Cohaloalkyl" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or bromopropyl

It will be appreciated that throughout the specification, the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.

In another embodiment of the present invention, the compound of formula I is selected from

N-[2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidin-l-yl]-2 -hydroxypropyl}oxy)-4- hy droxypheny 1] acetamide , 5-Chloro-2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidin-l-yl ]-2-hydroxypropyl}oxy)-4-

[(4-methoxybenzyl)oxy]-N-methylbenzamide,

5-Chloro-2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidin-l -yl]-2-hydroxypropyl}oxy)-4- hydroxy-N-methylbenzamide,

N-[5-Chloro-2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidi n-l-yl]-2- hydroxypropyl}oxy)-4-methoxyphenyl]acetamide, or a pharmaceutically acceptable salt thereof.

In a further embodiment of the present invention, the compound of formula I is selected from N-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)-4- hydroxyphenyljacetamide. TFA,

N-[2-({(2S)-3-[(4S)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2-hydroxypropyl}oxy)-4- hydroxyphenyljacetamide. TFA,

N-5 -chloro- [2-( {(2S)-3 - [(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2- hydroxypropyl} oxy)-4-hydroxyphenyl]acetamide. TFA, 5 N-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)-4- fluorophenyljacetamide. TFA,

5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2-hydroxypropyl}oxy)-

4-hydroxy-N-methylbenzamide. TFA,

5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2-hydroxypropyl}oxy)- i o 4- [(4-methoxybenzyl)oxy] -N-methylbenzamide,

2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl} oxy)-N- cyclopropylbenzamide. TFA,

N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazol idin-2-yl]-2- hydroxypropyl}oxy)-4-hydroxyphenyl}-N'-cyclopropylurea. TFA, is N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-[(4-methoxybenzyl)oxy]phenyl}-N'-cyclop ropylurea.,

N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazol idin-2-yl]-2- hydroxypropyl} oxy)phenyl}urea. TFA,

Ethyl [2-( {(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2-hydrox ypropyl} oxy)- 20 phenyljcarbamate. TFA,

N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazol idin-2-yl]-2- hydroxypropyl} oxy)4-hydroxyphenyl}urea. TFA,

N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazol idin-2-yl]-2- hydroxypropyl}oxy)4-[(4-methoxybenzyl)oxy]phenyl}urea. TFA , 25 5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2- yl]-2-hydroxypropyl}oxy)-

4-(cyanomethoxy)-N-methylbenzamide,

5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2-hydroxypropyl}oxy)-

4-(2-methoxyethoxy)-N-methylbenzamide,

2-[2-Chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazoli din-2-yl]-2- 30 hydroxypropyl}oxy)-4-(methylcarbamoyl)phenoxy]ethyl acetate,

5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2-hydroxypropyl}oxy)-

4-(2-hydroxyethoxy)-N-methylbenzamide,

Ethyl 2-[2-chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2- hydroxypropyl}oxy)-4-(methylcarbamoyl)phenoxy]-2-methylpropa noate, 5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2- yl]-2-hydroxypropyl}oxy)- 4-(2-hydroxy- 1 , 1 -dimethylethoxy)-N-methylbenzamide, 4-(2-Amino-l,l-dimethyl-2-oxoethoxy)-5-chloro-2-({(2S)-3-[(4 R)-4-(4- chlorophenoxy)isoxazolidin-2-yl]-2-hydroxypropyl}oxy)-N-meth ylbenzamide, 5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2- yl]-2-hydroxypropyl}oxy)- 4-[l,l-dimethyl-2-(methylamino)-2-oxoethoxy]-N-methylbenzami de, (3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazo lidin-2-yl]-2- hydroxypropyl} oxy)-4-hydroxybenzoyl]pyrrolidin-3-ol,

[2-Chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2-hydroxypropyl}oxy)- 4-{[(3S)-3-hydroxypyrrolidin-l-yl]carbonyl}phenoxy]acetonitr ile, (3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazo lidin-2-yl]-2- hydroxypropyl}oxy)-4-(2-methoxyethoxy)benzoyl]pyrrolidin-3-o l, (3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazo lidin-2-yl]-2- hydroxypropyl}oxy)-4-(2-hydroxyethoxy)benzoyl]pyrrolidin-3-o l, 2- [2-chloro-5 -( {(2S)-3 - [(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2- hydroxypropyl} oxy)-4- { [(3 S)-3 -hydroxypyrrolidin- 1 -yl] carbonyl} phenoxy] ethyl acetate, 1 - [5 -Chloro-2-( {(2S)-3 - [(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2- hydroxypropyl} oxy)-4-(cyanomethoxy)phenyl]urea, l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2- hydroxypropyl}oxy)-4-(2-methoxyethoxy)phenyl]urea,

2-[5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazol idin-2-yl]-2-hydroxy- propoxy]phenoxy]-N,N-dimethyl-acetamide, 2-[4-chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy- propoxy]phenoxy]-N,N-dimethyl-acetamide,

2-{2-chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-isoox azolidin-2-yl]-2- hydroxypropoxy}oxy-4-[methylamino)carbonyl]phenoxy} -2 -methyl propanoic acid, TFA, 5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidin-2 -yl]-2-hydroxy-propoxy]-4- (2-dimethylaminoethoxy)-N-methyl-benzamide,

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy-propoxy]- N-methyl-4-(methylsulfanylmethoxy)benzamide,

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy-propoxy]- N-methyl-4-(2-methylsulfanylethoxy)benzamide,

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy-propoxy]- N-methyl-4-(2-methylsulfonylethoxy)benzamide, N-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)- phenyljformamide. TFA,

3-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl} oxy)benzaldehyde. TFA, l-[3-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)phenyl]ethanone. TFA, and

3-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)benzamide.

TFA, or a pharmaceutically acceptable salt thereof.

Each exemplified compound represents a particular and independent aspect of the invention.

The compounds of formula I are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula I and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Thus, compounds of formula I or relevant intermediates can be prepared as an enantiomeric mixture of the R, S, RR, RS, SR and SS enantiomers and optionally separated to provide enantiomerically pure compounds.

The compounds of formula I may be used in the form of a pharmaceutically acceptable salt thereof, conceivably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, 2-fiuorobenzoate, 2,6-difiuorobenzoate, (hemi)fumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate or/?-toluenesulphonate. Pharmaceutically acceptable salts may also be formed together with metals such as calcium, magnesium, sodium, potassium or zinc or bases such as piperazine, 2-aminoethanol, choline, diethylamine or diethanol amine.

Furthermore, the compounds of formula I may be used in the form of a pharmaceutically acceptable salt thereof, like an amino acid addition salt such as L-lysine, glycine, L- glutamine, L-asparagine or L-arganine A pharmaceutically acceptable salt also includes internal salt (zwitterionic) forms. Any reference to compounds of formula I or salts thereof also encompasses solvates of such compounds and solvates of such salts (e.g. hydrates).

Certain intermediates and processes that are usefull for the making of the compounds of formula I of this invention may be synthesised using the procedures set out in WO04/005295 and WO05/049620.

Thus, the present invention further provides a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof as defined above which comprises:

(a) reacting a compound of formula IV

wherein R ¹ and integer m are as defined in formula I with a compound of formula V

wherein L is a suitable leaving group, like a bromine; or (b) converting a compound of formula VI

wherein R ¹ and integer m are as defined in formula I, to a compound of formula VII,

wherein R ¹ and integer m are as defined in formula I and P is a hydrogen or a suitable protecting group, using a suitable amine; or (c) where R ³ is a hydroxyl group, converting a compound of formula VIII

wherein A, R ² , R ⁴ , R ⁵ , R ⁶ and integer n are as defined in formula I, to a compound of formula IX,

wherein A, R ² , R ⁴ , R ⁵ , R ⁶ and integer n are as defined in formula I and P' is a hydrogen or a suitable protecting group, using a suitable amine; or

(d) where R ³ is a hydroxyl group, reacting a compound of formula VIII,

wherein A, R ² , R ⁴ , R ⁵ , R ⁶ and integer n are as defined in formula I with a compound of formula VII

wherein R ¹ and integer m are as defined in formula I and P is a hydrogen; or (e) where R ³ is a hydroxyl group, reacting a compound of formula IX,

IX

wherein A, R ² , R ⁴ , R ⁵ , R ⁶ and integer n are as defined in formula I and P' is a hydrogen with a compound of formula VI

wherein R ¹ and integer m are as defined in formula I; or (f) converting a compound of formula X,

\— O wherein P" is a hydrogen or a suitable protecting group, to a compound of formula XI

^L' ^r^N- ^p" xi \— o wherein L is a suitable leaving group, like a nosylate, and P" is a hydrogen or a suitable protecting group in the presence of a suitable base like DMAP and pyridine; or

(g) reacting a compound of formula IV

wherein R ¹ and integer m are as defined in formula I with a compound of formula XI

wherein L' is a suitable leaving group, like a nosylate and P" is a hydrogen or a suitable protecting group, in the presence of a suitable base like cesium carbonate; or (h) where R ³ is a hydroxyl group, reacting a compound of formula XII

wherein R ¹ and integer m are as defined in formula I and P" is a hydrogen, with a compound of formula VIII

wherein A, R ² , R ⁴ , R ⁵ , R ⁶ and integer n are as defined in relation to formula I,

and therafter, if desired or necessary, carrying out one or more of the following steps (i) converting a compound of formula I obtained to a different compound of formula I; (ii) removing of any protecting groups; and

(iii) forming a pharmaceutically acceptable salt and/or polymorph of the compound of formula I.

As will be apparent to a person skilled in the art, following the epoxide opening of intermediates like VIII with an amine, will produce an enantiomeric mixture of intermediates IX and final product, which can be separated.

Process (a) - (h) may conveniently be carried out in a suitable solvent, e.g. an organic solvent selected from alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene), cyanides (e.g. acetonitrile or butyronitrile), ethers (THF, dioxane), NMP, DCM, DMPU or DMF at a temperature of, for example -20 ⁰ C or above, such as a temperature in the range from 0-150 ⁰ C.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as carboxyl, hydroxyl, or amino groups in the starting reagents or intermediate compounds my need to be protected by protecting groups. Thus, the preparation of the compounds of formula I may involve, at an appropriate stage, the introduction c.q. removal of one or more protecting groups.

The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective

Groups in Organic Synthesis', 3 ^rd edition, T. W. Greene and P.G.M. Wuts, Wiley- Interscience (1999).

Intermediates of formula IV and intermediates of formula VI and salts thereof are novel and comprise an independent aspect of the invention.

A further embodiment of the invention relates to compounds selected from

λ/-(2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-hydroxypheny l)acetamide;

λ/-(5-chloro-2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-hyd roxyphenyl) acetamide;

2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-[(4-methoxybenxyl )oxy]-N,λ/-dimethyl benzamide;

2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-[(4-methoxybenxyl )oxy]-N-methyl benzamide;

λ/-(5-chloro-2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-met hoxyphenyl) acetamide;

3-(4-chlorophenoxy)pyrroldin-2-one;

Tert-butyl (4S)-4-{[(3-nitrophenyl)sulfonyl]oxy}isoxazolidin-2-carboxyl ate; (4R)-4-(4-chlorophenoxy)isoxazolidine.TFA;

Tert-butyl (4R)-4-{[(3-nitrophenyl)sulfonyl]oxy}isoxazolidin-2-carboxyl ate; and

(4S)-4-(4-chlorophenoxy)isoxazolidine.TFA.

Another embodiment related to the use of these compounds as intermediates in the preparation of compounds of formula I.

Pharmaceutical composition

The active ingredients of the present invention may be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions. The active ingredients may also be administered topically (e.g. to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations. These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants. As will

be understood by those skilled in the art, the most appropriate method of administering the active ingredients is dependent on a number of factors.

One embodiment relates to a pharmaceutical composition comprising a compound of formula I, or pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions of the present invention may be prepared by mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition, which comprises mixing a compound of formula I, or pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.

In one embodiment of the present invention, the active ingredient of the present invention is administered by inhalation.

The active ingredient is conveniently administered via inhalation (e.g. topically to the lung and/or airways) in the form of solutions, suspensions, aerosols or dry powder formulations. Administration may be by inhalation orally or intranasally. The active ingredient is preferably adapted to be administered, from a dry powder inhaler, pressurised metered dose inhaler, or a nebuliser.

The active ingredient may be used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers. Examples of suitable diluents or carriers include lactose (e.g. the monohydrate), dextran, mannitol or glucose.

Metered dose inhaler devices may be used to administer the active ingredients, dispersed in a suitable propellant and with or without additional excipients such as ethanol, a surfactant, a lubricant, an anti-oxidant or a stabilising agent. Suitable propellants include hydrocarbon, chlorofiuorocarbon and hydrofiuoroalkane (e.g. heptafiuoroalkane) propellants, or mixtures of any such propellants. Preferred propellants are P 134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other

excipients. Nebulised aqueous suspensions, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.

Dry powder inhalers may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture. The dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.

When the active ingredient is adapted to be administered, via a nebuliser it may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a single dose or multidose device.

Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.

In one embodiment the present invention provides a pharmaceutical product comprising, an active ingredient which is a compound of formula I, or a pharmaceutically acceptable salt thereof, formulated for inhaled administration. In an embodiment of the present invention, the compound of formula I, or a pharmaceutically acceptable salt thereof, may be administered orally.

Medical use

The compounds of formula I, salts and solvates thereof, have activity as pharmaceuticals, and are surprisingly potent modulators of chemokine receptor (especially CCRl receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases.

A compound of the invention, or a pharmaceutically acceptable salt thereof, may be used in the treatment of:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including

aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; 2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial

Mediterranean fever, Muckle- Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;

3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis); 4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;

5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;

6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);

7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer;

acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);

9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;

10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;

12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes;

13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,

15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.

Combination therapies

The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutical composition or composition comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below; non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention still further relates to the combination of a compound of the invention, together with a cytokine or agonist or antagonist of cytokine function, (including

agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal 5 antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular- weight agents such as pentoxyfylline.

In addition the invention relates to a combination of a compound of the invention, with a o monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention, with a modulator of chemokine receptor function such as an antagonist of s CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX ₃ CRl for the C-X ₃ -C family.

The present invention further relates to the combination of a compound of the invention, 0 with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP- 1), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP- 12, including agents such as doxycycline. 5

The present invention still further relates to the combination of a compound of the invention, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5- lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2- o alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene

compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compound of the invention, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of a compound of the invention, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention still further relates to the combination of a compound of the invention, and an endothelin antagonist such as Tezosentan, Bosentan, Enrasentan, and Sixtasentan.

The present invention still further relates to the combination of a compound of the invention, and an angiotensin II antagonist such as Azilzartan, Losartan, Valsartan, Candesartan, and Telmisartan.

The present invention still further relates to the combination of a compound of the invention, or a pharmacuetically acceptable salt thereof, and a dual antagonists for both angiotensin II and endothelin A receptors (DARAs) such as disclosed in WO2000001389 and WO2001044239.

The present invention further relates to the combination of a compound of the invention, and an adenosine A2a agonist such as CGS-21680 and/or an adenosine A3 agonist such as IB-MECA and/or an adenosine A2b antagonist.

The present invention further relates to the combination of a compound of the invention, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.

The present invention still further relates to the combination of a compound of the invention, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention, and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the invention, and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of a compound of the invention, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.

The present invention further relates to the combination of a compound of the invention, and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention further relates to the combination of a compound of the invention, with an agent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of a compound of the invention, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).

The present invention further relates to the combination of a compound of the invention, and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The present invention still further relates to the combination of a compound of the invention, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.

The present invention further relates to the combination of a compound of the invention, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The present invention still further relates to the combination of a compound of the invention, and a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.

The present invention further relates to the combination of a compound of the invention, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.

The present invention still further relates to the combination of a compound of the invention, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.

The present invention further relates to the combination of a compound of the invention, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.

A compound of the present invention, can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.

The present invention still further relates to the combination of a compound of the invention, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v)

adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or inhibitors of kappaB kinases, such as IKKl, IKK2 or IKK3), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl. - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK. sub 1. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.

A compound of the invention, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fiuorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a

topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin);

(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-a mine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;

(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);

(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme

pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as trans fection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. For example, for the treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma, the compounds of the invention can be combined with one or more agents for the treatment of such a condition. Where such a combination is to be administered by inhalation, then the one or more agents is selected from the list comprising: • a PDE4 inhibitor including an inhibitor of the isoform PD E4D;

• a selective β.sub2. adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;

• a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;

• a steroid (such as budesonide);

• an inhibitor of p38 kinase function;

• an inhibitor of matrix metalloproteases, most preferably targeting MMP-2, -9 or MMP- 12; or,

• an inhibitor of neutrophil serine proteases, most preferably neutrophil elastase or proteinase 3.

In another embodiment of the invention where such a combination is for the treatment of airway disease, respiratory disease and/or an inflammatory disease such as for example chronic obstructive pulmonary disease and asthma, the compounds of the invention, can be

administered by inhalation or by the oral route and the other agent can be administered by inhalation or by the oral route. The compounds of the invention and the other agent, may be administered together. They may be administered sequencially. Or they may be administered separately.

One embodiment of the present invention provides a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts, as hereinbefore defined for use in therapy.

Another embodiment of the present invention provides the use of a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of CCRl activity is beneficial.

A further embodiment of the present invention provides the use of a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts, as hereinbefore defined in the manufacture of a medicament for treating a respiratory disease.

Yet another embodiment of the present invention provides the use of a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts, as hereinbefore defined in the manufacture of a medicament for treating an airways disease.

Yet a further embodiment of present invention provides the use of a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts, as hereinbefore defined in the manufacture of a medicament for treating an inflammatory disease.

One embodiment of the present invention provides the use of a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts, as hereinbefore defined in the manufacture of a medicament for treating chronic obstructive pulmonary disease (COPD).

Another embodiment of the present invention provides the use of a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts, as hereinbefore defined in the manufacture of a medicament for treating asthma.

A further embodiment of the present invention provides a method of treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, or any of the other disorders mentioned above, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvates or solvated salts, as hereinbefore defined.

One embodiment of the invention relates to an agent for the treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, , or any of the other disorders mentioned above, which comprises as active ingredient a compound of formula I or a pharmaceutically-acceptable salt, solvates or solvated salts.

Another embodiment relates to the use of a pharmaceutical composition comprising the compound of formula I for the treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, or any of the other disorders mentioned above.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

In this specification, unless stated otherwise, the terms "inhibitor" and "antagonist" mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist.

The term "disorder", unless stated otherwise, means any condition and disease associated with CCRl receptor activity.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula I may be in the range from 0.001 mg/kg to 30 mg/kg.

The compound of formula I and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula I compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable djuvants, diluents and/or carriers. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

Examples

The present invention will now be further understood by reference to the following illustrative examples.

The following abbreviations are used:

APCI-MS Atmospheric Pressure Chemical Ionisation Mass Spectroscopy;

BOC t-butoxycarbonyl

CAN Ammonium cerium(IV) nitrate

DCM Dichloromethane DIPEA 7V,7V-Diz ^' sopropylethylamine

DMF λ/,λ/-Dimethylformamide

DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone

DMSO Dimethylsulfoxide

HPLC High Performance Liquid Chromatography LC/MS Liquid Column Chromatography / Mass Spectroscopy

PMB /?-methoxybenzyl

TEA triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran r.t. room temperature or ambient temperature, i.e. a temperature in the range of from 16 to 25 ⁰ C.

General Methods

¹ H NMR and ¹³ C NMR spectra were recorded on a Varian Inova 400 MHz or a Varian Mercury-VX 300 MHz instrument. The central peaks of chloroform-J (δπ 7.27 ppm), dimethylsulfoxide-Jg (δu 2.50 ppm), acetonitrile-dj (δu 1.95 ppm) or methanol-^ (δu 3.31 ppm) were used as internal references. Flash chromatography was carried out using silica gel (0.040-0.063 mm, Merck). Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.

The following method was used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate 0.7 ml/min; Wavelength 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA; Gradient 15-95%/B 2.7 min, 95% B 0.3 min.

The following method was used for LC analysis:

Method A. Instrument Agilent 1100; Column: Kromasil Cl 8 100 x 3 mm, 5μ particle size, Solvent A: 0.1 %TF A/water, Solvent B: 0.08%TFA/acetonitrile Flow: 1 ml/min, Gradient 10-100% B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm. Method B. Instrument Agilent 1100; Column: XTerra C8, 100 x 3 mm, 5 μ particle size, Solvent A: 15 mM NH ₃ /water, Solvent B: acetonitrile Flow: 1 ml/min, Gradient 10-100% B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm.

Intermediate 1 3-(4-Chlorophenoxy)dihydrofuran-2(3H)-one

To an ice-cooled solution of sodiumethoxide (0.69 g) and 4-chlorophenol (4.4 g) in EtOH (20 mL), 3-bromodihydrofuran-2(3H)-one (5 g) was added. The mixture was stirred at room temperature for 18 h, refluxed to neutrality and the solvents removed in vacuo. The residue was diluted with water and extracted with ether. The combined organic phases were washed with 5% aq. NaOH and brine, dried over sodiumsulphate, filtered and removed in vacuo, yielding 4 g of the desired intermediate; APCI-MS: m/z 212 (M ⁺ )

Intermediate 2

N-(2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-hydroxyphenyl) acetamide

A solution of 4-(acetylamino)-[(2R)-oxiran-2ylmethoxy]phenyl acetate (100 mg; synthesized following procedure described in WO2004005295) in 7 M NH ₃ /Me0H (5 mL) was stirred at 40 ⁰ C for 18 h. The solvent was removed in vacuo, yielding 99 mg of the desired intermediate that is used without further purification.

Intermediate 2a

N-(5-chloro-2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-hydro xyphenyl) acetamide

Prepared using to the procedure as described for intermediate 2, using 7V-{5-chloro-4- hydroxy-2-[(2S)-oxiran-2ylmethoxy]phenyl}acetamide (see also WO2004005295 for preparation).

Intermediate 2b

2-{ [(2S)-3-amino-2-hydroxypropyl] oxy}-4- [(4-methoxybenxyl)oxy] -N,N-dimethyl benzamide

Prepared using to the procedure as described for intermediate 2, using 4-[(4- methoxybenzyl)oxy]-N,λ/-dimethyl-2-[(2S)-oxiran-2ylmethoxy] benzamide (see also WO2004005295 for preparation).

Intermediate 2c

2-{ [(2S)-3-amino-2-hydroxypropyl] oxy}-4- [(4-methoxybenxyl)oxy] -N-methyl benzamide

Prepared using to the procedure as described for intermediate 2, using 4-[(4- methoxybenzyl)oxy]-λ/-methyl-2-[(2S)-oxiran-2ylmethoxy]benz amide (see also WO2004005295 for preparation).

Intermediate 2d

N-(5-chloro-2-{[(2S)-3-amino-2-hydroxypropyl]oxy}-4-metho xyphenyl) acetamide

Prepared using to the procedure as described for intermediate 2.

Intermediate 3

3-(4-chlorophenoxy)pyrroldin-2-one

i) A mixture of intermediate 1 (2 g) and 4-methoxy-benzylamine (2.6 g) in toluene (20 ml) was heated to 110 ⁰ C for 24 h. The solvent was removed in vacuo yieldint the PMB protected amide intermediate that was used without further purification ii) A solution of the PMB-protected amide and CAN (15.5 g) in a mixture of acetonitrile (70 ml) and water (30 ml) was stirred at room temperature for 45 min. The solution was poored in an aqueous saturated solution of sodiumbicarbonate and extracted with DCM (4x200 ml). The combined organic layers were dried over sodium sulphate, filtrated and removed in vacuo. The residue purified using flash chromatography (EtOAc), yielding 2.2 g of the desired intermediate.

Intermediate 4

Tert-butyl (4S)-4-hydroxyisoxazolidin-2-carboxylate

To an ice-cooled solution of (4S)-isoxazolidin-4-ol.HCl (528 mg; syntesized following a procedure as described in the Journal of Molecular Catalysis B: Enzymatic, 11(4-6), 255- 263, 2001) and TEA (2.5 eq) in DCM (10 ml), (BOC) ₂ O (2.5 eq) is added dropwise. The reaction is stirred at room temperature for 24 h after which it is carefully concentrated in vacuo. The residue is partitioned between water and ethylacetate and the pH of the aqueous

phase is adjusted to <2 with 1 M HCl (aq). The mixture is stirred for 5 min. at room temperature, the layers are separated and the organic phase is washed several times with water, dried over Na ₂ SO ₄ and removed in vacuo. The residue is purified over HPLC (gradient water/acetonitrile with 0.1% TFA) and the pooled fractions are freezedried, yielding 509 mg of the desired intermediate.

¹ H-NMR (acetone-de, 300 MHz): δ 4.74 (m, IH), 3.89-3.54 (m, 4H), 1.45 (s, 9H); APCI- MS: m/z 190 (MH ⁺ ).

Intermediate 5 Tert-butyl (4S)-4-{[(3-nitrophenyl)sulfonyl]oxy}isoxazolidin-2-carboxyl ate

To a solution of intermediate 4 (190 mg), DMAP(0.5 eq) and pyridin (0.5 ml) in DCM (5 ml), 3-nitrophenylsulfonylchloride (1.2 eq) is added. The solution is stirred at room temperature for 24 h, washed with IM NaHCO ₃ (aq) and water, dried over Na ₂ SO ₄ and removed in vacuo. The residue is purified by gradient flash chromatography (DCM/MeOH), yielding 200 mg of the desired intermediate.

¹ H-NMR (CDCl ₃ , 300 MHz): δ 8.78 (m, IH), 8.54 (m, IH), 8.28 (m, IH), 7.82 (m, IH), 4.47 (m, IH), 4.31-4.22 (m, 2H), 3.97-3.82 (m, 2H), 1.51(s, 9H); λPCI-MS: m/z 274 (MH ⁺ -IOO).

Intermediate 6

(4R)-4-(4-chlorophenoxy)isoxazolidine.TFA

To a solution of intermediate 5 (190 mg) and 4-chlorophenol (77 mg) in DMPU(2 ml) cesium carbonate (196 mg) is added. The suspension is stirred at room temperature for 24

h, partitioned between water and DCM and the organic phase is washed with water, dried over Na ₂ SO ₄ and removed in vacuo. The residue is purified by HPLC chromatography (gradient water/acetonitrile with 0.1% TFA), and the BOC-protected intermediate is redissolved in DCM (2 ml) and treated with TFA (2 ml) for 30 min. at room temperature. The solvents are removed in vacuo and the resulting oil is purified by HPLC chromatography (gradient water/acetonitrile with 0.1% TFA), yielding 80 mg of the desired intermediate.

¹ H-NMR (CDCl ₃ , 300 MHz): δ 9.14 (br.s), 7.29 (m, 2H), 6.82 (m, 12), 5.37 (m, IH), 4.47- 4.38 (m, 2H), 3.97-3.83 (m, 2H); APCI-MS: m/z 200 (MH ⁺ ).

Intermediate 7

Tert-butyl (4R)-4-hydroxyisoxazolidin-2-carboxylate

Prepared using to the procedure as described for intermediate 4. ¹ H-NMR (acetone-de, 300 MHz): δ 4.74 (m, IH), 3.89-3.54 (m, 4H), 1.45 (s, 9H); APCI- MS: m/z 190 (MH ⁺ ).

Intermediate 8

Tert-butyl (4R)-4-{[(3-nitrophenyl)sulfonyl]oxy}isoxazolidin-2-carboxyl ate

Prepared using to the procedure as described for intermediate 5.

¹ H-NMR (CDCl ₃ , 300 MHz): δ 8.78 (m, IH), 8.54 (m, IH), 8.28 (m, IH), 7.82 (m, IH),

4.47 (m, IH), 4.31-4.22 (m, 2H), 3.97-3.82 (m, 2H), 1.51(s, 9H); .4PCI-MS: m/z 274

(MH ⁺ -IOO).

Intermediate 9

(4S)-4-(4-chlorophenoxy)isoxazolidine.TFA

Prepared using to the procedure as described for intermediate 6.

¹ H-NMR (CDCl ₃ , 300 MHz): δ 9.14 (br.s), 7.29 (m, 2H), 6.82 (m, 12), 5.37 (m, IH), 4.47-

4.38 (m, 2H), 3.97-3.83 (m, 2H); APCI-MS: m/z 200 (MH ⁺ ).

Example 1

N-[2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidin-l-yl]-2 -hydroxypropyl}oxy)-4- hydroxyphenyl] acetamide

A mixture of intermediate 1 (87 mg), intermediate 2 (95 mg) in toluene (4 ml) was refluxed for 18 h. The solvent was removed in vacuo and the residue purified with HPLC (Xterra), yielding 5 mg of the desired product.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.91 (br.s), 7.88 (br.s), 7.70 (m, IH), 7.23 (m, 2H), 6.95 (m, 2H), 6.86 (m, IH), 6.42 (m, IH), 4.87 (m, IH), 4.22 (m, IH), 4.02-3.88 (m, 2H), 4.02- 3.88 (m, 4H), 2.55 (m, IH), 2.18 (m, IH), 2.06 (s, 3H); APCI-MS: m/z 435 (MH ⁺ ).

Example 2

5-Chloro-2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidin-l -yl]-2-hydroxypropyl}oxy)-4- [(4-methoxybenzyl)oxy]-N-methylbenzamide

A mixture of intermediate 1 (34 mg), intermediate 2c (54 mg) in toluene (4 ml) was refluxed for 18 h. The solvent was removed in vacuo and the residue purified with HPLC (Xterra), yielding 18 mg of the desired product. APCI-MS: m/z 589 (MH ⁺ ).

Example 3

5-Chloro-2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidin-l -yl]-2-hydroxypropyl}oxy)-4- hydroxy-N-methylbenzamide

To a solution of 5-chloro-2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidin-l-yl ]-2- hydroxypropyl}oxy)-4-[(4-methoxybenzyl)oxy]-λ/-methylbenzam ide (18 mg) in a mixture of acetonitrile and water (7:3), CAN (3 eq) was added. The reaction was stirred at room temperature for 3 h. The reaction was diluted with MeOH and stirred for an additional 15 min. at room temperature, after which the solvents were removed in vacuo and the residue purified with HPLC (Xterra), yielding 6 mg of the desired product. ¹ H-NMR (acetone-de, 500 MHz): δ 9.64 (br.s), 8.16 (br.s), 7.97 (m, IH), 7.28 (m, 2H), 7.09 (m, 2H), 6.89 (m, IH), 5.03 (m, IH), 4.33 (m, IH), 4.20-4.07 (m, 2H), 3.73-3.51 (m, 4H), 2.86 (m, 3H), 2.66 (m, IH), 2.11 (m, IH); APCI-MS: m/z 469 (MH ⁺ ).

Example 4

N-[5-Chloro-2-({(2S)-3-[3-(4-chlorophenoxy)2-oxopyrrolidi n-l-yl]-2-hydroxypropyl}oxy)- 4 -methoxy phenyl] 'acetamide

A mixture of intermediate 1 (893 mg), intermediate 2d (900 mg) in xylene (40 ml) was refluxed for 24 h. The solvent was removed in vacuo and the residue purified with HPLC (Xterra), yielding 180 mg of the desired product.

¹ H-NMR (acetone-de, 500 MHz): δ 8.81 (br.s), 8.29 (m, IH), 7.27 (m, 2H), 7.08 (m, 2H), 6.89 (m, IH), 5.03 (m, IH), 4.26 (m, IH), 4.12 (m, 2H), 3.86 (s, 3H), 3.77-3.54 (m, 4H), 2.64 (m, IH), 2.12 (m, IH), 2.08 (s, 3H); APCI-MS: m/z 483 (MH ⁺ ).

Example 5

N-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2-hydroxypropyl}oxy)-4- hydroxyphenyl] acetamide. TFA

The free base of intermediate 6 was obtained by extraction between EtOAc and 1 M

NaHCO ₃ (aq). A solution of the free base of intermediate 1 (45 mg) and N- {4-hydroxy-2- [(2S)-oxiran-2-ylmethoxy]phenyl} acetamide (60 mg) in EtOH (2 ml) is stirred at 90 ⁰ C for 18 h. Water (2 ml) and 1 M NaOH (aq; 10 drops) ared added and the mixture is stirred at 90 ⁰ C for 5 min. The pH is adjusted with TFA, the mixture is concentrated in vacuo and the residue purified over HPLC (gradient water/acetonitrile with 0.1% TFA), yielding 63 mg of the desired product as a TFA salt.

¹ H-NMR (acetone-d6, 400 MHz): δ 8.45 (br.s, IH)), 8.16 (br.s, IH), 7.92 (m, IH), 7.30 (m, 2H), 6.95 (m, 2H), 6.55 (m, IH), 6.40 (m, IH), 5.30 (m, IH), 4.34 (m, IH), 4.18 (m,

2H), 3.95 (m, IH), 3.89 (m, IH), 3.25-2.96 (m, 5H), 2.84 (s, 3H); APCI-MS: m/z 423 (MH ⁺ ).

Example 6 N- [2- ({(2 S) -3-[(4S) -4- (4-chlorophenoxy) isoxazolidin-2-yl]-2-hydroxypropyl} oxy) -4- hydroxyphenyl] acetamide. TFA

Prepared using to the procedure as described for example 5, reacting intermediate 9 with N- {4-hydroxy-2-[(2S)-oxiran-2-ylmethoxy]phenyl} acetamide. APCI-MS: m/z 423 (MH ⁺ ).

Example 7

N-5-chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazoli din-2-yl]-2- hydroxypropyl}oxy)-4-hydroxyphenyl] acetamide. TFA

Synthesized following the procedure as described for example 5, using intermediate 6 and N-5-chloro-{4-hydroxy-2-[(2S)-oxiran-2-ylmethoxy]phenyl} acetamide. ¹ H-NMR (DMSO-d6, 400 MHz): δ 8.92 (br.s, IH)), 7.89 (s, IH), 7.33 (m, 2H), 6.95 (m, 2H), 6.62 (s, IH), 5.29 (m, IH), 4.26 (m, IH), 4.03 (m, 2H), 3.82 (m, 2H), 3.17-2.94 (m, 5H), 2.04 (s, 3H); APCI-MS: m/z 457 (MH ⁺ ).

Example 8

N-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2-hydroxypropyl}oxy)-4- fluorophenyl] acetamide. TFA

Synthesized following the procedure as described for example 5, using intermediate 6 and N- {4-fluoro-2-[(2S)-oxiran-2-ylmethoxy]phenyl} acetamide.

¹ H-NMR (acetone-d6, 400 MHz): δ 8.58 (br.s, IH)), 8.15 (m, IH), 7.27 (m, 2H), 6.92 (m, 2H), 6.86 (m, IH), 6.64 (m, IH), 5.33 (m, IH), 4.32-3.94 (m, 5H), 3.28-3.05 (m, 4H), 2.05 (s, 3H); APCI-MS: m/z 425 (MH ⁺ ).

Example 9

5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2-hydroxypropyl}oxy)- 4-hydroxy-N-methylbenzamide. TFA

i) 5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2 -yl]-2- hydroxypropyl}oxy)-4- [(4-methoxybenzyl)oxy] -N-methylbenzamide

Synthesized following the procedure as described for example 5, using intermediate 6 and

5-chloro-4-hydroxy-λ/-methyl-2-[(2S)-oxiran-2ylmethoxy]b enzamide.

APCI-MS: m/z 577 (MH ⁺ ).

U) 5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2 -yl]-2- hydroxypropyl}oxy)-4-hydroxy-N-methylbenzamide

A solution of 5-chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2 -yl]-2- hydroxypropyl}oxy)-4-[(4-methoxybenzyl)oxy]-7V-methylbenzami de in a mixture of

DCM/TFA (1:2 vol) was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue suspended in MeOH. The precipitate was filtered of and MeOH was removed in vacuo. The residue was purified over HPLC (gradient water/acetonitrile with

0.1 % TFA), yielding the desired product in an overall yield of 46%.

¹ H-NMR (acetone-d6, 400 MHz): δ 8.22 (br.s, IH)), 8.00 (s, IH), 7.31 (m, 2H), 6.96 (m, 2H), 6.80 (s, IH), 5.38 (m, IH), 4.33 (m, 3H), 4.17 (m, IH), 4.00 (m, IH), 3.38-3.10 (m, 4H), 2.86 (m, 3H); APCI-MS: m/z 457 (MH ⁺ ).

Example 10

2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)-N- cyclopropylbenzamide. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and N- cyclopropyl-2-[(2S)-oxiran-2ylmethoxy]benzamide.

¹ H-NMR (acetone-d6, 400 MHz): δ 8.37 (br.s, IH)), 8.02 (m, IH), 7.45 (m, IH), 7.30 (m,

2H), 7.13 (m, IH), 7.05 (m, IH), 6.95 (m, 2H), 5.35 (m, IH), 4.31 (m, 4H), 4.22 (m, IH),

3.95 (br.s, IH), 3.24 (br.s, 2H), 3.11-2.95 (m, 2H), 2.05 (m, IH), 0.72-0.60 (m, 4H); APCI-

MS: m/z 433 (MH ⁺ ).

Example 11

N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazol idin-2-yl]-2- hydroxypropyl}oxy)-4-hydroxyphenyl}-N'-cyclopropylurea. TFA

i) N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-[(4-methoxybenzyl)oxy]phenyl}-N'-cyclop ropylurea.

Prepared using to the procedure as described for example 5, using intermediate 9 and N-

(sec-butyl)-λ^-{5-chloro-4-hydroxy-2-[(2S)-oxiran-2ylmet hoxy]phenyl}urea. ii) N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-hydroxyphenyl}-N'-cyclopropylurea. TFA

A solution of N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-[(4-methoxybenzyl)oxy]phenyl}-7V'-cyclo propylurea in a mixture of DCM/TFA (1:2 vol) was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue suspended in MeOH. The precipitate was filtered of and MeOH was removed in vacuo. The residue was purified over HPLC (gradient water/acetonitrile with 0.1 % TFA), yielding the desired product in an overall yield of

48%.

¹ H-NMR (acetone-d6, 400 MHz): δ 8.21 (s, IH)), 7.57 (br.s, IH), 7.31 (m, 2H), 6.97 (m,

2H), 6.68 (s, IH), 5.40 (m, IH), 4.37-4.03 (m, 5H), 3.37 (br.s, 2H), 3.18 (m, 2H), 2.59 (m, IH), 0.71 (m, 2H), 0.50 (m, 2H); APCI-MS: m/z 498 (MH ⁺ ).

Example 12

N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazol idin-2-yl]-2- hydroxypropyl}oxy)phenyl}urea. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and N- {5- chloro-2-[(2S)-oxiran-2ylmethoxy]phenyl}urea.

¹ H-NMR (acetone-d6, 400 MHz): δ 8.40 (m, IH)), 7.95 (br.s, IH), 7.32 (m, 2H), 6.98 (m, 3H), 6.87 (m, IH), 5.44 (m, IH), 4.42-4.08 (m, 5H), 3.49 (m, 2H), 3.29 (br.s, 2H); APCI- MS: m/z 442 (MH ⁺ ).

Example 13

Ethyl [2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2-hydroxypropyl}oxy)- pheny I] carbamate. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and ethyl- {2-[(2S)-oxiran-2-ylmethoxy]phenyl} carbamate.

¹ H-NMR (acetone-d6, 400 MHz): δ 8.04 (m, IH)), 7.92 (br.s, IH), 7.31 (m, 2H), 7.05-6.92 (m, 5H), 5.33 (m, IH), 4.24 (m, 3H), 4.14 (m, 2H), 4.07 (m, 2H), 3.15 (br.s, 2H), 3.04 (m, 2H), 1.25 (m, 3H); APCI-MS: m/z 437 (MH ⁺ ).

Example 14

N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazol idin-2-yl]-2- hydroxypropyl}oxy)4-hydroxyphenyl}urea. TFA

i) N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)4-[(4-methoxybenzyl)oxy]phenyl}urea. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and N-{5- chloro-4-[(4-methoxybenzyl)oxy]-2-[(2S)-oxiran-2ylmethoxy]ph enyl}urea. H) N-{5-Chloro-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)4-hydroxyphenyl}urea. TFA

Para-methoxybenzyl was removed as described in example 9.

¹ H-NMR (acetone-d6, 400 MHz): δ 7.93 (br.s, IH), 7.32 (m, 3H), 6.98 (m, 2H), 6.87 (m,

IH), 5.39 (m, IH), 4.37-4.03 (m, 5H), 3.35 (m, 2H), 3.14 (m, 2H); APCI-MS: m/z 458 (MH ⁺ ).

Example 15

5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2-hydroxypropyl}oxy)-4- (cyanomethoxy)-N-methylbenzamide

A mixture of 5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidin-2 -yl]-2- hydroxypropyl}oxy)-4-hydroxy-7V-methylbenzamide (example 9) (28.6 mg, 50 μmol), bromoacetonitrile (6 mg, 50 μmol), and cesium carbonate (65 mg, 200 μmol) in dry DMF (1.5 ml) was stirred at r.t. for 1 h. The inorganic material was removed, the product isolated by HPLC. Yield 24 mg (79 %).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.17 (s, IH), 8.13 (br.s, IH), 7.30 (s, IH), 6.79 (dd, J = 12.4, 3.4 Hz, 2H), 6.73 (s, IH), 5.24 (br.s, IH), 4.89 (s, 2H), 4.48 (br.s, IH), 4.32 (br.s, IH), 4.30 (dd, J= 9.7, 3.4 Hz, 2H), 4.18 (dd, J= 9.7, 6.2 Hz, IH), 3.64 (s, 4H), 3.21 (br.s, IH), 2.98 (d, J= 4.7 Hz, 3H); APCI-MS: m/z 496 (MH ⁺ ).

Example 16

5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2-hydroxypropyl}oxy)-4- (2-methoxyethoxy)-N-methylbenzamide

A mixture of 5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidin-2 -yl]-2- hydroxypropyl}oxy)-4-hydroxy-λ/-methylbenzamide (example 9) (28.6 mg, 50 μmol), 1- bromo-2-methoxyethane (7 mg, 50 μmol), and cesium carbonate (65 mg, 200 μmol) in dry DMF (1.5 ml) was stirred at r.t. overnight. A second portion of l-bromo-2-methoxyethane (7 mg, 50 μmol), was added, and the mixture was stirred at 45 ⁰ C for 5 h. The mixture was then cooled to r.t., the inorganic material was removed, the product isolated by HPLC. Yield 25 mg (79 %).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.11 (br.s, IH), 8.08 (s, IH), 7.30 (s, IH), 6.78 (dd, J= 12.4, 3.4 Hz, 2H), 6.56 (s, IH), 5.24 (br.s, IH), 4.46 (br.s, IH), 4.33 (brs, IH), 4.22 (m,

3H), 4.09 (m, 5H), 3.83 (t, J= 4.7 Hz, 2H), 3.49 (s, 3H), 3.21 (br.s, IH), 2.96 (d, J= 4.3 Hz, 3H).; APCI-MS: m/z 515 (MH ⁺ ).

Example 17

2-[2-Chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazoli din-2-yl]-2- hydroxypropyl}oxy)-4-(methylcarbamoyl)phenoxy] ethyl acetate Chiral

A mixture of 5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidin-2 -yl]-2- hydroxypropyl}oxy)-4-hydroxy-7V-methylbenzamide (example 9) (28.6 mg, 50 μmol), 2- bromoethyl acetate (16.7 mg, 100 μmol), and cesium carbonate (65 mg, 200 μmol) in dry DMF (1.5 ml) was stirred at 45 ⁰ C overnight. The mixture was then cooled to r.t, the inorganic material was removed, the product isolated by HPLC. Yield 21 mg (64 %). APCI-MS: m/z 543 (MH ⁺ ).

Example 18

5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2-hydroxypropyl}oxy)-4- (2-hydroxyethoxy)-N-methylbenzamide Chiral

To a stirred solution of 2-[2-chloro-5-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidi n-2- yl]-2-hydroxypropyl}oxy)-4-(methylcarbamoyl)phenoxy]ethyl acetate (16 mg, 24 μmol, Example 17) in ethanol (1 ml) was added aq. NaOH solution(2 M, 0.5 ml). The mixture was kept at r.t. overnight, then acidified with TFA. The solvent was removed in vacuo, the product isolated by HPLC. Yield 12 mg (80 %).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.92 (s, IH), 7.28 (d, J= 9.0 Hz, 2H), 6.90 (d, J= 9.0 Hz, 2H), 6.85 (s, IH), 5.32 (s, IH), 4.34 (m, 3H), 4.21 (m, 4H), 4.08 (br.s, IH), 3.93 (t, J= 4.8 Hz, 2H), 3.16 (dd, J= 14.7 Hz, J= 8.3 Hz, IH), 2.03 (s, 3H); APCI-MS: m/z 501 (MH ⁺ ).

Example 19

Ethyl 2-[2-chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2- hydroxypropyl}oxy)-4-(methylcarbamoyl)phenoxy]-2-methylpropa noate Chiral

A mixture of 5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidin-2 -yl]-2- hydroxypropyl}oxy)-4-hydroxy-7V-methylbenzamide (example 9) (143 mg, 250 μmol), ethyl 2-bromo-2-methylpropanoate (98 mg, 500 μmol), and cesium carbonate (325 mg, 1 mmol) in dry DMF (5 ml) was stirred at 50 ⁰ C overnight. The mixture was then cooled to r.t, the inorganic material was removed, the product isolated by HPLC. Yield 122 mg (71 %). APCI-MS: m/z 571 (MH ⁺ ).

Example 20

5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2-hydroxypropyl}oxy)-4- (2-hydroxy-l,l-dimethylethoxy)-N-methylbenzamide Chiral

To a stirred solution of ethyl 2-[2-chloro-5-({(25)-3-[(4i?)-4-(4- chlorophenoxy)isoxazolidin-2-yl]-2-hydroxypropyl}oxy)-4-(met hylcarbamoyl)phenoxy]- 2-methylpropanoate (35 mg, 51 μmol, Example 19) in dry THF (10 ml) was added under argon a solution OfLiAlH ₄ (IM in THF, 200 μmol, 200 μl). The mixture was stirred at r.t.

for 30 min, then quenched with water and acidified with TFA. The solvent was removed in vacuo, the product isolated by HPLC. Yield 28 mg (85 %).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.88 (s, IH), 7.29 (d, J= 9.0 Hz, 2H), 6.92 (d, J= 9.0 Hz, 2H), 6.80 (s, IH), 5.36 (br.s, IH), 4.43 - 4.09 (m, 6H), 3.21 (dd, J= 6.8 Hz, J= 12.8 Hz, 2H), 2.91 (s, 3H), 1.36 (s, 6H); APCI-MS: m/z 529 (MH ⁺ ).

Example 21

4-(2-Amino-l,l-dimethyl-2-oxoethoxy)-5-chloro-2-({(2S)-3- [(4R)-4-(4- chlorophenoxy)isoxazolidin-2-yl]-2-hydroxypropyl}oxy)-N-meth ylbenzamide

Ethyl 2-[2-chloro-5-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-(methylcarbamoyl)phenoxy]-2-methylpropa noate (16 mg, 23 μmol, Example 19) was added to a solution of NH ₃ in methanol (7 M, 1 ml). The mixture was stirred at 50 ⁰ C for 4 days. The solvent was then removed in vacuo, the product isolated by HPLC. Yield 12 mg (80 %).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.92 (s, IH), 7.29 (d, J= 8.8 Hz, 2H), 7.07 (s, IH), 6.92 (d, J= 8.8 Hz, 2H), 5.39 (br.s, IH), 4.49 - 4.05 (m, 6H), 3.29 (m, 2H), 2.91 (s, 3H), 1.61 (s, 6H); APCI-MS: m/z 542 (MH ⁺ ).

Example 22

5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2-hydroxypropyl}oxy)-4- [1 , 1 -dimethyl-2-(methylamino)-2-oxoethoxy]-N-methylbenzamide Chiral

Ethyl 2-[2-chloro-5-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-(methylcarbamoyl)phenoxy]-2-methylpropa noate (16 mg, 23 μmol, Example 19) was added to a solution of methylamin in ethanol (33 % wt, 1 ml). The mixture was stirred at 50 ⁰ C for 24 h. The solvent was then removed in vacuo, the product isolated by HPLC. Yield 13 mg (87 %).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.92 (s, IH), 7.29 (dd, J= 6.9, 2.1 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 6.68 (s, IH), 5.35 (br.s, IH), 4.38 (br.s, IH), 4.29 (m, IH), 4.21 (d, J= 9.9 Hz, J= 3.7 Hz, IH), 4.13 (d, J= 10.0 Hz, J= 5.8 Hz, 2H), 3.23 (br.s, IH), 3.19 (d, J= 7.4 Hz, J= 15.8 Hz, IH), 2.91 (s, 3H), 2.80 (s, 3H), 1.59 (s, 6H); APCI-MS: m/z 556 (MH ⁺ ).

Example 23

Methyl {2-chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2 -yl] -2- hydroxypropyl}oxy)-4-[(methylamino)carbonyl]phenoxy}acetate

Prepared using to the procedure as described for example 17, using methyl bromoacetate. APCI-MS: m/z 530 (MH ⁺ ).

Example 24

(3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isox azolidin-2-yl]-2- hydroxypropyl}oxy)-4-hydroxybenzoyl]pyrrolidin-3-ol

(i) Ethyl 5-chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2- yl]-2- hydroxypropyl}oxy)-4- [(4-methoxybenzyl)oxy] benzoate

Prepared using to the procedure as described for example 5, using intermediate 9 and ethyl 5-chloro-4-[(4-methoxybenzyl)oxy]-2-[(2S)-oxiran-2-ylmethoxy ]benzoate. APCI-MS: m/z 593 (MH ⁺ ).

(U) (3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazo lidin-2-yl]-2- hydroxypropyl}oxy)-4-hydroxybenzoyl]pyrrolidin-3-ol

To a stirred solution of ethyl 5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidin- 2-yl]-2-hydroxypropyl}oxy)-4-[(4-methoxybenzyl)oxy]benzoate; example 23) (118 mg, 0.2 mmol) in ethanol (5 ml) an aq. NaOH solution (2M, 1 ml) was added. The mixture was heated at 80 ⁰ C for 30 min, then cooled to r.t, and diluted with water (5 ml). The pH was adjusted to 1 by addition of aq. HCl (2M). Ethanol was removed i.vac, and the solution extracted with dichloromethane (2 x 20 ml). The combined extracts were dried with Na2SO4, and the solvent was evaporated. The residue was dissolved in dry DMF (5 ml). DIPEA (1 ml) and HBTU (200 μm, 75 mg) were added, and the mixture was stirred at r.t. for 30 min. (35)-Pyrrolidin-3-ol (220 μm, 19 mg) was added, and stirring was continued for 16 h. then the mixture was diluted with ethyl acetate (20 ml), ad washed with sat. aq. NH ₄ Cl (10 ml), NaHCO ₃ (IM, 10 ml), and brine (10 ml). The solvent was removed, the residue dissolved in dichloromethane (5 ml). TFA (1 ml) was added, and the mixture was stirred at r.t. for 3 h. Evaporation of solvent and purifiation by HPLC afforded 63 mg (50 %). ¹ H-NMR (</ ₆ -acetone, 400 MHz): δ 7.31 (d, J= 8.9 Hz, 2H), 7.22 (d, J= 1.6 Hz, IH), 6.97 (d, J= 8.7 Hz, 2H), 6.76 (d, J= 3.9 Hz, IH), 5.37 (s, IH), 4.47 (t, J= 1.9 Hz, IH), 4.40 (t, J= 2.1 Hz, IH), 4.18 (m, 2H), 4.05 (m, 2H), 3.66 - 3.48 (m, 3H), 3.40 - 3.28 (m, 2H), 3.15 - 3.06 (m, 2H), 2.03 - 1.83 (m, 4H). APCI-MS: m/z 513 (MH ⁺ ).

Example 25

[2-Chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2-hydroxypropyl}oxy)- 4-{ [(3S)-3-hydroxypyrrolidin-l -yl] carbonyljphenoxy] acetonitrile

Prepared from (35)-l-[5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxaz olidin-2-yl]-2- hydroxypropyl}oxy)-4-hydroxybenzoyl]pyrrolidin-3-ol (10 mg, 16 μmol, example 25) as described in Example 15. Yield 6 mg (57 %). ¹ H-NMR (</ ₆ -acetone, 400 MHz): δ 7.34 (d, J= 3.2 Hz, 2H), 7.31 (d, J= 8.9 Hz, 2H), 7.12 (d, J= 4.2 Hz, IH), 6.97 (d, J= 8.9 Hz, 2H), 5.36 (s, IH), 5.30 (s, 2H), 4.47 (s, IH), 4.40 (s, IH), 4.31 (d, J= 6.6 Hz, IH), 4.17 (m, 2H), 3.66 - 3.48 (m, 4H), 3.39 - 3.25 (m, 3H), 3.14 - 3.02 (m, IH), 2.03 - 1.84 (m, 2H). APCI-MS: m/z 513 (MH ⁺ ).

Example 26

(3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isox azolidin-2-yl]-2- hydroxypropyl}oxy)-4-(2-methoxyethoxy)benzoyl]pyrrolidin-3-o l

Prepared from (35)-l-[5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxaz olidin-2-yl]-2- hydroxypropyl}oxy)-4-hydroxybenzoyl]pyrrolidin-3-ol (10 mg, 16 μmol, example 25) as described in example 16. Yield 8 mg (72 %).

¹ H-NMR (</ ₆ -acetone, 400 MHz): δ 7.31 (d, J= 8.9 Hz, 2H), 7.26 (d, J= 2.3 Hz, 2H), 6.97

(d, J= 8.9 Hz, 2H), 6.94 (d, J= 4.8 Hz, IH), 5.35 (br.s, IH), 4.47 (t, J= 2.0 Hz, IH), 4.40 (t, J= 2.1 Hz, IH), 4.29 (m, 5H), 4.20 - 4.10 (m, 3H), 3.76 (t, J= 4.5 Hz, 3H), 3.65 - 3.49

(m, 4H), 3.39 (s, 3H), 3.38 - 3.27 (m, 2H), 3.11 - 3.00 (m, 2H), 2.02 - 1.84 (m, 2H).

APCI-MS: m/z 571 (MH ⁺ ).

Example 27

(3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isox azolidin-2-yl]-2- hydroxypropyl}oxy)-4-(2-hydroxyethoxy)benzoyl]pyrrolidin-3-o l

i) 2-[2-chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2- hydroxypropyl}oxy)-4-{ [(3S)-3-hydroxypyrrolidin-l -yl] carbonyljphenoxy] ethyl acetate Prepared from (35)-l-[5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxaz olidin-2-yl]-2- hydroxypropyl}oxy)-4-hydroxybenzoyl]pyrrolidin-3-ol (10 mg, 16 μmol, example 25) as described in example 17. Used in the next step without further purification. APCI-MS: m/z 599 (MH ⁺ ).

U) (3S)-l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazo lidin-2-yl]-2- hydroxypropyl}oxy)-4-(2-hydroxyethoxy)benzoyl]pyrrolidin-3-o l

Prepared from 2-[2-chloro-5-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-{[(35)-3-hydroxypyrrolidin-l-yl]carbony l}phenoxy]ethyl acetate as described in example 18. Overall yield for two steps 8 mg (72 %).

¹ H-NMR (</ ₆ -acetone, 400 MHz): δ 7.31 (d, J= 9.0 Hz, 2H), 7.26 (d, J= 2.2 Hz, IH), 6.96 (m, 3H), 5.35 (br.s, IH), 4.47 (d, J= 1.9 Hz, IH), 4.40 (t, J= 2.0 Hz, IH), 4.31 (d, J= 6.4 Hz, 4H), 4.23 (t, J= 4.4 Hz, IH), 4.14 (m, 5H), 3.92 (t, J= 4.9 Hz, 3H), 3.65 - 3.49 (m, 4H), 3.39 - 3.27 (m, 2H), 3.11 - 3.00 (m, 2H), 2.02 - 1.83 (m, 2H) APCI-MS: m/z 557 (MH ⁺ ).

Example 28 l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2- hydroxypropyl}oxy)-4-(cyanomethoxy)phenyl]urea

A mixture of l-[5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-hydroxyphenyl]urea (example 14) (16.5 mg, 29 μmol), bromoacetonitrile (3.5 mg, 29 μmol), and cesium carbonate (38 mg, 115 μmol) in dry DMF (1.5 ml) was stirred at r.t. for 4 h. The inorganic material was removed, the product isolated by HPLC. Yield 14 mg (79 %).

¹ H-NMR (</ ₆ -acetone, 500 MHz): δ 8.40 (s, IH), 7.85 (s, IH), 7.32 (m, 2H), 7.05 (s, IH), 7.00 (d, J= 8.6 Hz, 2H), 5.49 (br.s, IH), 5.12 (s, 2H), 4.45 (br.s, IH), 4.34 (d, J= 4.9 Hz, 2H), 4.23 (s, IH), 4.15 (dd, J= 9.9, 5.5 Hz, IH), 3.59 (d, J= 11.5 Hz, 2H), 3.39 (br.s, 3H). APCI-MS: m/z 497 (MH ⁺ ).

Example 29 l-[5-Chloro-2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2-yl]-2- hydroxypropyl}oxy)-4-(2-methoxyethoxy)phenyl]urea

A mixture of l-[5-chloro-2-({(25)-3-[(4i?)-4-(4-chlorophenoxy)isoxazolidi n-2-yl]-2- hydroxypropyl}oxy)-4-hydroxyphenyl]urea (example 14) (16.5 mg, 29 μmol), l-bromo-2- methoxyethane (4 mg, 29 μmol), and cesium carbonate (38 mg, 115 μmol) in dry DMF (1.5 ml) was stirred at 20 ⁰ C for 20 h. The mixture was then cooled to r.t., the inorganic material was removed, the product isolated by HPLC. Yield 13 mg (71 %). ¹ H-NMR (</ ₆ -acetone, 500 MHz): δ 8.260 (s, IH), 7.76 (s, IH), 7.33 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.87 (s, IH), 5.52 (br.s, IH), 4.46 (br.s, IH), 4.34 (br.s, IH), 4.21 (br.s, IH), 4.18 - 4.12 (m, 3H), 3.72 - 3.69 (m, 2H), 3.64 (d, J= 11.6 Hz, IH), 3.37 (s, 3H).

APCI-MS: m/z 516 (MH ⁺ ).

Example 30

2-[5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazol idin-2-yl]-2-hydroxy- propoxy]phenoxy]-N,N-dimethyl-acetamide

i) 2-(5-Chloro-2-hydroxyphenoxy)-N,N-dimethylacetamide

A mixture of 4-chlorobenzene-l,2-diol (290 mg, 2 mmol), 2-chloro-N,N- dimethylacetamide (243 mg, 2 mmol) and Et ₃ N (0.279 ml, 2 mmol) in DMF (3 mL) was stirred at 75 ⁰ C overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum spirit 40-60) to give sub title compound (28 mg) and 2-(4-chloro-2-hydroxy- phenoxy)-7V,7V-dimethyl-acetamide (26 mg).

¹ H-NMR (DMSOd ₆ , 400 MHz): for 2-(5-chloro-2-hydroxyphenoxy)-N,N- dimethylacetamide, δ 6.95 (d, J= 2.4 Hz, IH); 6.85 (dd, J= 2.4, 8.5 Hz, IH); 6.80 (s, IH); 4.80 (s, 2H); 2.98 (s, 3H); 2.92 (s, 3H). ¹ H-NMR (DMSOd ₆ , 400 MHz): for 2-(4-chloro-2- hydroxy-phenoxy)-7V,7V-dimethyl-acetamide, 6.89 (d, J= 8.6 Hz, IH); 6.82 (d, J= 2.3 Hz, IH); 6.75 (dd, J= 2.3, 8.6 Hz, IH); 4.70 (s, 2H); 2.99 (s, 3H); 2.85 (s, 3H).

U) 2-[5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy- propoxy]phenoxy]-N,N-dimethyl-acetamide

A mixture of 2-(5-chloro-2-hydroxyphenoxy)-N,N-dimethylacetamide (24 mg, 0.104 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (27 mg, 0.104 mmol) and Cs ₂ CO ₃ (41 mg, 0.125 mmol) in DMF (1.5 ml) was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was taken into ethanol (1 ml) and (4R)-4-(4-chlorophenoxy)isoxazolidine (33 mg, 0.104 mmol)

was added and the reaction mixture was stirred at 75 ⁰ C over night. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% NH4OH) to give the title compound (26 mg). ¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.32-7.25 (m, 2H); 6.99-6.89 (m, 3H); 6.80 (m, 2H); 5.14 (m, IH); 4.74 (s, 2H); 4.34-3.93 (m, 6H); 3.22-1.96 (m, 10H). APCI-MS: m/z 485 (MH ⁺ )

Example 31

2-[4-chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazol idin-2-yl]-2-hydroxy- propoxy]phenoxy]-N,N-dimethyl-acetamide

Chiral

A mixture of 2-(4-chloro-2-hydroxy-phenoxy)-N,N-dimethyl-acetamide (24 mg, 0.104 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (27 mg, 0.104 mmol) and Cs ₂ CO ₃ (41 mg, 0.125 mmol) in DMF (1.5 ml) was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was taken into ethanol (1 ml) and (4R)-4-(4-chlorophenoxy)isoxazolidine (33 mg, 0.104 mmol) was added and the reaction mixture was stirred at 75 ⁰ C overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% NH4OH) to give the title compound (19 mg). ¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.28 (m, 2H); 7.00-6.77 (m, 5H); 5.18 (br.s, IH); 4.53 (s, 2H); 4.38-3.90 (m, 6H); 3.34-2.96 (m, 10H). APCI-MS: m/z 485 (MH ⁺ )

Example 32

2-{2-chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-isoox azolidin-2-yl]-2- hydroxypropoxy}oxy-4-[methylamino)carbonyl]phenoxy}-2-methyl propanoic acid, TFA

(Salt)

To a solution of ethyl 2-{2-chloro-5-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin -2- yl]-2-hydroxypropyl} oxy)-4-[(methylamino)carbonyl]phenoxy } -2-methylpropanoate (32 mg, 0.056 mmol) in THF (4.5 ml) was added aqueous NaOH (160 mg NaOH in 1.5 ml water) and the reaction mixture was stirred at room temperature over night, cooled to 0 ⁰ C and pH was adjusted to 2 by addition of aqueous TFA. The volatiles were removed in vacuo and the residue was purified by HPLC (10-80% CH ₃ CN in water, 0.1% TFA) to give the title compound (26 mg). ¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.92 (s, IH); 7.28 (m, 2H); 6.90 (m, 2H); 6.74 (s, IH); 5.30 (br.s, IH); 4.42-4.38 (m, 5H); 3.28-3.07 (m, 3H); 2.90 (s, 3H); 1.64 (s, 6H). APCI- MS: m/z 543 (MH ⁺ )

Example 33

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l ,2-oxazolidin-2-yl] -2-hydroxy-propoxy] -4- (2-dimethylaminoethoxy)-N-methyl-benzamide

duct (Salt)

A mixture of 5-chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidin-2 -yl]-2- hydroxy-propoxy]-4-hydroxy-7V-methyl-benzamide (40 mg, 0.07 mmol), 2- chloroethyl)N,N-dimethyl amine hydrochloride (20 mg, 0.14 mmol) and Cs ₂ CO ₃ (91 mg, 0.28 mmol) in DMF (2 ml) was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by HPLC (10-75% CH ₃ CN in H ₂ O, 0.1% TFA) to give the title compound (14 mg).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.97 (s, IH); 7.27 (m, 2H); 6.95-6.85 (m, 3H); 5.29 (m, IH); 4.55 (t, J= 4.7 Hz, 2H); 4.43-4.20 (m, 5H); 3.97 (br.s, IH); 3.69 (t, J= 4.8 Hz, 2H); 3.04 (m, 9H); 2.90 (s, 3H). APCI-MS: m/z 528 (MH ⁺ )

Example 34

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy-propoxy]-N- methyl-4-(methylsulfanylmethoxy)benzamide

To a mixture of 5-chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidin-2 -yl]-2- hydroxy-propoxy]-4-hydroxy-N-methyl-benzamide (80 mg, 0.14 mmol) and Cs ₂ CO ₃ (110 mg, 0.336 mmol) in DMF (2 ml) was added chloro(methylthio)methane (0.015 ml, 0.168 ml) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH ₄ OH) to give the title compound (50 mg).

¹ H-NMR (CDCl ₃ , 300 MHz): δ 8.20 (s, IH); 8.08 (br. m, IH); 7.26 (m, under CDC13 peak, 2H); 6.77 (m, 2H); 6.60 (s, IH); 5.28 (s, 2H); 5.18 (br.s, IH); 4.42-4.00 (m, 6H); 3.40 (d, J = 3.7 Hz, IH); 3.20 (br.s, 2H); 2.97 (d, J= 4.8 Hz, 4H); 2.12 (s, 3H). APCI-MS: m/z 517 (MH ⁺ )

Example 35

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy-propoxy]-N- methyl-4-(2-methylsulfanylethoxy)benzamide

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidin-2 -yl]-2-hydroxy-propoxy]-4- hydroxy-N-methyl-benzamide (80 mg, 0.14 mmol) was dissolved in DMF (2 ml), then Cs ₂ CO ₃ (110 mg, 0.336 mmol) and chloro(ethylthio)methane (19 mg, 0.168 ml) were added and the mixture was stirred at room temperature for 6h. Another portion OfCs ₂ CO ₃ (110 mg, 0.336 mmol) and chloro(ethylthio)methane (19 mg, 0.168 ml) were added and the reaction mixture was stirred at room temperature over the week end. Methanol (0.5 ml) was added and stirred at room temperature for 10 min, partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH ₄ OH) to give the title compound (57 mg). ). ¹ H-NMR (CDCl ₃ , 300 MHz): δ 8.20 (s, IH); 8.08 (br.s, IH); 7.25 (m, 2H); 6.78 (m, 2H); 6.50 (s, IH); 5.20 (br.s, IH); 4.48-4.04 (m, 8H); 3.42 (d, J= 3.5 Hz, IH); 2.96 (m, 7H); 2.29 (s, 3H). APCI-MS: m/z 530.8 (MH ⁺ )

Example 36

5-Chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidi n-2-yl]-2-hydroxy-propoxy]-N- methyl-4-(2-methylsulfonylethoxy)benzamide

dduct (Salt)

To a solution of 2(methylsulfonyl)ethanol (124 mg, 1 mmol) in CH ₂ Cl ₂ (3 ml) was added Et ₃ N (0.418 ml, 3 mmol) followed by methanesulfonyl chloride (171 mg, 1.5 mmol) at 0 ⁰ C. After 2h at 0 ⁰ C methanol (0.3 ml) was added and the mixture was stirred at room temperature for 15 min, partitioned between CH ₂ Cl ₂ and water. The organic layer was

dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. This residue was taken into DMF (1 ml), 5-chloro-2-[(2S)-3-[(4R)-4-(4-chlorophenoxy)l,2-oxazolidin-2 - yl]-2-hydroxy-propoxy]-4-hydroxy-N-methyl-benzamide (15 mg, 0.026 mmol) and K ₂ CO ₃ (276 mg, 2 mmol) were added and the mixture was stirred at 124 ⁰ C for 30 min. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by HPLC (20-95% CH ₃ CN in H ₂ O, 0.1% TFA) to give the title compound (2 mg). APCI-MS: m/z 562.8 (MH ⁺ )

Example 37

N-[2-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2-hydroxypropyl}oxy)- phenyljformamide. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and N-2- [(2S)-oxiran-2-ylmethoxy]phenyl}formamide. APCI-MS: m/z 392 (M ⁺ )

Example 38 3-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)benzaldehyde. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and 3- [(2S)-oxiran-2-ylmethoxy]benzaldehyde. APCI-MS: m/z 377 (M ⁺ )

Example 39

l-[3-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl] -2- hydroxypropyl}oxy)phenyl]ethanone. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and l-{3- [(2S)-oxiran-2-ylmethoxy]phenyl} ethanone. APCI-MS: m/z 392 (MH ⁺ )

Example 40

3-({(2S)-3-[(4R)-4-(4-chlorophenoxy)isoxazolidin-2-yl]-2- hydroxypropyl}oxy)benzamide. TFA

Prepared using to the procedure as described for example 5, using intermediate 6 and l-{3- [(2S)-oxiran-2-ylmethoxy]phenyl} ethanone. APCI-MS: m/z 392 (M ⁺ )

Assay

Human CCRl binding, assay Membranes

HEK293 cells, from ECACC, stably expressing recombinant human CCRl (HEK-CCRl) were used to prepare cell membranes containing CCRl . The membranes were stored at -70 ⁰ C. The concentration of membranes of each batch was adjusted to 10% specific binding of 33 pM [ ¹²⁵ I] MIP-Ia.

Binding assay 100 μL of HEK-CCRl membranes diluted in assay buffer pH 7.4 ((137 mM NaCl (Merck, Cat No 1.06404), 5.7 mM Glucose (Sigma, Cat No G5400), 2.7 mM KCl (Sigma, Cat No P-9333), 0.36 mM NaH ₂ PO ₄ x H ₂ O (Merck, Cat No 1.06346), 10 mM HEPES (Sigma, Cat

No H3375), 0.1% (w/v) Gelatine (Sigma, Cat No G2625)) with the addition of 17500 units/L Bacitracin (Sigma, Cat No B 1025) were added to each well of the 96 well filter plate (0.45 μm opaque Millipore cat no MHVB N4550). 12 μl of compound in assay buffer, containing 10% DMSO, was added to give final compound concentrations of IxIO ^{"5 5} -lxl0 ^{"9 5} M. 12 μl cold human recombinant MIP-Ia (270-LD-050, R&D Systems, Oxford, UK), 10 nM final concentration in assay buffer supplemented with 10% DMSO, was included in certain wells (without compound) as non-specific binding control (NSB). 12 μl assay buffer with 10% DMSO was added to certain wells (without compound) to detect maximal binding (BO).

12 μl [ ¹²⁵ I] MIP-Ia, diluted in assay buffer to a final concentration in the wells of 33 pM, was added to all wells. The plates with lid were then incubated for 1.5 hrs at room temperature. After incubation the wells were emptied by vacuum filtration (MultiScreen Resist Vacuum Manifold system, Millipore) and washed once with 200 μl assay buffer. After the wash, all wells received an addition of 50 μl of scintillation fluid (OptiPhase "Supermix", Wallac Oy, Turko, Finland). Bound [ ¹²⁵ I] MIP- lα was measured using a Wallac Trilux 1450 MicroBeta counter. Window settings: Low 5-High 1020, 1-minute counting/well.

Calculation of percent displacement and IC ₅₀

The following equation was used to calculate percent displacement.

Percent displacement = 1- ((cpm test - cpm NSB) / (cpm BO- cpm NSB)) where: cpm test = average cpm in wells with membranes and compound and [ ¹²⁵ I] MIP- lα;

NSB = average cpm in the wells with membranes and MIP-Ia and [ ¹²⁵ I] MIP- lα (non- specific binding);

BO = average cpm in wells with membranes and assay buffer and [ ¹²⁵ I] MIP-Ia (maximum binding).

The molar concentration of compound producing 50% displacement (IC50) was derived using the Excel-based program XLfit (version 2.0.9) to fit data to a 4-parameter logistics function.

In one embodiment of the present invention the following examples have an IC50 value of 1 μM or less for the human CCRl receptor.

In another embodiment of the present invention the following examples have an IC50 value of 100 nM or less for the human CCRl receptor.