WO2015032942A1

WO2015032942A1 - N-substituted 3,3'-(biphenyl-4,4'-diyl)bis-2-aminopropanenitriles as dppi inhibitors

Info

Publication number: WO2015032942A1
Application number: PCT/EP2014/069080
Authority: WO
Inventors: Conni Lauritzen; John Pedersen
Original assignee: Prozymex A/S
Priority date: 2013-09-09
Filing date: 2014-09-08
Publication date: 2015-03-12

Abstract

The invention relates to a compound of Formula (I) and its use as a selective dipeptidyl peptidase I inhibitor, as well as pharmaceutical compositions comprising said compound, and methods of treatment involving said compounds.

Description

N-SUBSTITUTED 3,3'-(BIPHENYL-4,4'-DIYL)BIS-2-AMINOPROPANENITRILES AS DPPI INHIBITORS

FIELD OF THE INVENTION

The present invention relates to N-substituted 3,3'-(biphenyl-4,4'-diyl)bis-2- aminopropanenitriles and their use as inhibitors of dipeptidyl peptidase I, pharmaceutical compositions containing the same, and methods of using these agents for treatment and/or prevention of inflammatory diseases in which dipeptidyl peptidase I is involved, especially inflammatory diseases mediated by mast cells and neutrophil cells, e.g. chronic obstructive pulmonary disease and other respiratory diseases. BACKGROUND OF THE INVENTION

Dipeptidyl peptidase I (DPPI; EC 3.4.14.1) also known as cathepsin C is a lysosomal cysteine peptidase belonging to the papain family. The enzyme is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen. The cDNAs encoding rat, human and murine DPPI have been cloned and sequenced and it has been shown that the enzyme is highly conserved. DPPI is synthesized as an inactive precursor (Zymogen), and is activated by a non-autocatalytic excision of an internal activation peptide within the N-terminal propeptide. DPPI is the only member of the papain family that is functional as a tetramer, consisting of four identical subunits. Each is composed of an N-terminal fragment (the residual propart), a heavy chain and a light chain. Once activated, DPPI catalyzes the removal of dipeptides from the N-termina! end of polypeptide substrates with broad specificity. The pH optimum lies in the region of pH 5-7 using human DPPI. Numereous data show that, beside of being an important enzyme in lysosomal protein degradation, DPPI also functions as a key enzyme in the activation of granule serine peptidases in neutrophils (cathepsin G, proteinase 3 and elastase), mast cells (chymase and tryptase) and cytotoxic T lymphocytes and natural killer cells (granzymes A and B).

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. Mast cells are also located in the perivascular tissue surrounding small blood vessels. 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 mucose while the TC-type cells predominate in skin and conjuctiva. Mast cells can release a range of potent inflammatory mediators including cytokines, leukotrienes, prostaglandins, histamine and proteoglycans, but among the most abundant products of mast cell activation are the serine peptidases of the chymotrypsin family; tryptase and chymase. These peptidases are situated in the mast cell lysosomes as fully active enzymes. The exact site of tryptase and chymase activation from zymogen precursors is not known, but the Golgi apparatus might play a role in that regard. DPPI, which is particular abundant in mast cells, seems to be the key enzyme responsible for activation of chymase and tryptase. Moreover, tryptase and chymase are emerging as important mediators of allergic diseases such as asthma, inflammatory bowel disease and psoriasis. After secretion from activated mast cells, there is evidence that these peptidases are heavily involved in processes of inflammation, tissue remodelling, bronchoconstriction and mucus secretion, which have made these peptidases attractive for therapeutic intervention.

Neutrophils cause considerable damage in a number of pathological conditions. When activated, neutrophils secrete destructive granular enzymes including elastase and cathepsin G and undergo oxidative bursts to release reactive oxygen intermediates. Numerous studies have been conducted on each of these activating agents in isolation. Pulmonary emphysema, COPD, cystic fibrosis, sepsis and rheumatoid arthritis are just some examples of pathological conditions associated with the potent enzymes elastase and cathepsin G. The strong evidence associating tryptase, chymase, elastase, cathepsin G and other similar inflammatory peptidases with inflammatory diseases, points out DPPI as an attractive target enzyme for therapeutic intervention against the above mentioned diseases and other similar inflammatory diseases, due to its central role in activating these peptidases (Adkison et al. 2002, J. Clin. Invest, 109, 363-271; Pham. et al. 2004, J. Immunol, 173,7277-7281).

WO2012130299 and WO2012119941 to PROZYMEX disclose nitrile compounds and use thereof as dipeptidyl peptidase inhibitors. WO 2009074829A1 to Astrazeneca also discloses peptidyl nitriles and use thereof as dipeptidyl peptidase inhibitors. WO 2010128324A1, W01154677A1 and WO 2010142985A1 to Astrazeneca discloses further nitrile compounds and use thereof as dipeptidyl peptidase inhibitors. WO2013041497A1 to Boehringer

Ingelheim International GMBH discloses nitrile compounds as dipeptidyl peptidase inhibitors. Jon Bondebjerg, Henrik Fuglsang, Kirsten Rosendal Valeur, John Pedersen and Lars Naerum, Dipeptidyl nitriles as human dipeptidyl peptidase I inhibitors, Bioorganic & Medicinal

Chemistry Letters 16 (2006) 3614-3617 disclose compounds having a dipeptide nitrile scaffold as inhibitors of human dipeptidyl peptidase I. OBJECT OF TH E INVENTION

It is an object of embodiments of the invention to provide novel compounds being inhibitors of dipeptidyl peptidase I, suitable for treatment of inflammatory diseases, cancers and infections. SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula (I) :

(I) wherein X¹ and X² independently represent a cyclic alpha amino acid moiety, in which · the alpha carbon atom forms part of the cyclic structure;

• the carbonyl group of said cyclic alpha amino acid moiety and the -NH- group to which it is attached form an amide bond ;

• the amino acid moiety of said cyclic alpha amino acid moiety is optionally substituted on a ring carbon atom with one or two substituents R¹- · R¹ independently represents halogen ; hydroxyl ; cyano; oxo (=0) ; mercapto; or C^- alkyl ; which C_1-3-alkyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano and mercapto as well as pharmaceutically-acceptable salts, solvates and hydrates thereof.

In an embodiment of interest X¹ represents

or ¾ 0

r optionally substituted on a ring carbon atom with one or two R¹ and wherein each Z independently represents O (oxygen) or S (sulfur).

The following compounds according to the invention are of particular interest:

The invention also provides a pharmaceutical composition comprising a compound of the formula (I) :

(I) wherein X¹, X², Z and R¹ are as defined above. All details regarding the compounds of formula (I) are also relevant for the pharmaceutical composition. A compound or composition as defined herein for use as a medicament is also provided.

Further details of the invention will become apparent from the following.

The term "DPPI" as used herein is intended to mean dipeptidyl peptidase I (EC 3.4.14.1) also known as cathepsin C, cathepsin 1, dipeptidyl aminopeptidase I and dipeptidyl transferase. DPPI cleaves a dipeptide Xaa-Xbb from the H terminus of a polypeptide chain Xaa-Xbb-Xcc- [Xxx]_n, except when Xaa is Arg or Lys, or when Xbb or Xcc is Pro.

In the formulas, the group -CN is a nitrile group (— C=N ) . The term "alpha amino acid moiety" is defined as an amino acid moiety in which the amine nitrogen atom is attached directly to the alpha carbon atom. The term "alpha amino acid" includes alpha amino acids that either occur naturally or are chemically synthesized.

The wavy line in depicted substituents as e.g.

is used to indicate the bond, which is connected to the core molecule (formula I) as defined.

Then, for example, if X¹ = X² =

, the compound of the invention has the following formula :

The description: cyclic alpha amino acid moiety in which amino acid moiety, the alpha carbon atom forms part of the cyclic structure" as used herein is intended to mean an amino acid moiety in which the alpha carbon together with side chain atoms forms a mono- or polycyclic ring structure (e.g. bridged, fused or spiro structures). In a certain aspect, the cyclic alpha amino acid moiety represented by X¹ and/or X² is a monocyclic alpha amino acid moiety. The ring structure can be heterogenic, containing one or more heteroatoms selected from N, O or S, and can include the amine nitrogen. The ring structure may contain one or more double bonds. Ring structures of X¹ and/or X² suitably contain 4-10 ring atoms (i.e. atoms which constitute the ring structure), including the alpha-carbon atom. Suitably, the cyclic alpha amino acid moiety represented by X¹ and/or X² is a cyclic alpha amino acid moiety in which one ring atom is nitrogen, which cyclic alpha amino acid moiety contains a bridge between two carbon ring atoms of X¹ and/or X², said bridge having the general structure -(CH₂)_n-, where n = 1 or 2.The amino acid moiety of each cyclic alpha amino acid moiety is optionally substituted on a ring carbon atom with one or two substituents R¹. "Ring carbon atom(s)" are those carbon atoms which form part of the ring structure of the cyclic alpha amino acid moiety. When present, the substituents R¹ may be present on the same ring carbon atom, or different ring carbon atoms.

Importantly, the alpha carbon atom forms part of the cyclic structure. In line with standard nomenclature, the term "alpha carbon atom" in an amino acid moiety is defined as the first carbon atom that is attached to the carbonyl group of the moiety.

H

O

Possible cyclic alpha amino acid moieties for X¹ (wherein the "alpha carbon atom" is marked with an asterisk) include, but are not limited to:

Possible cyclic alpha amino acid moieties for X² (wherein the "alpha carbon atom" is marked with an asterisk) include, but are not limited to:

Suitably, X² represents

wherein each cyclic structure of X² is optionally substituted on a ring carbon atom with one or two R¹, and wherein R¹ is as defined above.

As set out a ove, the cyclic alpha amino acid moieties for X² may be substituted or non- substituted. In one embodiment, X¹ = X².

The term "treatment" is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the compound of the present invention to prevent the onset of the symptoms or the

complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder. "Half-life" (or "half-lives") refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.

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

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

Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. The compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. If there is a cycloalkyi or cycloalkenyl group present, some substituent patterns may result in and axial or an equatorial configuration. Both forms are included, unless specified otherwise.

All tautomeric forms are also included in Formula (I), whether such tautomers exist in equilibrium or predominately in one form.

Preferred are the above compounds of formula (I), in their enantiomerically pure form as per formula (II) or formula (III):

(II) (III) wherein X¹ and X² are as defined above.

Preferably, X¹ has an enantiomerically pure form selected from:

wherein Z is as defined above.The skilled artisan will appreciate that pharmaceutically- acceptable salts of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the non-salt form because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-acceptable salts of the compounds according to Formula (I).

As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired

toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L- arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol,

diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2- aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, lH-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2- disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid,

ethylenediamonotetraacetic acid, formic acid, fumaric acid, galacaric acid, gentisic acid, D- glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutantic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene- 1,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66, 1- 19).

The pharmaceutically-acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.

In the solid state, the compound of the invention can exist in crystalline, semi- crystalline and amorphous forms, as well as mixtures thereof. The skilled artisan will appreciate that pharmaceutically-acceptable solvates of the compound of the invention may be formed wherein solvent molecules are incorporated into the solid-state structure during

crystallization. Solvates may involve water or non-aqueous solvents, or mixtures thereof. In addition, the solvent content of such solvates can vary in response to environment and upon storage. For example, water may displace another solvent over time depending on relative humidity and temperature. Solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "hydrates." Solvates wherein more than one solvent is incorporated into the solid-state structure are typically referred to as "mixed solvates". Solvates include "stoichiometric solvates" as well as compositions containing variable amounts of solvent (referred to as "non-stoichiometric solvates"). Stoichiometric solvates wherein water is the solvent that is Incorporated into the solid-state structure are typically referred to as "stoichiometric hydrates", and non-stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "non-stoichiometric hydrates". The invention includes both stoichiometric and non- stoichiometric solvates. In addition, crystalline forms of the compound of the invention, including solvates thereof, may contain solvent molecules, which are not incorporated into the solid-state structure. For example, solvent molecules may become trapped in the crystals upon isolation. In addition, solvent molecules may be retained on the surface of the crystals. The invention includes such forms. In the context of the present specification, unless otherwise stated, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched.

The compounds of the invention may be administered by any suitable route of

administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's iungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.

Compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for compounds of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the amount administered and the duration such regimens are administered, for compounds of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 1 mg to 1000 mg.

Compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of compounds of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.

Administration of the compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following : (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of

pharmacologically active agents that overcome barriers to a drug's usefulness.

Coupling of short peptides or single amino acids as carriers of a therapeutic agent can be used as an effective type of prodrug approach. In this approach an amino acid or a di- or oligo-peptide moiety is linked to a free amino group of the drug through an amide bond, that can be specifically cleaved by an endogenous peptidase, e.g. dipeptidyl peptidase IV

(DPPIV/CD26), dipeptidyl peptidase I (DPPI/cathepsin C), aminopeptidase N (APN/CD13), pyroglutamyl aminopeptidase (PGAP), aminopeptidase P, elastase, cathepsin G, proteinase 3, tryptase or chymase. The amino acid or a di- or oligo-peptide moiety can consist of proteinogenic amino acids (i.e. amino acids that occur naturally in proteins), or non-proteinogenic amino acids (i.e. non- proteinogenic amino acids that either occur naturally or are chemically synthesized). In one aspect, the compound disclosed herein is linked via a free amino group to an amino acid or a di- or oligo-peptide moiety. These prodrugs may be converted to the desired active compound by a peptidase-catalyzed reaction.

Starting materials and reagents are either commercially-available or may be prepared by one skilled in the art using methods described in the literature.

Compounds of the invention in which the structures of X¹ and X² in Formula (I) (including the substitution by R¹) are the same, can be made essentially as described in Examples 1-4, using the appropriate Boc(t-butyloxycarbonyl)-protected amino acid.

Compounds of the invention wherein the structures of X¹ and X² in Formula (I) (including the substitution by R¹) are different, can be made essentially as described in the following synthetic scheme (exemplified for synthesis of compound PZ1092) using the appropriate Boc (t-butyloxycarbonyl) protected amino acids.

In this procedure it is possible for a person skilled in the art of peptide synthesis to control the amount of the first Boc protected cyclic amino acid (BocNH-Al-OH) added to the intermediate product named IP1 (see the structural formula below), and how it is added to the reaction, to ensure the mono protected amide IP2 (see the structural formula below) is the major product in the first instance.

IPl IP2

Following coupling of the first Boc protected cyclic amino acid (BocNH-Al-OH), the second Boc protected cyclic amino acid (BocNH-A2-OH) will be coupled by a similar process.

Using this procedure both ends of IPl could be protected by the same amino acid, resulting in the bis-protected amide. A person skilled in the art of peptide synthesis can control the reaction conditions to minimize the formation of the bis-protected amide, but it may be necessary to remove unwanted bis-protected amide.

Alternatively, compounds of the invention wherein the structures of X¹ and X² in Formula (I) (including the substitution by R¹) are different, can be made essentially as described in the following synthetic scheme (exemplified for synthesis of compound PZ1092) by coupling the two compounds PZ1092A and PZ1092B by a Suzuki coupling followed by deprotection.

PZ1092A PZ1092

PZ1092A and PZ1092B can easily be synthesized by a person skilled in the art of peptide synthesis and medicinal chemistry.

The compounds of general formula I may be used on their own or combined with other active substances of formula I according to the invention. The compounds of general formula I may optionally also be combined with other pharmacologically active substances. These include, B2-adrenoceptor-agonists (short and long-acting), anti-cholinergics (short and long-acting), anti- inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives, FPRU modulators, LTB4- receptor (BLTI, BLT2) antagonists, Histamine HI receptor

antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3 -receptor antagonists, PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases as for example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases as for example p38, ERK1, ERK2, J Kl, J K2, J K3 or SAP, inhibitors of the NF-κΒ signalling pathway as for example IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors or leukotriene biosynthese inhibitors.

The compounds disclosed herein will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect a pharmaceutical composition comprising, as an active substance, a compound as disclosed herein or a pharmaceutically acceptable salt thereof together with a

pharmaceutically acceptable adjuvant, carrier or diluent, is provided.

The pharmaceutical compositions disclosed herein may be prepared and packaged in bulk form wherein a safe and effective amount of the compound disclosed herein can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.

Alternatively, the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of the compound as disclosed herein. When prepared in unit dosage form, the pharmaceutical compositions disclosed herein typically contain from 1 mg to 1000 mg.

The pharmaceutical compositions disclosed herein typically contain one compound as disclosed herein. However, in certain embodiments, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient. As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable. The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral

administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

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

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

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

Pharmaceutical Association and the Pharmaceutical Press).

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

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of the compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc. In another aspect, the invention is directed to a dosage form adapted for administration to a patient by inhalation. For example, the compound of the invention may be inhaled into the lungs as a dry powder, an aerosol, a suspension, or a solution.

Dry powder compositions for delivery to the lung by inhalation typically comprise the compound of the invention as a finely divided powder together with one or more

pharmaceutically-acceptable excipients as finely divided powders. Pharmaceutically- acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.

The dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form. RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position. For example, the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation. Alternatively, the dry powder may be presented in capsules (e.g. gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament. When the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form. The blisters are typically arranged in regular fashion for ease of release of the medicament therefrom. For example, the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape.

Aerosols may be formed by suspending or dissolving the compound of the invention in a liquified propellant. Suitable propellants include halocarbons, hydrocarbons, and other liquified gases. Representative propellants include : trichlorofluoromethane (propellant 11 ), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1 , 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA- 12), heptafluoropropane (HFA-227a), perfluoropropane,

perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising the compound of the invention will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art. The aerosol may contain additional pharmaceutically-acceptabie excipients typically used with MDIs such as surfactants, lubricants, co-solvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.

Suspensions and solutions comprising the compound of the invention may also be

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

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

The compound according to Formula I is prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction schemes.

Starting materials and reagents depicted below in the general reaction schemes are commercially available or can be made from commercially available starting materials using methods known by those skilled in the art.

The compound disclosed herein may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydro bromide,

trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methane sulphonate or p-toluenesulphonate. The compound of formula ( 1) 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. In a further aspect, the compound disclosed herein is in the form of a pharmaceutically acceptable salt thereof.

In a further aspect, the compound disclosed herein is for use in medicine such as for use as a dipeptidyl peptidase I (DPPI) inhibitor. In one aspect, they 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) ; acute lung injury; acute respiratory distress syndrome; bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; alpha- 1 antitrypsin deficiency;

sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis; dermatitis herpetiformis, lichen planus; lichen sclerosus et atrophica; pyoderma gangrenosum; skin sarcoid; discoid lupus erythematosus; pemphigus; pemphigoid;

epidermolysis bullosa; urticaria; angioedema; vasculitides; toxic erythemas; cutaneous eosinophilias; alopecia areata; male-pattern baldness; Sweet's syndrome; Weber-Christian syndrome; erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dyspiastic lesions; drug-induced disorders including fixed drug eruptions; blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including

sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial; sepsis; nephritis including interstitial and glomerulonephritis; nephritic 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); acute and chronic implications following following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; rheumatoid arthritis; irritable bowel syndrome; inflammatory bowel disease; gout; pseudogout;

Alzheimer's disease; systemic lupus erythematosus; multiple sclerosis; Hashimoto's thyroiditis; Graves' disease; Addison's disease; diabetes mellitus, including type 1 diabetes mellitus; idiopathic thrombocytopaenic purpura; eosinophilic fasciitis; hyper-lgE syndrome; antiphospholipid syndrome and Sazary syndrome; cancers with neutrophil involvement;

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; virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (H IV), human papilloma virus (HPV), cytomegalovirus (C V), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as malaria, fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis camii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis; congestive heart failure;

atherosclerosis; coronary artery disease; myocardial infarction; reperfusion injury; abdominal aortic aneurysms (AAA) ; diabetic cardiomyopathy (DCM); hypertension; peripheral artery disease; cardiac arrhythmia; stroke and cardiomegaly. In a further aspect, the compound disclosed herein is for use as a dipeptidyl peptidase I inhibitor.

In a further aspect, the compound or pharmaceutical composition disclosed herein is for use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis. In a further aspect, the compound or pharmaceutical composition disclosed herein is for for use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, acute lung injury; acute respiratory distress syndrome, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis or sepsis.

In yet a further aspect, the compound or pharmaceutical composition disclosed herein is for use in treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.

In a further aspect, the pharmaceutical composition in unit dosage form, comprised from about 1 g to about 1000 mg such as, e.g., from about 10 ng to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg, of the active substance.

In yet a further aspect, disclosed herein is a compound which 24 hours after a single subcutaneous animal dosing at a concentration of 10 pmol/kg, has a concentration in bone marrow of 250 nM or more, such as 500 n or, 750 nM or more or 1000 nM or more. In yet a further aspect, disclosed herein is a compound which 12 hours after a single subcutaneous animal dosing at a concentration of 10 pmol/kg, has a concentration in bone marrow of 1000 nM or more, such as 1500 nM or more, 2000 nM or more, 3000 nM or more, or 5000 nM or more.

In a further aspect, the pharmaceutical composition disclosed herein is for oral, nasal, transdermal, pulmonal or parenteral administration. In one aspect, a method of treating an obstructive airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a

therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, is provided herein.

In one aspect, a method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of the compound as disclosed herein or of a composition as disclosed herein, is provided.

In a further aspect, an effective amount of the compound as disclosed herein is in a range of from about 1 ng to about 1000 mg such as, e.g., from about 10 g to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg per day. In one aspect, the use of the compound or pharmaceutical composition as disclosed herein for the preparation of a medicament, is provided.

In one aspect, the use of the compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition as disclosed herein for the preparation of a medicament for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis, is provided. In one aspect, the use of the compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis or sepsis, is provided. In one aspect, the use of the compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition as disclosed herein in the manufacture of a medicament for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis is provided.

In one aspect, a method for modulating DPPI levels in a subject in need thereof comprising administering to said subject an amount of the compound or a pharmaceutically acceptable salt thereof as disclosed herein or a composition as disclosed herein in an amount effective to modulate said DPPI levels in said subject, is provided.

In one aspect, said DPPI is inhibited.

In one aspect, a combination of the compound or a pharmaceutically acceptable salt thereof as disclosed herein and one or more agents independently selected from : a non-steroidal glucocorticoid receptor agonist; a selective β2 adrenoceptor agonist; a phosphodiesterase inhibitor; a peptidase inhibitor; a glucocorticoid; an anticholinergic agent; a modulator of chemokine receptor function; and an inhibitor of kinase function, is provided.

In another aspect, a method for treatment of a medical condition selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis, is provided, said method comprising administration of a pharmaceutically effective amount of a compound of formula (I) or the composition according to the invention. Suitably, in this method, the medical condition is selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis. ASPECTS OF THE INVENTION

The invention relates to the following numbered aspects: Aspect 1. A compound of the formula (I) :

• the carbonyl group of said cyclic alpha amino acid moiety and the -NH- group to which it is attached form an amide bond;

• the amino acid moiety of said cyclic alpha amino acid moiety is optionally substituted on a ring carbon atom with one or two substituents ¹ _;

· R¹ independently represents halogen; hydroxy I; cyano; oxo (=0); mercapto; or C_1-3- alkyl; which C^-alky! is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano and mercapto; as well as pharmaceutically-acceptable salts, solvates and hydrates thereof.

Aspect 2. The compound according to any one of the preceding aspects, wherein the cyclic alpha amino acid moiety represented by X¹ and/or X² comprises 4-10 ring atoms.

Aspect 3. The compound according to any one of the preceding aspects, wherein the cyclic alpha amino acid moiety represented by X¹ and/or X² is a monocyclic alpha amino acid moiety.

Aspect 4. The compound according to any one of the preceding aspects, wherein the cyclic alpha amino acid moiety represented by X¹ and/or X² is a cyclic alpha amino acid moiety in which one ring atom is nitrogen, which cyclic alpha amino acid moiety contains a bridge between two carbon ring atoms of X¹ and/or X², said bridge having the general structure - (CH₂)_n-, where n = 1 or 2.

Aspect 5. The compound according to any one of the preceding aspects, wherein X¹ represents:

optionally substituted on a ring carbon atom with one or two R¹, wherein R¹ is as defined in aspect 1, and wherein each Z independently represents O (oxygen) or S (sulfur).

Aspect 6. A compound according to any one of aspects 1-5, wherein X² represents

wherein each cyclic structure of X² is optionally substituted on a ring carbon atom with one or two R¹, and wherein R¹ is defined in aspect 1.

Aspect 7. A compound according to any one of aspects 1-6, wherein X² represents

wherein each cyclic structure of X² is independently optionally substituted with one or two R¹, and wherein R¹ is defined in aspect 1.

Aspect 8. A compound according to any one of aspects 1-7, wherein X² represents

Aspect 9. A compound according to any one of the preceding aspects wherein X¹ = X²

Aspect 10. A compound according to any one of aspects 1-9, wherein R¹ independently represents C_1-3-alkyl. Aspect 11. A compound according to any one of aspects 1-lOwherein X¹ = , opti on a ring carbon atom with one or two R¹, and wherein R¹ isΫ °

onally substituted defined in any one of aspects 1-10.

Aspect 12. A compound according to any one of aspects 1-lOwherein X¹

, optionally substituted on a ring carbon atom with one or two R\ and wherein R¹ is defined in any one of aspects 1- 10.

Aspect 13. A compound according to any one of aspects 1- lOwherein XI =

optionally substituted on a ring carbon atom with one or two substituents Rl, wherein Rl is as defined in any one of aspects 1-10.

Aspect 14. A compound according to any one of aspects 1-10, wherein X¹ =

in which R¹ is as defined in any one of aspects 1-10. Aspect 15. A compound according to any one of aspects 1-14, selected from:

Aspect 17. A compound of formula (I) according to any one of the preceding aspects, in the enantiomerically pure form as per formula (II) or formula (III) :

(II) (HI) wherein X¹ and X² are as defined in any of the preceding aspects.

Aspect 18. A compound of formula (I), (II) or (III) according to any one of the preceding aspects, wherein X¹ is in the enantiomerically pure form :

wherein R¹ is as defined in any one of the preceding aspects, and Z independently represents O (oxygen) or S (sulfur).

Aspect 19: A pharmaceutical composition comprising a compound of the formula (I) :

(I) wherein X¹ and X² are as described in any one of the preceding aspects. Aspect 20. A compound according to any one of aspects 1 - 18 or composition according to aspect 19 for use as a medicament.

Aspect 21. A compound according to any one of aspects 1 - 18 or composition according to aspect 19 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis. Aspect 22. A compound according to any one of aspects 1 - 18 or composition according to aspect 19 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis. Aspect 23. A method for treatment of a medical condition selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria,

Alzheimer's disease or sepsis, said method comprising administration of a pharmaceutically effective amount of a compound of formula (I) according to any one of aspects 1 - 18 or composition according to aspect 19.

Aspect 24. The method according to aspect 23, wherein the medical condition is selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.

Aspect 25. Use of a compound of formula (I) according to any one of aspects 1 - 18 for the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis.

Aspect 26. Use according to aspect 25, wherein the medicament is for the treatment of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.

MATERIALS AND METHODS Human DPPI inhibition assay

Using this assay, the IC₅₀ value of the compound of the invention may be determined using Gly-Phe-paranitroanilide as a DPPI specific substrate.

Assay buffer: 20 mM citric acid (2.1 g citric acid), 150 mM NaCI (4.4 g NaCI) and 2 mM EDTA (370 mg EDTA) was dissolved in 500 mL H₂0, and pH was adjusted to 4.5 with HCI. Substrate: Gly-Phe-paranitroanilide (Sigma Aldrich; Cat. No G0142) was used as the substrate for determination of IC₅₀ values. Km was 2.2 mM. The substrate was solubilized in dimethylformamid to give a 0.2-0.5 M stock solution, which was then further diluted with stirring in assay buffer to a final concentration of 1 mM.

DPPI: Human DPPI (obtained from UNIZYME Laboratories A/S, DK-2970 Horsholm, Denmark) was stored at -20 °C in a buffer containing 2.5 mM Na-phosphate, 150 mM NaCI, 2 mM cysteamine, 50% glycerol, pH 7.0 at a concentration of 1-2 mg/mL (5-10 μΜ). This stock solution was diluted 500-1000 times in assay buffer to a concentration of 10-20 nM.

Assay conditions: The assay was performed in 96-well plates. Diluted enzyme (25 pL) was added to the well, followed by 25 pL of test substance in varying concentrations, and the solution was mixed. The plate was incubated at 37 °C for 5 minutes, followed by addition of 150 yL of 1 mM substrate prewarmed to 37 °C (corresponding to a substrate concentration of 750 μΜ in the assay). The absorption was measured at 405 nm at 37 °C for every 90 seconds for 12 minutes or every 20 seconds for 4 minutes. Each measurement was made in duplicate. IC₅₀ was determined using a 4-parameter logistic equation in a non-linear curve fitting routine.

EXAMPLE 1. (PZ1079)

Procedure (S)-fert-ButyS 2-(4-bromophenyl)-l-cyanoethylcarbamate ( 1)

A solution of (S)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (20.0 g, 58.3 mol) in DC (400 mL) was cooled in an ice-water bath and D TMM (24.2 g, 87.5 mol) was added. The mixture was stirred at 0°C for 1 h before addition of 25% NH₃-H₂0 (6 g, 87.5 mol) . The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was extracted with ethyl acetate three times and the combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated to afford compound (S)-tert-Butyl l-amino-3-(4-bromophenyl)-l-oxopropan-2-ylcarbamate ( 19.0 g, yield 95%) as a white solid. A solution of compound (S)-tert- Butyl l-amino-3-(4-bromophenyl)-l-oxopropan-2- ylcarbamate ( 14.73 g, 43 mmol) in anhydrous pyridine (150 mL) was cooled in an ice-water batch and POCI₃ (8 mL, 77.4 mmol) was added dropwise over 30 min. The reaction mixture was stirred at 0°C for 2 h and then allowed to warm to room temperature and stirred overnight. The mixture was treated with ice-water and extracted with ethyl acetate. The combined organic layers were washed with 1 M HCI solution, saturated aqueous NaHC0₃ and brine, respectively. The organic layer was dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum

ether/EtOAc = 50: 1 to 10: 1) to give compound 1 (9.67 g, yield 69.3%) as a white solid. terf-Butyl jlS_fl 'S)-2_f2'-CWphgn_lyi-4,4'-diyi)bif Cl-cyanpathan^t-illvlWicarbamiHia

OJ

A mixture of compound 1 (2.4 g, 7.38 mmol), pinacolatodiboron (0.75 g, 2.95 mmol), Pd(dppf)CI₂ (0.81 g, 1.11 mmol) and KOAc (4.3 g, 44.28 mmol) in dioxane (30 mL) was stirred at 100°C for 5 h. The mixture was cooled to room temperature and after filtration the solvent was removed under reduced pressure. To the residue was added ethyl acetate (50 mL) and the resulting solution was washed with aqueous NaOH (1 N, 30 mLx 5) and brine (50 mL). The organics were dried over anhydrous Na₂S0 and concentrated. The residue was purified by flash column chromatography on silica gel to afford the title compound 2 as a yellow solid (1.3 g, yield 36%). f2S.2'S 3.3'-fBiDhenvl-4.4'-divl^bisf2-aminoDrooanenitrileH f3¾

A solution of compound 2 (2.0 g, 4.08 mmol) in formic acid (25 mL) was stirred at room temperature for 5 h. The solution was added to cold saturated aqueous NaHC0₃ (200 mL) with stirring. DCM (150 mL) was added to the resulting mixture and the organic phase was separated. The aqueous phase was extracted with DCM (150 mLx2). The organics were combined, washed with brine (200 mL), dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1 : 1) to afford the title compound 3 as a yellow solid (1.2 g, quantitative).

BOC-PZ1079

A solution of compound 3 (0.5 g, 1.72 mmol) in DCM (30 mL) was cooled to 0°C. DMTMM (1.57 g, 5.68 mmol) and (S)-l-(ierf-butoxycarbonyl)piperidine-2-carboxylic acid (0.79 g,

3.44 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with DCM (50 mLx2). The organics were combined, washed with brine (200 mL), dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel to afford the title compound Boc- PZ1079 as a white solid (0.37 g). PZ1079

A solution of compound Boc-PTZ1079 (0.37 g) in formic acid (5 mL) was stirred at room temperature for 5 h. The solution was added to cold saturated aqueous NaHC0₃ (50 mL) with stirring. DCM (50 mL) was added to the resulting mixture and the organic phase was separated. The aqueous phase was extracted with DCM (50 mLx2). The organics were combined, washed with brine (100 mL), dried over anhydrous Na₂S0₄ and concentrated to afford the title compound PZ1079 as a yellow solid (0.20 g, yield 23% over two steps).

¹H NMR (DMSO-d₆, 300 MHz) : δ 8.51 (d, J = 7.5 Hz, 2H), 7.62 (d, J = 8.1 Hz, 4H), 7.38 (d, J = 8.4 Hz, 4H), 5.02 (m, 2H), 3.18 (m, 4H), 3.08 (d, J = 8.7 Hz, 2H), 2.78 (d, J = 12.3 Hz, 2H), 2.47 (m, 2H), 2.35 (m, 2H), 1.58 (m, 4H), 1.44-1.10 (m, 8H). PZ1079 was found to have an IC₅₀ of « 95 nM in the human DPPI inhibition assay

EXAMPLE 2. (PZ1082)

PZ1082

Scheme

3 PZ1082 Procedure

A solution of compound 3 (Example 1)(0.3 g, 1.03 mmol) in DCM (20 mL) was cooled to 0°C. DMT (0.94 g, 3.4 mmol) and (i«,3S,4S)-2-(te -butoxycarbonyl)-2-azabicyclo[2.2.1] heptane-3-carboxylic acid (0.50 g, 2.06 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with DCM (50 mLx2). The organics were combined, dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel to afford the title compound Boc- PZ1082 as a white solid (0.32 g).

£211252

A solution of compound Boc-PZ1082 (0.32 g) in formic acid (5 mL) was stirred at room temperature for 5 h. The solution was added to cold saturated aqueous NaHC0₃ (50 mL) with stirring. DCM (50 mL) was added to the resulting mixture and the organic phase was separated. The aqueous phase was extracted with DCM (50 mLx2). The organics were combined, washed with brine (100 mL), dried over anhydrous Na₂S0₄ and concentrated to afford the title compound PZ1082 as a yellow solid (0.22 g, yield 40% over two steps). H NMR (DMSO- ₆, 300 MHz): δ 8.54 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.1 Hz, 4H), 7.36 (d, J = 8.1 Hz, 4H), 5.01 (m, 2H), 3.32 (d, J = 6.6 Hz, 2H), 3.22 (d, J = 8.1 Hz, 2H), 3.06 (s, 2H), 2.52 (m, 2H), 2.31 (s, 2H), 1.60-1.20 (m, 10H), 0.9 (m, 4H).

PZ1082 was found to have an IC₅₀ of « 28 nM in the human DPPI inhibition assay

EXAMPLE 3. (PZ1078)

PZ1078

Scheme

Procedure

BoctP lOZfi

To a solution of compound 3 (Example 1) (0.5 g, 1.7 mmol) in dichloromethane (20 mL) was added a solution of l-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.9 g, 3.8 mmol) and DMTMM (1.93 g, 6.9 mmol) in dichloromethane (30 mL) at 0°C. The reaction mixture was stirred overnight at ambient temperature and then treated with a mixture of water/dichloromethane (1 : 1, 200 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mLx2). The organic phases were combined, washed with brine, dried over anhydrous Na₂S0 and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/MeOH = 10: 1) to yield compound Boc-PZ1078 (0.63 g, yield 49%).

PZ1078

Compound Boc-PZ1078 (0.6 g, 0.8 mmol) was treated with an excess of HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0₃ in water and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dichloromethane (200 mLx3). The organic phases were combined, washed with brine, dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/MeOH = 5: 1) to afford compound PZ1078 (170 mg, yield 39%).

^!H IMMR (CDCI₃, 300 MHz) : δ 8.42 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 8.1 Hz, 4H), 7.37 (d, J = 7.8 Hz, 4H), 5.15 (m, 2H), 3.15 (d, J = 6.6 Hz, 4H), 1.85-2.02 (m, 4H), 1.69 (m, 6H), 1.27- 1.43 (m, 10H).

PZ1078 was found to have an IC₅₀ of « 14 nM in the human DPPI inhibition assay EXAMPLE 4. (PZ1080)

Procedure BOC-PZ1080

To a solution of compound 3 (Example 1) (0.5 g, 1.7 mmol) in dichloromethane (20 mL) was added a solution of 4-(ierf-butoxycarbonylamino)tetrahydro-2W-pyran-4-carboxylic acid

(0.93 g, 3.8 mmol) and DMTMM (1.93 g, 6.9 mmol) in dichloromethane (30 mL) at 0°C. The reaction mixture was stirred overnight at ambient temperature and then treated with a mixture of water/dichloromethane (1 : 1, 200 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mLx2). The organic phases were combined, washed with brine, dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/MeOH = 10: 1) to yield compound Boc-PZ1080 (0.68 g, yield 54%).

PZ1080

Compound Boc-PZ1080 (0.6 g, 0.8 mmol) was treated with an excess of HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0₃ in water and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dichloromethane (200 mLx3). The organic phases were combined, washed with brine, dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/MeOH = 5: 1) to afford compound PZ1080 (210 mg, yield 44%).

^XH NMR (DMSO- s, 300 MHz) : δ 7.61 (d, J = 8.1 Hz, 4H), 7.37 (d, J = 8.1 Hz, 4H), 5.00 (m, 2H), 3.65 (m, 6H), 3.47 (m, 2H), 3.19 (d, J = 6.3 Hz, 4H), 1.91 (m, 2H), 1.76 (m, 2H), 1.22 (m, 4H).

PZ1080 was found to have an IC₅₀ of « 8 nM in the human DPPI inhibition assay.

EXAMPLE 5. (PZ1095)

Synthetic scheme

(S)-Methyl 3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoate (1)

Methyl iodide (25 g, 0.177 ml) and potassium carbonate (60.2 g, 0.436 ml) were added to a solution of Boc-(S)-2-amino-3-(4-bromophenyl)propanoic acid (50 g, 0.145 moi) in DMF (500 mL) under argon and the reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with water (500 mL) and then extracted with EtOAc (500 mL). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated to afford compound 1 (50 g, 96% yield).

(S)-Methyl 2-Cfert-Butoxycarbonylamino)-3-(4-(4,4_f5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate (2)

To a mixture of compound 1 (5.0 g, 13.97 mmol), pinacolatodiboron (7.3 g, 28.74 mmol) and K₂C0₃ (4.9 g, 35.5 mmol) in DMSO (50 mL) was added Pd(PPh₃)₄ (168 mg, 0.14 mmol) The reaction mixture was heated at 80°C for 1 h under N₂. The mixture was cooled to room temperature and water ( 100 mL) was added. The resulting mixture was extracted with EtOAc (100 mL 2) . The combined organic layers were washed with brine ( 100 mL), dried over anhydrous sodium sulfate and concentrated to afford crude compound 2, which was used in the next step directly without further purification.

(A)-Methyl 2-(benzyloxycarbonylamino)-3-(4-bromophenyl)propanoate (3)

(R)-Methyl 2-amino-3-(4-bromophenyl)propanoate was prepared following the same procedure for compound 1.

4-Br-Phe-OMe (20 g, 77.8 mmol) was suspended in THF/H₂0 (2: 1, 200 mL) and Na₂C0₃ ( 16.4 g, 155 mmol) and Cbz-OSu (20.3 g, 81.5 mmol) were added at room temperature. The reaction mixture was stirred overnight at room temperature and then IN aqueous HCI was added. The resulting mixture was extracted with EtOAc (200 mL χ 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 50 : 1) to afford compound 3 (20.0 g, 66% yield) as a white solid .

(ft)-Methyl 2-(((benzyloxy)carbonyl)amino)-3-(4'-((S)-2-((tert-butoxycarbonyl) amino)-3-methoxy-3-oxopropyl)-[l,l'-biphenyl]-4-yl)propanoate (4)

A solution of compound 2 (37 g, crude, 91.36 mmol), compound 3 (36 g, 91.84 mmol) and sodium carbonate ( 19.4 g, 183 mmol) in 1,4-dioxane (300 mL) and water (20 mL) was purged with N₂ three times. Pd(dppf)CI₂ (3.72 g, 4.568 mmol) was added and the reaction mixture was heated at 60°C for 0.5 h under N₂. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was concentrated and the residue was diluted with ethyi acetate (500 mL) and water (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 50 : 1 to 10 : 1) to afford compound 4 (20 g, 37% yield) as a brown solid.

Benzyl ferf-butyl ((2S_/2'/?)-[l, l'-biphenyl]-4,4'-diylbis( l-amino-l-oxopropane- 3,2- diyl))dicarbamate (5) A mixture of compound 4 (20 g, 33.90 mmol) in ammonium hydroxide (1.2 L) was stirred (under 1 atm) at 50°C overnight and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford compound 5 (17.0 g, 89% yield), which was used directly in the next step without further purification

(9H-Fluoren-9-yl)methyl terf-butyi ((lS_/l ' ?)-[l,l'-biphenyl]-4,4'-diylbis(l- cyanoethane-2,l-diyl))dicarbamate (6) To a solution of compound 5 (5.0 g, 8.93 mmol) in THF (50 mL) was added Pd/C (250 mg, 10%). The mixture was stirred under hydrogen atmosphere (1 atm) at 50°C overnight and then filtered through a pad of celite. The filtrate was concentrated and the residue was treated with water (10 mL) and stirred for 10 min. The resulting solid was collected by filtration and dried to afford compound DeCbz-5 (3.8 g, quantitative), which was used directly in the next step without further purification.

Crude DeCbz-5 (7.9 g, 18.54 mmol) was suspended in THF/H₂0 (2: 1, 100 mL) and NaHC0₃ (3.9 g, 46.43 mmol) and Fmoc-OSu (12.5 g, 37.09 mmol) were added. The reaction mixture was stirred for 3 h at room temperature and the resulting precipitate was collected by filtration, washed with THF (20 mL) and dried to afford the desired intermediate (12.0 g). TFAA (3.8 g, 18.10 mmol) was added dropwise to a solution of the intermediate (3.0 g, 4.63 mmol) and TEA (5.2 mL, 37.6 mmol) in THF (30 mL) at 0°C. The reaction mixture was stirred at room temperature for 1.5 h. Aqueous saturated Na₂C0₃ (100 mL) was added and the resulting mixture was extracted with EtOAc (100 mLx2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (DC /MeOH = 5: 1) to afford compound 6 (480 mg, 17% yield over three steps).

PZ1095

Compound 6 (3.0 g, 4.9 mmol) was dissolved in 98% HCOOH (40 mL) and the reaction mixture was stirred at room temperature for 36 h. Saturated aqueous NaHC0₃ was added dropwise and the resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 20: 1) to afford DeBoc- 6 (2.0 g, 80% yield) as a white solid.

To a solution of DeBoc-6 (2.0 g, 3.87 mmol) in DMF (20 mL) in an ice-water bath was added HATU (2.2 g, 5.8 mmol). The mixture was stirred at 0°C for 0.5 h and 4-(tert- butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid (BocHN-Al-OH, 950 mg, 3.87 mmol) and DIPEA (0.9 mL) were added. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. Water (50 mL) was added and the resulting mixture was extracted with EtOAc (50 mLx3) . The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated . The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 20 : 1) to afford the desired intermediate (2.0 g, 69% yield) as a yellow solid.

Piperidine (1.2 g, 14.11 mmol) was added to a solution of the intermediate (2.0 g, 2.71 mmol) in DCM (8.0 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was treated with diethyl ether and stirred for 0.5 h. The resulting precipitate was collected by filtration and purified by prep-HPLC to afford the corresponding amine ( 1.3 g, 92% yield) as a white solid.

To a solution of the amine ( 1.3 g, 2.5 mmol) in DMF (20 mL) in an ice-water bath was added HATU ( 1.8 g, 9.96 mmol) . The mixture was stirred at 0°C for 0.5 h and ( lR,3S,4S)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (BocHN-A2-OH, 600 mg, 2.5 mmol) and DIPEA (0.6 mL) were added. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. Water (50 mL) was added and the resulting mixture was extracted with EtOAc (50 mL χ 3). The combined organic layers were washed with brine ( 100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 5 : 1) to afford the intermediate ( 1.0 g, 71% yield) as a yellow solid . The intermediate ( 1.0 g, 1.35 mmol) was dissolved in 98% HCOOH ( 10 mL) and the reaction mixture was stirred at room temperature for 12 h. Saturated aqueous NaHC0₃ was added dropwise and the resulting mixture was extracted with DCM . The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 5 : 1) and prep-HPLC to afford compound PZ1095 (160 mg, 22% yield ) as a light solid. H NMR (300 MHz, CDCI₃) : δ 8.30 (br s, 1H), 8.25 (d, 1H, J = 9.6 Hz), 7.59-7.55 (m, 4H), 7.36-7.33 (m, 4H), 5.15 (m, 2H), 3.90-3.85 (m, 2H), 3.67-3.62 (m, 2H), 3.52 (s, 1H), 3.30 (m, 1H), 3.14-3.11 (m, 4H), 2.76 (m, 1H), 2.40-2.05 (m, 3H), 1.67-1.31 (m, 12H), 1.26- 1.16 (m, 7H). LC-MS (ESI) : m/z 541.27 [M+H]⁺. PZ1095 was found to have an IC₅₀ of ~ 11 nM in the human DPPI inhibition assay.

Claims

1. A compound of the formula (I):

(I) wherein X¹ and X² independently represent a cyclic alpha amino acid moiety, in which

• the alpha carbon atom forms part of the cyclic structure;

» the carbonyl group of said cyclic alpha amino acid moiety and the -NH- group to which it is attached form an amide bond;

• the amino acid moiety of said cyclic alpha amino acid moiety is optionally substituted on a ring carbon atom with one or two substituents R¹;

• R¹ independently represents halogen; hydroxyl; cyano; oxo (=0); mercapto; or C_{1 3}- alkyl; which C_1-3-alkyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano and mercapto; as well as pharmaceutically-acceptable salts, solvates and hydrates thereof.

2. The compound according to any one of the preceding claims, wherein X¹ represents:

optionally substituted on a ring carbon atom with one or two substituents R¹, where R¹ is as defined in claim 1 and wherein each Z independently represents O (oxygen) or S (sulfur).

3. The compound according to any one of the preceding claims, wherein X² represents:

optionally substituted on a ring carbon atom with one or two substituents R¹, wherein R¹ is defined in claim 1.

4. A compound according to any one of the preceding claims, wherein X² represents:

wherein each cyclic structure of X² is optionally substituted on a ring carbon atom with one or two R¹, and wherein R¹ is defined in claim 1.

5. A compound according to any one of the preceding claims, wherein X¹ = X².

6. A compound according to any one of the preceding claims wherein X¹ =

optionally substituted on a ring carbon atom with one or two substituents R¹, wherein R¹ is as defined in any one of the preceding claims.

7. A compound according to any one of the preceding claims, selected from:

8. A compound of formula (I) according to any one of claims 1-6, in the enantiomerically pure form as per formula (III):

(III)

wherein X¹ and X² are as defined in any of the preceding aspects.

9. A pharmaceutical composition comprising a compound of the formula (I) :

(I) wherein X¹, X², Z and ¹ are as described in any one of claims 1-6; or a compound according to claim 7.

10. A compound according to any one of claims 1 - 8 or composition according to claim 9 for use as a medicament.

11. A compound according to any one of claims 1 - 8 or composition according to claim 9 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis.

12. A compound according to any one of claims 1 - 8 or composition according to claim 9 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis..

13. A method for treatment of a medical condition selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha- 1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis, said method comprising administration of a pharmaceutically effective amount of a compound of formula (I) according to any one of claims 1 - 8 or composition according to claim 9.

14. The method according to claim 13, wherein the medical condition is selected from the group selected from asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion Injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.

15. Use of a compound of formula (I) according to any one of claims 1 - 8 for the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis.

16. Use according to claim 15, wherein the medicament is for the treatment of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, rheumatoid arthritis or sepsis.