WO2009007747A2

WO2009007747A2 - Hydantoin derivatives used as mmp12 inhibitors

Info

Publication number: WO2009007747A2
Application number: PCT/GB2008/050545
Authority: WO
Inventors: Balint Gabos; Magnus Munck af Rosenschöld; Lena Ripa
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2007-07-11
Filing date: 2008-07-08
Publication date: 2009-01-15
Also published as: WO2009007747A3

Abstract

The invention provides novel hydantoin derivatives; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use as MMP12 inhibitors.

Description

NOVEL COMPOUNDS

The present invention relates to novel hydantoin derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N. M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMPs) such as the collagenases (MMPl, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMPlO, MMPl 1), matrilysin (MMP7), metalloelastase (MMP 12), enamelysin (MMP 19), the MT-MMPs (MMP 14, MMP 15, MMP 16, MMP 17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAMlO and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.

Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al, (1997) Biochem. J. 321:265-279).

Metalloproteinases have been associated with many diseases or conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these diseases or conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer's disease; extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis; asthma; rhinitis; and chronic obstructive pulmonary diseases (COPD).

MMP 12, also known as macrophage elastase or metalloelastase, was initially cloned in the mouse by Shapiro et al [1992, Journal of Biological Chemistry 267: 4664] and in man by the same group in 1995. MMP 12 is preferentially expressed in activated macrophages, and has been shown to be secreted from alveolar macrophages from smokers [Shapiro et al, 1993, Journal of Biological Chemistry, 268: 23824] as well as in foam cells in atherosclerotic lesions [Matsumoto et al, 1998, Am. J. Pathol. 153: 109]. A mouse model of COPD is based on challenge of mice with cigarette smoke for six months, two cigarettes a day six days a week. Wild-type mice developed pulmonary emphysema after this treatment. When MMP 12 knock-out mice were tested in this model they developed no significant emphysema, strongly indicating that MMP 12 is a key enzyme in the COPD pathogenesis. The role of MMPs such as MMP 12 in COPD (emphysema and bronchitis) is discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1(1): 29-38. It was recently discovered that smoking increases macrophage infiltration and macrophage-derived MMP- 12 expression in human carotid artery plaques Kangavari [Matetzky S, Fishbein MC et al., Circulation 102:08). 36-39 Suppl. S, Oct 31, 2000].

A number of metalloproteinase inhibitors are known (see for example the reviews of MMP inhibitors by Beckett R.P. and Whittaker M., 1998, Exp. Opin. Ther. Patents, 8(3):259-282. and by Whittaker M. et al, 1999, Chemical Reviews 99(9):2735-2776). WO 02/074767 discloses hydantoin derivatives of formula

that are useful as MMP inhibitors. Further hydantoin derivatives are disclosed in WO 2006/004532 and WO 2006/004533.

We now disclose a group of compounds that are inhibitors of metalloproteinases and are of particular interest in being potent and selective inhibitors of MMP 12. The compounds of the present invention have beneficial potency, selectivity and/or pharmacokinetic properties.

Thus in one aspect we disclose a compound selected from:

(55)-5-methyl-5-({[4-{[l-(methylsulfonyl)-2,3-dihydro-7H-indol-4-yl]ethynyl}-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

N-(3-chloro-5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-7V-methylformamide;

N-ethyl-N-(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide;

Λ/-cyclopropyl-Λ/-(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)- l,2,3,6-tetrahydropyridin-4-yl]ethynyl}phenyl)formamide;

(5S)-5 -( { [4- { [2-(dimethylamino)pyridin-4-yl] ethynyl} -3 ,6-dihydropyridin- 1 (2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-({[4-{[3-fluoro-5-(2-oxopyrrolidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-({[4-{[3-fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; (55)-5-methyl-5-({[4-{[3-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; methyl(3- { [ 1 -( { [(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3 ,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide; 4-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}indoline-l-carbaldehyde;

(5S)-5 -methyl-5 -( { [4- { [3 -(2-oxopyrrolidin- 1 -yl)phenyl] ethynyl} -3 ,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

1 -(3- { [ 1 -( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)cyclopropanecarbonitrile;

2-methoxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile;

2-hydroxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile; (5 S)-5 -methyl-5 -({[4-(quinolin-5-ylethynyl)-3,6-dihydropyridin- 1(2H)- yl]sulfonyl}methyl)imidazolidine-2,4-dione;

(55)-5-({[4-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-5-yl)ethynyl]-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl} -3 ,4-dihydroisoquinoline-2( l//)-carbaldehyde;

(55)-5-methyl-5-({[4-{[2-(methylsulfonyl)-l,2,3,4-tetrahydroisoquinolin-5-yl]ethynyl}-

3,6-dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

(55)-5 -methyl-5 -({[4- [(2 -methyl- l-oxo-l,2,3,4-tetrahydroisoquinolin-5-yl)ethynyl]-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; N-(3-fluoro-5-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-Λ/-methylformamide;

(5S)-5 -({ [4-(cyclohexylethynyl)-3 ,6-dihydropyridin- 1 (2H)-yl] sulfonyl} methyl)-5 - methylimidazolidine-2,4-dione;

tetrahydropyridin-4-yl]ethynyl}phenyl)methanesulfonamide;

5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}-3,4-dihydroquinoline-l(2H)-carbaldehyde; (5S)-5 -methyl-5 -( { [4- { [ 1 -(methylsulfonyl)- lH-indol-4-yl] ethynyl} -3 ,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

(55)-5-({[4-{[3-(3,3-dimethyl-2-oxoazetidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin- 1 (2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; and 5 -methyl-5 - [4-(tetrahydro-thiopyran-4-ylethynyl)-3 ,6-dihydro-2H-pyridine- 1 - sulfonylmethyl]-imidazolidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

The disclosed compounds may exist in enantiomeric forms. It is to be understood that all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.

The disclosed compounds above may also exist in various tautomeric forms. All possible tautomeric forms and mixtures thereof are included within the scope of the invention.

In one embodiment, we disclose a compound selected from:

(55)-5-({[4-{[3-fluoro-5-(2-oxopyrrolidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; (55)-5-({[4-{[3-fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-methyl-5-({[4-{[3-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; methyl(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide;

⁴-{[¹-({[(45)-4-^methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}indoline-l-carbaldehyde; (55)-5 -methyl-5 -( { [4- { [3 -(2-oxopyrrolidin- 1 -yl)phenyl] ethynyl} -3 ,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

(55)-5-({[4-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-5-yl)ethynyl]-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; 5 5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl} -3 ,4-dihydroisoquinoline-2( lH)-carbaldehyde;

(55)-5-methyl-5-({[4-[(2-methyl-l-oxo-l,2,3,4-tetrahydroisoquinolin-5-yl)ethynyl]-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

N-(3-fluoro-5-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- i o tetrahydropyridin-4-yl] ethynyl} phenyl)-7V-methylformamide;

5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}-3,4-dihydroquinoline-l(2H)-carbaldehyde; and

(55)-5-({[4-{[3-(3,3-dimethyl-2-oxoazetidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; is or a pharmaceutically acceptable salt thereof.

In one embodiment, we disclose a compound selected from:

(55)-5-methyl-5-({[4-{[l-(methylsulfonyl)-2,3-dihydro-7H-indol-4-yl]ethynyl}-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; 20 N-(3-chloro-5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-Λ/-methylformamide;

(5S)-5 -( { [4- { [2-(dimethylamino)pyridin-4-yl] ethynyl} -3 ,6-dihydropyridin- 1 (2H)- 25 yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-({[4-{[3-fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; 30 methyl(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide; 1 -(3- { [ 1 -( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)cyclopropanecarbonitrile;

2-methoxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile; 5 (5S)-5-methyl-5-({[4-(quinolin-5-ylethynyl)-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)imidazolidine-2,4-dione;

5-{[l<{[(45)^-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl} -3 ,4-dihydroisoquinoline-2( l//)-carbaldehyde;

(55)-5 -({ [4-(cyclohexylethynyl)-3 ,6-dihydropyridin- 1 (2H)-yl] sulfonyl} methyl)-5 - methylimidazolidine-2,4-dione; is or a pharmaceutically acceptable salt thereof.

In one embodiment, we disclose a compound selected from:

(55)-5-methyl-5-({[4-{[l-(methylsulfonyl)-2,3-dihydro-7H-indol-4-yl]ethynyl}-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; 20 (55)-5-({[4-{[2-(dimethylamino)pyridin-4-yl]ethynyl}-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-({[4-{[3-fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- 25 1 (2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

2-methoxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile; 30 (5S)-5-methyl-5-({[4-(quinolin-5-ylethynyl)-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)imidazolidine-2,4-dione; and (55)-5 -( { [4-(cyclohexylethynyl)-3 ,6-dihydropyridin- 1 (2H)-yl] sulfonyl} methyl)-5 - methylimidazolidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

In one embodiment, we disclose a compound selected from:

1 -(3- { [ 1 -( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)cyclopropanecarbonitrile; and 2-methoxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l, 2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile; or a pharmaceutically acceptable salt thereof.

Each exemplified compound or a pharmaceutically acceptable salt thereof represents a particular and independent aspect of the invention.

The disclosed compounds may exist in enantiomeric forms. Therefore, all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation, or HPLC. Alternatively the optical isomers may be obtained by asymmetric synthesis, or by synthesis from optically active starting materials.

Where optically isomers exist in the compounds of the invention, we disclose all individual optically active forms and combinations of these as individual specific embodiments of the invention, as well as their corresponding racemates.

Preferably the hydantoin (imidazolidine-2,4-dione) derivatives disclosed above have (S)-stereochemistry. Where tautomers exist in the compounds of the invention, we disclose all individual tautomeric forms and combinations of these as individual specific embodiments of the invention.

The present invention includes compounds in the form of salts. Suitable salts include those formed with organic or inorganic acids or organic or inorganic bases. Such salts will normally be pharmaceutically acceptable salts although non-pharmaceutically acceptable salts may be of utility in the preparation and purification of particular compounds. Such salts include acid addition salts such as hydrochloride, hydrobromide, citrate, tosylate and maleate salts and salts formed with phosphoric acid or sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt, for example, sodium or potassium, an alkaline earth metal salt, for example, calcium or magnesium, or an organic amine salt, for example, triethylamine.

Salts of the disclosed compounds may be formed by reacting the free base or another salt thereof with one or more equivalents of an appropriate acid or base.

The disclosed compounds are useful because they possess pharmacological activity in animals and are thus potentially useful as pharmaceuticals. In particular, the compounds of the invention are selective metalloproteinase inhibitors and may thus be used in the treatment of diseases or conditions mediated by MMP 12 such as asthma, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related diseases such as Alzheimer's disease and Multiple Sclerosis (MS), and haematological disorders.

In general, the compounds of the present invention are potent and selective inhibitors of MMP12. The compounds of the present invention show good selectivity with respect to a relative lack of inhibition of various other MMPs such as MMP2, MMP8 and MMP9. In one aspect, the compounds of the present invention are potent and selective inhibitors of MMP 12 that show good selectivity with respect to a relative lack of inhibition of MMP9.

Selective MMP inhibitors are expected to show favourable pharmacological profiles.

The disclosed compounds or their pharmaceutically acceptable salts can be used in the treatment of diseases of the respiratory tract such as obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug- induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper- responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; adult respiratory distress syndrome (ARDS); cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus.

The disclosed compounds or their pharmaceutically acceptable salts can also be used in the treatment of diseases of bone and joints such as arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal- induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle -Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies.

The disclosed compounds or their pharmaceutically acceptable salts can also be used in the treatment of pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example, sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis).

The disclosed compounds or their pharmaceutically acceptable salts can also be used in the treatment of diseases of skin such as psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions.

The disclosed compounds or their pharmaceutically acceptable salts can also be used in the treatment of diseases of the eye such as blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial.

The disclosed compounds or their pharmaceutically acceptable salts can also be used in the treatment of diseases of the gastrointestinal tract such as glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, non-inflammatory diarrhoea, and food-related allergies which may have effects remote from the gut (for example, migraine, rhinitis or eczema).

The disclosed compounds or their pharmaceutically acceptable salts can also be used in the treatment of diseases of the cardiovascular system such as atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto- immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins.

The disclosed compounds or their pharmaceutically acceptable salts can also be used in oncology such as in the treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes. In one aspect, the disclosed compounds or their pharmaceutically acceptable salts may be used in the treatment of adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosis, MS, periodontal disease and gastric mucosal injury.

In another aspect, the disclosed compounds or their pharmaceutically acceptable salts may be used in the treatment or prophylaxis of inflammatory diseases or conditions and diseases associated with uncontrolled degradation of the extracellular matrix and remodelling.

In another aspect, the disclosed compounds or their pharmaceutically acceptable salts may be used in the treatment or prophylaxis of inflammatory respiratory diseases or conditions.

More particularly, the disclosed compounds or their pharmaceutically acceptable salts may be used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and rhinitis.

Even more particularly, the disclosed compounds or their pharmaceutically acceptable salts may be used in the treatment of chronic obstructive pulmonary disease (COPD).

Accordingly, the present invention provides a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined for use as a medicament.

In another aspect, the invention provides the use of a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In another aspect, the invention provides the use of a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in the treatment of diseases or conditions in which inhibition of MMP 12 is beneficial. In another aspect, the invention provides the use of a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in the treatment of inflammatory disease.

In another aspect, the invention provides the use of a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in the treatment of an obstructive airways disease such as asthma or COPD.

In another aspect, the invention provides the use of a compound as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, osteoarthritis, atherosclerosis, periodontal disease or multiple sclerosis.

In another aspect, the invention provides a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined for the treatment of diseases or conditions in which inhibition of MMP 12 is beneficial.

In another aspect, the invention provides a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined for the treatment of inflammatory disease.

In another aspect, the invention provides a compound as listed above, or a pharmaceutically acceptable salt thereof, as hereinbefore defined for the treatment of an obstructive airways disease such as asthma or COPD.

In another aspect, the invention provides a compound as defined above or a pharmaceutically acceptable salt thereof for the treatment of rheumatoid arthritis, osteoarthritis, atherosclerosis, periodontal disease or multiple sclerosis. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

The invention further provides a method of treating a disease or condition in which inhibition of MMP 12 is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as listed above or a pharmaceutically acceptable salt thereof as hereinbefore defined.

The invention also provides a method of treating, or reducing the risk of, an inflammatory disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as listed above or a pharmaceutically acceptable salt thereof as hereinbefore defined.

The invention also provides a method of treating an obstructive airways disease, for example, asthma or COPD, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as listed above or a pharmaceutically acceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder to be treated. The daily dosage of the active ingredient may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. The disclosed compounds or pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the active ingredient is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w, of active ingredient, and, from 1 to 99.95 %w, more preferably from 30 to 99.90 %w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

Thus, the present invention also provides a pharmaceutical composition comprising a compound as disclosed above or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions of this invention may be administered in a standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. The present invention further provides a process for the preparation of a disclosed compound or a pharmaceutically acceptable salt thereof as defined above which, comprises: a) reaction of a compound of formula (II)

(H) wherein L represents a leaving group, with a compound of formula (III) (or a salt thereof)

wherein R¹ is: l-(methylsulfonyl)-2,3-dihydro-iH-indol-4-yl;

3-chloro-5-(Λ/-formyl-Λ/-methylamino)phenyl

3 -(Λ/-ethyl-Λ/-formylamino)phenyl;

3-(Λ/-cyclopropyl-Λ/-formylamino)phenyl;

(2-dimethylamino)pyridin-4-yl;

3-fluoro-5-(2-oxopyrrolidin- 1 -yl)phenyl;

3 -fluoro-5 -(2-oxo- 1 ,3 -oxazolidin-3 -yl)phenyl;

3-(2-oxo-l,3-oxazolidin-3-yl)phenyl;

3-(Λ/-formyl-7V-methylamino)phenyl;

4-(l -formyl)indolinyl;

3-(2-oxopyrrolidin- 1 -yl)phenyl;

3 -(I -cyanocyclopropyl)phenyl;

4-cyano-3-methoxyphenyl; 4-cyano-3 -hydroxyphenyl; quinolin-5-yl;

2-acetyl-l,2,3,4-tetrahydroisoquinolin-5-yl;

2-formyl-l,2,3,4-tetrahydroisoquinolin-5-yl; 2-(methylsulfonyl)-l ,2,3,4-tetrahydroisoquinolin-5-yl;

2-methyl- 1 -oxo- 1,2,3 ,4-tetrahydroisoquinolin-5 -yl;

3 -fluoro-5 -(Λ/-formyl-Λ/-methylamino)phenyl; cyclohexyl;

3-(Λ/-methyl-Λ/-(methylsulfonyl)amino)phenyl; l-formyl-l,2,3,4-tetrahydroquinolin-5-yl;

4-[ 1 -(methylsulfonyl)- lH-indol-4-yl] ;

3-(3,3-dimethyl-2-oxoazetidin-l-yl)phenyl;

4-(tetrahydro-thiopyran-4-yl); or or b) reaction of a compound of formula (X)

(X)

2 wherein R is H or a suitable protecting group and X is a leaving group such as halide or triflate; with an acetylenic compound of formula (IX)

wherein R is as defined above and R represents H or trimethylsilyl; or c) reaction of a compound of formula (XI)

(Xl)

3 2 wherein R represents H or trimethylsilyl and R is H or a suitable protecting group; with an aryl halide or triflate of formula (VI)

R^X

(Vl) wherein R is as defined above and X represents halide or triflate; and optionally thereafter forming a pharmaceutically acceptable salt thereof.

In the above process (a), suitable leaving groups L include halo, particularly chloro. The reaction is preferably performed in a suitable solvent optionally in the presence of an added base for a suitable period of time, typically 0.5 to 24 h, at ambient to reflux temperature. Typically solvents such as pyridine, dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane are used. When used, the added base may be an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine, or an inorganic base such as an alkali metal carbonate. The reaction is typically conducted at ambient temperature for 0.5 to 16 h, or until completion of the reaction has been achieved, as determined by chromatographic or spectroscopic methods. Reactions of sulfonyl halides with various primary and secondary amines are well known in the literature, and the variations of the conditions will be evident for those skilled in the art.

Sulfonylchlorides of formula (II) (wherein L represents chlorine) are conveniently prepared by oxidative chlorination of compounds of formula (IV)

using methods that will be readily apparent to those skilled in the art (Mosher, J., J. Org. Chem. 1958. 23, 1257; Griffith, O., J Biol. Chem. 1983. 258, (3), 1591; WO 02/074767).

Compounds of formula (III) can be prepared by various methods described in the literature or variations thereon as will be appreciated by those skilled in the art of synthetic organic chemistry. Suitable methods include, but are not limited to, those described in the Examples.

It will be appreciated by those skilled in the art that in the processes of the present invention certain potentially reactive functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by suitable protecting groups. Thus, the preparation of the compounds of the invention may involve, at various stages, the addition and removal of one or more protecting groups.

Suitable protecting groups and details of processes for adding and removing such groups are described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

Specific processes for the preparation of the above disclosed compounds are disclosed within the Examples section of the present specification. Such processes form an aspect of the present invention.

The necessary starting materials are either commercially available, are known in the literature or may be prepared using known techniques. Specific processes for the preparation of certain key starting materials are disclosed within the Examples section of the present specification and such processes form an aspect of the present invention.

Certain novel intermediates are disclosed within the Examples section of the present specification and such intermediates form an aspect of the present invention.

The compounds of the invention and intermediates thereto may be isolated from their reaction mixtures and, if necessary further purified, by using standard techniques.

The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.

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

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

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 23, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline. In addition the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CRl for the C-X₃-

C family.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

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

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

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

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

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

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

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.

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

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

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

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

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof. A compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl. - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK. sub 1. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS. A compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride;

(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab

[C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; (v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin); (vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or

(ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as trans fection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

In one aspect, the invention provides a pharmaceutical product comprising, in combination, two or more active ingredients including a first active ingredient which is a disclosed compound of the present invention as defined above, and one or more further active ingredients which are selected from;

- a phosphodiesterase inhibitor;

- a β2-adrenoceptor agonist;

- a modulator of chemokine receptor function; - an inhibitor of kinase function;

- a protease inhibitor;

- a glucocorticoid;

- an anticholinergic agent; and

- a non-steroidal glucocorticoid receptor agonist.

Examples of a phosphodiesterase inhibitor are a PDE4 inhibitor, including an inhibitor of the isoform PDE4D, or a PDE5 inhibitor; examples of a selective β2-adrenoceptor agonist include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol; examples of a muscarinic receptor antagonist are a Ml, M2 or M3 antagonist, such as a selective M3 antagonist such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; examples of a modulator of chemokine receptor function are a CCRl receptor antagonist; examples of a kinase inhibitor are an inhibitor of p38 or IKK2 function; examples of a protease inhibitor are a neutrophil elastase inhibitor; examples of a glucocorticoid include flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

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

General Methods

¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 400 MHz or a Varian Mercury-VX 300 MHz instrument. The central peaks of chloroform-J (5_H 7.27 ppm), dimethylsulfoxide-β?_<5 (5_H 2.50 ppm), acetonitrile-Jj (5_H 1-95 ppm) or methanol-^ (5_H 3.31 ppm) were used as internal references. Column chromatography was carried out using silica gel (0.040-0.063 mm, Merck). A Kromasil KR- 100-5 -C is column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitrile/water with 0.1 % TFA at a flow rate of 10 mL/min were used for preparative HPLC. Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.

The following method was used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1 x 30 mm; Mass APCI; Flow rate 0.7 mL/min; Wavelength 254 or 220 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile + 0.1% TFA ; Gradient 15-95%/B 2.7 min, 95% B 0.3 min.

The following method was used for GC/MS analysis:

Instrument Hewlett Packard 5890 Series II; Column Agilent HP-5 (30 m x 0.32 mm ID); Mass selective detector Hewlett Packard 5971 Series ; Pressure 55 kPa He; Oven program 100⁰C (3 min) to 300⁰C, 25°C/ min.

The following method was used for LC analysis: Method A. Instrument Agilent 1100; Column: Kromasil C18 100 x 3 mm, 5μ particle size, Solvent A: 0.1 %TF A/water, Solvent B: 0.08%TFA/acetonitrile Flow rate 1 mL/min, Gradient 10-100%/B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm.

Method B. Instrument Agilent 1100; Column: XTerra C 8, 100 x 3 mm, 5μ particle size, Solvent A: 15mM NH₃/water, Solvent B: acetonitrile Flow rate 1 mL/min, Gradient 10- 100%/B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm.

Abbreviations:

Ac acetyl

DABCO 1 ,4-diazabicyclo[2.2.2]octane

DCM dichloromethane

DIPEA 7V-ethyldiisopropylamine

DMF Λ/,7V-dimethylfbrmamide

DMSO dimethyl sulfoxide eq. equivalent

Et ethyl

LDA lithium diisopropyl amide

Me methyl

MS mass spectroscopy

RT room temperature

Rt retention time tert tertiary

THF tetrahydrofuran

TFA trifiuoroacetic acid

Example 1

(5^-5-Methyl-5-({r4-{ri-(methylsulfonvn-2.3-dihvdro-7H-indol-4-yllethvnvU-3.6- dihvdropyridin-l(2H)-yllsulfonylimethyl)imidazolidine-2.4-dione

The title compound was prepared following the general method of Soheili et al, Org. Lett., 2003, 5(22), 4191-4194. To 4-bromo-l-(methylsulfonyl)indoline (83 mg, 0.30 mmol) and

(AllylPdCl)2 (0.01 g, 0.03 mmol) was added DMF (0.75 mL). The solution was degassed and the vessel backfilled with argon three times. Then, P(t-Bu)₃ (96 μL of a 10% solution in hexanes, 0.05 mmol), (55)-5-{[(4-ethynyl-3,6-dihydropyridin-l(2H)- yl)sulfonyl]methyl}-5-methylimidazolidine-2,4-dione (98 mg, 0.33 mmol) (WO

2006/004532) and DABCO (72 mg, 0.6 mmol) were added. The reaction mixture was stirred at RT overnight and filtered through a plug of silica gel. Preparative HPLC gave the title compound as a white solid (30 mg, 20%).

¹H-NMR (DMSO-d₆): δ 10.76 (s, IH), 8.02 (s, IH), 7.29 - 7.18 (m, 2H), 7.12 - 7.06 (m, IH), 6.27 - 6.21 (m, IH), 3.97 (t, J= 8.4 Hz, 2H), 3.87 - 3.80 (m, 2H), 3.57 - 3.35 (m, 2H), 3.31 - 3.27 (m, 2H), 3.14 (t, J= 8.4 Hz, 2H), 3.00 (s, 3H), 2.41 - 2.33 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 493 [MH⁺].

The starting material was prepared as follows:

4-Bromo- 1 -(methylsulfonvDindoline

4-Bromo-2,3-dihydro-lH-indole (1.0 g, 5.0 mmol) and DIPEA (0.95 mL, 5.5 mmol) were mixed in dry DMF (5 mL) and cooled to 0 ⁰C. Methanesulphonylchloride (0.60 mL, 5.0 mmol) was added dropwise at 0 ⁰C. The reaction mixture was allowed to reach RT and stirred overnight. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with 0.1N HCl, dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography eluting with heptane/EtOAc 3:1, concentrated, washed with heptane/EtOAc 3:1 and filtered to give a solid product (0.73 g, 83%). ¹H-NMR (CDCl₃): δ 7.37 - 7.32 (m, IH), 7.21 - 7.16 (m, IH), 7.12 - 7.05 (m, IH), 4.03 (t, J= 8.7 Hz, 2H), 3.17 (t, J= 8.5 Hz, 2H), 2.90 (s, 3H); GC-MS m/z: 275/277 1 : 1 [M⁺].

The compounds of Examples 2 to 12 were prepared from (55)-5-{[(4-ethynyl-3,6- dihydropyridin-l(2H)-yl)sulfonyl]methyl}-5-methylimidazolidine-2,4-dione (WO 2006/004532) and the stated bromo compound by a method analogous to that described in Example 1.

Example 2

N-(3-Chloro-5-{ri-(^'{r(^'4^-4-methyl-2.5-dioxoimidazolidin-4-yllmethvUsulfonvn-1.2.3.6- tetrahydropyridin-4-vH ethynyl} phenvD-JV-methylformamide

The title compound was prepared in 47% yield using (3-bromo-5- chloropheny l)methy lformamide .

¹H-NMR (DMSO-d₆): δ 10.76 (IH, s), 8.63 (IH, s), 8.01 (IH, s), 7.55 (IH, t), 7.44 (IH, brt), 7.39 (IH, brt), 6.27 (IH, m), 3.84 (2H, m), 3.53+3.41 (1H+1H, d+d), 3.31 (2H, m), 3.20 (3H, s), 2.37 (2H, m), 1.33 (3H, s); APCI-MS m/z: 465/467 3:1 [MH⁺].

The starting material was prepared as follows:

(3 -Bromo-5 -chlorophenvDmethylformamide l,3-Dibromo-5-chlorobenzene (1.0 g, 3.7 mmol), N-methylformamide (0.26 mL, 4.4 mmol), CuI (35 mg, 0.02 mmol), N,N'-dimethyl ethylenediamine (0.04 mL, 0.37 mmol) and K₂CO₃ (1.02 g, 7.4 mmol) in 1,4-dioxane (4 mL) were heated to 110 ⁰C in a sealed tube for 20 h. The blue slurry was diluted with EtOAc (10 mL) and filtered through a short silica plug that was washed with several portions of EtOAc. The solvent was removed by evaporation and the resulting yellow oil was purified by flash chromatography using 70 g silica and a gradient of 0%EtOAc to 50%EtO Ac/Heptane. The subtitle compound was obtained as a colourless solid (385 mg, 41%).

¹H-NMR (CDCl₃): δ 8.52 (IH, s), 7.43 (IH, t), 7.24 (IH, t), 7.13 (IH, t), 3.30 (3H, s); GC-MS m/z: 247/249/251 [M⁺].

Example 3

N-Ethyl-N-(3-{ri-({r(4^-4-methyl-2.5-dioxoimidazolidin-4-yllmethvUsulfonvn-1.2.3.6- tetrahvdropyridin-4-vHethvnvUphenyl)formamide

The title compound was prepared in 56% yield using (3-bromophenyl)ethylformamide. ¹H-NMR (DMSO-d₆): δ 10.76 (IH, s), 8.41 (IH, s), 8.03 (IH, s), 7.48-7.30 (4H, m), 6.24

(IH, m), 3.83 (2H, m), 3.80 (2H, q), 3.54+3.41 (1H+1H, d+d), 3.30 (2H, m), 2.37 (2H, m), 1.33 (3H, s), 1.03 (3H, t);

APCI-MS m/z: 445 [MH⁺].

The starting material was prepared as follows:

a) (3 -BromophenvDethylformamide (3-Bromophenyl)ethylamine (488 mg, 2.4 mmol), CHCl₃ (1 mL, 12.5 mmol) and KF/AI2O3 (5.5 mmol/g) (2 g, 11 mmol) in MeCN (3 mL) were stirred in a sealed tube at RT for 24 h and then at +80 ⁰C for 2 h. The slurry was then filtered and the filter cake was washed several times with DCM and EtOAc. The solvents were removed by evaporation and the crude product was purified by flash chromatography using a gradient of 0% EtOAc to 50%EtOAc/heptane. (3-Bromophenyl)ethylformamide was obtained as a red oil (358 mg, 65%). NMR showed that the product displayed restricted rotation of the amide group at RT giving double signals with a ratio of 1 to 0.12.

¹H-NMR (CDCl₃): δ 8.37 +8.35 (minor) (IH, s), 7.44 (IH, ddd), 7.35 (IH, t), 7.30 (IH, t), 7.12 (IH, ddd), 3.86 + 3.73 (minor) (2H, q), 1.18 + 1.21 (minor) (3H, t); APCI-MS m/z: 228/230 1:1 [MH⁺].

b) (3 -BromophenvDethylamine l-Bromo-3-iodobenzene (1 g, 3.5 mmol), CuI (34 mg, 0.17 mmol), K₃PO₄ (1.49 g, 7 mmol), ethylamine (180 mg, 4 mmol) and ethyleneglycol (0.39 mL, 7 mmol) in 2-propanol (3.5 mL) were heated in a sealed tube to +80 ⁰C for 16 h. The resulting slurry was partitioned between water (5 mL) and Et₂O (10 mL), the organic phase was separated and the water phase was extracted three times more with EtOAc. The combined organics were filtered through a short silica plug and evaporated. The residual material was purified by flash chromatography using heptane as eluent. (3-Bromophenyl)ethylamine was obtained as a slightly yellow oil (488 mg, 89%).

¹H-NMR (CDCl₃): δ 7.03 (IH, t), 6.84 (IH, ddd), 6.78 (IH, t), 6.56 (IH, ddd), 4.02 (IH, vbrs), 3.15 (2H, q), 1.27 (3H, t); GC-MS m/z: 199/201 1:1 [M⁺].

Example 4

N-Cvclopropyl-N-(3-(ri-((r(4y)-4-methyl-2.5-dioxoimidazolidin-4-yl1methylisulfonyl)- l,2,3,6-tetrahvdropyridin-4-yllethvnvUphenyl)formamide

The title compound was prepared in 29% yield using (3-bromophenyl)cyclopropyl- formamide.

¹H-NMR (DMSOd₆): δ 10.75 (IH, s), 8.51 (IH, s), 8.07 (IH, s), 7.60-7.24 (4H, m), 6.23

(IH, m), 3.54+3.41 (1H+1H, d+d), 3.31 (2H, m), 3.23+2.98 (0.5H+0.5H, m+m), 2.37 (2H, m), 1.33 (3H, s), 0.91 (2H, m), 0.68 (IH, m), 0.43 (IH, m);

APCI-MS m/z: 457 [MH⁺].

The starting material was prepared as follows:

(3-BromophenvDcvclopropylfbrmamide

The subtitle compound was prepared in 31% yield in two steps, starting from l-bromo-3- iodobenzene and cyclopropylamine by a method analogous to that described in Example 3. NMR showed that the product displayed restricted rotation of the amide group at RT giving double signals with a ratio of 1 to 0.73. 1H-NMR (CDCl₃): δ 8.61+8.51 (total IH, s+s), 7.71-7.04 (4H, m), 3.08+3.00 (total IH, m+m), 1.02+0.75+0.60 (total 4H, m+m+m); APCI-MS m/z: 240/242 1:1 [MH⁺].

Example 5

(5S)-5 -( ( [4- ( r2-(Dimethylamino)pyridin-4-yl1 ethynylj -3.6-dihydropyridin- 1 (2H)- yllsulfonylimethvπ-5-methylimidazolidine-2.4-dione

The title compound was prepared in 32% yield using 4-bromo-7V,7V-dimethylpyridin-2- amine.

¹H-NMR (DMSOd₆): δ 10.76 (IH, s), 8.06 (IH, d), 8.02 (IH, s), 6.62 (IH, m), 6.55 (IH, dd), 6.28 (IH, m), 3.83 (2H, m), 3.54+3.41 (1H+1H, d+d), 3.30 (2H, m), 3.01 (6H, s), 2.37 (2H, m), 1.33 (3H, s);

APCI-MS m/z: 418 [MH⁺].

The starting material was prepared as follows:

4-Bromo-Λ/,Λ/-dimethylpyridin-2-amine

To a solution of 2-amino-4-bromo-pyridine (200 mg, 1.16 mmol) and 37% aqueous formaldehyde (1 mL, 13.4 mmol) in MeCN (5 mL) was added NaBH₃CN (364 mg, 5.8 mmol). MeCN (0.5 mL) was used to get all the reducing agent into the reaction vessel. The mixture was cooled in an ice/water bath and AcOH (0.4 mL, 7 mmol) was added. The reaction mixture was allowed to reach RT when an opaque solution was formed. A small volume of water was added to form a clear solution and the reaction mixture was stirred over the weekend at RT. AcOH (1 mL) was added and the reaction mixture was evaporated to remove MeCN, the residual material was made basic with 2M NaOH and extracted four times with DCM. The organic solution was dried over Na₂SO₄, filtered and evaporated onto silica gel and this gel was then applied to a silca column containing 2Og of silica. Flash chromatography was made with a gradient of 0% to 30% EtOAc / heptane. The subtitle compound was obtained as a colourless oil that slowly crystallised (110 mg, 47%).

¹H-NMR (CDCl₃): δ 7.98 (IH, d), 6.71-6.67 (2H, m), 3.09 (6H, s); GC-MS m/z: 200/202 1:1 [M⁺].

Example 6

(56^f)-5-(([4-([3-Fluoro-5-(2-oxopyrrolidin-l-vπphenyllethvnyl|-3.6-dihvdropyridin- l(2//)-yllsulfonvUmethyl)-5-methylimidazolidine-2,4-dione

The title compound was prepared using l-(3-bromo-5-fluorophenyl)pyrrolidin-2-one. ¹H NMR (DMSOd₆): δ 10.76 (s, IH), 8.01 (s, IH), 7.68 - 7.63 (m, IH), 7.58 - 7.56 (m,

IH), 7.10 - 7.05 (m, IH), 6.30 - 6.24 (m, IH), 3.87 - 3.80 (m, 4H), 3.57 - 3.38 (m, 2H), 3.31 - 3.27 (m, 2H), 2.56 - 2.50 (m, 2H), 2.40 - 2.33 (m, 2H), 2.11 - 1.98 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 475 [MH⁺].

The starting material was prepared as follows:

l-(3-Bromo-5-fluorophenyl)pyrrolidin-2-one

The subtitle compound was prepared from l,3-dibromo-5-fluorobenzene following the general method of Buchwald et al, J Am. Chem. Soc, 2002, 124(25), 7421-7428.

¹H-NMR (CDCl₃): δ 7.58 - 7.52 (m, 2H), 7.06 - 7.00 (m, IH), 3.83 (t, J= 7.2 Hz, 2H), 2.64 (t, J= 8.1 Hz, 2H), 2.24 - 2.13 (m, 2H); APCI-MS m/z: 258/260 1:1 [MH⁺].

Example 7

(56^f)-5-({r4-{r3-Fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyllethvnvU-3,6-dihvdropyridin- l(2//)-yllsulfonvUmethyl)-5-methylimidazolidine-2,4-dione

The title compound was prepared using 3-(3-bromo-5-fluorophenyl)- 1 ,3-oxazolidin-2-one. ¹H-NMR (DMSOd₆): δ 10.75 (s, IH), 8.00 (s, IH), 7.57 - 7.49 (m, IH), 7.46 (s, IH), 7.11

- 7.04 (m, IH), 6.30 - 6.25 (m, IH), 4.48 - 4.42 (m, 2H), 4.10 - 4.04 (m, 2H), 3.86 - 3.81 (m, 2H), 3.57 - 3.37 (m, 2H), 3.30 - 3.26 (m, 2H), 2.41 - 2.34 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 477 [MH⁺].

The starting material was prepared as follows:

3 -(3 -Bromo-5 -fluorophenyl)- 1 ,3 -oxazolidin-2-one

¹H-NMR (CDCl₃): δ 7.47 - 7.40 (m, 2H), 7.07 - 7.01 (m, IH), 4.55 - 4.49 (m, 2H), 4.07 -

4.01 (m, 2H);

GC-MS m/z: 259/261 1:1 [M⁺].

Example 8

(5y>-5-Methyl-5-(([4- ([3-(2-QXQ-1.3-oxazolidin-3-vπphenyl]ethvnyli-3.6-dihvdropyridin- l(2//)-yl1sulfonvUmethyl)imidazolidine-2,4-dione The title compound was prepared using 3-(3-bromophenyl)-l,3-oxazolidin-2-one. 1H-NMR (400 MHz, DMSOd₆): δ 10.75 (s, IH), 8.00 (s, IH), 7.66 (s, IH), 7.59 - 7.54

(m, IH), 7.41 (t, J= 8.0 Hz, IH), 7.20 (d, J= 7.7 Hz, IH), 6.26 - 6.22 (m, IH), 4.44 (t, J = 7.9 Hz, 2H), 4.07 (t, J= 8.0 Hz, 2H), 3.85 - 3.79 (m, 2H), 3.57 - 3.37 (m, 2H), 3.30 - 3.27 (m, 2H), 2.41 - 2.34 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 459 [MH⁺].

The starting material was prepared as follows:

3-(3-BromophenvD-l,3-oxazolidin-2-one

The subtitle compound was prepared from 1,3-dibromobenzene following the general method of Buchwald et al, J Am. Chem. Soc, 2002, 124(25), 7421-7428.

¹H-NMR (400 MHz, CDCl₃): δ 7.74 - 7.70 (m, IH), 7.57 - 7.51 (m, IH), 7.31 - 7.21 (m, 2H), 4.51 (t, J= 8.0 Hz, 2H), 4.05 (t, J= 8.0 Hz, 2H); GC-MS m/z: 241/243 1:1 [M⁺].

Example 9

Methyl(3-([l-(([(4y)-4-methyl-2.5-dioxoimidazolidin-4-yl]methylisulfonvπ-1.2.3.6- tetrahvdropyridin-4-yl1ethvnyl|phenyl)formamide.

The title compound was prepared using 3-bromophenyl(methyl)formamide. 1H NMR (DMSOd₆): δ 10.76 (s, IH), 8.57 and 8.37 amide rotamers 7:1 (s, IH), 8.04 (s,

IH), 7.47 - 7.29 (m, 4H), 6.26 - 6.21 (m, IH), 3.90 - 3.67 (m, 5H), 3.58 - 3.26 (m, 4H), 2.42 - 2.31 (m, 2H), 1.33 (s, 3H); APCI-MS m/z: 431 [MH]. The starting material was prepared as follows:

3 -BromophenvKmethvDformamide 3-Bromo-7V-methylaniline (1 g, 5.4 mmol) in ethylformate (2 mL) was heated to 80 ⁰C for 60 h. The reaction mixture was concentrated and purified by column chromatography eluting with a heptane to heptane/ethyl acetate 4:1 to give the subtitle compound (0.7 g, 60%).

¹H-NMR (DMSOd₆): δ 8.58 and 8.37 rotamers 7:1 (s, IH), 7.83 - 7.80 and 7.63 - 7.61 rotamers 1:7 (m, IH), 7.47 - 7.35 (m, 3H), 3.20 (s, 3H); APCI-MS m/z: 214/216 1:1 [MH⁺].

Example 10

4-{ri-({r(4^)-4-Methyl-2.5-dioxoimidazolidin-4-yllmethylisulfonvn-1.2.3.6- tetrahvdropyridin-4-vHethvnylHndoline-l-carbaldehvde

The title compound was prepared using 4-bromoindoline-l-carbaldehyde. 1H NMR (400 MHz, DMSOd₆): δ 10.76 (s, IH), 9.04 and 8.48 rotamers 3:1 (s, IH), 8.01

(s, IH), 7.89 and 7.45 rotamers 1:3 (d, J= 8.0 Hz, IH), 7.20 (t, J= 7.8 Hz, IH), 7.09 (t, J = 7.6 Hz, IH), 6.26 - 6.21 (m, IH), 4.16 and 3.94 (t, J= 8.5 Hz, 2H), 3.86 - 3.81 (m, 2H), 3.56 - 3.38 (m, 2H), 3.30 - 3.28 (m, 2H), 3.20 - 3.08 (m, 2H), 2.41 - 2.34 (m, 2H), 1.33 (s, 3H); APCI-MS m/z: 443 [MH⁺].

The starting material was prepared as follows: 4-Bromoindoline- 1 -carbaldehyde

4-Bromo-2,3-dihydro-lH-indole (0.9 g, 4.5 mmol) was mixed with ethyl formate (5 mL) and stirred at 80 ⁰C for 24h. When cooling to RT, white needles precipitated that were collected by filtration to give the product (1.0 g, 92%). 1H-NMR (300 MHz, CDCl₃): δ 8.91 and 8.51 rotamers 4:1 (s, IH), 8.05 - 8.00 and 7.24 - 7.02 (m, 3H), 4.21 - 4.05 (m, 2H), 3.24 - 3.08 (m, 2H); APCI-MS m/z: 226/228 1:1 [MH⁺].

Example 11

(56^f)-5-Methyl-5-({r4-{r3-(2-oxopyrrolidin-l-yl)phenyllethynvU-3,6-dihvdropyridin- l(2H)-yl]sulfonylimethv0imidazolidine-2,,4-dione

The title compound was prepared using l-(3-bromophenyl)pyrrolidin-2-one.

¹H NMR (DMSOd₆): δ 10.75 (s, IH), 8.03 (s, IH), 7.78 (s, IH), 7.64 (d, IH), 7.38 (t,

IH), 7.20 (d, IH), 6.23 (m, IH), 3.87-3.80 (m, 4H), 3.47 (dd, 2H), 3.30 (m, 2H), 2.50 (m, 2H), 2.41-2.33 (m, 2H), 2.00-2.12 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 457 [MH⁺].

The starting material was prepared as follows:

l-(3-BromophenvDpyrTOlidin-2-one

¹H-NMR (CDCl₃): δ 7.80 (t, IH), 7.62 (dt, IH), 7.29-7.20 (m, 2H), 3.85 (t, 2H), 2.63 (t, 2H), 2.18 (quint, 2H); APCI-MS m/z: 240/242 1:1 [MH⁺].

Example 12

l-(3-{ri-({r(4SV4-Methyl-2.5-dioxoimidazolidin-4-yllmethvUsulfonvn-1.2.3.6- tetrahvdropyridin-4-yllethvnvUphenyl)cvclopropanecarbonitrile

The title compound was prepared using l-(3-bromophenyl)cyclopropanecarbonitrile (WO 2004/000821).

¹H-NMR (DMSO-d6): δ 10.75 (s, IH), 8.23 (s, IH), 7.44 - 7.34 (m, 4H), 6.26 - 6.21 (m,

IH), 3.85 - 3.80 (m, 2H), 3.56 - 3.38 (m, 2H), 3.31 - 3.27 (m, 2H), 2.39 - 2.33 (m, 2H), 1.78 - 1.74 (m, 2H), 1.58 - 1.54 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 439 [MH⁺].

Example 13

2-Methoxy-4- (Fl-(I [(4S)-4-methyl-2.5-dioxoimidazolidin-4-yl]methyli sulfonvD- 1.2.3.6- tetrahydropyridin-4-vHethvnvUbenzonitrile

A mixture of 4-bromo-2-methoxybenzonitrile (0.32 g, 1.5 mmol), PdCl₂(PPrIs)₂ (7 mg, 0.01 mmol), PPh₃ (6 mg, 0.024 mmol), CuI (2 mg, 0.01 mmol) and DIPEA (0.42 mL, 3.0 mmol) in toluene (1.7 mL) was degassed and the vessel back-filled with argon three times. (55)-5-{[(4-Ethynyl-3,6-dihydropyridin-l(2H)-yl)sulfonyl]methyl}-5- methylimidazolidine-2,4-dione (0.29 g, 1.0 mmol) (WO 2006/004532) in DMF (1.0 mL) was added and reaction was stirred at 80 ⁰C until LC-MS analysis indicated consumption of the starting material. The mixture was filtered through a plug of silica gel and precipitation from a water/CH₃CN mixture gave the title compound as a white solid (90 mg, 14%).

¹H-NMR (DMSOd₆): δ 10.76 (s, IH), 8.03 (s, IH), 7.74 (d, J= 8.1 Hz, IH), 7.29 (d, J =

1.1 Hz, IH), 7.17 - 7.13 (m, IH), 6.35 - 6.28 (m, IH), 3.93 (s, 3H), 3.87 - 3.82 (m, 2H), 3.58 - 3.38 (m, 2H), 3.30 - 3.28 (m, 2H), 2.42 - 2.35 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 429 [MH⁺].

The starting material was prepared as follows:

4-Bromo-2-methoxybenzonitrile

4-Bromo-2-fluorobenzonitrile (10 g, 0.05 mol) was mixed with K2CO3 (20 g, 0.15 mol) and MeOH (9.5 mL, 0.23 mol) in DMF (100 mL) and heated to 55 ⁰C under argon for 2Oh. Water was added and the mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated to give the subtitle compound as a white solid (10 g, 95%).

¹H-NMR (400 MHz, CDCl₃): δ 7.42 (d, J= 8.1 Hz, IH), 7.20 - 7.13 (m, 2H), 3.95 (s, 3H); GC-MS m/z: 211/213 1:1 [M⁺].

The compounds of Examples 14 to 16 were prepared from (55)-5-{[(4-ethynyl-3,6- dihydropyridin-l(2H)-yl)sulfonyl]methyl}-5-methylimidazolidine-2,4-dione (WO 2006/004532) and the stated bromo compound by a method analogous to that described in Example 13.

Example 14

2-Hvdroxy-4-(ri-((r(4S)-4-methyl-2.5-dioxoimidazolidin-4-yl1methylisulfonyl)-1.2.3.6- tetrahvdropyridin-4-yllethynvUbenzonitrile

The title compound was prepared using 4-bromo-2-hydroxybenzonitrile (Ismail et al, Synth. Commun. 2004, 34(5), 751-758).

¹H-NMR (DMSOd₆): δ 11.35 (s, IH), 11.35 (s, IH), 8.03 (s, IH), 7.62 (d, J= 7.9 Hz,

IH), 7.02 - 6.95 (m, 2H), 6.33 - 6.25 (m, IH), 3.87 - 3.80 (m, 2H), 3.58 - 3.37 (m, 2H), 3.30 - 3.25 (m, 2H), 2.41 - 2.31 (m, 2H), 1.33 (s, 3H); APCI-MS m/z: 415 [MH⁺].

Example 15

(5S)-5-Methyl-5-((r4-(quinolin-5-ylethvnvn-3.6-dihvdropyridin-l(2H)- yllsulfonvUmethyl)imidazolidine-2,4-dione trifluoroacetate

The title compound was prepared using 5-bromoquinoline. 1H-NMR (DMSOd₆): δ 10.78 (s, IH), 9.04 - 9.00 (m, IH), 8.69 - 8.64 (m, IH), 8.11 -

8.03 (m, 2H), 7.84 - 7.77 (m, 2H), 7.74 - 7.68 (m, IH), 6.46 - 6.39 (m, IH), 3.93 - 3.83 (m, 2H), 3.62 - 3.40 (m, 2H), 3.40 - 3.32 (m, 2H), 2.54 - 2.46 (m, 2H), 1.35 (s, 3H);

APCI-MS m/z: 425 [MH⁺].

Example 16

(56^f)-5-({r4-r(2-Acetyl-l,2,3,4-tetrahvdroisoquinolin-5-yl)ethvnyll-3,6-dihvdropyridin- l(2H)-yllsulfonylimethvπ-5-methylimidazolidine-2.4-dione

The title compound was prepared using 2-acetyl-5-bromo-l,2,3,4-tetrahydroisoquinoline. ¹H-NMR (DMSOd₆): δ 10.75 (s, IH), 8.03 (s, IH), 7.34 - 7.27 (m, IH), 7.25 - 7.16 (m,

2H), 6.27 - 6.17 (m, IH), 4.64 and 4.59 rotamers 4:6 (s, 2H), 3.87 - 3.80 (m, 2H), 3.72 - 3.65 (m, 2H), 3.56 - 3.37 (m, 2H), 3.35 - 3.28 (m, 2H), 2.93 and 2.81 rotamers 6:4 (t, J = 6.1 Hz, 2H), 2.44 - 2.34 (m, 2H), 2.09 and 2.08 rotamers 6:4 (s, 3H), 1.33 (s, 3H);

APCI-MS m/z: 471 [MH⁺].

The starting material was prepared as follows:

2-Acetyl-5-bromo-l,2,3,4-tetrahydroisoquinoline

5-Bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.0 mmol) was taken up in diethyl ether (20 mL) and washed with NaOH (aq, IN), dried (Na₂SO₄) and concentrated to give the free amine (1.67 g) that was dissolved in pyridine (15 mL) and cooled to 0 ⁰C. Acetic anhydride (0.82 mL, 8.7 mmol) was added dropwise and the reaction was stirred at RT overnight. Azeotropic evaporation with toluene several times gave the product as a white solid (1.9 g, 94%).

¹H NMR (SOO MHz, DMSO-d₆): δ 7.53 - 7.46 (m, IH), 7.27 - 7.11 (m, 2H), 4.66 and 4.61 rotamers 4:6 (s, 2H), 3.73 - 3.66 (m, 2H), 2.83 and 2.71 rotamers 6:4 (t, J= 6.1 Hz, 2H), 2.09 and 2.07 rotamers 6:4 (s, 3H); APCI-MS m/z: 254/256 1:1 [MH⁺].

Example 17

5-(ri-((r(4^-4-Methyl-2.5-dioxoimidazolidin-4-yllmethylisulfonvn-1.2.3.6- tetrahvdropyridin-4-yllethynvU -3 ,4-dihvdroisoquinoline-2( l//)-carbaldehvde

A mixture of 5-bromo-3,4-dihydroisoquinoline-2(lH)-carbaldehyde (0.12 g, 0.5 mmol), PdCl₂(PPh₃)₂ (7 mg, 0.01 mmol), CuI (2 mg, 0.01 mmol) and 0.5M aq 2-ethanolamine (2 mL, 1.0 mmol) in THF (2 mL) was degassed and the vessel back-filled with argon three times . (5S)-5 - { [(4-Ethynyl-3 ,6-dihydropyridin- 1 (2H)-yl)sulfonyl]methyl} -5 - methylimidazolidine-2,4-dione (0.18 g, 0.6 mmol) (WO 2006/004532) was added and the reaction mixture was stirred at 60 ⁰C until LC-MS analysis indicated consumption of the starting material. The mixture was, after cooling to RT, extracted with ethyl acetate, dried (Na₂SO₄) and concentrated. Filtration through a plug of silica gel followed by preparative HPLC gave the title compound as a white solid (17 mg, 7%). 1H NMR (DMSO-d₆): δ 10.76 (s, IH), 8.21 and 8.16 rotamers 4:6 (s, IH), 8.04 (s, IH),

7.36 - 7.16 (m, 3H), 6.27 - 6.19 (m, IH), 4.59 and 4.56 rotamers 4:6 (s, 2H), 3.87 - 3.80 (m, 2H), 3.72 - 3.64 (m, 2H), 3.58 - 3.37 (m, 2H), 3.34 - 3.27 (m, 2H), 2.90 and 2.83 rotamers 6:4 (t, J= 6.1 Hz, 2H), 2.43 - 2.34 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 457 [MH⁺].

The starting material was prepared as follows:

5-Bromo-3.4-dihvdroisoquinoline-2(lH)-carbaldehyde

5-Bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride was suspended in diethyl ether and washed with IN NaOH, dried with Na₂SO₄ and concentrated to give the free amine as an oil. The amine (405 mg, 1.9 mmol) was mixed with ethyl formate (1 mL) and stirred at 80 ⁰C for 2h. The mixture was concentrated to give the product as a white solid (0.45 g, 100%). ¹H NMR (300 MHz, CDCl₃): δ 8.26 and 8.21 (s, IH), 7.52 - 7.42 (m, IH), 7.14 - 7.04 (m, 2H), 4.70 and 4.54 (s, 2H), 3.83 and 3.68 (t, J= 6.2 Hz, 2H), 2.98 - 2.85 (m, 2H); APCI-MS m/z: 240/242 1:1 [MH⁺].

Example 18

(^'5y)-5-Methyl-5-(^'(r4-(r2-(^'methylsulfonyl)-1.2.3.4-tetrahvdroisoquinolin-5-yl1ethvnvU- 3,6-dihvdropyridin-l(2//)-yllsulfonvUmethyl)imidazolidine-2,4-dione

The title compound was prepared from 5-bromo-2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinoline and (55)-5 - { [(4-ethynyl-3 ,6-dihydropyridin- 1 (2H)- yl)sulfonyl]methyl}-5-methylimidazolidine-2,4-dione (WO 2006/004532) by a method analogous to that described in Example 17. 1H NMR (DMSOd₆): δ 10.76 (s, IH), 8.25 (s, IH), 7.38 - 7.30 (m, IH), 7.28 - 7.19 (m,

2H), 6.27 - 6.21 (m, IH), 4.37 (s, 2H), 3.86 - 3.81 (m, 2H), 3.58 - 3.38 (m, 4H), 3.30 - 3.27 (m, 2H), 3.00 - 2.91 (m, 5H), 2.43 - 2.34 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 507 [MH⁺].

The starting material was prepared as follows:

5-Bromo-2-(methylsulfonyl)-l,2,3,4-tetrahvdroisoquinoline

5-Bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride was suspended in diethyl ether and washed with IN NaOH, dried with Na₂SO₄ and concentrated to give the free amine as an oil. The amine (405 mg, 1.9 mmol) and DIPEA (0.36 mL, 2.1 mmol) were dissolved in DCM (2 mL) and cooled to 0 ⁰C. Methanesulphonylchloride (0.60 mL, 5.0 mmol) was added dropwise at 0 ⁰C. The reaction mixture was allowed to reach RT and stirred for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated to give the product as a white solid (0.5 g, 91%).

¹H NMR (300 MHz, CDCl₃): δ 7.55 - 7.44 (m, IH), 7.16 - 7.00 (m, 2H), 4.46 (s, 2H), 3.60 (t, J = 6.1 Hz, 2H), 2.99 (t, J = 6.1 Hz, 2H), 2.86 (s, 3H); APCI-MS m/z: 290/292 1:1 [MH⁺].

Example 19

(5y)-5-Methyl-5-((r4-r(2-methyl-l-oxo-1.2.3.4-tetrahvdroisoquinolin-5-vπethvnyl1-3.6- dihvdropyridin-l(2//)-yllsulfonvUmethyl)imidazolidine-2,4-dione

The title compound was prepared from 5-bromo-2-methyl-3,4-dihydroisoquinolin-l(2H)- one and (55)-5-{[(4-ethynyl-3,6-dihydropyridin-l(2H)-yl)sulfonyl]methyl}-5- methylimidazolidine-2,4-dione (WO 2006/004532) by a method analogous to that described in Example 17.

¹H NMR (300 MHz, DMSO-d₆): δ 10.76 (s, IH), 8.05 - 8.02 (m, IH), 7.91 - 7.86 (m, IH),

7.61 - 7.56 (m, IH), 7.36 (t, J= 7.8 Hz, IH), 6.30 - 6.24 (m, IH), 3.87 - 3.81 (m, 2H), 3.61 - 3.58 (m, 2H), 3.55 - 3.38 (m, 2H), 3.35 - 3.28 (m, 2H), 3.12 - 3.05 (m, 2H), 3.03 (s, 3H), 2.43 - 2.34 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 457 [MH⁺].

The starting material was prepared as follows:

5-Bromo-2-methyl-3,4-dihvdroisoquinolin-l(2//)-one

The subtitle compound was prepared according to the procedure described by Wang et al,

Tetrahedron Lett. 1998, 39, 6609-6612. ¹H NMR (300 MHz, CDCl₃) δ 8.11 - 8.05 (m, IH), 7.69 - 7.62 (m, IH), 7.22 (t, J= 7.9 Hz, IH), 3.58 (t, J= 6.7 Hz, 2H), 3.17 (s, 3H), 3.11 (t, J= 6.8 Hz, 2H); APCI-MS m/z: 240/242 1:1 [MH⁺].

Example 20

N-r3-Fluoro-5-(ri-r(rr4SV4-methyl-2.5-dioxoimidazolidin-4-yllmethvUsulfonylV1.2.3.6- tetrahydropyridin-4-vH ethynyl} phenvD-JV-methylformamide

_:/V-{3-Fluoro-5[(trimethylsilyl)ethynyl]phenyl}-_:Λ/-methylformamide (269 mg, 1 mmol) was dissolved in MeOH and treated with KF at RT. Removal of the TMS protecting group was followed by LC-MS. When no starting material remained, the mixture was evaporated to dryness, redissolved in 33% EtOAc/heptane and filtered through a short silica plug and evaporated to give a yellow oil. This material was dissolved in DMF (1.0 mL) and added to a solution of l-({[(4S)-4-methyl-2,5-dioxo-l-{[2-

(trimethylsilyl)ethoxy]methyl} imidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl trifluoromethanesulfonate (275 mg, 0.5 mmol), (allylPdCl)2 (12.9 mg, 0.035 mmol) and P(t-Bu)₃ (0.404 mL of a 10% solution in hexanes, 0.14 mmol) in DMF (0.5 mL). DABCO (112 mg, 1 mmol) was added last and the reaction vessel was purged with argon and stirred at RT for 2 h. The reaction mixture was diluted with EtOAc and filtered through a short silica plug, solvents were removed by evaporation and the residual material was purified by flash chromatography using a gradient of 0% EtOAc to 80% EtO Ac/heptane, to afford 127 mg of the SEM protected product as a yellow oil. This material was deprotected at RT by dissolving the oil in DCM (2 mL) and TFA (0.5 mL). After 2.5 h the mixture was evaporated and the residue was redissolved in MeOH (2 mL) and 28% NH₃ (aq) (2 mL) and stirred for 1 h. Evaporation and purification by preparative HPLC afforded the title compound as a colourless solid (18 mg, 8% overall yield). ¹H-NMR (DMSO-d₆): δ 10.76 (IH, s), 8.66 (IH, s), 8.02 (IH, s), 7.38 (IH, dt), 7.32 (IH, m), 7.18 (IH, m), 6.27 (IH, m), 3.84 (2H, m), 3.54+3.40 (1H+1H, d+d), 3.30 (2H, m), 3.20 (3H, s), 2.37 (2H, m), 1.33 (3H, s);

APCI-MS m/z: 449 [MH⁺].

The starting materials were prepared as follows:

a) N- (3-Fluoro-5 [(trimethylsilvOethvnyliphenvU -N-methylformamide l,3-Dibromo-5-fluorobenzene (1.0 g, 3.9 mmol), N-methylformamide (286 mg, 4.3 mmol), CuI (37 mg, 0.2 mmol), N, N' -dimethyl ethylenediamine (0.042 mL, 0.39 mmol) and

K₂CO₃ (1.08 g, 7.8 mmol) in toluene (10 mL) were heated in a sealed tube at +100 ⁰C for 22 h. The slurry was filtered through a silica plug that was washed with EtOAc, the solvents were removed by evaporation and the residual material was purified by flash chromatography on 70 g of silica gel using a gradient of 0% EtOAc to 40% EtO Ac/heptane. (3-Bromo-5-fluorophenyl)methylformamide was obtained as a colourless oil that slowly crystallised (260 mg, 28%).

GC-MS m/z: 231/233 1:1 [M⁺].

The (3-bromo-5-fluorophenyl)methylformamide (260 mg, 1.12 mmol) was dissolved in DMF (1.5 mL) and flushed with argon and to this solution was added TMS-acetylene (0.17 mL, 1.2 mmol), (allylPdCl)₂ (10 mg, 0.027 mmol), P(t-Bu)₃ (0.322 mL of a 10% solution in hexanes, 0.11 mmol) and DABCO (251 mg, 2.2 mmol). The initially yellow solution was stirred overnight at RT. The formed red suspension was diluted with EtOAc and filtered through a silica plug that was washed with EtOAc. The solvents were removed by evaporation and the residual black oil was purified by dry flash chromatography using silica gel (20 g). The column was washed with heptane (50 mL) followed by 10%

EtOAc/heptane (100 mL), the product was then eluted using 33% EtO Ac/heptane. The subtitle compound was obtained as a yellow oil (269 mg, 27% overall yield). The material was found to contain 5% unreacted (3-bromo-5-fluorophenyl)methylformamide but was used without further purification. 1H-NMR (CDCl₃): δ 8.53 (IH, s), 7.10-7.02 (2H, m), 6.87 (IH, dt), 3.30 (3H, s), 0.27 (9H, s); APCI-MS m/z: 250 [MH⁺].

b) 1 -( ( IY45V4-Methyl-2.5-dioxo- 1 - ( r2-(trimethylsilv0ethoxylmethyli imidazolidin-4- yllmethyl} sulfonyl)- 1 ,2,3 ,6-tetrahvdropyridin-4-yl trifluoromethanesulfonate l-({[(45)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl trifluoromethanesulfonate (WO 2006/004532) (5.25 g, 12.5 mmol) and DIPEA (4.3 mL, 25 mmol) in a DCM:DMF (4:1 mixture, 50 mL) were cooled on an ice/water bath. To the stirred solution was slowly added SEM-Cl (4.4 mL, 25 mmol) and after addition the reaction mixture was allowed to slowly reach RT and stirred overnight. The reaction mixture was washed with water, dilute HCl (aq) and brine, dried over sodium sulfate, filtered and evaporated. The crude product was further purified by flash chromatography on silica gel using EtOAc:heptane (1:1) as eluent to afford the subtitle compound (6.0 g, 87%).

¹H-NMR (DMSOd₆): δ 8.51 (IH, s), 6.09 (IH, s), 4.74 (2H, s), 3.87 (2H, m), 3.70-3.48 (4H, m), 3.41 (2H, t), 2.52 (2H, m), 1.35 (3H, s), 0.84 (2H, t), -0.03 (9H, s); 1³C-NMR (DMSOd₆): δ 174.81, 154.76, 146.12, (112.58+119.40+116.22+113.04), 116.10, 67.07, 65.75, 58.10, 54.24, 42.47, 41.82, 27.59, 24.44, 17.28, -1.38.

Example 21

(5^-5-({r4-(Cvclohexylethvnvn-3.6-dihvdropyridin-U2H)-yllsulfonvUmethvn-5- methylimidazolidine-2.4-dione.

4-(Cyclohexylethynyl)-l,2,3,6-tetrahydropyridine (131 mg, 0.69 mmol) was stirred in NMP (1.3 mL) with DIPEA (0.13 mL, 0.76 mmol), cooled in an ice salt bath (temperature ~ -10 ⁰C) and [(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (156 mg, 0.69 mmol) was added in 3 portions over 5 minutes. After 5 minutes, LC-MS showed that the reaction had gone to completion. Water (50 mL) was added and the mixture was stirred overnight at RT and the solid filtered off. The product was purified by silica gel chromatography eluting with ethyl acetate to give the product as a white solid (132 mg, 50%).

¹H-NMR (400 MHz, CDCl₃): δ 1.20 (s, 3H), 1.25 - 1.56 (m, 8H), 1.61 - 1.75 (m, 7H), 1.74

- 1.86 (m, 4H), 2.33 (s, 2H), 2.47 (dd, IH), 3.19 - 3.27 (m, 2H), 3.31 - 3.48 (m, 3H), 3.85 (d, 2H), 5.91 (s, IH), 6.68 (s, IH), 8.83 (s, IH);

APCI-MS m/z: 380 [MH⁺].

The starting material was prepared as follows:

4-(CvclohexylethvnvD- 1 ,2,3 ,6-tetrahydropyridine

4- { [(Trifluoromethyl)sulfonyl]oxy } - 1 ,2,3 ,6-tetrahydropyridinium chloride (WO 2006/004532) was coupled to cyclohexylethyne using a method analogous to that described in Example 13 and the crude product was purified by silica gel chromatography eluting with ethyl acetate containing 10% v/v triethylamine to give the product as a colourless oil (131 mg).

¹H-NMR (300 MHz, CDCl₃): δ 1.21 - 1.60 (m, 4H), 1.60 - 1.90 (m, 4H), 2.03 - 2.36 (m, 6H), 2.46 (d, IH), 3.13 (t, 2H), 3.56 (t, IH), 5.94 (s, IH); GC-MS m/z: 189 [M⁺].

Example 22

N-Methyl-N-(3-{ri-(^'{r(^'4^-4-methyl-2.5-dioxoimidazolidin-4-yllmethvUsulfonvn-1.2.3.6- tetrahvdropyridin-4-yllethvnyliphenvπmethanesulfonamide

The title compound was prepared following the general method of Erdelyi et al, J Org. Chem., 2001, 66, 4165-4169. (5S>5-[(4-Ethynyl-3,6-dihydro-2H-pyridin-l- yl)sulfonylmethyl]-5-methyl-3-(2-trimethylsilylethoxymethyl)imidazolidine-2,4-dione(237 mg, 0.55 mmol) was added to a solution of 7V-(3-bromophenyl)-7V- methylmethanesulfonamide (133 mg, 0.5 mmol), Pd(PPhS)₂Cl₂ (10 mg) and CuI (3 mg) in DMF (1 mL). Diisopropylamine (0.21 mL) was added last and the heavy- walled vial was purged with argon and sealed. The reaction mixture was stirred and heated at 120 ⁰C for 30 min in a microwave reactor, then diluted with EtOAc and filtered through a short silica plug and concentrated. The residual material was purified by flash chromatography using a gradient of EtO Ac/heptane 0:100 to EtO Ac/heptane 100:0, giving the SEM protected product as a yellow oil. This material was deprotected at RT by dissolving the oil in DCM (5 mL) and TFA (0.5 mL). After 12 h, the mixture was evaporated and the residue was re- dissolved in MeOH/DMF (5 mL/0.5 mL) and 28% NH₃ (aq) (2 mL) and stirred for 5h. Evaporation and purification by preparative HPLC afforded the title compound as a white solid (93 mg, 39% overall yield). 1H-NMR (300 MHz, DMSO-d₆): δlθ.76 (s, IH), 8.04 - 8.02 (m, IH), 7.50 - 7.47 (m, IH),

7.45 - 7.35 (m, 3H), 6.29 - 6.21 (m, IH), 3.85 - 3.79 (m, 2H), 3.42 - 3.34 (m, 2H), 3.34 - 3.27 (m, 2H), 3.24 (s, 3H), 3.24 (s, 3H), 2.41 - 2.32 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 481 [MH⁺].

The starting material was prepared as follows:

a) Λ/-(3-Bromophenyl)-Λ/-methylmethanesulfonamide

3-Bromo-N-methylaniline (0.24 mL, 1.9 mmol) and DIPEA (0.36 mL, 2.1 mmol) were mixed in dry DCM (5 mL) and cooled to 0 ⁰C. Methanesulphonylchloride (0.15 mL, 1.9 mmol) was added dropwise at 0 ⁰C. The reaction mixture was allowed to reach RT and stirred overnight. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with 0.1N HCl, dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography eluting with heptane/EtOAc 3:1 to give a solid product (0.27 g, 53%).

¹H-NMR (300 MHz, DMSOd₆): δ 7.63 (t, J= 2.0 Hz, IH), 7.53 - 7.49 (m, IH), 7.46 - 7.34 (m, 2H), 3.24 (s, 3H), 2.98 (s, 3H); GC-MS m/z: 263/265 1:1 [M⁺].

b) (5^-5-r(4-Ethvnyl-3.6-dihvdro-2H-pyridin-l-vnsulfonylmethyll-5-methyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione

Potassium fluoride (0.87 g, 15 mmol) and (55)-5-methyl-3-(2-trimethylsilylethoxymethyl)- 5 - [[4-(2-trimethylsilylethynyl)-3 ,6-dihydro-2H-pyridin- 1 -yl] sulfonylmethyl] imidazolidine- 2,4-dione (3 g, 6 mmol) were mixed in methanol (35 mL) and stirred overnight. The mixture was cooled in an ice bath and the solid material was collected. To the mother liquid was added water (50 mL) and more solid material was collected. The combined solids were dried in vacuum at 40 ⁰C to give the product as a white solid (2.4 g, 94%). ¹H NMR (SOO MHZ, DMSOd₆): 5 8.50 (s, IH), 6.15 - 6.11 (m, IH), 4.73 (s, 2H), 3.98 (s,

IH), 3.77 - 3.72 (m, 2H), 3.64 - 3.45 (m, 4H), 3.24 (t, J= 5.8 Hz, 2H), 2.28 - 2.19 (m, 2H), 1.35 (s, 3H), 0.88 - 0.80 (m, 2H), -0.03 (s, 9H).

c) (5y)-5-Methyl-3-(2-trimethylsilylethoxymethvπ-5-rr4-(2-trimethylsilylethynvπ- 3,6-dihvdro-2H-pyridin-l-yllsulfonylmethyllimidazolidine-2,4-dione 2-(Trimethylsilyl)ethoxymethyl chloride (4.8 mL, 27 mmol) was added dropwise to a solution of a (55)-5-methyl-5-[[4-(2-trimethylsilylethynyl)-3,6-dihydro-2H-pyridin-l- yl]sulfonylmethyl]imidazolidine-2,4-dione (WO2006/004532) (5 g, 13.5 mmol) and DIPEA (4.6 mL, 27 mmol) in DCM/DMF 4:1 (90 mL) at 0 ⁰C. The mixture was stirred at RT overnight, washed with water, brine and concentrated. The residual material was purified by flash chromatography using a gradient of EtO Ac/heptane 0:100 to EtO Ac/heptane 100:0, giving the product as a white solid (5.4 g, 81%).

¹H NMR (SOO MHz, DMSO-d₆): δ 8.49 (s, IH), 6.15 - 6.10 (m, IH), 4.73 (s, 2H), 3.76 -

3.72 (m, 2H), 3.63 - 3.44 (m, 4H), 3.22 (t, J= 5.7 Hz, 2H), 2.27 - 2.19 (m, 2H), 1.35 (s, 3H), 0.88 - 0.79 (m, 2H), 0.16 (s, 9H), -0.03 (s, 9H);

APCI-MS m/z: 571 [MH⁺].

Example 23

5-(ri-((r(4y)-4-Methyl-2.5-dioxoimidazolidin-4-yl1methylisulfonvπ-1.2.3.6- tetrahvdropyridin-4-yl1ethvnyli-3.4-dihvdroquinoline-l(2//)-carbaldehyde The title compound was prepared from 5-bromo-3,4-dihydroquinoline-l(2H)-carbaldehyde and (55)-5-[(4-ethynyl-3,6-dihydro-2H-pyridin-l-yl)sulfonylmethyl]-5-methyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione by a method analogous to that described in Example 22. 1H-NMR (DMSOd₆): δ 10.76 (s, IH), 8.83 and 8.65 rotamers 8:2 (s, IH), 8.04 (s, IH),

7.46 - 7.38 (m, IH), 7.28 - 7.18 (m, 2H), 6.27 - 6.20 (m, IH), 3.87 - 3.80 (m, 2H), 3.71 - 3.64 (m, 2H), 3.57 - 3.37 (m, 2H), 3.31 (t, J= 5.7 Hz, 2H), 2.85 (t, J= 6.7 Hz, 2H), 2.43 - 2.34 (m, 2H), 1.92 - 1.81 (m, 2H), 1.33 (s, 3H);

APCI-MS m/z: 457 [MH⁺].

The starting material was prepared as follows:

5-Bromo-3,4-dihvdroquinoline-l(2//)-carbaldehyde

5-Bromoquinoline (0.21 g, 1 mmol) was mixed with a 2:1 mixture of triethylammonium formate/ formic acid (2 mL) prepared according to J Chem. Res. (S) 2001, 525-527 and heated at 150 ⁰C in a sealed heavy-walled vial in the microwave reactor for 2.5 h. The mixture was diluted with water, extracted with EtOAc and concentrated. The residual material was purified by flash chromatography using heptane/EtOAc 4:1, giving the product as a white solid (0.16 g, 65%). 1H-NMR (300 MHz, CDCl₃): δ 8.94 and 8.75 rotamers 1 :9 (s, IH), 7.44 - 7.39 (m, IH),

7.12 - 7.08 (m, 2H), 3.84 - 3.79 and 3.67-3.62 rotamers 9:l(m, 2H), 2.87 (t, J= 6.7 Hz, 2H), 2.04 - 1.94 (m, 2H);

APCI-MS m/z: 240/242 1:1 [MH⁺].

Example 24

(55V5-Methyl-5-( ([4-(Pl -(methylsulfonvO- lH-indol-4-yllethynvU -3.6-dihydropyridin- l(2H)-yllsulfonyl|methvπimidazolidine-2.4-dione

The title compound was prepared from 4-bromo-l -(methylsulfonyl)- IH- indole and (5S)-5- [(4-ethynyl-3,6-dihydro-2H-pyridin-l-yl)sulfonylmethyl]-5-methyl-3-(2- trimethylsilylethoxymethyl)imidazolidine-2,4-dione by a method analogous to that described in Example 22.

¹H-NMR (DMSOd₆): δ 10.76 (s, IH), 8.05 (s, IH), 7.89 - 7.84 (m, IH), 7.69 (d, J= 3.6

Hz, IH), 7.43 - 7.35 (m, 2H), 6.90 - 6.87 (m, IH), 6.36 - 6.30 (m, IH), 3.89 - 3.82 (m, 2H), 3.60 - 3.39 (m, 5H), 3.34 (t, J= 5.9 Hz, 2H), 2.48 - 2.39 (m, 2H), 1.34 (s, 3H);

APCI-MS m/z: 491 [MH⁺].

The starting material was prepared as follows:

4-Bromo- 1 -(methylsulfonyl)- IH- indole

Sodium hydride (122 mg, 55% in mineral oil, 2.8 mmol) was slurried in dry DMF (2 mL) and 4-bromoindole (0.5 g, 2.5 mmol) in dry DMF (1 mL) was added dropwise at 0 °C. After 0.5 h, methanesulphonyl chloride (0.19 mL, 2.5 mmol) was added dropwise at 0 ⁰C and the reaction was stirred at RT overnight. DCM was added and the mixture was washed with water and brine, dried (Na₂SO₄) and concentrated. The residual material was purified by flash chromatography heptane/EtOAc 3:1, giving the product as a 1:1 mixture of the product and starting material (0.48 g) that was used in the coupling reaction above without further purification.

APCI-MS m/z: 273/275 1:1 [MH⁺].

Example 25

(56^f)-5-({r4-{r3-(3,3-Dimethyl-2-oxoazetidin-l-yl)phenyllethvnvU-3,6-dihvdropyridin- l(2H)-yllsulfonylimethvπ-5-methylimidazolidine-2.4-dione

The title compound was prepared following the general method of Erdelyi et al, J Org. Chem., 2001, 66, 4165-4169. l-(3-Ethynylphenyl)-3,3-dimethyl-2-azetanone (199 mg, 1.0 mmol) was added to a solution of l-({[(45)-4-methyl-2,5-dioxo-l-{[2- (trimethylsilyl)ethoxy]methyl} imidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl trifluoromethanesulfonate (see Example 20) (496 mg, 0.9 mmol), Pd(PPh₃)₂Cl₂ (12 mg), CuI (7 mg), LiCl (60 mg) in DMF (0.5 mL). Diisopropylamine (0.5 mL) was added last and the heavy- walled vial was purged with argon and sealed. The reaction mixture was stirred and heated at 120 ⁰C for 7 min in a microwave reactor, then diluted with EtOAc and filtered through a short silica plug and concentrated. The residual material was purified by flash chromatography using a gradient of EtO Ac/heptane 0:100 to EtO Ac/heptane 100:0, giving the SEM protected product as a yellow oil. This material was deprotected at RT by dissolving the oil in DCM (6 mL) and TFA (0.6 mL). After 12 h the mixture was evaporated and the residue was re-dissolved in MeOH (5 mL) and 28% NH₃(aq) (2 mL) and stirred for 12 h. Evaporation and purification by preparative HPLC afforded the title compound as a white solid (216 mg, 46% overall yield).

¹H-NMR (DMSO-d₆): δ 10.76 (s, IH), 8.05 - 8.01 (m, IH), 7.42 - 7.33 (m, 3H), 7.19 - 7.13 (m, IH), 6.24 (s, IH), 3.85 - 3.79 (m, 2H), 3.51 (s, 2H), 3.45 - 3.36 (m, 2H), 3.33 - 3.26 (m, 2H), 2.41 - 2.32 (m, 2H), 1.33 (s, 3H), 1.30 (s, 6H);

APCI-MS m/z: 471 [MH⁺].

Example 26

5-Methyl-5-[4-(tetrahvdro-thiopyran-4-ylethvnyl)-3,6-dihvdro-2H-pyridine-l- sulfonylmethyll-imidazolidine-2.4-dione

A mixture of trimethyl-(tetrahydro-thiopyran-4-ylethynyl)-silane (0.020 g, 0.1 mmol), PdCl₂(PPh₃)₂ (7 mg, 0.01 mmol) and CuI (2 mg, 0.01 mmol) in DMF (2 mL) was degassed and the vessel back-filled with argon three times. l-({[(4S)-4-Methyl-2,5- dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3 ,6-tetrahydropyridin-4-yl trifiuoromethanesulfonate (0.042 g, O.lmmol) (WO 2006/004532) in DMF (1.0 mL) was added and reaction was stirred at 80 ⁰C for 3 h. The mixture was filtered through a plug of silica gel. Preparative HPLC gave the title compound as a solid (10 mg, 25%).

¹H-NMR (DMSOd₆): δ 10.74 (s, IH), 8.01 (s, IH), 6.01 (m, IH), 3.74 (m, 2H), 3.58 -

3.38 (m, 2H), 2.78-2.64 (m, 3H), 2.58-2.5 (m, 3H), 2.22 (m, 2H), 2.05-1.96 (m, 2H), 1.76- 1.65 (m, 2H) 1.33 (s, 3H);

APCI-MS m/z: 398 [MH⁺].

The starting material was prepared as follows:

a) Trimethyl(tetrahvdro-2H-thiopyran-4-ylethvnyl)silane 4-Ethynyltetrahydro-2H-thiopyran (47.4 g, 0.38 mol) was dissolved in THF (300 mL) and cooled to -75 ⁰C. Butyllithium (1.6M in hexane, 305 mL. 0.49 mol) was added slowly whilst the temperature was kept below -65 ⁰C. After 15 min at -75 ⁰C, trimethylchlorosilane (53 g/62 mL, 0.49 mol) was added whilst the temperature was kept below -60 ⁰C. After 15 min at -75 ⁰C, the reaction mixture was allowed to reach RT. Saturated aqueous NH4CI (75 mL) was added slowly, the volatiles were evaporated off, the residue was partitioned between water and tøt-butylmethylether, the organic layer was separated, washed with brine and adsorbed onto silica and evaporated. Purification by a short dry flash chromatography using tert-butyl methyl ether as eluent, yielded the title compound (75 g, 92%).

¹H NMR (400MHz, CDCl₃) δ 2.91 - 2.83 (m, 2H), 2.65 - 2.59 (m, IH), 2.52 - 2.45 (m, 2H), 2.08 - 2.00 (m, 2H), 1.93 - 1.84 (m, 2H), 0.17 - 0.16 (m, 9H); GC-MS: 198 [MH⁺]. b) 4-Ethvnyltetrahvdro-2H-thiopyran

4-(Methoxymethylene)tetrahydro-2H-thiopyran (50 g, 350 mmol) was dissolved in THF (400 mL) and cooled to 5 ⁰C. 3M HCl(aq) (150 mL) was added slowly. After 4 h at RT, the reaction mixture was poured into a cooled solution of sodium carbonate (60 g, 0.38 mol in 400 mL water). After addition of sodium chloride, the phases were separated. The aqueous phase was extracted three times with DCM. The combined organic phases were washed with brine, dried over Na₂SO₄ and evaporated to yield tetrahydro-2H-thiopyran-4- carbaldehyde (45 g, 99%). Trimethylsilyl-diazomethane (193 mL, 0.39 mol, 2M in heptane) was diluted with dry THF (500 mL) and cooled to -75 ⁰C. LDA (2M in THF, 193 mL, 0.39 mol) was added slowly whilst the temperature was kept below -65 ⁰C. After 15 min at -75 ⁰C, tetrahydro-2H- thiopyran-4-carbaldehyde (45 g, 0.35 mol) dissolved in THF (200 mL) was added slowly whilst the temperature was kept below - 65 ⁰C. After 15 minutes at -70 ⁰C, the mixture was allowed to reach the RT during 1 h. Volatiles were evaporated and the crude product was extracted into tert-butyl methyl ether from water, the water phase was acidified with 3M HCl(aq). The organic layer was dried with Na₂SO₄ and evaporated. The crude product was purified by distillation (b.p. 62 - 65 ⁰C, 9 -11 mBar) to yield the title compound (27 g, 61%). 1H NMR (400MHz, CDCl₃) δ 2.90 - 2.82 (m, 2H), 2.64 - 2.57 (m, IH), 2.55 - 2.48 (m, 2H), 2.14 (d, J= 2.4 Hz, IH), 2.11 - 2.03 (m, 2H), 1.94 - 1.85 (m, 2H); GC-MS: 126 [M⁺].

c) 4-(Methoxymethylene)tetrahvdro-2H-thiopyran A slurry of (methoxymethyl)triphenylphosphonium chloride (266 g, 770 mmol) and THF (400 mL) was cooled to - 50 ⁰C. LDA (390 mL, 0.78 mol, 2M in THF) was added slowly and the temperature was kept below -20 ⁰C. After 15 min, tetrahydrothiopyran-4-one dissolved in THF (250 mL) was added slowly at -40 ⁰C. After 15 min, the reaction mixture was allowed to reach RT and was then stirred overnight. The mixture was cooled to 3 ⁰C and the precipitate was filtered off, the filtrate was evaporated and the crude residue purified by distillation, (B.p. 90 -105 ⁰C, 14 mbar) to yield the title compound (68 g,

73%).

¹H NMR (400MHz, CDCl₃) δ 5.82 (s, IH), 3.54 (s, 3H), 2.63 - 2.58 (m, 4H), 2.56 - 2.50 (m, 2H), 2.30 - 2.26 (m, 2H); GC-MS: m/z 144 [M⁺].

Pharmacological Example

Isolated Enzyme Assays

MMP12

Recombinant human MMP 12 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20, 152. The purified enzyme can be used to monitor inhibitors of activity as follows: MMP 12 (50 ng/ml final concentration) is incubated for 60 minutes at room temperature with the synthetic substrate

Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH₂ (10 μM) in assay buffer (0.1M "Tris-HCl"

(trade mark) buffer, pH 7.3 containing 0.1M NaCl, 2OmM CaCl₂, 0.020 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (10 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 320 nm and λem 405 nm. Percent inhibition is calculated as follows:

% Inhibition is equal to the [Fluorescence^/^ inhibi_tor - Fluorescence b_ack_ground] divided by the [Fluorescence_røWM5 inhibitor - Fhiσresc&i∞background]-

MMP8 Purified pro-MMP8 is purchased from Calbiochem. The enzyme (at 10 μg/ml) is activated by p-amino-phenyl-mercuric acetate (APMA) at 1 mM for 2.5 h, 35 ⁰C. The activated enzyme can be used to monitor inhibitors of activity as follows: MMP8 (200 ng/ml final concentration) is incubated for 90 minutes at 35 ⁰C (80% H₂O) with the synthetic substrate

Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH₂ (12.5 μM) in assay buffer (0.1M "Tris-HCl" (trade mark) buffer, pH 7.5 containing 0. IM NaCl, 3OmM CaCl₂, 0.040 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (10 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 320 nm and λem 405 nm. Percent inhibition is calculated as follows:

% Inhibition is equal to the [Fluorescence^/^ inhibi_tor - Fluorescence£_αc£_gr_OMW</] divided by the [Fluorescence_røWM5 inhibi_tor - Fluorescence£_αc£_gr_OMW</] .

MMP9

Recombinant human MMP9 catalytic domain was expressed and then purified by Zn chelate column chromatography followed by hydroxamate affinity column chromatography. The enzyme can be used to monitor inhibitors of activity as follows: MMP9 (5 ng/ml final concentration) is incubated for 30 minutes at RT with the synthetic substrate Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH₂ (5 μM) in assay buffer (0.1M "Tris-

HCl" (trade mark) buffer, pH 7.3 containing 0.1M NaCl, 2OmM CaCl₂, 0.020 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (10 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 320 nm and λem 405 nm. Percent inhibition is calculated as follows:

% Inhibition is equal to the [Fluorescence^/^ inhibi_tor ~ Fluorescence^^c^ j] divided by the [Fluorescence_røWM5 inhibitor -

MMP14

Recombinant human MMP 14 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20, 152. The purified enzyme can be used to monitor inhibitors of activity as follows: MMP 14 (10 ng/ml final concentration) is incubated for 60 minutes at room temperature with the synthetic substrate Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH₂ (10 μM) in assay buffer (0.1M "Tris-HCl"

(trade mark) buffer, pH 7.5 containing 0.1M NaCl, 2OmM CaCl₂, 0.020 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (5 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 320 nm and λem 405 nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescence^/^ inhibi_tor ~ Fluorescence b_ack_ground] divided by the [Fluorescence_røWM5

inhibitor - FluorescencefødfcgroiWl ^•

A protocol for testing against other matrix metalloproteinases, including MMP9, using expressed and purified pro MMP is described, for instance, by C. Graham Knight et ah, (1992) FEBS Lett., 296(3), 263-266.

MMP19

Recombinant human MMP 19 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20: 152. The purified enzyme can be used to monitor inhibitors of activity as follows: MMP 19 (40 ng/ml final concentration) is incubated for 120 minutes at 35 ⁰C with the synthetic substrate Mca-Pro-

Leu-Ala-Nva-Dpa-Ala-Arg-NH₂ (5 μM) in assay buffer (0.1M "Tris-HCl" (trade mark) buffer, pH 7.3 containing 0.1M NaCl, 2OmM CaCl₂, 0.020 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (5 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 320 nm and λem 405 nm. Percent inhibition is calculated as follows: % Inhibition is equal to the

[Fluorescence^ inhibi_tor - ^^orescence b_ack_ground! divided by the [Fluorescence^^

inhibitor - FluorescencefødfcgroiWl ^•

The following table shows data for a representative selection of the compounds of the present invention and for selected compounds from WO 02/074767, WO 2006/004532 and WO 2006/004533. Table

Claims

C L A I M S

1. A compound selected from: (55)-5-methyl-5-({[4-{[l-(methylsulfonyl)-2,3-dihydro-7H-indol-4-yl]ethynyl}-3,6- dihydropyridm-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

N-(3-chloro-5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-Λ/-methylformamide;

(5S)-5 -( { [4- { [2-(dimethylamino)pyridin-4-yl] ethynyl} -3 ,6-dihydropyridin- 1 (2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; (55)-5-({[4-{[3-fluoro-5-(2-oxopyrrolidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-({[4-{[3-fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-methyl-5-({[4-{[3-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- 1 (2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; methyl(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide;

4-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}indoline-l-carbaldehyde; (55)-5-methyl-5-({[4-{[3-(2-oxopyrrolidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

2-hydroxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile; (5S)-5-methyl-5-({[4-(quinolin-5-ylethynyl)-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)imidazolidine-2,4-dione;

(55)-5-({[4-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-5-yl)ethynyl]-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; 5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl} -3 ,4-dihydroisoquinoline-2( l//)-carbaldehyde;

3,6-dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

(55)-5-methyl-5-({[4-[(2 -methyl- l-oxo-l,2,3,4-tetrahydroisoquinolin-5-yl)ethynyl]-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

N-(3-fluoro-5-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-7V-methylformamide;

(55)-5 -( { [4-(cyclohexylethynyl)-3 ,6-dihydropyridin- 1 (2H)-yl] sulfonyl} methyl)-5 - methylimidazolidine-2,4-dione;

tetrahydropyridin-4-yl]ethynyl}phenyl)methanesulfonamide;

5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}-3,4-dihydroquinoline-l(2H)-carbaldehyde;

(55)-5-methyl-5-({[4-{[l-(methylsulfonyl)-lH-indol-4-yl]ethynyl}-3,6-dihydropyridin- 1 (2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;

(55)-5-({[4-{[3-(3,3-dimethyl-2-oxoazetidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

5 -methyl-5 - [4-(tetrahydro-thiopyran-4-ylethynyl)-3 ,6-dihydro-2H-pyridine- 1 - sulfonylmethyl]-imidazolidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

2. A compound according to Claim 1 selected from:

N-(3-chloro-5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-Λ/-methylformamide; N-ethyl-N-(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide; Λ/-cyclopropyl-Λ/-(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)- l,2,3,6-tetrahydropyridin-4-yl]ethynyl}phenyl)formamide;

(55)-5-methyl-5-({[4-{[3-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; methyl(3- { [ 1 -( { [(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3 ,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide;

4-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}indoline-l-carbaldehyde;

(55)-5 -methyl-5 -( { [4- { [3 -(2-oxopyrrolidin- 1 -yl)phenyl] ethynyl} -3 ,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; (55)-5-({[4-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-5-yl)ethynyl]-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

5-{[l<{[(45)^-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl} -3 ,4-dihydroisoquinoline-2( lH)-carbaldehyde;

N-(3-fluoro-5-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-Λ/-methylformamide;

5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}-3,4-dihydroquinoline-l(2H)-carbaldehyde; (55)-5-({[4-{[3-(3,3-dimethyl-2-oxoazetidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

3. A compound according to Claim 1 selected from: (55)-5-methyl-5-({[4-{[l-(methylsulfonyl)-2,3-dihydro-7H-indol-4-yl]ethynyl}-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; N-(3-chloro-5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl] ethynyl} phenyl)-7V-methylformamide;

N-ethyl-N-(3-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide; (55)-5-({[4-{[2-(dimethylamino)pyridin-4-yl]ethynyl}-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-({[4-{[3-fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- 1 (2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; methyl(3- { [ 1 -( { [(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3 ,6- tetrahydropyridin-4-yl]ethynyl}phenyl)formamide;

1 -(3- { [ 1 -( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)cyclopropanecarbonitrile; 2-methoxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile;

(5S)-5-methyl-5-({[4-(quinolin-5-ylethynyl)-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)imidazolidine-2,4-dione;

5-{[l-({[(45)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}-3,4-dihydroquinoline-l(2H)-carbaldehyde; (55)-5-({[4-(cyclohexylethynyl)-3,6-dihydropyridin-l(2H)-yl]sulfonyl}methyl)-5- methylimidazolidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

4. A compound according to Claim 1 selected from: (55)-5-methyl-5-({[4-{[l-(methylsulfonyl)-2,3-dihydro-7H-indol-4-yl]ethynyl}-3,6- dihydropyridin-l(2H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione; (5S)-5 -( { [4- { [2-(dimethylamino)pyridin-4-yl] ethynyl} -3 ,6-dihydropyridin- 1 (2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

(55)-5-({[4-{[3-fluoro-5-(2-oxopyrrolidin-l-yl)phenyl]ethynyl}-3,6-dihydropyridin-l(2H)- yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione; 5 (55)-5-({[4-{[3-fluoro-5-(2-oxo-l,3-oxazolidin-3-yl)phenyl]ethynyl}-3,6-dihydropyridin- l(2H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;

2-methoxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- i o tetrahydropyridin-4-yl] ethynyl} benzonitrile;

(5S)-5-methyl-5-({[4-(quinolin-5-ylethynyl)-3,6-dihydropyridin-l(2Η)- yl]sulfonyl}methyl)imidazolidine-2,4-dione;

5. A compound according to Claim 1 selected from:

20 1 -(3- { [ 1 -( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]ethynyl}phenyl)cyclopropanecarbonitrile;

2-methoxy-4-{[l-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-l,2,3,6- tetrahydropyridin-4-yl]ethynyl}benzonitrile; or a pharmaceutically acceptable salt thereof.

25

6. A process for the preparation of a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 5.

7. A pharmaceutical composition comprising a compound or a pharmaceutically 30 acceptable salt thereof as claimed in any one of claims 1 to 5 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

8. A process for the preparation of a pharmaceutical composition as claimed in claim 7 which comprises mixing a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 for use as a medicament.

10. Use of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 in the manufacture of a medicament for use in the treatment of an obstructive airways disease.

11. Use according to claim 10, wherein the obstructive airways disease is asthma or chronic obstructive pulmonary disease.

12. Use of a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5 in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, osteoarthritis, atherosclerosis, periodontal disease or multiple sclerosis.

13. A method of treating a disease or condition mediated by MMP 12 which comprises administering to a patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5.

14. A method of treating an obstructive airways disease which comprises administering to a patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5.

15. A pharmaceutical product comprising, in combination, two or more active ingredients including a first active ingredient which is a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, and one or more further active ingredients which are selected from: - a phosphodiesterase inhibitor;

- a β2-adrenoceptor agonist;

- a modulator of chemokine receptor function;

- an inhibitor of kinase function;

- a protease inhibitor;

- a glucocorticoid;

- an anticholinergic agent; and

- a non-steroidal glucocorticoid receptor agonist.