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WO2012119941A1 - Composés de peptidylnitrile à titre d'inhibiteurs de peptidases - Google Patents

Composés de peptidylnitrile à titre d'inhibiteurs de peptidases Download PDF

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Publication number
WO2012119941A1
WO2012119941A1 PCT/EP2012/053624 EP2012053624W WO2012119941A1 WO 2012119941 A1 WO2012119941 A1 WO 2012119941A1 EP 2012053624 W EP2012053624 W EP 2012053624W WO 2012119941 A1 WO2012119941 A1 WO 2012119941A1
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Prior art keywords
alkyl
optionally substituted
cyano
substituent
piperazin
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PCT/EP2012/053624
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English (en)
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John Pedersen
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Prozymex A/S
Lauritzen, Conni
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Publication of WO2012119941A1 publication Critical patent/WO2012119941A1/fr

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Definitions

  • the present invention relates to novel peptidase inhibitors, more specifically to inhibitors of cysteine and/or serine peptidases useful in the treatment/prevention of inflammatory diseases in which peptidases are involved, especially inflammatory diseases mediated by mast cells and neutrophil cells. More specifically the invention relates to peptidyl nitriles capable of selectively inhibiting dipeptidylpeptidase I (DPPI), also known as cathepsin C, an enzyme that cleaves a dipeptide from the N-terminus of a polypeptide chain.
  • DPPI dipeptidylpeptidase I
  • cathepsin C an enzyme that cleaves a dipeptide from the N-terminus of a polypeptide chain.
  • 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 showed 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-terminal end of polypeptide substrates with broad specificity. The pH optimum lies in the region of pH 5-7 using human DPPI.
  • DPPI also functions as a key enzyme in the activation of granule serine peptidases in neutrophils (cathepsin G 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.
  • T-type mast cells 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.
  • the T-type mast cells 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 conjunctiva. 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.
  • 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.
  • 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.
  • WO2006094003 discloses cathepsin C inhibitors and their use.
  • WO2011112685 to Janssen Pharmaceutica NV disclose 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase I.
  • Pharmaceutica NV disclose bicyclic derivatives useful as inhibitors of dipeptidyl peptidase I.
  • WO2011059731 to Janssen Pharmaceutica NV disclose alkynyl derivatives useful as inhibitors of dipeptidyl peptidase I.
  • WO2011075631 to Janssen Pharmaceutica NV disclose substituted benzothiazole and benzoxazole derivatives useful as inhibitors of dipeptidyl peptidase I.
  • WO 2007137738 to Sanofi-Aventis discloses spirocyclic nitriles as cathepsin cysteine protease inhibitors.
  • WO2005028429 to Axys Pharmaceuticals, Inc. discloses haloalkyl containing compounds as cysteine protease.
  • WO2005025554 to Japan Tobacco Inc. discloses dipeptidyl peptidase IV inhibitors.
  • WO 2004108661 to Axys Pharmaceuticals, Inc. discloses amidino compounds as cysteine protease inhibitors.
  • WO2003029200 to Boehringer Ingelheim Pharmaceuticals, Inc discloses compounds useful as reversible inhibitors of cysteine proteases.
  • the compounds of the invention are cysteine peptidase inhibitors, particularly selective cysteine peptidase inhibitors.
  • the compounds of the invention are inhibitors of cysteine peptidases of the papain superfamily such as dipeptidyl peptidase I.
  • A represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent R 20 ;
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, Ci-3-alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ; C ⁇ -alkyl optionally substituted with Ci -6 - alkoxy, -NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, C ⁇ -alkyl or C 3 _ 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a Ci- 6 -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or C ⁇ -alkyl;
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci_ 3 -alkyl, which Ci-3-alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
  • R 18 represents a hydrogen atom, or C ⁇ -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • n 0, 1 or 2;
  • R 0 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci_ 5 -alkyl which Ci-6-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • the present invention relates to a compound of the formula (II)
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(0)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, Ci-3-alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ;
  • Ci_ 6 -alkyl optionally substituted with Ci- 6 -alkoxy, - NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 5 and R 6 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl;
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci_ 3 -alkyl, which Ci- 3 -alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yl;
  • R 18 represents a hydrogen atom, or Ci_ 3 -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • R each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci-6-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • the present invention relates to a compound of the formula (III)
  • R 3 and R 4 each independently represent hydrogen, C ⁇ -alkyl or C 3-6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, C ⁇ -alkyl or C 3-6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci -6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci -3 -alkyl, which Ci -3 -alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
  • R 18 represents a hydrogen atom, or C ⁇ -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • R 0 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci_ 5 -alkyl which Ci-6-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • the present invention also provides pharmaceutical composition
  • a pharmaceutical composition comprising, as an active substance, a compound as defined herein or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable adjuvant, carrier or diluent.
  • the present invention also provides a compound according to the invention for use in medicine such as for treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, periodontitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application in target cell apoptosis.
  • the present invention also provides a method for treatment of inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, periodontitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application in target cell apoptosis, the method comprising administering to a subject in need thereof an effective amount of a compound as defined herein or of a composition as defined herein.
  • the present invention also provides a combination of a compound as defined herein and one or more agents independently selected from : a non-steroidal glucocorticoid receptor agonist; a selective ⁇ 2 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.
  • agents independently selected from : a non-steroidal glucocorticoid receptor agonist; a selective ⁇ 2 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.
  • the present invention relates to a compound of the formula (II)
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, Ci- 3 -alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ;
  • Ci_ 6 -alkyl optionally substituted with Ci- 6 -alkoxy, - NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci_ 3 -alkyl, which Ci-3-alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
  • R 18 represents a hydrogen atom, or Ci-3-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • R 20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci-6-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof. So, in another aspect the present invention relates to a compound of the formula (II)
  • R 2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH 3 ; -0-C 2 H 5 ; -S-CH 3 ; -S-C 2 H 5 ; or Ci- 3 -alkyl, which -0-CH 3 , -0-C 2 H 5 , -S-CH 3 , -S-C 2 H 5 or Ci-3-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto; or when y represents 2, then the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 3- to 7-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen atom,
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, Ci- 3 -alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ;
  • Ci_ 6 -alkyl optionally substituted withCi- 6 -alkoxy, - NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -
  • R 3 and R 4 each independently represent hydrogen, C ⁇ -alkyl or C 3 _ 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl or Ci_ 3 -alkyl optionally substituted with halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
  • R 18 represents a hydrogen atom, or C ⁇ -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or Ci- 6 -alkyl;
  • R 0 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci_ 5 -alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • the present invention relates to a compound of the formula (III)
  • Q is at least one substituent selected from R 20 ; C ⁇ -alkyl optionally substituted with Ci -6 - alkoxy, -NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a Ci- 6 -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci_ 3 -alkyl, which Ci- 3 -alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
  • R 18 represents a hydrogen atom, or Ci_ 3 -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R represents hydrogen, -C 3 _ 6 -cycloalkyl, -C ⁇ -alkyl-Cs-e-cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or
  • R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • R each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci_ 5 -alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof. So, in another aspect the present invention relates to a compound of the formula (III)
  • Q is at least one substituent selected from R 20 ; Ci_ 6 -alkyl optionally substituted with d -6 - alkoxy, -NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl or Ci-3-alkyl optionally substituted with halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
  • R 18 represents a hydrogen atom, or C ⁇ -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or Ci- 6 -alkyl;
  • R 20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • DPPI dipeptidyl-peptidase I (EC 3.4. 14. 1) also known as cathepsin C, cathepsin J, dipeptidyl aminopeptidase I and dipeptidyl transferase.
  • DPPI cleaves a dipeptide Xaa-Xbb from the N terminus of a polypeptide chain Xaa-Xbb-Xcc-[Xxx] n , except when Xaa is Arg or Lys, or when Xbb or Xcc is Pro.
  • 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 a 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.
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • ena ntiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
  • Enantiomeric excess or “ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee) .
  • the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
  • Enantiomerically pure refers to products whose enantiomeric excess is 99% ee or greater.
  • Half-life 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.
  • Optionally substituted indicates that a group, such as -0-CH 3 , -0-C 2 H 5 , -S-CH 3 , -S-C 2 H 5 , cycloalkyl, d -3 -alkyl, heterocycloalkyl, or an aromatic or non-aromatic ring, may be unsubstituted or substituted with one or more substituents as defined herein. "Substituted" in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced.
  • substituted includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination).
  • a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • Suitable substituents are defined herein for each substituted or optionally substituted group.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the compounds according to Formula (I), (II), (III) or (IV) may 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), (II), (III) or (IV) or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof.
  • compounds according to Formula (I), (II), (III) or (IV) containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • the compounds according to Formula (I), (II), (III) or (IV) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), (II), (III) or (IV) , or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. If there is a cycloalkyl or cycloalkenyl group present, some substituent patterns may result in and axial or an equatorial configuration. Both forms are included, unless specified otherwise.
  • compounds according to Formula (I), (II), (III) or (IV) may contain an acidic functional group and are therefore capable of forming pharmaceutically-acceptable base addition salts by treatment with a suitable base.
  • compounds according to Formula (I), (II), (III) or (IV) may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid.
  • pharmaceutically-acceptable salts of the compounds according to Formula (I), (II), (III) or (IV) may be prepared.
  • pharmaceutically-acceptable salts of the compounds according to Formula (I), (II), (III) or (IV) may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-acceptable salts of the compounds according to Formula (I), (II), (III) or (IV) .
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired
  • compositions of the invention can exist in crystalline, semi- crystalline and amorphous forms, as well as mixtures thereof.
  • pharmaceutically-acceptable solvates of a compound of the invention may be formed wherein solvent molecules are incorporated into the solid-state structure during crystallization.
  • Solvates may involve water or nonaqueous solvents, or mixtures thereof.
  • 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.
  • crystalline forms of a compound of the invention may contain solvent molecules, which are not incorporated into the solid-state structure.
  • solvent molecules may become trapped in the crystals upon isolation.
  • solvent molecules may be retained on the surface of the crystals.
  • the invention includes such forms.
  • an alkyl or alkenyl substituent group or an alkyl or alkenyl moiety in a substituent group may be linear or branched.
  • Ci-alkyl denotes a straight or branched, saturated hydrocarbon chain having from one to six carbon atoms.
  • Examples of Ci- 6 -alkyl include methyl, ethyl, propyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3- methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-pentyl, 3-methyl-l- pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, n-butyl, isobutyl, tert-butyl, n- pentyl, isopentyl, neopen
  • C 2 - 6 -alkenyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond, e.g. C 2 - 6 -alkenyl, C 3 - 6 -alkenyl, and the like.
  • Representative examples are ethenyl (or vinyl), propenyl (e.g. prop-l-enyl, prop-2-enyl), butadienyl (e.g. buta-l,3-dienyl), butenyl (e.g. but- l-en-l-yl, but-2-en-l-yl), pentenyl (e.g.
  • pent-l-en-l-yl pent-2-en-2-yl
  • hexenyl e.g. hex-l-en-2-yl, hex-2-en-l-yl
  • l-ethylprop-2-enyl l,l-(dimethyl)prop-2-enyl, l-ethylbut-3-enyl, l,l-(dimethyl)but-2-enyl, and the like.
  • C 3 - 6 -cycloalkyl represents a saturated monocyclic carbocyclic ring having from 3 to 6 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • C 3 - 7 -cycloalkyl represents a saturated monocyclic carbocyclic ring having from 3 to 7 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Ci-6-thioalkyl refers to the radical Ci- 6 -alkyl-S-. Representative examples are methylthio, ethylthio, propylthio (e.g. 1-propylthio, 2-propylthio, 3-propylthio), butylthio, pentylthio, hexylthio, and the like.
  • C 3 - 6 -heterocycloalkyl as used herein means a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • a heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatoms double bonds in the ring as long as the ring is not rendered aromatic by their presence.
  • heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl.
  • Ci-6-alkoxy refers to the radical Ci- 6 -alkyl-0-. Representative examples are methoxy, ethoxy, propoxy (e.g. 1-propoxy, 2-propoxy), butoxy (e.g. 1-butoxy, 2-butoxy, 2- methyl-2-propoxy), pentoxy (1-pentoxy, 2-pentoxy), hexoxy (1-hexoxy, 3-hexoxy), and the like.
  • benzyloxy refers to the radical C 6 H5CH 2 0-
  • halogen or “halo” means fluorine, chlorine, bromine or iodine.
  • carboxyl shall mean the radical -COOH.
  • hydroxy shall mean the radical -OH.
  • oxy shall mean the radical -0-.
  • nitro shall mean the radical -N0 2 .
  • cyano shall mean the radical -CN.
  • mercapto shall mean the radical -SH.
  • amino shall mean the radical -NH 2 .
  • alkyl or cycloalkyl groups may be the same as, or different from, one another.
  • the term "optionally substituted with at least one substituent” mean unsubstituted or substituted with at least one substituent, preferably one or two substituents.
  • R 3 and R 4 together with the nitrogen to which they are attached, form a 4- to 7-membered saturated heterocyclic ring will optionally contain at least one further ring heteroatom selected from nitrogen, oxygen and sulphur and represents but are not limited to morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, and the like.
  • the definitions of the heterocyclic rings in formula (I), (II), (III) or (IV) are not intended to include structures having any 0-0, 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.
  • the definitions of the 3- to 7- or 4- to 7- membered saturated heterocyclic rings in formula (I), (II), (III) or (IV) are not intended to include structures wherein the groups -S-, -0- and -S(O)- are adjacent to each other, i.e. that the rings does not include any 0-0, 0-S or S-S bonds in the ring structure.
  • any substituent on the heterocyclic ring may be attached to any suitable ring carbon atom provided the resulting compound is not inherently unstable.
  • the 5- to 10-membered aromatic ring system may be carbocylic or heterocyclic.
  • phenyl, naphtyl, pyrrolyl e.g. pyrrol-l-yl, pyrrol-2-yl, pyrrol-3- yl
  • furanyl e.g. furan-2-yl, furan-3-yl
  • thienyl e.g. thien-2-yl, thien-3-yl
  • oxazolyl e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl
  • thiazolyl e.g. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl
  • imidazolyl e.g.
  • l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl 1,2,5- oxadiazolyl (e.g. l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (e.g. 1,3,4- oxadiazol-2-yl, l,3,4-oxadiazol-5-yl), 1,2,3-thiadiazolyl (e.g. l,2,3-thiadiazol-4-yl, 1,2,3- thiadiazol-5-yl), 1,2,4-thiadiazolyl (e.g.
  • l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl 1,2,5- thiadiazolyl (e.g. l,2,5-thiadiazol-3-yl, l,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g. 1,3,4- thiadiazol-2-yl, l,3,4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-l-yl, tetrazol-5-yl), pyranyl (e.g. pyran-2-yl), pyridinyl (e.g.
  • pyridine-2-yl pyridine-3-yl, pyridine-4-yl
  • pyridazinyl e.g. pyridazin-2-yl, pyridazin-3-yl
  • pyrimidinyl e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5- yl
  • Representative examples are indolyl (e.g. indol-l-yl, indol-2-yl, indol-3-yl, indol-5- yl), isoindolyl, benzofuranyl (e.g.
  • phthalazin-l-yl phthalazin-5-yl
  • pteridinyl purinyl (e.g. purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl, purin-9-yl), quinazolinyl (e.g. quinazolin- 2-yl, quinazolin-4-yl, quinazolin-6-yl), cinnolinyl, quinoliny (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl), isoquinolinyl (e.g.
  • carbazolyl e.g. carbazol-2-yl, carbazol-3-yl, carbazol-9-yl
  • phenoxazinyl e.g. phenoxazin-10-yl
  • phenazinyl e.g. phenazin-5-yl
  • acridinyl e.g. acridin- 9-yl, acridin-10-yl
  • phenothiazinyl e.g. phenothiazin-10-yl
  • carbolinyl e.g.
  • Other representative examples are pyrrolinyl, pyrazolinyl, imidazolinyl (e.g. 4,5- dihydroimidazol-2-yl, 4,5-dihydroimidazol-l-yl), indolinyl (e.g. 2,3-dihydroindol- l-yl, 2,3- dihydroindol-5-yl), dihydrobenzofuranyl (e.g.
  • tetrahydroindazolyl e.g. 4,5,6,7-tetrahydroindazol-l-yl, 4,5,6,7-tetrahydroindazol-3-yl, 4,5,6,7-tetrahydroindazol-4-yl, 4,5,6,7-tetrahydroindazol-6-yl
  • tetrahydrobenzimidazolyl e.g. 4,5,6,7-tetrahydrobenzimidazol-l-yl, 4,5,6,7-tetrahydrobenzimidazol-5-yl
  • tetrahydroimidazo[4,5-c]pyridyl e.g .
  • tetrahydroquinolinyl e.g. 1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl
  • tetrahydroisoquinolinyl e.g. 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl
  • tetrahydroquinoxalinyl e.g. 1,2,3,4-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl
  • the 5- to 10-membered aromatic ring systems include phenyl, furanyl, pyrazolyl, pyridinyl, indolyl, oxazolyl, quinolinyl, pyrimidinyl, thienyl, 2,3- dihydrobenzoxazinyl, 3,4-dihydrobenzoxazinyl, benzothiazinyl, benzoxazolinyl and
  • y is 0. In a further aspect, y is 1. In a further aspect, y is 2. In a further aspect, n is 1. In a further aspect, n is 2. In a further aspect, n is 3. In a further aspect, n is 4. In a further aspect, n is 5. In one aspect, y is 0 and n is 4. In a further aspect, y is 1 and n is 4.
  • R 2 independently represents halogen; hydroxyl; cyano; mercapto; -0-CH 3 ; - 0-C 2 H 5 ; -S-CH 3 ; -S-C 2 H 5 ; or Ci- 3 -alkyl; which -0-CH 3 , -0-C 2 H 5 , -S-CH 3 , -S-C 2 H 5 or C h alky! is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto.
  • the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 3- to 7-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen atom, and which aromatic ring or non-aromatic ring is optionally substituted with at least one substituent R 20 .
  • the two R 2 are attached to the same carbon atom.
  • y there are two intervening carbon atoms in between the carbon atoms to which the two R 2 are attached . In one aspect, wherein y is 2, there are intervening three carbon atoms in between the carbon atoms to which the two R 2 are attached . In one aspect, wherein y is 2, the two R 2 together with the carbon atom(s) to which they are attached represents a 3-membered saturated heterocyclic ring containing -0-.
  • the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atom(s) represents a 4-membered saturated heterocyclic ring containing 1 or 2 groups independently selected from -S- and -0-.
  • the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 5-membered saturated heterocyclic ring containing 1 or 2 groups independently selected from -S- and -0-.
  • the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 6-membered saturated heterocyclic ring containing 1, 2 or 3 groups independently selected from -S- and -0-.
  • the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 7-membered saturated heterocyclic ring containing 1, 2 or 3 groups independently selected from -S- and -0-.
  • X is a single bond.
  • A represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent R 20 .
  • the 5- to 10-membered aromatic ring system is optionally substituted with one, two or three substituent(s).
  • the aromatic ring or non-aromatic ring is un-substituted.
  • A represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises one, two or three ring heteroatom(s) selected from nitrogen, oxygen and sulphur and which aromatic ring system is optionally substituted with at least one substituent R 20 .
  • A represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises one or two ring heteroatom(s) selected from nitrogen, oxygen and sulphur, and which aromatic ring system is optionally substituted with at least one substituent R 20 .
  • A represents furanylene, benzothiazolene, naphthylene, thienylene, benzotriazol, triazolopyridinylene, indolylene, or phenylene. In a further aspect, A represents furanylene, indolylene, or phenylene.
  • A represents indolylene, or phenylene.
  • A represents phenylene
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one substituent Q selected from R 20 ; trifluoromethyl; Ci-6-thioalkyl; -(Ci- 2 -alkyl)-4-R 19 -piperazin- l-yl in which the Ci_ 2 -alkyl is optionally substituted with at least one substituent R 17 ; -S(0) 2 -(4-(Ci- 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; (4-(Ci- 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; and piperidinyl optionally substituted with -NR 14 R 15 or Ci- 6 -alkyl.
  • Q is at least one substituent selected from halogen; cyano; trifluoromethyl; - S(0) 2 -(4-(Ci- 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; -(Ci- 2 -alkyl)-4-R 19 -piperazin- l-yl in which the Ci- 2 -alkyl is optionally substituted with at least one substituent R 17 ; 4-(Ci- 6 -alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 ; and piperidinyl optionally substituted with -NR 14 R 15 or C 1-6 -alkyl.
  • Q represents -S(0) 2 -(4-(Ci- 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 .
  • Q represents - S(0) 2 -(4-(methyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 .
  • Q represents 4-(C 1 _ 6 -alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 .
  • Q represents 4-(methyl)- piperazin-l-yl.
  • Q represents is optionally substituted with at least one substituent R 17 .
  • Ci- 2 -alkyl is methyl.
  • Ci- 2 -alkyl is ethyl.
  • R 17 is selected from cyano; cyclopropyl; methyl substituted with cyclopropyl; ethyl substituted with cyclopropyl; and ethyl substituted with cyclopropyl which cyclopropyl is substituted with cyano.
  • two R 17 together with the carbon atom to which they are attached form a cyclopropyl. In a further aspect, two R 17 together with the carbon atoms to which they are attached form a cyclopropyl.
  • R 19 is selected from methyl; ethyl; propyl; cyclopropyl; cyclobutyl;
  • cyclopentyl cyclohexyl; isopropyl; methylcyclopropyl; ethylcyclopropyl; and
  • B represents optionally substituted benzothiazolyl, pyrrolyl, pyrazolyl, indolyl, thiazolyl, pyridazinyl, phenyl, triazolopyridinyl, or imidazolyl.
  • B represents benzothiazolyl, pyrrolyl, pyrazolyl, indolyl, thiazolyl, pyridazinyl, phenyl, triazolopyridinyl, or imidazolyl.
  • B represents optionally substituted benzothiazolyl, indolyl, thiazolyl, pyridazinyl, imidazolyl, or phenyl.
  • B represents optionally substituted thiazolyl. In a further aspect, B represents optionally substituted imidazolyl. In a further aspect, B represents substituted phenyl. In a further aspect, B represents optionally substituted benzothiazolyl. In a further aspect, B represents optionally substituted pyrazolyl. In a further aspect, B represents optionally substituted pyrrolyl. In a further aspect, B represents optionally substituted indolyl. In a further aspect, B represents optionally substituted pyridazinyl.
  • B represents optionally substituted triazolopyridinyl.
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one substituent Q selected from R 20 ; trifluoromethyl; Ci-6-thioalkyl; -(Ci- 2 -alkyl)-4-R 19 -piperazin- l-yl in which the Ci_ 2 -alkyl is optionally substituted with at least one substituent R 17 ; -S(0) 2 -(4-(Ci- 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; (4-(C 1 _ 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; and piperidinyl optionally substituted with -NR 14 R 15 or Ci- 6 -alkyl.
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one 4-(Ci- 6 -alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent selected from halogen, Ci-3-alkyl optionally substituted with halogen, C ⁇ -alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifluoromethyl.
  • B is substituted with -S(0) 2 -4-R 19 -piperazin- l- yl.
  • B is substituted with -S(0) 2 -4-R 19 -piperazin- l-yl is -S(0) 2 -(4-(Ci-6- alkyl)-piperazin- l-yl), -S(0) 2 -(4-(C 3 - 6 -cycloalkyl)-piperazin-l-yl) or -S(0) 2 -(4-(C 3 - 6 - cycloalkyl-Ci- 3 -alkyl)-piperazin- l-yl) .
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one (4-(C 1 _ 6 -alkyl)piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 .
  • A represents phenyl
  • X is a bond
  • B is as defined above.
  • a and B together represents 4,4'-biphenyl, 4-(thiazol-5-yl)phenyl, 4- (thiazol-4-yl)phenyl, or 4-([l,2,4]triazolo[ l,5-a]pyridine-6-yl)phenyl, wherein B is optionally substituted as defined herein.
  • a and B together represents an 4,4'-biphenyl, and wherein B is optionally substituted with -S(0) 2 -(4-C 1 _ 6 -alkyl-piperazin- l-yl), which - S(0) 2 -(4-C 1 _ 6 -alkyl-piperazin- l- yl) is optionally substituted at a carbon atom with at least one substituent selected from halogen, Ci-3-alkyl optionally substituted with halogen, Ci-6-alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifluoromethyl.
  • a and B together represents an 4,4'-biphenyl, and wherein B is substituted with -S(0) 2 -(4-methyl-piperazin- l-yl). In a further aspect, A and B together represents an 4,4'-biphenyl, and wherein B is substituted with -rmethyl-4-rmethyl-piperazin- l-yl.
  • a and B together represents an 4,4'-biphenyl, and wherein B is substituted with -ethyl-4-rmethyl-piperazin- l-yl.
  • a and B together represents 4-(thiazol-4-yl)phenyl, and wherein B is optionally substituted with -S(0) 2 -(4-methyl-piperazin- l-yl) .
  • a and B together represents 4-(thiazol-5-yl)phenyl, and wherein B is optionally substituted with 4-methyl-piperazin- l-yl.
  • a and B together represents 4-(thiazol-5-yl)phenyl, and wherein B is optionally substituted with -S(0) 2 -(4-methyl-piperazin- l-yl) .
  • a and B together represents 4-(thiazol-4-yl)phenyl, and wherein B is optionally substituted with 4-methyl-piperazin- l-yl.
  • a and B together represents an optionally substituted 4- ([ l,2,4]triazolo[ l,5-a]pyridine-6-yl) phenyl.
  • a and B together represents a 4-[l,2,4]triazolo[ l,5-a] and wherein B is optionally substituted with 4-Ci- 6 -alkyl-piperazin- l-yl.
  • a and B together represents a 4-[l,2,4]triazolo[ l,5-a] and wherein B is optionally substituted with 4-methyl-piperazin- l-yl.
  • a and B together represents a 4-[l,2,4]triazolo[ l,5-a] and wherein B is optionally substituted with -S(0) 2 -(4-methyl-piperazin- l-yl) .
  • X represents a single bond .
  • A represent phenylene and X is a bond.
  • substituent -A-X-B is selected from the group of:
  • a herein disclosed compound is selected from the group consisting of:
  • a herein disclosed compound is selected from the group consisting of
  • a herein disclosed compound is selected from the group consisting of:
  • a herein disclosed compound is selected from the group consisting of:
  • the compounds of the invention may be administered by any suitable route of
  • 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 lungs 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.
  • the 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 a compound 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.
  • suitable dosing regimens, including the amount administered and the duration such regimens are administered, for a compound 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.
  • a prodrug of a compound 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 a 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
  • Coupling of short peptides or single amino acids as carriers of a therapeutic agent can be used as an effective type of prodrug approach.
  • an amino acid or a di- (or oligopeptide moiety is linked to a free (primary) 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 (DDPI/cathepsin C), aminopeptidase N (APN/CD13), pyroglutamyl aminopeptidase (PGAP), aminopeptidase P, elastase, cathepsin G, tryptase or chymase.
  • the compounds disclosed herein is linked via a free (primary) amino group to an amino acid or a di- (or oligopeptide moiety.
  • These prodrugs may be converted to the desired active compound by a peptidase catalyzed reaction.
  • 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
  • compositions disclosed herein may be prepared and packaged in bulk form wherein a safe and effective amount of a compound disclosed herein can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • compositions disclosed herein may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound as disclosed herein.
  • pharmaceutical compositions disclosed herein typically contain from 1 mg to 1000 mg.
  • compositions disclosed herein typically contain one compound as disclosed herein. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, 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
  • the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient.
  • 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.
  • 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.
  • dosage forms include those adapted for (1 ) oral
  • administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols 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.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • 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.
  • pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds 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, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • 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).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of 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.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
  • the invention is directed to a dosage form adapted for administration to a patient by inhalation.
  • 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 a 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.
  • 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.
  • 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).
  • MDPI multi-dose dry powder inhaler
  • 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.
  • the dry powder 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.
  • 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 a 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,
  • Aerosols comprising a 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.
  • MDI metered dose inhaler
  • the aerosol may contain additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • Suspensions and solutions comprising a 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-acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof.
  • Saline solutions utilize salts which display little or no pharmacological activity after administration.
  • 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.
  • 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.
  • organic acids e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
  • compositions 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.
  • 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 compounds according to Formula (I), (II), (III) or (IV) are prepared using conventional organic syntheses. Suitable synthetic routes are shown in the examples. Starting materials and reagents shown are commercially available or can be made from commercially available starting materials using methods known by those skilled in the art.
  • the invention also includes various deuterated forms of the compounds of Formula (I), (II), (III) or (IV) .
  • a person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I), (II), (III) or (IV) .
  • a-deuterated a- amino acids are commercially available or may be prepared by conventional techniques (see for example Elemes, Y. and Ragnarsson, U. J. Chem. Soc. Perkin Trans. I, 1996,6, 537-40).
  • a-amino acids in which deuterium atoms have been incorporated into the side-chains are commercially available or may be prepared by conventional techniques.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used.
  • reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • the compounds disclosed herein may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydro bromide,
  • the compounds 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.
  • the compound(s) disclosed herein is in the form of a pharmaceutically acceptable salt thereof.
  • the compound(s) 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
  • obstructive diseases of the airways including : asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID- induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillos
  • panniculitis includingcutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions; eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; crizis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial; genitourinary: 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); allograft rejection
  • the compound(s) disclosed herein is for use as a peptidase inhibitor. In a further aspect, the compound(s) disclosed herein is for use as a cysteine peptidase inhibitor.
  • the compound(s) disclosed herein is for use in treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, periodontitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application in target cell apoptosis.
  • the compound(s) disclosed herein is for use in treating for use in treating asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel diseases, cystic fibrosis, sepsis or allergic rhinitis.
  • the compound(s) disclosed herein is for use in treating congestive heart failure, atherosclerosis, coronary artery disease, acute myocardial infarction, hypertension, peripheral artery disease, cardiac arrhythmia, stroke and cardiomegaly.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the pharmaceutical composition in unit dosage form comprised from about 1 ⁇ g 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, of the active substance.
  • the pharmaceutical composition disclosed herein is for oral, nasal, transdermal, pulmonal or parenteral administration.
  • 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
  • a method for the treatment of ailments comprising administering to a subject in need thereof an effective amount of a compound as disclosed herein or of a composition as disclosed herein, is provided.
  • an effective amount of a compound as disclosed herein is in a range of from about 1 ⁇ g 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.
  • a compound or a pharmaceutically acceptable salt thereof as disclosed herein for the preparation of a medicament for treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application in target cell apoptosis, is provided.
  • a compound or a pharmaceutically acceptable salt thereof as disclosed herein in the manufacture of a medicament for use in treating asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel diseases, cystic fibrosis, sepsis or allergic rhinitis, is provided.
  • a compound or a pharmaceutically acceptable salt thereof as disclosed herein in the manufacture of a medicament for use in treating asthma, chronic obstructive pulmonary disease or allergic rhinitis, is provided.
  • a method for modulating DPPI levels in a subject in need thereof comprising administering to said subject an amount of a 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.
  • said DPPI is inhibited.
  • a compound, which has a IC 50 (Cathepsin H)/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more, is provided.
  • a compound which has a IC 50 (Cathepsin L)/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more, is provided.
  • IC 50 Cathepsin L
  • DPPI assay a compound, which has a IC 50 (Cathepsin L)/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more, is provided.
  • a compound, which has a IC 50 (Cathepsin S)/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more, is provided.
  • a compound which has a IC 50 (DPPI assay)/ IC 50 (neutrophil cell based DPPI inhibitor assay) of 0.25 or more, such as e.g. 0.5 or more, 1 or more, 2 or more, 5 or more, 10 or more or 20 or more, is provided.
  • a compound which has a IC 50 (neutrophil cell based DPPI inhibitor assay) of 50 nM or lower, such as e.g. 25 nM or lower, 10 nM or lower, 5 nM or lower, 2 nM or lower, 1 nM or lower, 0.5 nM or lower or 0.25 or lower, is provided.
  • IC 50 neurotrophil cell based DPPI inhibitor assay
  • agents independently selected from : a non-steroidal glucocorticoid receptor agonist; a selective ⁇ 2 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.
  • the herein disclosed compounds have an apparent Hill-coefficient in the DPPI assay or in the neutrophil cell based DPPI inhibitor assay of 1.25 or more, such as e.g. 1.5 or more, 1.75 or more, 2 or more, 2.5 or more or 3.0 or more.
  • the herein disclosed compounds have an apparent Hill-coefficient in the DPPI assay or in the neutrophil cell based DPPI inhibitor assay of 1.25 or more, such as e.g. 1.35 or more, 1.6 or more, 2 or more, 2.5 or more or 3.0 or more.
  • the advantage of having high Hill coefficients has been highlighted by pharmacokinetic studies that suggest that in vivo inhibition of elastase and cathepsin G requires a high fractional and sustained level of DPPI inhibition, probably as high as 99 % or more. It may therefore be desirable to have inhibitors with a Hill coefficient significantly greater than 1 (e.g. 1.4 -1.8), because this may results in e.g. lower IC 99 or IC 99 . 5 values.
  • the Hill coefficient n (also called the cooperativity factor) provides a quantitative method for characterizing DPPI inhibition.
  • the macromolecule (P) is assumed to bind to n ligands (L) simultaneously (where n is to be determined) to form the complex C.
  • the dissociation constant equals
  • variable ⁇ represents the fraction of binding sites that are occupied on the
  • 1 - ⁇ represents the fraction of binding sites that are not occupied, giving the ratio
  • plotting log [ ⁇ /1- ⁇ ] versus log [L] and taking the slope gives the effective number of ligands n that are binding cooperatively at a particular ligand concentration [L].
  • the degree of cooperativity is characterized by the maximum slope n in the "ramping up” region, which is ⁇ 2.8 for hemoglobin; thus, at its most cooperative, hemoglobin effectively binds three ligands in concert.
  • the "ramping up” corresponds to an increase in the affinity (decrease in Kd) that occurs as the amount of bound ligand increases.
  • Such plots are sometimes characterized as "sigmoid” due to their subtle "S"-shape.
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, Ci- 3 -alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ;
  • Ci_ 6 -alkyl optionally substituted with d -6 - alkoxy, -NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 9 and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3 _ cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci_ 3 -alkyl, which Ci- 3 -alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 1 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-
  • R 18 represents a hydrogen atom, or Ci-3-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • n 0, 1 or 2;
  • R 20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci-6-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • Aspect 2 A compound of the formula (I)
  • y represents 0, 1 or 2; when y is 1 or 2, then R 2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH 3 ; -0-C 2 H 5 ; -S-CH 3 ; -S-C 2 H 5 ; or Ci -3 -alkyl; which -0-CH 3 , -0-C 2 H 5 , -S-CH 3 , -S-C 2 H 5 or Ci-3-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto; or when y represents 2, then the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 3- to 7-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen atom, and which aromatic
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, d_ 3 -alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ;
  • Ci_ 6 -alkyl optionally substituted with d -6 - alkoxy, -NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -
  • R 3 and R 4 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, C ⁇ -alkyl or C 3-6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci -6 -alkyl or C 3-6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, C ⁇ -alkyl or C 3-6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a Ci -6 -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci -6 -alkyl;
  • R 17 represents halogen, cyano, cyclopropyl or C ⁇ -alkyl optionally substituted with halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
  • R 18 represents a hydrogen atom, or Ci_ 3 -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or -Ci_ 6 -alkyl;
  • R 20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci_ 5 -alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • Aspect 3 The compound according to any one of aspects 1-2, wherein A represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent R 20 .
  • Aspect 4 The compound according to any one of aspects 1-3, wherein A represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises one, two or three ring heteroatom(s) selected from nitrogen, oxygen and sulphur and which aromatic ring system is optionally substituted with at least one substituent R 20 .
  • Aspect 5 The compound according to any one of aspects 1-3, wherein A represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises one or two ring heteroatom(s) selected from nitrogen, oxygen and sulphur, and which aromatic ring system is optionally substituted with at least one substituent R 20 .
  • Aspect 6 The compound according to any one of aspects 1-5, wherein A represents furanylene, benzothiazolene, naphthylene, thienylene, benzotriazol, triazolopyridinylene, indolylene, or phenylene.
  • Aspect 7 The compound according to aspect 6, wherein A represents indolylene, or phenylene.
  • Aspect 8 The compound according to aspect 7, wherein A represents phenylene.
  • Aspect 9 The compound according to any one of aspects 1-8, wherein B is phenyl and Q is in the para position (4-position).
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, C 1-3 -alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ;
  • Ci_ 6 -alkyl optionally substituted with Ci- 6 -alkoxy, - NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci_ 3 -alkyl, which Ci- 3 -alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3-
  • R 18 represents a hydrogen atom, or Ci_ 3 -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • R each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci-6-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • y represents 0, 1 or 2; when y is 1 or 2, then R 2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH 3 ; -0-C 2 H 5 ; -S-CH 3 ; -S-C 2 H 5 ; or Ci- 3 -alkyl, which -0-CH 3 , -0-C 2 H 5 , -S-CH 3 , -S-C 2 H 5 or Ci_ 3 -alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto; or when y represents 2, then the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 3- to 7-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen
  • X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0) 2 -, -N(R 16 )-, - C(0)-N(R 16 )-, -N(R 16 )C(0)-, -S(0) 2 N(R 16 )-, -N(R 16 )S(0) 2 -, Ci- 3 -alkylene, ethenylene or ethynylene;
  • B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at least one substituent Q selected from R 20 ;
  • Ci_ 6 -alkyl optionally substituted with Ci- 6 -alkoxy, - NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, C ⁇ -alkyl or C 3 _ 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci_ 6 -alkyl or C 3 - 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a C ⁇ -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl or Ci-3-alkyl optionally substituted with halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
  • R 18 represents a hydrogen atom, or C ⁇ -alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or Ci- 6 -alkyl;
  • R 20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • Aspect 12 The compound according to any one of aspects 1-11, wherein X is a single bond.
  • Aspect 16 The compound according to any one of aspects 1-15, wherein B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system is substituted with at least one substituent Q selected from -S(0) 2 -4-R 19 -piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 ; or -(Ci- 2 -alkyl)-4-R 19 -piperazin-l-yl in which the Ci- 2 -alkyl is optionally substituted with at least one substituent R 17 .
  • Aspect 17 The compound according to any one of aspects 1-16, wherein B represents a phenyl substituted with at least one substituent Q selected from -S(0) 2 -4-R 19 -piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 ; or -(Ci- 2 - alkyl)-4-R 19 -piperazin- l-yl in which the Ci- 2 -alkyl is optionally substituted with at least one substituent R 17 .
  • Aspect 18 The compound according to any one of aspects 1- 17, wherein B is phenyl and Q is in the para position (4-position).
  • Aspect 19 The compound according to any one of aspects 1- 18, wherein B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one substituent Q selected from R 20 ; trifluoromethyl; Ci- 6 -thioalkyl; -(Ci- 2 -alkyl)-4-R 19 - piperazin- l-yl in which the Ci_ 2 -alkyl is optionally substituted with at least one substituent R 17 ; -S(0) 2 -(4-(C 1 _ 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; (4-(Ci- 6 -alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; and piperidinyl which is optionally substituted with -NR 14 R 15 or Ci- 6 -alkyl.
  • Aspect 20 The compound according to aspect 19, wherein B represents a 5- to 10- membered aromatic ring system, which aromatic ring system is substituted with at least one 4-(C 1 _ 6 -alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 .
  • Aspect 21 The compound according to any one of aspects 1-20, wherein B represents optionally substituted benzothiazolyl, pyrrolyl, pyrazolyl, indolyl, thiazolyl, pyridazinyl, phenyl, triazolopyridinyl or imidazolyl.
  • Aspect 22 The compound according to any one of aspects 1-21, wherein B represents optionally substituted thiazolyl.
  • Aspect 23 The compound according to any one of aspects 1-21, wherein B represents optionally substituted imidazolyl.
  • Aspect 24 The compound according to any one of aspects 1-21, wherein B represents optionally substituted benzothiazolyl.
  • Aspect 25 The compound according to any one of aspects 1-21, wherein B represents optionally substituted pyrazolyl.
  • Aspect 26 The compound according to any one of aspects 1-21, wherein B represents optionally substituted pyrrolyl.
  • Aspect 27 The compound according to any one of aspects 1-21, wherein B represents optionally substituted indolyl.
  • Aspect 28. The compound according to any one of aspects 1-21, wherein B represents optionally substituted triazolopyridinyl.
  • Aspect 29 The compound according to any one of aspects 1-21, wherein B represents substituted phenyl.
  • Aspect 30 The compound according to any one of aspects 1-21, wherein A and B together represents 4,4'-biphenyl, 4-(thiazol-4-yl)phenyl, 4-(thiazol-5-yl)phenyl or 4- ([ l,2,4]triazolo[ l,5-a]pyridine-6-yl)phenyl, wherein B is optionally substituted as defined above.
  • Aspect 31 The compound according to any one of aspects 1-30, wherein A represent phenylene and X is a bond.
  • Q is at least one substituent selected from R 20 ; Ci_ 6 -alkyl optionally substituted with d -6 - alkoxy, -NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, Ci_ 6 -alkyl or C 3 _ 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a Ci- 6 -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl;
  • R 17 represents halogen, cyano, cyclopropyl, oxetan-3-yl or d -3 -alkyl, which C ⁇ -alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
  • R 18 represents a hydrogen atom, or Ci-3-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • R each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci_ 5 -alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • Q is at least one substituent selected from R 20 ; Ci_ 6 -alkyl optionally substituted with Ci-6- alkoxy, -NR 14 R 15 , phenyl or morpholinyl; C 3 - 6 -cycloalkyl; C 2 - 6 -alkenyl; trifluoromethyl;
  • R 3 and R 4 each independently represent hydrogen, C ⁇ -alkyl or C 3 _ 6 -cycloalkyl, or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 5 and R 6 each independently represent hydrogen, Ci- 6 -alkyl or C 3 - 6 -cycloalkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 9 and R 10 each independently represent hydrogen, Ci_ 5 -alkyl or C 3 _ 6 -cycloalkyl, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 14 and R 15 each independently represent hydrogen, C ⁇ -alkyl or C 3 _ 6 -cycloalkyl, or R 14 and R 15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
  • R 7 , R 8 , R 11 , R 12 and R 13 each independently represent a hydrogen atom or a Ci- 6 -alkyl or C 3-6 - cycloalkyl;
  • R 16 represents a hydrogen atom or Ci- 6 -alkyl
  • R 17 represents halogen, cyano, cyclopropyl or C ⁇ -alkyl optionally substituted with halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
  • R 18 represents a hydrogen atom, or Ci-3-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or Ci- 6 -alkyl;
  • R 20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci_ 5 -alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • Aspect 34 The compound according to any one of aspects 1-33, wherein R 19 is selected from -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -Ci_ 6 -alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4
  • n 0, 1 or 2.
  • Aspect 35 The compound according to any one of aspects 1-34, wherein R represents - C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or Ci_ 6 -alkyl, which Ci- 6 -alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino.
  • Aspect 36 The compound according to any one of aspects 1-35, wherein R 19 represents - C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or Ci- 6 -alkyl.
  • Aspect 37 The compound according to any one of aspects 1-36, wherein y is 0.
  • Aspect 38 The compound according to any one of aspects 1-36, wherein y is 1.
  • Aspect 39 The compound according to any one of aspects 1-36, wherein y is 2.
  • Aspect 40 The compound according to any one of aspects 1-36, wherein n is 1.
  • Aspect 41 The compound according to any one of aspects 1-36, wherein n is 2.
  • Aspect 42 The compound according to any one of aspects 1-36, wherein n is 3.
  • Aspect 43 The compound according to any one of aspects 1-36, wherein n is 4.
  • Aspect 44 The compound according to any one of aspects 1-36, wherein n is 5.
  • Aspect 45 The compound according to any one of aspects 1-44, wherein R 2 independently represents halogen; hydroxyl; cyano; mercapto; -0-CH 3 ; -0-C 2 H 5 ; -S-CH 3 ; -S-C 2 H 5 ; or C h alky!; which -0-CH 3 , -O-C2H5, -S-CH 3 , -S-C 2 H 5 or d_ 3 -alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto.
  • Aspect 46 The compound according to any one of aspects 1-45, wherein y is 0 and n is 4.
  • Aspect 47 The compound according to any one of aspects 1-45, wherein y is 1 and n is 4.
  • Aspect 48 The compound according to any one of aspects 1-45, wherein y is 2 and the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 3- to 7-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen atom, and which aromatic ring or non- aromatic ring is optionally substituted with at least one substituent R 20 .
  • Aspect 49 The compound according to aspect 48, wherein the two R 2 together with the carbon atom(s) to which they are attached represents a 3-membered saturated heterocyclic ring containing -0- .
  • Aspect 50 The compound according to aspect 48, wherein the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atom(s) represents a
  • Aspect 52 The compound according to aspect 48, wherein the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 6- membered saturated heterocyclic ring containing 1, 2 or 3 groups independently selected from -S- and -0-.
  • Aspect 53 The compound according to aspect 48, wherein the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 7- membered saturated heterocyclic ring containing 1, 2 or 3 groups independently selected from -S- and -0-.
  • Aspect 54 The compound according to any one of aspects 48-53, wherein there is one intervening carbon atom in between the carbon atoms to which the two R 2 are attached.
  • Aspect 55 The compound according to any one of aspects 48-53, wherein there are two intervening carbon atoms in between the carbon atoms to which the two R 2 are attached.
  • Aspect 56 The compound according to any one of aspects 48-53, wherein there are three intervening carbon atoms in between the carbon atoms to which the two R 2 are attached.
  • Aspect 57 The compound according to any one of aspects 1-56, wherein Q is at least one substituent selected from halogen; cyano; trifluoromethyl; -S(0) 2 -(4-(Ci- 6 -alkyl)-piperazin-l- yl) which is optionally substituted at a carbon atom with at least one substituent R 20 ; -(C ⁇ - alkyl)-4-R 19 -piperazin- l-yl in which the C ⁇ -alkyl is optionally substituted with at least one substituent R 17 ; 4-(Ci- 6 -alkyl)-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 ; and piperidinyl optionally substituted with -NR 14 R 15 or C h alky!.
  • Q is at least one substituent selected from halogen; cyano; trifluoromethyl; -S(0) 2 -(4-(Ci- 6 -al
  • Aspect 61 The compound according to any one of aspects 1-60, wherein Q is selected from -S(0) 2 -4-R 19 -piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 ; or -(Ci- 2 -alkyl)-4-R 19 -piperazin-l-yl in which the Ci- 2 -alkyl is optionally substituted with at least one substituent R 17 .
  • Aspect 62 The compound according to any one of aspects 1-61, wherein Q is in the para position (4-position).
  • Aspect 63 The compound according to any one of aspects 1-62, wherein Q is -S(0) 2 -(4- (Ci- 6 -alkyl)-piperazin-l-yl) which is optionally substituted at a carbon atom with at least one substituent R 20 .
  • Aspect 64 The compound according to any one of aspects 1-62, wherein Q is -(Ci- 2 -alkyl)- 4-R 19 -piperazin-l-yl in which the Ci_ 2 -alkyl is optionally substituted with at least one substituent R 17 .
  • Aspect 65 The compound according to aspect 64, wherein C ⁇ -alkyl is methyl.
  • Aspect 66 The compound according to aspect 64, wherein Ci- 2 -alkyl is ethyl.
  • Aspect 67 The compound according to any one of aspects 1-66, wherein Q is selected from -S(0) 2 -4-R 19 -piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 .
  • Aspect 68 The compound according to any one of aspects 1-67, wherein R 17 is selected from cyano; cyclopropyl; methyl substituted with cyclopropyl; ethyl substituted with cyclopropyl; and ethyl substituted with cyclopropyl which cyclopropyl is substituted with cyano.
  • Aspect 69 The compound according to any one of aspects 1-68, wherein two R 17 together with the carbon atom to which they are attached form a cyclopropyl.
  • Aspect 70 The compound according to any one of aspects 1-69, wherein R 19 is selected from methyl; ethyl; propyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; isopropyl;
  • R 17 each independently represents halogen, cyano, cyclopropyl, oxetan-3-yl or Ci- 3 -alkyl which Ci-3-alkyl is optionally substituted with at least one substituent selected from halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R 17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3-yl;
  • R 19 represents hydrogen, -C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl, -Ci_ 6 -alkyl, which -C h alky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R 19 represents formula XI, formula X2, formula X3 or formula X4;
  • R each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci-6-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • R 20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci- 6 -alkyl which Ci_ 5 -alkyl is optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, a pharmaceutically acceptable salt, solvates, and hydrates thereof.
  • Aspect 76 The compound according to any one of aspects 1-74, wherein R 19 represents - C 3 - 6 -cycloalkyl, -Ci- 3 -alkyl-C 3 - 6 -cycloalkyl or Ci_ 6 -alkyl, which Ci- 6 -alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino.
  • Aspect 78 The compound according to any one of aspects 74-77, wherein m is 0.
  • Aspect 79 The compound according to any one of aspects 74-77, wherein m is 1.
  • Aspect 80 The compound according to any one of aspects 74-77, wherein m is 2.
  • Aspect 81 The compound according to any one of aspects 1-77, wherein R 2 represents deuterium.
  • Aspect 82 The compound according to any one of aspects 74-81, wherein y or z is 0.
  • Aspect 83 The compound according to any one of aspects 74-81, wherein y or z is 1 or 2.
  • Aspect 84. The compound according to any one of aspects 1-81, wherein R 2 independently represents deuterium; halogen; hydroxyl; cyano; oxo ( 0) ; mercapto; -0-CH 3 ; -0-C 2 H 5 ; - S-CH 3 ; -S-C 2 H 5 ; or Ci- 3 -alkyl; which -0-CH 3 , -0-C 2 H 5 , -S-CH 3 , -S-C 2 H 5 or Ci- 3 -alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto.
  • Aspect 85 The compound according to any one of aspects 74-84, wherein y or z is 2 and the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 3- to 7-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen atom, and which aromatic ring or non- aromatic ring is optionally substituted with at least one substituent R 20 .
  • Aspect 86 The compound according to aspect 85, wherein the two R 2 together with the carbon atom(s) to which they are attached represents a 3-membered saturated heterocyclic ring containing -0- .
  • Aspect 87. The compound according to aspect 85, wherein the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atom(s) represents a
  • Aspect 88 The compound according to aspect 85, wherein the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 5- membered saturated heterocyclic ring containing 1 or 2 groups independently selected from -
  • Aspect 89 The compound according to aspect 85, wherein the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 6- membered saturated heterocyclic ring containing 1, 2 or 3 groups independently selected from -S- and -0-.
  • Aspect 90 The compound according to aspect 85, wherein the two R 2 together with the carbon atom(s) to which they are attached and any intervening carbon atoms represents a 7- membered saturated heterocyclic ring containing 1, 2 or 3 groups independently selected from -S- and -0-.
  • Aspect 91 The compound according to any one of aspects 1-90, wherein there is one intervening carbon atom in between the carbon atoms to which the two R 2 are attached .
  • Aspect 92 The compound according to any one of aspects 1-91, wherein there are two intervening carbon atoms in between the carbon atoms to which the two R 2 are attached.
  • Aspect 93 The compound according to any one of aspects 1-92, wherein there are three intervening carbon atoms in between the carbon atoms to which the two R 2 are attached.
  • Aspect 94 The compound according to any one of aspects 74-93, wherein s is 1.
  • Aspect 95 The compound according to any one of aspects 74-94, wherein s is 2.
  • each R 17 is independently selected from cyano; cyclopropyl; methyl substituted with cyclopropyl; ethyl substituted with cyclopropyl; and ethyl substituted with cyclopropyl which cyclopropyl is substituted with cyano.
  • Aspect 97 The compound according to any one of aspects 74-96, wherein r is 1 and R 17 is independently selected from cyano; cyclopropyl; methyl substituted with cyclopropyl; ethyl substituted with cyclopropyl; and ethyl substituted with cyclopropyl which cyclopropyl is substituted with cyano.
  • Aspect 98 The compound according to any one of aspects 74-97, wherein r is 0.
  • Aspect 99 The compound according to any one of aspects 74-98, wherein r is 2 and the two R 17 together with the carbon atom to which they are attached form a cyclopropyl and two R 17 are hydrogen.
  • Aspect 100 The compound according to any one of aspects 1-99, wherein R 19 is selected from methyl; ethyl; propyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; isopropyl;
  • Aspect 101 The compound according to any one of aspects 1-100, wherein R 19 is selected from cyano methyl or cyano ethyl.
  • Aspect 102 The compound according to any one of aspects 1-101, in the form of a pure stereoisomer thereof.
  • Aspect 103 The compound according to any one of aspects 1-102, in the form of a pharmaceutically acceptable salt thereof.
  • Aspect 105 The compound according to any one of the preceding aspects for use as a cysteine peptidase inhibitor.
  • Aspect 106 The compound according to any one of the preceding aspects for use as a dipeptidyl peptidase I (DPPI) inhibitor.
  • DPPI dipeptidyl peptidase I
  • Aspect 107 The compound according to any one of the preceding aspects for use in treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, periodontitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application in target cell apoptosis.
  • Aspect 108 The compound according to any one of aspects 1-107 for use in treating asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel diseases, cystic fibrosis, sepsis or allergic rhinitis.
  • Aspect 109 The compound according to any one of aspects 1-108, which has a
  • IC 50 Cathepsin B/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more.
  • Aspect 110 The compound according to any one of aspects 1-109, which has a
  • IC 50 Cathepsin H/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more.
  • Aspect 111 The compound according to any one of aspects 1-110, which has a
  • IC 50 Cathepsin L/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more.
  • Aspect 112 The compound according to any one of aspects 1-111, which has a
  • IC 50 Cathepsin K/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more.
  • Aspect 113 The compound according to any one of aspects 1-112, which has a
  • IC 50 Cathepsin S/ IC 50 (DPPI assay) of 25 or more such as, e.g., 50 or more, 75 or more, 100 or more, 250 or more, 1000 or more or 3000 or more.
  • Aspect 114 The compound according to any one of aspects 1-113, which has a IC 50 (DPPI assay)/ IC 50 (neutrophil cell based DPPI inhibitor assay) of 0.25 or more, such as e.g. 0.5 or more, 1 or more, 2 or more, 5 or more, 10 or more or 20 or more.
  • IC 50 DPPI assay
  • IC 50 neurotrophil cell based DPPI inhibitor assay
  • Aspect 115 The compound according to any one of aspects 1-114, which has a IC 50 (neutrophil cell based DPPI inhibitor assay) of 50 nM or lower, such as e.g. 25 nM or lower, 10 nM or lower, 5 nM or lower, 2 nM or lower, 1 nM or lower, 0.5 nM or lower or 0.25 or lower.
  • IC 50 neurotrophil cell based DPPI inhibitor assay
  • Aspect 116 The compound according to any one of aspects 1-115, 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 nM or, 750 nM or more or 1000 nM or more.
  • Aspect 117 The compound according to any one of aspects 1-116, 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.
  • Aspect 118 The compound according to any one of aspects 1-117, which have an apparent Hill-coefficient in the DPPI assay or in the neutrophil cell based DPPI inhibitor assay of 1.25 or more, such as e.g. 1.35 or more, 1.6 or more, 2 or more, 2.5 or more or 3.0 or more.
  • Aspect 119 A combination of a compound as defined in any one of aspects 1-118 or a pharmaceutically acceptable salt thereof and one or more agents independently selected from : a non-steroidal glucocorticoid receptor agonist; a selective ⁇ 2 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.
  • agents independently selected from : a non-steroidal glucocorticoid receptor agonist; a selective ⁇ 2 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.
  • a pharmaceutical composition comprising, as an active substance, a compound as defined in any one of aspects 1-118 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable adjuvant, carrier or diluent.
  • composition according to aspect 120 in unit dosage form, comprising from about 1 ⁇ g 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, of the active substance.
  • Aspect 122 The pharmaceutical composition according to aspect 120 or 121 for oral, nasal, transdermal, pulmonal or parenteral administration.
  • Aspect 123 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 a compound as defined in any one of aspects 1 to 118 or a
  • Aspect 124 A method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of aspects 1-118 or of a composition as defined in any one of aspects 120-122.
  • Aspect 125 The method according to any one of aspects 123-124, wherein the effective amount of the compound is in a range of from about 1 ⁇ g 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.
  • Aspect 126 Use of a compound as defined in any one of aspects 1-118 for the preparation of a medicament.
  • Aspect 127 Use of a compound as defined in any one of aspects 1-118 for the preparation of a medicament for treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application in target cell apoptosis.
  • Aspect 128 Use of a compound as defined in any one of aspects 1-118 or a
  • a method for modulating DPPI levels in a subject in need thereof comprising administering to said subject an amount of a compound as defined in any one of aspects 1- 118 or a composition as defined in any one of aspects 120-122 in an amount effective to modulate said DPPI levels in said subject.
  • Aspect 130 A method according to aspect 129, wherein said DPPI is inhibited.
  • the IC 50 value of a 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 IC 50 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 ⁇ ) . 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 pL of 1 mM substrate prewarmed to 37 °C (corresponding to a substrate concentration of 750 ⁇ in the assay).
  • the absorption was measured at 405 nm at 37 °C for every 90 sec for 12 minutes or every 20 sec for 4 min. Each measurement was made in duplicate.
  • IC 50 was determined using a 4-parameter logistic equation in a non-linear curve fitting routine.
  • the herein described compounds are DPPI inhibitors, which indirectly inhibit the activity of serine peptidases that are activated by DPPI, such as elastase.
  • DPPI inhibitors which indirectly inhibit the activity of serine peptidases that are activated by DPPI, such as elastase.
  • the biological activity of compounds of the invention may be determined.
  • Cells were seeded in 12-well plates at 0.2 to 0.4 x 10 6 cells/ml in volumes of 1.5 ml per well in the presence of no or increasing concentrations of DPPI inhibitor. 12 points in duplicate in the range of 0.02 nM to 50 ⁇ inhibitor were tested. After 24 or 48 hours cells were harvested, washed twice with PBS and lysed in 20 mM Tris-HCI, pH 7.5, 100 mM NaCI, 0.2% Triton X- 100. Debris was removed by centrifugation and supernatants were retained.
  • the extracts were mixed with assay buffer (50 mM Tris, 0.1% Triton X-100, 0.5 M NaCI, pH 8.0) supplemented with substrate (MetOSuc-Ala-Ala-Pro-Val-pNA; Bachem; Cat. No. L-1335) to a final concentration of 0.9 mM.
  • assay buffer 50 mM Tris, 0.1% Triton X-100, 0.5 M NaCI, pH 8.0
  • substrate MetalOSuc-Ala-Ala-Pro-Val-pNA; Bachem; Cat. No. L-1335
  • the activity of neutrophil elastase was determined by measuring the enzymatic release of chromogenic p-nitroaniline from the substrate MetOSuc-Ala-Ala-Pro-Val-pNA, which leads to an increase in absorbance at 405 nm. Assays were carried out in 96-well plates in a final volume of 200 pL at 37°C, and absorbance was measured 8 times during 35 minutes using a plate reader. IC 50 was determined using a 4-parameter logistic equation in a non-linear curve fitting routine.
  • test compound (DPPI inhibitor) was dissolved in 100 % DMSO at a concentration of 10 mM.
  • the reaction mixture consisted of Mouse or human Microsomes ( 1.0 mg/mL), 1 mM NADPH, 100 mM Potassium Phosphate, pH 7.4, 10 mM Magnesium Chloride and test compound at a concentration of 5 ⁇ .
  • reaction mixture (without cofactors) was incubated in a shaking water bath at 37°C for 3 minutes. Another aliquot of the reaction mixture was prepared as the negative control. The test compound was added into both the reaction mixture and the negative control at a final concentration of 5 ⁇ .
  • the reaction was initiated by the addition of NADPH to 1 mM (not into the negative controls) and then incubated in a shaking water bath at 37°C. Aliquots (100 pL) were withdrawn at 0, 10, 20, 30, and 60 minutes or at 0, 15, 30 and 60 min and combined with 900 pL of ice-cold 50/50 acetonitrile/dH20 to terminate the reaction.
  • a control (testosterone) was run simultaneously with the test compound in a separate reaction.
  • LC/MS/MS is used to determine the peak area response ratio (peak area corresponding to test compound or control divided by that of an analytical internal standard). The natural log of the percent remaining was plotted versus time. A linear fit was used to determine the rate constant. The fit was truncated if the percent remaining of test compound was less than 10%.
  • the elimination half-lives associated with the disappearance of the test and control compounds were determined to compare their relative metabolic stability.
  • Example A Procedure for preparation of starting compounds 3, 4, 7, 11 and 14 for synthesis of compounds PZ1041, PZ1044, PZ1063, PZ1064 and PZ1066 (examples 4, 5, 6, 7 and 8)
  • D 6 -l-Aminocyclohexanecarboxylic acid (compound 13 of example A): To a suspension of D 6 -cyclohexanone (1.0 g, 9.6 mmol) and (NH 4 ) 2 C0 3 (4.62 g, 48.0 mmol) in ethanol/water (20 mL, 1 : 1) was added sodium cyanide (0.47 g, 9.6 mmol). The reaction mixture was heated at 50°C for 12 h. After the starting material had disappeared as verified by TLC monitoring, the mixture was heated to 80°C to let an excess of (NH 4 ) 2 C0 3 decompose
  • PZ1015-5 l-Methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )benzyl)piperazine (PZ1015-5) : A mixture of l-bromo-4-(bromomethyl)benzene ( 15.0 g, 0.06 mol), N- methylpiperidine (7.2 g, 0.07 mol) and potassium carbonate ( 16.6 g, 0.12 mol) in DM F (50 mL) was stirred overnight at ambient temperature. After potassium carbonate was filtered off, the filtrate was poured into ethyl acetate (200 mL) and then washed with water ( 100 mL x 2) .
  • the compound obtained above was dissolved in dioxane (150 mL), and pinacolatodiboron ( 14.2 g, 55.8 mmol) and potassium acetate ( 10.9 g, 111.6 mmol) were added. The mixture was purged with N 2 for three times and Pd(PPh 3 ) 4 (0.1 g, 0.087 mmol) was added . The mixture was refluxed overnight under N 2 protection. After the mixture was cooled to room temperature, it was treated with ethyl acetate (200 mL) and water (200 mL) . The ethyl acetate phase was separated and the aqueous phase was extracted with EA (200 mL ⁇ 2) .
  • PZ1047-1 A mixture of piperazine (19.4 g, 100 mmol), Et 3 N (5.05 g, 50 mmol) and 1-bromopropane (6.15 g, 50 mmol) in EtOH (100 ml) was heated to reflux overnight. TLC showed the reaction was almost complete. EtOH was removed under reduced pressure. The residue was dissolved in H 2 0 and extracted with DCM. The combined organic phase was dried over Na 2 S0 4 and concentrated in vacuo to give PZ1047-1 (10 g, 100%) as yellow oil.
  • PZ1047-2 The preparation of PZ1047-2: To a solution of PZ1047-1 (5.12 g, 40 mmol), 4- bromobenzaldehyde (7.8 g, 42 mmol) and HOAc (3 g, 48 mmol) in EtOH (100 ml) was added NaBH 3 CN (3.6 g, 52 mmol) in portion. The mixture was stirred at RT for 16 h. The ethanol was removed under reduced pressure. The residue was extracted with DCM and NaHC0 3 solution. The combined DCM layer was dried over Na 2 S0 4 and concentrated in vacuo. The residue was treated with Et 2 0 and filtered to give PZ1047-2 (500 mg, 5%) as white solid.
  • PZ1047-3 (178 mg, 75.1%) as a white solid.
  • PZ1051-2 To a solution of PZ1051-1 (120 mg, 0.41 mmol), in DMF (4 ml) and water (1 ml) were added compound PZ1036-8 from example B described in the MATERIALS AND METHODS section (244 mg, 0.49 mmol), Na 2 C0 3 (130 mg, 1.23 mmol) and Pd (dppf)CI 2 (20 mg). This mixture was reacted in micro wave oven at 100°C and stirred for lh. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by Pre-HPLC to give PZ1051-2 (120 mg, 50.3%) as a white solid.
  • PZ1018 is nearly 5 times more potent compared to Example 29 of WO2010/128324A1 when judged by U937 IC 50 measured in the U937 cellular assay despite the fact that they have nearly the same potency in the DPPI enzyme assay.
  • table 3 shows that the Hill coefficient for PZ1018 in the U937 cellular assay is significant higher than the Hill coefficient for Example 29 of WO2010/128324A1, which means that the cellular inhibition curve for PZ1018 is significant steeper than the curve for Example 29 of WO2010/128324A1.
  • PZ1018 and Example 29 of WO2010/128324A1 have IC99 values of 24 nM and 414 nM, respectively, i.e. PZ1018 is about 17 times more effective than Example 29 of

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Abstract

Cette invention concerne des composés de Formule (II) et leur utilisation en thérapie à titre d'inhibiteurs de peptidases.
PCT/EP2012/053624 2011-03-04 2012-03-02 Composés de peptidylnitrile à titre d'inhibiteurs de peptidases WO2012119941A1 (fr)

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WO2014140081A1 (fr) * 2013-03-14 2014-09-18 Boehringer Ingelheim International Gmbh Inhibiteurs 1-acide carboxylique (benzyl-cyano-methyl)-amides bicycliques substitués de la cathépsine c
WO2014140091A1 (fr) * 2013-03-14 2014-09-18 Boehringer Ingelheim International Gmbh (benzyl-cyano-méthyl)-amides de l'acide 2-aza-bicyclo[2.2.2]octane-3-carboxylique substitués inhibiteurs de la cathepsine c
US8841463B2 (en) 2011-02-11 2014-09-23 Glaxosmithkline Intellectual Property Development Limited Cathepsin C inhibitors
US8871783B2 (en) 2013-03-14 2014-10-28 Boehringer Ingelheim International Gmbh Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides inhibitors of cathepsin C
WO2015032943A1 (fr) * 2013-09-09 2015-03-12 Prozymex A/S Composés peptidylnitrile en tant qu'inhibiteurs de la dipeptidyle peptidase i
US8987249B2 (en) 2013-03-14 2015-03-24 Boehringer Ingelheim International Gmbh Substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C
WO2016139351A1 (fr) 2015-03-05 2016-09-09 Prozymex A/S Composés de peptidyl-nitrile en tant qu'inhibiteurs de la dipeptidyl-peptidase i
WO2016139355A1 (fr) 2015-03-05 2016-09-09 Prozymex A/S 3,3'-(biphényl-4,4'-diyl)bis-2-aminopropanenitriles n-substitués en tant qu'inhibiteurs de dppi
US9440960B2 (en) 2014-08-01 2016-09-13 Boehringer Ingelheim International Gmbh Substituted oxetanes and their use as inhibitors of cathepsin C
US9522894B2 (en) 2014-01-24 2016-12-20 Astrazeneca Ab Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
US9540373B2 (en) 2014-09-12 2017-01-10 Boehringer Ingelheim International Gmbh Substituted spirocycles
CN111233704A (zh) * 2020-03-16 2020-06-05 湖北三宁碳磷基新材料产业技术研究院有限公司 一种制备6-氨基己腈产品的方法
US10774075B2 (en) 2015-04-24 2020-09-15 Children's Medical Center Corporation Compounds for treating rac-GTPase mediated disorder
WO2022042591A1 (fr) 2020-08-26 2022-03-03 四川海思科制药有限公司 Dérivé de nitrile agissant comme inhibiteur de la dipeptidyle peptidase 1 et son utilisation
WO2022117059A1 (fr) 2020-12-04 2022-06-09 瑞石生物医药有限公司 Inhibiteur à petites molécules de la cathepsine c et son utilisation médicinale
WO2023236877A1 (fr) 2022-06-07 2023-12-14 瑞石生物医药有限公司 Sel pharmaceutiquement acceptable d'un composé benzo[c]chromane, forme polymorphe et utilisation d'un sel pharmaceutiquement acceptable
WO2023236879A1 (fr) 2022-06-07 2023-12-14 瑞石生物医药有限公司 Polymorphe de composé benzo[c]chromane, son procédé de préparation et son utilisation
US11998553B2 (en) 2018-07-17 2024-06-04 Insmed Incorporated Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating lupus nephritis
US12059424B2 (en) 2018-03-01 2024-08-13 Astrazeneca Ab Pharmaceutical compositions comprising (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide

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