WO2012119941A1 - Peptidyl nitrilcompounds as peptidase inhibitors - Google Patents

Peptidyl nitrilcompounds as peptidase inhibitors Download PDF

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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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alkyl
optionally substituted
cyano
substituent
piperazin
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PCT/EP2012/053624
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French (fr)
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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/en

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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

Abstract

The invention relates to compounds of Formula (II) and their use in theraphy as peptidase inhibitors.

Description

PEPTIDYL NITRILCOM POUNDS AS PEPTIDASE INHIBITORS FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION Dipeptidyl peptidase I (DPPI; EC 3.4.14.1) also known as cathepsin C is a lysosomal cysteine peptidase belonging to the papain family. The enzyme is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen. The cDNAs encoding rat, human and murine DPPI have been cloned and sequenced and 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. Recent data suggests that, beside of being an important enzyme in lysosomal protein degradation, DPPI also functions as a key enzyme in the activation of granule serine peptidases in neutrophils (cathepsin G and elastase), mast cells (chymase and tryptase) and cytotoxic T lymphocytes and natural killer cells (granzymes A and B). Mast cells are found in many tissues, but are present in greater numbers along the epithelial linings of the body, such as the skin, respiratory tract and gastrointestinal tract. Mast cells are also located in the perivascular tissue surrounding small blood vessels. In humans, two types of mast cells have been identified; the T-type, which expresses only tryptase, and the MC-type, which expresses both tryptase and chymase. In humans, the T-type mast cells are located primarily in alveolar tissue and intestinal mucose while the TC-type cells predominate in skin and 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. These peptidases are situated in the mast cell lysosomes as fully active enzymes. The exact site of tryptase and chymase activation from zymogen precursors is not known, but the Golgi apparatus might play a role in that regard. DPPI, which is particular abundant in mast cells, seems to be the key enzyme responsible for activation of chymase and tryptase. Moreover, tryptase and chymase are emerging as important mediators of allergic diseases such as asthma, inflammatory bowel disease and psoriasis. After secretion from activated mast cells, there is evidence that these peptidases are heavily involved in processes of inflammation, tissue remodelling, bronchoconstriction and mucus secretion, which have made these peptidases attractive for therapeutic intervention.
Neutrophils cause considerable damage in a number of pathological conditions. When activated, neutrophils secrete destructive granular enzymes including elastase and cathepsin G and undergo oxidative bursts to release reactive oxygen intermediates. Numerous studies have been conducted on each of these activating agents in isolation. Pulmonary emphysema, COPD, cystic fibrosis, sepsis and rheumatoid arthritis are just some examples of pathological conditions associated with the potent enzymes elastase and cathepsin G.
The strong evidence associating tryptase, chymase, elastase, cathepsin G and other similar inflammatory peptidases with inflammatory diseases, points out DPPI as an attractive target enzyme for therapeutic intervention against the above mentioned diseases and other similar inflammatory diseases, due to its central role in activating these peptidases (Adkison et al. 2002, J. Clin. Invest, 109, 363-271; Pham. et al. 2004, J . Immunol, 173,7277-7281). WO2009074829 to Astrazeneca discloses peptidyl nitriles and use thereof as dipeptidyl peptidase inhibitors. WO2011154677, WO2010128324 and WO2010142985 to Astrazeneca discloses further nitrile compounds and use thereof as dipeptidyl peptidase inhibitors.
WO2006094003, WO2011025799, WO2009129371, WO2009129365, WO2009129370, WO 2011019801A1 to Glaxo Group Ltd. 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. WO2011075634 to Janssen
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. WO2006034004 to Axys Pharmaceuticals, Inc. discloses a process of preparing cyanomethyl peptide analogous useful as 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. Nathalie Methot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin, Christian Beaulieu, T. Jagadeeswar Reddy, Denis Riendeau, and M. David Percival : In Vivo Inhibition of Serine protease Processing Requires a High Fractional Inhibition of Cathepsin C, Mol Pharmacol 73: 1857-1865, 2008 disclose dipeptide nitrile cathepsin C inhibitors. Nathalie Methot, Joel Rubin, Daniel Guay, Christian Beaulieu, Diane Ethier T. Jagadeeswar Reddy, Denis Riendeau, and M. David Percival : Inhibition of the Activation of Multiple Serine proteases with a Cathepsin C Inhibitor Requires Sustained Exposure to Prevent Pro-enzyme Processing J. Biol. Chem., Vol. 282, Issue 29, 20836-20846, July 20, 2007 disclose dipeptide nitrile cathepsin C inhibitors. Jon Bondebjerg, Henrik Fuglsang, Kirsten Rosendal Valeur, John Pedersen and Lars Naerum, Dipeptidyl nitriles as human dipeptidyl peptidase I inhibitors, Bioorganic & Medicinal Chemistry Letters 16 (2006) 3614-3617 disclose compounds having a dipeptide nitrile scaffold as inhibitors of human dipeptidyl peptidase I. Daniel Guay, Christian Beaulieu, T. Jagadeeswar Reddy, Robert Zamboni, Nathalie Methot, Joel Rubin, Diane Ethier and M. David Percival, Design and synthesis of dipeptidyl nitriles as potent, selective, and reversible inhibitors of cathepsin C, , Bioorganic & Medicinal Chemistry Letters, Vol. 19, 5392-5396, September 15, 2009 disclose a series of dipeptide nitriles with a thienyl alanine in P2 as potent and selective cathepsin C inhibitors.
OBJECT OF THE INVENTION
It is an object of embodiments of the invention to provide novel compounds having pharmacological activity as inhibitors of peptidases such as serine and/or cysteine peptidases. In an embodiment, the compounds of the invention are cysteine peptidase inhibitors, particularly selective cysteine peptidase inhibitors. In an embodiment, the compounds of the invention are inhibitors of cysteine peptidases of the papain superfamily such as dipeptidyl peptidase I.
SUMMARY OF THE INVENTION The present invention provides a compound of the formula (I)
Figure imgf000005_0001
wherein y represents 0, 1, 2 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5;
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 R20; X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; C^-alkyl optionally substituted with Ci-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; -
N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(C1_2-alkyl)-4-R19-piperazin- l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4-R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R9 and R10 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a Ci-6-alkyl or C3-6- cycloalkyl; R16 represents a hydrogen atom or C^-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
R18 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, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000007_0001
wherein m is 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. In a further aspect, the present invention relates to a compound of the formula (II)
Figure imgf000007_0002
(Π) wherein y represents 0, 1, 2 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci_3-alkyl, which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5;
X represents a single bond, an oxygen atom or a sulphur atom, -S(0)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; Ci_6-alkyl optionally substituted with Ci-6-alkoxy, - NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-C^-alkyl; -S(0)2NR9R10; -
N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4- R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl; R3 and R4 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3-6- cycloalkyl; R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yl;
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000009_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2;
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.
In another aspect the present invention relates to a compound of the formula (III)
Figure imgf000010_0001
(III) wherein y represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5; Q is at least one substituent selected from R ; Ci_6-alkyl optionally substituted with Ci-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(C1_2-alkyl)-4-R19-piperazin-l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or d-6-alkyl;
R3 and R4 each independently represent hydrogen, C^-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, C^-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi; R18 represents a hydrogen atom, or C^-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000012_0001
X1 X2 X3 X4 wherein m is 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 also provides 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 β2 adrenoceptor agonist; a phosphodiesterase inhibitor; a peptidase inhibitor; a glucocorticoid; an anticholinergic agent; a modulator of chemokine receptor function; and an inhibitor of kinase function.
Further details of the invention are found in the dependent claims and the following description of the invention.
DETAILED DISCLOSURE OF THE INVENTION
In an aspect, the present invention relates to a compound of the formula (II)
Figure imgf000013_0001
(Π) wherein y represents 0, 1, 2 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci_3-alkyl, which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5;
X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; Ci_6-alkyl optionally substituted with Ci-6-alkoxy, - NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4- R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or C^-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000015_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2;
R20 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)
Figure imgf000016_0001
(Π) wherein y represents 0, 1 or 2; when y is 1 or 2, then R2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl, which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; n represents 1, 2, 3, 4 or 5;
X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; Ci_6-alkyl optionally substituted withCi-6-alkoxy, - NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R °; -(C1_2-alkyl)-4-R -piperazin-l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4- R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl; R18 represents a hydrogen atom, or C^-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-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.
In another aspect, the present invention relates to a compound of the formula (III)
Figure imgf000018_0001
(III) wherein y represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0); mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5;
Q is at least one substituent selected from R20; C^-alkyl optionally substituted with Ci-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4-R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R9 and R10 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a Ci-6-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
R18 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, -C3_6-cycloalkyl, -C^-alkyl-Cs-e-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000020_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2;
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)
Figure imgf000020_0002
(III) wherein y represents 0, 1 or 2; when y is 1 or 2, then R2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; n represents 1, 2, 3, 4 or 5;
Q is at least one substituent selected from R20; Ci_6-alkyl optionally substituted with d-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4- R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
R18 represents a hydrogen atom, or C^-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or Ci-6-alkyl; R20 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.
The term "DPPI" as used herein is intended to mean 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.
The term "treatment" is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of 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. For example, 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) . However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
"Enantiomerically pure" refers to products whose enantiomeric excess is 99% ee or greater.
"Half-life" (or "half-lives") refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.
"Optionally substituted" indicates that a group, such as -0-CH3, -0-C2H5, -S-CH3, -S-C2H5, 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. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination). In certain embodiments, a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
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. Thus, 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.
Individual stereoisomers of a compound according to Formula (I), (II), (III) or (IV) which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be
synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. The compounds according to Formula (I), (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.
All tautomeric forms are also included in Formula (I), (II), (III) or (IV) whether such tautomers exist in equilibrium or predominately in one form. In certain embodiments, 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. In certain other embodiments, 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. Thus, the skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds according to Formula (I), (II), (III) or (IV) may be prepared. Indeed, in certain embodiments of the invention, 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) .
As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired
toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. In the solid state, compounds of the invention can exist in crystalline, semi- crystalline and amorphous forms, as well as mixtures thereof. The skilled artisan will appreciate that pharmaceutically-acceptable solvates of 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. In addition, the solvent content of such solvates can vary in response to environment and upon storage. For example, water may displace another solvent over time depending on relative humidity and temperature. Solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "hydrates." Solvates wherein more than one solvent is incorporated into the solid-state structure are typically referred to as "mixed solvates".
Solvates include "stoichiometric solvates" as well as compositions containing variable amounts of solvent (referred to as "non-stoichiometric solvates"). Stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "stoichiometric hydrates", and non-stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "non- stoichiometric hydrates". The invention includes both stoichiometric and non- stoichiometric solvates.
In addition, crystalline forms of a compound of the invention, including solvates thereof, may contain solvent molecules, which are not incorporated into the solid-state structure. For example, solvent molecules may become trapped in the crystals upon isolation. In addition, solvent molecules may be retained on the surface of the crystals. The invention includes such forms.
In the context of the present specification, unless otherwise stated, an alkyl or alkenyl substituent group or an alkyl or alkenyl moiety in a substituent group may be linear or branched.
As used herein, alone or in combination, the term "C^-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, neopentyl and n-hexyl. Examples of C^-alkyl include e.g. methyl, ethyl and propyl.
The term "C2-6-alkenyl" as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond, e.g. C2-6-alkenyl, C3-6-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.
The term "C3-6-cycloalkyl" as used herein represents a saturated monocyclic carbocyclic ring having from 3 to 6 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "C3-7-cycloalkyl" as used herein 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" as used herein 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. "C3-6-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. Examples of heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl.
"Ci-6-alkoxy" as used herein 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.
"Ci-6-alkylcarbonyl" as used herein refers to the radical Ci-6-alkyl-C( = 0)-. Representative examples are acetyl (methylcarbonyl), propionyl (ethylcarbonyl), butanoyl (prop-l-ylcarbonyl, prop-2-ylcarbonyl), and the like. "Ci-6-alkylcarbonyloxy" as used herein refers to the radical Ci-6-alkyl-C(=O)0-.
"Ci-6-alkoxycarbonyl" as used herein refers to the radical Ci-6-alkoxy-C(=0)-. Representative examples are methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, 2-methyl-2-propoxycarbonyl, 3-methylbutoxycarbonyl, 1-hexoxycarbonyl, and the like.
The term "benzyloxy" as used herein refers to the radical C6H5CH20- The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine. The term "carboxyl" shall mean the radical -COOH. The term "carbonyl" shall mean the radical -C( = 0)-. The term "hydroxy" shall mean the radical -OH. The term "oxo" shall mean the radical =0. The term "oxy" shall mean the radical -0-. The term "nitro" shall mean the radical -N02. The term "cyano" shall mean the radical -CN. The term "mercapto" shall mean the radical -SH. The term "amino" shall mean the radical -NH2.
Where, for example, two substituents (such as R1 and R2) both represent a Ci_6-alkyl group or both represent a C3-6-cycloalkyl group, the alkyl or cycloalkyl groups may be the same as, or different from, one another.
In one aspect, the term "optionally substituted with at least one substituent" mean unsubstituted or substituted with at least one substituent, preferably one or two substituents.
The term, for example, "R3 and R4 together with the nitrogen to which they are attached, form a 4- to 7-membered saturated heterocyclic ring" as used herein 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. For the avoidance of doubt, it should be understood that 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. For the avoidance of doubt, it should be understood that 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. Moreover, it should be understood that 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. Examples of suitable ring systems, which may be monocyclic or polycyclic (e.g. bicyclic or tricyclic) where two or more rings (at least one of which is aromatic) are fused, which aromatic rings may contain one or more heteroatoms selected from nitrogen, oxygen, sulfur, SO and S(=0)2.
Representative examples are 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. imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), pyrazolyl (e.g. pyrazol-l-yl, pyrazol-3-yl, pyrazol-5-yl), isoxazolyl (e.g. isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), isothiazolyl (e.g. isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), 1,2,3-triazolyl (e.g. 1,2,3- triazol-l-yl, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl), 1,2,4-triazolyl (e.g. 1,2,4-triazol-l-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl), 1,2,3-oxadiazolyl (e.g. l,2,3-oxadiazol-4-yl, 1,2,3- oxadiazol-5-yl), 1,2,4-oxadiazolyl (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), pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, azecinyl, and the like. Aromatic ring system is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S( = 0) and S(=0)2. Representative examples are indolyl (e.g. indol-l-yl, indol-2-yl, indol-3-yl, indol-5- yl), isoindolyl, benzofuranyl (e.g. benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5- yl, benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl), benzothienyl (e.g. benzo[b]thien-2-yl, benzo[b]thien-3-yl, benzo[b]thien-5-yl, benzo[c]thien-2-yl,
benzo[c]thien-3-yl, benzo[c]thien-5-yl), indazolyl (e.g. indazol-l-yl, indazol-3-yl, indazol-5- yl), indolizinyl (e.g. indolizin-l-yl, indolizin-3-yl), benzopyranyl (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yl, benzo[c]pyran-l-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g.
benzimidazol-l-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl (e.g. benzothiazol- 2-yl, benzothiazol-5-yl), benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl (e.g. l,8-naphthyridin-2-yl, l,7-naphthyridin-2-yl, 1,6- naphthyridin-2-yl), phthalazinyl (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. isoquinolin-l-yl, isoquinolin-3-yl, isoquinolin- 4-yl), quinoxalinyl (e.g. quinoxalin-2-yl, quinoxalin-5-yl), pyrrolopyridinyl (e.g. pyrrolo[2,3- b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g. furo[2,3- b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-c]pyridinyl), thienopyridinyl (e.g. thieno[2,3- b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl), imidazopyridinyl (e.g.
imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[l,5-a]pyridinyl, imidazo[l,2- a]pyridinyl), imidazopyrimidinyl (e.g. imidazo[l,2-a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl), pyrazolopyridinyl (e.g. pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[l,5- a] pyridinyl), pyrazolopyrimidinyl (e.g. pyrazolo[l,5-a]pyrimidinyl, pyrazolo[3,4- d]pyrimidinyl), thiazolopyridinyl (e.g. thiazolo[3,2-d]pyridinyl), thiazolopyrimidinyl (e.g. thiazolo[5,4-d]pyrimidinyl), imdazothiazolyl (e.g. imidazo[2,l-b]thiazolyl), triazolopyridinyl (e.g. triazolo[4,5-b]pyridinyl), triazolopyrimidinyl (e.g. 8-azapurinyl), and the like. Aromatic ring system is also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=0) and S(=0)2.
Representative examples are 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. pyrido[3,4- b] indol- l-yl, pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl), and the like. 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. 2,3-dihydrobenzo[b]furan-2-yl, 2,3- dihydrobenzo[b]furan-4-yl), dihydrobenzothienyl (e.g. 2,3-dihydrobenzo[b]thien-2-yl, 2,3- dihydrobenzo[b]thien-5-yl), 4,5,6,7-tetrahydrobenzo[b]furan-5-yl), dihydrobenzopyranyl (e.g. 3,4-dihydrobenzo[b]pyran-3-yl, 3,4-dihydrobenzo[b]pyran-6-yl, 3,4- dihydrobenzo[c]pyran-l-yl, dihydrobenzo[c]pyran-7-yl), oxazolinyl (e.g. 4,5-dihydrooxazol- 2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl), isoxazolinyl, oxazepinyl,
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 . 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid- l-yl, 4,5,6,7- tetrahydroimidazo[4,5-c]pyrid-5-yl, 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-6-yl),
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), and the like.
In one aspect, 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
benzothiazolinyl.
In one aspect, 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. In one aspect, R2 independently represents halogen; hydroxyl; cyano; mercapto; -0-CH3; - 0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 or Chalky! is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto.
In one aspect, wherein y is 2, the two R2 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 R20. In one aspect, wherein y is 2, the two R2 are attached to the same carbon atom.
In one aspect, wherein y is 2, there is one intervening carbon atom in between the carbon atoms to which the two R2 are attached .
In one aspect, wherein y is 2, there are two intervening carbon atoms in between the carbon atoms to which the two R2 are attached . In one aspect, wherein y is 2, there are intervening three carbon atoms in between the carbon atoms to which the two R2 are attached . In one aspect, wherein y is 2, the two R2 together with the carbon atom(s) to which they are attached represents a 3-membered saturated heterocyclic ring containing -0-.
In one aspect, wherein y is 2, the two R2 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-.
In one aspect, wherein y is 2, the two R2 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-.
In one aspect, wherein y is 2, the two R2 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-.
In one aspect, wherein y is 2, the two R2 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-. In one aspect, X is a single bond.
In one aspect, 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 R20. In a further aspect, the 5- to 10-membered aromatic ring system is optionally substituted with one, two or three substituent(s). In a further aspect, the aromatic ring or non-aromatic ring is un-substituted.
In a further aspect, 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 R20.
In a further aspect, 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 R20.
In a further aspect, A represents furanylene, benzothiazolene, naphthylene, thienylene, benzotriazol, triazolopyridinylene, indolylene, or phenylene. In a further aspect, A represents furanylene, indolylene, or phenylene.
In a further aspect, A represents indolylene, or phenylene.
In a further aspect, A represents phenylene.
In a further aspect, B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one substituent Q selected from R20; trifluoromethyl; Ci-6-thioalkyl; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci_2-alkyl is optionally substituted with at least one substituent R17; -S(0)2-(4-(Ci-6-alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20; (4-(Ci-6-alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl optionally substituted with -NR14R15 or Ci-6-alkyl. In one aspect, 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 R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl optionally substituted with -NR14R15 or C1-6-alkyl.
In one aspect, 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 R20. In one aspect, Q represents - S(0)2-(4-(methyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20. In one aspect, Q represents 4-(C1_6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20. In one aspect, Q represents 4-(methyl)- piperazin-l-yl. In one aspect, Q represents
Figure imgf000033_0001
is optionally substituted with at least one substituent R17. In a further aspect, Ci-2-alkyl is methyl. In yet a further aspect, Ci-2-alkyl is ethyl.
In one aspect, R17 is selected from cyano; cyclopropyl; methyl substituted with cyclopropyl; ethyl substituted with cyclopropyl; and ethyl substituted with cyclopropyl which cyclopropyl is substituted with cyano.
In a further aspect, two R17 together with the carbon atom to which they are attached form a cyclopropyl. In a further aspect, two R17 together with the carbon atoms to which they are attached form a cyclopropyl.
In a further aspect, R19 is selected from methyl; ethyl; propyl; cyclopropyl; cyclobutyl;
cyclopentyl; cyclohexyl; isopropyl; methylcyclopropyl; ethylcyclopropyl; and
propylcyclopropyl.
In a further aspect, B represents optionally substituted benzothiazolyl, pyrrolyl, pyrazolyl, indolyl, thiazolyl, pyridazinyl, phenyl, triazolopyridinyl, or imidazolyl.
In a further aspect, B represents benzothiazolyl, pyrrolyl, pyrazolyl, indolyl, thiazolyl, pyridazinyl, phenyl, triazolopyridinyl, or imidazolyl.
In another aspect, B represents optionally substituted benzothiazolyl, indolyl, thiazolyl, pyridazinyl, imidazolyl, or phenyl.
In a further aspect, 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.
In a further aspect, B represents optionally substituted triazolopyridinyl.
In a further aspect, B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one substituent Q selected from R20; trifluoromethyl; Ci-6-thioalkyl; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci_2-alkyl is optionally substituted with at least one substituent R17; -S(0)2-(4-(Ci-6-alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20; (4-(C1_6-alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl optionally substituted with -NR14R15 or Ci-6-alkyl. In a further aspect, 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. In one aspect, B is substituted with -S(0)2-4-R19-piperazin- l- yl. In a further aspect, B is substituted with -S(0)2-4-R19-piperazin- l-yl is -S(0)2-(4-(Ci-6- alkyl)-piperazin- l-yl), -S(0)2-(4-(C3-6-cycloalkyl)-piperazin-l-yl) or -S(0)2-(4-(C3-6- cycloalkyl-Ci-3-alkyl)-piperazin- l-yl) .
In a further aspect, B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one (4-(C1_6-alkyl)piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20.
In one aspect, A represents phenyl, X is a bond and B is as defined above.
In a further aspect, 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. In a further aspect, A and B together represents an 4,4'-biphenyl, and wherein B is optionally substituted with -S(0)2-(4-C1_6-alkyl-piperazin- l-yl), which - S(0)2-(4-C1_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. In a further aspect, 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.
In a further aspect, A and B together represents an 4,4'-biphenyl, and wherein B is substituted with -ethyl-4-rmethyl-piperazin- l-yl. In a further aspect, 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) .
In a further aspect, A and B together represents 4-(thiazol-5-yl)phenyl, and wherein B is optionally substituted with 4-methyl-piperazin- l-yl.
In a further aspect, 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) .
In a further aspect, A and B together represents 4-(thiazol-4-yl)phenyl, and wherein B is optionally substituted with 4-methyl-piperazin- l-yl.
In a further aspect, A and B together represents an optionally substituted 4- ([ l,2,4]triazolo[ l,5-a]pyridine-6-yl) phenyl. In a further aspect, 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.
In a further aspect, 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.
In a further aspect, 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) .
In a further aspect, X represents a single bond .
In a further aspect, A represent phenylene and X is a bond.
Compounds of formula (I), (II), (III) or (IV) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I), (II), (III) or (IV) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Ena ntiomerically pure forms are particularly desired. In an aspect, the compound(s) disclosed herein is in the form of a pure stereoisomer thereof.
In one aspect the substituent -A-X-B is selected from the group of:
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Specific embodiments of the invention
In one aspect, a herein disclosed compound is selected from the group consisting of:
(S)-l-amino-/V-(l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000039_0002
(S)-l-amino-/V-(l-cyano-2-(4-(2-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl)ethyl)cyclohexanecarboxamide;
Figure imgf000039_0003
(S)-2-Amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)- l,2,3,4-tetrahydronaphthalene-2-carboxamide;
Figure imgf000040_0001
(S)-l-amino-/V-(l-cyano-2-(4-(3-(2-hydroxyethyl)-2,3-dihydrobenzo[a']thiazol-5- yl)phenyl)ethyl)cyclohexanecarboxamide;
Figure imgf000040_0002
(S)-l-amino-/V-(l-cyano-2-(4'-ethylbiphenyl-4-yl)ethyl)cyclohexanecarboxamide;
Figure imgf000040_0003
(S)-l-amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000040_0004
(S)-l-amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl)ethyl)-4- methylcyclohexanecarboxamide;
Figure imgf000040_0005
l-amino-/V-((lS)-l-cyano-2-(4'-(2-(4-met ylpiperazin-l-yl)cyclopropyl)bip enyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000041_0001
(S)-l-amino-/V-(l-cyano-2-(4'-((4-cyclopropylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000041_0002
(S)-l-amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)cyclopentanecarboxamide;
Figure imgf000041_0003
3-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)bicyclo[3.1.0]hexane-3-carboxamide;
Figure imgf000041_0004
6-amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4-yl)ethyl)-4,5,6,7- tetrahydrobenzo[6]thiophene-6-carboxamide;
Figure imgf000042_0001
3-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin- 1-yl) methyl) biphenyl-4-yl)ethyl)-6- oxabicyclo[3.1.0]hexane-3-carboxamide;
Figure imgf000042_0002
6-a mino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin- 1-yl) methyl) biphenyl-4-yl)ethyl)-5- oxabicyclo[2. l. l]hexane-6-carboxamide;
Figure imgf000042_0003
(S)-l-amino-/V-( 1-cya no-2-(2-(4-((4-methylpiperazin- 1-yl) methyl) phenyl)- l/- -indol-5- yl)ethyl)cyclopentanecarboxamide;
Figure imgf000042_0004
(R)-l-amino-/V-(cyano(5-(4-((4-methylpiperazin- 1-yl) methyl) phenyl)thiophen-2- yl)methyl)cyclohexanecarboxamide;
Figure imgf000043_0001
(S)-l-amino-/V-(l-cyano-2-(2-(4-((4-methylpiperazin-l-yl) methyl) phenyl)- l - -indol-5- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000043_0002
l-amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4-yl)ethyl)-2- methylcyclopropanecarboxamide;
Figure imgf000043_0003
(S)-l-amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclopropanecarboxamide;
Figure imgf000043_0004
1-a mino-2-cyano-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclopropanecarboxamide;
Figure imgf000043_0005
(l ?,5 ?)-3-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)bicyclo[3.1.1]heptane-3-carboxamide;
Figure imgf000044_0001
(l ?,5S)-3-amino-/V-((S)-l-cyano-2-(4'-((4-met ylpiperazin-l-yl)met yl)bip enyl-4-yl)et yl)- 6-oxabicyclo[3.1.1] eptane-3-carboxamide;
Figure imgf000044_0002
2-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl)ethyl)-l,2,3,4- tetrahydronaphthalene-2-carboxamide;
Figure imgf000044_0003
6-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl)ethyl)-4,5,6,7- tetrahydrobenzo[6]thiophene-6-carboxamide;
Figure imgf000044_0004
(S)-l-amino-/V-(l-cyano-2-(4'-(l, l-dicyano-2-(4-methylpiperazin-l-yl)ethyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000045_0001
6-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl)ethyl)-2- fluoro-4,5,6,7-tetrahydrobenzo[0]thiophene-6-carboxamide;
Figure imgf000045_0002
(S)-l-amino-/V-(l-cyano-2-(4'-(2-(4-methylpiperazin-l-yl)ethyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000045_0003
(S)-l-amino-/V-(l-cyano-2-(4'-(dicyano(4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000045_0004
5-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl)ethyl)-5,6- dihydro-4/-/-cyclopenta[6]thiophene-5-carboxamide;
Figure imgf000045_0005
(S)-2-amino-/V-(l-cyano-2-(4'-((4-met ylpiperazin-l-yl)met yl)bip enyl-4-yl)et yl)-2,3- dihydro-l - -indene-2-carboxamide;
Figure imgf000046_0001
5-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl)ethyl)-5,6- dihydro-4 - -cyclopenta[0]thiophene-5-carboxamide;
Figure imgf000046_0002
5-amino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl)ethyl)-5,6- dihydro-4 - -cyclopenta[a']isothiazole-5-carboxamide;
Figure imgf000046_0003
((S)-l-amino-/V-(l-cyano-2-(2-(4-((4-methylpiperazin-l- yl)methyl)phenyl)benzo[0]thiophen-5-yl)ethyl)cyclohexanecarboxamide;
Figure imgf000046_0004
3-amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)bicyclo[4.1.0]heptane-3-carboxamide;
Figure imgf000047_0001
l-amino-3-cyano-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000047_0002
2-amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)decahydronaphthalene-2-carboxamide;
Figure imgf000047_0003
3-a mino-/V-((S)-l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)spiro[5.5]undecane-3-carboxamide;
Figure imgf000047_0004
(S)-l-amino-/V-(l-cyano-2-(3'-cyano-4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000048_0001
6-amino-/V-((S)-l-cyano-2-(4'-((4-met ylpiperazin-l-yl)met yl)bip enyl-4- yl)ethyl)spiro[2.5]octane-6-carboxamide;
Figure imgf000048_0002
(S)-l-amino-/V-(l-cyano-2-(4'-(4-propylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000048_0003
(S)-l-amino- V-(l-cyano-2-(4'-(4-ethylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000048_0004
(S)-l-amino-yv-(l-cyano-2-(3'-methyl-4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;
Figure imgf000049_0001
6-amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)spiro[3.5]nonane-6-carboxamide;
Figure imgf000049_0002
8-amino-/V-((S)-l-cyano-2-(2-(4-((4-methylpiperazin-l-yl)methyl)phenyl)benzo[0]thiophen- 5-yl)ethyl)spiro[4.5]decane-8-carboxamide;
Figure imgf000049_0003
2-amino-/V-((S)-l-cyano-2-(2-(4-((4-methylpiperazin-l-yl) methyl) phenyl) benzo[0]thiophen- 5-yl)ethyl)bicyclo[4.1.0]heptane-2-carboxamide;
Figure imgf000049_0004
2-amino-/V-((S)-l-cyano-2-(2-(4-((4-methylpiperazin-l-yl) methyl) phenyl) benzo[0]thiophen- 5-yl)ethyl)-7-oxabicyclo[4.1.0]heptane-2-carboxamide;
Figure imgf000050_0001
2-amino-/V-((S)-l-cyano-2-(2-(4-((4-methylpiperazin-l-yl) methyl) phenyl)- l - -indol-5- yl)ethyl)octahydropentalene-2-carboxamide; or
2-amino-/V-((S)-l-cyano-2-(2-(4-((4-ethylpiperazin-l-yl) methyl) phenyl)- l - -indol-5- yl)ethyl)octahydropentalene-2-carboxamide.
Figure imgf000050_0002
In a further aspect, a herein disclosed compound is selected from the group consisting of
Structure Names
(S)-l-amino-/V-(l-cyano-2-(4'-((4- ethylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
Figure imgf000050_0003
Structure Names
Figure imgf000051_0001
Structure Names
l-amino-/V-((lS)-l-cyano-2-(4'- (cyclopropyl(4-methylpiperazin-l- yl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
l-amino-/V-((lS)-l-cyano-2-(4'-(fluoro(4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
l-amino-/V-((lS)-l-cyano-2-(4'-(2-(2- methylcyclopropyl)-l-(4-methylpiperazin-l- yl)ethyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
l-amino-/V-((lS)-l-cyano-2-(4'-(cyano(4- cyclopropylpiperazin-l-yl)methyl)biphenyl- 4-yl)ethyl)cyclohexanecarboxamide
Figure imgf000052_0001
Structure Names
l-amino-/V-((lS)-l-cyano-2-(4'-(2-cyano-l- (4-methylpiperazin-l-yl)ethyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
(S)-l-amino-/V-(l-cyano-2-(4'-((4-(oxetan- 3-yl)piperazin-l-yl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
(S)-/V-(2-(4'-((4-((l,3-dioxolan-2- yl)methyl)piperazin-l-yl)methyl)biphenyl-4- yl)-l-cyanoethyl)-l- aminocyclohexanecarboxamide
yv-((lS)-2-(4'-((4-(2-oxaspiro[3.3]heptan- 6-yl)piperazin-l-yl)methyl)biphenyl-4-yl)-l- cyanoethyl)-l- aminocyclohexanecarboxamide
Figure imgf000053_0001
Structure Names
Figure imgf000054_0001
Structure Names
(S)-l-amino-/V-(l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-4,4- dideuteriumcyclohexanecarboxamide
5-amino-/V-((S)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-5,6-dihydro-4H- cyclopenta[-?]furan-5-carboxamide
(S)-l-amino-/V-(l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3,3,4,4- tetradeuteriumcyclopentanecarboxamide
Figure imgf000055_0001
2-amino-/V-((S)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)bicyclo[4.1.0]heptane-2- carboxamide
Figure imgf000055_0002
Structure Names
5-amino-/V-((S)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)tetrahydro-3aH- cyclopenta[d][l,3]dioxole-5-carboxamide
(S)-l-amino-/V-(l-cyano-2-(4'-(2-(4- methylpiperazin-l-yl)propan-2-yl)biphenyl- 4-yl)ethyl)cyclohexanecarboxamide
(S)-l-amino-/V-(l-cyano-2-(4'-(l-(4- methylpiperazin-l-yl)cyclopropyl)biphenyl- 4-yl)ethyl)cyclohexanecarboxamide
l-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3,5- dihydroxycyclohexanecarboxamide
Figure imgf000056_0001
Structure Names
l-amino-3-cyano-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
(R)-l-amino-/V-(l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-4- mercaptocyclohexanecarboxamide
(R)-l-amino-/V-(l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-4- methoxycyclohexanecarboxamide
l-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3- (ethylthio)cyclohexanecarboxamide
Figure imgf000057_0001
Structure Names
(R)-l-amino-/V-(l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-4-propylcyclohexanecarboxamide
l-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3- isopropylcyclohexanecarboxamide
l-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3-methyl-5- (trifluoromethyl)cyclohexanecarboxamide
(lR,5S)-3-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-8-oxabicyclo[3.2.1]octane-3- carboxamide
Figure imgf000058_0001
Structure Names
7-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3a,4,5,6,7,7a- hexahydrobenzo[c/]oxazole-7-carboxamide
l-amino-/V-((lR)-l-cyano-2-(4'-((4- cyclohexylpiperazin-1- yl)(cyclopropyl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
l-amino-/V-((lR)-l-cyano-2-(4'-(l-(4- ethylpiperazin-l-yl)-3,3,3- trifluoropropyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
6-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)bicyclo[3.1.0]hexane-6- carboxamide
6-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3-oxabicyclo[3.1.0]hexane-6- carboxamide
Figure imgf000059_0001
Structure Names
2-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)spiro[3.3]heptane-2-carboxamide
6-amino-/V-((R)-l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-2-oxaspiro[3.3]heptane-6- carboxamide
(R)-l-amino-/V-(l-cyano-2-(4'-((4- methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-3,3- difluorocyclobutanecarboxamide
(R)-l-amino-/V-(l-cyano-2-(4'-(3-(4- methylpiperazin-l-yl)oxetan-3-yl)biphenyl- 4-yl)ethyl)cyclohexanecarboxamide
(R)-l-amino-/V-(l-cyano-2-(4'-(3-(4- (oxetan-3-yl)piperazin-l-yl)oxetan-3- yl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide
6-amino-/V-((R)-l-cyano-2-(4'-(3-(4- (oxetan-3-yl)piperazin-l-yl)oxetan-3- yl)biphenyl-4-yl)ethyl)-2- oxaspiro[3.3]heptane-6-carboxamide
Figure imgf000060_0001
Structure Names
6-amino-/V-((R)-l-cyano-2-(4'-((4- cyclopropylpiperazin-l-yl)methyl)biphenyl- 4-yl)ethyl)-2-oxaspiro[3.3]heptane-6- carboxamide
Figure imgf000061_0001
In one aspect, a herein disclosed compound is selected from the group consisting of:
(S)-l-Amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide, (S)-l-amino-N-(l-cyano-2-(4'-(4-methylpiperazin-l- ylsulfonyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide and (S)-2-Amino-/V-((S)-l-cyano-2- (4'-(4-methylpiperazin- l-ylsulfonyl)biphenyl-4- yl)ethyl)- 1,2,3, 4-tetrahydronaphthalene-2- carboxamide.
In one aspect, a herein disclosed compound is selected from the group consisting of:
(S)-l-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide, (S)-l-amino-N-(l-cyano-2-(4'-(4-methylpiperazin- l- ylsulfonyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (S)-2-Amino-/V-((S)-l-cyano-2-(4'- (4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)- 1,2,3, 4-tetrahydronaphthalene-2- carboxamide, (S)-8-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)- l,4-dioxaspiro[4.5]decane-8-carboxamide, (S)-l-Amino-N-(l-cyano-2-(4'-((4- methylpiperazin-l-yl) methyl)biphenyl-4-yl) ethyl)cyclopentanecarboxamide, (S)-2-Amino-N- (l-cyano-2-(4'-((4-methylpiperazin- l-yl) methyl) biphenyl-4-yl) ethyl)-2,3-dihydro-lH- indene-2-carboxamide, (S)-2-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)
methyl)biphenyl-4-yl) ethyl)bicyclo[2.2. l]heptane-2-carboxamide, (S)-D6-l-Amino-N-(l- cyano-2-(4'-((4-methyl-piperazin-l-yl) methyl)biphenyl-4-yl) ethyl)cyclohexanecarboxamide, (R)-l-amino-N-(l-cyano-2-(4'-((4-propylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide, (R)-l-amino-N-(l-cyano-2-(4'-((4-cyclopropyl-piperazin- 1-yl) methyl) biphenyl-4-yl) ethyl)cyclohexanecarboxamide, (R)-l-amino-N-(l-cyano-2-(4'- ((4-(cyanomethyl) piperazin-l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide and (S)-l-amino-N-(l-cyano-2-(4'-((4-(oxazol-2-ylmethyl) piperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide.
The compounds of the invention may be administered by any suitable route of
administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's 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. In addition, 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.
The compounds of the invention may be administered as prodrugs. As used herein, 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
pharmacologically active agents that overcome barriers to a drug's usefulness.
Coupling of short peptides or single amino acids as carriers of a therapeutic agent can be used as an effective type of prodrug approach. In this approach an amino acid or a di- (or 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.
In one aspect, 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
pharmaceutically acceptable adjuvant, carrier or diluent, is provided. The pharmaceutical compositions disclosed herein may be prepared and packaged in bulk form wherein a safe and effective amount of a compound disclosed herein can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
Alternatively, the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound as disclosed herein. When prepared in unit dosage form, the pharmaceutical compositions disclosed herein typically contain from 1 mg to 1000 mg.
The pharmaceutical compositions disclosed herein typically contain one compound as disclosed herein. However, in certain embodiments, the pharmaceutical compositions of the invention 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
pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient. As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable. The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral
administration such as tablets, capsules, caplets, pills, troches, powders, syrups, 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. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain
pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound 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. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American
Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of 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. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc. In another aspect, the invention is directed to a dosage form adapted for administration to a patient by inhalation. For example, the compound of the invention may be inhaled into the lungs as a dry powder, an aerosol, a suspension, or a solution.
Dry powder compositions for delivery to the lung by inhalation typically comprise 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. For example, the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation. Alternatively, the dry powder may be presented in capsules (e.g. gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament. When the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form. The blisters are typically arranged in regular fashion for ease of release of the medicament therefrom. For example, the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape.
Aerosols may be formed by suspending or dissolving 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,
perfluorobutane, perfluoropentane, butane, isobutane, and pentane. 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.
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.
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. Both organic salts, such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.
Other pharmaceutically-acceptable excipients may be added to the suspension or solution. The compound of the invention may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid. These may be used alone or together to stabilize the compound of the invention. Preservatives may be added such as benzalkonium chloride or benzoic acid and salts thereof. Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.
The 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) . For example 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.
The skilled artisan will appreciate that if 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). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the 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,
trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methane sulphonate or p-toluenesulphonate. 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. In a further aspect, the compound(s) disclosed herein is in the form of a pharmaceutically acceptable salt thereof.
In a further aspect, 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
pharmaceuticals, in particular as inhibitors of dipeptidyl peptidase I activity, and thus may be used in the treatment of: respiratory tract: 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 aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; skin : psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma
gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective;
panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions; eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial; 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 : acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper- lgE syndrome, antiphospholipid syndrome and Sazary syndrome; oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; infectious diseases: virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as malaria, fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis camii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis; and cardiovascular diseases: congestive heart failure, atherosclerosis, coronary artery disease, acute myocardial infarction, hypertension, peripheral artery disease, cardiac arrhythmia, stroke and cardiomegaly.
In a further aspect, 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.
In a further aspect, 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. In a further aspect, 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.
In yet a further aspect, 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.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
In a further aspect, the pharmaceutical composition in unit dosage form, comprised from about 1 μg to about 1000 mg such as, e.g., from about 10 μg to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg, of the active substance.
In yet a further aspect, disclosed herein is compound(s) 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. In yet a further aspect, disclosed herein is compound(s) which 12 hours after a single subcutaneous animal dosing at a concentration of 10 pmol/kg, has a concentration in bone marrow of 1000 nM or more, such as 1500 nM or more, 2000 nM or more, 3000 nM or more, or 5000 nM or more.
In a further aspect, the pharmaceutical composition disclosed herein is for oral, nasal, transdermal, pulmonal or parenteral administration.
In one aspect, a method of treating an obstructive airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a
therapeutically effective amount of a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, is provided herein. In one aspect, a method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound as disclosed herein or of a composition as disclosed herein, is provided.
In a further aspect, an effective amount of a compound as disclosed herein is in a range of from about 1 μg to about 1000 mg such as, e.g., from about 10 μg to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg per day.
In one aspect, the use of a compound as disclosed herein for the preparation of a
medicament, is provided.
In one aspect, the use of 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. In one aspect, the use of 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.
In one aspect, the use of 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.
In one aspect, 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.
In one aspect, said DPPI is inhibited.
In one aspect, a compound, which has a IC50(Cathepsin B)/ IC50(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. In one aspect, a compound, which has a IC50(Cathepsin H)/ IC50(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.
In one aspect, a compound, which has a IC50(Cathepsin L)/ IC50(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.
In one aspect, a compound, which has a IC50(Cathepsin K)/ IC50(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. In one aspect, a compound, which has a IC50(Cathepsin S)/ IC50(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.
In one aspect, a compound, which has a IC50(DPPI assay)/ IC50 (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.
In one aspect, a compound, which has a IC50 (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.
In one aspect, a combination of a compound or a pharmaceutically acceptable salt thereof as disclosed herein and one or more agents independently selected from : a non-steroidal glucocorticoid receptor agonist; a selective β2 adrenoceptor agonist; a phosphodiesterase inhibitor; a peptidase inhibitor; a glucocorticoid; an anticholinergic agent; a modulator of chemokine receptor function; and an inhibitor of kinase function, is provided.
In one aspect, 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.
In one aspect, 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 IC99 or IC99.5 values.
In the present context, 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)
Figure imgf000073_0001
to form the complex C. Hence the dissociation constant equals
Figure imgf000073_0002
The variable Θ represents the fraction of binding sites that are occupied on the
macromolecule. Therefore, 1 - Θ represents the fraction of binding sites that are not occupied, giving the ratio
Figure imgf000073_0003
Taking the logarithm yields an equation linear in n
Θ
Log = n log: [Ll — loE K d
1 - Θ
Hence, the slope of this line yields n, whereas its intercept is determined by log Kd .
More generally, plotting log [θ/1-θ] versus log [L] and taking the slope gives the effective number of ligands n that are binding cooperatively at a particular ligand concentration [L]. In a non-cooperative system such as myoglobin, the plot is a straight line with slope n = 1 at all ligand concentrations. By contrast, in a system with positive cooperativity such as hemoglobin, the plot begins as a line with slope n = 1, then ramps up to a new line (also with slope n = 1) that is offset upwards. 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.
The Hill factor (n) can also be determined using a 4-parameter logistic equation in a nonlinear curve fitting routine, using the curve formula Y=A-D/(1 + (X/C)^n) + D. Further aspects according to the invention:
Aspect 1. A compound of the formula (I)
Figure imgf000074_0001
wherein y represents 0, 1, 23, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0); mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or C1-3-alkyl; which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5; 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 R20;
X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; Ci_6-alkyl optionally substituted with d-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4-R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one R20; and piperidinyl which is optionally substituted with -NR14R15 or C^-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R9 and R10 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R9 and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3_ cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R1 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000076_0001
wherein m is 0, 1 or 2;
R20 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)
Figure imgf000077_0001
wherein y represents 0, 1 or 2; when y is 1 or 2, then R2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; n represents 1, 2, 3, 4 or 5; 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 R20;
X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; Ci_6-alkyl optionally substituted with d-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-C1-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4-R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(C1_6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, C^-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R14 and R15 each independently represent hydrogen, C^-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a Ci-6-alkyl or C3-6- cycloalkyl; R16 represents a hydrogen atom or Ci-6-alkyl; R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or -Ci_6-alkyl;
R20 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 R20.
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 R20.
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 R20.
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).
Aspect 10. A compound of the formula (II)
Figure imgf000080_0001
(Π) wherein y represents 0, 1, 2 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or C1-3-alkyl, which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5;
X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)S(0)2-, C1-3-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 R20 ; Ci_6-alkyl optionally substituted with Ci-6-alkoxy, - NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; -
N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4- R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or C^-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R9 and R10 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3-
R18 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; R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000082_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2;
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.
Aspect 11. A compound of the formula (II)
Figure imgf000082_0002
(Π) wherein y represents 0, 1 or 2; when y is 1 or 2, then R2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl, which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; n represents 1, 2, 3, 4 or 5;
X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; Ci_6-alkyl optionally substituted with Ci-6-alkoxy, - NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; C^-alkoxy; Ci_6-thioalkyl; C^-alkylcarbonyl; C^-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-C1-3-alkyl; -S(0)2NR9R10; -
N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4- R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(C1.6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(C1_6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R9 and R10 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci_6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a C^-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl; R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
R18 represents a hydrogen atom, or C^-alkyl optionally substituted with halogen or methyl cyclopropyl, wherein methyl cyclopropyl is optionally substituted with methyl or halogen; R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or Ci-6-alkyl;
R20 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 13. The compound according to any one of aspects 1-12, 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-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(C1_2-alkyl)-4-R19-piperazin-l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R , 4-(C1_6-alkyl)-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl.
Aspect 14. The compound according to any one of aspects 1-13, 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-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin-l-yl which is substituted at a carbon atom with at least one substituent R20; and piperidinyl which is substituted with -NR14R15 or Ci-6-alkyl. Aspect 15. The compound according to any one of aspects 1-14, 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-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(C1_2-alkyl)-4-R19-piperazin-l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl;or -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20.
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-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; or -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17.
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-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; or -(Ci-2- alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17. 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 R20; trifluoromethyl; Ci-6-thioalkyl; -(Ci-2-alkyl)-4-R19- piperazin- l-yl in which the Ci_2-alkyl is optionally substituted with at least one substituent R17; -S(0)2-(4-(C1_6-alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20; (4-(Ci-6-alkyl)-piperazin- l-yl) which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 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-(C1_6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20. 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.
Aspect 32. A compound of the formula (III)
Figure imgf000087_0001
(III) wherein y represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5;
Q is at least one substituent selected from R20; Ci_6-alkyl optionally substituted with d-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-C1-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4-R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(C1_6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R14 and R15 each independently represent hydrogen, Ci_6-alkyl or C3_6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a Ci-6-alkyl or C3-6- cycloalkyl; R16 represents a hydrogen atom or Ci-6-alkyl; R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000089_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2;
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.
Aspect 33. A compound of the formula (III)
Figure imgf000089_0002
(III) wherein y represents 0, 1 or 2; when y is 1 or 2, then R2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; n represents 1, 2, 3, 4 or 5;
Q is at least one substituent selected from R20; Ci_6-alkyl optionally substituted with Ci-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(C1_2-alkyl)-4-R19-piperazin-l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or C^-alkyl;
R3 and R4 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci_5-alkyl or C3_6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R14 and R15 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a Ci-6-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl; R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or Ci-6-alkyl;
R20 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 R19 is selected from -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Ci_6-alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4
Figure imgf000091_0001
X1 X2 X3 X4
wherein m is 0, 1 or 2.
Aspect 35. The compound according to any one of aspects 1-34, wherein R represents - C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-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 R19 represents - C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-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 R2 independently represents halogen; hydroxyl; cyano; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Chalky!; which -0-CH3, -O-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20.
Aspect 49. The compound according to aspect 48, wherein the two R2 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 R2 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-. Aspect 51. The compound according to aspect 48, wherein the two R2 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 -
5- and -0-.
Aspect 52. The compound according to aspect 48, wherein the two R2 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 R2 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 R2 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 R2 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 R2 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 R20; -(C^- alkyl)-4-R19-piperazin- l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; 4-(Ci-6-alkyl)-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl optionally substituted with -NR14R15 or Chalky!. Aspect 58. The compound according to any one of aspects 1-57, wherein Q is selected from -S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R 20 ; -(C^-alkyl^-R -piperazin-l-yl in which the C^-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl;or -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)- piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl.
Aspect 59. The compound according to any one of aspects 1-58, wherein Q is selected from -S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl;or -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)- piperazin-l-yl which is substituted at a carbon atom with at least one substituent R20; and piperidinyl which is substituted with -NR14R15 or Ci-6-alkyl. Aspect 60. The compound according to any one of aspects 1-59, wherein Q is selected from -S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl;or -S(0)2-(C1.6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20.
Aspect 61. The compound according to any one of aspects 1-60, wherein Q is selected from -S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; or -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17. 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 R20. Aspect 64. The compound according to any one of aspects 1-62, wherein Q is -(Ci-2-alkyl)- 4-R19-piperazin-l-yl in which the Ci_2-alkyl is optionally substituted with at least one substituent R17. 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-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20.
Aspect 68. The compound according to any one of aspects 1-67, wherein R17 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 R17 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 R19 is selected from methyl; ethyl; propyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; isopropyl;
methylcyclopropyl; ethylcyclopropyl; and propylcyclopropyl. Aspect 71. The compound according to any one of aspects 1-68, wherein R19 is selected from cyano methyl or cyano ethyl.
Aspect 72. A compound selected from (S)- l-Amino-/V-( l-cyano-2-(4'-((4-methylpiperazin- 1-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (S)- l-amino-N-( l-cyano-2-(4'-(4- methylpiperazin- l-ylsulfonyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide and (S)-2-Amino- /V-((S)- l-cyano-2-(4'-(4-methylpiperazin- l-ylsulfonyl)biphenyl-4- yl)ethyl)- 1,2,3,4- tetrahydronaphthalene-2-carboxamide.
Aspect 73. A compound selected from (S)- l-Amino-N-( l-cyano-2-(4'-((4-methylpiperazin- 1-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (S)- l-amino-N-( l-cyano-2-(4'-(4- methylpiperazin- l-ylsulfonyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (S)-2-Amino-/V- ((S)- l-cyano-2-(4'-(4-methylpiperazin- l-ylsulfonyl)biphenyl-4- yl)ethyl)- 1,2,3,4- tetrahydronaphthalene-2-carboxamide, (S)-8-Amino-N-( l-cyano-2-(4'-((4-methylpiperazin- 1-yl) methyl) biphenyl-4-yl)ethyl)- l,4-dioxaspiro[4.5]decane-8-carboxamide, (S)- l-Amino-N- ( l-cyano-2-(4'-((4-methylpiperazin- l-yl) methyl) biphenyl-4-yl)
ethyl)cyclopentanecarboxamide, (S)-2-Amino-N-( l-cyano-2-(4'-((4-methylpiperazin- l-yl) methyl)biphenyl-4-yl) ethyl)-2,3-dihydro- lH-indene-2-carboxamide, (S)-2-Amino-N-( l- cyano-2-(4'-((4-methylpiperazin- l-yl) methyl)biphenyl-4-yl) ethyl)bicyclo[2.2.1]heptane-2- carboxamide, (S)-D6- l-Amino-N-( l-cyano-2-(4'-((4-methyl-piperazin- l-yl) methyl) biphenyl- 4-yl) ethyl)cyclohexanecarboxamide, (R)- l-amino-N-( l-cyano-2-(4'-((4-propylpiperazin- l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (R)- l-amino-N-( l-cyano-2-(4'-((4- cyclopropyl-piperazin- l-yl)methyl)biphenyl-4-yl) ethyl)cyclohexanecarboxamide, (R)- l- amino-N-( l-cyano-2-(4'-((4-(cyanomethyl) piperazin- l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide and (S)- l-amino-N-( l-cyano-2-(4'-((4-(oxazol-2-ylmethyl) piperazin- l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide.
Aspect 74. A compound of the formula (IV)
Figure imgf000096_0001
(IV) wherein R is of the formula :
Figure imgf000096_0002
y represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; z represents 0, 1, 2, 3, 4, 5, 6, 7 or 8; when y is 1 or 2 or when z is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -O-CH3, -O-C2H5, -S-CH3, -S-C2H5 or C^-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto; or when y represents 2 or when z represents 2, then the two R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10 or when z represents 3, 4, 5, 6, 7 or 8, then R2 represents deuterium; s represents 1 or 2; r represents 0, 1, 2, 3 or 4;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3-yl;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000097_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2;
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.
Aspect 75. A compound of the formula (IV)
Figure imgf000098_0001
(IV) wherein R is of the formula :
Figure imgf000098_0002
y represents 0, 1 or 2; z represents 0, 1 or 2; when y is 1 or 2 or when z is 1 or 2, then R2 independently represents halogen; hydroxyl; cyano; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 or Ci-3-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto; or when y represents 2 or when z represents 2, then the two R2 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 R20; s represents 1 or 2; r represents 0, 1, 2, 3 or 4; R17 each independently represents halogen, cyano, cyclopropyl, oxetan-3-yl or C^-alkyl which Ci-3-alkyl is optionally substituted with halogen, cyano, or cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or halogen; or two R17 together with the carbon atom(s) to which they are attached form a cyclopropyl; R19 represents -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or Ci-6-alkyl;
R20 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 R19 represents - C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or Ci_6-alkyl, which Ci-6-alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino.
Aspect 77. The compound according to any one of aspects 1-76, wherein R19 represents
Figure imgf000099_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2.
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 R2 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 R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; - S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20.
Aspect 86. The compound according to aspect 85, wherein the two R2 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 R2 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-.
Aspect 88. The compound according to aspect 85, wherein the two R2 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 -
5- and -0-.
Aspect 89. The compound according to aspect 85, wherein the two R2 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 R2 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 R2 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 R2 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 R2 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.
Aspect 96. The compound according to any one of aspects 1-95, wherein each R17 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 R17 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 R17 together with the carbon atom to which they are attached form a cyclopropyl and two R17 are hydrogen.
Aspect 100. The compound according to any one of aspects 1-99, wherein R19 is selected from methyl; ethyl; propyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; isopropyl;
methylcyclopropyl; ethylcyclopropyl; and propylcyclopropyl.
Aspect 101. The compound according to any one of aspects 1-100, wherein R19 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 104. The compound according to any one of the preceding aspects for use in medicine.
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.
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
IC50(Cathepsin B)/ IC50(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
IC50(Cathepsin H)/ IC50(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
IC50(Cathepsin L)/ IC50(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
IC50(Cathepsin K)/ IC50(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
IC50(Cathepsin S)/ IC50(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 IC50 (DPPI assay)/ IC50 (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.
Aspect 115. The compound according to any one of aspects 1-114, which has a IC50 (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.
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 β2 adrenoceptor agonist; a phosphodiesterase inhibitor; a peptidase inhibitor; a glucocorticoid; an anticholinergic agent; a modulator of chemokine receptor function; and an inhibitor of kinase function.
Aspect 120. 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.
Aspect 121. The pharmaceutical composition according to aspect 120 in unit dosage form, comprising from about 1 μg to about 1000 mg such as, e.g., from about 10 μg 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
pharmaceutically acceptable salt thereof.
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 μg to about 1000 mg such as, e.g., from about 10 μg 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
pharmaceutically acceptable salt thereof 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.
Aspect 129. 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. MATERIALS AND METHODS
Abbreviations
The following abbreviations are used in the non-limiting Examples:
Figure imgf000105_0001
HOAc Acetic acid
RT Room temperature
Pre-HPLC Preparative High performance liquid chromatography
Min Minute(s)
g Gram(s)
mL Millilitre(s)
Human DPPI assay
Using this assay, the IC50 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 IC50 values. Km was 2.2 mM. The substrate was solubilized in dimethylformamid to give a 0.2-0.5 M stock solution, which was then further diluted with stirring in assay buffer to a final concentration of 1 mM .
DPPI : Human DPPI (obtained from UNIZYME Laboratories A/S, DK-2970 Horsholm, Denmark) was stored at -20 °C in a buffer containing 2.5 mM Na-phosphate, 150 mM NaCI, 2 mM cysteamine, 50% glycerol, pH 7.0 at a concentration of 1-2 mg/mL (5-10 μΜ) . This stock solution was diluted 500-1000 times in assay buffer to a concentration of 10-20 nM. Assay conditions: The assay was performed in 96-well plates. Diluted enzyme (25 pL) was added to the well, followed by 25 pL of test substance in varying concentrations, and the solution was mixed. The plate was incubated at 37 °C for 5 minutes, followed by addition of 150 pL of 1 mM substrate prewarmed to 37 °C (corresponding to a substrate concentration of 750 μΜ in the assay). The absorption was measured at 405 nm at 37 °C for every 90 sec for 12 minutes or every 20 sec for 4 min. Each measurement was made in duplicate. IC50 was determined using a 4-parameter logistic equation in a non-linear curve fitting routine.
Using this assay the results shown in table 1 was obtained. Table 1
DPPI IC
Compound
nM
PZ1024 37
(Example 1)
PZ1018
8
(Example 2)
PZ1022
155
(Example 3)
PZ1041
2970
(Example 4)
PZ1044
198
(Example 5)
PZ1063
1170
(Example 6)
PZ1064
658
(Example 7)
PZ1066
31
(Example 8)
PZ1047
33
(Example 9)
PZ1050
57
(Example 10)
PZ1051
58
(Example 11)
PZ1057
(Example 12)
Cell based DPPI inhibitor assay
The herein described compounds are DPPI inhibitors, which indirectly inhibit the activity of serine peptidases that are activated by DPPI, such as elastase. Using the cell based assay described below, the biological activity of compounds of the invention may be determined.
Neutrophil elastase enzymatic activities in U937 cells grown in the presence of DPPI inhibitors were measured by methods modified from Methot N; Rubin J; Guay D; Beaulieu C; Ethier D; Reddy TJ; Riendeau D and Percival MD (2007) J Biol Chem, 282, 20836-20846. U937 cells were propagated in culture media (RPMI 1640, supplemented with 10% FBS, 10 mM Hepes, 1 mM sodium pyrovate, 100 units/ml of each of penicillin and streptomycin). Cells were seeded in 12-well plates at 0.2 to 0.4 x 106 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 μΜ 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.
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. IC50 was determined using a 4-parameter logistic equation in a non-linear curve fitting routine.
Using this assay the results shown in table 2 was obtained.
Table 2
U937 ICso
Compound
nM
PZ1024 2
(Example 1)
PZ1018
2
(Example 2)
PZ1022
159
(Example 3)
PZ1041
3700
(Example 4)
PZ1044
7
(Example 5)
PZ1063
143
(Example 6)
PZ1064
36
(Example 7)
PZ1066
2
(Example 8)
PZ1047
3
(Example 9)
PZ1050
4
(Example 10)
PZ1051
3
(Example 11)
PZ1057
(Example 12) Test for metabolic stability
The test for metabolic stability was performed by Absorption System, Exton, PA 19341, USA.
The 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 μΜ .
An aliquot of the 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 μΜ.
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.
Using this assay for testing of metabolic stability more than 2 of the exemplified compounds were found to have an elimination half-life of more than 30 min.
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)
Figure imgf000110_0001
12 13 14
Reaction schemes
8-Amino-l,4-dioxaspiro[4.5]decane-8-carboxylic acid (compound 2 of example A):
To a suspension of l,4-dioxaspiro[4.5]decan-8-one (10.0 g, 0.064 mol) and (NH4)2C03 (31.0 g, 0.32 mol) in ethanol/water (300 mL, 1 : 1) was added sodium cyanide (3.2 g, 0.064 mol). 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 (NH4)2C03 decompose (compound 1 of example A). Then NaOH (14.5 g, 0.36 mol) was added and ethanol was removed under reduced pressure and the resulting solution was refluxed overnight. The mixture was cooled to room temperature, and used directly without further purification (compound 2 of example A).
8-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-l,4-dioxaspiro[4.5]decane-8- carboxylic acid (compound 3 of example A): After the solution of compound 2 of example A was adjusted to pH = 10 with 2 N HCI, Fmoc-Osu (15.87 g, 45.0 mmol) and acetonitrile (50.0 mL) were added. The reaction mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure and the resulting mixture was adjusted to pH = 2 with 2 N HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 50: 1) to afford
compound 3 of example A (5.0 g, 13% yield over three steps) as a white solid.
1- (((9H-Fluoren-9-yl)methoxy)carbonylamino)cyclopentanecarboxylic acid
(compound 4 of example A): Fmoc-OSu (3.13 g, 9.3 mmol) was added to a solution of 1- aminocyclo- pentanecarboxylic acid (1.0 g, 7.8 mmol) and NaHC03 (1.63 g, 19.4 mmol) in acetonitrile/water (100 mL, 1 : 1). The reaction mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure and the resulting mixture was adjusted to pH = 2 with 2 N HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA = 20: 1) to afford compound 4 of example A (0.75 g, 28% yield) as a white solid.
2- Amino-2,3-dihydro-lH-indene-2-carboxylic acid (compound 6 of example A): To a suspension of lAV-inden-2(3AV)-one (10.0 g, 0.076 mol) and (NH4)2C03 (36.4 g, 0.38 mol) in ethanol/water (300 mL, 1 : 1) was added sodium cyanide (3.7 g, 0.076 mol). 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 (NH4)2C03 decompose (compound 5 of example A). Then NaOH (12.0 g, 0.30 mol) was added and ethanol was removed under reduced pressure and the resulting solution was refluxed overnight. The mixture was cooled to room temperature, which was used directly without further purification (compound 6 of example A). 2-(tert-Butoxycarbonylamino)-2,3-dihydro-lH-indene-2-carboxylic acid (compound 7 of example A): Boc20 (33.0 g, 0.15 mol) and a solution of DMAP (cat.) in acetonitrile (20.0 mL) were added to the solution of compound 6 of example A and the reaction mixture was stirred at room temperature for 48 h. Most of the solvent was removed under reduced pressure and the resulting mixture was adjusted to pH = 2 with 2 N HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA/DCM = 10: 1 : 1) to afford compound 7 of example A (4.0 g, 19% yield over three steps) as a white solid.
2-Aminobicyclo[2.2.1]heptane-2-carboxylic acid (compound 9 of example A): To a suspension of bicyclo[2.2. l]heptan-2-one (10.0 g, 0.091 mol) and (NH4)2C03 (43.7 g, 0.45 mol) in ethanol/water (300 mL, 1 : 1) was added sodium cyanide (4.46 g, 0.091 mol) . 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 (NH4)2C03 decompose (compound 8 of example A). Then NaOH (14.5 g, 0.36 mol) was added and ethanol was removed under reduced pressure and the resulting solution was refluxed overnight. The mixture was cooled to room temperature, and used directly without further purification (compound 9 of example A).
2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid (compound 11 of example A): After the solution of compound 9 of example A was adjusted to pH= 10 with 2 N HCI, Fmoc-Osu (15.87 g, 45.0 mmol) and acetonitrile (50.0 mL) were added. The reaction mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure and the resulting mixture was adjusted to pH = 2 with 2 N HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 50: 1) to afford compound 11 of example A (9.0 g, 21% yield over three steps) as a white solid.
D6-l-Aminocyclohexanecarboxylic acid (compound 13 of example A): To a suspension of D6-cyclohexanone (1.0 g, 9.6 mmol) and (NH4)2C03 (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 (NH4)2C03 decompose
(compound 12 of example A). Then NaOH (1.92 g, 48.0 mmol) was added and ethanol was removed under reduced pressure and the resulting solution was refluxed overnight. The mixture was cooled to room temperature, and was used directly without further purification (compound 13 of example A).
D6-l-(((9H-Fluoren-9-yl)methoxy)carbonylamino)cyclohexanecarboxylic acid (compound 14 of example A): After the solution of compound 13 of example A was adjusted pH = 10 with 2 N HCI, Fmoc-Osu (2.63 g, 9.6 mmol) and acetonitrile (20.0 mL) were added. The reaction mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure and the resulting mixture was adjusted to pH = 2 with 2 N HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column
chromatography on silica gel (DCM/MeOH = 100: 1) to afford compound 14 of example A (0.65 g, 16% yield over three steps) as a white solid. Example B
Procedure for preparation of the starting compound (S)-tert-butyl l-(l-cyano-2-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamoyl)cyclohexylcarba-mate (PZ1036- 8) for synthesis of PZ1047, PZ1050 and PZ1051 (examples 9, 10 and 11)
Figure imgf000113_0001
PZ1036-8
Compound 1 of example B
Figure imgf000113_0002
To a solution of (S)-2-amino-3-(4-bromophenyl)propanoic acid (2.44 g, 10 mmol) in methanol (20 mL) and water (20 mL) was added (Boc)20 (2.29 g, 10.5 mmol) drop wise. This mixture was stirred at room temperature for 16 h. Then the solvent was evaporated under reduced pressure. The residue was adjusted to pH = 5 and extracted with EA (50 mL x 3). The combined organic layers were dried over Na2S04 and concentrated in vacuo to give compound 1 of example B (3.2 g, 93.0%) as a white solid, which was used for next step without further purification.
Compound 2 of example B
Figure imgf000114_0001
To a solution of compound 1 of example B (3.2 g, 9.3 mmol) and K2C03 (2.6 g, 18.6 mmol) in DMF (50 mL) was added Mel (Methyl Iodide) (1.5 g, 10.2 mmol). Then this mixture was stirred at room temperature for 4 h. This reaction mixture was added water (30 ml) and extracted with EA (30 mL x 3). The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo to give compound 2 of example B (3.1 g, 93%) as a white solid.
Figure imgf000114_0002
NH3(gas) was bubbled into a solution of compound 2 of example B (3.1 g, 8.7 mmol) in methanol (50 mL) at -50 °C for 15 min. Then the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was washed with Et20 and filtered to give compound 3 of example B (2.9 g, 97%) as a white solid.
Figure imgf000114_0003
A solution of compound 3 of example B (2.9 g, 8.5 mmol) and Et3N (3.6 g, 35.7 mmol) in CH2CI2 (60 mL) was cooled to 0°C and (CF3CO)20 (3.9 g, 18.7 mmol) was added drop wise under nitrogen. After 3.5 h stirring at room temperature, volatiles were removed in vacuo. The residue was taken in EA and washed with brine. The organic layer was dried over Na2S04 and concentrated in vacuum to afford compound 4 of example B (2.4 g, 87%) as a white solid. Compound 5 of example B
Figure imgf000115_0001
4 5
A solution of compound 4 (2.4 g, 7.4 mmol) in HCOOH (40 mL) was heated to 40°C and stirred for 4 h. The solution was slowly added into cold aqueous NaHC03 solution with stirring. Then the mixture was extracted with EA (50 mL x 3) and CH2CI2 (50 mL x 3). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA/PE = 1/10) to give compound 5 of example B (1.5 g, 90%) as a white solid.
Compound 6 of example B
Figure imgf000115_0002
6
To a solution of 1-aminocyclohexanecarboxylic acid (5.0 g, 34.9 mmol) in MeOH(30 ml) and H2O(30 ml) was added K2C03 (12.1 g, 87.3 mmol). Then (Boc)20 (9.1 g, 41.9 mmol) was added drop wise at 0 °C. The mixture was reacted at room temperature for 16 h. The solvent was removed in vacuum and the residue was cooled to 0 °C, IN HCI was added to adjust to pH = 5, then the mixture was extracted with ethyl acetate (100 mL x 3). Combined organic layer was washed by brine, dried over Na2S04, and evaporated to give a crude product which was washed with Et20 to afford compound 6 of example B (6.0 g, 70%) as a white solid.
Compound 7 of example B
Figure imgf000115_0003
6
7
To a solution of compound 6 of example B (1.6 g, 6.7 mmol) in CH2CI2 (20 mL) was added DMTMM (4-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4-methyl morpholinium chloride) (2.8 g, 10.1 mmol) and compound 5 (1.5 g, 6.7 mmol) at 0 °C. The mixture was stirred at ambient temperature overnight and then a mixture of water/CH2CI2 (50 mL/50 mL) was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with CH2CI2 (50 mL x 3). The combined organic phases were dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA/PE/DCM= 1/20/1) to give compound 7 of example B (2.0 g, 66%) as a white solid. (S)-tert-butyl l-( l-cyano-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl)ethylcarbamoyl)cyclohexylcarbamate (PZ1036-8)
Figure imgf000116_0001
To a solution of compound 7 of example B (0.5 g, 1.11 mmol) in 1,4-dioxane (20 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.333 g, 1.33 mmol) and Pd(dppf)CI2 (50 mg). The mixture was reacted in micro wave oven at 110°C and stirred for 1.5 h. LCMS showed that the reaction was complete. The reaction mixture was extracted with EA and brine. The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/PE/DCM = 1/20/1) to afford PZ1036-8 (0.405 g, 73%) as a white solid. Example C
Procedure for preparation of starting compound l-Methyl-4-(4-(4,4,5,5-tetramethyl
-l,3,2-dioxaborolan-2-yl)benzyl)piperazine (PZ1015-5) for synthesis of the intermediate (S)- 2-Amino-3-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl)
propanenitrile (PZ1024-6) described in example 1.
Scheme
Figure imgf000116_0002
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 ethyl acetate phase was dried over anhydrous Na2S04 and concentrated . The residue was purified by HPFC (DCM : MeOH = 9 : 1) to yield l-(4-bromobenzyl)-4- methylpiperazine (9.8 g, 61% yield). LC-MS: 269.2 [M + H]+.
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 N2 for three times and Pd(PPh3)4 (0.1 g, 0.087 mmol) was added . The mixture was refluxed overnight under N2 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 χ 2) . The organic phases were combined, dried over anhydrous Na2S04 and concentrated. The residue was purified by HPFC (DCM : MeOH = 9 : 1) to yield PZ1015-5 (7.1 g, 60% yield) . LC- MS: 317.2 [M + H]+ .
Example 1.
Procedure for preparation of (S)-l-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l- yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide (PZ1024)
Figure imgf000118_0001
Reaction scheme
Figure imgf000118_0002
(S)-Methyl 2-amino-3-(4-bromophenyl)propanoate (PZ1024-1) : To a solution of (S)- 2-amino-3-(4-bromophenyl)propanoic acid (20.0 g, 82.0 mmol) in methanol (200 mL) was added SOCI2 (7.2 mL, 98.8 mmol) . The mixture was heated under reflux overnight and then concentrated to give PZ1024-1 (17.6 g, 73% yield) as a yellow solid, which was used without further purification. LC-MS: 258 [M + H]+.
(S)-Methyl 3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoate (PZ1024-
2) : To a solution of PZ1024-1 (3.0 g, 11.7 mmol) in acetone (10 mL) were added saturated NaHC03 solution (10 mL) and (Boc)20 (3.06 g, 14.0 mmol) . The mixture was stirred at room temperature overnight and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated to give PZ1024-2 (3.2 g, 78% yield) as a light yellow solid, which was used without further purification. LC-MS: 380 [M + Na]+.
(S)-tert-Butyl l-amino-3-(4-bromophenyl)-l-oxopropan-2-ylcarbamate (PZ1024-
3) : Ammonia gas was bubbled into a solution of PZ1024-2 (2.3 g, 6.4 mmol) in methanol (50 mL) at -50°C for 15 min. Then the mixture was stirred at room temperature overnight.
The mixture was concentrated to give PZ1024-3 (2.0 g, 90% yield) as a white solid. LC-MS: 243 [M-B0C+2H]+.
(S)-tert-Butyl 2-(4-bromophenyl)-l-cyanoethylcarbamate (PZ1024-4) : To a solution of PZ1024-3 (2.5 g, 7.3 mmol) in DMF (50 mL) was added a solution of cyanuric chloride (3.4 g, 18.2 mmol) in DMF (20 mL) at 0°C. The mixture was stirred at 0°C for 15 min and then at 40°C for 1 h. The mixture was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (PE: EA = 3: 1) to give PZ1024-4 (1.7 g, 73% yield). *H NMR (CDCI3, 300 MHz) : d 7.50 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 4.81 (br, 2H), 3.06 (m, 2H), 1.44 (s, 9H).
(S)-tert-Butyl l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethylcarbamate (PZ1024-5) : To a solution of PZ1024-4 (2.24 g, 6.9 mmol) in
DMF/H20 (112 mL, 4: 1) were added l-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzyl)piperazine (PZ1015-5 described in example C in the MATERIALS AND METHODS section) (2.61 g, 8.3 mmol), PdCI2(dppf)2 (0.25 g, 0.34 mmol) and Na2C03 (2.19 g, 20.7 mmol). The mixture was heated at 100°C for 3 h and then partitioned between water and ethyl acetate. The organic phase was dried over anhydrous Na2S04 and
concentrated. The residue was purified by flash column chromatography on silica gel (DCM : EtOH = 50 : 1) to give PZ1024-5 (2.0 g, 68% yield). LC-MS: 435 [M + H]+. (S)-2-Amino-3-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl)propanenitrile (PZ1024-6) : A solution of PZ1024-5 (1.3 g, 3.0 mmol) in HCOOH (20 mL) was heated at 40°C for 4 h. The solution was slowly added into cold aqueous NaHC03 solution with stirring. Then the mixture was extracted with ethyl acetate (20 mL x 3) and dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM : EtOH = 40: 1) to give PZ1024-6 (0.43 g, 43% yield). LC-MS: 335 [M + H]+.
(S)-(9H-Fluoren-9-yl)methyl l-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)- biphenyl-4-yl)ethylcarbamoyl)cyclohexylcarbamate (PZ1024-7) : To a solution of PZ1024-6 (0.40 g, 1.1 mmol) in DCM (20 mL) were added DMTMM (0.46 g, 1.65 mmol) and Fmoc-l-aminocyclohexanecarboxylic acid (0.4 g, 1.1 mmol) at 0°C. The mixture was stirred at ambient temperature overnight and then a mixture of water/dichloromethane (20 mL/20 mL) was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phases were dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (PE: EA = 1 : 1) to give PZ1024-7 (0.40 g, 70% yield). LC-MS: 682 [M + H]+.
(S)-l-Amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide (PZ1024) : A solution of PZ1024-7 (0.50 g, 0.7 mmol) containing piperidine (1 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The whole mixture was directly subjected to flash column chromatography on silica gel (DCM : EtOH = 20 : 1) to give PZ1024 (0.18 g, 53% yield) . LC-MS: 460 [M + H]+. *H NMR (CDCI3, 300 MHz) : d 8.40 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.13 (m, 1H), 3.56 (s, 2H), 3.13 (d, J = 6.6 Hz, 2H), 2.50 (br, 8H), 2.31 (s, 3H), 1.90 (m, 2H), 1.67 (m, 4H), 1.31 (m, 6H).
Example 2.
Procedure for preparation of (S)-l-amino-N-(l-cyano-2-(4'-(4-methylpiperazin-l- ylsulfonyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide (PZ1018)
Figure imgf000121_0001
Figure imgf000121_0002
(S)-tert-Butyl l-amino-3-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4-yl)-l- oxopropan-2-ylcarbamate (PZ1018-1): A mixture of PZ1024-3 (3.0 g, 8.8 mmol), 1- methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prienylsulfonyl)- piperazine (3.6 g, 9.7 mmol) and aqueous Na2C03 solution (2.0 M, 14.2 mL, 28.4 mmol) in DMF (50 mL) was purged with nitrogen three times and PdCI2(dppf)2 (0.3 g, 0.41 mmol) was added. The mixture was stirred at 80°C overnight. After the mixture was cooled to room temperature, water (150 mL) and ethyl acetate (150 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic phases were dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (EA/MeOH = 20: 1) to give PZ1018-1 (3.3 g, 82% yield). LC-MS: 503 [M + H]+. (S)-tert-Butyl l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4-yl)ethyl- carbamate (PZ1018-2): Cyanuric chloride (0.74 g, 4.0 mmol) was added to a solution of PZ1018-1 (0.67 g, 1.3 mmol) in DMF (10 mL). The mixture was stirred at ambient temperature for 4 h. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (EA/MeOH = 30: 1) to give PZ1018-2 (0.54 g, 84% yield). LC-MS: 485 [M + H]+.
(S)-(9H-Fluoren-9-yl)methyl l-(l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)- biphenyl-4-yl)ethylcarbamoyl)cyclohexylcarbamate (PZ1018-3): A solution of
PZ1018-2 (0.54 g, 1.1 mmol) in HCOOH (10 mL) was stirred at ambient temperature for 4 h. The solution was slowly added into cold aqueous NaHC03 solution with stirring. Then the mixture was extracted with ethyl acetate (200 mL x 3) and dichloromethane (200 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and concentrated to give the amine (0.4 g, 93% yield). LC-MS: 385 [M + H]+.
A solution of the amine (0.37 g, 1.0 mmol) in dichloromethane (20 mL) was added to a solution of l-(((9H-fluoren-9-yl)methoxy)carbonylamino)- cyclohexanecarboxylic acid (0.36 g, 1.0 mmol) and DMTMM (0.53 g, 1.9 mmol) in dichloromethane (30 mL) at 0°C. The mixture was stirred at ambient temperature overnight and then a mixture of
water/dichloromethane (100 mL/100 mL) was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL x 2). The combined organic phases were dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (EA/MeOH = 30: 1) to give PZ1018-3 (0.58 g, 80% yield). LC-MS: 732 [M + H]+.
(S)-l-amino-N-( l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide (PZ1018): A solution of PZ1018-3 (0.58 g, 0.8 mmol) containing piperidine (2 mL) in DCM (25 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography on silica gel to give PZ1018 (300 mg, 74% yield) as a white solid. LC-MS: 510 [M + H]+. *H NMR (CDCI3, 300 MHz) : d 8.42 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 5.19 (m, 1H), 3.16 (m, 6H), 2.59 (br, 4H), 2.34 (s, 3H), 1.94 (m, 2H), 1.68 (m, 4H), 1.38 (m, 6H).
Example 3.
Procedure for preparation of (S)-2-Amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l- ylsulfonyl)biphenyl-4- yl)ethyl)-l,2,3,4-tetrahydronaphthalene-2-carboxamide (PZ1022)
Figure imgf000123_0001
Reaction scheme 3
Figure imgf000123_0002
(9H-Fluoren-9-yl)methyl (S)-2-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfon- yl)biphenyl-4-yl)ethylcarbamoyl)-l,2,3,4-tetrahydronaphthalen-2-ylcarbamate (PZ1022-1): A solution of PZ1018-2 (0.54 g, 1.1 mmol; see example 2) in HCOOH (10 mL) was stirred at ambient temperature for 4 h. The solution was slowly added into cold aqueous NaHC03 solution with stirring. The mixture was extracted with ethyl acetate (200 mL x 3) and dichloromethane (200 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and concentrated to give the amine (0.4 g, 93% yield). LC-MS: 385.0 (M + H) .
A solution of the amine (0.37 g, 1.0 mmol) in dichloromethane (20 mL) was added to a solution of (S)-2-(((9 - -fluoren-9-yl)methoxy)carbonylamino)-l,2,3,4- tetrahydronaphthalene-2-carboxylic acid (0.41 g, 1.0 mmol) and DMTMM (0.53 g, 1.9 mmol) in dichloromethane (30 mL) at 0°C. The mixture was stirred at ambient temperature overnight. A mixture of water/dichloromethane (100 mL/100 mL) was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL x 2). The combined organic phases were dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel to give PZ1022-1 (0.58 g, 75 % yield). LC-MS: 780 [M + H]+.
(S)-2-Amino-/V-((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)-l,2,3,4-tetrahydronaphthalene-2-carboxamide (PZ1022): A solution of PZ1022-1 (0.58 g, 0.75 mmol) containing piperidine (2 mL) in DCM (25 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography to give PZ1022 (290 mg, 76% yield) as a foamy solid. LC-MS: 558 [M + H]+. *H NMR (CDCI3, 300 MHz) : d 8.48 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.16 (m, 4H), 5.24 (m, 1H), 3.43 (d, J = 16.8 Hz, 1H), 3.20 (d, J = 6.6 Hz, 2H), 3.12 (br, 4H), 2.89 (m, 2H), 2.57 (br, 5H), 2.36 (m, 4H), 1.63 (m, 1H), 1.40 (br, 2H).
Example 4.
Procedure for preparation of (S)-8-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl)ethyl)-l,4-dioxaspiro[4.5]decane-8-carboxamide (PZ1041)
Figure imgf000125_0001
(S)-(9H-Fluoren-9-yl)methyl 8-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)
methyl) biphenyl-4-yl) ethylcarbamoyl)-l,4-dioxaspiro [4.5]decan-8-yl
carbamate (Fmoc-PZ1041): DMTMM (663 mg, 2.4 mmol) was added to a solution of compound PZ1024-6 from example 1 (400 mg, 1.2 mmol) in DCM (10.0 mL) in an ice-water bath. The mixture was stirred at 0°C for 0.5 h and compound 3 from example A described in the MATERIALS AND METHODS section (608 mg, 1.32 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. Water was added and the resulting mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 50: 1 to 10: 1) to afford compound
Fmoc-PZ1041 (380 mg, 43% yield) as a white solid.
(S)-8-Amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4- yl)ethyl)-l,4-dioxaspiro[4.5]decane-8-carboxamide (PZ1041): Piperidine (2.0 mL) was added to a solution of Fmoc-PZ1041 (380 mg, 0.68 mmol) in DCM (8.0 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was treated with diethyl ether and the resulting mixture was stirred for 0.5 h. The precipitate was collected by filtration and washed with cooled diethyl ether to afford compound PZ1041 (200 mg, 81% yield) as a white solid. *H NMR (300 MHz, CDCI3) : δ 8.28 (d, J = 9.3 Hz, 1H), 7.60-7.52 (m, 4H), 7.42-7.33 (m, 4H), 5.17-5.12 (m, 1H), 3.95 (m, 4H), 3.57 (s, 2H), 3.13 (m, 2H), 3.01 (m, 4H), 2.48 (m, 8H), 2.31 (m, 4H), 1.77-1.61 (m, 8H); MS (ESI) : m/z 518.5 [M + H]+. Example 5.
Procedure for preparation of (S)-l-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l- yl)methyl)biphenyl-4-yl) ethyl)cyclopentanecarboxamide (PZ1044)
Figure imgf000126_0001
(S)-(9H-Fluoren-9-yl)methyl l-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl) biphenyl-4-yl)ethylcarbamoyl)cyclopentylcarbamate (Fmoc-PZ1044)
DMTMM (663 mg, 2.4 mmol) was added to a solution of compound PZ1024-6 from example 1 (400 mg, 1.2 mmol) in DCM (25.0 mL) in an ice-water bath. The mixture was stirred at 0°C for 0.5 h and compound 4 from example A described in the MATERIALS AND METHODS section (444 mg, 1.32 mol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. Water was added and the resulting mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA = 1 : 1 then EA/MeOH = 40 : 1) to afford compound Fmoc-PZ1044 (452 mg, 56% yield) as a white solid.
(S)-l-Amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl) ethyl)cyclopentanecarboxamide (PZ1044): Piperidine (2.0 mL) was added to a solution of Fmoc-PZ1044 (450 mg, 0.68 mmol) in DCM (10.0 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was treated with diethyl ether and the resulting mixture was stirred for 0.5 h. The precipitate was collected by filtration and washed with cooled diethyl ether to afford compound PZ1044 (160 mg, 53% yield) as a white solid. *H NMR (300 MHz, CDCI3) : δ 8.35 (d, J = 9.3 Hz, 1H), 7.61-7.53 (m, 4H), 7.42-7.34 (m, 4H), 5.15 (m, 1H), 3.58 (m, 4H), 3.16-3.12 (m, 4H), 2.54-2.24 (m, 8H), 2.12 (s, 3H), 1.87-1.86 (m, 8H); MS (ESI) : m/z 446.4 [M + H]+. Example 6.
Procedure for preparation of (S)-2-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl) ethyl)-2,3-dihydro-lH-indene-2-carboxamide (PZ1063)
Figure imgf000127_0001
(S)-tert-Butyl 2-( l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl)biphenyl-4-yl) ethylcarbamoyl)-2,3-dihydro-lH-inden-2-ylcarbamate (Boc-PZ1063): DMTMM (756 mg, 2.81 mmol) was added to a solution of compound PZ1024-6 from example 1 (470 mg, 1.47 mmol) in DCM (10.0 mL) in an ice-water bath. The mixture was stirred at 0°C for 0.5 h and compound 7 from example A described in the MATERIALS AND METHODS section (275 mg, 1.47 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. Water was added and the resulting mixture was extracted with DCM . The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel
(DCM/MeOH = 50 : 1 to 10: 1) to afford compound Boc-PZ1063 (527 mg, 63% yield) as a white solid.
(S)-2-Amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl) ethyl)-2,3-dihydro-lH-indene-2-carboxamide (PZ1063): A solution of compound Boc- PZ1063 (527 mg, 0.89 mmol) in HCOOH (10.0 mL) was stirred at room temperature overnight. The solution was added slowly into a mixture of NaHC03 in water and ice with stirring. After neutralization, the mixture was extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 100 : 1 to 30: 1) to afford compound PZ1063 (248 mg, 56% yield) as an off-white solid. *H NMR (300 MHz, CDCI3) : δ 8.32 (d, J = 9.3 Hz, 1H), 7.66-7.55 (m, 4H), 7.43-7.29 (m, 4H), 5.21 (m, 1H), 3.77 (m, 1H), 3.57 (m, 2H), 3.19 (m, 2H), 2.77-2.51 (m, 8H), 2.32 (s, 3H); MS (ESI) : m/z 494.2 [M + H]+. Example 7.
Procedure for preparation of (S)-2-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl)biphenyl-4-yl) ethyl)bicyclo[2.2.1]heptane-2-carboxamide (PZ1064)
Figure imgf000128_0001
(S)-(9H-Fluoren-9-yl)methyl 2-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl)bi phenyl-4-yl)ethylcarbamoyl)bicyclo[2.2.1]heptan-2-ylcarbamate (Fmoc- PZ1064): DMTMM (592 mg, 2.14 mmol) was added to a solution of compound PZ1024-6 from example 1 (358 mg, 1.07 mmol) in DCM (10.0 mL) in an ice-water bath. The mixture was stirred at 0°C for 0.5 h and compound 11 from example A described in the MATERIALS AND METHODS section (275 mg, 0.82 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. Water was added and the resulting mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column
chromatography on silica gel (DCM/MeOH = 50: 1 to 10: 1) to afford compound Fmoc- PZ1064 (306 mg, 53% yield) as a white solid.
(S)-2-Amino-/V-(l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl) ethyl)bicyclo[2.2.1]heptane-2-carboxamide (PZ1064): Piperidine (2.0 mL) was added to a solution of Fmoc-PZ1064 (420 mg, 0.68 mmol) in DCM (6.0 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was treated with diethyl ether and the resulting mixture was stirred for 0.5 h. The precipitate was collected by filtration and purified by flash column chromatography on silica gel (DCM/MeOH = 100: 1 to 30: 1) to afford compound PZ1064
(160 mg, 48% yield) as a white solid. *Η NMR (300 MHz, CDCI3) : δ 8.03 (d, J = 9.9 Hz, 1H), 7.60-7.53 (m, 4H), 7.42-7.34 (m, 4H), 5.14-5.11 (m, 1H), 3.58 (s, 2H), 3.14 (m, 2H), 2.53- 2.44 (m, 8H), 2.32 (s, 3H), 2.22-2.11 (m, 3H), 1.68-0.90 (m, 8H); MS (ESI) : m/z 472.3 [M + H]+. Example 8. Procedure for preparation of (S)-D6-l-Amino-N-(l-cyano-2-(4'-((4-methyl- piperazin-l-yl) methyl)biphenyl-4-yl) ethyl)cyclohexanecarboxamide (PZ1066)
Figure imgf000129_0001
(S)-D6-(9H-Fluoren-9-yl)methyl l-( l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl)ethylcarbamoyl)cyclohexylcarbamate (Fmoc-PZ1066):
DMTMM (670 mg, 2.4 mmol) was added to a solution of compound PZ1024-6 from example 1 (400 mg, 1.2 mmol) in DCM (10.0 mL) in an ice-water bath. The mixture was stirred at 0°C for 0.5 h and compound 14 from example A described in the MATERIALS AND METHODS section (670 mg, 1.32 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. Water was added and the resulting mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel
(DCM/MeOH = 50 : 1 to 10: 1) to afford compound Fmoc-PZ1066 (420 mg, 41% yield) as a white solid.
(S)-D6-l-Amino-/V-( l-cyano-2-(4'-((4-methylpiperazin-l-yl)methyl)biphenyl-4-yl) ethyl)cyclohexanecarboxamide (PZ1066): Piperidine (2.0 mL) was added to a solution of Fmoc-PZ1066 (420 mg, 0.68 mmol) in DCM (8.0 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was treated with diethyl ether and the resulting mixture was stirred for 0.5 h. The precipitate was collected by filtration and washed with cooled diethyl ether to afford compound PZ1066 (160 mg, 56% yield) as a white solid. *H NMR (300 MHz, CDCI3) : δ 8.40 (d, J = 9.3 Hz, 1H), 7.60-7.53 (m, 4H), 7.47-7.33 (m, 4H), 5.17-5.12 (m, 1H), 3.57 (s, 2H), 3.13 (m, 2H), 2.52 (m, 8H), 2.17 (s, 3H), 1.98-1.86 (m, 2H), 1.47-1.25 (m, 2H); MS (ESI) : m/z 466.4 [M + H]+.
Example 9 Procedure for preparation of (R)-l-amino-N-(l-cyano-2-(4'-((4-propylpiperazin-l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide (PZ1047)
Reaction scheme
Figure imgf000130_0001
The preparation of PZ1047-1: A mixture of piperazine (19.4 g, 100 mmol), Et3N (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 H20 and extracted with DCM. The combined organic phase was dried over Na2S04 and concentrated in vacuo to give PZ1047-1 (10 g, 100%) as yellow oil.
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 NaBH3CN (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 NaHC03 solution. The combined DCM layer was dried over Na2S04 and concentrated in vacuo. The residue was treated with Et20 and filtered to give PZ1047-2 (500 mg, 5%) as white solid.
The preparation of PZ1047-3: To a solution of PZ1047-2 (120 mg, 0.404 mmol) in DMF (4 ml) and water (1 ml) was added compound PZ1036-8 from example B described in the MATERIALS AND METHODS section (241 mg, 0.485 mmol), Na2C03 (128 mg, 1.21 mmol) and Pd(dppf)CI2 (25 mg). This mixture was reacted in micro wave oven at 100°C and stirred for 1.5 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (EA/PE/DCM = 1/20/1) to give
PZ1047-3 (178 mg, 75.1%) as a white solid.
(R)-l-amino-N-(l-cyano-2-(4'-((4-propylpiperazin-l-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide (PZ1047): A solution of PZ1047-3 (178 mg, 0.3 mmol) in HC02H (3 ml) was stirred at 0°C for 48 h. LCMS showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (5ml). NaHC03 (0.2g) and water (0.2ml) were added. The resulting solution was stirred at room temperature for 30 min and filtered. The filtrated was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/EtOH = 50/1) to give PZ1047 (35 mg, 23.7 %) as a yellow solid. LC-MS: RT = 2.70 min; m/z =
488.4[M + H] + . *H NMR (300MHz, CD3OD) δ = 7.57 (m, 4H), 7.38 (m, 4H), 5.04 (t, J = 5.4Hz, 1H), 3.56 (s, 2H), 3.21 (m, 2H), 2.30-2.53 (m, 10H), 1.75 (m, 2H), 1.53 (m, 7H), 1.30 (m, 3H), 0.91 (t, J = 5.7Hz, 3H).
Example 10 Procedure for preparation of (R)-l-amino-N-( l-cyano-2-(4'-((4-cyclopropyl- piperazin-l-yl) methyl) biphenyl-4-yl) ethyl)cyclohexanecarboxamide (PZ1050)
Figure imgf000131_0001
The preparation of PZ1050-1: To a solution of 1-cyclopropylpiperazine (2.0 g, 15.9 mmol) in EtOH (20 ml) was added 4-bromobenzaldehyde (2.9 g, 15.9 mmol) and CH3COOH (1.1 g, 19.1mmol). Then this mixture was stirred at room temperature overnight. This mixture was adjusted pH = 9 with NaHC03 and extracted with DCM. Then the organic phase was washed with IN HCI. The organic phase were combined, dried and concentrated in vacuo. The residue was purified by Pre-HPLC to give PZ1050-1 (1.1 g, 23.5%) as yellow solid.
The preparation of PZ1050-2: To a solution of PZ1050-1 (300 mg, 1.0 mmol) in DMF (10 ml) and water (2.5 ml) were added compound PZ1036-8 from example B described in the MATERIALS AND METHODS section (646 mg, 1.3 mmol), Na2C03 (318 mg, 3.0 mmol) and Pd(dppf)CI2 (30 mg). This mixture was stirred in micro wave oven at 100 °C and stirred for 1.5 h. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (EA/PE/ = 1 : 10) to give PZ1050-2 (320 mg, 53.8%) as a yellow solid. (R)-l-amino-N-( l-cyano-2-(4'-((4-cyclopropyl-piperazin-l-yl)methyl)biphenyl-4- yl) ethyl )cyclohexanecarboxamide (PZ1050): A solution of PZ1050-2 (200 mg, 0.34 mmol) in HCOOH (4 ml) was stirred at 0°C for 48 h. LCMS showed that the reaction was complete. Then the mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (5 ml), NaHC03 (0.2 g) and water (0.2 ml) were added. The mixture was stirred at room temperature for 30 min, then filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (DCM/EtOH = 50/1) to afford PZ1050 (70 mg, 42.2%) as a white solid. LC-MS: RT = 2.75 min; m/z = 486.4[M + H]VH NMR (300MHz, CD3OD) δ = 7.60 (t, J = 6Hz, 4H), 7.40 (t, J = 8.1Hz, 4H), 5.08 (t, J = 5.7Hz, 1H), 3.59 (s, 2H), 3.26 (m, 2H), 2.50-2.70 (br, 8H), 1.30-1.81 (m, 10H), 0.49 (m, 2H), 0.40 (m, 2H).
Example 11
Procedure for preparation of (R)-l-amino-N-( l-cyano-2-(4'-((4-(cyanomethyl) piperazin-1- yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide (PZ1051)
Reaction scheme
Figure imgf000133_0001
The preparation of PZ1051-1: To a solution of 2-(piperazin-l-yl)acetonitrile (2.0 g, 16 mmol) in EtOH (20 ml) was added 4-bromobenzaldehyde (2.9 g, 16 mmol) and AcOH (1.1 g, 19.1 mmol). Then this mixture was stirred at room temperature overnight. This mixture was adjusted pH = 9 with NaHC03 and extracted with DCM. Then the organic phase was washed with IN HCI. The combined organic layer was dried and concentrated in vacuum. The residue was purified by Pre-HPLC to give PZ1051-1 (0.9 g, 19.1%) as yellow solid.
The preparation of 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), Na2C03 (130 mg, 1.23 mmol) and Pd (dppf)CI2 (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.
(R)-l-amino-N-( l-cyano-2-(4'-((4-(cyanomethyl) piperazin-l-yl) methyl )biphenyl- 4-yl)ethyl)cyclohexanecarboxamide (PZ1051) : A solution of PZ1051-2 (120 mg, 0.21 mmol) in HCOOH (5ml) was stirred at RT for 5 h. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (5 ml), and NaHC03 (0.2 g) and water (0.2 ml) were added. The mixture was stirred at room temperature for 30 min, and then filtered. The filtrate was concentrated in vacuum. The residue was purified by Pre-HPLC to give PZ1051 (37 mg, 37.2%) as a grey solid. LCMS: RT = 2.48 min; m/z = 485.4[M + H] + . *H NMR (300MHz, CD3OD) δ = 7.58 (m, 4H), 7.40 (m, 4H), 5.05 (t, J = 8.1Hz, 1H), 3.65 (s, 2H), 3.58 (s, 2H), 3.29 (m, 2H), 2.50-2.67 (br, 8H), 1.81 (m, 2H), 1.58 (m, 6H), 1.35 (m, 4H).
Example 12 Procedure for preparation of (S)-l-amino-N-(l-cyano-2-(4'-((4-(oxazol-2-ylmethyl) piperazin-l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide (PZ1057)
Reaction scheme
Figure imgf000134_0001
The preparation of A-2: To a solution of compound A-l (20 g, 0.11 mol), piperazine (9.3 g, 0.11 mol) in MeOH (400 mL) was added the CH3C02H (7.78 g, 130 mmol). After 30 min, the NaBH3CN ( 8.85 g, 140 mmol was added, and the mixture was stirred at RT overnight. Then pH was adjusted to about 7, and the solvent was removed by vacuum. The residue was extracted by EA (100mLx5), and the organic phase was dried over Na2S04 and concentrated in vacuum. The residue was purified by silica gel column chromatography (DCM/MeOH = 100/1~5/1) to give a pale yellow solid (7g, 26%) . ^ NMR (300Hz, CDCI3) δ = 7.41 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 3.42 (s, 2H), 2.89 (t, J = 4.8 Hz, 4H), 2.40 (br, 4H).
The preparation of A: To a solution of compound A-2 (950 mg, 3.7 mmol), oxazole-2- carbaldehyde (200 mg, 3.1 mmol) in MeOH (17 mL) was added the CH3C02H (0.26 g, 4.3 mmol). After 30 min, NaBH3CN ( 310 mg, 5 mmol) was added , the mixture was stirred at RT overnight. Then pH was adjusted to about 7, and the solvent was removed by vacuum. The residue was extracted by EA (30mLx5), and the organic phase was dried over Na2S04, evaporated, and purified by silica gel column chromatography (PE/EA = 100/1~2/1) to give a pale yellow solid (300 mg, 25%). The preparation of PZ1057-2: To a solution of PZ1057-1 (55 mg, 0.11 mmol) in DMF (4 mL) and H20 (1 mL) was added compound A (30 mg, 0.09 mmol), Na2C03 (29 mg, 0.27 mmol) and Pd(dppf)CI2 (6 mg). the mixture was reacted in micro wave oven at 100 °C and stirred for 1 h, then the reaction mixture was added water and extracted with EA (30 mLx4), the organic layer was dried and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EA = 100/1~10/1) to give a pale yellow oil (20 mg, 35%).
(S)-l-amino-N-( l-cyano-2-(4'-((4-(oxazol-2-ylmethyl)piperazin-l-yl)
methyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide (PZ1057): A solution of
PZ1057-2 (20 mg, 0.03 mmol) in HCOOH (2 mL) was stirred at 0 °C for 12 hours. The solution was slowly added into cold aqueous NaHC03 solution with stirring. The mixture was extracted with EA (10 mLx5), the combined organic phases were dried over Na2S04, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA = 100/1~30/1) to give PZ1057 as a pale yellow solid (5 mg, 35%). LCMS(M + H) = 527.3, Rt = 1.76 min; *H NMR (300Hz, CD3OD) δ = 7.81 (s, 1H), 7.47 (t, J = 5.7 Hz, 2H), 7.28 (t, J = 5.1 Hz, 2H), 7.05 (s, 1H), 4.95 (t, J = 5.7 Hz, 1H), 3.63 (s, 2H), 3.46 (s, 2H), 3.11 (m, 1H), 2.44 (br, SH), 1.75 (m, 2H), 1.43 (m, 4H), 1.26 (m, 4H) .
Example 13
Comparison of PZ1018 (example 2) with Example 29 of WO2010/128324A1 The table below compares PZ1018 (example 2) and Example 29 of WO2010/128324A1. The cyclohexane group in PZ1018 is in Example 29 of WO2010/128324A1 displaced with a tetrahydro-2H-pyran group. This is typical for compounds of WO2010/128324A1.
As shown in table 3 below, PZ1018 is nearly 5 times more potent compared to Example 29 of WO2010/128324A1 when judged by U937 IC50 measured in the U937 cellular assay despite the fact that they have nearly the same potency in the DPPI enzyme assay.
Furthermore, 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. As a consequence of these different Hill coefficients, 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
WO2010128324A1 when measured by U937 IC99.
This feature of the compounds of the present invention is very beneficial, as pharmacokinetic studies (Nathalie Methot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin, Christian Beaulieu, T. Jagadeeswar Reddy, Denis Riendeau, and M. David Percival : In Vivo Inhibition of Serine protease Processing Requires a High Fractional Inhibition of Cathepsin C, Mol Pharmacol 73: 1857- 1865, 2008) have shown, that in vivo inhibition of elastase and cathepsin G require a high fractional and sustained level of DPPI inhibition, probably as high as 99 % or more.
Table 3
Compound
Figure imgf000136_0001

Claims

1. A compound of formula (II)
Figure imgf000137_0001
(Π) wherein y represents 0, 1, 2 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci_3-alkyl, which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5; X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0)2-, -N(R16)-, - C(0)-N(R16)-, -N(R16)C(0)-, -S(0)2N(R16)-, -N(R16)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 R20 ; Ci_6-alkyl optionally substituted with Ci-6-alkoxy, - NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-C1-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4- R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(C1_6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl;
R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R14 and R15 each independently represent hydrogen, C^-alkyl or C3_6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a Ci-6-alkyl or C3-6- cycloalkyl; R16 represents a hydrogen atom or Ci-6-alkyl;
R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan-3- yi;
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000139_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2;
R20 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.
2. The compound according to claim 1, wherein X is a single bond.
3. The compound according to any one of claims 1-2, 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-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci_6-alkyl.
4. The compound according to any one of claims 1-3, 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-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; or -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17.
5. The compound according to any one of claims 1-4, wherein B represents optionally substituted benzothiazolyl, pyrrolyl, pyrazolyl, indolyl, thiazolyl, pyridazinyl, phenyl, triazolopyridinyl or imidazolyl.
6. A compound of the formula (III)
Figure imgf000140_0001
(III) wherein y represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; when y is 1 or 2, then R2 independently represents deuterium; halogen; hydroxyl; cyano; oxo (=0) ; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0- C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; or when y represents 3, 4, 5, 6, 7, 8, 9 or 10, then R2 represents deuterium; n represents 1, 2, 3, 4 or 5;
Q is at least one substituent selected from R20; Ci_6-alkyl optionally substituted with d-6- alkoxy, -NR14R15, phenyl or morpholinyl; C3-6-cycloalkyl; C2-6-alkenyl; trifluoromethyl;
trifluoromethoxy; Ci-6-alkoxy; Ci-6-thioalkyl; Ci-6-alkylcarbonyl; Ci-6-alkylcarbonyloxy; Ci-6- alkoxycarbonyl; -NR3R4; -C(0)NR5R6; -N(R7)C(0)R8; -S-Ci-3-alkyl; -S(0)2NR9R10; - N(Rn)S(0)2R12; -S(0)aR13 wherein a is 0, 1 or 2; -NHC( = NH)NH2; -C( = NH)NH2; benzyloxy; - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin- l-yl; -0-4-R19- piperazin- l-yl; -C(=0)-4-R19-piperazin- l-yl; -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl; R3 and R4 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R5 and R6 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R9 and R10 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R14 and R15 each independently represent hydrogen, Ci-6-alkyl or C3-6-cycloalkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7, R8, R11, R12 and R13 each independently represent a hydrogen atom or a Ci-6-alkyl or C3-6- cycloalkyl;
R16 represents a hydrogen atom or Ci-6-alkyl; R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl or oxetan- yi;
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl, -Ci_6-alkyl, which -Chalky! is optionally substituted with at least one substituent selected from hydroxyl, cyano o amino, or R19 represents formula XI, formula X2, formula X3 or formula X4;
Figure imgf000142_0001
X1 X2 X3 X4 wherein m is 0, 1 or 2; R20 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.
7. The compound according to any one of claims 1-7, wherein y represents 0, 1 or 2; when y is 1 or 2, then R2 independently represents halogen; hydroxyl; cyano; mercapto; -0- CH3; -0-C2H5; -S-CH3; -S-C2H5; or Ci-3-alkyl; which -0-CH3, -0-C2H5, -S-CH3, -S-C2H5 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 R2 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 R20; R17 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 R17 together with the carbon atom(s) to which they are attached form a cyclopropyl;
R18 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;
R19 represents hydrogen, -C3-6-cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or -Ci_6-alkyl;
R20 each independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci_5-alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto.
8. The compound according to any one of claims 1-7, wherein R19 represents -C3-6- cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or Ci-6-alkyl, which Ci-6-alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino.
9. The compound according to any one of claims 1-8, wherein R19 represents -C3-6- cycloalkyl, -Ci-3-alkyl-C3-6-cycloalkyl or Ci-6-alkyl.
10. The compound according to any one of claims 1-9, wherein n is 3 or 4.
11. The compound according to any one of claims 1- 10, wherein y is 0, 1 or 2.
12. The compound according to any one of claims 1- 11, wherein R2 independently represents halogen; hydroxyl; cyano; mercapto; -0-CH3; -0-C2H5; -S-CH3; -S-C2H5; or Chalky!; which -0-CH3, -O-C2H5, -S-CH3, -S-C2H5 or d_3-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto.
13. The compound according to any one of claims 1- 11, wherein y is 2, and the two R2 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 R20.
14. The compound according to any one of claims 1- 13, wherein Q is selected from - S(0)2-4-R19-piperazin- l-yl which is optionally substituted at a carbon atom with at least one substituent R20; -(Ci-2-alkyl)-4-R19-piperazin- l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17; -N(R18)-4-R19-piperazin-l-yl; -0-4-R19- piperazin-l-yl; -C(=0)-4-R19-piperazin-l-yl;or -S(0)2-(Ci-6-alkyldiazepanyl) which is optionally substituted at a carbon atom with at least one substituent R20; 4-(Ci-6-alkyl)- piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; and piperidinyl which is optionally substituted with -NR14R15 or Ci-6-alkyl.
15. The compound according to any one of claims 1-14, wherein Q is selected from - S(0)2-4-R19-piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20; or -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17.
16. The compound according to claim 15, wherein Q is -(Ci-2-alkyl)-4-R19-piperazin-l-yl in which the Ci-2-alkyl is optionally substituted with at least one substituent R17.
17. The compound according to claim 16, wherein Ci_2-alkyl is methyl or ethyl.
18. The compound according to any one of claims 1-15, wherein Q is -S(0)2-4-R19- piperazin-l-yl which is optionally substituted at a carbon atom with at least one substituent R20.
19. The compound according to any one of claims 1- 18, wherein R17 is selected from cyano; cyclopropyl; methyl substituted with cyclopropyl; ethyl substituted with cyclopropyl; and ethyl substituted with cyclopropyl which cyclopropyl is substituted with cyano.
20. A compound selected from (S)-l-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l- yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (S)-l-amino-N-(l-cyano-2-(4'-(4- methylpiperazin-l-ylsulfonyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (S)-2-Amino-/V- ((S)-l-cyano-2-(4'-(4-methylpiperazin-l-ylsulfonyl)biphenyl-4- yl)ethyl)- 1,2,3,4- tetrahydronaphthalene-2-carboxamide, (S)-8-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin- 1-yl) methyl) biphenyl-4-yl)ethyl)- l,4-dioxaspiro[4.5]decane-8-carboxamide, (S)-l-Amino-N- (l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl)
ethyl)cyclopentanecarboxamide, (S)-2-Amino-N-(l-cyano-2-(4'-((4-methylpiperazin-l-yl) methyl) biphenyl-4-yl) ethyl)-2,3-dihydro-lH-indene-2-carboxamide, (S)-2-Amino-N-( l- cyano-2-(4'-((4-methylpiperazin-l-yl) methyl)biphenyl-4-yl) ethyl)bicyclo[2.2.1]heptane-2- carboxamide, (S)-D6-l-Amino-N-(l-cyano-2-(4'-((4-methyl-piperazin- l-yl) methyl) biphenyl- 4-yl) ethyl)cyclohexanecarboxamide, (R)-l-amino-N-(l-cyano-2-(4'-((4-propylpiperazin-l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide, (R)-l-amino-N-(l-cyano-2-(4'-((4- cyclopropyl-piperazin-l-yl)methyl)biphenyl-4-yl) ethyl)cyclohexanecarboxamide, (R)-l- amino-N-(l-cyano-2-(4'-((4-(cyanomethyl) piperazin- 1-yl) methyl) biphenyl-4- yl)ethyl)cyclohexanecarboxamide and (S)-l-amino-N-(l-cyano-2-(4'-((4-(oxazol-2-ylmethyl) piperazin-l-yl) methyl) biphenyl-4-yl)ethyl)cyclohexanecarboxamide.
21. The compound according to any one of claims 1-20, in the form of a pharmaceutically acceptable salt thereof.
22. The compound according to any one of the preceding claims for use in medicine.
23. The compound according to any one of the preceding claims 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.
24. A combination of a compound as defined in any one of the preceding claims and one or more agents independently selected from: a non-steroidal glucocorticoid receptor agonist; a selective β2 adrenoceptor agonist; a phosphodiesterase inhibitor; a peptidase inhibitor; a glucocorticoid; an anticholinergic agent; a modulator of chemokine receptor function; and an inhibitor of kinase function.
25. A pharmaceutical composition comprising, as an active substance, a compound as defined in any one of claims 1-22 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable adjuvant, carrier or diluent.
26. 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 in any one of claims 1- 22 or of a composition as defined in claim 25.
27. Use of a compound as defined in any one of claims 1-22 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.
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