WO2009112475A1 - Pyrrolo [2, 3-b] pyridin derivatives as ikk2 inhibitors - Google Patents

Abstract

The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds according to formula (I):and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular IKK2 activity.

Description

PYRROLO [2 , 3-B] PYRIDIN DERIVATIVES AS IKK2 INHIBITORS

FIELD OF THE INVENTION

The invention is directed to certain novel compounds which are inhibitors of kinase activity. More specifically, the compounds are IKK2 inhibitors. Compounds which are

IKK2 inhibitors may be useful in the treatment of disorders associated with inappropriate

IKK2 (also known as IKKβ) activity, in particular in the treatment and prevention of disorders mediated by IKK2 mechanisms including inflammatory and tissue repair disorders. Such disorders include rheumatoid arthritis, COPD (chronic obstructive pulmonary disease), asthma and rhinitis.

BACKGROUND OF THE INVENTION

An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 500 different known protein kinases. However, because three to four percent of the human genome is a code for the formation of protein kinases, there may be many thousands of distinct and separate kinases in the human body. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the γ-phosphate of the ATP-Mg²⁺ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside cells, thereby governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase will itself be regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity. Due to their physiological relevance, variety and ubiquitousness, protein kinases have become one of the most important and widely studied family of enzymes in biochemical and medical research.

The protein kinase family of enzymes is typically classified into two main subfamilies:

Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino acid residue they phosphorylate. The serine/threonine kinases (PSTK) include cyclic AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Accordingly, serine/threonine kinases and the signal transduction pathways which they are part of are important targets for drug design. The tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also in progress to identify modulators of tyrosine kinases as well.

Nuclear factor KB (NF-KB) represents a family of closely related dimeric transcription factor complexes composed of various combinations of the Rel/NF-κB family of polypeptides. The family consists of five individual gene products in mammals, ReIA (p65), NF-κB1 (p50/ p105), NF-κB2 (p52/ p100), c-Rel, and ReIB, all of which can form hetero- or homo-dimers. These proteins share a highly homologous 300 amino acid "ReI homology domain" which contains the DNA binding and dimerization domains. The NFkBs also carry a nuclear localisation sequence near the C-terminus of the ReI homology domain which is important in the transport of NF-κB from the cytoplasm to the nucleus. In addition, p65 and cRel possess potent transactivation domains at their C-terminal ends.

The activity of NF-κB is regulated by its interaction with a member of the inhibitor IKB family of proteins. This interaction effectively blocks the nuclear localization sequence on the NF-κB proteins, thus preventing migration of the dimer to the nucleus. A wide variety of stimuli activate NF-κB through what are likely to be multiple signal transduction pathways. Included are bacterial products (LPS), some viruses (HIV-1 , HTLV-1 ), inflammatory cytokines (TNFα, IL-1 ), environmental and oxidative stress and DNA damaging agents. Apparently common to all stimuli however, is the phosphorylation and subsequent degradation of IKB. lκBα and β for example, are phosphorylated on two N- terminal serines by the recently identified IKB kinases (IKK-α and IKK-β), whilst NF-κB2, which carries an IkB-like C terminal region is phosphorylated on N and C terminal serines by IKK-α. IKK-β is also known as IKK2 and its now widely accepted that it is essential for rapid NFkB activation in response to pro-inflammatory stimuli. IKK2 is an example of a serine/threonine kinase. Site-directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF-κB in that once phosphorylated the protein is flagged for degradation via the ubiquitin-proteasome pathway. Free from IKB, the active NF-κB complexes are able to translocate to the nucleus where they bind in a selective manner to preferred gene-specific enhancer sequences. Included in the genes regulated by NF-κB are a number of cytokines and chemokines, cell adhesion molecules, acute phase proteins, immunoregualtory proteins, eicosanoid metabolizing enzymes and anti-apoptotic genes.

It is well-known that NF-κB plays a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as TNF, IL-1 β, IL-6 and IL-8, cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (iNOS). Such mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some inflammatory and autoimmune diseases.

The importance of NF-κB in inflammatory disorders is further strengthened by studies of airway inflammation including asthma, in which NF-κB has been shown to be activated.

This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders. In addition, inhaled steroids are known to reduce airway hyperresponsiveness and suppress the inflammatory response in asthmatic airways. In light of the recent findings with regard to glucocorticoid inhibition of NF-κB, one may speculate that these effects are mediated through an inhibition of NF-κB.

Further evidence for a role of NF-κB in inflammatory disorders comes from studies of rheumatoid synovium. Although NF-κB is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-κB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF- KB has been shown to be activated in human synovial cells in response to stimulation with TNF-α or I L- 1 β . Such a distribution may be the underlying mechanism for the increased cytokine and eicosanoid production characteristic of this tissue. See Roshak, A. K., et a/., J. Biol. Chem., 271 , 31496-31501 (1996). Expression of IKK-β has been shown in synoviocytes of rheumatoid arthritis patients and gene transfer studies have demonstrated the central role of IKK-β in stimulated inflammatory mediator production in these cells. See Aupperele, K. R., et al., J. Immunology, 1999, 163:427-433 and Aupperle, K. R, ef al., J. Immunology, 2001 , 166:2705-11. More recently, the intra-articular administration of a wild type IKK-β adenoviral construct was shown to cause paw swelling while intra- articular administration of dominant-negative IKKβ inhibited adjuvant-induced arthritis in rat. See Tak, P. P., ef a/., Arthritis and Rheumatism, 2001 , 44:1897-1907.

The NF-κB/Rel and IKB proteins are also likely to play a key role in neoplastic transformation and metastasis. Family members are associated with cell transformation in vitro and in vivo as a result of over expression, gene amplification, gene rearrangements or translocations. In addition, rearrangement and/or amplification of the genes encoding these proteins are seen in 20-25% of certain human lymphoid tumors. Further, NF-κB is activated by oncogenic ras, the most common defect in human tumors and blockade of NF-κB activation inhibits ras mediated cell transformation. In addition, a role for NF-κB in the regulation of apoptosis has been reported strengthening the role of this transcription factor in the regulation of tumor cell proliferation. TNF, ionizing radiation and DNA damaging agents have all been shown to activate NF-κB which in turn leads to the upregulated expression of several anti-apoptotic proteins. Conversely, inhibition of NF-κB has been shown to enhance apoptotic-killing by these agents in several tumor cell types. As this likely represents a major mechanism of tumor cell resistance to chemotherapy, inhibitors of NF-κB activation may be useful chemotherapeutic agents as either single agents or adjunct therapy. Recent reports have implicated NF-κB as an inhibitor of skeletal cell differentiation as well as a regulator of cytokine-induced muscle wasting (Guttridge, D. C, et al., Science, 2000, 289: 2363-2365) further supporting the potential of N FKB inhibitors as novel cancer therapies.

Several NF-κB and IKK inhibitors are described in Wahl, C, et al., J. Clin. Invest. 101 (5), 1 163-1174 (1998); Sullivan, R. W., et al., J. Med. Chem., 41 , 413-419 (1998); Pierce, J. W., et al., J. Biol. Chem. 272, 21096-21 103 (1997); and Coish, P. D. G., et al., Expert Opin. Ther. Patents, 2006, vol 16(1 ) 1-12.

The marine natural product hymenialdisine is known to inhibit NF-κB. See Roshak, A., et al., JPET, 283, 955-961 (1997); and Breton, J. J., and Chabot-Fletcher, M. C, JPET, 282, 459-466 (1997).

Attempts have been made to prepare compounds that inhibit IKK2 activity and a number of such compounds have been disclosed in the art. However, in view of the number of pathological responses that are mediated by IKK2, there remains a continuing need for inhibitors of IKK2 which can be used in the treatment of a variety of conditions.

The present inventors have discovered novel compounds which are inhibitors of kinase activity, in particular IKK2 activity. Compounds which are IKK2 inhibitors may be useful in the treatment of disorders associated with inappropriate kinase activity, in particular inappropriate IKK2 activity, for example in the treatment and prevention of disorders mediated by IKK2 mechanisms. Such disorders include inflammatory and tissue repair disorders (including rheumatoid arthritis, inflammatory bowel disease, COPD (chronic obstructive pulmonary disease), asthma and rhinitis), fibrotic diseases, osteoarthritis, osteoporosis, dermatosis (including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage), autoimmune diseases (including Sjogren's syndrome, systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection), Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer (including Hodgkins disease), cachexia, inflammation associated with infection and certain viral infections (including acquired immune deficiency syndrome (AIDS)), adult respiratory distress syndrome, and Ataxia Telangiestasia.

In one embodiment, the compounds show selectivity for IKK2 over other kinases.

In one embodiment, the compounds are particularly suitable for development as a drug due to their pharmacokinetic profile. For example, compounds for oral administration show good oral bioavailability.

SUMMARY OF THE INVENTION

The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds according to formula (I):

(I) wherein R , R and R are as defined below, and salts thereof.

The compounds of the invention are inhibitors of IKK2 activity. Compounds which are IKK2 inhibitors may be useful in the treatment of disorders associated with inappropriate IKK2 (also known as IKKβ) activity, such as rheumatoid arthritis, COPD (chronic obstructive pulmonary disease), asthma and rhinitis (including seasonal rhinitis, allergic rhinitis and vasomotor rhinitis). Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention is still further directed to methods of inhibiting IKK2 activity and treatment of disorders associated therewith using a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the invention is directed to compounds according to formula (I):

(I)

wherein

R² is -CHR⁶R⁷, -CHF₂, -CF₃ or -C(CH₃)₃;

R³ is hydrogen or methyl;

R⁴ is

R⁶ is hydrogen and R⁷ is hydrogen, C^alkyl, -(CH₂)_dOR¹⁰, -NR¹¹R¹², -CO₂Ci.₆alkyl, - CONR¹³R¹⁴, phenyl, or 5-membered heteroaryl containing from one to four nitrogen atoms wherein the heteroaryl is optionally substituted by one or two substituents independently selected from Ci-salkyl, -COCi-βalkyl, -(CH₂)_ephenyl and thienyl, R⁶ is methyl and R⁷ is methyl or hydroxyl, or

R⁶ and R⁷ are linked to form C3_6cycloalkyl optionally substituted by methyl;

R¹⁰ is hydrogen, phenyl optionally substituted by -(CH₂)_fCO₂R¹⁵, or pyridyl optionally substituted by one or two substituents independently selected from chlorine and Ci_₆alkyl;

R¹¹ is hydrogen and R¹² is hydrogen, d.₆alkyl optionally substituted by hydroxyl,

-(CH₂)_kpyridyl, or -(CH₂)_mheterocyclyl wherein the heterocyclyl is optionally substituted by Ci_-6alkyl, R¹¹ is Ci_-Salkyl and R¹² is Ci_-6alkyl optionally substituted by hydroxyl or -SO₂phenyl,

R¹¹ and R¹² are linked to form a 6-membered heterocyclyl optionally containing one further nitrogen or an oxygen wherein the heterocyclyl is optionally substituted by -CO₂C_1-salkyl or piperidinyl, or R¹¹ and R¹² are linked to form

R¹³ is hydrogen and R¹⁴ is hydrogen, d_-6alkyl, -(CH₂)_nOR¹⁸, -(CH₂)_PNR¹⁹R²⁰, - (CH₂)_qCO₂R²¹ , -(CH₂)_rSO₂NH₂, C₃-₆cycloalkyl, or phenyl optionally substituted by chlorine or -OCi_-6alkyl, R¹³ and R¹⁴ are each independently C_1-6alkyl, or R¹³ and R¹⁴ are linked to form pyrrolidinyl;

R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently hydrogen or C,.₆alkyl;

a, b and c are each independently selected from 0 or 1 ;

d, e, f, i, j, k and m are each independently an integer selected from 0 to 4; g, h, n, p, q and r are each independently an integer selected from 1 to 4;

X is S or SO;

Y and Y¹ are each independently selected from S, SO or SO2; and

Z is alkylene;

and salts thereof (hereinafter "compounds of the invention").

In one embodiment, R² is -CHR⁶R⁷. In another embodiment, R² is -CF₃. In a further embodiment, R² is -C(CH₃)₃.

In one embodiment, R³ is hydrogen.

In one embodiment R⁴ is

^a . In a further embodiment, R⁴ is

In one embodiment, R⁶ is hydrogen and R⁷ is hydrogen, -CO₂C₁.₆alkyl, or 5-membered heteroaryl containing from one to four nitrogen atoms wherein the heteroaryl is optionally substituted by one or two substituents independently selected from C_1-6alkyl, -COC^ealkyl, -(CH₂)_Θphenyl and thienyl, or R⁶ and R⁷ are linked to form C₃.₆cycloalkyl.

In another embodiment, R⁶ is hydrogen, and R⁷ is hydrogen or 5-membered heteroaryl containing from one to four nitrogen atoms, or R⁶ and R⁷ are linked to form cyclopropyl.

In another embodiment, R⁶ is hydrogen and R⁷ is hydrogen or 1 H-1 ,2,3-triazol-1-yl.

In another embodiment, R⁶ is hydrogen and R⁷ is hydrogen.

In a further embodiment, R⁶ is hydrogen and R⁷ is 1 H-1 ,2,3-triazol-1-yl.

In one embodiment, R¹⁰ is pyridyl optionally substituted by one or two substituents independently selected from chlorine and C_halky!. In one embodiment, R is hydrogen and R is hydrogen, Ci.εalkyl optionally substituted

by hydroxyl, , -(CH₂)_gNR¹⁶R¹⁷, -(CH₂)_hNCOC_1-6alkyl, -(CH₂),C_Mcycloalkyl, -

(CH₂)_jPhenyl, -(CH₂)_kpyridyl, or -(CH₂)_mheterocyclyl wherein the heterocyclyl is a 5- or 6- membered heterocyclyl containing one or two heteroatoms independently selected from nitrogen and oxygen and is optionally substituted by C_1-6alkyl, R¹¹ is C_1-5alkyl and R¹² is C_1-6alkyl optionally substituted by hydroxyl or -SO₂phenyl, R¹¹ and R¹² are linked to form a 6-membered heterocyclyl optionally containing one further nitrogen or an oxygen wherein the heterocyclyl is optionally substituted by -CO₂Ci_-6alkyl or piperidinyl, or

R¹¹ and R¹² are linked to form

In another embodiment, R¹¹ is hydrogen and R¹² is hydrogen, -(CH₂)_gNR¹⁶R¹⁷, - (CH₂)_hNCOC_1-6alkyl, -(CH₂),C_3-6cycloalkyl, -(CH^phenyl, -(CH₂)_kpyridyl, or

(CH₂)_mheterocyclyl, for example -(CH₂)_mpiperidinyl, wherein the heterocyclyl is optionally substituted by C_1-6alkyl,

R¹¹ is C_1-Salkyl and R¹² is C_1-6alkyl or -SO₂phenyl,

R¹¹ and R¹² are linked to form a 6-membered heterocyclyl optionally containing one further nitrogen wherein the heterocyclyl is optionally substituted by -CO₂C₁.₆alkyl or piperidinyl, or

R¹¹ and R¹² are linked to form

In another embodiment, R¹¹ is hydrogen and R¹² is hydrogen, - (CH₂)_gNR¹⁶R¹⁷, -(CH₂)_hNCOCi_-6alkyl, -(CH₂),C₃-₆cycloalkyl, -(CH^phenyl, -(CH₂)_kpyridyl, or -(CH₂)_mheterocyclyl wherein the heterocyclyl is optionally substituted by d_₆alkyl. In a further embodiment, R¹¹ and R¹² are each independently

for example R¹¹ and R¹² are each methyl. In one embodiment, R¹³ is hydrogen and R¹⁴ is hydrogen, C_1-6alkyl, -(CH₂)_nOR¹⁸, - (CH₂)pNR¹⁹R²⁰, -(CH₂)C₁CO₂R²¹, -(CH₂)_rSO₂NH₂, C«cycloalkyl, or phenyl optionally substituted by chlorine or -OCi.₆alkyl.

In one embodiment, R¹⁵ is hydrogen. In a further embodiment, R¹⁵ is methyl.

In one embodiment, R¹⁶ is methyl.

In one embodiment, R¹⁷ is methyl.

In one embodiment, R¹⁸ is hydrogen. In a further embodiment, R¹⁸ is methyl.

In one embodiment, R¹⁹ is hydrogen.

In one embodiment, R²⁰ is hydrogen.

In one embodiment, R²¹ is hydrogen.

In one embodiment, a is 0. In a further embodiment, a is 1.

In one embodiment, b is 0. In a further embodiment, b is 1.

In one embodiment, c is 0. In a further embodiment, c is 1.

In one embodiment, d is 0. In another embodiment, d is 2. In a further embodiment d is 3.

In one embodiment, e is 1.

In one embodiment, f is 0. In a further embodiment, f is 1.

In one embodiment, g is 2.

In one embodiment, h is 2.

In one embodiment, i is 1. In one embodiment, j is 1.

In one embodiment, k is 0. In a further embodiment, k is 1.

In one embodiment, m is 0.

In one embodiment, n is 3. In a further embodiment, n is 4.

In one embodiment, p is 2.

In one embodiment, q is 1.

In one embodiment, r is 3.

In one embodiment, X is S. In an alternative embodiment, X is SO.

In one embodiment, Y is SO2.

In one embodiment, Z is Ci.₃alkylene, for example Z is methylene, ethylene or propylene. In a further embodiment, Z is -CH(CH₃)-. When Z is an alkylene group larger than methyl,

the NR group and the group may be attached to the same carbon or to different carbons of the alkylene chain.

It is to be understood that the present invention covers all combinations of substituent groups described hereinabove.

In one embodiment, the invention is directed to compounds according to formula (I) wherein:

R² is -CHR⁶R⁷, -CHF₂, -CF₃ or -C(CH₃)₃;

R³ is hydrogen or methyl;

R⁶ is hydrogen and R⁷ is hydrogen, -CO₂C_1-6alkyl, or 5-membered heteroaryl containing from one to four nitrogen atoms wherein the heteroaryl is optionally substituted by one or two substituents independently selected from C_1-6alkyl, -COC-ι_₆alkyl, -(CH₂)_ephenyl and thienyl, or R⁶ and R⁷ are linked to form C₃_₆cycloalkyl.

a is 0 or 1.

b is 0 or 1.

X is S or SO;

Y is S, SO or SO₂; and

and salts thereof.

In a further embodiment, the invention is directed to compounds according to formula (I) wherein:

R² is -CHR⁵R⁷ or -CF₃;

R³ is hydrogen;

R⁶ is hydrogen and R⁷ is hydrogen or 1 H-1 ,2,3-triazol-1-yl;

a and b are each independently selected from 0 or 1 ; X is S or SO;

Y is SO₂; and

Z is alkylene;

and salts thereof.

Compounds of the invention include the compounds of Examples 1 to 6 and salts and solvates thereof.

In one embodiment, the compound of the invention is:

/V-(tetrahydro-2H-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1 H-pyrrolo[2,3-ιb]pyridin-4- yl]benzenesulfonamide; N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4- yl]benzenesulfonamide;

Λ/-(1-oxidotetrahydro-2/-/-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1 H-pyrrolo[2,3-ib]pyridin-4- yl]benzenesulfonamide;

/V-[1-(1 ,1-dioxidotetrahydro-3-thienyl)ethyl]-4-(2-methyl-1 H-pyrrolo[2,3-ό]pyridin-4- yl)benzenesulfonamide;

4-(2-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-N-(1-oxidotetrahydro-2H-thiopyran-4- yl)benzenesulfonamide; or

N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(1 H-1 ,2,3-triazol-1-ylmethyl)-1 H-pyrrolo[2,3- b]pyridin-4-yl]benzenesulfonamide, or a salt thereof.

Terms and Definitions

"Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, Ci_-6alkyl refers to an alkyl group having from 1 to 6 member atoms, for example 1 to 4 members. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. In one embodiment, alkyl is methyl. In a further embodiment, alkyl is ethyl. "Alkylene" refers to a saturated divalent hydrocarbon chain having the specified number of member atoms. For example, C-^alkylene refers to an alkylene group having from 1 to 4 member atoms. Alkylene groups may be straight or branched. Representative branched alkylene groups have one or two branches. Alkylene includes methylene, ethylene, propylene (n-propylene and isopropylene) and butylene (n-butylene, isobutylene, and t-butylene).

"Cycloalkyl" refers to a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems. For example, C₃. ₆cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. In one embodiment, the cycloalkyl groups have 3 or 4 member atoms. In a further embodiment, the cycloalkyl groups have 5 or 6 member atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. It will be appreciated that the substituent may be at any position on the ring, including the carbon atom which is the point of attachment to the rest of the molecule. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, cycloalkyl is cyclopropyl.

"Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.

"Enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).

"Enantiomerically pure" refers to products whose enantiomeric excess is 99% ee or greater.

"Half-life" (or "half-lives") refers to the time required for half of a quantity of a substance to be converted to another chemically distinct species in vitro or in vivo.

"Heteroaryl", unless otherwise defined, refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Heteroaryl groups are monocyclic ring systems or are fused bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 1 1 member atoms. Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocyclyl ring are attached forming a fused bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl ring are attached forming a fused bicyclic ring system. Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and napthyridinyl. For example, 5-membered heteroaryl groups having from 1 to 4 nitrogen atoms include pyrrolyl, pyrazolyl, imidazolyl, triazolyl (including 1 ,2,3-triazolyl and 1 ,2,4-triazolyl) and tetrazolyl.

"Heteroatom" refers to a nitrogen, sulphur, or oxygen atom.

"Heterocyclyl", unless otherwise defined, refers to a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. However, heterocyclyl rings are not aromatic. Heterocyclyl groups containing more than one heteroatom may contain different heteroatoms. Heterocyclyl groups may be optionally substituted with one or more substituents as defined herein. Heterocyclyl groups are monocyclic ring systems having from 4 to 7 member atoms. In certain embodiments, heterocyclyl is saturated. In other embodiments, heterocyclyl is unsaturated but not aromatic. Heterocyclyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, and azetidinyl. In one embodiment, heterocyclyl is piperidinyl. In a further embodiment, heterocyclyl is piperazinyl.

"Member atoms" refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring. "Optionally substituted" indicates that a group, such as heterocyclyl, may be unsubstituted or substituted with one or more substituents as defined herein.

"Substituted" in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term

"substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination). In certain embodiments, a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

Ac (acetyl); Aq (aqueous);

ATP (adenosine triphosphate);

BOC (ferf-butyloxycarbonyl);

BSA (bovine serum albumin);

Bu (butyl); nBu (n-butyl); tBu (t-butyl);

CHAPS (3[(3-Cholamidopropyl)dimethylammonio]-propanesulfonic acid); DCE (dichloroethane);

DCM (dichloromethane);

DIAD (diisopropyl azodicarboxylate);

DIPEA (diisopropylethylamine); DMF (Λ/,Λ/-dimethylformamide);

DMSO (dimethylsulfoxide); dppf (1 ,1 '-bis(diphenylphosphino)ferrocene);

DTT (1 ,4-dithiothreitol);

EDTA (ethylenediaminetetraacetic acid); Et (ethyl);

EtOAc (ethyl acetate); g (grams);

HATU (O-(7azabenzobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HOBT (1-hydroxybenzotriazole);

HPLC (high pressure liquid chromatography);

H, hr or hrs (hours);

Hz (Hertz);

IMS (industrial methylated spirits); L (liters);

LDA (lithium diisopropylamide);

M (molar);

MCPBA (meta-chloroperbenzoic acid);

MDAP (mass directed autopreparative HPLC); Me (methyl);

MeOH (methanol); mg (milligrams);

MHz (megahertz);

Min or mins (minutes); ml or mL(milliliters); mw (microwave); μl (microliters); mM (millimolar); mmol (millimoles); mol (moles); mp (melting point);

MTBE (methyl tertiary butyl ether); Ph (phenyl);

¹Pr (isopropyl); rt (retention time);

SPE (solid phase extraction); TBAF (tetra-n-butylammonium fluoride);

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

TEA (triethylamine);

TFA (trifluoroacetic acid);

THF (tetrahydrofuran); TLC (thin layer chromatography);

TMS (trimethylsilyl);

Tos (tosyl or p-toluenesulfonyl); pTSA (p-toluenesulfonic acid); and

WSCDI (water soluble carbodiimide).

All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI.

Included within the scope of the "compounds of the invention" are all solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and salts thereof.

The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The invention also includes isotopically-labelled compounds, which are identical to the compounds of formula (I) and salts thereof, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 3H, 1 1 C, 14C and 18F.

The compounds according to formula (I) may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in formula (I), or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, compounds according to formula (I) containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound according to formula (I) which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer- specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

The terms enantiomer 1 and enantiomer 2 are used herein to refer to the enantiomers of a compound of the invention based on the order of their elution using the chiral chromatography methodology described herein. Enantiomer 1 refers to the first enantiomer to elute, and enantiomer 2 refers to the second enantiomer to elute.

It will be appreciated by those skilled in the art that although the absolute retention time on chromatography can be variable, the order of elution remains the same when the same column and conditions are employed. However, the use of a different chromatography column and conditions may alter the order of elution.

The compounds according to formula (I) may also contain centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans geometric isomer, the cis geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in formula (I) whether such tautomers exist in equilibrium or predominately in one form.

It is to be understood that the references herein to compounds of formula (I) and salts thereof covers the compounds of formula (I) as the free base or as salts thereof, for example as a pharmaceutically acceptable salt thereof.

The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds according to formula (I) may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts of the compounds according to formula (I) may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to compounds of formula (I) and pharmaceutically acceptable salts thereof.

As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts. Thus one embodiment of the invention embraces compounds of formula (I) and salts thereof.

In certain embodiments, compounds according to formula (I) may contain an acidic functional group. Suitable pharmaceutically-acceptable salts include salts of such acidic functional groups. Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, TEA, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p- aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2- hydroxyethanesulfonate, benzenesulfonate (besylate), p-aminobenzenesulfonate, p- toluenesulfonate (tosylate), and napthalene-2-sulfonate. In one embodiment, the pharmaceutically acceptable acid addition salt is a hydrochloride.

Compound Preparation

The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Examples section.

In one embodiment of the invention, the compounds of formula (I) or salts thereof, may be prepared by a process comprising reacting a compound of formula (NA) or (NB)

(HA)

(HB) wherein R¹ is SO₂NR³R⁴ as defined above or a group convertible to SO₂NR³R⁴, with a compound of formula (INA)

(NIA)

wherein P is hydrogen or a protecting group, R^2a is R² as defined above or a group convertible to R², and X is halogen, for example bromine or chlorine, in the presence of a catalyst, for example a palladium (II) complex.

Alternatively, the compounds of formula (I), and salts thereof, may be prepared by a process comprising reacting a compound of formula (HC)

wherein R¹ is SO₂NR³R⁴ as defined above or a group convertible to SO₂NR³R⁴, and Y is chlorine, bromine, iodine or triflate, with a compound of formula (IIIB) or (NIC)

(IIIB) (NIC)

wherein P is hydrogen or a protecting group and R^2a is R² as defined above or a group convertible to R², in the presence of a catalyst, for example a palladium (II) complex.

The above processes may be followed, if required, by subjecting the resulting compound to one or more of the following operations: i) removal of the protecting group P, ii) conversion of R¹ to SO₂NR³R⁴, iii) conversion of R^2a to R², and iv) conversion of the resultant compound of formula (I) into a salt thereof. A comprehensive discussion of the ways in which groups may be protected and methods for cleaving the resulting protected derivatives is given by for example T.W. Greene and P. G. M Wuts in Protective Groups in Organic Synthesis 2^nd ed., John Wiley & Son, Inc., 1991 and by P.J. Kocienski in Protecting Groups, Georg Thieme Verlag, 1994. Examples of suitable protecting groups, P, include phenylsulfone and 4-methylphenylsulfone. Such protecting groups may be removed under basic conditions, for example using sodium hydroxide or potassium hydroxide.

In a further embodiment of the invention, the compounds of formula (I), and salts thereof, may be prepared by conversion of one compound of formula (I) into another compound of formula (I).

Suitable functional group transformations for converting one compound of formula (I) into another compound of formula (I), or converting R¹ to SO₂NR³R⁴ when R¹ is a group convertible to SO₂NR³R⁴ or R^2a to R², are well known in the art and are described in, for instance, Comprehensive Heterocyclic Chemistry II, eds. A. R. Katritzky, C. W. Rees and

E. F. V. Scriven (Pergamon Press, 1996), Comprehensive Organic Functional Group

Transformations, eds. A. R. Katritzky, O. Meth-Cohn and CW. Rees (Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry, eds. D. Barton and W. D. Ollis

(Pergamon Press, Oxford, 1979), and Comprehensive Organic Transformations, R. C.

Larock (VCH Publishers Inc., New York, 1989).

Compounds of formula (NA) or (MB) may be prepared from compounds of formula (IV) wherein R¹ is as defined above and Z is a halogen, for example bromine, by reaction with bis(pinacolato)diboron (in the case of compounds of formula (NB)) or triisopropyl borate (in the case of compounds of formula (NA)) in the presence of a catalyst, for example a palladium (II) complex, optionally followed by aqueous hydrolysis.

In compounds of formula (IV) wherein R¹ is a group convertible to is SO₂NR³R⁴, suitable groups that may enable this conversion include sulfonyl chloride and sulfonylpentafluorophenyl ester. Such groups may be reacted with the required amine under suitable conditions, for example in the presence of a hindered organic base, for example TEA, and in an inert solvent, for example 1 ,4-dioxane. Sulfonylpentafluorophenyl ester may be obtained from sulfonyl chloride by reaction with pentafluorophenol in the presence of a hindered organic base, for example TEA, and in an inert solvent, for example DCM. Sulfonyl chloride groups may be obtained from sulfonic acids using a chlorinating reagent such as thionyl chloride.

Compounds of formula (MIB) or (NIC) may be prepared from compounds of formula (MIA) by reaction with bis(pinacolato)diboron (in the case of compounds of formula (HIC)) or triisopropyl borate (in the case of compounds of formula (IMB)) in the presence of a catalyst, for example a palladium (II) complex, optionally followed by aqueous hydrolysis.

Compounds of formula (MIA) wherein P is a protecting group may be obtained by reacting compounds of formula (V) wherein P is a protecting group, X is as defined above and L is a leaving group such as a halogen, for example iodine, with a suitable terminal alkyne in the presence of a catalyst, for example a palladium (M) complex. In a further embodiment, compounds of formula (III) may also be obtained by reacting compounds of formula (V) wherein L is a leaving group such as a halogen, for example iodine, with a Grignard reagent, for example isopropylmagnesium chloride, and subsequent reaction with a suitable electrophile, for example paraformaldehyde.

(V)

Compounds of formula (V) may be obtained from the reaction of compounds of formula (Vl), wherein P is a protecting group and X is as defined above, via generation of an anion at the 2-position with a strong hindered base, for example lithum di-isopropylamide, at low temperature, for example -78⁰C, and subsequent reaction with an electrophile such as an alkyl halide, for example methyl iodide, or an acid chloride, for example acetyl chloride or a formylating reagent, for example dimethylformamide.

(Vi)

Compounds of formula (V) may also be obtained from compounds of formula (Vl) by reaction comprising deprotonation with a strong hindered base, for example lithum di- isopropylamide, at low temperature, for example -78°C and subsequent reaction with an electrophile, for example iodine.

Compounds of formula (Vl) may be obtained by reacting compounds of formula (VII), wherein X is as defined above, in the presence of aryl sulphonyl chloride, for example benzene sulfonyl chloride, under phase transfer conditions with biphasic solvents such as water and DCM and in the presence of a phase transfer catalyst such as tetrabutylammonium sulphate.

(VII)

Compounds of formula (VII) may be obtained by reacting from compounds of formula (VI II) in the presence of a suitable halogenating reagent, for example tetrabutylammonium bromide, with methansulfonic anhydride in a suitable solvent, for example dimethylformamide.

(VIM) Compounds of formula (VIII) may be obtained by reacting compounds of formula (IX) with a suitable oxidising agent, for example meta-chloroperbenzoic acid, in a suitable solvent, for example EtOAc.

(IX)

Compounds of formula (III) wherein P is hydrogen may or a protecting group be prepared by reacting a compound of formula (X), wherein R^2a is as defined above, with a suitable halogenating reagent, for example methane sulfonyl chloride, in a suitable suitable solvent, for example dimethylformamide, and at elevated temperatures, for example 50- 7O⁰C.

(X)

Compounds of formula (X) may be prepared by reacting a compound of formula (Xl), wherein R^2a is as defined above, with a suitable oxidising agent, for example meta- chloroperbenzoic acid, in a suitable solvent, for example EtOAc.

(Xl)

Compounds of formula (Xl) may be prepared by reacting a compound of formula (XII) with a suitable strong base, for example butyl lithium, at low temperature, for example -4 to 0⁰C, in an inert solvent, for example THF, and subsequently reacting with a N, N- dimethylamide or N-methyl-N-methoxy (Weinreb) amide at low temperature, for example 0 to 1 O⁰C, followed by optional protection of the pyrrole nitrogen atom. The preparation of compounds of formula (Xl) may be completed by acidification with a strong mineral acid, for example hydrochloric acid, at low temperature, for example 0 to 5°C, followed by heating at an elevated temperature, for example 50 to 9O⁰C.

(XII)

Compounds of formula (1MB) can be prepared, for example, according to Scheme 1 below:

Scheme 1

Conditions a. (i) nBuLi / THF / , N-methoxy-N-methyltrifloroacetamide (ii) 5M HCI(_aq) b. MCPBA / EtOAc c. CH₃SO₂CI / DMF d. 4M HCI / dioxane then NaI / acetonitrile e. NaH / THF / then n-butyl-lithium / then triisopropylborate

Methods of Use

The compounds of the invention are inhibitors of IKK2. Compounds which are IKK2 inhibitors may be useful in the treatment of disorders wherein the underlying pathology is (at least in part) attributable to inappropriate IKK2 (also known as IKKβ) activity such as rheumatoid arthritis, COPD (chronic obstructive pulmonary disease), asthma and rhinitis. "Inappropriate IKK2 activity" refers to any IKK2 activity that deviates from the normal IKK2 activity expected in a particular patient. Inappropriate IKK2 activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of IKK2 activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation. Accordingly, in another aspect the invention is directed to methods of treating such disorders.

Such disorders include inflammatory and tissue repair disorders (including rheumatoid arthritis, inflammatory bowel disease, COPD (chronic obstructive pulmonary disease), asthma and rhinitis), fibrotic diseases, osteoarthritis, osteoporosis, dermatosis (including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage), autoimmune diseases (including Sjogren's syndrome, systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection), Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer (including Hodgkins disease), cachexia, inflammation associated with infection and certain viral infections (including acquired immune deficiency syndrome (AIDS)), adult respiratory distress syndrome, and Ataxia Telangiestasia.

The methods of treatment of the invention comprise administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. Individual embodiments of the invention include methods of treating any one of the above-mentioned disorders by administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

As used herein, "treat" in reference to a disorder means: (1 ) to ameliorate or prevent the disorder or one or more of the biological manifestations of the disorder, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the disorder or (b) one or more of the biological manifestations of the disorder, (3) to alleviate one or more of the symptoms or effects associated with the disorder, or (4) to slow the progression of the disorder or one or more of the biological manifestations of the disorder.

As indicated above, "treatment" of a disorder includes prevention of the disorder. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a disorder or biological manifestation thereof, or to delay the onset of such disorder or biological manifestation thereof. As used herein, "safe and effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the disorder being treated; the severity of the disorder being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.

As used herein, "patient" refers to a human (including adults and children) or other animal. In one embodiment, "patient" refers to a human.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration. Parenteral administration refers to routes of administration other than enteral or transdermal, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhaled and intranasal administration. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. In one embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered orally. In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered by inhalation. In a further embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered intranasally.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. In one embodiment, a dose is administered once per day. In a further embodiment, a dose is administered twice per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half- life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.001 mg to 50mg per kg of total body weight, for example from 1 mg to 10mg per kg of total body weight. For example, daily dosages for oral administration may be from 0.5mg to 2g per patient, such as 10mg to 1g per patient.

Additionally, the compounds of formula (I) may be administered as prodrugs. As used herein, a "prodrug" of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formula (I) in vivo. Administration of a compound of formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the activity of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleavable in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

The invention thus provides a method of treating a disorder mediated by inappropriate IKK2 activity comprising administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. In one embodiment, the disorder mediated by inappropriate IKK2 activity is selected from the group consisting of inflammatory and tissue repair disorders (including rheumatoid arthritis, inflammatory bowel disease, COPD (chronic obstructive pulmonary disease), asthma and rhinitis), fibrotic diseases, osteoarthritis, osteoporosis, dermatosis (including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage), autoimmune diseases (including Sjogren's syndrome, systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection), Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer (including Hodgkins disease), cachexia, inflammation associated with infection and certain viral infections (including acquired immune deficiency syndrome (AIDS)), adult respiratory distress syndrome, and Ataxia Telangiestasia.

In another embodiment, the disorder mediated by inappropriate IKK2 activity is an inflammatory or tissue repair disorder. In another embodiment, the disorder mediated by inappropriate IKK2 activity is rheumatoid arthritis, COPD, asthma or rhinitis. In another embodiment, the disorder mediated by inappropriate I KK2 activity is rheumatoid arthritis.

In another embodiment, the disorder mediated by inappropriate IKK2 activity is COPD. In another embodiment, the disorder mediated by inappropriate IKK2 activity is asthma. In a further embodiment, the disorder mediated by inappropriate IKK2 activity is rhinitis

(including seasonal rhinitis, allergic rhinitis and vasomotor rhinitis).

In another embodiment, the disorder mediated by inappropriate IKK2 activity is an autoimmune disease. In a further embodiment, the disorder mediated by inappropriate IKK2 activity is Sjogren's syndrome, systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, or alkylosing spondylitis.

In another embodiment, the disorder mediated by inappropriate IKK2 activity is selected from the group consisting of Alzheimer's disease, stroke atherosclerosis, restenosis, diabetes, glomerulonephritis, osteoarthritis, osteoporosis, and Ataxia Telangiestasia.

In another embodiment, the disorder mediated by inappropriate IKK2 activity is cancer or cachexia. In a further embodiment, the disorder mediated by inappropriate IKK2 activity is cancer. The term "rhinitis" is used herein to refer to all types of rhinitis including allergic rhinitis such as seasonal rhinitis (for example hayfever) or perennial rhinitis, and non-allergic rhinitis or vasomotor rhinitis.

The invention also provides a compound of formula (I) of a pharmaceutically acceptable salt thereof for use in medical therapy, particularly in the treatment of disorders mediated by IKK2 activity. Thus, in a further aspect, the invention is directed to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disorder characterized by inappropriate I KK2 activity.

Compositions

The compounds of formula (I) and pharmaceutically acceptable salts thereof will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically-acceptable excipients.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a compound of formula (I) or a pharmaceutically acceptable salt thereof. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically may contain, for example, from 0.5mg to 1g, or from 1 mg to 700mg, or from 5mg to 100mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the invention typically contain one compound of formula (I) or a pharmaceutically acceptable salt thereof.

As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of formula (I) or a pharmaceutically acceptable salt thereof when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be pharmaceutically- acceptable eg of sufficiently high purity.

The compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols, solutions, and dry powders; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of formula (I) or pharmaceutically acceptable salts thereof once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other excipients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect the invention is directed to process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically-acceptable excipients which comprises mixing the ingredients. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by, for example, admixture at ambient temperature and atmospheric pressure.

In one embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for oral administration. In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for inhaled administration. In a further embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for intranasal administration.

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

In another aspect, the invention is directed to a liquid oral dosage form. Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Syrups can be prepared by dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added. In another aspect, the invention is directed to a dosage form adapted for administration to a patient by inhalation. For example, as a dry powder, an aerosol, a suspension, or a solution composition.

Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as a finely divided powder together with one or more pharmaceutically-acceptable excipients as finely divided powders. Pharmaceutically-acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. The finely divided powder may be prepared by, for example, micronisation and milling. Generally, the size-reduced (eg micronised) compound can be defined by a D₅₀ value of about 1 to about 10 microns (for example as measured using laser diffraction).

The dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form. RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position. For example, the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.

Alternatively, the dry powder may be presented in capsules (e.g. gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament. When the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form. The blisters are typically arranged in regular fashion for ease of release of the medicament therefrom. For example, the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape. Each capsule, cartridge, or blister may, for example, contain between 20μg-10mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Aerosols may be formed by suspending or dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a liquified propellant. Suitable propellants include halocarbons, hydrocarbons, and other liquified gases. Representative propellants include: trichlorofluoromethane (propellant 1 1 ), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 1 14), tetrafluoroethane (HFA-134a), 1 ,1 - difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.

The aerosol may contain additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.

There is thus provided as a further aspect of the invention a pharmaceutical aerosol formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a cosolvent.

According to another aspect of the invention, there is provided a pharmaceutical aerosol formulation wherein the propellant is selected from 1 , 1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane and mixtures thereof.

The formulations of the invention may be buffered by the addition of suitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain from 20μg to 10mg of the compound of formula (I) or pharmaceutically acceptable salt thereof. Alternatively, the compound of formula (I) or pharmaceutically acceptable salt thereof may be presented without excipients such as lactose.

The proportion of the active compound of formula (I) or pharmaceutically acceptable salt thereof in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.001 to 10% by weight. Generally, for most types of preparations, the proportion used will be within the range of from 0.005 to 1 %, for example from 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will normally be within the range of from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered dose or "puff" of aerosol contains from 20μg to 10mg, preferably from 20μg to 2000μg, more preferably from about 20μg to 500μg of a compound of formula (I). Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time. The overall daily dose with an aerosol will be within the range from 100μg to 10mg, preferably from 200μg to 2000μg. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that delivered with aerosol formulations.

In the case of suspension aerosol formulations, the particle size of the particulate (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and in particular in the range of from 1 to 10 microns, such as from 1 to 5 microns, more preferably from 2 to 3 microns.

The formulations of the invention may be prepared by dispersal or dissolution of the medicament and a compound of formula (I) or a pharmaceutically acceptable salt thereof in the selected propellant in an appropriate container, for example, with the aid of sonication or a high-shear mixer. The process is desirably carried out under controlled humidity conditions.

The chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product. Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis. The stability of the suspension aerosol formulations according to the invention may be measured by conventional techniques, for example, by measuring flocculation size distribution using a back light scattering instrument or by measuring particle size distribution by cascade impaction or by the "twin impinger" analytical process. As used herein reference to the "twin impinger" assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A" as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated. One method used to calculate the "respirable fraction" is by reference to "fine particle fraction" which is the amount of active ingredient collected in the lower impingement chamber per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above.

The term "metered dose inhaler" or MDI means a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap. MDI system includes a suitable channelling device. Suitable channelling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.

MDI canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, aluminium or an alloy thereof which may optionally be anodised, lacquer-coated and/or plastic-coated (for example incorporated herein by reference WO96/32099 wherein part or all of the internal surfaces are coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers), which container is closed with a metering valve. The cap may be secured onto the can via ultrasonic welding, screw fitting or crimping. MDIs taught herein may be prepared by methods of the art (e.g. see Byron, above and WO96/32099). Preferably the canister is fitted with a cap assembly, wherein a drug-metering valve is situated in the cap, and said cap is crimped in place.

In one embodiment of the invention the metallic internal surface of the can is coated with a fluoropolymer, more preferably blended with a non-fluoropolymer. In another embodiment of the invention the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES). In a further embodiment of the invention the whole of the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES).

The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.

The gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and white butadiene- acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK357) and 3M-

TM

Neotechnic Ltd, UK (e.g. Spraymiser ).

In various embodiments, the MDIs may also be used in conjunction with other structures such as, without limitation, overwrap packages for storing and containing the MDIs, including those described in U.S. Patent Nos. 6,1 19,853; 6,179,1 18; 6,315,1 12; 6,352,152; 6,390,291 ; and 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431 ,168.

Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large-scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method for preparing suspension aerosol formulations a metering valve is crimped onto an aluminium can to form an empty canister. The particulate medicament is added to a charge vessel and liquefied propellant together with the optional excipients is pressure filled through the charge vessel into a manufacturing vessel. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister. In one example bulk manufacturing method for preparing solution aerosol formulations a metering valve is crimped onto an aluminium can to form an empty canister. The liquefied propellant together with the optional excipients and the dissolved medicament is pressure filled through the charge vessel into a manufacturing vessel.

In an alternative process, an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure the formulation does not vaporise, and then a metering valve crimped onto the canister. Typically, in batches prepared for pharmaceutical use, each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.

Suspensions and solutions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered to a patient via a nebulizer. The solvent or suspension agent utilized for nebulization may be any pharmaceutically-acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof. Saline solutions utilize salts which display little or no pharmacological activity after administration. Both organic salts, such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.

Other pharmaceutically-acceptable excipients may be added to the suspension or solution. The compound of formula (I) or pharmaceutically acceptable salt thereof may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid. These may be used alone or together to stabilize the compound of formula (I) or pharmaceutically acceptable salt thereof. Preservatives may be added such as benzalkonium chloride or benzoic acid and salts thereof. Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.

In a further aspect, the invention is directed to a dosage form adapted for intranasal administration.

Formulations for administration to the nose may include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable formulations contain water as the diluent or carrier for this purpose. Aqueous formulations for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated as a fluid formulation for delivery from a fluid dispenser, for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity. A fluid dispenser of the aforementioned type is described and illustrated in WO05/044354, the entire content of which is hereby incorporated herein by reference. The dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation. The housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing. In one embodiment, the fluid dispenser is of the general type illustrated in Figures 30-40 of WO05/044354.

Pharmaceutical compositions adapted for intranasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the patient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

Ointments, creams and gels, may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non- aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.

For treatments of the eye or other external tissues, for example mouth and skin, the compositions may be applied as a topical ointment or cream. When formulated in an ointment, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the compound of formula (I) or pharmaceutically acceptable salt thereof may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

The compound and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M₁ZM₂ZM₃ receptor antagonist), β₂-adrenoreceptor agonists, antiinfective agents, such as antibiotics or antivirals, or antihistamines. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent, such as a corticosteroid or an NSAID, an anticholinergic agent, a β₂-adrenoreceptor agonist, an antiinfective agent, such as an antibiotic or an antiviral, or an antihistamine. One embodiment of the invention encompasses combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β₂-adrenoreceptor agonist, and/or an anticholinergic, andZor a PDE-4 inhibitor, andZor an antihistamine.

One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents. Pharmaceutical compositions comprising an IKK2 inhibitor and a second active ingredient are disclosed for example in WO2008Z002246.

It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates to optimise the activity and/or stability andZor physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

In one embodiment, the invention encompasses a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β₂-adrenoreceptor agonist. Examples of β -adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer such as the f?-enantiomer), salbutamol (which may be a racemate or a single enantiomer such as the R-enantiomer), formoterol (which may be a racemate or a single duastereomer such as the R,R-diastereomer), salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1 -hydroxy-2- naphthalenecarboxylate) salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. In one embodiment, long-acting β₂-adrenoreceptor agonists, for example, compounds which provide effective bronchodilation for about 12 hrs or longer, are preferred.

Other β₂-adrenoreceptor agonists include those described in WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 and WO03/042160.

Examples of β₂-adrenoreceptor agonists include: 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) hexyl] oxy} butyl) benzenesulfonamide; 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl) phenyl] ethyl}-amino) heptyl] oxy} propyl) benzenesulfonamide;

4-{(1 R)-2-[(6-{2-[(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]-1-hydroxyethyl}-2-

(hydroxymethyl) phenol;

4-{(1 R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol;

N-[2-hyd roxyl-5-[( 1 R)- 1 -hyd roxy-2-[[2-4-[[(2 R)-2-hyd roxy-2- phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide;

N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1 /-/)- quinolinon-5-yl)ethylamine; and 5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1- hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one.

The β₂-adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.

Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids which may be used in combination with the compounds of formula (I) or pharmaceutically acceptable salts thereof are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α- methyl-17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β- hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6α,9α-difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, 6α,9α- difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethycyclopropylcarbonyl)oxy- androsta-1 ,4-diene-17β-carbothioic acid S-cyanomethyl ester and 6α,9α-difluoro-11 β- hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester, beclomethasone esters (for example the 17- propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (for example mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide (16α,17-[[(R)-cyclohexylmethylene]bis(oxy)]-1 1 β,21-dihydroxy-pregna-1 ,4- diene-3,20-dione), butixocort propionate, RPR-106541 , and ST- 126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-1 1 β-hydroxy-16α-methyl- 17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α- difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethycyclopropylcarbonyl)oxy- androsta-1 ,4-diene-17β-carbothioic acid S-cyanomethyl ester and 6α,9α-difluoro-11 β- hydroxy-16α-methyl-17α-(1-methycydopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester. In one embodiment the corticosteroid is 6α,9α- difluoro-17α-[(2-furanylcarbonyl)oxy]-1 1 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene- 17β-carbothioic acid S-fluoromethyl ester.

Examples of corticosteroids may include those described in WO2002/088167, WO2002/100879, WO2002/12265, WO2002/12266, WO2005/005451 , WO2005/005452, WO2006/072599 and WO2006/072600. Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patents: WO03/082827, WO98/54159, WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 and WO03/08277. Further non-steroidal compounds are covered in: WO2006/000401 , WO2006/000398 and WO2006/015870.

Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).

Examples of NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (for example montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (for example chemokine antagonists, such as a CCR3 antagonist) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors. An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration. Examples of iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875. Examples of CCR3 inhibitors include those disclosed in WO02/26722.

In one embodiment, the invention provides the use of the compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a formulation adapted for inhalation. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.

Compounds include c/s-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-ol]. Also, c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1-carboxylic acid (also known as cilomilast) and its salts, esters, pro-drugs or physical forms, which is described in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.

Other compounds include AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC lnt Syrmp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as Cl- 1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk- Gulden; Pumafentrine, (-)-p-[(4aR^*,10ιbS^*)-9-ethoxy-1 , 2,3,4,4a, 10b-hexahydro-8- methoxy-2-methylbenzo[c][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1 ): 162), and T2585.

Further compounds are disclosed in the published international patent application WO04/024728 (Glaxo Group Ltd), WO04/056823 (Glaxo Group Ltd) and WO04/103998 (Glaxo Group Ltd) (e.g. Example 399 or 544 disclosed therein). Further compounds are also disclosed in WO2005/058892, WO2005/090348, WO2005/090353, and WO2005/090354, all in the name of Glaxo Group Limited.

Examples of anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M₁ or M₃ receptors, dual antagonists of the M₁ZM₃ or M₂/M₃, receptors or pan-antagonists of the M₁ZM₂ZM₃ receptors. Exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286-75-0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva). Also of interest are revatropate (for example, as the hydrobromide, CAS 262586-79-8) and LAS- 34273 which is disclosed in WO01Z041 18. Exemplary compounds for oral administration include pirenzepine (CAS 28797-61 -7), darifenacin (CAS 133099-04-4, or CAS 133099- 07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51- 5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1 , or CAS 242478-38-2 for the succinate also known as YM-905 and sold under the name Vesicare).

Additional compounds are disclosed in WO 2005/037280, WO 2005/046586 and WO

2005/104745, incorporated herein by reference. The present combinations include, but are not limited to: (3-enQto)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane iodide;

(3-enαto)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide;

4-[hydroxy(diphenyl)methyl]-1 -{2-[(phenylmethyl)oxy]ethyl}-1 -azoniabicyclo[2.2.2]octane bromide; and (1 R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-[(phenylmethyl)oxy]ethyl}-8- azoniabicyclo[3.2.1]octane bromide.

Other anticholinergic agents include compounds which are disclosed in US patent application 60/487981 including, for example: (3-enc/o)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide;

(3-enc/o)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide;

(3-enc/o)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane A- methylbenzenesulfonate;

(3-enc/o)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octane bromide; and/or

(3-enc/o)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8-azoniabicyclo[3.2.1]octane bromide.

Further anticholinergic agents include compounds which are disclosed in US patent application 60/511009 including, for example:

(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;

3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;

(enc/o)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane; 3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1 ]oct-3-yl)-2,2-diphenyl-propionamide;

3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1 ]oct-3-yl)-2,2-diphenyl-propionic acid;

(enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide;

3-((encfo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;

/V-benzyl-3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;

(enc/o)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1 ]octane iodide;

1-benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1 ]oct-3-yl)-2,2-diphenyl-propyl]-urea;

1-ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;

Λ/-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;

Λ/-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzamide; 3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;

(enc/o)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;

/V-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- benzenesulfonamide; [3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;

Λ/-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- methanesulfonamide; and/or

{endo )-3-{2,2-diphenyl-3-[(1 -phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane bromide.

Further compounds include:

(endo )-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;

(enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide;

(enαfo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1 ]octane iodide;

(enc/o)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; and/or {endo )-3-{2, 2-diphenyl-3-[(1 -phenyl-methanoyl)-amino]-propyl}-8, 8-dimethyl-8-azonia- bicyclo[3.2.1]octane bromide.

In one embodiment the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an H1 antagonist. Examples of H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine, particularly cetirizine, levocetirizine, efletirizine and fexofenadine. In a further embodiment the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an H3 antagonist (and/or inverse agonist). Examples of H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416. Other histamine receptor antagonists which may be used in combination with the compounds of the present invention include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003).

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a non-steroidal GR agonist.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a β₂-adrenoreceptor agonist. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will readily be appreciated by those skilled in the art.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a non-steroidal GR agonist. The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a β_∑-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE4 inhibitor.

The invention will now be illustrated by way of the following non-limiting examples.

EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all temperatures are expressed in ⁰C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted. All references to ether are to diethyl ether; brine refers to a saturated aq. solution of NaCI.

¹H NMR spectra were recorded using a Bruker DPX 400MHz, referenced to tetramethylsilane. LC/MS was conducted using either Method A or Method B:

Method A: LC/MS (5 min system) was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solvent A) and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using the following elution gradient 0.0-0.7 min 0%B, 0.7-4.2 min 0-100%B, 4.2-4.6 min 100%B, 4.6-4.8 min 100-0%B at a flow rate of 3 ml/min. The mass spectra were recorded on a Waters ZQ Mass spectrometer using electrospray positive and negative mode (ES+ve and ES-ve)

Method B: LC/MS (2 min system) was conducted on a Acquity UPLC BEH C₁₈ column (5.0 cm x 2.1 mm) at 40⁰C, eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solvent A) and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using the following elution gradient 0.0-0.1 min 3%B, 0.1-1 .4 min 3-100%B, 1.4-1.9 min 100%B, 1.9-2 min 3%B at a flow rate of 1 ml/min. The mass spectra were recorded on a Waters ZQ Mass spectrometer using electrospray with positive / negative switching (ES+ve and ES-ve).

In the LCMS data reported herein, the mass ion was mathematically rounded to the nearest integer.

"Mass directed autoprep" / "MDAP" / "preparative mass directed HPLC" was conducted on a system such as; a Waters FractionLynx system comprising of a Waters 600 pump with extended pump heads, Waters 2700 autosampler, Waters 996 diode array and Gilson 202 fraction collector on a 10 cm 2.54 cm ID ABZ+ column, eluting with either 0.1% formic acid or TFA in water (solvent A) and 0.1 % formic or TFA in acetonitrile (solvent B) using the appropriate elution gradient. Mass spectra were recorded on Micromass ZMD mass spectrometer using electrospray positive and negative mode, alternate scans. The software used was MassLynx 3.5 with OpenLynx and FractionLynx optio or using equivalent alternative systems.

"Hydrophobic frits" refers to filtration tubes sold by Whatman. SPE (solid phase extraction, SCX-2 and aminopropyl) refers to the use of cartridges sold by International Sorbent Technology Ltd. The Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions. The system is equipped with a Knauer variable wavelength uv-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.

Silica chromatography techniques include either automated (Flashmaster) techniques or manual chromatography on pre-packed cartridges (SPE) or manually-packed flash columns.

Microwave chemistry was typically performed in sealed vessels, irradiating with a suitable microwave reactor system, such as a Biotage Initiator™ Microwave Synthesiser.

When the name of a commercial supplier is given after the name of a compound or a reagent, for instance "compound X (Aldrich)" or "compound X / Aldrich", this means that compound X is obtainable from a commercial supplier, such as the commercial supplier named. For example, 1 ,1 '-bis(diphenylphosphino) ferrocenedichloro palladium(ll), complex with dichloromethane may be purchased from Acros, and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran) and trifuoroacetic acid may be purchased from Aldrich. H cubes are commercially available from, for example, Asynt.

Similarly, when a literature or a patent reference is given after the name of a compound, for instance compound Y (EP 0 123 456), this means that the preparation of the compound is described in the named reference.

The names of the Examples have been obtained from the structures using the compound naming programme "ACD Name Pro 6.02".

Description 1 (D1) 2-(Trifluoromethyl)-1W-pyrrolo[2,3-b]pyridine

1 ,1-Dimethylethyl (3-methyl-2-pyridinyl)carbamate (Synthesis, 1996, 7, 877) (5.2g, 25mmol) was stirred in dry THF (60ml) and cooled in an ice bath (ice/salt) to -4°C. The mixture was treated with 2M-Bu lithium in cyclohexane (25ml, 50mmol) under nitrogen in a drop wise fashion over 45 mins while maintaining the temperature below 0⁰C. The red suspension was stirred for an hour at -3°C then treated with Λ/-methoxy-Λ/-methyl trifluoro acetamide (4.71 g, 30mmol). There was a temperature rise to 2O⁰C. The dark red solution was cooled to 2⁰C and then allowed to warm to 1 O⁰C over an hour. The dark orange solution was added to 5M HCI (55ml) over 30 mins at 3°C. The mixture was then heated at 60⁰C for an hour. The reaction was heated at 8O⁰C for a further hour. The phases were separated and the aq. phase was made alkaline with 10M sodium hydroxide. The mixture was extracted with EtOAc (2x50ml). The organic phase was dried then evaporated to give a pale orange solid which was filtered through silica (7Og) eluting with DCM to DCM: ether 9:1. The main fraction was evaporated to give the title compound as a pale yellow crystalline solid (2.66g, 57%). LC/MS (Method A): MH+187 seen at retention time 2.73 mins.

Description 2 (D2) 2-(Trifluoromethyl)-1W-pyrrolo[2,3-fc]pyridine 7-oxide

A stirred, cooled (0⁰C ice/salt) solution of 2-(trifluoromethyl)-1 H-pyrrolo[2,3-6]pyridine (D1 ) (1.86g, l Ommol) in EtOAc (35ml) was treated drop wise with a solution of m- chloroperoxybenzoic acid (2.78g, 12.2mmol) in EtOAc (35ml) over 30 mins. The reaction temperature was maintained below 5°C during the addition. The reaction was warmed to 1O⁰C over 2 hrs. The reaction was cooled to 0⁰C and treated with an additional portion of MCPBA (0.70Og, 4mmol) in EtOAc (10ml). The reaction was warmed to room temperature over 2 hrs. The solid precipitate was collected to give the title compound as a white solid (0.95Og, 47%). LC/MS (Method B): MH+ 202.9 seen at retention time 0.68 mins.

Description 3 (D3)

4-Chloro-2-(trifluoromethyl)-1 H-pyrrolo[2,3-fe]pyridine

2-(Trifluoromethyl)-1 H-pyrrolo[2,3-ό]pyridine 7-oxide (D2) (1.26g, 6.25mmol) was suspended in dimethylformamide (7.5ml) and heated to 50⁰C. The mixture was treated with methanesulfonyl chloride (2.5ml) drop wise. The solid went into solution on addition of the sulphonyl chloride and there was a temperature increase to 60⁰C. The reaction was heated at 70⁰C for 2 hrs and cooled to room temperature. The reaction was poured into water (50ml) and neutralised with 1 OM sodium hydroxide. The solid was collected and dried under air to give (1.24g). This material was triturated with hot aq. ethanol, collected and was dried in vacuo (50⁰C) to afford the title compound as a cream solid (1.1 g, 80%). LC/MS (Method A): MH+ 220.97 seen at retention time 3.22 mins.

Description 4 (D4) 4-lodo-2-(trifluoromethyl)-1W-pyrrolo[2,3-b]pyridine

To 4-chloro-2-(trifluoromethyl)-1H-pyrrolo[2,3-o]pyridine (D3) (23.92g, 0.108mole) dissolved in hot 1 ,4-dioxane (120ml, 5 volumes) was added 4M HCI in dioxane (30ml, 0.119mole, 1.1 eq). The resulting suspension was cooled to room temperature and the solid collected by filtration washing well with diethyl ether. The solid was then suspended in anhydrous acetonitrile (480ml, 20 volumes) and then sodium iodide (97.7g, 0.652mole, 6eq) was added. The mixture was then heated to 8O⁰C and maintained at that temperature overnight. It was then cooled to room temperature and 2M NaOH added till mixture was basic. The layers were then separated and the organic layer was washed with brine, dried over magnesium sulphate, filtered then concentrated in vacuo to a yield the title compound as a brown solid (9.98g, 29%). LC/MS (Method B): MH+ 313 seen at retention time 1.19 mins.

The magnesium sulfate was then suspended in ethyl acetate and the mixture heated to 65°C. The mixture was filtered and the filtrate concentrated in vacuo to yield a second crop of the title compound as a cream solid (15.8g, 47%). LC/MS (Method B): MH+ = 313 seen at retention time 1.19 mins.

Description 5 (D5)

[2-(Trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]boronic acid

H

To a degassed solution of 4-iodo-2-(trifluoromethyl)-1H-pyrrolo[2,3-6]pyridine (D4) (1.Og, 3.2mmol) in anhydrous tetrahydrofuran (2OmL) at 20°C was added sodium hydride as a

60% dispersion on mineral oil (160mg 4mmol) and stirred at 20⁰C for 75 min. The mixture was degassed and cooled to -78°C before addition of n-butyl-lithium 1.5M in hexanes

(4.91 mL, 7.36mmol) over 10 min. Reaction stirred at -78°C for 20 min. Triisopropylborate

(2.26mL, 9.6mmol) was added over 5 min. Reaction was warmed to 20⁰C over 1.5 h and water (2OmL) added. The aqueous was extracted with ethyl acetate. The aqueous was adjusted to pH = 7 (citric acid) and further extracted with ethyl acetate. The combined extracts were dried (hydrophobic frit) and concentrated in vacuo to a yellow solid. Purification by aminopropyl cartridge (1 Og, eluent 4M ammonia in methanol) gave the title compound as a pale yellow solid (343mg, 47%). LC/MS (Method B): MH+ 231 seen at retention time 0.76 mins.

Description 6 (D6) 4-bromo-W-(tetrahydro-2W-thiopyran-4-yl)benzenesulfonamide

To a stirred solution of tetrahydro-2/-/-thiopyran-4-amine (0.96 g, 8.2 mmol) and 4- bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in chloroform (25 ml_) at ambient temperature was added triethylamine (1.2 ml_, 8.6 mmol). After 2 h the reaction was washed sequentially with water (50 ml_), saturated aqueous sodium carbonate (5OmL), saturated aqueous citric acid (50 ml_), dried (hydrophobic frit) and concentrated in vacuo to furnish the title compound as a yellow solid. (2.26g, 86%) LC/MS (Method A): MH⁺ 336/338 seen at retention time 3.17 mins.

Description 7 4-bromo-W-(1-oxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (D7)

Silica gel (1.8g) was stirred vigorously and water (0.7 ml) added dropwise over 5 mins. The hydrated gel was then stirred for 10 mins. A solution of 4-bromo-Λ/-(tetrahydro-2/-/- thiopyran-4-yl)benzenesulfonamide (D6) (250 mg, 0.74 mmol) in dichloromethane (5 ml) was added to the reaction mixture. To this was added N-Bromosuccinimide (146 mg, 0.81 mmol) in dichloromethane (5 ml) dropwise and the reaction mixture stirred for 1.5 hrs. The reaction mixture was filtered and the cake washed with 10% methanol in dichloromethane (30 ml). The filtrate was collected and treated with 1 M aqueous sodium bicarbonate (40 ml) then water (40 ml), dried using a hydrophobic frit and concentrated in vacuo to afford the title compound as a colourless foam (130 mg, 50%).

LC/MS (Method A): MH⁺ 352/354 seen at retention time 2.14 mins.

Description 7a 4-bromo-/V-(1-oxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (D7)

In a 50 ml_ round bottom flask stirred silica gel (1 .8 g) was treated dropwise with Water (0.7 ml_) over 5 mins. Further stirring over 10 mins led to a free flowing solid. To this was added a solution of 4-bromo-Λ/-(tetrahydro-2/-/-thiopyran-4-yl)benzenesulfonamide (250 mg, 0.74 mmol) in Dichloromethane (5 ml_). To this was added a suspension of N- Bromosuccinimide (146 mg, 0.814 mmol) in Dichloromethane (5 ml_) dropwise over 10 mins. The reaction was stirred for 1.5 h. The reaction was filtered and the cake washed with 10% Methanol in Dichloromethane (30 ml_). The combined filtrate was washed with aqueous 1 M Sodium Bicarbonate (40 ml_), Water (40 ml), dried using a hydrophobic frit and concentrated in vacuo to give the title compound as colourless foam (218 mg, 84%) LC/MS (Method A): MH⁺ 352/354 seen at retention time 2.14 mins.

Description 8 (D8) 4-bromo-N-[1-(1,1 -dioxidotetrahydro-3-thienyl)ethyl]benzenesulfonamide

A mixture of [1 -(1 ,1-dioxidotetrahydro-3-thienyl)ethyl]amine (52 mg, 0.319 mmol), 4- bromobenzenesulfonyl chloride (81 mg, 0.317 mmol), triethylamine (0.088 ml_, 0.634 mmol) in anhydrous DCM (5 ml_) was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with DCM (10ml), washed with water (10ml) and evaporated in vacuo to give a colourless oil (1 10mg) which was dissolved in DCM (20ml), washed with 2M HCI (15ml) and the DCM extract evaporated in vacuo to give the title compound as a white foam. (86mg) LC/MS (Method A): MH+ 384 and MNH₄+ 401 seen at retention time 2.7 mins.

Description 9 (D9) 4-Bromo-2-methyl-1 -(phenylsulfonyl)-1W-pyrrolo[2,3-b]pyridine

To the solution of 4-bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-Jb]pyridine (9.4g, 28.0mmol) in dry THF (100ml) stirred at -35°C was added 2M LDA in heptane/THF/ethylbenzene (28.0ml, 56.0mmol) and the reaction was stirred at -35°C for 30 min. Methyl iodide (10.5ml, 168.0mmol) was added drop wise to the solution and the mixture was allowed to warm to room temperature over 2 hrs. The reaction was quenched with aqueous ammonium chloride solution (100ml) and extracted with AcOEt (3x60ml). The combined organic layers were dried (phase separator) and concentrated in vacuo. Purification was by FlashMaster on silica gel (2x70g) using AcOEt - cyclohexane (0-100% gradient) to give the title compound as a white solid (7.85g, 80%). LC/MS (Method A): MH+ 350.79/352.75 seen at retention time 3.45 mins.

Description 10 4-bromo-2-methyl-1W-pyrrolo[2,3-b]pyridine

To a solution of 4-bromo-2-methyl-1 -(phenylsulfonyl)-1 H-pyrrolo[2,3-5]pyridine (D9) (16 g, 0.045 mol) in 1 ,4 dioxane (320 mL) was added 2M aqueous sodium hydroxide (114 rmL, 0.228 mol).The reaction was heated to 6O⁰C for 16 h. The reaction was cooled to ambient temperature. The organic layer was separated and the aqueous extracted with ethylacetate. The combined organics were washed with brine and dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a cream solid (10.07 g, 104%) LC/MS (Method B): MH⁺ 21 1/213 seen at retention time 1.04 mins. Description 11 (2-methyl-1W-pyrrolo[2,3-b]pyridin-4-yl)boronic acid

H

To a stirred suspension of sodium hydride 60% dispersion on mineral oil (380 mg, 9.48 mmol) in tetrahydrofuran (8 ml_) at 0⁰C under nitrogen was added a solution of 4-bromo-2- methyl-1 H-pyrrolo[2,3-ό]pyridine (D10) (1.6 g, 7.58 mmol) in tetrahydrofuran (24 ml.) dropwise. The reaction was degassed and cooled to -78°C and to the reaction was added n-butyllithium 2.5M in hexanes (6 ml_, 14.96 mmol) dropwise. The reaction was stirred at - 78°C for 30 mins. To the reaction was added triisopropylborate (5.7 ml_, 22.74 mmol) and stirring at -78°C continued for 1 h. The reaction was allowed to warm to 0⁰C and was treated with water (50 ml_) the organic layer was separated and the aqueous extracted with ethylacetate (2 x 40 ml_) the combined organics were washed with 2M aqueous sodium hydroxide (50 ml_). The aqueous phases were combined and the pH adjusted to pH = 7 using 2M aqueous hydrochloric acid. The neutral aqueous was extracted with ethylacetate (2 x 50 ml_). The extracts were concentrated in vacuo to yield the title compound as a cream solid (550 mg, 41 %). LC/MS (Method A): MH⁺ = 177 seen at retention time 1.73 mins.

Description 12 (D12) [4-Bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-fo]pyridin-2-yl]methanol

To a solution of 4-bromo-2-methyl-1 -(phenylsulfonyl)-1 H-pyrrolo[2,3-Jb]pyridine (10.0g, 29.7mmol) in dry THF (150ml) at -40⁰C under nitrogen was added 2M LDA in heptane/THF/ethylbenzene (30.0ml, 60.0mmol) drop wise. The reaction was stirred -40⁰C for 30 min then cooled to -6O⁰C. Paraformaldehyde (7g, 23.3mmol) was added in one portion. After 3 hrs the reaction was cooled to -60⁰C and saturated ammonium chloride solution (100ml) was added to pH5-6. It was allowed to warm to room temperature and extracted with DCM (2x100ml). The combined extracts were washed with 2M hydrochloric acid, brine, dried (MgSO₄) and evaporated to give a brown oil (1 Og). Purification was by silica SPE cartridge (5Og) eluting with DCM to 90% DCM / AcOEt to give the title compound as a yellow foam (2.5g, 23%). LC/MS (Method B): MH+ 368.91 seen at retention time 1.03 mins.

Description 13 (D13) [4-Bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-fo]pyridin-2-yl]methyl methanesulfonate

To a solution of [4-bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-6]pyridin-2-yl]methanol (D12) (2.5g, 6.81 mmol) in dry DCM (30ml) at room temperature under nitrogen was added TEA (1.1 ml, δ.Ommol) followed by methanesulfonic anhydride (1.4g, 8.05mmol) in one portion. The reaction was left standing at room temperature over the weekend. DCM (50ml) was added and washed with 2M hydrochloric acid (50ml), brine (50ml), dried (MgSO₄) and evaporated to give the title compound as a brown foam (2.8g, 89%). 1H NMR (400MHz; CDCI₃) δ: 3.10 (3H₁ s), 5.72 (2H₁ s), 6.86 (1 H, s), 7.40 (1 H, d), 7.52 (2H, t), 7.61 (1 H, t), 8.27 (3H, m).

Description 14 (D14)

4-Bromo-1 -(phenylsulfonyl)-2-(1 H- 1 ,2,3-triazol-1 -ylmethyl)-1 H-pyrrolo[2,3-£>]pyridine

Triazole (1.15Og, 16.54mmol) in THF was added to a solution of potassium t-butoxide (1.Og, 9.1 mmol) in THF (total volume 50ml) at room temperature. After stirring for 30 mins [4-Bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-6]pyridin-2-yl]methyl methanesulfonate (D13) (3.68g, 8.27mmol) was added and left to stir for 2 hrs. The reaction mixture was poured onto aqueous sodium bicarbonate (100ml), organic layer was separated and the aqueous fraction was extracted with DCM (2 x 100ml). The combined organic fractions were passed through a phase separator and solvent removed under vacuum. Crude product was purified with a Flashmaster Si Il cartridge (10Og) in a gradient 0-100% EtOAc in cyclohexane over 40 minutes to afford the title compound as a pale yellow solid (1.48g). LC/MS (Method A): MH+ 419.82 seen at retention time 2.98 mins.

Description 15 (D15) 4-Bromo-2-(1W-1 ,2,3-triazol-1-ylmethyl)-1W-pyrrolo[2,3-b]pyridine

4-Bromo-1-(phenylsulfonyl)-2-(1 H-1 ,2,3-triazol-1-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine (D14)

(1.0g, 2.4mmol) was diluted in THF (15ml) and mixed with TBAF (1 M in THF) (3.1 ml, 3.1 mmol) and stirred at room temperature for 2 hrs. The reaction mixture was applied to a SCX cartridge (5Og) and eluted with MeOH followed by 2M ammonium in MeOH.

Appropriate fractions were combined and solvent was removed in vacuo to afford the title compound as yellow solid (0.76g).

LC/MS (Method B): M-H+ 275.67/277.67 seen at retention time 0.87 mins.

Example 1 (E1)

W-(tetrahydro-2H-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1W-pyrrolo[2,3-b]pyridin-4- yl]benzenesulfonamide

To solution of 4-bromo-/V-(tetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (D6) (70 mg, 0.21 mmol), [2-(trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (D5) (40 mg, 0.174 mmol)_and potassium phosphate (37mg, 0.174 mmol) in 5:1 Dioxane:water (2.4 ml.) was added 2'-(dimethylamino)-2-biphenyl-palladium(ll) chloride dinorbonylphosphine complex (14 mg, 0.02 mmol) and the reaction heated to 120⁰C for 30 mins (Biotage Initiator). The reaction was diluted with water (10 ml_) was extracted with 1 :1 Chloroform/Ethylacetate (2x20 ml_). The combined extracts were dried (hydrophobic frit) and concentrated in vacuo to a yellow solid. Purification by MDAP (open access) gave the title compound as a white solid (25mg, 32%).

LC/MS (Method A): MH⁺ 442 seen at retention time 3.36 mins.

Example 2 (E2)

N-(1 -oxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridin-4-yl]benzenesulfonamide Triflouroacetate salt

A solution of 4-bromo-Λ/-(1-oxidotetrahydro-2/-/-thiopyran-4-yl)benzenesulfonamide (D7) (130 mg, 0.37 mmol) [2-(trifluoromethyl)-1 H-pyrrolo[2,3-&]pyridin-4-yl]boronic acid (D5) (72 mg, 0.31 mmol), chloro(di-2-norbomylphosphino)(2'-dimethylamino-1 ,1 '-biphenyl-2-yl) palladium(ll) (17 mg, 0.03 mmol) and potassium phosphate (tribasic) (66 mg, 0.31 mmol) in dioxane:water (5:1 ) (5 ml) was heated at 12O⁰C in a microwave for 30 mins. The reaction mixture was treated with water (20 ml) and extracted with dichloromethane:methanol (9:1 ) (2x 20 ml), dried using a hydrophobic frit and concentrated in vacuo to afford a yellow oil. The oil was purified by MDAP and the fractions concentrated in a greenhouse affording the title compound as the Triflouroacetate salt as a white/cream solid (50 mg, 30%). LC/MS (Method A): MH⁺ 458 seen at retention time 2.74 mins.

Example 3 (E3)

/V-(1 -oxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1W-pyrrolo[2,3- fc>]pyridin-4-yl]benzenesulfonamide Formic Acid salt

A suspension of 4-bromo-Λ/-(1-oxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (D7) (46 mg, 0.13 mmol) [2-(trifluoromethyl)-1H-pyrrolo[2,3-6]pyridin-4-yl]boronic acid (D5) (25 mg, 0.1 1 mmol), chloro(di-2-norbornylphosphino)(2'-dimethylamino-1 ,1 '-biphenyl- 2-yl) palladium(ll) (8.7 mg, 0.01 mmol) and potassium phosphate (tribasic) (23 mg, 0.11 mmol) in dioxane:water (5:1 ) (1.5 ml) was heated at 12O⁰C in a microwave (Biotage Intitiator) for 30 mins. The reaction was diluted with Water (20 ml.) and extracted with 1 :1 Ethylacetate:Chloroform (10 ml_). The extract was dried using a hydrophobic frit and concentrated in vacuo to a yellow oil. Purification by MDAP (open access) (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water + 0.1% Formic acid, B: MeCN:Water 95:5 + 0.05% Formic acid), gave the title compound as a formate salt (10mg, 19%). LC/MS (Method A): MH⁺ 458 seen at retention time 2.76 mins.

Example 4 (E4)

/V-II-ti J-dioxidotetrahydro-S-thienyOethylJ^^-methyl-IH-pyrrolo^^-blpyridin^- yl)benzenesulfonamide

A mixture of (2-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (D11 ) (39 mg, 0.222 mmol), 4-bromo-N-[1-(1 ,1 -dioxidotetrahydro-3-thienyl)ethyl]benzenesulfonamide (D8) (86 mg, 0.225 mmol), potassium phosphate (144 mg, 0.678 mmol), chloro[2'- (dimethylamino)-2-biphenylyl]palladium - (1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (1 :1 ) (13mg, 0.023 mmol) in 1 ,4-Dioxane (1.8 ml_) and water (0.45 ml_) was heated in a sealed tube in a Biotage Initiator microwave using initial very high absorption to 120 ⁰C for 30 min. After cooling the reaction mixture was purified by SPE on reverse phase (C18, 5g) eluting with water then 10%TFA/acetonitrile. The 10%TFA/acetonitrile fractions were evaporated in vacuo and then the sample was dissolved in DMSO (2x 1 ml) and purified by MDAP. The solvent was evaporated in vacuo to give the title compound (28 mg) as a yellow solid. LC/MS (Method A): MH+ 434 seen at retention time 2.77 mins. Example 5 (E5)

4-(2-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-N-(1 -oxidotetrahydro-2H-thiopyran-4- yl)benzenesulfonamide trifluoroacetate

A solution of tetrahydro-2H-thiopyran-4-amine 1-oxide (80mg, O.θmmol) in dry DMF (0.5mL) was treated with triethylamine (200μL) and a solution of 4,4,5,5-tetramethyl-2-(4- {[(pentafluorophenyl)methyl]sulfonyl}phenyl)-1 ,3,2-dioxaborolane (67.5mg, 0.15mmol) (described as Intermediate 2 in WO2007/076230) in dry DMF (0.5ml_). The reaction mixture was heated at 12O⁰C in the microwave for 10 minutes prior to concentration in vacuo. The reaction mixture was resuspended in 1 :1 CH₃ChMeOH (1 mL) and applied to an SCX cartridge (1g, pre-equilibrated with 1 :1 CH₃CI:MeOH) and the title compound eluted with 1 :1 CH₃ChMeOH. The resultant material was suspended in 5:1 Dioxan:Water (2m L). 1 mL of this solution was dispensed into a microwave vessel and was treated with a solution of potassium phosphate (21 mg, O.i mmol) in water (100μl), 2'(dimethylamino)-2- biphenyl-palladium Il chloride dinorbornylphosphine complex (0.25mg, 0.5 mol%) and a solution of 4-bromo-2-methyl-1/-/-pyrrolo[2,3-6]pyridine (D10) (19mg, 0.09mmol) in dioxan (0.5m L). The reaction mixture was heated at 13O⁰C in the microwave for 30 minutes. The reaction mixture was applied directly to a C18 cartridge (500mg) and eluted with 0.1 % TFA in acetonitrile (3 x 1 mL). Concentration by blow down followed by purification by mass directed HPLC gave the title compound.

LC/MS (Method A): MH⁺ 519 seen at retention time 2.49 mins.

Example 6 (E6)

N-(1 -oxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(1 H-1 ,2,3-tιϊazoM -yl methyl )-1 H- pyrrolo[2,3-b]pyridin-4-yl]benzenesulfonamide

A solution of tetrahydro-2H-thiopyran-4-amine 1-oxide (80mg, O.θmmol) in dry DMF (0.5m L) was treated with triethylamine (200μL) and a solution of 4,4,5,5-tetramethyl-2-(4- {[(pentafluorophenyl)methyl]sulfonyl}phenyl)-1 ,3,2-dioxaborolane (67.5mg, 0.15mmol) (described as Intermediate 2 in WO2007/076230) in dry DMF (0.5ml_). The reaction mixture was heated at 12O⁰C in the microwave for 10 minutes prior to concentration in vacuo. The reaction mixture was resuspended in 1 :1 CH₃CI:MeOH (1 mL) and applied to an SCX cartridge (1g, pre-equilibrated with 1 :1 CH₃CI:MeOH) and the title compound eluted with 1 :1 CH₃CkMeOH.

The resultant material was suspended in 5:1 Dioxan:Water (2mL). 0.5mL of this solution was dispensed into a microwave vessel and was treated with a solution of potassium phosphate (21 mg, O.i mmol) in water (1 OOμl), 2'(dimethylamino)-2-biphenyl-palladium Il chloride dinorbornylphosphine complex (0.25mg, 0.5 mol%) and a solution of 4-Bromo-2- (1 H-1 ,2,3-triazol-1-ylmethyl)-1 H-pyrrolo[2,3-ό]pyridine (D15) (21 mg, O.i mmol) in dioxan (0.5mL) was added. The reaction mixture was heated at 13O⁰C^* in the microwave for 30 minutes. The reaction mixture was applied directly to a C18 cartridge (500mg) and eluted with 0.1 % TFA in acetonitrile (3 x 1 mL). Concentration by blow down followed by purification by mass directed HPLC gave the title compound. LC/MS (Method A): MH⁺ 472 seen at retention time 2.4 mins.

BIOLOGICAL DATA

1. In Vitro Data IKK2 Assay

Recombinant human IKKβ (residues 5-756) was expressed in baculovirus as a C-terminal GST-tagged fusion protein, and its activity was assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Briefly, IKKβ (0.5 - 4 nM final concentration) diluted in assay buffer (50 mM HEPES, 10 mM MgC^, 1 mM CHAPS pH 7.4 with 1 mM DTT and 0.01 % w/v BSA) was added to wells containing various concentrations of compound or DMSO vehicle (1.7% v/v final). The reaction was initiated by the addition of GST-lkappaBalpha substrate (25 nM final)/ATP (1 μM final), in a total volume of 6 μl. The reaction was incubated for 15 mins at room temperature, then terminated by the addition of 3 μl of 50 mM EDTA in buffer (100 mM HEPES pH 7.4, 150 mM NaCI and 0.1 % w/v BSA) containing antiphosphoserine-lkappaBalpha-32/36 monoclonal antibody clone 12C2 (Cell Signalling Technology, Beverly Massachusetts, USA) labelled with W-1024 europium chelate (Wallac OY, Turku, Finland), and an APC- labelled anti-GST antibody (Prozyme, San Leandro, California, USA). The reaction was further incubated for 60 mins at room temperature and the degree of phosphorylation of GST-lkappaBalpha measured using a Rubystar plate reader (BMG Instruments, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.

Human Peripheral Blood Mononuclear Cell Assay and Human Whole Blood Assay

Human Peripheral Blood Mononuclear Cell Assay

The cellular potency of compounds is assessed in human peripheral blood mononuclear cells (PBMC) by measuring their impact on lipopolysaccharide (LPS) stimulated TNFa production. PBMCs are prepared from heparinised human blood from normal volunteers by centrifugation on hystopaque in Accuspin tubes at 800 g for 20 minutes. The cells are collected from the interface, washed by centrifugation (130Og, 10 minutes) and resuspended in assay buffer (RPMI 1640 containing 10% foetal calf serum, 1% L-glutamine and 1 % penicillin/streptomycin) at 1 x10⁶ cells/ml. 50 μl cells are added to microtitre wells containing 1.0 μl of an appropriately diluted compound solution which has been solvated and diluted in DMSO. 75 μl LPS (s.typhosa Sigma Cat L6386, 1 ng/ml final) is added and the samples are incubated at 37 ⁰C, 5% CO₂ for 20 hours. The supernatant is removed and the concentrations of TNF are determined by electrochemiluminescence assay using the MSD technology.

Human Whole Blood Assay Heparinised blood drawn from normal volunteers is dispensed (100 μl) into microtitre plate wells containing 1.0 μl of an appropriately diluted compound solution in DMSO. After 1 hr incubation at 37 ⁰C, 5% CO₂, 25 μl LPS solution (S. typhosa) in RPMI 1640 (containing 1% L-glutamine and 1 % Penicillin/ streptomycin) is added (50 ng/ml final). The samples are incubated at 37 ⁰C, 5% CO₂ for 20 hours, 50 μls physiological saline (0.138% NaCI) is added and diluted plasma is collected using a Biomek FX liquid handling robot after centrifugation at 1300 g for 10 min. Plasma TNFα content is determined by electrochemiluminescence assay using the Mesoscale (MSD) technology.

TNFα Assay associated with PBMC and Whole Blood Assays 20 μl supernatant from PBMC plates or 40 μl from whole blood plates is transferred using the Biomek FX to a 96 well High-Bind MSD assay plate precoated with anti-hTNF alpha capture antibody and containing 25 μl of MSD human serum cytokine assay diluent. Each plate also contains a TNFα standard curve (0-5000 pg/ml: R+D Systems, 210-TA). For the Whole blood assay, plates are sealed and shaken for 2 hours at room temperature after which they are washed and 40 μl of MSD detection antibody is added. The plates are shaken at room temperature for a further 1 hour before washing again and adding 150μl of MSD Read Buffer T (2X). Plates are then read on the MSD Sector 6000 plate reader. For the PBMC assay, supernatant addition to the MSD plates is followed immediately by 20 μl of MSD detection antibody, the plates are then sealed and shaken for 2 hours before addition of 90 μl of MSD Read Buffer P (2.5X). Plates are read on the MSD Sector 6000.

TNF concentrations are derived from the standard curve run on the same plate and plC50 values for inhibition of TNF production are derived from the compound dose response curves with non-linear least squares curve fitting using Activity base software.

NFkB Reporter Assay

A 70% confluent T225 flask of A549 SPAP cells are harvested by centrifugation for 5 min at 200 g, resuspended in assay buffer (DMEM supplemented with 10% FCS 2xHI, 2mM L- Glutamine,1 % Pen/Strep and Non essential amino acids) and diluted to 0.16 x 10⁶/ml. 60 μl of cell solution is dispensed to each well of clear Nunc 384-well plates, containing 0.5 μl compound in neat DMSO at 14Ox the required final assay concentration. Plates are incubated for 1 h at 37 ⁰C, 95% humidity, 5% CO₂ before 10 ml of TNF solution in assay buffer is added to give a final concentration of 3.2 ng/ml and is then returned to the cell incubator for 15 h. Plates are equilibrated to room temperature for 1 h prior to the addition of 25 μl of pNPP buffer (1 M Diethanolamine pH 9.8, 0.5mM MgCI₂, 0.28M NaCI, 2 mg/ml pNPP) to each well of assay plates. The plates are covered to protect the reagents from light, and then incubated at room temperature for approximately 1 hour before reading them on an Ascent using a 405 nm single filter.

All data is normalized to the mean of 16 high and 16 low control wells on each plate. A four parameter curve fit of the following form is then applied

2. In Vivo Testing

Intranasals dosed LPS induced neutrophilia in the male CD rat

Compound/Vehicle Pretreatment

Male CD rats (150-25Og) are anaesthetised with isoflurane (5%, 2 L/min O₂, 1 L/min NO) and are held vertically whilst being dosed with test compound or vehicle (0.2% Tween 80 in phosphate buffered saline or in a vehicle comprising an aqueous solution of 5% dextrose, 1.5% Avicel RC591 , 0.15% EDTA, 0.025% polysorbate 80, 0.015% benzalkonium chloride) at a dose volume of 25 μl per nostril, using a 100 μl Gilson pipette. The tip of the pipette is inserted approximately 3 mm into the nostril and the dosing substance is instilled. After dosing, animals are placed in a supine position during recovery from anaesthesia.

LPS Challenge Protocol

Approximately thirty minutes following dosing of compound or vehicle the rats are re- anaesthetised as above then dosed in the same manner with 25 μl/nostril of either phosphate buffered saline vehicle, (PBS) or 10 mg/ml lipopolysaccharide (LPS).

Nasal Lavage Protocol

Four hours following the PBS/LPS challenge the animals are culled with an overdose of sodium pentobarbitone given intra peritoneally. The trachea is exposed and a small incision made, into which a tube is inserted orthograde towards the nasal cavity. The nose is then washed with 15 mis of heparinised (10U/ml) PBS. Cell Counts

The NALF samples are centrifuged at 1300 rpm for 7 minutes. The supernatant is removed and the resulting cell pellet is resuspended in 0.5 ml PBS. A cell slide of the resuspension fluid is prepared by placing 75 μl of resuspended NAL fluid into cytospin holders and then spinning at 500 rpm for 5 minutes. The slides are allowed to air dry and then stained with Leishmans stain (20 minutes) to allow differential cell counting. The total cells are also counted from the resuspension using a Sysmex counter. From these two counts, the total numbers of neutrophils in the NALF are determined.

LPS-induced TNFα Production in Rats

Male Lewis rats (180-20Og) from Charles River Breeding Laboratories (Portage) ACUC Protocol# 05051 are pretreated orally with compound or vehicle. After a determined pretreatment time, the rats are given LPS (lipopolysaccharide from Escherichia coli Serotype 055-B5, Sigma Chemical Co., St Louis, MO) 30 μg/rat in 0.5 ml saline, intraperitoneal^. The rats are euthanized by CO₂ inhalation 90 minutes after the LPS injection and blood samples are collected by cardiac puncture, transferred into heparinized tubes and stored on ice. The blood samples are centrifuged at 2000 rpm for 10 minutes and the plasma collected for analysis by specific ELISA for TNFα levels.

The plasma samples are assayed for TNFα according to manufactures specifications. TNFα levels are expressed as pg/ml. Elisa kits are purchased from R&D Systems Inc. (Rat TNFα Quantikine Kit Catalog* RTAOO).

Results

The compounds of Examples 1-4 and 6 were tested for activity against IKK2 in the IKK2 assay and were found to be inhibitors of IKK2 with plC₅₀ potency of 5.0 or greater.

Preferred compounds have plC50 >6 in the human peripheral blood mononuclear cell assay.

Preferred compounds have plC50 >5 in the human whole blood assay.

Preferred compounds have plC50 >6 in the NFkB reporter assay.

Claims

What is claimed is:

1. A compound according to formula (I):

(I)

wherein

RMs -CHR⁶R', -CHF₂, -CF₃ or -C(CH₃)₃;

R³ is hydrogen or methyl;

R⁶ is hydrogen and R⁷ is hydrogen, C_1-6alkyl, -(CH₂)_dOR¹⁰, -NR¹¹R¹², -CO₂C,.₆alkyl, - CONR¹³R¹⁴, phenyl, or 5-membered heteroaryl containing from one to four nitrogen atoms wherein the heteroaryl is optionally substituted by one or two substituents independently selected from d.₆alkyl, -COCi_-5alkyl, -(CH₂)_Θphenyl and thienyl, R⁶ is methyl and R⁷ is methyl or hydroxyl, or

R⁶ and R⁷ are linked to form Cs-ecycloalkyl optionally substituted by methyl;

R¹⁰ is hydrogen, phenyl optionally substituted by -(CH₂)_fCO₂R¹⁵, or pyridyl optionally substituted by one or two substituents independently selected from chlorine and Ci-salkyl;

R¹¹ is hydrogen and R¹² is hydrogen, d-βalkyl optionally substituted by hydroxyl,

-(CH₂)_gNR^1bR¹⁷, -(CH₂)_hNCOC_1-6alkyl, -(CH₂),C₃.₆cycloalkyl, -(CH^phenyl, -(CH₂)_kPyιϊdyl, or -(CH₂)_mheterocyclyl wherein the heterocyclyl is optionally substituted by

Ci_-6alkyl,

R¹¹ is Ci_-Salkyl and R¹² is Ci_-6alkyl optionally substituted by hydroxyl or -SO₂phenyl,

R¹¹ and R¹² are linked to form a 6-membered heterocyclyl optionally containing one further nitrogen or an oxygen wherein the heterocyclyl is optionally substituted by -CO₂C-ι.6alkyl or piperidinyl, or

R¹¹ and R¹² are linked to form

R¹³ is hydrogen and R¹⁴ is hydrogen, d_-6alkyl, -(CH₂)_nOR¹⁸, -(CH₂)_PNR¹⁹R²⁰, -

(CH₂)_qCO₂R²¹ , -(CH₂)_rSO₂NH₂, C₃.₆cycloalkyl, or phenyl optionally substituted by chlorine or -OCi_-6alkyl,

R¹³ and R¹⁴ are each independently Ci_₆alkyl, or

R¹³ and R¹⁴ are linked to form pyrrolidinyl;

R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently hydrogen or C_1-6alkyl;

a, b and c are each independently selected from 0 or 1 ;

d, e, f, i, j, k and m are each independently an integer selected from 0 to 4;

g, h, n, p, q and r are each independently an integer selected from 1 to 4;

X is S or SO;

Y and Y¹ are each independently selected from S, SO or SO₂; and

Z is alkylene;

and salts thereof.

2. A compound according to claim 1 wherein R² is -CHR⁶R⁷ , -CF₃ or -C(CH₃)₃.

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

4. A compound according to any one of the preceding claims wherein R is

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

6. A compound according to any one of the preceding claims wherein R^s is hydrogen and R⁷ is hydrogen, -CO₂Ci_-6alkyl, or 5-membered heteroaryl containing from one to four nitrogen atoms wherein the heteroaryl is optionally substituted by one or two substituents independently selected from C_1-6alkyl, -COC_1-6alkyl, -(CH₂)_ephenyl and thienyl, or R⁶ and R⁷ are linked to form C₃_₆cycloalkyl.

7. A compound according to claim 6 wherein R⁶ is hydrogen and R⁷ is hydrogen or 1 H-1 ,2,3-triazol-1-yl.

8. A compound substantially as described in any one of Examples 1 to 6, or a salt thereof.

9. A compound which is:

/V-(tetrahydro-2H-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1 /-/-pyrrolo[2,3-6]pyridin-4- yl]benzenesulfonamide;

N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridin-4- yl]benzenesulfonamide; Λ/-(1-oxidotetrahydro-2/-/-thiopyran-4-yl)-4-[2-(trifluoromethyl)-1 H-pyrrolo[2,3-ιb]pyridin-4- yl]benzenesulfonamide;

Λ/-[1-(1 ,1-dioxidotetrahydro-3-thienyl)ethyl]-4-(2-methyl-1 H-pyrrolo[2,3-ό]pyridin-4- yl)benzenesulfonamide;

4-(2-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-N-(1-oxidotetrahydro-2H-thiopyran-4- yl)benzenesulfonamide; or

N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-4-[2-(1 H-1 ,2,3-triazol-1-ylmethyl)-1 H-pyrrolo[2,3- b]pyridin-4-yl]benzenesulfonamide, or a salt thereof.

10. A compound according to any one of claims 1 to 9 in the form of a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

12. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in medical therapy

13. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of disorders mediated by inappropriate I KK2 activity.

14. Use of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate IKK2 activity.

15. A method of treating a disorder mediated by inappropriate IKK2 activity comprising administering a safe and effective amount of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

16. A method according to claim 15 wherein the disorder mediated by inappropriate IKK2 activity is selected from selected from the group consisting of:

- inflammatory and tissue repair disorders, fibrotic diseases, osteoarthritis, osteoporosis, dermatosis, autoimmune diseases, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer (including Hodgkins disease), cachexia, inflammation associated with infection and certain viral infections (including acquired immune deficiency syndrome (AIDS)), adult respiratory distress syndrome, and Ataxia Telangiestasia; or

- rheumatoid arthritis, inflammatory bowel disease, COPD (chronic obstructive pulmonary disease), asthma, rhinitis, fibrotic diseases, osteoarthritis, osteoporosis, psoriasis, atopic dermatitis, ultraviolet radiation (UV)-induced skin damage, Sjogren's syndrome, systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue rejection, and organ rejection.

17. A method according to claim 16 wherein the autoimmune disease is Sjogren's syndrome, systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, or alkylosing spondylitis.

18. A method according to claim 16 wherein the disorder mediated by inappropriate I KK2 activity is rheumatoid arthritis, COPD, asthma or rhinitis.

19. A process for preparing a compound as claimed in any one of claims 1 to 9, or a salt thereof, comprising reacting a compound of formula (HA) or (NB)

H

H

(HA)

(HB) wherein R¹ is SO₂NR³R⁴ as defined above or a group convertible to SO₂NR³R⁴, with a compound of formula (INA)

wherein P is hydrogen or a protecting group, R^2a is R² as defined in claim 1 or a group convertible to R², and X is halogen, in the presence of a catalyst.

20. A process for preparing a compound as claimed in any one of claims 1 to 9, or a salt thereof, comprising reacting a compound of formula (HC)

wherein R¹ is SO₂NR³R⁴ as defined in claim 1 or a group convertible to SO₂NR³R⁴, and Y is chlorine, bromine, iodine or triflate, with a compound of formula (NIB) or (NIC)

(MIB) (NIC)

wherein P is hydrogen or a protecting group and R^2a is R² as defined in claim 1 or a group convertible to R², in the presence of a catalyst.