WO2008121066A1

WO2008121066A1 - Novel tricyclic spiropiperidines or spiropyrrolidines and their use as modulators of chemokine receptors

Info

Publication number: WO2008121066A1
Application number: PCT/SE2008/050359
Authority: WO
Inventors: Marguerite Mensonides-Harsema
Original assignee: Astrazeneca Ab
Priority date: 2007-03-30
Filing date: 2008-03-28
Publication date: 2008-10-09

Abstract

The present invention relates to new compounds of formula (I) or salts, solvates or solvated salts thereof, wherein Q, X, Y, Z, R1, R2, R3, R4 and m, n and p are defined as in claim 1, processes for their preparation and to new intermediates used in the preparation thereof, pharmaceutical compositions comprising said compounds and to the use of said compounds as modulators of chemokine receptor activity in the treatment of airway diseases, inflammatory diseases, COPD and asthma.

Description

Novel tricyclic spiropiperidines or spiropyrrolidines and their use as modulators of chemokine receptors

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.

DETAILED DESCRIPTION OF THE INVENTION

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

wherein: m is 0, 1 or 2;

R¹ is halogen, cyano or Ci-C₆(halo)alkyl;

X and Y are a bond, -O-, -NH-, or CH₂- and Z is a bond, -O-, -NH-, CH₂ or -C(O)-, provided that only one of X, Y and Z is a bond, and provided that X and Y are not simultaneously -O-; n is 0, 1 or 2;

R² is Ci-C₆(cyclo)alkyl; p is 0 or 1 ;

R³ is hydrogen or Ci-C₆alkyl; R⁴ is hydrogen, hydroxy 1 or NH₂;

Q is a group selected from a 5 to 14-membered ring system having 0 to 5 heterotaoms independently selected from nitrogen, oxygen, or sulfur; wherein Q is optionally substituted with s independent occurances of R⁵ or A-R⁵; s is 0, 1, 2 or 3; A is a bond, oxygen or Ci-C₆(halo)alkyl;

R⁵ is hydrogen, halogen, cyano, NH₂, hydroxyl, -NHC(O)R⁶, -NHCOOR⁹, -NHC(O)NR⁷R⁸, -NHS(O)₂R⁶, -C(O)NR⁷R⁸, -COOR⁹, SO₃R⁹, Ci-C₆ alkoxy Or Ci-C₆ alkyl optionally substituted by t substituents independently selected from halogen, cyano, -NH₂, - COOR⁹, -CONH₂, hydroxyl, oxo (=0), Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylcarbonylamino and a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, COOR⁹, C₁- C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ (halo)alkyl; t is O, 1, 2 or 3;

R⁶ is hydrogen, Ci-C₆alkyl or a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, Ci-C₆ alkyl, C i -C₆ hydroxyalkyl and C i -C₆ (halo)alkyl, =0 and -OR⁹;

R⁷ and R⁸ each independently represent (i) hydrogen; or

(ii) a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ (halo)alkyl; or (iii) Ci-C₆ alkyl, optionally substituted by one or more substituent independently selected from halogen, -NH₂, hydroxyl, =0, Ci-C₆ (halo)alkyl, carboxyl, Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylcarbonylamino and a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, Ci-C₆ alkyl, Q-C₆ hydroxyalkyl and Ci-C₆ (halo)alkyl; or (iv) Ci-C₆ alkylsulphonyl; or (v) R⁷ and R⁸ 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 optionally fused to a benzene ring to form a 8 to 11 -membered heterocyclic ring, the heterocyclic ring or ring system being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, -CONH₂, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ (halo)alkyl, Ci-C₆ alkylamino, di-Ci-C₆ alkylamino, Ci-C₆ alkylcarbonyl, Ci-C₆ alkylcarbonylamino, Ci-C₆ alkylaminocarbonyl, di-Ci-C₆ alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl; and

R⁹ is hydrogen or Ci-C₆ alkyl; or a pharmaceutically acceptable salt thereof.

One embodiment relates to compounds wherein: m is 1; R¹ is halogen; X and Y are a bond or CH₂- and Z is -O-; n is 0; p is 1; R³ is hydrogen; R⁴ is hydroxyl; Q is a group selected from a 5 to 14-membered ring system having 0 to 5 heterotaoms independently selected from nitrogen, oxygen, or sulfur; wherein Q is optionally substituted with s independent occurances of R⁵; s is 0, 1, 2 or 3; R⁵ is hydrogen, halogen, hydroxyl, -NHC(O)R⁶, -NHCOOR⁹, -NHC(O)NR⁷R⁸, -C(O)NR⁷R⁸, -COOR⁹, Ci-C₆ alkoxy OrCi-C₆ alkyl optionally substituted by t substituents independently selected from halogen, -COOR⁹ or hydroxyl; t is O, 1, 2 or 3; R⁶ is Ci- C₆alkyl; R⁷ and R⁸ each independently represent hydrogen or Ci-C₆ alkyl; and R⁹ is hydrogen or Ci-C₆ alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of the invention m is 1 and R is a halogen atom. In a further embodiment R¹ is chlorine or fluorine.

In another embodiment where the first active ingredient is a compound of formula (I), X, and Y are a bond or CH₂- and Z is -O- .

In a further embodiment the integer n is O, 1 or 2. In one embodiment n is 0. In another embodiment n is 1 or 2.

2 In another embodiment R is Ci-C₆ alkyl. In one embodiment of the present invention, n is

2 and R is methyl.

In yet a further embodiment R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or

3 3 tert-butyl. In one embodiment R is methyl or ethyl. In another embodiment R is hydrogen.

In yet another embodiment R⁴ is hydrogen. In one embodiment R⁴ is hydrogen. In yet another embodiment R⁴ is hydroxyl.

In one embodiment Q is an optionally substituted group selected from a 5 to 14-membered ring system having 0, 1, 2, 3, 4 or 5 heterotaoms independently selected from nitrogen, oxygen, or sulfur; wherein Q is substituted with s independent occurances of R⁵. In a further embodiment Q is a 6-membered ring selected from phenyl, pyridinyl, pyrazyl or pyrimidyl. In one embodiment Q is pyrimidyl. In another embodiment Q is phenyl. In one embodiment Q is pyridinyl. In another embodiment Q is a 12-membered ring selected from naphtyl, isoquinolinyl, phtalazinyl or quinazolinyl. In one embodiment Q is quinazolinyl.

In yet another embodiment of the present invention, the integer s is 0. In yet another embodiment s is 1. In yet a further embodiment s is 2. In one embodiment s is 3. In one embodiment A is a bond. In another embodiment A is oxygen. In a further embodiment A is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoroethyl, in particular methyl or ethyl.

In a further embodiment of the present invention, R⁵ is hydrogen, halogen, hydroxyl, -NHC(O)R⁶, -NHCOOR⁹, -NHC(O)NR⁷R⁸, -C(O)NR⁷R⁸, -COOR⁹, Ci-C₆ alkoxy OrCi-C₆ alkyl optionally substituted by t substituents independently selected from halogen, -COOR⁹ or hydroxyl.

In yet another embodiment of the present invention R⁶ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, in particular methyl.

In yet another embodiment of the present invention R⁷ and R⁸ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, in particular hydrogen or methyl. In one embodiment R⁷ and R⁸ are both hydrogen. In another embodiment R⁷ and R⁸ are both methyl. In yet a further embodiment one of R⁷ and R⁸ is hydrogen and one is methyl.

In yet another embodiment of the present invention R⁹ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, in particular methyl.

In a particular embodiment s is 2, A is a bond and R⁵ is trifluoromethyl or A is oxygen and R⁵ is methyl. In another embodiment s is 1 or 2, A is a bond and R⁵ is selected from halogen, in particular fluorine, hydroxyl or R⁵ is -NHC(O)R⁶, -NHS(O)₂R⁶, -C(O)NR⁷R⁸, -COOR⁹ or SO₃R⁹ and suitable R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen, R⁵ is or Ci-C₆ alkyl, such as methyl. In yet another embodiment s is 1 or 2, A is a bond and R⁵ is selected from halogen, in particular fluorine, hydroxyl or Ci-C₆ alkyl, where t is 1 or 2 substituents selected from hydroxyl and =0. In particular, s is 1 or 2, A is a bond and R⁵ is selected from fluorine, hydroxyl, C(O)H or C(O)CH₃. In a further embodiment A is an oxygen and R⁵ is Ci-C₆ alkyl, where t is 1 substituent selected from - COOR⁹ and R⁹ is hydrogen or methyl.

One embodiment relates to compounds where Q is a phenyl ring as shown in formulae II:

where the 1 -position of the phenyl ring is substituted preferably with A-R⁵, where A is a bond or oxygen and R⁵ substituents include -NHC(O)CH₃, -C(O)NH₂, -COOH, C(O)H, C(O)CH₃, NHC(O)NH₂ and CH₂COOH. Examples of substituents at the 4-position of the phenyl ring include fluorine, chlorine, bromide, hydroxyl, methoxy, ethoxy, isopropoxy, isopropoxycarbonyl (OC(CH₃)₂COOH), isomethoxycarbonyl (OCH₂COOH), or hydroxyethoxy. Examples of substituents at the 5- and 6-position of the phenyl ring include fluorine, chlorine, bromide, cyano, trifiuoromethyl, methoxy or hydroxyl.

In another embodiment Q is a pyridine ring as shown in formula III:

where the 6-position of the pyridine ring is preferably occupied by R⁵ such as hydrogen or trifiuoromethyl.

One embodiment relates to compounds where Q is a pyrimidinyl ring as shown in formula IV or formula V:

The 4-position of the pyrimidine ring in formula IV and the 2-position of the pyrimidine ring in formula V are preferably occupied by R⁵ such as hydrogen, methyl or trifluoromethyl.

In another embodiment of the current invention, Q is a quinazolinyl ring as shown in formula VI:

The 2-position of the quinazoline ring is preferably occupied by R⁵ such as hydrogen or trifluoromethyl. The 6- or 7-position of the quinazoline ring may be substituted or unsubstituted. Examples of substituents in the 6-position include fluorine, chlorine, bromide, hydroxyl, methoxy, ethoxy, isopropoxy, isopropoxycarbonyl (OC(CH₃)₂COOH), isomethoxycarbonyl (OCH₂COOH) and hydroxyethoxy . Examples of sustituents in the 7- position include chlorine and trifluoromethyl.

In one embodiment of the invention there is provided a compound of formula (Ia)

wherein: m is O, 1 or 2;

R¹ is halogen, cyano or Ci-C_όhaloalkyl; X and Y are a bond, -O-, -NH-, or CH₂- and Z is a bond, -O-, -NH-, CH₂ or -C(O)-, provided that only one of X, Y and Z is a bond, and provided that X and Y are not simultaneously -O-; n is 0, 1 or 2;

R² is Ci-C₆(cyclo)alkyl; p is 0 or 1 ;

R³ is hydrogen or Ci-C_όalkyl; R⁴ is hydrogen, OH or NH₂;

Q is a group selected from a 5-14-membered partially unsaturated or saturated ring system having 0-5 heterotaoms independently selected from nitrogen, oxygen, or sulfur; wherein Q is optionally substituted with s independent occurances of R⁵ or A-R⁵; s is 0, 1, 2 or 3;

A is a bond, oxygen or Ci-C₆(halo)alkyl;

R⁵ is hydrogen, halogen, cyano, NH₂, hydroxy, -NHC(O)R⁶, -NHS(O)₂R⁶, -C(O)NR⁷R⁸, -COOR⁹, SO₃R⁹ or Ci-C₆ alkyl optionally substituted by t substituents independently selected from halogen, cyano, -NH₂, -COOR⁹, -CONH₂, hydroxyl, oxo (=0), Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylcarbonylamino and a 3- to 8- membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, COOR⁹, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ haloalkyl; t is O, 1, 2 or 3;

R⁶ is hydrogen, Ci-C₆alkyl, a 3- to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ haloalkyl, =0 and -OR⁹;

R⁷ and R⁸ each independently represent (i) hydrogen; or

(ii) a 3- to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ haloalkyl; or

(iii) a Ci-C₆ alkyl group, optionally substituted by one or more substituent independently selected from halogen, -NH₂, hydroxyl, =0, Ci-C₆ haloalkyl, carboxyl, Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylcarbonylamino and a 3- to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ haloalkyl; or (iv) Ci-C₆ alkylsulphonyl; or (v) R⁷ and R⁸ 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 that is optionally fused to a benzene ring to form a 8- to 11- membered ring system, the heterocyclic ring or ring system being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, -CONH₂, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ haloalkyl, C₁- C₆ alkylamino, di-Ci-C₆ alkylamino, Ci-C₆ alkylcarbonyl, Ci-C₆ alkylcarbonylamino, Ci-C₆ alkylaminocarbonyl, di-Ci-C₆ alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl; R⁹ is hydrogen or Ci-C₆ alkyl; and q is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

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_-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_-4 alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or tert-butyl. The term "alkoxy", 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.

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-₆cycloalkyl" may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In this specification, unless stated otherwise, the term "3 to 8 membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur", refers to a ring system 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 and azepane.

In this specification, unless stated otherwise, the term "bicyclic ring" refers to a ring system in which one (carbo)cycle is fused to another (carbo)cycle. The term "a 5 to 14- membered ring system having 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur" refers to a hydrocarbon moiety comprising one to three fused rings, optionally having 6, 10 or 14 π atoms shared in a cyclic array and having, in addition to carbon atoms, zero to five heteroatoms. Fused ring systems may include but are not limited to indole, indoline, benzofuran, benzothiophene, naphtalene, chroman, quinazoline, phenoxazine, azulene, adamantane, anthracene and phenoxazine.

In this specification, unless stated otherwise, the term "a 4 to 7-membered saturated heterocyclic ring optionally further comprising a ring nitrogen, oxygen or sulphur atom" or "a 8 to 11 -membered heterocyclic ring" refers to a ring system 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 "(halo)alkyl" means an alkyl group as defined above, which is substituted with halogen as defined above. The term "C_1- ₆(halo)alkyl" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or bromopropyl. The term "Ci.C₃(halo)alkylO" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.

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.

Another embodiment of the invention relates to the following compounds:

Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -phenylpyrrolidin-3- ol trifluoroacetate,

Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -phenylpyrrolidin-3- ol. trifluoroacetate,

Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-7V-methylbenzamide trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l-benzofuran-2.4'-piperidin] l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-7V-methylbenzamide trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-fluoro-7V-methylbenzamide trifluoroacetate, Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-N-methylbenzamide trifluoroacetate,

Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-N,N-dimethylbenzamide trifluoroacetate, Trans-2-{2-chloro-5-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-[(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid trifluoroacetate,

Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-(2,2-difluoroethoxy)-TV-methylbenzamide trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin-l-yl)-TV-methylbenzoic acid trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-fluoro-TV-methylbenzoic acid trifluoroacetate, Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l-benzofuran-2.4'-piperidin] l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-fluoro-TV-methylbenzoic acid trifluoroacetate, Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)phenyl} acetamide trifluoroacetate, Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-methoxyphenyl} acetamide trifluoroacetate,

Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenyl} acetamide trifluoroacetate, Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-fluorophenyl} acetamide trifluoroacetate, Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenyl} acetamide trifluoroacetate, Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-(2,2-difluoroethoxyphenyl} acetamide trifluoroacetate, Trans-2-[4-(acetylamino)-2-chloro-5-(3-{5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'- piperidin] 1 -yl} -4-hydroxypyrrolidin- 1 -yl)-4-[(methylamino)carbonyl]phenoxy } -2- methylpropanoic acid trifluoroacetate,

Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)phenyl}urea trifluoroacetate, Trans-TV'- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)phenyl} -TV,TV-dimethylurea trifluoroacetate,

Trans-TV'- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-fluoro-phenyl} -TV-ethylurea trifluoroacetate, Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-hydroxyphenyl}urea trifluoroacetate, Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-hydroxyphenyl}urea trifluoroacetate, Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-(2,2-difluoroethoxyphenyl}urea trifluoroacetate, Trans-2-[4-(urea)-2-chloro-5-(3- {5-chloro- l 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 - yl}-4-hydroxypyrrolidin-l-yl)-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid trifluoroacetate, Trans-methyl-[2-(3- {5-chloro- 1 'H,3H-spiro[l-benzofuran-2.4'-piperidin] l-yl}-4- hydroxypyrrolidin- 1 -yl)phenyl] acetate trifluoroacetate, Trans-[2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin-l-yl)phenyl]acetic acid trifluoroacetate, Trans-ethyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-fluorophenyl] acetate trifluoroacetate,

Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenyl]acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-(2hydroxyethoxy)phenyl] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin-l-yl)-4-(2,2-difluoroethoxy)phenyl]acetic acid trifluoroacetate, Trans-[2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin-l-yl)phenoxy] acetic acid trifluoroacetate, Trans-dimethyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin-l-yl)phenoxy]acetate trifluoroacetate,

Trans-ethyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-fluorophenoxy] acetate trifluoroacetate, Trans-[2-(3-{5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenoxy] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-fluorophenoxy]acetic acid trifluoroacetate, Trans-[5-chloro-2-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-(2-hydroxyethoxy)phenoxy] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin-l-yl)-4-(2,2-difluoroethoxy)phenoxy]acetic acid trifluoroacetate, Trans-[2-(3-{5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin-l-yl)phenoxy] acetic acid trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[ 1 -benzofuran-2.4 ' -piperidin] 1 -yl} - 1 -pyridin-2- ylpyrrolidin-3-ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[6- (trifluoromethyl)pyridin-2-yl]pyrrolidin-3-ol trifluoroacetate,

Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[4-methyl-6- (trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-l -[4,6- di(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[4- (trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[2- (trifluoromethyl)pyrimidin-4-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -pyrimidin-4- ylpyrrolidin-3-ol trifluoroacetate,

4-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-l-[5,6-dimethyl-2- (trifluoromethyl)pyrimidin-4-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[4-methyl-6- (trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-l -[4,6- di(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -(6- methoxyquinazolin-4-yl)pyrrolidin-3-ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[2- (trifluoromethyl)quinazolin-4-yl]pyrrolidin-3-ol trifluoroacetate,

Trans-4-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-quinazoline-2-trifluoromethyl-6-carboxylic acid trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[6-methoxy-2- (trifluoromethyl)quinazolin-4-yl]pyrrolidin-3-ol trifluoroacetate, Trans-methyl- {4-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-trifluoromethylquinazoline} -6-carboxylate trifluoroacetate, Trans-4-(3- {5-chloro- 1 'H,3H-spiro[l-benzofuran-2.4'-piperidin] l-yl}-4- hydroxypyrrolidin- 1 -yl)quinazoline-2-trifluoromethyl-6-carboxamide trifluoroacetate, and Trans-methyl- {4-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-2-trifluoromethylquinazoline} -6-carbamate trifluoroacetate, or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) - (VI) 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) - (VI) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Thus, compounds can be prepared as an enantiomeric mixture of the (3R,4R and 3S,4S)- trans-4-(piperidin-4-yl]amino)pyrrolidin-3-ol or can be separated to provide both the (3R,4R) and (3S,4S) compounds.

It will be appreciated that the compounds of formula (I) - (VI) and salts may exist as zwitterions. Thus, whilst the compounds are drawn and referred to in the neutral form, they may exist also in internal salt (zwitterionic) form. The representation of compounds of formula (I) - (VI) and the examples of the present invention covers both neutral and zwitterionic forms and mixtures thereof in all proportions.

The compounds of formula (I) - (VI) 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-fluorobenzoate, 2,6- difluorobenzoate, (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) - (VI) 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) - (VI) or salts thereof also encompasses solvates of such compounds and solvates of such salts (e.g. hydrates).

Process

Certain intermediates that are usefull for the making of the compounds of formula (I) - (VI) of this invention may be synthesised using the procedures set out in WO04/005295, WO05/049620 and US 60/831776.

Thus, the present invention further provides a process for the preparation of a compound of formula (I) - (VI) or a pharmaceutically acceptable salt thereof as defined above which comprises: (a) where R⁴ is hydroxyl, reacting a compound of formula VII

wherein R¹, R², X, Y and Z and integers m, n and p are as defined as in formula (I) or (Ia) with a compound of formula VIII,

wherein the R³ is as defined as in formula (I) or (Ia), and Pg¹ is a suitable protecting group; or

(b) where R >4 is hydroxy, reacting a compound of formula IX

« wherein R¹, R², R³, X, Y and Z and integers m, n and p are as defined as in formula (I) or (Ia), with a compound of formula X

L¹— Q-(A- R⁵)_s X wherein Q, A and R⁵ and integer s are as defined as in formula (I) or (Ia), and L¹ is a leaving group, such as halogen (Br for Buchwald, Cl/F for S_NAΓ), or a protected derivative thereof; or (c) where R⁴ is hydroxyl, reacting a compound of formula VIII

wherein R³ is defined in relation to formula (I) or (Ia), with a compound of formula X L¹— Q-(A- R⁵)_s X wherein Q, A, R⁵ and integer s are as defined as in formula (I) or (Ia), or a protected derivative thereof and L¹ is a leaving group, such as a halogen (Br for Buchwald, Cl/F for S_NAΓ); or (d) where R⁴ is hydroxyl, reacting a compound of formula VII,

wherein R¹, R², X, Y and Z and integers m, n and p are as defined as in formula (I) or (Ia) with a compound of formula XI

wherein Q, A, R³ and R⁵ and integer s are as defined as in formula (I) or (Ia), or a protected derivative thereof; and therafter, if desired or necessary, carrying out one or more of the following steps (i) converting a compound of formula (I) - (VI) obtained to a different compound of formula (I) - (VI); (ii) removing of any protecting groups; and (iii) forming a pharmaceutically acceptable salt and/or polymorph of the compound of formula (I) - (VI).

As will be apparent to a person skilled in the art, following the epoxide opening of intermediates like VIII, IX or XI with an amine, will produce an enantiomeric mixture of trans (3R,4R) and (3S,4S) intermediates XI, XIII, XIV and final product, which can be separated to provide both the (3R,4R) and (3S,4S) compounds.

Process (a) - (d) 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.), cyanides (e.g. acetonitrile or butyronitrile), ethers (THF, dioxane), NMP, DCM or DMF at a temperature of, for example 20 ⁰C or above, such as a temperature in the range from 25- 150 ⁰C.

In processes (b) and (c), the choice of a suitable leaving group L¹ would be routine for a person skilled in the art. In the event of the leaving group being a bromine atom, Buchwald conditions may be applied, reacting intermediates in the presence OfPd₂(DBA)₃, BINAP and sodium t-butoxide. In the event of the leaving group being a chlorine or fluorine atom, S_NAΓ conditions may be applied, reacting the intermediates in the presence of an organic base, such as DIPEA or DBU.

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 may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I)-(VI) 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). The compounds of formula (I) or (Ia) or a pharmaceutically acceptable or a pharmaceutically acceptable salt, solvate or solvated salt thereof, as defined above may also be prepared according to the preparation routes described in schemes 1 below.

Scheme 1: degr reflux

Intermediates

Intermediates of the formula IX and XI and salts thereof are novel and comprise an independent aspect of the invention.

A further embodiment of the invention relates to compounds selected from trans-tert-butyl-3-(5-chloro-r//,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl)-4- hydroxypyrroldine- 1 -carboxylate, and trans-4-(5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl)-pyrrolidin-3-ol 3 hydrochloride.

Another embodiment related to the use of these compounds as intermediates in the preparation if compounds of formula (I) or (Ia).

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 (Ia), 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 (Ia), 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, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) 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 (Ia), or a pharmaceutically acceptable salt thereof, formulated for inhaled administration. In an embodiment of the present invention, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, may be administered orally.

Medical use

The compounds of formula (I) or (Ia), 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, can be used in the treatment of:

A compound of the invention, can 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 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 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 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 CX₃CRl for the C-X₃-C family.

The present invention further relates to the combination of a compound of the invention, 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.

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- 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-fluorouracil 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-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; (v) an antiangio genie 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 PDE4D; • 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 (Ia) 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 (Ia) 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 (Ia) 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 (Ia) 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 (Ia) 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 (Ia) 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 (Ia) 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 (Ia), 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 (Ia) 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) or (Ia) 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) or (Ia) may be in the range from 0.001 mg/kg to 30 mg/kg.

The compound of formula (I) or (Ia) 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) or (Ia) 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;

DCM Dichloromethane DIEA 7V,7V-Diz^'sopropylethylamine;

DMF 7V,7V-Dimethylformamide

DMSO Dimethylsulfoxide;

HPLC High Performance Liquid Chromatography;

LC/MS Liquid Column Chromatography / Mass Spectroscopy; TFA Trifluoroacetic acid;

THF Tetrahydrofuran General Methods

¹H NMR and ¹³C NMR spectra are 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), dimethylsulfbxide-β?_<5 (δπ 2.50 ppm), acetonitrile-β?_? (δπ 1-95 ppm) or methanol-^ (δπ 3.31 ppm) are used as internal references. Flash chromatography is carried out using silica gel (0.040-0.063 mm, Merck). Unless stated otherwise, starting materials are commercially available. All solvents and commercial reagents are of laboratory grade and are used as received.

The following method is 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 is 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 is 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 NH₃/water, Solvent B: acetonitrile Flow: 1 ml/min, Gradient 10-100% B 20 min, 100% B 1 min. Absorption is measured at 220, 254 and 280 nm.

Intermediate 1 Trans-tert-butyl-3-(5-chloro-l 'H, 3H-spiro[l-benzofuran-2.4 '-piperidin] l-yl)-4- hydroxypyrroldine-1-carboxylate

A solution of l-(4-chlorobenzyl)piperidin-4-amine (2.1 mmol) and 6-oxa-3-aza- bicyclo[3.1.9]hexane-3-carboxylic acid tert-butyl ester (2.0 mmol) in toluene (10 mL) is heated to 110 ⁰C for 24 h. The solvent is removed in vacuo and the residue purified by flash chromatography to yield trans-tert-butyl-3-{[l-(4-chlorobenzyl)piperidin-4- yljamino} -4-hydroxypyrroldine- 1 -carboxylate.

Intermediate 2

Trans-4-(5-chloro-l 'H,3H-spiro[l-benzofuran-2.4 '-piperidin]l-yl)-pyrrolidin-3-ol 3 hydrochloride

A solution of trans-tøt-butyl-3- {[ 1 -(4-chlorobenzyl)piperidin-4-yl] amino} -4- hydroxypyrroldine-1 -carboxylate (2 mmol) in 4M hydrochloride/dioxane (10 mL) and DCM (1 mL) is stirred at room temperature for 4 h. The mixture is diluted with diethyl ether and filtered. The precipitate is collected and dried to give the desired trans-4-{[l-(4- chlorobenzyl)piperidin-4-yl] amino }pyrrolidin-3-ol as a hydrochloric acid salt.

Example 1

Trans-4-{5-chloro-l Η, 3H-spiro[l-benzofuran-2.4 '-piperidin] ' l-yl}-l-phenylpyrrolidin-3- ol. trifluoroacetate

A solution of trans-4-(5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl)-pyrrolidin- 3-ol hydrochloride (0.5 mmol), chlorobenzene (0.5 mmol) and DIPEA (2 mmol) in DMF (1 mL) is stirred at 90⁰C for 18 h. After cooling to room temperature, the reaction mixture is partitioned between water (10 mL) and EtOAc (10 mL) and the aqueous phase is extracted with EtOAc (3 x 5 mL). The combined organic layers are ished with water (2 x 5 mL), dried over sodiumsulphate and after filtration removed in vacuo. The residue is purified by gradient HPLC (water to acetonitrile with 0.1% trifluoroacetate), giving the titled compound as a trifluoroacetate salt.

Example 2

Trans-4-{5-chloro-l Η, 3H-spiro[l-benzofuran-2.4 ' -piperidin] l-yl}-l-phenylpyrrolidin-3- ol trifluoroacetate

A solution of trans-4-(5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl)-pyrrolidin- 3-ol 3 hydrocholide (0.5 mmol), 2-chlorobenzamide (0.5 mmol) and DIPEA (2 mmol) in DMF (1 mL) is stirred at 90⁰C for 18 h. After cooling to room temperature, the reaction mixture is partitioned between water (10 mL) and EtOAc (10 mL) and the aqueous phase is extracted with EtOAc (3 x 5 mL). The combined organic layers are washed with water (2 x 5 mL), dried over sodiumsulphate and after filtration removed in vacuo. The residue is purified by gradient HPLC (water to acetonitrile with 0.1% trifluoroacetate), giving the titled compound as a trifluoroacetate salt.

The following compounds may be synthesised following the procedure described in example 1:

Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-7V-methylbenzamide trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-7V-methylbenzamide trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-fluoro-7V-methylbenzamide trifluoroacetate, Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-7V-methylbenzamide trifluoroacetate, Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-hydroxy-N,7V-dimethylbenzamide trifluoroacetate, Trans-2-{2-chloro-5-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-[(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid trifluoroacetate, and

Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-(2,2-difluoroethoxy)-Λ/-methylbenzamide trifluoroacetate.

Example 3

Trans-2-(3-{5-chloro-l Η,3H-spiro[l-benzofuran-2.4 '-piperidin] l-yl}-4- hydroxypyrrolidin-l-yl)-N-methylbenzoic acid trifluoroacetate

The following compounds may be synthesised following the procedure described in example 1 , reacting 2-chlorobenzoic acid with intermediate 2 .

The following compounds may be synthesised following the procedure described in example 1;

Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-fiuoro-7V-methylbenzoic acid trifluoroacetate, and Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-fiuoro-7V-methylbenzoic acid trifluoroacetate.

Examples series 4: acetamides

Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)phenyl} acetamide trifluoroacetate,

Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-methoxyphenyl} acetamide trifluoroacetate,

Trans-N- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenyl} acetamide trifluoroacetate,

Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-fluorophenyl} acetamide trifluoroacetate,

Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenyl} acetamide trifluoroacetate,

Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-(2,2-difluoroethoxyphenyl} acetamide trifluoroacetate, and

Trans-2-[4-(acetylamino)-2-chloro-5-(3-{5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'- piperidin] 1 -yl} -4-hydroxypyrrolidin- 1 -yl)-4-[(methylamino)carbonyl]phenoxy } -2- methylpropanoic acid trifluoroacetate. Examples series 5: ureas

Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)phenyl}urea trifluoroacetate,

Trans-TV'- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)phenyl} -TVTV-dimethylurea trifluoroacetate,

Trans-TV'- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin- 1 -yl)-4-fluoro-phenyl} -TV-ethylurea trifluoroacetate,

Trans-TV- {2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin-l-yl)-4-hydroxyphenyl}urea trifluoroacetate,

Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin-l-yl)-4-hydroxyphenyl}urea trifluoroacetate, Trans-TV- {5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-(2,2-difluoroethoxyphenyl}urea trifluoroacetate, and Trans-2-[4-(urea)-2-chloro-5-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l- yl}-4-hydroxypyrrolidin-l-yl)-4-[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid trifluoroacetate.

Examples series 6: acetic acids

Trans-methyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)phenyl] acetate trifluoroacetate,

Trans-[2-(3-{5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin-l-yl)phenyl]acetic acid trifluoroacetate,

Trans-ethyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-fluorophenyl] acetate trifluoroacetate, Trans-[5-chloro-2-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenyl] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin-l-yl)-4-(2hydroxyethoxy)phenyl] acetic acid trifluoroacetate, and Trans-[5-chloro-2-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin-l-yl)-4-(2,2-difluoroethoxy)phenyl]acetic acid trifluoroacetate.

Examples series 7: phenoxy acetic acids

Trans-[2-(3-{5-chloro-l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin-l-yl)phenoxy] acetic acid trifluoroacetate,

Trans-dimethyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)phenoxy] acetate trifluoroacetate, Trans-ethyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin-l-yl)-4-fluorophenoxy] acetate trifluoroacetate, Trans-[2-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenoxy] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-fluorophenoxy]acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-(2-hydroxyethoxy)phenoxy] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin-l-yl)-4-(2,2-difluoroethoxy)phenoxy]acetic acid trifluoroacetate, and Trans-[2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin-l-yl)phenoxy] acetic acid trifluoroacetate,

In another embodiment Q is a pyridine ring as shown in formula III:

Examples series 8: pyridines

The following compounds may be synthesised following the procedure described in example 1 , reacting intermediate 2 with the appropriately substituted chloropyridine reagent:

Trans-4- {5-chloro- 1 'H,3H-spiro[ 1 -benzofuran-2.4 ' -piperidin] 1 -yl} - 1 -pyridin-2- ylpyrrolidin-3-ol, trifluoroacetate and

Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[6- (trifluoromethyl)pyridin-2-yl]pyrrolidin-3-ol trifluoroacetate. One embodiment relates to compounds where Q is a pyrimidinyl ring as shown in formula IV or formula V:

Examples series 9

The following compounds may be synthesised following the procedure described in example 1 , reacting intermediate 2 with the appropriately substituted chloropyrimidine reagent:

Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[4-methyl-6- (trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- r//,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-l -[4,6- di(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[4- (trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[2- (trifluoromethyl)pyrimidin-4-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -pyrimidin-4- ylpyrrolidin-3-ol trifluoroacetate, 4-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-l-[5,6-dimethyl-2- (trifluoromethyl)pyrimidin-4-yl]pyrrolidin-3 -ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[4-methyl-6- (trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3 -ol trifluoroacetate, and Trans-4- {5-chloro- rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-l -[4,6- di(trifluoromethyl)pyrimidin-2-yl]pyrrolidin-3-ol trifluoroacetate.

Examples series 10

The following compounds may be synthesised following the procedure described in example 1, reacting intermediate 2 with the appropriately substituted chloroquinazoline:

Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -(6- methoxyquinazolin-4-yl)pyrrolidin-3-ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[2- (trifluoromethyl)quinazolin-4-yl]pyrrolidin-3-ol trifluoroacetate, Trans-4-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-quinazoline-2-trifluoromethyl-6-carboxylic acid trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -[6-methoxy-2- (trifluoromethyl)quinazolin-4-yl]pyrrolidin-3-ol trifluoroacetate, Trans-methyl- {4-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-trifluoromethylquinazoline} -6-carboxylate trifluoroacetate, Trans-4-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)quinazoline-2-trifluoromethyl-6-carboxamide trifluoroacetate, and Trans-methyl- {4-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-2-trifluoromethylquinazoline} -6-carbamate trifluoroacetate.

Claims

1. A compound of formula (I)

wherein: m is 0, 1 or 2;

R¹ is halogen, cyano or Ci-C₆(halo)alkyl;

X and Y are a bond, -O-, -NH-, or CH₂- and Z is a bond, -O-, -NH-, CH₂ or -C(O)-, provided that only one of X, Y and Z is a bond, and provided that X and Y are not simultaneously -O-; n is 0, 1 or 2; R² is Ci-C₆(cyclo)alkyl; p is 0 or 1 ;

R³ is hydrogen or Ci-C₆alkyl; R⁴ is hydrogen, hydroxy 1 or NH₂;

R⁵ is hydrogen, halogen, cyano, NH₂, hydroxyl, -NHC(O)R⁶, -NHCOOR⁹, -NHC(O)NR⁷R⁸, -NHS(O)₂R⁶, -C(O)NR⁷R⁸, -COOR⁹, SO₃R⁹, Ci-C₆ alkoxy OrCi-C₆ alkyl optionally substituted by t substituents independently selected from halogen, cyano, -NH₂, - COOR⁹, -CONH₂, hydroxyl, oxo (=0), Q-C₆ alkoxy, Ci-Ce alkoxycarbonyl, Q-C₆ alkylcarbonylamino and a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, COOR⁹, C₁- C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ (halo)alkyl; t is O, 1, 2 or 3; R⁶ is hydrogen, Ci-C₆alkyl or a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ (halo)alkyl, =0 and -OR⁹;

R⁷ and R⁸ each independently represent (i) hydrogen; or

(ii) a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl and Ci-C₆ (halo)alkyl; or

(iii) Ci-C₆ alkyl, optionally substituted by one or more substituent independently selected from halogen, -NH₂, hydroxyl, =0, Ci-C₆ (halo)alkyl, carboxyl, Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylcarbonylamino and a 3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, and optionally further comprising a bridging group, the ring being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, =0, Ci-C₆ alkyl, Q-C₆ hydroxyalkyl and Q-C₆ (halo)alkyl; or (iv) Ci-C₆ alkylsulphonyl; or

(v) R⁷ and R⁸ 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 optionally fused to a benzene ring to form a 8 to 11-membered heterocyclic ring, the heterocyclic ring or ring system being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, -CONH₂, Ci-C₆ alkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ (halo)alkyl, Ci-C₆ alkylamino, di-Ci-C₆ alkylamino, Ci-C₆ alkylcarbonyl, Ci-C₆ alkylcarbonylamino, Ci-C₆ alkylaminocarbonyl, di-Ci-C₆ alkylaminocarbonyl, phenyl, halophenyl, phenylcarbonyl, phenylcarbonyloxy and hydroxydiphenylmethyl; and R⁹ is hydrogen or Ci-C₆ alkyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R¹ is halogen.

3. A compound according to any one of the preceding claims, wherein R² is Ci-C₆ alkyl.

4. A compound according to any one of the preceding claims, wherein R³ is hydrogen.

5. A compound according to any one of the preceding claims, wherein R⁴ is hydroxyl.

6. A compound according to any one of the preceding claims, wherein Q is phenyl, pyridinyl, pyrazyl, pyrimidinyl, naphtyl or quinazolinyl.

7. A compound according to any one of the preceding claims, wherein hydrogen, halogen, hydroxyl, -NHC(O)R⁶, -NHCOOR⁹, -NHC(O)NR⁷R⁸, -C(O)NR⁷R⁸, -COOR⁹, Ci-C₆ alkoxy OrCi-C₆ alkyl optionally substituted by t substituents independently selected from halogen, -COOR⁹ or hydroxyl.

8. The compound

Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -phenylpyrrolidin-3- ol trifluoroacetate, Trans-4- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} - 1 -phenylpyrrolidin-3- ol. trifluoroacetate,

Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-7V-methylbenzamide trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-7V-methylbenzamide trifluoroacetate, Trans-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-fluoro-7V-methylbenzamide trifluoroacetate, Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-7V-methylbenzamide trifluoroacetate, Trans-5-chloro-2-(3- {5-chloro- 1 'H,3H-spiro[l-benzofuran-2.4'-piperidin] l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-hydroxy-7V,7V-dimethylbenzamide trifluoroacetate, Trans-2-{2-chloro-5-(3-{5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl}-4- hydroxypyrrolidin- 1 -yl)-4-[(methylamino)carbonyl]phenoxy } -2-methylpropanoic acid trifluoroacetate,

Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-hydroxyphenyl] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin- 1 -yl)-4-(2hydroxyethoxy)phenyl] acetic acid trifluoroacetate, Trans-[5-chloro-2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin-l-yl)-4-(2,2-difluoroethoxy)phenyl]acetic acid trifluoroacetate, Trans-[2-(3- {5-chloro- l 'H,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl} -4- hydroxypyrrolidin-l-yl)phenoxy] acetic acid trifluoroacetate, Trans-dimethyl- [2-(3- {5-chloro- 1 'H,3H-spiro[l -benzofuran-2.4'-piperidin] 1 -yl} -A- hydroxypyrrolidin-l-yl)phenoxy]acetate trifluoroacetate,

9. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvates or solvated salts, as claimed in any one of claims 1 to 8, in association with a pharmaceutically acceptable adjuvants, diluents and/or carriers.

10. A compound of formula (I), or a pharmaceutically acceptable salt, solvates or solvated salts, as claimed in any one of claims 1 to 8 for use in therapy.

11. Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvates or solvated salts, as claimed in any one of claims 1 to 8, in the manufacture of a medicament for treating a respiratory disease.

12. Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvates or solvated salts, as claimed in any one of claims 1 to 8, in the manufacture of a medicament for treating airway diseases, inflammatory diseases, COPD and/or asthma.

13. A method of treatment of respiratory diseases, airway diseases, inflammatory diseases, COPD and/or asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, solvates or solvated salts, as claimed in any one of claims 1 to 8.

14. A compounds trans-tert-butyl-3-(5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl)-4- hydroxypyrroldine- 1 -carboxylate, and trans-4-(5-chloro-rH,3H-spiro[l-benzofuran-2.4'-piperidin]l-yl)-pyrrolidin-3-ol 3 hydrochloride.

15. The use of the compounds according to claim 14 as intermediates in the preparation if compounds of formula (I) according to claim 1.