WO2011154677A1 - Composés n-[1-cyano-2-(phényl)éthyl] 1-aminocycloalk-1-ylcarboxamide substitués - 760 - Google Patents

Composés n-[1-cyano-2-(phényl)éthyl] 1-aminocycloalk-1-ylcarboxamide substitués - 760 Download PDF

Info

Publication number
WO2011154677A1
WO2011154677A1 PCT/GB2010/050963 GB2010050963W WO2011154677A1 WO 2011154677 A1 WO2011154677 A1 WO 2011154677A1 GB 2010050963 W GB2010050963 W GB 2010050963W WO 2011154677 A1 WO2011154677 A1 WO 2011154677A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
amino
cyano
ethyl
oxo
Prior art date
Application number
PCT/GB2010/050963
Other languages
English (en)
Inventor
Rhonan Ford
Elizabeth Kinchin
Andrew Mather
Antonio Mete
Ian Millichip
Andrew Geoffrey Stanier
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to PCT/GB2010/050963 priority Critical patent/WO2011154677A1/fr
Publication of WO2011154677A1 publication Critical patent/WO2011154677A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • C07C255/44—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to nitrile compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Dipeptidyl peptidase I (DPPI; EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine protease belonging to the papain family having a molecular weight of 200 kDa.
  • DPPI was first discovered by Gutman and Fruton in 1948 (J Biol Chem, 174, 851-858); however, the cDNA of the human enzyme was first described in 1995 (Paris et al. 1995, FEBS Lett, 369, 326-330).
  • DPPI is the only member of the papain family that is functional as a tetramer, consisting of four identical subunits. Each subunit is composed of an N-terminal fragment, a heavy chain and a light chain (Dolenc et al. 1995, J Biol Chem, 270, 21626- 21631).
  • DPPI is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen. DPPI catalyses the removal of dipeptides from the N-terminal end of polypeptide substrates with broad specificity. Recent data suggest that besides being an important enzyme in lysosomal protein degradation, DPPI also functions as a key enzyme in the activation of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G and elastase).
  • granzymes A and B cytotoxic T lymphocytes and natural killer cells
  • mast cells chymase and tryptase
  • neutrophils cathepsin G and elastase
  • Mast cells are found in many tissues but are present in greater numbers along the epithelial linings of the body, such as the skin, respiratory tract and gastrointestinal tract. In humans, two types of mast cells have been identified. The T-type, which expresses only tryptase, and the MC-type, which expresses both tryptase and chymase. In humans, the T- type mast cells are located primarily in alveolar tissue and intestinal mucosa while the TC- type cells predominate in skin and conjunctiva. Tryptase and chymase appear to be important mediators of allergic diseases, being involved in processes of inflammation,
  • Neutrophils are produced in the bone marrow and are fully mature when released into the circulation to take up their role as the first line of cellular defence.
  • Pro -inflammatory mediators and chemotactic attractants activate neutrophils and draw them to the site of infection, where they act to engulf bacteria by phagocytosis, assaulting them with an arsenal of anti-bacterial compounds that use both oxidative and non-oxidative methods of attack.
  • the powerful serine protease, neutrophil elastase is one of those anti-bacterial compounds that are clearly involved in destroying bacteria. Neutrophil elastase is released into the phagolysome surrounding the microorganism, which it proceeds to destroy.
  • Neutrophil elastase is able to attack the outer membrane protein, OmpA, in gram-negative bacteria, helping to directly kill the pathogen by degrading its membrane, as well as enabling other anti -bacterial compounds to gain access to the pathogen.
  • neutrophil elastase may help process other antibacterial compounds, converting them from inactive pro-peptides into their active states, such as for cathelicidin.
  • neutrophil elastase can also cause problems for its host. It is one of the most destructive enzymes in the body, with the capability of degrading extracellular matrix proteins (including collagens, proteoglycan, fibronectin, platelet receptors, complement receptor, thrombomodulin, lung surfactant and cadherins) and key plasma proteins (including coagulation and complement factors, immunoglobulin, several proteases and protease inhibitors). Under physiological conditions, endogenous protease inhibitors, such as al- antitrypsin, tightly regulate the activity of neutrophil elastase.
  • extracellular matrix proteins including collagens, proteoglycan, fibronectin, platelet receptors, complement receptor, thrombomodulin, lung surfactant and cadherins
  • key plasma proteins including coagulation and complement factors, immunoglobulin, several proteases and protease inhibitors.
  • endogenous protease inhibitors such as al- antitrypsin, tightly regulate the activity of neutrophil e
  • neutrophil elastase is able to evade regulation, and once unregulated it can induce the release of pro-inflammatory cytokines, such as interleukin-6 and interleukin-8, leading to acute lung injury. It can even impair host defence against infection by degrading phagocyte surface receptors and opsonins. Its negative role is illustrated by its involvement in the tissue destruction and inflammation that characterise numerous diseases, including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemic-reperfusion injury and rheumatoid arthritis.
  • nitrile derivatives are inhibitors of DPPI.
  • One of the disclosed compounds is (5)-2-amino-N- ((S)-2-(biphenyl-4-yl)- 1 -cyanoethyl)butanamide.
  • a nitrile compound which bears a saturated carbocyclic ring (for example cyclopentyl) between the NH 2 and amide groups.
  • y 0, 1 or 2;
  • n 1, 2, 3 or 4;
  • R 1 is hydroxyl, halogen, Ci_ 3 alkoxy (optionally substituted with one or more substituents selected from halogen, hydroxy and Ci_ 3 alkoxy) or Ci_ 3 alkyl (optionally substituted with one or more substituents independently selected from halogen, hydroxy and Ci_ 3 alkoxy);
  • R is selected from hydrogen, halogen, CN, CF 3 , Ci_ 3 alkyl and Ci_ 3 alkoxy;
  • Q represents phenyl, a 5- to 10-membered heteroaryl ring system or Q is of the formula
  • X is CH or N
  • Y is CH or N
  • B is a 5- or 6-membered heterocyclic ring containing 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulphur; the phenyl , 5- to 10-membered heteroaryl ring system and ring system A being optionally substituted by more or more substituents independently selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_ 6 alkyl group, Ci_ 6 alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_ 6 alkoxy, C 3 - 6 cycloalkyl, NR 61 S0 2 R 62 , S(0)vR 63 , NR 65 R 66 , phenyl and C-linked morpholinyl), C 3 _ 6 cycloalkyl, C 2 _ 6 alkenyl, trifluor
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group; provided that R 62 , R 63 and R 64 are not hydrogen;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • halogen is CI, F, Br or I;
  • cycloalkyl is a non-aromatic carbocyclic ring containing the requisite number of carbon atoms, optionally containing, where possible, up to 3 double bonds, and optionally substituted with 1 to 3 substituents selected from (Ci-6)alkyl,
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentene, cyclopenta-l,3-diene, cyclohexene and cyclohexa-1,4- diene (optionally substituted as stated above).
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl, preferably furyl, thienyl, oxazolyl, isoxazolyl, imidazoly
  • the present invention allows for heteroaryl groups to be optionally substituted by on oxo group.
  • a heteroaryl group such as pyridine could be substituted by an oxo group to form a pyridone.
  • These 'heteroaryl' groups are within the scope of the invention.
  • alkyl and alkoxy groups containing the requisite number of carbon atoms can be branched or unbranched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl.
  • suitable alkoxy groups include methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy, i-propoxy, n-butoxy, sec- butoxy and t-butoxy.
  • a saturated 4- to 7-membered heterocyclic ring may be partially unsaturated but not fully unsaturated.
  • a heterocylic ring will contain at least one ring heteroatom selected from nitrogen, oxygen and sulphur. It is, for example, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl.
  • ring system A examples include:
  • R' is selected from hydrogen, C 3 _ 7 cycloalkyl and Ci_ 6 alkyl the alkyl group being optionally substituted by 1 or 2 substituents
  • ring system A has no further substituents in addition to R'.
  • heterocyclic rings in formula (I) are not intended to include unstable structures or any O-O, 0-S or S-S bonds and that a substituent, if present, may be attached to any suitable ring atom provided the resulting compound is not unstable.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
  • pharmaceutically acceptable base addition salts that can be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, tosylates,
  • benzenesulfonates maleates, fumarates, xinafoates, p-acetamidobenzoates, succinates, ascorbates, oleates, bisulfates, furoates, propionates, stearates, isethionates and the like.
  • pharmaceutically acceptable salts may include salts of
  • organic acids especially carboxylic and sulfonic acids, including, but not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, butyrate, camphorate, camphorsulfonate, camsylate, citrate, p- chlorobenzenesulfonate, cyclopentate, 2,5-dichlorobesylate, digluconate, edisylate, esylate, fumarate, formate, gluconate, glucoheptanoate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2-hydroxyethane sulfonate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, 2-naphthalenesulfonate, 2-
  • inorganic acids such as hydrobromide, hydrochloride, hydroiodide, sulphate, bisulfate, phosphate, nitrate, hemisulfate, thiocyanate, persulfate, phosphoric and sulfonic acids.
  • Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
  • the compounds of the invention can exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when the solvent is water.
  • enantiomeric, diastereomeric and tautomeric forms including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms.
  • a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques).
  • such isomers can be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).
  • the invention relates to compounds of the formula (I) in which the stereochemistry at the carbon adjacent to the NH group and substituted by cyano has the S stereochemistry.
  • y 0, 1 or 2;
  • n 1, 2, 3 or 4;
  • R 1 is hydroxyl, halogen, Ci_ 3 alkoxy (optionally substituted with one or more substituents selected from halogen, hydroxy or Ci_ 3 alkoxy) or Ci_ 3 alkyl (optionally substituted with one or more substituents selected from halogen, hydroxy or Ci_ 3 alkoxy)
  • R is selected from hydrogen, halogen, CN, CF 3 , Ci_ 3 alkyl or Ci_ 3 alkoxy;
  • Q represents phenyl or a 5- to 10-membered heteroaryl ring system, the phenyl or 5- to 10-membered heteroaryl ring system being optionally substituted by halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_ 6 alkyl group (itself optionally substituted by hydroxyl, Ci_ 6 alkoxy, NR 65 R 66 , phenyl or C-linked morpholinyl),
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • Each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group; R 62 , R 63 and R 64 are not hydrogen;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R , R , y, n and Q are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter:
  • y 0, 1 or 2.
  • y 1
  • y 0 or 1.
  • n 1 , 2, 3, or 4 . n represents 1.
  • n 2.
  • n 3.
  • n 4.
  • n 2 or 3.
  • R 1 is Ci_ 3 alkyl optionally substituted with one or more substituents selected from halogen, hydroxy or Ci_ 3 alkoxy.
  • R 1 is Ci_ 3 alkyl optionally substituted with one or more substituents selected from halogen or hydroxy.
  • R 1 is Ci_ 3 alkyl optionally substituted with one or more substituents selected from halogen.
  • R 1 is Ci_ 3 alkyl optionally substituted with one or more substituents selected from alkoxy.
  • R 1 is Ci_ 3 alkyl optionally substituted with one or more substituents selected from Ci_ 3 alkoxy.
  • R is selected from hydrogen, halogen, CN, CF 3 , Ci_ 3 alkyl or Ci_ 3 alkoxy;
  • R is hydrogen
  • Q represents phenyl or a 5- to 10-membered heteroaryl ring system which is optionally substituted by at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the phenyl or heteroaryl ring system being optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_ 6 alkyl group (itself optionally substituted by hydroxyl, Ci_ 6 alkoxy, NR 65 R 66 , phenyl or morpholinyl),
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; each R , R , R , R , R and R independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • Q represents phenyl optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_ 6 alkyl, Ci_ 6 alkoxy (the alkyl and alkoxy groups being optionally substituted by hydroxyl, halogen, NR 65 R 66 , S(0) v R 63 , NR 61 S0 2 R 62 , phenyl or morpholinyl), C 3 _ 6 cycloalkyl, C 2 _ 6 alkenyl, trifluoromethyl, Ci_ 6 alkoxy, Ci_ 6 alkylcarbonyl,
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • Q represents phenyl optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, nitro, cyano, mercapto, Ci_ 6 alkyl group (itself optionally substituted by hydroxyl, Ci_ 6 alkoxy, NR 65 R 66 , phenyl or morpholinyl),
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • Q represents a 5- to 10-membered heteroaryl ring system which is optionally substituted by at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the heteroaryl ring system being optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_ 6 alkyl group (itself optionally substituted by hydroxyl, Ci_ 6 alkoxy, NR 65 R 66 , phenyl or morpholinyl),
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R and R each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • Q represents a 5- to 6-membered heteroaryl ring system which is optionally substituted by at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the heteroaryl ring system being optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_ 6 alkyl group (itself optionally substituted by one or more substituents independently selected from hydroxyl, haogen, Ci_ 6 alkoxy, NR 65 R 66 , phenyl and morpholinyl),
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • Q represents phenyl optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, nitro, cyano, mercapto, Ci_ 6 alkyl group (itself optionally substituted by hydroxyl, Ci_ 6 alkoxy, NR 65 R 66 , phenyl or morpholinyl),
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • Q represents phenyl optionally substituted by at least one substituent selected from halogen, cyano, trifluoromethyl, CONR 55 R 56 , S0 2 NR 59 R 60 , S(0) v R 63 , OS(0 2 )R 64 ;
  • v 0, 1 or 2;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 63 and R 64 independently represents a Ci_ 6 alkyl.
  • Q represents phenyl optionally substituted by at least one substituent selected from halogen, cyano, trifluoromethyl, S0 2 NR 59 R 60 , S(0) v R 63 , OS(0 2 )R 64
  • R and R each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 63 and R 64 independently represents a Ci_ 6 alkyl.
  • Q represents benzoxazolinone, benzothiazolone, dioxobenzisothiazol and isoindolinone optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_ 6 alkyl group (itself optionally substituted by hydroxyl, Ci_ 6 alkoxy, NR 65 R 66 , phenyl or morpholinyl),
  • R 53 and R 54 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • v 0, 1 or 2;
  • R 55 and R 56 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 59 and R 60 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 59 and R 60 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 57 , R 58 , R 61 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group;
  • R 65 and R 66 each independently represent hydrogen, Ci_ 6 alkyl or C 3 _ 6 cycloalkyl, or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • Q is optionally substituted phenyl, pyridyl, pyrimidyl, pyridazyl, or pyrazolyl wherein the optional substituents are as hereinabove defined.
  • Q is of the formula A.
  • X is N and Y is N. In another aspect X is CH and Y is N.
  • X is N and Y is CH.
  • X is CH and Y is CH.
  • the ring system of formula A is selected from:
  • R' is selected from hydrogen, C3_ 7 cycloalkyl and Ci_ 6 alkyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, Ci_
  • ring system A has no further substituents in addition to R' .
  • R' is selected from hydrogen, C3_ 7 cycloalkyl and Ci_ 6 alkyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, Ci_ 4 alkyoxy, C3_ 7 cycloalkyl, alklylamino and dialklylamino.
  • Q when Q is heteroaryl, it is optionally substituted by a substituent selected from Ci_ 4 alkyl, Ci_ 4 alkoxy, halogen, C3_ 7 cycloalkyl, carbamoyl, Ci_ 4 alkylcarbamoyl, and di Ci_ 4 alkylcarbamoyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, alkoxy, amino, Ci_ 4 alkylamino and di Ci_ 4 alkylamino.
  • Q when Q is heteroaryl, it is substituted by an oxo group and optionally substituted by one further substituent selected from Ci_ 4 alkyl, Ci_ 4 alkoxy, halogen, C 3- 7 cycloalkyl, carbamoyl, Ci_ 4 alkylcarbamoyl and di Ci_ 4 alkylcarbamoyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, alkoxy, amino, Ci_ 4 alkylamino and di Ci_ 4 alkylamino.
  • Q when Q is phenyl, it is substituted by 1 or 2 substituents independently selected from cyano, halogen, Ci_ 4 alkyl, Ci_ 4 alkoxy, halogen, C 3 _ 7 Cycloalkyl, alkaylsulphonyl, alkylsulphonyloxy, carbamoyl, Ci_ 4 alkylcarbamoyl and di Ci_ 4 alkylcarbamoyl; the alkyl and alkoxy groups group being optionally substituted by 1 or 2 substituents independently selected from halogen, alkoxy, alkylsulphonyl, alkylsulphonamido, amino, Ci_ 4 alkylamino, di Ci_ 4 alkylamino and morpholino.
  • a group optionally substituted by One or more' substituents is optionally substituted by 1 to 3 substituents.
  • a group optionally substituted by One or more' substituents is optionally substituted by 1 or 2 substituents.
  • a group optionally substituted by One or more' substituents is optionally substituted by 1 substituent.
  • a group optionally substituted by One or more' substituents is optionally unsubstituted.
  • the phenyl, 5- to 10-membered heteroaryl ring system and ring system A in Q are optionally substituted by substituents independently selected from halogen, hydroxyl, oxo, cyano, Ci_ 6 alkyl group, Ci_ 6 alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_ ealkoxy, C 3 - 6 cycloalkyl, NHS0 2 R 62 , S(0) 2 R 63 and NR 65 R 66 ), C 3 _ 6 cycloalkyl, trifluoromethyl, Ci_ 6 alkylcarbonyl, -NR 53 R 54 , -C(0)NR 55 R 56 , NHC(0)R 58 , S0 2 NR 59 R 60 , NHS0 2 R 62 ,
  • R 53 and R 54 each independently represent hydrogen or Ci_ 6 alkyl or R 53 and R 54 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 55 and R 56 each independently represent hydrogen or Ci_ 6 alkyl or R 55 and R 56 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R and R each independently represent hydrogen or Ci_ 6 alkyl or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • each R 58 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a
  • Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group provided that R 62 , R 63 and R 64 are not hydrogen;
  • R 65 and R 66 each independently represent hydrogen or Ci_ 6 alkyl or R 65 and R 66 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.
  • the phenyl, 5- to 10-membered heteroaryl ring system and ring system A in Q are optionally substituted by substituents independently selected from halogen, hydroxyl, oxo, cyano, Ci_ 6 alkyl group, Ci_ 6 alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_ ealkoxy, C 3 - 6 cycloalkyl, NHS0 2 R , S(0) 2 R w and NR b5 R bb ), C 3 _ 6 cycloalkyl, trifluoromethyl, Ci_ 6 alkylcarbonyl, -NR 53 R 54 , -C(0)NR 55 R 56 , NHC(0)R 58 , S0 2 NR 59 R 60 , NHS0 2 R 62 , S(0) 2 R 63 , OS(0 2 )R 64 , benzyloxy and Ci_ 6 alkylpiperaz
  • R and R each independently represent hydrogen or Ci_ 4 alkyl
  • R 55 and R 56 each independently represent hydrogen or Ci_ 4 alkyl
  • R 59 and R 60 each independently represent hydrogen or Ci_ 4 alkyl
  • each R 58 , R 62 , R 63 and R 64 independently represents a hydrogen atom or a
  • Ci_ 6 alkyl or C 3 _ 6 cycloalkyl group provided that R 62 , R 63 and R 64 are not hydrogen;
  • R 65 and R 66 each independently represent hydrogen or Ci_ 4 alkyl .
  • a class of com ounds is of the formula ( ⁇ ):
  • n and Q are as hereinabove defined; or a pharmaceutically-acceptable salt thereof.
  • the invention relates to a compound of the formula ( ⁇ ). Examples of compounds of the invention include but are not limited to:
  • the invention relates to a compound of the formula (I) as hereinabove defined excluding any 1 of the specific examples or pharmaceutically acceptable salts thereof.
  • the invention relates to a compound of the formula ( ⁇ ) as hereinabove defined excluding any 1 of the specific examples or pharmaceutically acceptable salts thereof.
  • the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula II)
  • PG represents a protecting group (e.g. tert-butoxycarbonyl)
  • R , n and y are as defined in formula (I), and optionally thereafter carrying out one or more of the following procedures:
  • the process of the invention is conveniently carried out in the presence of a base such as dizsopropylethylamine or triethylamine and an activating agent such as a "uranium” reagent (for example, 2-(l-H-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate) or a dehydrating agent (for example, propane phosphonic acid anhydride).
  • a base such as dizsopropylethylamine or triethylamine
  • an activating agent such as a "uranium” reagent (for example, 2-(l-H-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate) or a dehydrating agent (for example, propane phosphonic acid anhydride).
  • uranium for example, 2-(l-H-benzotriazole-l-yl)-l
  • tetrahydrofuran at a temperature, for example, in the range from 20 °C to 100 °C, in particular at ambient temperature (25°C).
  • PG 2 represents a protecting group (e.g. tert-butoxycarbonyl) and R 2 , and Q are as defined in formula (II), with a suitable reagent to remove the protecting group PG .
  • a suitable reagent is formic acid.
  • PG 2 and R are as defined in formula (IV) and Hal represents a halogen (e.g. I or Br), with a compound of formula (VI) or an ester thereof
  • PG 2 and R are as defined in formula (V) and Hal represents a halogen (e.g. I or Br), using standard literature procedures for the dehydration of an amide, for example with (methoxycarbonylsulfamoyl)tri-ethyl ammonium hydroxide, which can be prepared in situ with triethylamine and methyl chlorosulfonylcarbamate, in a solvent such as dichloromethane at a temperature in the range from -20°C to 35°C, for example at 0 °C.
  • a solvent such as dichloromethane
  • PG 2 and R 2 are as defined in formula (VII) and Hal represents a halogen (e.g. I or Br), with an aqueous ammonia solution, using standard literature procedures for the formation of an amide, for example, in the presence of a base such as N-ethyl-morpholine and an activating agent such as a "uranium” reagent (for example, 2-(l-H-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate).
  • a base such as N-ethyl-morpholine
  • an activating agent such as a "uranium” reagent (for example, 2-(l-H-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate).
  • the reaction is conveniently carried out in an organic solvent such as N,N-dimethylformamide, at a temperature in the range from -20°C to 100°
  • the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (X).
  • R , R , n, y, and Q are as defined above and PG represents a protecting group (e.g. tert-butoxycarbonyl), using standard literature procedures for the dehydration of an amide, for example with (methoxycarbonylsulfamoyl)tri-ethyl ammonium hydroxide, which can be prepared in situ with triethylamine and methyl chlorosulfonylcarbamate, in a solvent such as dichloromethane at a temperature in the range from -20°C to 25°C, for example at 0 °C.
  • a protecting group e.g. tert-butoxycarbonyl
  • a compound of formula (XIII) may be prepared by reacting a compound of formula (XIV)
  • R , R , n, y, and Q are as defined above and PG represents a protecting group (e.g. tert-butoxycarbonyl),
  • a compound of formula (XIV) may be prepared by reacting a compound of formula (XVI)
  • R , R , n, y, and Q are as defined above and PG represents a protecting group (e.g. tert-butoxycarbonyl) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) in the presence of a suitable catalyst such as 1 , l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex and l,l'-bis(diphenylphosphino)ferrocene or 1,1 3 ⁇ 4z5(di-fert-butylphosphino)ferrocene palladium dichloride, with a suitable base such as potassium acetate, in a solvent such as dimethylsulfoxide at a temperature in the range 60°C to 100°C, for example at 80°C. l/Br (XVI)
  • a compound of formula (XVI) may be prepared by reacting a compound of formula (XVII)
  • R , n, and y are as defined above and PG represents a protecting group (e.g. tert- butoxycarbonyl) in the presence of a base such as dizsopropylethylamine or triethylamine and a dehydrating agent (for example, propane phosphonic acid anhydride).
  • a base such as dizsopropylethylamine or triethylamine
  • a dehydrating agent for example, propane phosphonic acid anhydride.
  • the reaction is conveniently carried out in an organic solvent such as N,N-dimethylformamide or tetrahydrofuran at a temperature, for example, in the range from 20°C to 100°C, in particular at ambient temperature (25 °C).
  • PG 2" and R 2 are as defined in formula (VII), with an aqueous ammonia solution, using standard literature procedures for the formation of an amide, for example, in the presence of a base such as N-ethyl-morpholine and an activating agent such as a "uranium” reagent (for example, 2-(l-H-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium
  • reaction is conveniently carried out in an organic solvent such as N,N- dimethylformamide, at a temperature in the range from -20°C to 100°C, for example at 0°C.
  • organic solvent such as N,N- dimethylformamide
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetic acid salt, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or /?-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetic acid salt, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or /?-toluenesulphonate.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated, as well as unsolvated forms, and the present invention encompasses all such solvated forms.
  • the compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of dipeptidyl peptidase I activity, and thus may be used in the treatment of:
  • obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
  • COPD chronic obstructive pulmonary disease
  • lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; 2.
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo -vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • infectious diseases virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
  • virus diseases such as genital warts, common warts, plantar war
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • 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 compounds of the invention may be used in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper- responsiveness) ⁇ , chronic obstructive pulmonary disease (COPD) or allergic rhinitis.
  • asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper- responsiveness) ⁇ , chronic obstructive pulmonary disease (COPD) or allergic rhinitis.
  • COPD chronic obstructive pulmonary disease
  • the invention also provides a method of treating, or reducing the risk of, an obstructive airways disease or condition (e.g. asthma or COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • an obstructive airways disease or condition e.g. asthma or COPD
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating COPD.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating asthma.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating allergic rhinitis.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in treating allergic rhinitis.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in treating COPD.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in treating asthma.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
  • the compound is
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (I) and 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 formula (I) compound/salt (active ingredient) is in association with a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.
  • HFA heptafluoroalkane
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 micrometres ( ⁇ ), and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
  • Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active ingredient with or without a carrier substance, is delivered to the patient.
  • the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention 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.
  • the compounds of the invention may be combined with the following agents: non-steroidal anti-inflammatory agents
  • NSAIDs non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically
  • 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
  • COX-1 / COX-2 inhibitors whether applied topically or systemically
  • selective COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib, lum
  • hydroxychloroquine hydroxychloroquine
  • d-penicillamine d-penicillamine
  • auranofm other parenteral or oral gold preparations
  • analgesics diacerein
  • intra-articular therapies such as hyaluronic acid derivatives
  • nutritional supplements such as glucosamine.
  • the present invention still further relates to the combination of a compound of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin- like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-a) 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.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling pathways such as modulators of the SOCS system
  • the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRI for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRI for the C-X 3
  • the present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert- butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 100
  • the present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • LT leukotrienes
  • the present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine,
  • chlorpheniramine, promethazine, cyclizine, or mizolastine applied orally, topically or parenterally.
  • the present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine
  • the present invention further relates to the combination of a compound of the invention and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention still further relates to the combination of a compound of the invention and a beta-adrenoreceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
  • a beta-adrenoreceptor agonist including beta receptor subtypes 1-4
  • beta receptor subtypes 1-4 such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
  • the present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • the present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines.
  • the present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, 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
  • the present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • the present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropini
  • the present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally- acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a nonsteroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agent-s for example an opioid or derivative thereof
  • paracetamol for example an opioid or derivative thereof
  • nonsteroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a hormonal agent such as raloxifene
  • a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, TNK, 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 de
  • - or B.sub2. -receptor antagonist for example colchicine;
  • anti-gout agent for example colchicine;
  • xanthine oxidase inhibitor for example allopurinol;
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone;
  • growth hormone secretagogue for example transforming growth factor (TGF );
  • PDGF platelet-derived growth factor
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.subl .
  • NKP-608C NKP-608C
  • SB-233412 talnetant
  • D- 4418 D- 4418
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • 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; (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS; or (xxviii) a glucocorticoid receptor agonist.
  • the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) or a
  • GR-receptor a non-steroidal glucocorticoid receptor
  • a selective ⁇ 2 adrenoceptor agonist such as metaproterenol, isoproterenol,
  • isoprenaline albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol);
  • a phosphodiesterase inhibitor such as a PDE4 inhibitor
  • a protease inhibitor such as a neutrophil elastase or matrix metalloprotease MMP-12 inhibitor
  • a modulator of chemokine receptor function such as a CCR1 receptor antagonist
  • an inhibitor of kinase function (such as the kinases p38 or IKK).
  • the invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a compound of formula (I) or a
  • GR-receptor a non-steroidal glucocorticoid receptor
  • the invention provides a kit comprising a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is
  • GR-receptor a non-steroidal glucocorticoid receptor
  • a compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • 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
  • an alkylating agent for example cis-platin, carboplatin, cyclophosp
  • mithramycin 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);
  • an antimitotic agent for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere
  • a topoisomerase inhibitor for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin
  • 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 5a-reductase such as finasteride;
  • an antioestrogen for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene
  • an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function;
  • 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, AZD1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro- 4-fluoropheny
  • 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 ⁇ 3 function or an angiostatin);
  • 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
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ 3 function or an angiostatin
  • 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;
  • 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;
  • 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
  • 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 transfection 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.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor
  • Mass spectra were recorded on an Agilent MSD (+ve and -ve APCI and/or electrospray (e.g. in multimode)) following analytical HPLC. Where values for m/z are given, generally only ions which indicate the parent mass are reported, and the mass ions quoted are the positive or negative mass ions: [M] + , [M+H] + , [M-H] ⁇ , [M+H-BOC] + or [M+2H-BOC] + ;
  • reverse phase HPLC was conducted using a SunFire ® reverse phase silica column, available from Waters Corp.;
  • DIPEA Hunig's Base Diisopropylethylamine
  • reaction mixture was evaporated to dryness and the residue purified by chromatography on silica eluting with ethyl acetate in z ' sohexane (20/80) and then ethyl acetate in z ' sohexane (50:50) to afford the sub-titled compound (1.05 g).
  • reaction mixture was evaporated to dryness and absorbed onto silica and purified by chromatography on a silica column and eluted with ethyl acetate in z ' sohexane (20:80), then ethyl acetate in z ' so hexane (30:70) and finally ethyl acetate in z ' sohexane (50:50) to afford after evaporation of the relevant fractions the sub -titled compound (0.59 g) m/e (APCI+) 363 [M+2H-BOC]
  • step (iii) 200 mg was added formic acid (2 mL) and the mixture heated to 50°C for 30 min.
  • the mixture was diluted with water (10 mL) and the solution was basified to ⁇ pH 8-9 with 0.880 ammonia solution and then extracted with dichloromethane (2 x 10 mL).
  • the combined organic extracts were dried (magnesium sulfate) and evaporated to give a solid.
  • the crude product was purified on silica eluting with ethyl acetate in z ' sohexane (20/80) increasing to ethyl acetate in z ' so hexane (50/50).
  • the resulting material was then repurified on preprative HPLC chromatography (Waters SunFire column) eluting with acetonitrile in 0.1% aqueous trifluoroacetic acid to afford the purifed compound as a trifluoroacetic acid salt salt.
  • step (i) (S)-tert-butyl l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 1 g) was dissolved in 50% aqueous acetone (30 mL). The solution was treated with ammonium acetate (0.329 g) and sodium periodate (0.913 g) and stirred at ambient temperature for 20 h. The acetone was removed under vacuum at room temperature and the remaining aqueous treated with saturated brine (50 mL).
  • Potassium carbonate (161 mg) was added in water (1.6 mL) to (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 300 mg), 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (151 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (49.3 mg) in degassed acetonitrile (5 mL) at 20°C under an atmosphere of nitrogen.
  • Potassium carbonate (190 mg) in water (1.3 mL) was added to l-(l-amino-l- oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 354 mg), 6-chloro-2-ethylpyridazin- 3(2H)-one (Example 14, step (i), 109 mg) and 1,1 3 ⁇ 4z5(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg) in degassed acetonitrile (8 mL) at 20°C under at atmosphere of nitrogen.
  • the crude material was then purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent.
  • the fractions containing the desired compound were evaporated, washed with satuarted aqueous sodium hydrogen carbonate solutuion and extracted into dichloromethane.
  • the combined organic phases were dried over magnesium sulfate and evaporated to dryness to give the a product which was repurified by repeated HPLC chromatography to afford the titled compound (19 mg).
  • the crude material was then purified by preparative HPLC on a Waters X-Bridge column eluting with a gradient of methanol in aqueous 0.1% trifluoroacetic acid. The fractions containing the desired compound were evaporated, washed with saturated aqueous sodium hydrogen carbonate and extracted into dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to afford the subtitled compound (105 mg).
  • the crude material was purified by preparative HPLC on a Waters X-Bridge column eluting with methanol in aqueous 0.1% trifluoroacetic acid. The fractions containing the desired compound were evaporated then washed with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to afford the sub-titled compound (75 mg).
  • the resulting solution was stirred at 80°C for 35 min.
  • the reaction mixture was allowed to cool to room temperature and filtered.
  • the supematanet was diluted with ethyl acetate, and washed with water.
  • the aqueous layer was further extracted with dichloromethane and the organics were combined, dried over magnesium sulfate, filtered and evaporated to afford crude product.
  • the crude product was purified by chromatography on silica eluting with methanol / dichloromethane (2:98 to 8:92). Pure fractions were evaporated to dryness to afford the sub-titled compound (178 mg).
  • the crude material was then purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent.
  • the fractions containing the purified compound were evaporated, washed with saturated aqueous sodium hydrogen carbonate solution and extracted into dichloromethane.
  • the combined organic layers were dried over magnesium sulfate and evaporated to dryness to afford (19 mg).
  • the crude material was then purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent.
  • the fractions containing the desired compound were evaporated, washed with saturated aqueous sodium hydrogen carbonate solution and extracted into dichloromethane.
  • the combined organic layers were dried over magnesium sulfate and evaporated to dryness to give the sub-titled compound (102 mg).
  • Example 19 l-Amino- V- ⁇ (15)-l-cyano-2-[4-(2-methyl-l,l-dioxido-2,3-dihydro-l,2- benzisothiazol-5-yl)phenyl]ethyl ⁇ cyclohexanecarboxamide
  • the mixture was azeotroped with methanol and purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent.
  • the fractions containing the desired compound were combined, evaporated and then dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate.
  • the combined organic layers were dried over magnesium sulfate and evaporated.
  • the residue was triturated with diethyl ether and evaporated to afford the sub-titled compound (98 mg).
  • Nl,Nl-Dimethylethane-l,2-diamine (0.515 g) was added to a solution of methyl 5-bromo-3- (bromomethyl)picolinate (Example 13, step (ii), 2 g) in ethanol (15 mL) at 20°C. The resulting suspension was stirred under reflux for 17 h. The reaction mixture was cooled, and evaporated to dryness to afford crude product which was purified by reversed phase hplc (SunFireTM prep C 8 , 30-70% 0.1% aq TFA / MeCN). The sub-titled compound was isolated as a colourless solid (600 mg).
  • the reaction mixture was cooled, concentrated to dryness under vacuum, and the residue applied to a flash silica column.
  • the crude product was purified by eluting with a 5% triethylamine in acetonitrile. Pure fractions were evaporated to dryness to afford the sub-titled compound (300 mg).
  • the reaction mixture was concentrated under reduced pressure and the crude product was purified by reversed phase hplc chromatography (SunFireTM prep C 8 , 30-90% 0.1% aq TFA / MeCN). Pure fractions were freeze dried to afford the title compound TFA salt.
  • the product was converted to the free base by passing through a PL-HCO 3 cartridge in methanol / dichloromethane. The solvent was evaporated and dried to afford the titled compound (67 mg).
  • Example 21 step (i) crude, 200g was dissolved in a mixture of acetonitrile (100 mL) and 1% aqueous KHSO 4 solution (500 mL), and the mixture was heated to reflux for 2 h. The mixture was cooled to room temperature, the solvent was removed in vacuo and the aqueous phase was extracted with ethyl acetate ( 3 x 1000 mL). The combined organic layers were dried over Na 2 S0 4 and concentrated. The residue was purified by silica gel column (eluting with petrol ether / ethyl acetate using gradients from 10: 1 to 4: 1) to give the sub-titled compound (86 g) as a white solid.
  • the resulting mixture was stirred and heated at 90°C for 6h.
  • the reaction mixture was cooled to rt and diluted with water (75ml).
  • the products were extracted into dichloromethane (2 x 50 mL), and the combined extracts dried over magnesium sulfate.
  • the solution was concentrated to an oil, treated with formic (1 mL), and stirred for 4h at ambient temperature.
  • the formic acid was removed under reduced pressure, and the residue treated with 2 molar ammonia in methanol (50ml). After stirring for 3h the excess ammonia and solvent were removed under reduced pressure.
  • step (ii) 125mg was added formic acid (1 mL) and the mixture was heated at 48°C for 25 min. Sodium bicarbonate solution was added to the cooled mixture which was then extracted with dichloromethane (3x40ml). The organic layer was dried over sodium sulphate, filtered and evaporated.
  • step (ii) 43 mg was added formic acid (2 mL) and the mixture was heated at 45°C for 40 min. Acetonitrile was added and the solvent was evaporated. Sodium bicarbonate solution was added to the cooled mixture which was extracted with dichloromethane (3 x 40 mL). The organic layer was dried over sodium sulphate, filtered and evaporated.
  • step (ii) 135 mg was added formic acid (2 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The sample was purified on a Gemini-NX CI 8 5um 1 10A AXIA column eluting on a 5 to 95 gradient of methanol in water (0.1% TFA).
  • step (ii) 152mg was added formic acid (2 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The residue was purified on a SunFire Prep C8 lOum 30x100 OBD column eluting on a 5 to 95 gradient of methanol in aqueous 0.1% trifiuoroacetic acid. The product was loaded onto PL-HC03 MP cartridge in dichloromethane/methanol and then eluted with dichloromethane. The solvent was evaporated. 5% Acetonitrile/water (2 mL) was added and the mixture was stirred for 3 days. The suspension was filtered and the solid was washed with a water and the residue was dried under vacuum at 45°C to afford the titled compound (18 mg).
  • Example 31 (5)- V-(2-(4-(lH-Pyrazol-4-yl)phenyl)-l-cyanoethyl)-l- aminocyclohexanecarboxamide trifiuoroacetic acid salt
  • step (ii) 63mg was added formic acid (1.5 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The residue was purified on a SunFire Prep C8 lOum 30x100 OBD column eluting on an 11 to 46 gradient of methanol in aqueous 0.1%
  • step (i) 91mg was added formic acid (2 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The sample was purified on a Gemini-NX CI 8 5um 1 10A 30x100 AXIA column eluting on a 17 to 52 gradient of methanol in aqueous 0.1%trifluoroacetic acid. The solvent was evaporated and the residue was dried under vacuum at 45°C to afford the titled compound (26 mg).
  • step (iii) 98mg was added formic acid (2 mL) and the mixture was heated at 45°C for 25 min. Acetonitrile was added and the solvent was evaporated.
  • the sample was purified on SunFire Prep C8 lOum 30x100 OBD column eluting on a 5 to 39 gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid. The solvent was evaporated and the residue was dried under vacuum at 45 °C to afford the titled compound (36 mg).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) dans laquelle n, R1, R2 et Q sont tels que définis dans la description, un procédé pour leur préparation, des compositions pharmaceutiques les comprenant et leur utilisation thérapeutique.
PCT/GB2010/050963 2010-06-09 2010-06-09 Composés n-[1-cyano-2-(phényl)éthyl] 1-aminocycloalk-1-ylcarboxamide substitués - 760 WO2011154677A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/GB2010/050963 WO2011154677A1 (fr) 2010-06-09 2010-06-09 Composés n-[1-cyano-2-(phényl)éthyl] 1-aminocycloalk-1-ylcarboxamide substitués - 760

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/GB2010/050963 WO2011154677A1 (fr) 2010-06-09 2010-06-09 Composés n-[1-cyano-2-(phényl)éthyl] 1-aminocycloalk-1-ylcarboxamide substitués - 760

Publications (1)

Publication Number Publication Date
WO2011154677A1 true WO2011154677A1 (fr) 2011-12-15

Family

ID=43005344

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2010/050963 WO2011154677A1 (fr) 2010-06-09 2010-06-09 Composés n-[1-cyano-2-(phényl)éthyl] 1-aminocycloalk-1-ylcarboxamide substitués - 760

Country Status (1)

Country Link
WO (1) WO2011154677A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012119941A1 (fr) 2011-03-04 2012-09-13 Prozymex A/S Composés de peptidylnitrile à titre d'inhibiteurs de peptidases
WO2015044165A1 (fr) * 2013-09-26 2015-04-02 Bayer Pharma Aktiengesellschaft Dérivés de phénylalanine substitués
WO2015110826A1 (fr) * 2014-01-24 2015-07-30 Astrazeneca Ab (2s)-n-[(1s)-1-cyano-2-phényléthyl]-1,4-oxazépane-2-carboxamides en tant qu'inhibiteurs de la dipeptidyl peptidase i
JP2016510784A (ja) * 2013-03-14 2016-04-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング カテプシンｃの置換２−アザ−ビシクロ［２．２．１］ヘプタン−３−カルボン酸（シアノ−メチル）−アミド阻害剤
JP2016515110A (ja) * 2013-03-14 2016-05-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング カテプシンｃの置換２−アザ−ビシクロ［２．２．２］オクタン−３−カルボン酸（ベンジル−シアノ−メチル）−アミド阻害剤
US9856228B2 (en) 2013-09-09 2018-01-02 Prozymex A/S Peptidyl nitril compounds as dipeptidyl peptidase I inhibitors
US10479781B2 (en) 2015-03-05 2019-11-19 Neuprozyme Therapeutics ApS Peptidyl nitril compounds as dipeptidyl peptidase I inhibitors
WO2020215094A1 (fr) 2019-04-18 2020-10-22 The Johns Hopkins University Dérivés de 2-amino-pyrazolyl-[1,2,4]triazolo[1,5 a] pyridine substitués et leur utilisation
WO2021203048A1 (fr) * 2020-04-02 2021-10-07 Southern Research Institute Nouveaux analogues de la 2-pyrimidone utilisés comme agents antiviraux puissants contre les alphavirus
WO2024026433A3 (fr) * 2022-07-28 2024-04-11 Insmed Incorporated Nouveaux inhibiteurs de dpp1 et leurs utilisations
US11998553B2 (en) 2019-07-16 2024-06-04 Insmed Incorporated Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating lupus nephritis

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000040529A1 (fr) 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire
WO2000041669A2 (fr) 1999-01-15 2000-07-20 Angiogene Pharmaceuticals Ltd. Agents de degradation vasculaire aux benzimidazoles
WO2001092224A1 (fr) 2000-05-31 2001-12-06 Astrazeneca Ab Derives d'indole possedant une activite endommageant les vaisseaux sanguins
WO2002004434A1 (fr) 2000-07-07 2002-01-17 Angiogene Pharmaceuticals Limited Derives de colchinol utilises comme agents de degradation vasculaire
WO2002008213A1 (fr) 2000-07-07 2002-01-31 Angiogene Pharmaceuticals Limited Derives de colchinol utiles comme inhibiteurs de l'angiogenese
WO2004110998A1 (fr) * 2003-05-16 2004-12-23 Ambit Biosciences Corporation Composes pyrroliques et leurs utilisations
WO2004110988A1 (fr) 2003-06-18 2004-12-23 Prozymex A/S Inhibiteurs de la protease
US20070099835A1 (en) 2004-07-02 2007-05-03 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
WO2009074829A1 (fr) 2007-12-12 2009-06-18 Astrazeneca Ab Peptidyl-nitriles et leur utilisation en tant qu'inhibiteurs de la dipeptidylpeptidase i

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000040529A1 (fr) 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire
WO2000041669A2 (fr) 1999-01-15 2000-07-20 Angiogene Pharmaceuticals Ltd. Agents de degradation vasculaire aux benzimidazoles
WO2001092224A1 (fr) 2000-05-31 2001-12-06 Astrazeneca Ab Derives d'indole possedant une activite endommageant les vaisseaux sanguins
WO2002004434A1 (fr) 2000-07-07 2002-01-17 Angiogene Pharmaceuticals Limited Derives de colchinol utilises comme agents de degradation vasculaire
WO2002008213A1 (fr) 2000-07-07 2002-01-31 Angiogene Pharmaceuticals Limited Derives de colchinol utiles comme inhibiteurs de l'angiogenese
WO2004110998A1 (fr) * 2003-05-16 2004-12-23 Ambit Biosciences Corporation Composes pyrroliques et leurs utilisations
WO2004110988A1 (fr) 2003-06-18 2004-12-23 Prozymex A/S Inhibiteurs de la protease
US20070099835A1 (en) 2004-07-02 2007-05-03 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
WO2009074829A1 (fr) 2007-12-12 2009-06-18 Astrazeneca Ab Peptidyl-nitriles et leur utilisation en tant qu'inhibiteurs de la dipeptidylpeptidase i

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ADKISON ET AL., J CLIN INVEST, vol. 109, 2002, pages 363 - 271
BIOORG. MED. CHEM. LETT., vol. 12, 2002, pages 3059
DOLENC ET AL., JBIOL CHEM, vol. 270, 1995, pages 21626 - 21631
GUTMAN; FRUTON, JBIOL CHEM, vol. 174, 1948, pages 851 - 858
KAM, CM; GOTZ, MG; KOOT, G; MCGUIRE, MJ; THIELE, DL; HUDIG, D; POWERS, JC, ARCH BIOCHEM BIOPHYS, vol. 427, 2004, pages 123 - 134
MCGUIRE, MJ; LIPSKY, PE; THIELE, DL, ARCH BIOCHEM BIOPHYS, vol. 295, 1992, pages 280 - 288
PARIS ET AL., FEBS LETT, vol. 369, 1995, pages 326 - 330
PHAM ET AL., J IMMUNOL, vol. 173, 2004, pages 7277 - 7281
TETRAHEDRON: ASYMMETRY, vol. 9, 1998, pages 503

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012119941A1 (fr) 2011-03-04 2012-09-13 Prozymex A/S Composés de peptidylnitrile à titre d'inhibiteurs de peptidases
JP2016510784A (ja) * 2013-03-14 2016-04-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング カテプシンｃの置換２−アザ−ビシクロ［２．２．１］ヘプタン−３−カルボン酸（シアノ−メチル）−アミド阻害剤
JP2016515110A (ja) * 2013-03-14 2016-05-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング カテプシンｃの置換２−アザ−ビシクロ［２．２．２］オクタン−３−カルボン酸（ベンジル−シアノ−メチル）−アミド阻害剤
US9856228B2 (en) 2013-09-09 2018-01-02 Prozymex A/S Peptidyl nitril compounds as dipeptidyl peptidase I inhibitors
WO2015044165A1 (fr) * 2013-09-26 2015-04-02 Bayer Pharma Aktiengesellschaft Dérivés de phénylalanine substitués
EP3744714A1 (fr) * 2014-01-24 2020-12-02 Astrazeneca AB (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides en tant qu'inhibiteurs de dipeptidyl peptidase i
US11673872B2 (en) 2014-01-24 2023-06-13 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US9815805B2 (en) 2014-01-24 2017-11-14 Astrazeneca Ab Certain (25)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
KR20160111470A (ko) * 2014-01-24 2016-09-26 아스트라제네카 아베 디펩티딜 펩티다제 i 억제제로서의 (2s)-n-[(1s)-1-시아노-2-페닐에틸]-1,4-옥사제판-2-카르복스아미드
EP3323814A1 (fr) * 2014-01-24 2018-05-23 AstraZeneca AB (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides en tant qu'inhibiteurs de dipeptidyl peptidase i
JP2019070029A (ja) * 2014-01-24 2019-05-09 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ ジペプチジルペプチダーゼ１阻害剤としての（２ｓ）−ｎ−［（１ｓ）−１−シアノ−２−フェニルエチル］−１，４−オキサゼパン−２−カルボキサミド
US10287258B2 (en) 2014-01-24 2019-05-14 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
EA032794B1 (ru) * 2014-01-24 2019-07-31 Астразенека Аб (2s)-n-[(1s)-1-циано-2-фенилэтил]-1,4-оксазепан-2-карбоксамиды в качестве ингибиторов дипептидилпептидазы i
CN105980367B (zh) * 2014-01-24 2019-08-23 阿斯利康(瑞典)有限公司 (2s)-n-[(1s)-1-氰基-2-苯基乙基]-1，4-氧杂氮杂环庚烷-2-甲酰胺作为二肽基肽酶i抑制剂
US11814359B2 (en) 2014-01-24 2023-11-14 Astrazeneca Ab Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
CN110483492A (zh) * 2014-01-24 2019-11-22 阿斯利康(瑞典)有限公司 二肽基肽酶i抑制剂
US10669245B2 (en) 2014-01-24 2020-06-02 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides dipeptidyl peptidase 1 inhibitors
US11773069B2 (en) 2014-01-24 2023-10-03 Astrazeneca Ab Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
WO2015110826A1 (fr) * 2014-01-24 2015-07-30 Astrazeneca Ab (2s)-n-[(1s)-1-cyano-2-phényléthyl]-1,4-oxazépane-2-carboxamides en tant qu'inhibiteurs de la dipeptidyl peptidase i
JP2021046423A (ja) * 2014-01-24 2021-03-25 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ ジペプチジルペプチダーゼ１阻害剤としての（２ｓ）−ｎ−［（１ｓ）−１−シアノ−２−フェニルエチル］−１，４−オキサゼパン−２−カルボキサミド
US11117874B2 (en) 2014-01-24 2021-09-14 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
CN110483492B (zh) * 2014-01-24 2023-07-21 阿斯利康(瑞典)有限公司 二肽基肽酶i抑制剂
KR102417684B1 (ko) 2014-01-24 2022-07-05 아스트라제네카 아베 디펩티딜 펩티다제 i 억제제로서의 (2s)-n-[(1s)-1-시아노-2-페닐에틸]-1,4-옥사제판-2-카르복스아미드
JP7157791B2 (ja) 2014-01-24 2022-10-20 アストラゼネカ・アクチエボラーグ ジペプチジルペプチダーゼ１阻害剤としての（２ｓ）－ｎ－［（１ｓ）－１－シアノ－２－フェニルエチル］－１，４－オキサゼパン－２－カルボキサミド
US11680049B2 (en) 2014-01-24 2023-06-20 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11655222B2 (en) 2014-01-24 2023-05-23 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11655224B2 (en) 2014-01-24 2023-05-23 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11655221B2 (en) 2014-01-24 2023-05-23 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11655223B2 (en) 2014-01-24 2023-05-23 Astrazeneca Ab Certain (2S)-N-[(1 s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US11667615B2 (en) 2014-01-24 2023-06-06 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
JP2017503832A (ja) * 2014-01-24 2017-02-02 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ ジペプチジルペプチダーゼ１阻害剤としての（２ｓ）−ｎ−［（１ｓ）−１−シアノ−２−フェニルエチル］−１，４−オキサゼパン−２−カルボキサミド
US11673871B2 (en) 2014-01-24 2023-06-13 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US10479781B2 (en) 2015-03-05 2019-11-19 Neuprozyme Therapeutics ApS Peptidyl nitril compounds as dipeptidyl peptidase I inhibitors
WO2020215094A1 (fr) 2019-04-18 2020-10-22 The Johns Hopkins University Dérivés de 2-amino-pyrazolyl-[1,2,4]triazolo[1,5 a] pyridine substitués et leur utilisation
US11998553B2 (en) 2019-07-16 2024-06-04 Insmed Incorporated Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating lupus nephritis
US11566019B2 (en) 2020-04-02 2023-01-31 Southern Research Institute 2-pyrimidone analogs as potent antiviral agents against alphaviruses
WO2021203048A1 (fr) * 2020-04-02 2021-10-07 Southern Research Institute Nouveaux analogues de la 2-pyrimidone utilisés comme agents antiviraux puissants contre les alphavirus
US11932626B2 (en) 2020-04-02 2024-03-19 Southern Research Institute 2-pyrimidone analogs as potent antiviral agents against Alphaviruses
WO2024026433A3 (fr) * 2022-07-28 2024-04-11 Insmed Incorporated Nouveaux inhibiteurs de dpp1 et leurs utilisations

Similar Documents

Publication Publication Date Title
AU2010244218B2 (en) Substituted 1-cyanoethylheterocyclylcarboxamide compounds 750
US7902181B2 (en) Compounds 010
WO2011154677A1 (fr) Composés n-[1-cyano-2-(phényl)éthyl] 1-aminocycloalk-1-ylcarboxamide substitués - 760
CA2704214C (fr) Derives de pyrimidine pour le traitement de l'asthme, de la broncho-pneumopathie chronique obstructive (copd), de la rhinite allergique, de la conjonctivite allergique, de la dermatite atopique, du cancer, de l'hepatite b, de l'hepatite c, du vih, du vpp, des infections bacteriennes et de la dermatose
US7700782B2 (en) Compounds 569
WO2010142985A1 (fr) Composés 761 n-[1-cyano-2-(phényle)éthyle]pipéridine-2-ylcarboxamide substitués
DK2651943T3 (en) purine derivatives
US10676433B2 (en) Indole derivatives and their use in neurodegenerative diseases
WO2009007747A2 (fr) Nouveaux composés
US20130289043A1 (en) (4-tert-butylpiperazin-2-yl)(piperazin-1-yl)methanone-n-carboxamide derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10724565

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10724565

Country of ref document: EP

Kind code of ref document: A1